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Controlling focused-treatment of Prostate cancer with MRI

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Imaging-based Cancer Patient Management, Medical Device Therapies for Altzheimer’s Disease, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, tagged cancer treatment, focal treatment, HIFU, MRI, MRI imaging, Personalized medicine, Prostate biopsy, Prostate cancer, PSA on June 24, 2013| 4 Comments »

Controlling focused-treatment of Prostate cancer with MRI

Writer and reporter: Dror Nir, PhD.

In recent years there is a growing trend of treating prostate cancer in a way that will preserve, at least partially, the functionality of this organ. When patients are presenting at biopsy a low-grade localized disease, they might be offered focused treatment of the cancer lesion. One of the option is treatment by high-intensity focused ultrasound (HIFU).

The offering of such treatments created the need of controlling their outcome while the prostate is still inside the patient’s body. The most commonly used protocol is following up the patient’s PSA levels and performing “control” biopsies. The biopsies part is at best case; extremely unpleasant. It also bears some risk for complications.

Therefore, urologists are constantly seeking an imaging based protocol that will enable them to assess the treatment outcome without the need for biopsy. The publication I bring below presents the possibility of using MRI for this task. Although it is not recent, it contains many images that makes the story very clear for the reader. The main weakness of the study is the small number of patients – only 15.

MR Imaging of Prostate after Treatment with High-Intensity Focused Ultrasound

Alexander P. S. Kirkham, FRCR, Mark Emberton, FRCS, Ivan M. Hoh, MRCS, Rowland O. Illing, MRCS, A. Alex Freeman, FRCP and Clare Allen, FRCR

From the Department of Imaging, University College London Hospitals NHS Foundation Trust, England (A.P.S.K., C.A.); Institute of Urology (M.E., I.M.H., R.O.I.) and Department of Histopathology (A.A.F.), University College London, England.

Address correspondence to A.P.S.K., Imaging Department, University College Hospital, 235 Euston Road, London, England NW1 2BU (e-mail: alexkirkham@yahoo.com).

Radiology March 2008; 246 (3) – 833-844.

Abstract

Purpose: To prospectively evaluate magnetic resonance (MR) imaging findings after high-intensity focused ultrasound (HIFU) treatment of the prostate and to correlate them with clinical and histologic findings.

Materials and Methods: Local ethics committee approval and informed consent were obtained. Fifteen consecutive men aged 46–70 years with organ-confined prostate cancer underwent ultrasonographically guided ablation of the whole prostate. Postoperative MR images were obtained within 1 month (12 patients), at 1–3 months (five patients), and in all patients at 6 months. Prostate volume was measured on T2-weighted images, and enhancing tissue was measured on dynamic images after intravenous administration of gadopentetate dimeglumine. Prostate-specific antigen (PSA) level was measured at regular intervals, and transrectal biopsy was performed in each patient at 6 months after treatment.

Results: Initial post-HIFU images showed a central nonenhancing area, surrounded by an enhancing rim. At 6 months, the prostate was small (median volume reduction, 61%) and was of predominantly low signal intensity on T2-weighted images. The volume of prostate enhancing on the initial posttreatment image correlated well with serum PSA level nadir (Spearman r = 0.90, P < .001) and with volume at 6 months (Pearsonr = 0.80, P = .001). The three patients with the highest volume of enhancing prostate at the initial posttreatment acquisition had persistent cancer at 6-month biopsy.

Conclusion: MR imaging results of the prostate show a consistent sequence of changes after treatment with HIFU and can provide information to the operator about completeness of treatment.

There is currently little to offer men with localized prostate cancer between the two extremes of watchful waiting and radical treatment—most commonly prostatectomy or radiation therapy (1). Ablation of the gland has been proposed as an alternative that has the potential to completely treat the tumor while minimizing the sexual and urinary morbidity that still accompany established radical therapies (2). Several techniques have been used in the prostate—including microwave (3) and radiofrequency (4) ablation, cryotherapy (5), photodynamic therapy (6), and high-intensity focused ultrasound (HIFU) treatment (7).

HIFU is, in several respects, ideally suited to the prostate. In contrast to extracorporeal devices for the liver and kidney (8), with the transrectal approach, there is little movement of the target because of respiration or reflection by overlying bone. A focal distance of 3 or 4 cm allows the generation of coagulative necrosis in treatment voxels less than 0.2 mL and allows a treatment volume that conforms to the shape of the prostate (9)—a degree of precision that may be beyond that of other techniques. Even so, complete ablation is likely to affect periprostatic tissues, including the neurovascular bundles containing the cavernosal nerves (10) and the external urethral sphincter. Preservation of these structures—and the patient’s erectile and urinary function—must be balanced against full treatment of the gland.

Although impotence rates after HIFU treatment approach 50% (11), it is likely that in its current clinical implementation, the prostate is not being fully ablated: In published series, the recurrence rates for cancer range between 25% and 38% (7,11,12). To our knowledge, no groups have reported mean reductions in prostate volume of more than 50% (12,13), and several groups have found it difficult to treat the anterior gland (14).

If we are to improve outcomes, a fundamental requirement for HIFU treatment (and ablative technologies in general) is a method that provides anatomic information to the operator about areas that have been over- or undertreated. This might lead to modifications in future technique, and if obtained soon after treatment, might indicate the need for further ablation. Such a method might also help predict outcome earlier than established measures, such as prostate-specific antigen (PSA) measurement and biopsy.

Magnetic resonance (MR) imaging has great potential in this setting, and Rouviere et al (14) have described the appearance of the prostate on contrast material–enhanced MR images obtained up to 5 months after HIFU treatment. Rouviere et al found a good correlation between the theoretical treatment volume and the volume of nonenhancing prostate on a subsequent acquisition. The aim of our study was to prospectively evaluate MR imaging findings after HIFU treatment of the prostate and to correlate them with clinical and histologic findings.

MATERIALS AND METHODS

Misonix (the European distributors of the Sonablate device) funded the phase-II European study and provided equipment and reimbursed the hospital for costs. The company has funded two authors (I.M.H. and R.O.I.) through educational awards. One author (M.E.) has acted as a paid consultant to Misonix and also received honoraria for training and teaching. Authors other than I.M.H., R.O.I., and M.E. had control of the information and data submitted for publication. Misonix was not involved in the analysis of data or the writing of this article.

Patients

We included the first 15 men at University College Hospital (age range, 46–70 years; mean age, 59 years) who were taking part in a registered phase-II multicenter European study of HIFU therapy for organ-confined prostate cancer (Table 1). The study was approved by the local ethics committee, and full written consent was obtained from each patient. The patients understood that HIFU is an experimental treatment whose long-term outcome is unknown and were offered full conventional treatment as an alternative. The study was limited to men with a serum PSA level 15 μg/L or less, Gleason score less than 8, prostate volume less than 40 mL, life expectancy more than 5 years, and age less than 80 years. There was no limit to the number of biopsy cores that had a positive finding or the amount of cancer in each core removed. Patients with a history of previous prostate surgery were excluded, as were men who had undergone androgen deprivation therapy in the 6 months prior to recruitment or had intragland prostatic calcification more than 1 cm in diameter.

Table 1. Patients and Demographics

* Ratio of cores with a positive finding to cores obtained.

† Image not available for analysis; volume was calculated by using US measurements.

The Sonablate 500 (Focus Surgery, Indianapolis, Ind) consists of a power generator, water cooling system (the Sonachill), a treatment probe, and a positioning system. The probe contains two curved rectangular piezoceramic transducers with a driving frequency of 4 MHz and focal lengths of 30 and 40 mm. During treatment, these may be driven at low energy to provide real-time diagnostic imaging or at high energy for therapeutic ablation (in situ intensity, 1300–2200 W/cm²). The probe is covered with a condom, under which cold (17°–18°C) degassed water is circulated to help protect the rectum from thermal injury.

Patients were prepared before the procedure with two phosphate enemas to empty the rectum. Oral bowel preparation was used in some patients. Treatment was performed with general anesthesia in the lithotomy position and was performed or closely supervised in every case by an author (M.E., 2 years of experience in HIFU treatment). After gentle dilation of the anal sphincter, the treatment probe was introduced with a covering of ultrasonographic (US) gel to couple it to the rectal mucosa and was held in position with an articulated arm attached to the operating table. A 16-F Foley urethral catheter was inserted using sterile technique, and a 10-mL balloon was inflated to allow the bladder neck and median sagittal plane to be seen accurately. It was removed before treatment began.

Treatment was planned by using US-acquired volumes consisting of stacks of both sagittal and transverse sections (voxel size, 2 × 3 × 30 mm) and was applied in rows that extended in the craniocaudal axis, interleaved to avoid interference from adjacent, recently treated areas. After each 3-second period of ablation, diagnostic transverse and sagittal images in the plane of treatment were obtained to permit tailoring of the energy delivery in the next voxel according to visible changes on the gray-scale image. This is an important difference from the device used by Rouviere’s group (14), in which power is planned before the treatment begins. We aimed to set the power for each voxel at a level that produced hyperechoic change due to cavitation (as described by Illing et al [15]), and we invariably treated the whole anterior prostate. Neurovascular bundles were not identified at treatment (the Sonablate device does not yet have color Doppler capability); rather, we aimed to avoid treating outside the capsule where they lie posterolaterally (10). The time between the first ablation and the point at which treatment was considered complete was 3.0–4.4 hours (mean, 3.6 hours). A 16-F urethral catheter was placed immediately after the treatment and was left in place for 2 weeks.

MR Imaging

For most preoperative examinations and for all post-HIFU imaging, we used an MR machine (Symphony or Avanto; Siemens, Erlangen, Germany) with 1.5-T magnet and a pelvic-phased array coil. Except where stated, a full protocol of T1- and T2-weighted turbo spin-echo (Siemens) images and a dynamic fat-saturated postcontrast volume acquisition were used for both preoperative diagnostic and planning imaging and for postoperative assessment of HIFU treatment (Table 2). The contrast material used was 20 mL of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) given intravenously at 3 mL/sec.

Table 2. MR Sequences Used at Prostate Imaging

We aimed to image patients less than 1 month after treatment and did so in 12 patients. The remaining three patients were imaged between 1 and 3 months after treatment. Two patients were imaged in both time periods. Every patient underwent a 6-month MR examination.

Image Analysis

All volume measurements (except where stated) were acquired by using planimetry of contiguous 3-mm sections (16). T2-weighted images were used for measurement of prostatic volume both before and after treatment. The amount of intermediate- or high-signal-intensity material (ie, higher than muscle) remaining within the prostate was also measured on the 6-month posttreatment T2-weighted image.

The volume of nonenhancing prostate tissue at the post-HIFU acquisition was measured by using the final dynamic postcontrast image. On the initial posttreatment image, we also measured the volume of extraprostatic tissue that was both of low signal intensity on the T1-weighted image and nonenhancing. The distance between this tissue and the rectal mucosa was measured at its narrowest point. The mean thickness of the enhancing rim surrounding the treatment volume was measured on transverse postcontrast T1-weighted spin-echo images and was calculated by dividing the area of the rim by its circumference.

The volume of persistently enhancing prostate tissue on the initial image was calculated by subtracting the nonenhancing volume from the total volume of prostate on the T2-weighted image. This could be calculated in 13 patients; one patient did not receive contrast material at the post-HIFU MR acquisition, and the other was imaged more than 2 months after treatment.

All measurements were performed by a first-year radiology fellow (A.P.S.K.) without knowledge of PSA and histologic results. Two other observers independently measured the three key parameters that were used for correlation calculations for each patient: (a) the volume of nonenhancing prostate on the initial image, (b) the total volume of the prostate on the initial image, and (c) the final prostate volume at 6 months. One was a consultant uroradiologist with more than 10 years of experience in the interpretation of prostate MR images (C.A.); the other was a third-year urology research fellow with an interest in prostate imaging (R.O.I.). For each parameter, the mean of the three observers’ measurements was calculated and used for further analysis.

PSA Measurement and Prostate Biopsy

Serum PSA level was measured before and at 1.5, 3, and 6 months after HIFU treatment. The nadir was defined as the lowest of the three values.

Biopsies were performed by an author (A.P.S.K., with 4 years of experience in prostate biopsy) by using a transrectal approach with US guidance and an 18-gauge needle with a 2-cm throw soon after the 6-month MR examination. The number of cores obtained depended on the amount of residual prostate and varied between two and 10 (median, eight cores).

Erectile Function and Continence

The International Index of Erectile Function was used to assess erectile function both before and 3 months after HIFU treatment in each patient (17). The most important question was, “How often were your erections hard enough for penetration [with or without phosphodiesterase type 5 inhibitors]?” A score of 2 (a few times in 4 weeks) to 5 (always) was, for the purposes of this article, considered evidence of intact erectile function.

Men were asked to complete the International Continence Society–validated continence function questionnaire at baseline and at 3 and 6 months after therapy. The question deemed to be most informative was how often the patient required the use of pads or adult diapers. Responses could include “never,” “not more than one per day,” “1–2 per day,” or “more than 3 per day.”

Statistical Analysis

To assess the variance of results between observers, we used the intraclass correlation coefficient (18) applied to measurements obtained by three observers of the calculated volume of enhancing prostate on the initial post-HIFU image and the 6-month prostate volume.

The Spearman rank test was used to assess the correlation between enhancing prostate volume and serum PSA level nadir, and the Pearson test was used to examine the correlation between initial enhancing prostate volume and final prostate volume. Only the patients who were imaged less than 1 month after treatment were included in the analysis. These tests were performed by using software (GraphPad Prism for Mac, version 3; http://www.graphpad.com).

Because some of the covariance of volumes measured after treatment was likely to be due to their correlation with pretreatment prostate volume, we also applied a correction: The values were expressed as a proportion of the pretreatment volume, and a further correlation measurement was performed by using the Pearson test. In each case, a P value of less than .02 was considered to indicate a significant difference.

RESULTS

Up to 1 Month After Treatment

T2-weighted images.—Compared with that on the preoperative image, the prostate volume increased in every case (Table 1 and Table E1, Fig 1). The signal intensity from the prostate on T2-weighted images within the first month was always heterogeneous and variable. It was impossible to predict from the findings on T2-weighted images which areas of the prostate would enhance after intravenous contrast material administration. The periprostatic fat was also heterogeneous in signal intensity, which was consistent with edema (Fig 2).

Figure 1: Graph of change in prostate volume after HIFU treatment. Volume rises initially (less than 1 month after treatment) and is reduced in all cases at 6 months. Numbers = patient numbers.

Figure 2: MR images in patient 1 (a–d) and (e–h) patient 8 show low volume of enhancing prostate at initial imaging and small residual prostate at 6 months. Posttreatment serum PSA level was less than 0.05 μg/L in both cases.

Figure 2a:

Figure 2b:

Figure 2c:

Figure 2d:

Figure 2e:

Figure 2f:

Figure 2g:

Figure 2h:

T1-weighted images.—The prostate was of predominantly low signal intensity, although patchy areas of intermediate or high signal intensity, likely to represent hemorrhage, were a constant finding within the gland and in all but one of 28 seminal vesicles.

Postcontrast images.—In each patient, the postcontrast images showed a central area of nonenhancing tissue. This conformed to the treatment volume and was surrounded by an enhancing rim of mean thickness of 2–8 mm (median, 4 mm) that was continuous around the prostate in most patients (Fig 2; Table E1,).

The enhancing prostate varied in size and position. Part of the enhancing rim usually lay within the prostatic capsule and continued to the prostatic apex where there was almost always some enhancing tissue between the nonenhancing prostate and the external urethral sphincter. In many patients, more central areas of enhancement were seen: at the apex or base, either posteriorly or anteriorly (Table E1), and were almost always in continuity with the rim.

In every patient, the nonenhancing, low signal intensity within the prostate extended outside the gland and involved the periprostatic fat and the levator ani muscle, particularly anterolaterally (Table E1, Figs 2, 3). This varied considerably and tended to be most prominent in those who had no residual gland enhancement and had an undetectable serum PSA level after HIFU treatment (Table E1). In several patients, the nonenhancing area extended to involve the Denonvilliers fascia. (The distance between its margin and the rectal muscle is listed in Table E1.) In one patient, a proportion of the rectal wall enhanced avidly, but in no patient was there loss of rectal wall enhancement to suggest necrosis.

Figure 3: MR images obtained near the prostate apex show incomplete treatment and persisting high signal intensity in prostate. Serum PSA level nadir = 0.61 μg/L.

Figure 3a: Patient 4:

Figure 3b: Patient 4:

Figure 3c: Patient 4:

Figure 3d: Patient 4:

At 1–3 Months

In three patients, there was a “double rim” (Fig 4) on postcontrast images obtained at 36 and 56 days after HIFU treatment. The inner component lay within the prostate and the outer at the prostatic capsule; the intervening part was of low signal intensity on both T1- and T2-weighted images.

Figure 4: MR images of “double rim” at 56 days after HIFU treatment.

Figure 4a: Patient 3:

Figure 4b: Patient 3:

Figure 4c: Patient 3:

Six-month Appearance

T2-weighted images.—In every patient, the volume of the prostate was reduced by more than 45% (median, 61% reduction) (Table E1). On T2-weighted images, the majority of the persisting prostate was of low signal intensity, with poor definition to the capsule and with persisting heterogeneous signal intensity to the surrounding fat. However, in 12 of 15 patients, there was persisting high or intermediate signal intensity of the prostate—up to 5.34 mL in volume and most often seen posteriorly and at the apex (Table E1, Figs 3 and 5). In many patients (for example, those in Fig 2), low-signal-intensity prostate of reduced volume surrounded a capacious prostatic cavity continuous with the urethra, which is similar to the cavity seen after transurethral resection (19).

Figure 5: MR images of incomplete treatment of tumor and positive biopsy findings in three of 10 cores at 6 months (in right lateral midzone, right lateral base, and right parasagittal base samples). Serum PSA level nadir = 1.19 μg/L.

Figure 5a: Patient 13:

Figure 5b: Patient 13:

Figure 5c: Patient 13:

Figure 5d: Patient 13:

Figure 5e: Patient 13:

Postcontrast images.—Some small areas of nonenhancing tissue persisted in eight of 14 patients, but this was less than 1 mL in all but one (patient 13, in whom 4 mL of the gland volume of 18.7 mL was nonenhancing). The levator muscle showed a normal signal intensity.

Correlation Between Initial Imaging and Later Findings

In the 12 patients who underwent the initial acquisition within 1 month of HIFU treatment, the volume of enhancing tissue on the initial posttreatment image was positively correlated with the serum PSA level nadir (Fig 6) (Spearman r = 0.90, P < .001) and with the amount of residual tissue at 6 months (including all low-signal-intensity material that was likely to represent fibrosis or necrosis) (Fig 7) (Pearson r = 0.80, P = .001).

Figure 6: Graph of relationship between the proportion of the prostate still enhancing on initial image and serum PSA level nadir. There is a significant positive correlation (Spearman r = 0.90, P < .001). * = patient 13, who was included in graph but not in analysis (imaged 56 days after HIFU treatment). Patients 14 and 15 are not included because they did not undergo contrast-enhanced acquisition within 2 months of HIFU treatment. μgl⁻¹ = μg/L.

Figure 7: Graph of relationship between the proportion of the prostate still enhancing on initial image and final volume of prostate. There is a significant positive correlation between the variables (Pearson r = 0.80, P = .001). * = patient 13, who was included in graph but not in analysis (imaged 56 days after HIFU treatment). Patients 14 and 15 are not included because they did not undergo contrast-enhanced acquisition within 2 months of HIFU treatment.

When posttreatment volumes are expressed as a proportion of pretreatment prostate volume, the correlation between enhancing tissue volume on the initial posttreatment image and the 6-month prostate volume persists (Pearson r = 0.70, P = .001).

Interobserver Correlation

The interobserver variation was excellent for the calculated volume of prostate enhancing on the initial post-HIFU image, with an intraclass correlation coefficient of 0.92, and was good for final prostate volume (intraclass correlation coefficient = 0.73).

Clinical Findings

In five patients (patients 1, 3, 8, 11, and 13), there was imaging evidence (at MR imaging or retrograde urethrography) of a stricture in the mid- or distal prostatic urethra, which was confirmed by using flow rate studies and treated by using self-catheterization or with graded urethral dilators. None have required formal urethrotomy. Patient 14 developed a bladder neck stricture, which was treated successfully by incision.

Before treatment, no men required pads or adult diapers for incontinence. At 6 months after the treatment, four men still required not more than one pad per day. In two cases, this was for reassurance rather than actual leakage.

In the 14 patients in whom there was intact erectile function (score 2–5 for the question, “How often were your erections hard enough for penetration?”) before HIFU treatment, it was intact in nine patients after the procedure. One patient had stopped trying to achieve erections, and four could not achieve penetration.

Histologic Findings

In the three patients in whom there was no high-signal-intensity peripheral zone at 6 months and with serum PSA level less than 0.05 μg/L, there was either no prostatic tissue or only a small group of acini in one core. The remaining patients had a variable amount of residual prostate at core biopsy.

Five patients had residual tumor. In three patients, it was seen in at least two cores (Table E1), and these three patients also had the largest volume of enhancing prostate on the initial post-HIFU MR image (Figs 6 and 7) and more than 2 mL of intermediate- or high-signal-intensity gland on T2-weighted images at 6 months.

In four of five patients with residual cancer, it could not be identified on either contrast-enhanced or T2-weighted images. In one patient (Fig 4), the early dynamic images showed prominent enhancement in the anterior gland, which was consistent with residual cancer found at the distal (ie, nonrectal) end of three right-sided biopsy cores. Such enhancement was not seen in patients with no cancer found at core biopsy.

DISCUSSION

We found a consistent sequence of changes at MR imaging after HIFU treatment of the whole prostate. The proportion of enhancing tissue on the initial posttreatment MR image was predictive of gland volume at 6 months and serum PSA level nadir. A strong statistical relationship between the latter and outcome has recently been demonstrated (20).

Most patients with residual cancer had evidence of incomplete ablation early (a large volume of enhancing prostate on the initial image) and late (a large volume of high-signal-intensity residual prostate on T2-weighted images at 6 months).

In some patients it was possible to achieve an undetectable serum PSA level at 6 months and entirely low signal intensity on T2-weighted images in the region of the prostate. These patients had either no or a small amount of viable prostate in one core at biopsy.

Conversely, in spite of reductions in prostate volume of more than 45% at 6 months, the majority of patients had histologic evidence of persisting viable prostate, and in a group of patients with organ-confined disease but no limit to the volume of cancer pretreatment, one-third had evidence of residual tumor.

Persisting enhancing prostatic tissue usually occurred at the periphery (or extended toward the center of the gland from it) and was particularly common at the apex and near the rectum.

Results of one previously published study (14) of post-HIFU appearances with MR imaging show a similar sequence of acute changes, although there was no attempt to quantify prostate volume at 6 months. There is also a large body of work on the MR imaging appearances with thermotherapy (whether laser [21,22] or radiofrequency [23]) and cryotherapy (24) within the prostate and other organs. The hyperenhancing rim of tissue is a constant finding in several tissues, including the liver (25), the kidney (26), and the brain (27). In the liver and the kidney, it is thin (1 mm or less) and, in most cases, has disappeared by 2 months after ablation (28). Within the prostate, the hyperenhancing rim has been shown to occur after laser ablation of benign prostatic hyperplasia (21,22) and after HIFU treatment (14).

Histologic evidence in animal models—including rabbit and porcine liver (29)—suggests that the enhancing rim corresponds to an area of inflammation and then fibrosis, with a variable amount of residual, viable tissue. How much of the rim will be viable after ablation of the prostate in humans remains uncertain. On the one hand, after HIFU treatment, core biopsy results show “partial or complete necrosis” in the rim (14). On the other, after laser ablation of benign prostatic hyperplasia, the volume of coagulative necrosis at histologic examination correlates very well with the central nonenhancing region at MR imaging, not including the rim (22). The answer is likely to be that a variable amount of the rim contains viable tissue (depending on the organ being imaged [30], the nature of the treatment, and the interval before the acquisition), and the implication is that the only reliably necrotic area at MR imaging is that which does not enhance. We have avoided the term necrosis for the nonenhancing areas of prostate seen in our current study, but from these data it is likely that the areas of prostate without enhancement are truly necrotic.

The distribution of enhancing prostate on posttreatment MR images fits with histologic evidence that “ventral, lateral and dorsal sides of the prostate” have residual viable prostatic tissue at histologic examination after HIFU treatment (31). What all of these areas have in common is proximity to the more richly vascular prostatic capsule. Is it possible that increased vascularity here results in reduced efficacy? This is another area that has been addressed by Rouviere’s group (32), who did not find a correlation between successful ablation and prostate vascularity by using power Doppler US; they conclude, as others have (33,34), that short (3-second) high-intensity bursts of focused ultrasound are unlikely to be markedly affected by blood flow. An alternate explanation is a geometric one: Centrally lying voxels are easier to treat because they may be rendered necrotic either by direct treatment or by damage to supplying vessels in the periphery.

An implication of these results is that the best strategies for minimizing complications while ensuring destruction of the cancer are likely to involve a degree of targeting: If the tumor can be imaged with MR imaging, the patient might be treated with higher power and wider margins (including periprostatic fat, muscle, or even neurovascular bundles) at the site of the cancer and with a standard intensity to the rest of the gland. An analogous approach is the wide excision, including a unilateral neurovascular bundle, of bulky tumors at radical prostatectomy (35). Such an approach may well have benefited our patients 7 and 13.

One methodologic issue that is currently unresolved relates to the timing of MR imaging. A detailed within-patient study of MR imaging changes after HIFU treatment is needed to properly describe the longitudinal changes in the appearance of the prostate. Rouviere et al (14) found that the area of nonenhancing tissue decreases by 50% at 1 month compared with that at an immediate (<1 week) post-HIFU acquisition, which suggests that for an accurate assessment of necrosis volume, the prostate should be imaged as soon as possible after treatment. Of course, perfusion would ideally be assessed during HIFU treatment so that undertreated areas could be further ablated. There is some evidence that Doppler or contrast-enhanced US (36) could play this role, but, to our knowledge, there are no studies on the correlation of immediate findings with later clinical data, such as serum PSA level or histologic examination.

We used fast low-angle shot sequences to assess enhancement because we found that the subjective assessment (together with objective measurements of signal intensity) of the dynamic series helped us identify truly nonenhancing tissue. However, the T1-weighted spin-echo postcontrast sequence would have been adequate, and we consider, as others do (22), dynamic contrast-enhanced sequences not to be an essential part of the protocol for postablation assessment. What is certain is that unenhanced T2-weighted sequences are inadequate for assessing necrosis (14,22).

Our results differ from those of other published series of HIFU treatment in the marked reduction in gland volume and absence of zonal anatomy in many patients observed at 6 months. In contrast to the study of post-HIFU MR imaging by Rouviere et al (14) who used a different device, we did not find that “HIFU-induced abnormalities seem to disappear within 3–5 months.” Rather, in several patients, it was difficult to discern any residual prostate at all at both MR and US studies. The difference probably lies in the power used for treatment and the completeness of gland coverage. The stricture rate of six of 15 is high when compared with that in published series (7,37,38) and may be related to the power used, the degree of fibrosis occurring in the prostate, and the strategy for catheterization. The latter is considered likely to be important, and we have recently changed to using a suprapubic catheter (rather than urethral) after treatment. The rate of impotence after treatment is similar to that in published series (11), as is grade I incontinence.

Our work has implications for the conduct of HIFU. The finding that the volume of enhancing prostate on the initial posttreatment image correlates well with intermediate measures, such as serum PSA level nadir and biopsy evidence of residual cancer, suggests that MR imaging can provide the operator with feedback on the effectiveness of the intervention. This information might enable modification of the technique to treat areas that have been incompletely ablated in previous patients—in our series, those areas encompassed the apex and posterior gland and rarely anterior tissue (in contrast to other study results [14]). Conversely, we might have reduced power or treatment volume at the anterolateral aspect of the gland adjacent to the levator muscle. Such feedback has been cited as a desirable attribute for ablation technology (39) and up to now has been missing.

Our study had several limitations. Although it is likely that nonenhancing areas at MR imaging represent necrosis, we do not have direct histologic evidence. Sampling error and misregistration limit the utility of core biopsies in this context. We have shown that the MR imaging appearances soon after HIFU treatment correlate with findings at 6 months, but this is not the same as outcome. A considerably longer follow-up and a larger number of patients will be necessary to determine both the ultimate efficacy of HIFU treatment and the ability of MR imaging to help predict outcome. Last, while our findings suggest that MR imaging soon after treatment may be useful to assess areas of under- and overtreatment, this is not real-time feedback and does not allow modification of the treatment as it progresses.

In summary, MR imaging results in the first 6 months after HIFU treatment show a consistent sequence of changes, and appearances in the 1st month correlate with serum PSA level nadir and imaging findings at 6 months. Such imaging results hold promise for providing feedback to the operator about the effectiveness of treatment.

ADVANCES IN KNOWLEDGE

Treatment of prostate cancer by using ablation with high-intensity focused ultrasound (HIFU) results in a consistent series of changes within the gland during 6 months seen at contrast-enhanced MR imaging.
Within 1 month after treatment, a central nonenhancing area is surrounded by an enhancing rim of tissue lying variably within and outside the prostate.
At 6 months, the gland is markedly smaller and of partly or completely low signal intensity on T2-weighted images.
The amount of enhancing prostate on the initial image correlates with several findings at 6 months, including serum prostate-specific antigen level nadir and prostate volume.

IMPLICATION FOR PATIENT CARE

MR imaging after HIFU treatment may provide information about completeness of tumor ablation and the need for early retreatment or close monitoring in cases of incomplete coverage.

Footnotes

Trial registration: This trial started recruiting before the trial registration requirements of the International Committee of Medical Journal Editors were formalized.

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, A.P.S.K., I.M.H., C.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.P.S.K., M.E., I.M.H., R.O.I., C.A.; clinical studies, A.P.S.K., R.O.I., C.A.; statistical analysis, A.P.S.K.; and manuscript editing, all authors

Abbreviations:HIFU = high-intensity focused ultrasoundPSA = prostate-specific antigen

References

Parker C. Active surveillance: towards a new paradigm in the management of early prostate cancer. Lancet Oncol 2004; 5: 101–106.

Steineck G, Helgesen F, Adolfsson J, et al. Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002;347:790–796.

Huidobro C, Bolmsjo M, Larson T, et al. Evaluation of microwave thermotherapy with histopathology, magnetic resonance imaging and temperature mapping. J Urol 2004;171:672–678.

Shariat SF, Raptidis G, Masatoschi M, Bergamaschi F, Slawin KM. Pilot study of radiofrequency interstitial tumor ablation (RITA) for the treatment of radio-recurrent prostate cancer. Prostate 2005;65:260–267.

Onik G. The male lumpectomy: rationale for a cancer targeted approach for prostate cryoablation—a review. Technol Cancer Res Treat2004;3:365–370.

Moore CM, Hoh IM, Bown SG, Emberton M. Does photodynamic therapy have the necessary attributes to become a future treatment for organ-confined prostate cancer? BJU Int 2005;96:754–758.

Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU Int2006;97:56–61.

Kennedy JE. High-intensity focused ultrasound in the treatment of solid tumours. Nat Rev Cancer 2005;5:321–327.

Uchida T, Sanghvi NT, Gardner TA, et al. Transrectal high-intensity focused ultrasound for treatment of patients with stage T1b-2n0m0 localized prostate cancer: a preliminary report. Urology 2002;59:394–398.

Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492–497.

Blana A, Walter B, Rogenhofer S, Wieland WF. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience.Urology 2004;63:297–300.

Gelet A, Chapelon JY, Bouvier R, et al. Transrectal high-intensity focused ultrasound: minimally invasive therapy of localized prostate cancer. J Endourol 2000;14:519–528.

Chaussy C, Thuroff S. The status of high-intensity focused ultrasound in the treatment of localized prostate cancer and the impact of a combined resection. Curr Urol Rep 2003;4:248–252.

Rouviere O, Lyonnet D, Raudrant A, et al. MRI appearance of prostate following transrectal HIFU ablation of localized cancer. Eur Urol2001;40:265–274.

Illing RO, Leslie TA, Kennedy JE, Calleary JG, Ogden CW, Emberton M. Visually directed high-intensity focused ultrasound for organ-confined prostate cancer: a proposed standard for the conduct of therapy. BJU Int 2006;98:1187–1192.

Bakker J, Olree M, Kaatee R, de Lange EE, Beek FJ. In vitro measurement of kidney size: comparison of ultrasonography and MRI. Ultrasound Med Biol 1998;24:683–688.

Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319–326.

Fleiss JL. Reliability of measurement. In: The design and analysis of clinical experiments. New York, NY: Wiley, 1986; 1–32.

Sheu MH, Chiang H, Wang JH, Chang YH, Chang CY. Transurethral resection of the prostate-related changes in the prostate gland: correlation of MRI and histopathology. J Comput Assist Tomogr 2000;24:596–599.

Uchida T, Illing RO, Cathcart PJ, Emberton M. To what extent does the prostate-specific antigen nadir predict subsequent treatment failure after transrectal high-intensity focused ultrasound therapy for presumed localized adenocarcinoma of the prostate? BJU Int 2006;98:537–539.

Mueller-Lisse UG, Heuck AF, Schneede P, et al. Postoperative MRI in patients undergoing interstitial laser coagulation thermotherapy of benign prostatic hyperplasia. J Comput Assist Tomogr 1996;20:273–278.

Boni RA, Sulser T, Jochum W, Romanowski B, Debatin JF, Krestin GP. Laser ablation-induced changes in the prostate: findings at endorectal MR imaging with histologic correlation. Radiology 1997;202:232–236.

Zlotta AR, Djavan B, Matos C, et al. Percutaneous transperineal radiofrequency ablation of prostate tumour: safety, feasibility and pathological effects on human prostate cancer. Br J Urol 1998;81:265–275.

Vellet AD, Saliken J, Donnelly B, et al. Prostatic cryosurgery: use of MR imaging in evaluation of success and technical modifications. Radiology1997;203:653–659.

Guan YS, Sun L, Zhou XP, Li X, Zheng XH. Hepatocellular carcinoma treated with interventional procedures: CT and MRI follow-up. World J Gastroenterol 2004;10:3543–3548.

Merkle EM, Nour SG, Lewin JS. MR imaging follow-up after percutaneous radiofrequency ablation of renal cell carcinoma: findings in 18 patients during first 6 months. Radiology 2005;235:1065–1071.

Kahn T, Bettag M, Ulrich F, et al. MRI-guided laser-induced interstitial thermotherapy of cerebral neoplasms. J Comput Assist Tomogr1994;18:519–532.

Dromain C, de Baere T, Elias D, et al. Hepatic tumors treated with percutaneous radiofrequency ablation: CT and MR imaging follow-up. Radiology2002;223:255–262.

Raman SS, Lu DS, Vodopich DJ, Sayre J, Lassman C. Creation of radiofrequency lesions in a porcine model: correlation with sonography, CT, and histopathology. AJR Am J Roentgenol 2000;175:1253–1258.

Illing RO, Kennedy JE, Wu F, et al. The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population. Br J Cancer 2005;93:890–895.

Van Leenders GJ, Beerlage HP, Ruijter ET, de la Rosette JJ, van de Kaa CA. Histopathological changes associated with high intensity focused ultrasound (HIFU) treatment for localised adenocarcinoma of the prostate. J Clin Pathol 2000;53:391–394.

Rouviere O, Curiel L, Chapelon JY, et al. Can color doppler predict the uniformity of HIFU-induced prostate tissue destruction? Prostate2004;60:289–297.

Billard BE, Hynynen K, Roemer RB. Effects of physical parameters on high temperature ultrasound hyperthermia. Ultrasound Med Biol1990;16:409–420.

Chen L, ter Haar G, Hill CR, et al. Effect of blood perfusion on the ablation of liver parenchyma with high-intensity focused ultrasound. Phys Med Biol 1993;38:1661–1673.

Park EL, Dalkin B, Escobar C, Nagle RB. Site-specific positive margins at radical prostatectomy: assessing cancer-control benefits of wide excision of the neurovascular bundle on a side with cancer on biopsy. BJU Int 2003;91:219–222.

Sedelaar JP, Aarnink RG, van Leenders GJ, et al. The application of three-dimensional contrast-enhanced ultrasound to measure volume of affected tissue after HIFU treatment for localized prostate cancer. Eur Urol 2000;37:559–568.

Thuroff S, Chaussy C, Vallancien G, et al. High-intensity focused ultrasound and localized prostate cancer: efficacy results from the European multicentric study. J Endourol 2003;17:673–677.

Gelet A, Chapelon JY, Bouvier R, Rouviere O, Lyonnet D, Dubernard JM. Transrectal high intensity focused ultrasound for the treatment of localized prostate cancer: factors influencing the outcome. Eur Urol 2001;40:124–129.

Gillett MD, Gettman MT, Zincke H, Blute ML. Tissue ablation technologies for localized prostate cancer. Mayo Clin Proc 2004;79:1547–1555.

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Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Larry H. Bernstein, MD, Writer
And
Aviva Lev-Ari, PhD, RN, Curator

This is a summary of several studies, mostly reviewing one decade of work at Texas Heart Institute, Houston, TX.

Seminal treatments of the evolving methods, leading to a recent review of options for

Survival comparison of CABD vs PCI
Mitral valve repair or mitral valve replacement for the treatment of ischemic mitral regurgitation. This might further consolidate a series of articles in these chapters.

SOURCES

1. Bypass, Angioplasty Similar in Survival 10 Years After Heart Procedures, Survival Rates Differ Little. K Doheny. WebMD Health News Oct. 15, 2007

http://www.webmd.com/heart-disease/news/20071015/bypass-angioplasty-similar-survival

2. Will Drug-Eluting Stents Replace Coronary Artery Bypass Surgery?

RM Reul, Tex Heart Inst J. 2005; 32(3): 323–330

3. Will Stent Revascularization Replace Coronary Artery Bypass Grafting? JM Wilson Tex Heart Inst J. 2012; 39(6): 856–859

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/

4. Coronary Artery Bypass Surgery versus Coronary Stenting. Risk-Adjusted Survival Rates in 5,619 Patients. RP Villlareal,V-V Lee, MA Elayda, JM Wilson. Tex Heart Inst J. 2002; 29(1): 3–9.

http://www.ncbi.nlm.nih.gov/pubmed/11995845

5. Should all ischemic mitral regurgitation be repaired? When should we replace? DJ LaPar, IL Kron. Curr Opin Cardiol. 2011 March; 26(2): 113–117

6. Hybrid Cath Lab Combines Nonsurgical, Surgical Treatments

http://www.dicardiology.com/article/hybrid-cath-lab-combines-nonsurgical-surgical-treatments

Bypass, Angioplasty Similar in Survival 10 Years After Heart Procedures

The survival rates 10 years after coronary artery bypass surgery and angioplasty are similar, according to a new analysis of nearly 10,000 heart patients. Five years after the procedures, 90.7% of the bypass patients and 89.7% of the angioplasty patients were still alive, says Mark A. Hlatky, MD, senior author of the analysis and a professor of health research and policy and professor of medicine at Stanford University School of Medicine in Palo Alto.

Hlatky and colleagues stress that their analysis only applies to a select group of heart patients: those for whom either procedure would be considered a reasonable choice. For patients who are eligible for either heart intervention, “either is feasible,” Hlatky tells WebMD. The report is released early online and will be published in the Nov. 20 issue of the Annals of Internal Medicine.

CABG vs. Angioplasty

The researchers evaluated the results of 23 clinical trials in which 5,019 patients (average age 61 years; 73% men) were randomly assigned to get angioplasty with or without stents (PCI), and 4,944 were assigned to get coronary artery bypass graft surgery (CABG) In angioplasty, interventional cardiologists push a balloon-like device into the coronary arteries and inflate the balloon to widen the vessel. An expandable wire mesh tube called a stent may be inserted to keep the vessel open. Some stents are coated with drugs meant to help prevent the artery from clogging up. In 2005, about 645,000 angioplasty procedures were done in the U.S. In bypass surgery, cardiac surgeons harvest a segment of a healthy blood vessel from another part of the body and use it to bypass the clogged artery or arteries, rerouting the blood to improve blood flow to the heart. About 261,000 bypass procedures were done in the U.S. in 2005.

Findings

Besides similar survival rates overall, the researchers found no significant survival differences between the two procedures for patients with diabetes, although earlier research had seemed to favor bypass surgery. Similar numbers of patients suffered heart attacks within five years of the procedures. While 11.9 of those who got angioplasty had a heart attack within five years, 10.9% of those who got bypass did. Repeat procedures were more common in angioplasty patients. While 46.1% of angioplasty patients who didn’t get a stent needed repeat procedures, 40.1% of those who got a stent did. But just 9.8% of surgery patients needed another procedure. The study didn’t include information on drug-coated stents.

Second Opinions

The new analysis is “very complete,” says Kim A. Eagle, MD, director of the Cardiovascular Center and Albion Walter Hewlett Professor of Internal Medicine at the University of Michigan, Ann Arbor. The study shows, he says, that if either procedure is considered appropriate for an individual patient, the decision can rest on patient attitudes and preferences. Patients preferences might be based on lower need to repeat in favor of surgery, or on avoidance of surgery in favor of angioplasty. But it is important to note, acoording to Curtis Hunter at Santa-Monica-UCLA, that the studies cover the least sick with heart disease, so the two procedures are shown to be equal in a very small subset of the patients.

Coronary Artery Bypass Surgery versus Coronary Stenting – Risk-Adjusted Survival Rates in 5,619 Patients THIJ. 2002

We used the Texas Heart Institute Cardiovascular Research Database to retrospectively identify patients who had undergone their 1st revascularization procedure with coronary artery bypass surgery (CABG; n=2,826) or coronary stenting (n=2,793) between January 1995 and December 1999. Patients were classified into 8 anatomic groups according to the number of diseased vessels and presence or absence of proximal left anterior descending coronary artery disease. Mortality rates were adjusted with proportional hazards methods to correct for baseline differences in severity of disease and comorbidity.

We found that in-hospital mortality was significantly greater in patients undergoing CABG than in those undergoing stenting (3.6% vs 0.75%; adjusted OR 8.4; P <0.0001). At a mean 2.5-year follow-up, risk-adjusted survival was equivalent (CABG 91%, stenting 95%; adjusted OR 1.26; P = 0.06). When subgroups matched for severity of disease were compared, no differences in risk-adjusted survival were seen. A survival advantage of stenting was noted in 3 categories of patients: those >65 years of age (OR 1.33, P = 0.049), those with non-insulin-requiring diabetes (OR 2.06, P = 0.002), and those with any noncoronary vascular disease (OR 1.59, P = 0.009).

In this nonrandomized observational study, CABG had a higher periprocedural mortality rate than did percutaneous stenting. At 2.5 years, however, the survival advantage of stenting was no longer evident. These data suggest that there is no intermediate-term survival advantage of CABG over stenting in patients who have multivessel disease with lesions that can be treated percutaneously. (Tex Heart Inst J 2002;29:3–9)

Fig. 1 Adjusted and unadjusted survival rates in all patients treated with CABG or PCI-stenting
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/table/t3-2/?report=previmg

TABLE III. Multivariate Correlates of Intermediate-Term (2.5-Year) Mortality
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/table/t3-2/?report=previmg

Fig. 2 Adjusted odds ratios comparing the results of CABG and PCI-stenting in the 8 anatomic subgroups.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/bin/2FF2.jpg

TABLE IV. Intermediate-Term (2.5-Year) Survival According to Treatment in Each of the 8 Anatomic Groups
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/bin/2TT4.jpg

Fig. 3 Adjusted odds ratios comparing the results of CABG and PCI-stenting in the various prespecified subsets.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/bin/2FF3.gif

Will Drug-Eluting Stents Replace Coronary Artery Bypass Surgery?

Abstract

Introduction

The growth of the PCI industry and the consequent decline in the number of patients referred for CABG has produced much speculation about the future role of each type of intervention. Because the new drug-eluting stents allow PCI to be performed with lower rates of early restenosis than do bare-metal stents or percutaneous transluminal coronary angioplasty (PTCA) alone, 2–8 some have predicted that surgical revascularization will soon be obsolete.

CABG vs Pharmaco-Therapy

Randomized clinical trials performed during the 1970s and early 1980s clearly established the advantages of CABG over medical therapy in patients with triple-vessel CAD, left main coronary artery stenosis, double-vessel CAD with proximal left anterior descending (LAD) coronary artery stenosis, or left ventricular dysfunction. Problems arose subsequently because of the limitations built into the trial so that the results were biased in favor of medical therapy. These were:

stringent exclusion criteria that eliminated a large percentage of potential participants
left main CAD and an ejection fraction of less than 0.40, eliminated patients for whom CABG would have been beneficial
the high rate of crossover from the medical to the surgical groups

The numerous technical and technological advances made since these trials were completed limit the degree to which their results resemble those of the CAD treatments used today. The maximal medical therapy used during the trials did not routinely include lipid-lowering agents, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, clopidogrel, or some of the other drugs currently used for CAD. Nor did the CABG groups benefit from advances that were subsequently made in preoperative imaging, perfusion and myocardial protection, anesthesia, and perioperative and intensive care practices. CABG did not then include the use of left internal mammary artery (LIMA) grafts, much less other arterial conduits. Finally, PCIs, including balloon angioplasty and stenting, were not included in these trials.

CABG vs PTCA

Randomized trials comparing PTCA with CABG revealed dramatically higher re-intervention rates in the PTCA groups and better angina relief in the CABG groups, although there were no significant differences in death or myocardial infarction rates. The Duke database study. 9 showed better survival rates with PTCA than with CABG in patients with single-vessel CAD, whereas CABG produced better survival than did PTCA in patients with severe, triple-vessel CAD.

These results are not necessarily representative of the results obtainable today with PTCA and CABG, for several reasons.

1. stents were not used in the PTCA patients in these trials

2. operative mortality rates for the CABG groups were higher than the rates currently found in the Society of Thoracic Surgeons (STS) database

3. the inclusion/exclusion criteria of these studies eliminated a high percentage of those patients who might have benefited more from CABG than from PTCA

CABG vs Stents

The introduction of coronary artery stenting resulted in better outcomes than those produced by balloon angioplasty or by other adjuncts, including rotational atherectomy, brachytherapy, and laser angioplasty. Since then, stent designs and delivery techniques have advanced considerably. The use of coronary stents has greatly decreased the necessity of emergent CABG for technical failure of PCI and for dissection or rupture of coronary arteries during PCI. Another major advance in the application of PCI is the use of the antiplatelet agent clopidogrel in addition to aspirin after PCI, as well as the use of glycoprotein (GP) IIb/IIIa receptor inhibitors during the procedure. These adjuncts have significantly reduced the incidence of acute and subacute thrombosis after PTCA with stenting.

Randomized trials comparing PTCA plus stenting with PTCA alone have shown that stenting significantly reduces rates of restenosis and re-intervention, as well as the frequency of emergent CABG. On the other hand, randomized trials of stenting versus surgery have produced less conclusive results regarding the mid-term survival and freedom from adverse events. For example, the Stent or Surgery (SOS) trial reported a greater need for repeat revascularization in the stent group (21%) than in the CABG group (6%) and a survival advantage in the CABG group (hazard ratio, 2.91; 95% CI, 1.29–6.53; P = 0.01) during the 3-year follow-up period. Additionally, angina and the use of anti-angina medications were less common in the CABG group at 1-year follow-up.

The ARTS and ERACI trials also reported an increased need for revascularization in the stent groups but did not show a survival advantage in the CABG groups. This was due in part to a higher operative mortality rate in the CABG group than reported in the STS database. Like the PCI versus CABG trials mentioned previously, these randomized trials involved a select group of patients with relatively low expected mortality rates and relatively high expected technical success with PCI.

Observational data in retrospective analyses of large patient databases comparing CABG with PCI plus stenting does indicate that, because of the greater invasiveness of surgical revascularization, CABG produces greater operative mortality than does PCI. However, in patients with multivessel CAD, the risk-adjusted survival rates at 2.5 years of follow-up are no better for PCI than for CABG, and 3 recent risk-adjusted observational studies showed that the CABG patients had a significant survival advantage at 3- to 8-year follow-up. The CABG patients had significantly more preoperative risk factors than did the PCI patients in each study, so that unadjusted, the CABG groups in each study included significantly more patients with triple-vessel disease and fewer patients with double-vessel disease than did the PCI groups. Again, we have a moving target with recent advances in both surgery and PCI technology.

Disadvantages of Stenting

The Achilles’ heel of PCI is restenosis and the need for repeat revascularization. Stents have decreased the rate of acute and subacute periprocedural thrombosis. The newer, drug-eluting stents (DESs) have improved in-stent restenosis rates, especially in the carefully selected patient populations studied in the early DES trials. In the RAVEL trial, the early reports of zero in-stent restenosis compared favorably with the 27% in-stent restenosis rates in the bare-metal stent control group at 6-month follow-up. However, the RAVEL trial excluded patients with lesions longer than 18 mm, ostial targets, calcified or thrombosed targets, or target arteries less than 2.5 mm in diameter.

The media frenzy that followed the release of these findings created a public demand for these new “miracle” stents that apparently did not re-occlude. Stories of CAD patients refusing conventional PCI and CABG —instead, adding their names to the list of patients waiting for U.S. Food and Drug Administration (FDA) approval of DESs—appeared to change the practice patterns of cardiologists and cardiac surgeons overnight. And then there were the calls for class-action lawsuits and recall of various DES models. After the FDA approved the Cordis Cypher™ DES (Cordis Corporation, a Johnson & Johnson company; Miami Lakes, Fla), a few reports of subacute thrombosis and hypersensitivity reactions prompted the FDA to release a public health notification on 29 October 2003.

The SIRIUS trial had slightly less strict exclusion criteria than did the RAVEL trial, admitting patients with target lesions 2.5 to 3.5 mm in diameter and 15 to 30 mm long, as well as patients with diabetes mellitus (who constituted 26% of the total group). The SIRIUS trial also differed from the RAVEL trial in that the reported end-point was in-segment restenosis, rather than in-stent restenosis. The results showed a significant advantage of DESs over bare-metal stents for preventing in-segment restenosis (9.2% vs 32.3%) and target failures (10.5% vs 19.5%), but major adverse cardiac events were more frequent in the DES group than in the bare-metal stent group (3.7% vs 1.0%). Interestingly, the 6-month restenosis rates of the bare-metal stents in the RAVEL and SIRIUS control groups were much higher than the 19% 12-month restenosis rate associated with bare-metal stents in an earlier study comparing bare-metal stents with PTCA. In fact, the restenosis rates in the RAVEL and SIRIUS control groups more closely resembled the 40% restenosis rate reported for the PTCA control group in the earlier study.

The practical advantages of DESs over bare-metal stents are evident; nonetheless, we still do not have sufficient mid-term or long-term clinical data to argue that PTCA with DESs is preferable to CABG in “real-world” patients who require revascularization. Although DESs will likely provide better outcomes than bare-metal stents for many patients for whom stenting is indicated, a general extrapolation of existing data to justify the use of DESs in patients for whom CABG is currently indicated is unknown, perhaps undeterminable because the lesion and patient characteristics that lead to the failure of PCI are multifactorial, and the size of the population with lesions having unfavorable characteristics , such as,

longer
total occlusion
branch
small-diameter
calcified
multiple
left main
ostial, and
diffuse lesions

are being treated with PCI more often, as well as diabetics, multiple lesions, and patients with multiple comorbidities.

Advantages of CABG

Over the last 4 decades, surgical coronary artery revascularization techniques and technology have advanced significantly. As a result, despite an increasingly older and sicker patient population, CABG outcomes continue to improve. Observed operative mortality rates have decreased because advances in preoperative evaluation, including more precise coronary artery and myocardial imaging and diagnostic techniques, have allowed more appropriate patient selection and surgical planning. In addition, preoperative, intraoperative, and postoperative monitoring and therapeutic interventions have made CABG safer, even for critically ill and high-risk patients. Improvements in cardiopulmonary perfusion and careful myocardial protection, as well as the use of off-pump and on-pump beating- heart techniques in selected patients, have also decreased perioperative morbidity and mortality rates.

LIMA-to-LAD Long-Term Patency

The long-term benefits of CABG with regard to survival and quality of life are dependent on prolonged graft patency. The LIMA-to-LAD bypass, which is now performed in more than 90% of CABG procedures, shows excellent patency in 10- to 20-year angiographic follow-up studies, setting the gold standard with which other revascularization strategies should be compared. Tatoulis et al. reported that LIMA-to-LAD grafts had a 97.1% patency rate in patients who underwent angiography for cardiac symptoms. Those authors also found high patency rates at 5-year (98%), 10-year (95%), and 15-year (88%) follow-up. However, there are not yet long-term data on bare-metal stents or DESs, and by the time 10- or 20-year data are available, DESs probably will have been replaced by a newer, more advanced technology.

Because of the reported success of the LIMA-to-LAD bypass, other types of arterial conduits are also being used much more frequently. Conduit selection has become an area of great interest to cardiac surgeons, and conduit studies are expanding our understanding of the mechanisms of graft failure and ways to improve bypass graft patency. For example, studies have shown that patients who undergo CABG with both LIMA and right internal mammary artery (RIMA) conduits have better results than those who undergo CABG with one IMA and one or more saphenous vein grafts.

Techniques to Improve Conduit Patency

To maximize the odds of long-term graft patency, surgeons carefully harvest the graft as a pedicled or skeletonized conduit using “no touch” techniques. Using careful anastomotic technique to avoid excessive turbulence at the anastomosis site will prolong graft patency, and the quality of the conduit is crucial. Long-term graft patency depends not only on the conduit chosen but also on the target artery and the degree of stenosis proximal to the anastomosis. Maintaining flow patterns in the native artery, including residual flow (that is, competitive flow) and outflow, is important to avoid stasis in the graft, turbulence at the anastomosis, and vasospasm, especially in arterial conduits. Studies have shown an inverse relationship between the degree of proximal stenosis and graft patency. Targeting the LAD produces the highest patency rates. The characteristics of the target artery also determine graft patency, including –

1. the diameter of the target artery,

2. the presence or absence of diffuse disease within the artery,

3. whether or not the artery requires endarterectomy

Surgeons can avoid atheroembolic events by handling the aorta carefully or not at all. They can also improve safety by

1. using aggressive myocardial protection techniques;

2. avoiding the induction of inflammatory mediators; and

3. carefully controlling

blood pressure,
body temperature, and
electrolyte and glucose levels.

Although there have been major innovations that have enabled surgeons to perform cardiac surgery (including CABG) less invasively, minimally invasive surgical procedures are useful only if they are at least as efficacious as conventional surgery. New technology is being developed to enhance the evolving field of minimally invasive coronary bypass surgery.

Hybrid Coronary Revascularization

As PCI technology improves and techniques of LIMA-to-LAD grafting become less invasive, hybrid coronary revascularization is becoming a distinct possibility. For example, a minimally invasive, off-pump, direct LIMA-to-LAD anastomosis can be combined with DES placement in a focal mid-right-coronary-artery lesion in a patient with complex proximal LAD lesions. Hybrid coronary revascularization procedures are currently being performed, with promising early results. A few centers now have hybrid operating rooms with cardiac surgical and coronary angiographic capabilities that make it possible to perform simultaneous hybrid coronary revascularizations.

Although coronary artery bypass grafting (CABG) remains the treatment of choice for certain types of coronary artery disease (CAD), percutaneous coronary intervention (PCI)—particularly coronary angioplasty with stenting—has become the most popular nonmedical treatment approach to CAD. Some have speculated that, with the advent of drug-eluting stents (DESs), PCI will replace CABG entirely. However, the complete disappearance of CABG is both unlikely and unwarranted, for several reasons. Published randomized trials of CABG, PCI, and medical approaches to CAD compared only highly selected subgroups of patients because of strict exclusion criteria that often favored the PCI cohorts. Therefore, their results do not constitute sufficient evidence for the superiority of PCI over CABG in all CAD patients requiring revascularization. As PCI indications broaden to include more complex lesions and more high-risk patients, outcomes will not remain as favorable. In addition, although PCI is less invasive than surgery, CABG offers more complete revascularization and better freedom from repeat revascularization. Furthermore, no long-term patency data on DESs yet exist, whereas excellent 10- and 20-year patency rates have been reported for the left internal mammary artery-to-left anterior descending artery graft used in most CABG procedures. While PCI has been changing, CABG has not been stagnant; recently, advances in many aspects of the CABG procedure have improved short- and long-term outcomes in CABG patients. Both CABG and PCI technologies will continue to advance, not necessarily exclusive of one another, but no data yet exist to suggest that DESs will render CABG obsolete any time soon.

Will Stent Revascularization Replace Coronary Artery Bypass Grafting?

When we discuss revascularization outcomes, we are talking about 3 major endpoints: death, myocardial infarction, and symptom control. With respect to death, we know that revascularization benefits patients who have severe multivessel disease and left ventricular dysfunction or other physiologic indicators of high risk. 2-vessel disease with proximal left anterior descending coronary artery (LAD) stenosis has been accepted as an indication for revascularization, even though the supporting data come from a small subgroup in a single trial. There has been no success in proving that endovascular treatment has a positive impact on stable CAD, but it is relevant because we leave the native arteries relatively intact. Attempts to improve graft performance beyond the relatively spectacular performance of the pedicled internal mammary artery (IMA) graft to the LAD have been disappointing.

Fig. 1 Graph of graft patency shows deterioration rates over 10 years and the comparative superiority of using the internal mammary artery (IMA) instead of the saphenous vein (SVG).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25FF1.gif

Percutaneous Transluminal Coronary Angioplasty

When angioplasty was introduced, the hope was for a method of revascularization that would rival coronary artery bypass grafting. However, the results were mixed. Angioplasty worked well in patients with no major risk factors, such as diabetes mellitus, but failed miserably in diabetic patients. In fact, the Bypass Angioplasty Revascularization Investigation (BARI) taught us this: if revascularization is needed, regardless of physiologic markers of high risk, the use of percutaneous coronary intervention (PCI) is potentially harmful in comparison with an IMA bypass for the LAD.

Stents and Short-Term Outcomes

The use of stents drastically reduced the probability of emergent surgery after attempted; however, the probability of new lesion formation or restenosis after intervention did not decrease.

Fig. 2 Diagrams show the calculated success (after percutaneous revascularization) of A) percutaneous transluminal coronary angioplasty (PTCA), and B) bare-metal and C) drug-eluting stenting in patients with 3-vessel coronary artery disease (CAD).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25FF2.gif

At the same time, surgeons got better. Myocardial preservation techniques improved, and the use of the pedicled IMA graft changed the game. As a result, successful revascularization, meaning long-term success, became the domain of the surgeon. We at the Texas Heart Institute/St. Luke’s Episcopal Hospital (THI/SLEH) examined our long-term outcomes after stenting or surgery, and we initially reported that stenting was just as beneficial as surgery. This was in accord with the results of several trials: whenever placing a stent was feasible, stent therapy and surgery had the same outcome.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25TT1.jpg

success after PTCA vs bare-metal and drug-eluting stents

Stents and Long-Term Outcomes

Later, when we looked at longer-term follow-up data and the effects of multiple procedures, this picture began to change. Stented patients underwent more procedures. When the risk of one surgical procedure was compared with that of multiple endovascular procedures, the outcomes became more similar, especially in patients with bifurcation lesions or lesions with severe calcification. Drug-eluting stents, with their promise of no restenosis, substantially increased interventional cardiologists’ reach, but not their grasp. In patients with multivessel disease and high-risk lesions, DES placement was almost as risky as surgery and did not yield the same long-term benefit.

Nevertheless, we found locally that the introduction of the DES, with its lower risk of restenosis, was treated as a blessing to proceed with stenting (Table I). This did not follow the data, but cardiologists continued anyway, given the promise of less restenosis. Early risk was discounted, glycoprotein IIb/IIIa inhibitor use declined overnight, and the rate of endovascular procedural complications rose to meet that of surgery without the promise of an IMA graft in our future.

Table I. Independent Predictors of 30-Day Major Adverse Cardiac Events and 3-Year Survival after Drug-Eluting Stent Placement
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25TT1.jpg

Comparing Stenting and Surgery

For decades, methods have been sought to quantify lesion complexity in order to compare the early and late risks associated with stenting versus surgery. Although no perfect system has been devised, the SYNTAX was an important step forward. The SYNTAX score is a simple, computer-based tool for evaluating the risk of complications or failure after PCI. And there are other tools for estimating the same complications after surgery. These estimates enable cardiologists to give patients objective advice regarding the revascularization method that has the best short- and long-term probability of success.

In the patient with non-life-threatening disease (that is, not left main or severe multivessel CAD with left ventricular dysfunction or severely impaired function), stent revascularization has become a reasonable, although not ideal, alternative to surgical revascularization. However, this is true only if stenting is confined to patients whose anatomy and physiology are suited to it—considerations that are well quantified in the SYNTAX score. Whenever questions arise as to the most appropriate therapy, the SYNTAX score should be weighed against clinical characteristics that affect surgical risk. This will guide discussions between the cardiologist, cardiovascular surgeon, patient, and treating physician.

I think that our THI risk is more useful than the other available scores. It uses simple clinical data and can be easily calibrated to the geographic location of its use. Other scores require data that might not be available at the time of clinical decision-making or at all—making such predictions hazardous, at best.

Conclusion

With regard to the chosen mode of revascularization, it is perhaps safe to say that the decision goes beyond the individual physician and must become collective. When a patient has multivessel disease, a reasoned approach must be taken, using these predictive tools and considering the patient’s wishes. Treatment decisions should include all interested parties: the patient, cardiologist, cardiovascular surgeon, and anesthesiologist. The time of ad hoc angioplasty for the patient with multivessel CAD has passed.

Should all ischemic mitral regurgitation be repaired? When should we replace? Curr Opin Cardiol. 2011

Abstract

Purpose of review

Ischemic mitral regurgitation (IMR) is a major source of morbidity and mortality. Although mitral valve repair has become recently popularized for the treatment of IMR, select patients may derive benefits from replacement. The purpose of this review is to describe current surgical options for IMR and to discuss when mitral valve replacement (MVR) may be favored over mitral valve repair.

Recent findings

Current surgical options for the treatment of IMR include surgical revascularization alone, mitral valve repair, or MVR. Although surgical revascularization alone may benefit patients with mild–moderate IMR, most surgeons advocate the performance of revascularization in combination with either mitral valve repair or replacement. In the current era, mitral valve repair has proven to offer improved short-term and long-term survival, decreased valve-related morbidity, and improved left ventricular function compared with MVR. However, MVR should be considered for high-risk patients and those with specific underlying mechanisms of IMR.

Summary

In the absence of level one evidence, mitral valve repair offers an effective and durable surgical approach to the treatment of mitral insufficiency and remains the operation of choice for IMR. MVR, however, is preferred for select patients. Future randomized, prospective clinical trials are needed to directly compare these surgical techniques.

Introduction

Ischemic mitral regurgitation (IMR) describes insufficiency of the mitral valve in the setting of myocardial ischemia, resulting from coronary artery disease. Although IMR may present in the acute setting, usually as a papillary rupture (Carpentier type II), it is usually a consequence of chronic myocardial ischemia that typically presents weeks following a complete infarction. IMR describes mitral insufficiency in the absence of degenerative (structural) mitral valve disease. The underlying pathophysiologic mechanisms of IMR are often complex, resulting from several different structural changes involving left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Although changes to any one component may result in detectable mitral valve insufficiency, moderate-to-severe IMR requiring surgical correction often involves the complex interplay of several co-existent anatomic changes. These underlying mechanisms result in clinically significant valve incompetence due to the combined effects of decreased ventricular function and restricted motion of the valve itself due to tethering.

IMR is a major source of patient morbidity and mortality. Although the frequency of IMR differs based upon imaging modality, estimates have suggested that nearly 20–30% of patients experience mitral insufficiency following myocardial infarction. Furthermore, its intimate association with heart failure and poor outcomes for suboptimal medical management further complicates the management of clinically significant IMR. Recent evidence suggests that moderate or severe mitral regurgitation may be associated with a three-fold increase in the adjusted risk of heart failure and a 1.6-fold increase in risk-adjusted mortality at 5-year follow-up. In addition, unfavorable patient profiles and co-existing comorbid disease, including renal failure, chronic obstructive pulmonary disease, diabetes, and impaired left ventricular function, further complicate the clinical picture for those with IMR. Consequently, surgical correction of this condition is often required.

The purpose of this review is to analyze published results for the surgical correction of IMR and to provide current opinion regarding the selection of mitral valve procedure in the setting of myocardial ischemia. Herein, we review current surgical options for IMR and discuss when MVR may be favored over mitral valve repair.

Surgical options for ischemic mitral regurgitation: surgical revascularization alone

Surgical revascularization alone with CABG may be beneficial for some patients. Although CABG alone may be performed in cases of mild-to-moderate IMR, for the treatment of severe IMR, evidence supports performance of CABG with a mitral valve. In fact, a lack of evidence exists to support the performance of CABG alone for severe IMR. In one retrospective review of propensity-matched cohorts, Diodato et al. suggested that addition of a mitral valve procedure to patients undergoing CABG for moderately severe to severe IMR did not increase mortality or improve survival over the performance of CABG alone. This study, however, was limited by small sample sizes (51 CABG + mitral valve repair vs. 51 CABG alone) and 3-year follow-up. To the contrary, substantial evidence exists to support the performance of surgical revascularization alone in cases of mild-to-moderate IMR.

A study by Aklog et al. investigated the role of CABG alone in the correction of moderate IMR. In their series of 136 patients with moderate IMR, they demonstrated that performance of revascularization alone conferred improvement of mitral regurgitation in 51% of patients with complete resolution in an additional 9%. Despite these results, 40% of patients remained with 3–4+ mitral regurgitation, leading the authors to conclude that CABG alone may not be the optimal therapy for most patients and suggest that concomitant mitral annuloplasty may improve results. Other series similarly suggest that complete resolution of functional IMR is uncommon following revascularization alone. Despite the presence of residual mitral regurgitation following revascularization, the impact of performance of CABG without a valve procedure on long-term survival remains ill defined. Currently, on-going prospective evaluation may help to define the potential role of revascularization alone for patients with moderate IMR. Until the completion of these trials, however, evidence supports the performance of surgical revascularization combined with a mitral valve procedure for moderate-to-severe mitral regurgitation.

Surgical revascularization with a mitral valve procedure

The majority of patients with moderate-to-severe IMR require surgical revascularization with a concomitant mitral valve procedure (MVR or mitral valve repair). Historically, these procedures have been associated with high morbidity and mortality as well as poor long-term. However, improved surgical techniques and postoperative management have improved contemporary outcomes. Those favoring mitral valve repair promote its beneficial effects on survival, preserved ventricular function, and the avoidance of long-term anticoagulation, whereas those favoring MVR argue that it ensures long-term freedom from recurrent mitral insufficiency.

Mitral valve replacement vs. mitral valve repair

The use of MVR for IMR eliminates the possibility of recurrent IMR. In addition, previous literature suggests improvements in surgical technique for MVR 29–32. For patients with IMR, MVR with preservation of the subvalvular apparatus using a chordal sparing technique has been shown to be beneficial 33. David and Ho 33 demonstrated a significant survival benefit for patients undergoing MVR with preservation of chordae tendineae (89%) compared with complete excision of the mitral valves (59%) in a cohort of 51 patients with IMR. In addition, Cohn et al. suggested disproportionate survival benefits favoring MVR in a cohort of 150 patients with both functional and structural IMR, concluding that survival following performance of mitral valve procedures for IMR was more dependent on underlying pathophysiology rather than surgical technique. More recently, series have suggested equivalent results for the MVR and mitral valve repair. Mantovani et al. report that prosthetic MVR and mitral valve repair offer very similar results for chronic IMR, demonstrating similar operative mortality and 5-year actuarial survival for both techniques. In a similar report, Magne et al.•• compared short-term and long-term outcomes for 370 patients undergoing mitral valve repair (n = 186) and MVR (n = 184) for IMR. Although operative mortality was lower for mitral valve repair compared with MVR (9.7 vs. 17.4%, P = 0.03), 6-year survival was similar for both operations (73 ± 4 vs. 67 ± 4%, P = 0.17). Type of procedure was also not an independent predictor of mortality following risk adjustment. As a result, the authors suggest that mitral valve repair is not superior to MVR for patients with IMR.

In contrast, other series favor the performance of mitral valve repair for functional IMR. Although several repair techniques exist, restrictive annuloplasty remains the most commonly performed operation 37• and has been shown to be beneficial in both functional and chronic IMR 38•. The purported benefits of improved survival, decreased valve-related morbidity, and improved left ventricular function have been previously established, and several series have reported lower hospital mortality with mitral valve repair compared with MVR.

The Cleveland Clinic published a landmark review of 482 patients undergoing mitral valve procedures for IMR to study the influence of mitral valve procedure type on survival 1. In this series, propensity-matched cohorts were compared: mitral valve repair (n = 397) vs. MVR (n = 85). Concomitant CABG was performed in 95% of operations, and annuloplasty for repair occurred in 98% of cases. After matching, patients were risk stratified into five quintiles. Group 1 represented the highest-risk patients with higher degrees of heart failure and emergent operations, and group 5 represented the lowest-risk patients. Subsequent survival analysis revealed that overall 5-year survival was poor for patients with IMR (58% mitral valve repair vs. 36% MVR, P = 0.08). Moreover, within matched quintiles, the highest-risk patients (quintile 1) had the worst survival, but survival was similar (P = 0.4) despite mitral valve procedure type. In contrast, survival favored mitral valve repair over replacement for quintiles III–V (P = 0.003).

In the absence of published randomized trials, two recently published meta-analyses provide more robust comparisons of the influence of surgical mitral valve repair or replacement. Shuhaiber and Anderson compared outcomes of 29 studies, including over 10 000 patients. Study groups were stratified based upon mitral valve etiology into ischemic, degenerative/myxomatous, rheumatic, and mixed groups. Summary analyses indicated worse overall survival for MVR (early mortality odds ratio = 2.24 and total survival hazard ratio = 1.58) compared with repair. Mitral valve repair was also associated with lower rates of thromboembolism. Moreover, a nonsignificant trend toward lower 30-day mortality favored mitral valve repair for those with IMR. The most recent meta-analysis to date compared short-term and long-term survival of mitral valve repair vs. replacement specifically for IMR ••. In this analysis, nine studies were included based upon stringent exclusion criteria to ensure direct comparisons of survival for mitral valve procedures exclusively performed for IMR. Interestingly, in this series, although patients undergoing MVR were older, those undergoing repair often had higher rates of hypertension and diabetes with lower ejection fractions. Further, the proportion of patients with severe ventricular dysfunction was similar between procedure groups. These findings conflict with a common assumption that an inherent selection bias exists within published studies for the performance of mitral valve repair in healthier patients. Nevertheless, MVR was associated with worse short-term mortality (odds ratio = 2.667) and long-term mortality (hazard ratio = 1.35) compared with mitral valve repair, and the authors advocate that choice in mitral procedure should be based upon individual patient profile.

When not to repair ischemic mitral regurgitation?

Within the context of published literature and current dogma among practicing surgeons, the fundamental question of when not to repair an ischemic mitral valve remains. For several years, accumulated evidence supports the performance of mitral valve repair over replacement for the surgical treatment of functional IMR. The aforementioned benefits of repair include improved long-term survival, durability and efficacy, improved ventricular function, and avoidance of chronic anticoagulation therapy. Nevertheless, MVR still plays a select role in the treatment of IMR.

With respect to the performance of MVR, the use of bioprosthetic valves and the avoidance of mechanical valve replacement are preferred. This choice is largely driven by the avoidance of complications due to long-term anticoagulation use as well as by the belief that it is unlikely that the majority of patients requiring MVR are likely to encounter bioprosthetic deterioration in their lifetime. In addition, MVR with techniques to preserve the subvalvular apparatus should be performed when possible.

Summary

Undoubtedly, the debate regarding when to perform repair or replacement for IMR remains unsettled. In the recent era, mitral valve repair has proven efficacious and remains the preferred surgical strategy for most cases of IMR. MVR should be considered for severe tethering, complex or uncertain mechanisms of mitral insufficiency, regurgitation due to papillary muscle rupture, and perhaps for the sickest and highest-risk patients.

The present review was supported by Award Number 2T32HL007849-11A1 (D.J.L.) from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors.

Hybrid Cath Lab Combines Nonsurgical, Surgical Treatments 2008

A new cardiac treatment facility that couples the benefits of interventional cardiology with cardiothoracic surgery for critically ill newborns, children and adults has opened at Rush University Medical Center, Chicago. Toshiba’s new biplane hybrid cardiac suite, which is one of only three facilities of its kind in the U.S., is equipped with the latest in continuous, real-time imaging technology and radio frequency identification (RFID) technology which allows “all-in-one-room” care. The suite allows collaboration between the surgeon and interventional cardiologist on complex heart problems. For example, fixing a very large hole in the heart can be done by inserting a catheter through a small incision in the chest rather than relying on major surgery to open the chest to reach the heart. “Now, interventional cardiologists and cardiothoracic surgeons working together in this suite will reduce the amount of time required to correct complex heart problems and reduce the emotional and physical stress placed on a patient and their family – which translates into less pain, less scarring and a faster recovery time,” Ziyad Hijazi, M.D., director of the new Rush Center for Congenital and Structural Heart Disease. The hybrid suite is equipped with the latest technology for minimally invasive interventional cardiology that involves the use of a catheter and an image-guidance system to thread tiny instruments through blood vessels to repair the heart. Through these special catheters, physicians at Rush can implant stents, artificial heart valves and insert patches for holes in the heart. In many complex cardiac cases, patients who would otherwise have no other option but to undergo open-heart bypass surgery can now have minimally invasive procedures that would otherwise not be available to them. “We can now communicate with colleagues and obtain their expertise in real time for very complex situations,” said Dr. Hijazi. “If physicians decide another procedure is needed, even surgery, the suite can be converted into an operating room and the surgical team can be assembled in the new suite ”Patients at Rush will stay in one place in the new hybrid cardiac suite where all the imaging technology and implantable devices that might be needed are stored and located. The additional ability it gives us to provide surgical treatments allows us to provide the most comprehensive care in the most sensitive manner for patients with often extremely fragile conditions.” The new hybrid cardiac catheterization suite has the most advanced imaging technologies and can still get a precise, optimal image of any region of the heart regardless of the size or complexity of congenital heart disease. The imaging system also features eight-inch cardiac flat panel detectors designed to deliver distortion-free images. The suite also includes intravascular ultrasound machines, which takes real-time images to allow physicians to see the progress of the procedure taking place inside the patient’s body. A high-tech, automated clinical resource management system located in the suite stores and tracks the medication, surgical tools, medical devices, and implantable devices and supplies using the latest RFID enabled technology.

Hybrid Cath Lab/ORs Are the Way of the Future

Recent developments in cardiac surgery and interventional cardiology with new percutaneous alternatives for aneurysm repair, valve replacements, shunt closure devices and aortic arch reconstruction have led to the creation of integrated, hybrid cath lab/operating rooms (OR) that allow both surgical and intravascular procedures. These rooms offer both surgical equipment and high-end angiographic equipment. Creating such rooms requires special planning and design from both surgical and interventional cardiologists working closely together. Cath labs have high-quality fluoroscopy equipment, but generally are smaller rooms and lack the sterile requirements and equipment needed for surgical procedures. ORs tend to use lower quality mobile C-arms, which are not ideal for interventional procedures. The hybrids aim to provide the best of both worlds. The trend toward hybrid labs has been reinforced by digital angiography manufacturers partnering with surgical equipment companies to create easy-to-integrate hybrid room solutions with coordinated installation. Philips partners with both Skytron and Steris. Toshiba partners with MAQUET. GE Healthcare, Siemens and Toshiba also offer hybrid installations. Philips said while some hospitals want to combine interventional procedures with minimally invasive surgeries, they also want a properly equipped room in case emergency surgery is needed.

Philips said hybrids also allow hospitals with lower PCI numbers to get a bigger bang for their buck by allowing the same room to serve the needs of surgeons. Penn Presbyterian Medical Center in Philadelphia, PA, created a hybrid lab with help from Siemens, which opened in November. Wilson Szeto, M.D., cardio-thoracic surgeon, and William Matthai, M.D., interventionalist, both from Penn Presbyterian said hybrid labs are ideally suited for procedures that require both percutaneous and surgical interventions, percutaneous valve replacements, deploying percutaneous septal occluders or installing aortic stent grafts. Interventionalists can also be called in after cardiac surgery to perform a completion angiography.

Key References:

1. Davis KB, Alderman EL, Kosinski AS, Passamani E, Kennedy JW. Early mortality of acute myocardial infarction in patients with and without prior coronary revascularization surgery. A Coronary Artery Surgery Study Registry Study. Circulation 1992;85(6):2100–9. [PubMed]

2. Peduzzi P, Detre K, Murphy ML, Thomsen J, Hultgren H, Takaro T. Ten-year incidence of myocardial infarction and prognosis after infarction. Department of Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery. Circulation 1991;83(3):747–55. [PubMed]

3. Myocardial infarction and mortality in the coronary artery surgery study (CASS) randomized trial. N Engl J Med 1984; 310(12):750–8. [PubMed]

4. Long-term results of prospective randomised study of coronary artery bypass surgery in stable angina pectoris. European Coronary Surgery Study Group. Lancet 1982;2(8309):1173–80. [PubMed]

5. Frimerman A, Rechavia E, Eigler N, Payton MR, Makkar R, Litvack F. Long-term follow-up of a high risk cohort after stent implantation in saphenous vein grafts. J Am Coll Cardiol 1997;30(5):1277–83. [PubMed]

6. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators [published erratum appears in N Engl J Med 1997;336(2):147]. N Engl J Med 1996;335(4):217–25. [PubMed]

7. Coronary angioplasty versus coronary artery bypass surgery: the Randomized Intervention Treatment of Angina (RITA) trial. Lancet 1993;341:573–80. [PubMed]

8. Rodriguez A, Boullon F, Perez-Balino N, Paviotti C, Liprandi MI, Palacios IF. Argentine randomized trial of percutaneous transluminal coronary angioplasty versus coronary artery bypass surgery in multivessel disease (ERACI): in-hospital results and 1-year follow-up. ERACI Group. J Am Coll Cardiol 1993;22:1060–7. [PubMed]

9. Hamm CW, Reimers J, Ischinger T, Rupprecht HJ, Berger J, Bleifeld W. A randomized study of coronary angioplasty compared with bypass surgery in patients with symptomatic multivessel coronary disease. German Angioplasty Bypass Surgery Investigation (GABI). N Engl J Med 1994;331: 1037–43. [PubMed]

10. King SB 3rd, Lembo NJ, Weintraub WS, Kosinski AS, Barnhart HX, Kutner MH, et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. Emory Angioplasty versus Surgery Trial (EAST). N Engl J Med 1994;331:1044–50. [PubMed]

11 First-year results of CABRI (Coronary Angioplasty versus Bypass Revascularisation Investigation). CABRI Trial Participants. Lancet 1995;346:1179–84. [PubMed]

12. Carrie D, Elbaz M, Puel J, Fourcade J, Karouny E, Fournial G, Galinier M. Five-year outcome after coronary angioplasty versus bypass surgery in multivessel coronary artery disease: results from the French Monocentric Study. Circulation 1997; 96(9 Suppl):II-1–6. [PubMed]

13. Altmann DB, Racz M, Battleman DS, Bergman G, Spokojny A, Hannan EL, Sanborn TA. Reduction in angioplasty complications after the introduction of coronary stents: results from a consecutive series of 2242 patients. Am Heart J 1996;132:503–7. [PubMed]

14. Rankin JM, Spinelli JJ, Carere RG, Ricci DR, Penn IM, Hilton JD, et al. Improved clinical outcome after widespread use of coronary-artery stenting in Canada. N Engl J Med 1999;341:1957–65. [PubMed]

15. Jones RH, Kesler K, Phillips HR 3rd, Mark DB, Smith PK, Nelson CL, et al. Long-term survival benefits of coronary artery bypass grafting and percutaneous transluminal angioplasty in patients with coronary artery disease. J Thorac Cardiovasc Surg 1996;111:1013–25. [PubMed]

16. Hannan EL, Racz MJ, McCallister BD, Ryan TJ, Arani DT, Isom OW, Jones RH. A comparison of three-year survival after coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1999; 33:63–72. [PubMed]

17. Topol EJ, Mark DB, Lincoff AM, Cohne E, Burton J, Kleiman N, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting [published erratum appears in Lancet 2000;355:1104]. Lancet 1999;354:2019–24. [PubMed]

18. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331:489–95. [PubMed]

19. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496–501. [PubMed]

20. Coronary-artery bypass surgery in stable angina pectoris: survival at two years. European Coronary Surgery Study Group. Lancet 1979;1:889–93. [PubMed]

21. Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery: quality of life in patients randomly assigned to treatment groups. Circulation 1983; 68:951–60. [PubMed]

22. Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease II. Subgroup with significant left main lesions. Circulation 1976;54:III107–17. [PubMed]

23. Hueb WA, Bellotti G, de Oliveira SA, Arie S, de Albuquerque CP, Jatene AD, et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses. J Am Coll Cardiol 1995;26:1600–5. [PubMed]

24. Nordmann AJ, Hengstler P, Leimenstoll BM, Harr T, Young J, Bucher HC. Clinical outcomes of stents versus balloon angioplasty in non-acute coronary artery disease: a meta-analysis of randomized controlled trials. Eur Heart J 2004;25:69–80. [PubMed]

25. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. A comparison of coronary-artery stenting with angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. N Engl J Med 1997;336:817–22. [PubMed]

26. Krumholz HM, Cohen DJ, Williams C, Baim DS, Brinker J, Cabin HS, et al. Health after coronary stenting or balloon angioplasty: results from the Stent Restenosis Study. Am Heart J 1997;134:337–44. [PubMed]

27. Villareal RP, Lee VV, Elayda MA, Wilson JM. Coronary artery bypass surgery versus coronary stenting: risk-adjusted survival rates in 5,619 patients. Tex Heart Inst J 2002;29:3–9. [PMC free article] [PubMed]

28. van Domburg RT, Takkenberg JJ, Noordzij LJ, Saia F, van Herwerden LA, Serruys PW, et al. Late outcome after stenting or coronary artery bypass surgery for the treatment of multivessel disease: a single-center matched-propensity controlled cohort study. Ann Thorac Surg 2005;79:1563–9. [PubMed]

29. Brener SJ, Lytle BW, Casserly IP, Schneider JP, Topol EJ, Lauer MS. Propensity analysis of long-term survival after surgical or percutaneous revascularization in patients with multivessel coronary artery disease and high-risk features. Circulation 2004;109:2290–5. [PubMed]

30. Al-Ruzzeh S, Ambler G, Asimakopoulos G, Omar RZ, Hasan R, Fabri B, et al. Off-pump coronary artery bypass (OPCAB) surgery reduces risk-stratified morbidity and mortality: a United Kingdom multi-center comparative analysis of early clinical outcome. Circulation 2003;108 Suppl 1:II1–8. [PubMed]

31. Puskas JD, Williams WH, Mahoney EM, Huber PR, Block PC, Duke PG, et al. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life outcomes: a randomized trial. JAMA 2004;291:1841–9. [PubMed]

32. Goldman S, Zadina K, Moritz T, Ovitt T, Sethi G, Copeland JG, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol 2004;44:2149–56. [PubMed]

33. Shah PJ, Durairaj M, Gordon I, Fuller J, Rosalion A, Seevanayagam S, et al. Factors affecting patency of internal thoracic artery graft: clinical and angiographic study in 1434 symptomatic patients operated between 1982 and 2002. Eur J Cardiothorac Surg 2004;26:118–24. [PubMed]

34. Arima M, Kanoh T, Suzuki T, Kuremoto K, Tanimoto K, Oigawa T, et al. Serial angiographic follow-up beyond 10 years after coronary artery bypass grafting. Circ J 2005;69: 896–902. [PubMed]

35. Tatoulis J, Buxton BF, Fuller JA. Patencies of 2127 arterial to coronary conduits over 15 years. Ann Thorac Surg 2004; 77:93–101. [PubMed]

36. Beauford RB, Saunders CR, Lunceford TA, Niemeier LA, Shah S, Karanam R, et al. Multivessel off-pump revascularization in patients with significant left main coronary artery stenosis: early and midterm outcome analysis. J Card Surg 2005;20:112–8. [PubMed]

37. Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol 2010;55(11):1067–75. [PubMed]

38. Laham RJ, Carrozza JP, Berger C, Cohen DJ, Kuntz RE, Baim DS. Long-term (4- to 6-year) outcome of Palmaz-Schatz stenting: paucity of late clinical stent-related problems. J Am Coll Cardiol 1996;28(4):820–6. [PubMed]

39. Rodriguez A, Bernardi V, Navia J, Baldi J, Grinfeld L, Martinez J, et al. Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease (ERACI II): 30-day and one-year follow-up results. ERACI II Investigators [published erratum appears in J Am Coll Cardiol 2001;37(3):973–4]. J Am Coll Cardiol 2001;37(1):51–8. [PubMed]

40. Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schonberger JP, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001;344(15):1117–24. [PubMed]

41. Goy JJ, Kaufmann U, Goy-Eggenberger D, Garachemani A, Hurni M, Carrel T, et al. A prospective randomized trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis: the SIMA trial. Stenting vs Internal Mammary Artery. Mayo Clin Proc 2000;75(11):1116–23. [PubMed]

42. SoS Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet 2002;360 (9338):965–70. [PubMed]

43. Reul RM. Will drug-eluting stents replace coronary artery bypass surgery? Tex Heart Inst J 2005;32(3):323–30. [PMC free article] [PubMed]

44. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1(2):219–27. [PubMed]

45. Madan P, Elayda MA, Lee VV, Wilson JM. Predicting major adverse cardiac events after percutaneous coronary intervention: the Texas Heart Institute risk score. Am Heart J 2008; 155(6):1068–74. [PubMed]

46. Gillinov AM, Wierup PN, Blackstone EH, et al. Is repair preferable to replacement for ischemic mitral regurgitation? J Thorac Cardiovasc Surg. 2001;122:1125–1141. [PubMed]

47. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759–1764. [PubMed]

48. Lamas GA, Mitchell GF, Flaker GC, et al. Clinical significance of mitral regurgitation after acute myocardial infarction. Survival and Ventricular Enlargement Investigators. Circulation. 1997;96:827–833. [PubMed]

49. Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation. 2005;111:295–301. [PubMed]

50. Adams DH, Filsoufi F, Aklog L. Surgical treatment of the ischemic mitral valve. J Heart Valve Dis. 2002;11 (Suppl 1):S21–S25. [PubMed]

51. Filsoufi F, Salzberg SP, Adams DH. Current management of ischemic mitral regurgitation. Mt Sinai J Med. 2005;72:105–115. [PubMed]

52. Micovic S, Milacic P, Otasevic P, et al. Comparison of valve annuloplasty and replacement for ischemic mitral valve incompetence. Heart Surg Forum. 2008;11:E340–E345. [PubMed]

53. Aklog L, Filsoufi F, Flores KQ, et al. Does coronary artery bypass grafting alone correct moderate ischemic mitral regurgitation? Circulation. 2001;104 (12 Suppl 1):I68–I75. [PubMed]

54. Lam BK, Gillinov AM, Blackstone EH, et al. Importance of moderate ischemic mitral regurgitation. Ann Thorac Surg. 2005;79:462–470. discussion 462–470. [PubMed]

55. Ryden T, Bech-Hanssen O, Brandrup-Wognsen G, et al. The importance of grade 2 ischemic mitral regurgitation in coronary artery bypass grafting. Eur J Cardiothorac Surg. 2001;20:276–281. [PubMed]

56•. Goland S, Czer LS, Siegel RJ, et al. Coronary revascularization alone or with mitral valve repair: outcomes in patients with moderate ischemic mitral regurgitation. Tex Heart Inst J. 2009;36:416–424. This series documents current outcomes for the performance of CABG alone with/without concomitant mitral valve repair for ischemic mitral regurgitation. The authors report similar 5-year survival rates for both techniques; however, revascularization with repair resulted in significantly reduced mitral regurgitation grade, improved left ventricular function, and functional class compared with revascularization alone. This study provides an important comparison of these two techniques in the current surgical era. [PMC free article] [PubMed]

57••. Magne J, Girerd N, Senechal M, et al. Mitral repair versus replacement for ischemic mitral regurgitation: comparison of short-term and long-term survival. Circulation. 2009;120(11 Suppl):S104–S111. In this study, the authors compare postoperative outcomes for mitral valve repair and replacement for ischemic mitral regurgitation. Despite lower operative mortality following mitral valve repair, long-term survival was equivalent between surgical groups. This study adds important long-term comparisons of mitral valve procedures to accumulating data examining surgical treatments for ischemic mitral regurgitation. [PubMed]

58. Silberman S, Klutstein MW, Sabag T, et al. Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings. Ann Thorac Surg. 2009;87:1721–1726. discussion 1726–1727. This study provides a contemporary comparison between the use of flexible and rigid annuloplasty rings for the surgical treatment of IMR. The authors report significantly improved clinical and hemodynamic results for rigid mitral annuloplasty rings compared with flexible rings. [PubMed]

59•. Tekumit H, Cenal AR, Uzun K, et al. Ring annuloplasty in chronic ischemic mitral regurgitation: encouraging early and midterm results. Tex Heart Inst J. 2009;36:287–292. This study reports early and midterm results for the use of flexible annuloplasty rings for the surgical treatment of chronic IMR. The authors demonstrate that use of flexible mitral valve annuloplasty conferred a reduction in left ventricular diameter with improved New York Heart Association functional class. This study reports current, encouraging results and provides a context for future investigations comparing flexible and rigid annuloplasty rings for chronic IMR. [PMC free article] [PubMed]

60. Shuhaiber J, Anderson RJ. Meta-analysis of clinical outcomes following surgical mitral valve repair or replacement. Eur J Cardiothorac Surg. 2007;31:267–275. [PubMed]

61••. Vassileva CM, Boley T, Markwell S, Hazelrigg S. Meta-analysis of short-term and long-term survival following repair versus replacement for ischemic mitral regurgitation. Eur J Cardiothorac Surg. 2010 [Epub ahead of print] This meta-analysis provides a comparison of nine published series specifically addressing the performance of mitral valve repair vs. replacement for IMR. The authors demonstrate worse short-term and long-term mortality for MVR. Their analysis offers an up-to-date and robust comparison of these two surgical techniques. [PubMed]

Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, PCI, Stents & Tools, Technology Transfer: Biotech and Pharmaceutical, Uncategorized, Valves & Tools, tagged Angina pectoris, Aortic valve, Aortic valve replacement, CABG, Cardiovascular disease, Columbia University Medical Center, Coronary artery bypass surgery, Coronary artery disease, Edwards Lifesciences Corporation, Food and Drug Administration, Percutaneous coronary intervention, surgery, TAVR on June 17, 2013| 12 Comments »

Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Writer: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Significant, defined as a greater than 50 percent narrowing, left main coronary artery disease (LMCAD) is found in 4 to 6 percent of all patients who undergo coronary arteriography [1]. When present, it is associated with multivessel coronary artery disease (MVCAD) about 70 percent of the time [2,3].

Most patients are symptomatic and at high risk of cardiovascular events, since occlusion of this vessel compromises flow to at least 75 percent of the left ventricle, unless it is protected by collateral flow or a patent bypass graft to either the left anterior descending or circumflex artery. Studies performed before revascularization with coronary artery bypass graft surgery (CABG) became the standard of care revealed a poor prognosis for these patients, with three-year survival as low as 37 percent [4]. CABG, when directly compared to medical therapy, is associated with significantly better cardiovascular outcomes, including mortality [5].

Percutaneous coronary intervention (PCI) with stenting has generally been restricted to such patients considered inoperable or at high risk for CABG, or with prior CABG and at least one patent graft to the left anterior descending or circumflex artery (so-called “protected” left main disease). Graft patency is important in this setting in the event of acute or late closure after PCI. However, evidence is increasing to support the use of PCI with stenting in some cases. (See ‘PCI versus CABG’ below.)

Asymptomatic patients with left main lesions felt to not be hemodynamically significant should be managed with preventative therapies. Patients with anginal symptoms attributable to lesions elsewhere should be managed with therapies similar to those used in other patients with coronary artery disease. (See “Overview of the care of patients with stable ischemic heart disease”.)

This topic will discuss most aspects of the management of patients with LMCAD. The approach to patients with multivessel coronary artery disease without LMCAD is discussed elsewhere. (See “Bypass surgery versus percutaneous intervention in the management of stable angina pectoris: Recommendations”.)

http://www.uptodate.com/contents/management-of-left-main-coronary-artery-disease

Catheter Cardiovasc Interv. 2013 Feb 14.

http://dx.doi.org/10.1002/ccd.24865. [Epub ahead of print]

Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

Paradis JM, George I, Kodali S.

Source

Columbia University Medical Center, New York, New York; Cardiovascular Research Foundation, New York, New York.

Abstract

We report the case of an 81-year-old woman with symptomatic severe aortic stenosis, extremely significant peripheral arterial disease, and obstructive coronary artery disease who underwent percutaneous coronary intervention via a transaxillary conduit immediately before a trans-apical transcatheter aortic valve replacement performed with a transfemoral device. After deployment of the transcatheter heart valve, there was a left main coronary obstruction and the patient required an emergent PCI. This multifaceted case clearly underlines the importance of a well functioning heart team including the interventional cardiologist, the cardiovascular surgeon, and the echocardiographer. © 2013 Wiley Periodicals, Inc.

PMID: 23413172

Transapical deployment of an Aortic Valve

WATCH VIDEO

Investigational Devices: Edwards Sapien Transcatheter Aortic Valve Transapical Deployment

This is an interesting surgical case presented by the Columbia University Cardiovascular Surgery team, illustrating the importance of combined team skills in the most difficult of cases. It is part of a series on cardiovascular surgery.

Management of significant left main coronary disease before and after trans-apical transcatheter aortic valve replacement in a patient with severe and complex arterial disease.

Paradis JM, George I, and Kodali S

Catheterization and Cardiovascular Interventions (2013)

http://dx.doi.org/10.1002/ccd.24865

Introduction

Transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN transcatheter heart valve (THV) (Edwards Lifesciences, Irvin, CA) has been shown to reduce mortality when compared to medical therapy alone for patients with symptomatic severe aortic stenosis deemed unsuitable for surgical aortic valve replacement due to multiple co-morbidities. The Edwards SAPIEN THV, sizes 23 and 26 mm, and the RetroFlex 3 transfemoral delivery system, have been recently approved by the US Food and Drug Administration (FDA) for commercial use outside of the PARTNER clinical trial for patients considered inoperable. However, an alternative site needs to be selected for patients with peripheral arteries inadequate for transfemoral TAVR. Although not fully validated, the transapical approach or the transaortic route using a balloon expandable THV, appears to be appropriate for this specific purpose. Significant coronary artery disease (CAD) is often found in patients with severe aortic stenosis. in > 50% of patients with aortic stenosis over 70 years of age and in > 65% of patients who are over 80 years of age. There is no established guideline for managing significant CAD in the context of TAVR, including the appropriate revascularization strategy as well as the timing of interventions.

Case Report

An 81-year-old woman presented with symptomatic severe aortic stenosis, extremely significant peripheral arterial disease, and obstructive coronary artery disease. She had a six-month history prior to admission of progressive exertional shortness of breath and fatigue, and a long history fo hypertension, hyperlipidemia, obesity, and severe peripheral vascular disease. In 2003, she underwent a coronary artery bypass graft (CABG) surgery, with grafting of the left internal mammary artery (LIMA) to the left anterior descending (LAD) artery, a saphenous vein graft (SVG) to the first obtuse marginal (OM) branch, and a SVG to the right coronary artery (RCA). Due to associated severe mitral regurgitation, a mitral valve ring annuloplasty was also performed. A transthoracic echocardiogram (TTE) revealed severe aortic stenosis with a peak gradient across the aortic valve of 63 mm Hg, a mean gradient of 39 mm Hg, and an aortic valve area of 0.8 cm2. The left ventricular ejection fraction (LVEF) was 64% while the pulmonary artery systolic pressure was measured at 28 mm Hg. Extreme calcification and tortuosity precluded the advancement of any wire, catheter, or sheath, contributing to two attempts at cardiac catheterization prior to transfer with a total occlusion of the distal abdominal aorta, at the level of the aorto-iliac bifurcation, and the left main, proximal LAD, proximal left circumflex, and the proximal RCA all had greater than 70% coronary lesions. In addition, ostial total occlusions were seen in both SVGs.

After transfer, a cardiac catheterization through the right radial artery was attempted without success due to calcification and tortuosity in the arterial bed. An 80% distal left main lesion was clearly identified with a Judkins left 3.5 guiding catheter. There was non-flow limiting coronary disease in the left circumflex and competitive retrograde flow seen in the LIMA graft, but they still were unable to cannulate the RCA and the SVGs. It was determined that the patient was inoperable, on grounds of her significant frailty, reoperative status and overall comorbid state (Society of Thoracic Surgeons (STS) risk score of 11%). Furthermore, due to the occlusion of the distal aorta, the patient was unsuitable for a TAVR via the transfemoral approach.

They chose to approach her PCI via a conduit on the right axillary artery and perform a concomitant TAVR from a trans-apical approach due to the serious limiting condition of the patient. She underwent percutaneous coronary intervention via a transaxillary conduit immediately before a trans-apical transcatheter aortic valve replacement performed with a transfemoral device. Excellent flow from the conduit was noted. A 7 French (Fr) sheath was connected to the end of the conduit, which was kept long to allow better maneuverability (Fig. 1). A Rosen wire was passed with some difficulty to the aortic root, and was switched to a stiff wire in an attempt to straighten the vessel.

Fig. 1. Transaxillary conduit used during the procedure. A 7 French sheath was connected to an 8 mm dacron graft, which was previously sewn to the axillary artery.

After deployment of the transcatheter heart valve, there was a left main coronary obstruction and the patient required an emergent PCI. This multifaceted case clearly underlines the importance of a well functioning heart team including the interventional cardiologist, the cardiovascular surgeon, and the echocardiographer. A Xience

V everolimus eluting stent 3.5 mm 18 mm was implanted starting 2 mm distal to the ostium of the left main, extending in the proximal portion of the left circumflex artery. After one post-dilatation with a non-compliant balloon, the final angiographic result was excellent.

They used a Retroflex 3 transfemoral delivery sheath to perform the trans-apical TAVR. They estimated the size and length of the ventricular cavity, and then placed markers on the delivery sheath (prior to insertion) indicating the appropriate length of sheath to remain outside the heart (Fig. 2).

Fig. 2. Marker placed on the RetroFlex 3 transfemoral sheath to safely guide its insertion inside the left ventricular cavity during the trans-apical transcatheter aortic valve replacement.

A 23 mm Edwards SAPIEN valve was selected and deployed under fluoroscopic and transesophageal echocardiographic guidance. Immediately after deployment, turbulent flow was noted within the left main with the color Doppler on TEE, indicating a new obstruction of the left main, which a left coronary angiogram showed to be a severe proximal lesion. Through the trans-axillary conduit, a guiding catheter was laboriously brought in the ascending aorta and cannulated the left main artery which permitted a predilation and a stent insertion in the ostial portion of the left main. She was discharged to a rehabilitation facility 7 days after the procedure.

On follow-up TTE, the LVEF was 55% without any significant wall motion abnormality. There was no aortic regurgitation, and the peak and mean gradients were 14.9 mm Hg and 8.0 mm Hg, respectively. The patient is still doing well more than 6 months after the procedure. She is now in NYHA class 2 and has not had any recurrent hospitalization for congestive heart failure.

Discussion

This report is a case of a complex percutaneous coronary intervention of the left main coronary artery via a right axillary conduit followed immediately by an off label commercial transapical TAVR using the Retro-Flex 3 trans-femoral introducer sheath, complicated finally by a new left main coronary obstruction mandating another PCI. It is the first description of a TAVR procedure preceded and followed by a left main trans-axillary PCI. The role of TEE (color Doppler) in the diagnosis of a very rare TAVR complication is also noteworthy. In a recent meta-analysis of 3,519 patients from 16 studies using the Valve Academic Research Consortium (VARC) definitions, the pooled estimate rate of coronary

obstruction following TAVR was only 0.7%. Obviously, the early recognition and treatment of this hazard is imperative.

The surgical management of this patient also warrants discussion. The hybrid surgical approach of accessing the axillary artery via a conduit provides numerous advantages:

(1) the ascending aorta, coronaries, and aortic valve are easily accessible;

(2) transition to cardiopulmonary bypass or extra-corporeal membrane oxygenation, if needed, is quick; and

(3) long-term morbidity is minimal for the patient when compared to aorto-iliac, aortic, or femoral conduits.

Finally, the heart team approach not only allowed the realization of a difficult coronary

stent implantation through an unusual transaxillary graft followed by a transapical TAVR in a patient with significant peripheral arterial disease, but also permitted the early recognition and management of a potentially fatal left main obstruction. Considerations such as team-based care, close communication between the different specialties

involved and careful planning for outlining management of potential complications are therefore essential for the success of a TAVR program.

REFERENCES

1. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–1607.

2. Iung B. Interface between valve disease and ischaemic heart disease. Heart 2000;84:347–352.

3. Wenaweser P, Pilgrim T, Guerios E, Stortecky S, Huber C, Khattab AA, et al. Impact of coronary artery disease and percutaneous coronary intervention on outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation.

EuroIntervention 2011;7:541–548.

4. Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K, et al. Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: A weighted meta-analysis of 3,519 patients from 16 studies.

J Am Coll Cardiol 2012;59:2317–2326.

Postdilatation to Reduce Paravalvular Regurgitation During Transcatheter Aortic Valve Replacement (pharmaceuticalintelligence.com)
No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it? (pharmaceuticalintelligence.com)
TAVR for Aortic Regurgitation: Proceed with Caution (zedie.wordpress.com)
How to Get a Minimally Invasive Aortic Valve Replacement (tavrvalvereplacement.wordpress.com)
Medtronic CoreValve EU Cleared for Transcatheter Valve-In-Valve Procedures (medgadget.com)
Aortic stenosis?!! (myheartnet.wordpress.com)

Three coronary artery bypass grafts, a LIMA to LAD and two saphenous vein grafts – one to the right coronary artery (RCA) system and one to the obtuse marginal (OM) system. (Photo credit: Wikipedia)

heart with coronary arteries (Photo credit: Wikipedia)

Micrograph of an artery that supplies the heart with significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson’s trichrome. (Photo credit: Wikipedia)

Could Teleradiology contribute to “cross-borders” standardization of imaging protocols in cancer management?

Posted in Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, tagged Cancer - General, mammography, Medical imaging, Medical Specialties, Teleradiology on June 16, 2013| 4 Comments »

Could Teleradiology contribute to “cross-borders” standardization of imaging protocols in cancer management?

Writer: Dror Nir, PhD

Teleradiology is accepted as a legitimate medical service for several years now. It has many clinical utilities worldwide, ranging from services for expert or second opinions to comprehensive remote management of radiology departments in hospitals. Rapid advances in web-technologies infrastructure eliminated the barriers related to the transfer, reading and reporting of radiology images from remote locations. Today’s main controversies are related to issues that are relevant also to “in-house” radiology departments; e.g. clinical governance, quality assessment, work-flow and medico-legal issues.

The concept of Teleradiology is as simple as plotted in this chart.

Images are automatically uploaded from the imaging system itself or from the institution’s PACS. Reports are sent to the “client” within few hours.

The value for the users goes well beyond mere image interpretation, for example:

On-site physicians have more time to spend with patients.
Offering of additional subspecialty/multidisciplinary expertise.
Comprehensive image-interpretation and reporting service at reduced time-span and reduced cost
Sharing images and reports with referring physicians and patients with no effort.

As an example for “cross-border” standardization of a major existing radiology service, let’s consider the use-case of centralized review of mammography images. I know, quite ambitious! And; politically very challenging!

But; seem to be technologically and clinically feasible, at least according to the below quoted publication:

Teleradiology with uncompressed digital mammograms: Clinical assessment

Julia Fruehwald-Pallamar, Marion Jantsch, Katja Pinker, Ricarda Hofmeister, Friedrich Semturs, Kathrin Piegler, Daniel Staribacher, Michael Weber, Thomas H. Helbich

published online 13 April 2012.

Abstract

Purpose

The purpose of our study was to demonstrate the feasibility of sending uncompressed digital mammograms in a teleradiologic setting without loss of information by comparing image quality, lesion detection, and BI-RADS assessment.

Materials and methods

CDMAM phantoms were sent bidirectionally to two hospitals via the network. For the clinical aspect of the study, 200 patients were selected based on the BI-RAD system: 50% BI-RADS I and II; and 50% BI-RADS IV and V. Two hundred digital mammograms (800 views) were sent to two different institutions via a teleradiology network. Three readers evaluated those 200 mammography studies at institution 1 where the images originated, and in the two other institutions (institutions 2 and 3) where the images were sent. The readers assessed image quality, lesion detection, and BI-RADS classification.

Results

Automatic readout showed that CDMAM image quality was identical before and after transmission. The image quality of the 200 studies (total 600 mammograms) was rated as very good or good in 90–97% before and after transmission. Depending on the institution and the reader, only 2.5–9.5% of all studies were rated as poor. The congruence of the readers with respect to the final BI-RADS assessment ranged from 90% and 91% at institution 1 vs. institution 2, and from 86% to 92% at institution 1 vs. institution 3. The agreement was even higher for conformity of content (BI-RADS I or II and BI-RADS IV or V). Reader agreement in the three different institutions with regard to the detection of masses and calcifications, as well as BI-RADS classification, was very good (κ: 0.775–0.884). Results for interreader agreement were similar.

Conclusion

Uncompressed digital mammograms can be transmitted to different institutions with different workstations, without loss of information. The transmission process does not significantly influence image quality, lesion detection, or BI-RADS rating.

Keywords: Breast cancer, Imaging, Digital mammography, Teleradiology, Comparative studies

What could be the benefits from centralizing mammography interpretation through Teleradiology?

A baseline protocol that could enable pulling together large number of cases from different populations without having to worry about differences in practice and experience of reporters. This will enable better epidemiology studies of this disease.
Quantified measure, in real-time, of the relative quality of imaging between institutions could contribute to bringing all screening services to a maximal level.
Development of comprehensive training program for radiologists involved in mammography based screening of breast cancer.
Better information sharing between all players involved in the pathway of each individual patient could improve clinical decision making and patient’s support.
Lower costs of screening programs, disease treatment and follow-up.

Who could organize and carry out such an operation?

There are many reputable large university hospitals already offering Teleradiology services. They are already supported by government’s funds in addition to the fact that the service itself is carrying profits. I’m not listing any of these for obvious reasons, but; google “teleradiology” will bring you many results.

Full Text via CrossRef

Imaging of Non-tumorous and Tumorous Human Brain Tissues

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Surgery of the Heart, Imaging-based Cancer Patient Management, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, tagged Brain tumor, Cancer - General, Cell Biology, Clinical trial, Digital pathology, FF-OCT, future medicine, Glioma, health, Human brain, Medical imaging, medicine, OCT, optical coherence tomography, surgery on June 12, 2013| 4 Comments »

Imaging of Non-tumorous and Tumorous Human Brain Tissues

Reporter and Curator: Dror Nir, PhD

The point of interest in the article I feature below is that it represents a potential building block in a future system that will use full-field optical coherence tomography during brain surgery to improve the accuracy of cancer lesions resection. The article is featuring promising results for differentiating tumor from normal brain tissue in large samples (order of 1–3 cm2) by offering images with spatial resolution comparable to histological analysis, sufficient to distinguish microstructures of the human brain parenchyma. Easy to say, and hard to make…:) –> Intraoperative apparatus to guide the surgeon in real time during resection of brain tumors.

Imaging of non-tumorous and tumorous human brain tissues with full-field optical coherence tomography

Open Access Article

Osnath Assayag ^a^,¹, Kate Grieve ^a^,^,¹^,, Bertrand Devaux ^b^,^c, Fabrice Harms ^a, Johan Pallud ^b^,^c,Fabrice Chretien ^b^,^c, Claude Boccara ^a, Pascale Varlet ^b^,^c; ^aInserm U979 “Wave Physics For Medicine” ESPCI -ParisTech – Institut Langevin, 1 rue Jussieu, 75005, ^bFrance, Centre Hospitalier Sainte-Anne, 1 rue Cabanis 75014 Paris, France

^cUniversity Paris Descartes, France.

Abstract

A prospective study was performed on neurosurgical samples from 18 patients to evaluate the use of full-field optical coherence tomography (FF-OCT) in brain tumor diagnosis.

FF-OCT captures en face slices of tissue samples at 1 μm resolution in 3D to a penetration depth of around 200 μm. A 1 cm² specimen is scanned at a single depth and processed in about 5 min. This rapid imaging process is non-invasive and requires neither contrast agent injection nor tissue preparation, which makes it particularly well suited to medical imaging applications.

Temporal chronic epileptic parenchyma and brain tumors such as meningiomas, low-grade and high-grade gliomas, and choroid plexus papilloma were imaged. A subpopulation of neurons, myelin fibers and CNS vasculature were clearly identified. Cortex could be discriminated from white matter, but individual glial cells such as astrocytes (normal or reactive) or oligodendrocytes were not observable.

This study reports for the first time on the feasibility of using FF-OCT in a real-time manner as a label-free non-invasive imaging technique in an intraoperative neurosurgical clinical setting to assess tumorous glial and epileptic margins.

Abbreviations

FF-OCT, full field optical coherence tomography;
OCT, optical coherence tomography

Keywords

Optical imaging; Digital pathology; Brain imaging; Brain tumor; Glioma

1. Introduction

1.1. Primary CNS tumors

Primary central nervous system (CNS) tumors represent a heterogeneous group of tumors with benign, malignant and slow-growing evolution. In France, 5000 new cases of primary CNS tumors are detected annually (Rigau et al., 2011). Despite considerable progress in diagnosis and treatment, the survival rate following a malignant brain tumor remains low and 3000 deaths are reported annually from CNS tumors in France (INCa, 2011). Overall survival from brain tumors depends on the complete resection of the tumor mass, as identified through postoperative imaging, associated with updated adjuvant radiation therapy and chemotherapy regimen for malignant tumors (Soffietti et al., 2010). Therefore, there is a need to evaluate the completeness of the tumor resection at the end of the surgical procedure, as well as to identify the different components of the tumor interoperatively, i.e. tumor tissue, necrosis, infiltrated parenchyma (Kelly et al., 1987). In particular, the persistence of non-visible tumorous tissue or isolated tumor cells infiltrating brain parenchyma may lead to additional resection.

For low-grade tumors located close to eloquent brain areas, a maximally safe resection that spares functional tissue warrants the current use of intraoperative techniques that guide a more complete tumor resection. During awake surgery, speech or fine motor skills are monitored, while cortical and subcortical stimulations are performed to identify functional areas (Sanai et al., 2008). Intraoperative MRI provides images of the surgical site as well as tomographic images of the whole brain that are sufficient for an approximate evaluation of the abnormal excised tissue, but offers low resolution (typically 1 to 1.5 mm) and produces artifacts at the air-tissue boundary of the surgical site.

Histological and immunohistochemical analyses of neurosurgical samples remain the current gold standard method used to analyze tumorous tissue due to advantages of sub-cellular level resolution and high contrast. However, these methods require lengthy (12 to 72 h), complex multiple steps, and use of carcinogenic chemical products that would not be technically possible intra-operatively. In addition, the number of histological slides that can be reviewed and analyzed by a pathologist is limited, and it defines the number and size of sampled locations on the tumor, or the surrounding tissue.

To obtain histology-like information in a short time period, intraoperative cytological smear tests are performed. However tissue architecture information is thereby lost and the analysis is carried out on only a limited area of the sample (1 mm × 1 mm).

Intraoperative optical imaging techniques are recently developed high resolution imaging modalities that may help the surgeon to identify the persistence of tumor tissue at the resection boundaries. Using a conventional operating microscope with Xenon lamp illumination gives an overall view of the surgical site, but performance is limited by the poor discriminative capacity of the white light illumination at the surgical site interface. Better discrimination between normal and tumorous tissues has been obtained using fluorescence properties of tumor cells labeled with preoperatively administered 5-ALA. Tumor tissue shows a strong ALA-induced PPIX fluorescence at 635 nm and 704 nm when the operative field is illuminated with a 440 nm-filtered lamp. More complete resections of high-grade gliomas have been demonstrated using 5-ALA fluorescence guidance (Stummer et al., 2000), however brain parenchyma infiltrated by isolated tumor cells is not fluorescent, reducing the interest of this technique when resecting low-grade gliomas.

Refinement of this induced fluorescence technique has been achieved using a confocal microscope and intraoperative injection of sodium fluorescein. A 488 nm laser illuminates the operative field and tissue contact analysis is performed using a handheld surgical probe (field of view less than 0.5 × 0.5 mm) which scans the fluorescence of the surgical interface at the 505–585 nm band. Fluorescent isolated tumor cells are clearly identified at depths from 0 to 500 μm from the resection border (Sanai et al., 2011), demonstrating the potential of this technique in low-grade glioma resection.

Reviewing the state-of-the-art, a need is identified for a quick and reliable method of providing the neurosurgeon with architectural and cellular information without the need for injection or oral intake of exogenous markers in order to guide the neurosurgeon and optimize surgical resections.

1.2. Full-field optical coherence tomography

Introduced in the early 1990s (Huang et al., 1991), optical coherence tomography (OCT) uses interference to precisely locate light deep inside tissue. The photons coming from the small volume of interest are distinguished from light scattered by the other parts of the sample by the use of an interferometer and a light source with short coherence length. Only the portion of light with the same path length as the reference arm of the interferometer, to within the coherence length of the source (typically a few μm), will produce interference. A two-dimensional B-scan image is captured by scanning. Recently, the technique has been improved, mainly in terms of speed and sensitivity, through spectral encoding (De Boer et al., 2003, Leitgeb et al., 2003 and Wojtkowski et al., 2002).

A recent OCT technique called full-field optical coherence tomography (FF-OCT) enables both a large field of view and high resolution over the full field of observation (Dubois et al., 2002 and Dubois et al., 2004). This allows navigation across the wide field image to follow the morphology at different scales and different positions. FF-OCT uses a simple halogen or light-emitting diode (LED) light source for full field illumination, rather than lasers and point-by-point scanning components required for conventional OCT. The illumination level is low enough to maintain the sample integrity: the power incident on the sample is less than 1 mW/mm² using deep red and near infrared light. FF-OCT provides the highest OCT 3D resolution of 1.5 × 1.5 × 1 μm³ (X × Y × Z) on unprepared label-free tissue samples down to depths of approximately 200 μm–300 μm (tissue-dependent) over a wide field of view that allows digital zooming down to the cellular level. Interestingly, it produces en face images in the native field view (rather than the cross-sectional images of conventional OCT), which mimic the histology process, thereby facilitating the reading of images by pathologists. Moreover, as for conventional OCT, it does not require tissue slicing or modification of any kind (i.e. no tissue fixation, coloration, freezing or paraffin embedding). FF-OCT image acquisition and processing time is less than 5 min for a typical 1 cm² sample (Assayag et al., in press) and the imaging performance has been shown to be equivalent in fresh or fixed tissue (Assayag et al., in press and Dalimier and Salomon, 2012). In addition, FF-OCT intrinsically provides digital images suitable for telemedicine.

Numerous studies have been published over the past two decades demonstrating the suitability of OCT for in vivo or ex vivo diagnosis. OCT imaging has been previously applied in a variety of tissues such as the eye (Grieve et al., 2004 and Swanson et al., 1993), upper aerodigestive tract (Betz et al., 2008, Chen et al., 2007 and Ozawa et al., 2009), gastrointestinal tract (Tearney et al., 1998), and breast tissue and lymph nodes (Adie and Boppart, 2009, Boppart et al., 2004, Hsiung et al., 2007, Luo et al., 2005, Nguyen et al., 2009, Zhou et al., 2010 and Zysk and Boppart, 2006).

In the CNS, published studies that evaluate OCT (Bizheva et al., 2005, Böhringer et al., 2006, Böhringer et al., 2009, Boppart, 2003 and Boppart et al., 1998) using time-domain (TD) or spectral domain (SD) OCT systems had insufficient resolution (10 to 15 μm axial) for visualization of fine morphological details. A study of 9 patients with gliomas carried out using a TD-OCT system led to classification of the samples as malignant versus benign (Böhringer et al., 2009). However, the differentiation of tissues was achieved by considering the relative attenuation of the signal returning from the tumorous zones in relation to that returning from healthy zones. The classification was not possible by real recognition of CNS microscopic structures. Another study showed images of brain microstructures obtained with an OCT system equipped with an ultra-fast laser that offered axial and lateral resolution of 1.3 μm and 3 μm respectively (Bizheva et al., 2005). In this way, it was possible to differentiate malignant from healthy tissue by the presence of blood vessels, microcalcifications and cysts in the tumorous tissue. However the images obtained were small (2 mm × 1 mm), captured on fixed tissue only and required use of an expensive large laser thereby limiting the possibility for clinical implementation.

Other studies have focused on animal brain. In rat brain in vivo, it has been shown that optical coherence microscopy (OCM) can reveal neuronal cell bodies and myelin fibers (Srinivasan et al., 2012), while FF-OCT can also reveal myelin fibers (Ben Arous et al., 2011), and movement of red blood cells in vessels (Binding et al., 2011).

En face images captured with confocal reflectance microscopy can closely resemble FF-OCT images. For example, a prototype system used by Wirth et al. (2012) achieves lateral and axial resolution of 0.9 μm and 3 μm respectively. However small field size prevents viewing of wide-field architecture and slow acquisition speed prohibits the implementation of mosaicking. In addition, the poorer axial resolution and lower penetration depth of confocal imaging in comparison to FF-OCT limit the ability to reconstruct cross-sections from the confocal image stack.

This study is the first to analyze non-tumorous and tumorous human brain tissue samples using FF-OCT.

2. Materials and methods

2.1. Instrument

The experimental arrangement of FF-OCT (Fig. 1A) is based on a configuration that is referred to as a Linnik interferometer (Dubois et al., 2002). A halogen lamp is used as a spatially incoherent source to illuminate the full field of an immersion microscope objective at a central wavelength of 700 nm, with spectral width of 125 nm. The signal is extracted from the background of incoherent backscattered light using a phase-shifting method implemented in custom-designed software. This study was performed on a commercial FF-OCT system (LightCT, LLTech, France).

Capturing “en face” images allows easy comparison with histological sections. The resolution, pixel number and sampling requirements result in a native field of view that is limited to about 1 mm². The sample is moved on a high precision mechanical platform and a number of fields are stitched together (Beck et al., 2000) to display a significant field of view. The FF-OCT microscope is housed in a compact setup (Fig. 1B) that is about the size of a standard optical microscope (310 × 310 × 800 mm L × W × H).

2.2. Imaging protocol

All images presented in this study were captured on fresh brain tissue samples from patients operated on at the Neurosurgery Department of Sainte-Anne Hospital, Paris. Informed and written consent was obtained in all cases following the standard procedure at Sainte-Anne Hospital from patients who were undergoing surgical intervention. Fresh samples were collected from the operating theater immediately after resection and sent to the pathology department. A pathologist dissected each sample to obtain a 1–2 cm² piece and made a macroscopic observation to orientate the specimen in order to decide which side to image. The sample was immersed in physiological serum, placed in a cassette, numbered, and brought to the FF-OCT imaging facility in a nearby laboratory (15 min distant) where the FF-OCT images were captured. The sample was placed in a custom holder with a coverslip on top (Fig. 1C, D). The sample was raised on a piston to rest gently against the coverslip in order to flatten the surface and so optimize the image capture. The sample is automatically scanned under a 10 × 0.3 numerical aperture (NA) immersion microscope objective. The immersion medium is a silicone oil of refractive index close to that of water, chosen to optimize index matching and slow evaporation. The entire area of each sample was imaged at a depth of 20 μm beneath the sample surface. This depth has been reported to be optimal for comparison of FF-OCT images to histology images in a previous study on breast tissue (Assayag et al., in press). There are several reasons for the choice of imaging depth: firstly, histology was also performed at approximately 20 μm from the edge of the block, i.e. the depth at which typically the whole tissue surface begins to be revealed. Secondly, FF-OCT signal is attenuated with depth due to multiple scattering in the tissue, and resolution is degraded with depth due to aberrations. The best FF-OCT images are therefore captured close to the surface, and the best matching is achieved by attempting to image at a similar depth as the slice in the paraffin block. It was also possible to capture image stacks down to several hundred μm in depth (where penetration depth is dependent on tissue type), for the purpose of reconstructing a 3D volume and imaging layers of neurons and myelin fibers. An example of such a stack in the cerebellum is shown as a video (Video 2) in supplementary material. Once FF-OCT imaging was done, each sample was immediately fixed in formaldehyde and returned to the pathology department where it underwent standard processing in order to compare the FF-OCT images to histology slides.

2.3. Matching FF-OCT to histology

The intention in all cases was to match as closely as possible to histology. FF-OCT images were captured 20 μm below the surface. Histology slices were captured 20 μm from the edge of the block. However the angle of the inclusion is hard to control and so some difference in the angle of the plane always exists when attempting matching. Various other factors that can cause differences stem from the histology process — fixing, dehydrating, paraffin inclusion etc. all alter the tissue and so precise correspondence can be challenging. Such difficulties are common in attempting to match histology to other imaging modalities (e.g. FF-OCT Assayag et al., in press; OCT Bizheva et al., 2005; confocal microscopy Wirth et al., 2012).

An additional parameter in the matching process is the slice thickness. Histology slides were 4 μm in thickness while FF-OCT optical slices have a 1 μm thickness. The finer slice of the FF-OCT image meant that lower cell densities were perceived on the FF-OCT images (in those cases where individual cells were seen, e.g. neurons in the cortex). This difference in slice thickness affects the accuracy of the FF-OCT to histology match. In order to improve matching, it would have been possible to capture four FF-OCT slices in 1 μm steps and sum the images to mimic the histology thickness. However, this would effectively degrade the resolution, which was deemed undesirable in evaluating the capacities of the FF-OCT method.

3. Results

18 samples from 18 adult patients (4 males, 14 females) of age range 19–81 years have been included in the study: 1 mesial temporal lobe epilepsy and 1 cerebellum adjacent to a pulmonary adenocarcinoma metastasis (serving as the non-tumor brain samples), 7 diffuse supratentorial gliomas (4 WHO grade II, 3 WHO grade III), 5 meningiomas, 1 hemangiopericytoma, and 1 choroid plexus papilloma. Patient characteristics are detailed in Table 1.

3.1. FF-OCT imaging identifies myelinated axon fibers, neuronal cell bodies and vasculature in the human epileptic brain and cerebellum

The cortex and the white matter are clearly distinguished from one another (Fig. 2). Indeed, a subpopulation of neuronal cell bodies (Fig. 2B, C) as well as myelinated axon bundles leading to the white matter could be recognized (Fig. 2D, E). Neuronal cell bodies appear as dark triangles (Fig. 2C) in relation to the bright surrounding myelinated environment. The FF-OCT signal is produced by backscattered photons from tissues of differing refractive indices. The number of photons backscattered from the nuclei in neurons appears to be too few to produce a signal that allows their differentiation from the cytoplasm, and therefore the whole of the cell body (nucleus plus cytoplasm) appears dark.

Myelinated axons are numerous, well discernible as small fascicles and appear as bright white lines (Fig. 2E). As the cortex does not contain many myelinated axons, it appears dark gray. Brain vasculature is visible (Fig. 2F and G), and small vessels are distinguished by a thin collagen membrane that appears light gray. Video 1 in supplementary material shows a movie composed of a series of en face 1 μm thick optical slices captured over 100 μm into the depth of the cortex tissue. The myelin fibers and neuronal cell bodies are seen in successive layers.

The different regions of the human hippocampal formation are easily recognizable (Fig. 3). Indeed, CA1 field and its stratum radiatum, CA4 field, the hippocampal fissure, the dentate gyrus, and the alveus are easily distinguishable. Other structures become visible by zooming in digitally on the FF-OCT image. The large pyramidal neurons of the CA4 field (Fig. 3B) and the granule cells that constitute the stratum granulosum of the dentate gyrus are visible, as black triangles and as small round dots, respectively (Fig. 3D).

In the normal cerebellum, the lamellar or foliar pattern of alternating cortex and central white matter is easily observed (Fig. 4A). By digital zooming, Purkinje and granular neurons also appear as black triangles or dots, respectively (Fig. 4C), and myelinated axons are visible as bright white lines (Fig. 4E). Video 2 in supplementary material shows a fly-through movie in the reconstructed axial slice orientation of a cortex region in cerebellum. The Purkinje and granular neurons are visible down to depths of 200 μm in the tissue.

3.2. FF-OCT images distinguish meningiomas from hemangiopericytoma in meningeal tumors

The classic morphological features of a meningioma are visible on the FF-OCT image: large lobules of tumorous cells appear in light gray (Fig. 5A), demarcated by collagen-rich bundles (Fig. 5B) which are highly scattering and appear a brilliant white in the FF-OCT images. The classic concentric tumorous cell clusters (whorls) are very clearly distinguished on the FF-OCT image (Fig. 5D). In addition the presence of numerous cell whorls with central calcifications (psammoma bodies) is revealed (Fig. 5F). Collagen balls appear bright white on the FF-OCT image (Fig. 5H). As the collagen balls progressively calcify, they are consumed by the black of the calcified area, generating a target-like image (Fig. 5H). Calcifications appear black in FF-OCT as they are crystalline and so allow no penetration of photons to their interior.

Mesenchymal non-meningothelial tumors such as hemangiopericytomas represent a classic differential diagnosis of meningiomas. In FF-OCT, the hemangiopericytoma is more monotonous in appearance than the meningiomas, with a highly vascular branching component with staghorn-type vessels (Fig. 6A, C).

3.3. FF-OCT images identify choroid plexus papilloma

The choroid plexus papilloma appears as an irregular coalescence of multiple papillas composed of elongated fibrovascular axes covered by a single layer of choroid glial cells (Fig. 7). By zooming in on an edematous papilla, the axis appears as a black structure covered by a regular light gray line (Fig. 7B). If the papilla central axis is hemorrhagic, the fine regular single layer is not distinguishable (Fig. 7C). Additional digital zooming in on the image reveals cellular level information, and some nuclei of plexus choroid cells can be recognized. However, cellular atypia and mitosis are not visible. These represent key diagnosis criteria used to differentiate choroid plexus papilloma (grade I) from atypical plexus papilloma (grade II).

3.4. FF-OCT images detect the brain tissue architecture modifications generated by diffusely infiltrative gliomas

Contrary to the choroid plexus papillomas which have a very distinctive architecture in histology (cauliflower-like aspect), very easily recognized in the FF-OCT images (Fig. 7A to G), diffusely infiltrating glioma does not present a specific tumor architecture (Fig. 8) as they diffusely permeate the normal brain architecture. Hence, the tumorous glial cells are largely dispersed through a nearly normal brain parenchyma (Fig. 8E). The presence of infiltrating tumorous glial cells attested by high magnification histological observation (irregular atypical cell nuclei compared to normal oligodendrocytes) is not detectable with the current generation of FF-OCT devices, as FF-OCT cannot reliably distinguish the individual cell nuclei due to lack of contrast (as opposed to lack of resolution). In our experience, diffuse low-grade gliomas (less than 20% of tumor cell density) are mistaken for normal brain tissue on FF-OCT images. However, in high-grade gliomas (Fig. 8G–K), the infiltration of the tumor has occurred to such an extent that the normal parenchyma architecture is lost. This architectural change is easily observed in FF-OCT and is successfully identified as high-grade glioma, even though the individual glial cell nuclei are not distinguished.

4. Discussion

We present here the first large size images (i.e. on the order of 1–3 cm²) acquired using an OCT system that offer spatial resolution comparable to histological analysis, sufficient to distinguish microstructures of the human brain parenchyma.

Firstly, the FF-OCT technique and the images presented here combine several practical advantages. The imaging system is compact, it can be placed in the operating room, the tissue sample does not require preparation and image acquisition is rapid. This technique thus appears promising as an intraoperative tool to help neurosurgeons and pathologists.

Secondly, resolution is sufficient (on the order of 1 μm axial and lateral) to distinguish brain tissue microstructures. Indeed, it was possible to distinguish neuron cell bodies in the cortex and axon bundles going towards white matter. Individual myelin fibers of 1 μm in diameter are visible on the FF-OCT images. Thus FF-OCT may serve as a real-time anatomical locator.

Histological architectural characteristics of meningothelial, fibrous, transitional and psammomatous meningiomas were easily recognizable on the FF-OCT images (lobules and whorl formation, collagenous-septae, calcified psammoma bodies, thick vessels). Psammomatous and transitional meningiomas presented distinct architectural characteristics in FF-OCT images in comparison to those observed in hemangiopericytoma. Thus, FF-OCT may serve as an intraoperative tool, in addition to extemporaneous examination, to refine differential diagnosis between pathological entities with different prognoses and surgical managements.

Diffuse glioma was essentially recognized by the loss of normal parenchyma architecture. However, glioma could be detected on FF-OCT images only if the glial cell density is greater than around 20% (i.e. the point at which the effect on the architecture becomes noticeable). The FF-OCT technique is therefore not currently suitable for the evaluation of low tumorous infiltration or tumorous margins. Evaluation at the individual tumor cell level is only possible by IDH1R132 immunostaining in IDH1 mutated gliomas in adults (Preusser et al., 2011). One of the current limitations of the FF-OCT technique for use in diagnosis is the difficulty in estimating the nuclear/cytoplasmic boundaries and the size and form of nuclei as well as the nuclear-cytoplasmic ratio of cells. This prevents precise classification into tumor subtypes and grades.

To increase the accuracy of diagnosis of tumors where cell density measurement is necessary for grading, perspectives for the technique include development of a multimodal system (Harms et al., 2012) to allow simultaneous co-localized acquisition of FF-OCT and fluorescence images. The fluorescence channel images in this multimodal system show cell nuclei, which increase the possibility of diagnosis and tumor grading direct from optical images. However, the use of contrast agents for the fluorescence channel means that the multimodal imaging technique is no longer non-invasive, and this may be undesirable if the tissue is to progress to histology following optical imaging. This is a similar concern in confocal microscopy where use of dyes is necessary for fluorescence detection (Wirth et al., 2012).

In its current form therefore, FF-OCT is not intended to serve as a diagnostic tool, but should rather be considered as an additional intraoperative aid in order to determine in a short time whether or not there is suspicious tissue present in a sample. It does not aim to replace histological analyses but rather to complement them, by offering a tool at the intermediary stage of intraoperative tissue selection. In a few minutes, an image is produced that allows the surgeon or the pathologist to assess the content of the tissue sample. The selected tissue, once imaged with FF-OCT, may then proceed to conventional histology processing in order to obtain the full diagnosis (Assayag et al., in press and Dalimier and Salomon, 2012).

Development of FF-OCT to allow in vivo imaging is underway, and first steps include increasing camera acquisition speed. First results of in vivo rat brain imaging have been achieved with an FF-OCT prototype setup, and show real-time visualization of myelin fibers (Ben Arous et al., 2011) and movement of red blood cells in vessels (Binding et al., 2011). To respond more precisely to surgical needs, it would be preferable to integrate the FF-OCT system into a surgical probe. Work in this direction is currently underway and preliminary images of skin and breast tissue have been captured with a rigid probe FF-OCT prototype (Latrive and Boccara, 2011).

In conclusion, we have demonstrated the capacity of FF-OCT for imaging of human brain samples. This technique has potential as an intraoperative tool for determining tissue architecture and content in a few minutes. The 1 μm³ resolution and wide-field down to cellular-level views offered by the technique allowed identification of features of non-tumorous and tumorous tissues such as myelin fibers, neurons, microcalcifications, tumor cells, microcysts, and blood vessels. Correspondence with histological slides was good, indicating suitability of the technique for use in clinical practice for tissue selection for biobanking for example. Future work to extend the technique to in vivo imaging by rigid probe endoscopy is underway.

The following are the supplementary data related to this article.

Video 1. Shows a movie composed of a series of en face 1 μm thick optical slices captured over 100 μm into the depth of the cortex tissue. The myelin fibers and neuronal cell bodies are seen in successive layers. Field size is 800 μm × 800 μm.

Video 2. Shows a fly-through movie in the reconstructed cross-sectional orientation showing 1 μm steps through a 3D stack down to 200 μm depth in cerebellum cortical tissue. Purkinje and granular neurons are visible as dark spaces. Field size is 800 μm × 200 μm.

Acknowledgments

The authors wish to thank LLTech SAS for use of the LightCT Scanner.

References

Adie and Boppart, 2009

Adie, Boppart

Optical Coherence Tomography for Cancer Detection

SpringerLink (2009), pp. 209–250

Assayag et al., in press

Assayag et al.

Large field, high resolution full field optical coherence tomography: a pre-clinical study of human breast tissue and cancer assessment

Technology in Cancer Research & Treatment TCRT Express, 1 (1) (2013), p. e600254http://dx.doi.org/10.7785/tcrtexpress.2013.600254

Beck et al., 2000

Beck et al.

Computer-assisted visualizations of neural networks: expanding the field of view using seamless confocal montaging

Journal of Neuroscience Methods, 98 (2) (2000), pp. 155–163

Ben Arous et al., 2011

Ben Arous et al.

Single myelin fiber imaging in living rodents without labeling by deep optical coherence microscopy

Journal of Biomedical Optics, 16 (11) (2011), p. 116012

Betz et al., 2008

C.S. Betz et al.

A set of optical techniques for improving the diagnosis of early upper aerodigestive tract cancer

Medical Laser Application, 23 (2008), pp. 175–185

Binding et al., 2011

Binding et al.

Brain refractive index measured in vivo with high-NA defocus-corrected full-field OCT and consequences for two-photon microscopy

Optics Express, 19 (6) (2011), pp. 4833–4847

Bizheva et al., 2005

Bizheva et al.

Imaging ex vivo healthy and pathological human brain tissue with ultra-high-resolution optical coherence tomography

Journal of Biomedical Optics, 10 (2005), p. 011006 http://dx.doi.org/10.1117/1.1851513

Böhringer et al., 2006

Böhringer et al.

Time domain and spectral domain optical coherence tomography in the analysis of brain tumor tissue

Lasers in Surgery and Medicine, 38 (2006), pp. 588–597 http://dx.doi.org/10.1002/lsm.20353

Böhringer et al., 2009

Böhringer et al.

Imaging of human brain tumor tissue by near-infrared laser coherence tomography

Acta Neurochirurgica, 151 (2009), pp. 507–517 http://dx.doi.org/10.1007/s00701-009-0248-y

Boppart, 2003

Boppart

Optical coherence tomography: technology and applications for neuroimaging

Psychophysiology, 40 (2003), pp. 529–541 http://dx.doi.org/10.1111/1469-8986.00055

Boppart et al., 1998

Boppart et al.

Optical coherence tomography for neurosurgical imaging of human intracortical melanoma

Neurosurgery, 43 (1998), pp. 834–841 http://dx.doi.org/10.1097/00006123-199810000-00068

Boppart et al., 2004

Boppart et al.

Optical coherence tomography: feasibility for basic research and image-guided surgery of breast cancer

Breast Cancer Research and Treatment, 84 (2004), pp. 85–97

Chen et al., 2007

Chen et al.

Ultrahigh resolution optical coherence tomography of Barrett’s esophagus: preliminary descriptive clinical study correlating images with histology

Endoscopy, 39 (2007), pp. 599–605

Dalimier and Salomon, 2012

Dalimier, Salomon

Full-field optical coherence tomography: a new technology for 3D high-resolution skin imaging

Dermatology, 224 (2012), pp. 84–92 http://dx.doi.org/10.1159/000337423

De Boer et al., 2003

De Boer et al.

Improved signal-to-noise ratio in spectral-domain compared with time-domain optical coherence tomography

Optics Letters, 28 (2003), pp. 2067–2069

Dubois et al., 2002

Dubois et al.

High-resolution full-field optical coherence tomography with a Linnik microscope

Applied Optics, 41 (4) (2002), p. 805

Dubois et al., 2004

Dubois et al.

Ultrahigh-resolution full-field optical coherence tomography

Applied Optics, 43 (14) (2004), p. 2874

Grieve et al., 2004

Grieve et al.

Ocular tissue imaging using ultrahigh-resolution, full-field optical coherence tomography

Investigative Ophthalmology & Visual Science, 45 (2004), pp. 4126-3–4131

Harms et al., 2012

Harms et al.

Multimodal full-field optical coherence tomography on biological tissue: toward all optical digital pathology

Proc. SPIE 2011, Multimodal Biomedical Imaging VII, 8216 (2012)

Hsiung et al., 2007

Hsiung et al.

Benign and malignant lesions in the human breast depicted with ultrahigh resolution and three-dimensional optical coherence tomography

Radiology, 244 (2007), pp. 865–874

Imaging: seeing or imagining? (Part 1)

Ultrasound imaging as an instrument for measuring tissue elasticity: “Shear-wave Elastography” VS. “Strain-Imaging”

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Imaging-based Cancer Patient Management, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, tagged Cancer - General, cancer management, Clinical trial, elastography, Georg Salomon, guided biopsy, imaging, innovations in cancer management, malignant lesions, Medical imaging, Personalized medicine, Prostate cancer, screening, screening for cancer, shear-wave elastography, strain imaging, tissue elasticity, Transrectal ultrasonography, ultrasound imaging, ultrasound technology on June 6, 2013| 3 Comments »

Ultrasound imaging as an instrument for measuring tissue elasticity: “Shear-wave Elastography” VS. “Strain-Imaging”

Writer and curator: Dror Nir, PhD

In the context of cancer-management, imaging is pivotal. For decades, ultrasound is used by clinicians to support every step in cancer pathways. Its popularity within clinicians is steadily increasing despite the perception of it being less accurate and less informative than CT and MRI. This is not only because ultrasound is easily accessible and relatively low cost, but also because advances in ultrasound technology, mainly the conversion into PC-based modalities allows better, more reproducible, imaging and more importantly; clinically-effective image interpretation.

The idea to rely on ultrasound’s physics in order to measure the stiffness of tissue lesions is not new. The motivation for such measurement has to do with the fact that many times malignant lesions are stiffer than non-malignant lesions.

The article I bring below; http://digital.studio-web.be/digitalMagazine?issue_id=254 by Dr. Georg Salomon and his colleagues, is written for lay-readers. I found it on one of the many portals that are bringing quasi-professional and usually industry-sponsored information on health issues; http://www.dieurope.com/ – The European Portal for Diagnostic Imaging. Note, that when it comes to using ultrasound as a diagnostic aid in urology, Dr. Georg Salomon is known to be one of the early adopters for new technologies and an established opinion leader who published many peer-review, frequently quoted, papers on Elastography.

The important take-away I would like to highlight for the reader: Quantified measure of tissue’s elasticity (doesn’t matter if is done by ShearWave or another “Elastography” measure implementation) is information that has real clinical value for the urologists who needs to decide on the right pathway for his patient!

Note: the highlights in the article below are added by me for the benefit of the reader.

Improvement in the visualization of prostate cancer through the use of ShearWave Elastography

by:

Dr Georg Salomon¹ Dr Lars Budaeus¹, Dr L Durner²& Dr K Boe¹

1. Martini-Clinic — Prostate Cancer Center University Hospital Hamburg Eppendorf Martinistrasse 52, 20253 Hamburg, Germany

2. Urologische Kilnik Dr. Castringius Munchen-Planegg Germeringer Str. 32, 82152 Planegg, Germany

Corresponding author; PD Dr. Georg Salomon

Associate Professor of Urology

Martini Clinic

Tel: 0049 40 7410 51300

gsalornon@uke.de

Prostate cancer is the most common cancer in males with more than 910,000 annual cases worldwide. With early detection, excellent cure rates can be achieved. Today, prostate cancer is diagnosed by a randomized transrectal ultrasound guided biopsy. However, such randomized “blind” biopsies can miss cancer because of the inability of conventional TRUS to visualize small cancerous spots in most cases.

Elastography has been shown to improve visualization of prostate cancer.

The innovative ShearWave Elastography technique is an automated, user-friendly and quantifiable method for the determination of prostatic tissue stiffness.

The detection of prostate cancer (PCA) has become easier thanks to Prostate Specific Antigen (PSA) testing; the diagnosis of PCA has been shifted towards an earlier stage of the disease.

Prostate cancer is, in more than 80 % of the cases, a heterogeneous and multifocal tumor. Conventional ultrasound has limitations to accurately define tumor foci within the prostate. This is due to the fact that most PCA foci are isoechogenic, so in these cases there is no differentiation of benign and malignant tissue. Because of this, a randomized biopsy is performed under ultrasound guidance with at least 10 to 12 biopsy cores, which should represent all areas of the prostate. Tumors, however, can be missed by this biopsy regimen since it is not a lesion-targeted biopsy. When PSA is rising — which usually occurs in most men — the originally negative biopsy has to be repeated.

What urologists expect from imaging and biopsy procedures is the detection of prostate cancer at an early stage and an accurate description of all foci within the prostate with different (Gleason) grades of differentiation for best treatment options.

In the past 10 years a couple of new innovative ultrasound techniques (computerized, contrast enhanced and real time elastography) have been introduced to the market and their impact on the detection of early prostate cancer has been evaluated. The major benefit of elastography compared to the other techniques is its ability to provide visualization of suspicious areas and to guide the biopsy needle, in real time, to the suspicious and potentially malignant area.

Ultrasound-based elastography has been investigated over the years and has had a lot of success for increasing the detection rate of prostate cancer or reducing the number of biopsy samples required. [1-3]. Different companies have used different approaches to the ultrasound elastography technique (strain elastography vs. shear wave elastography). Medical centers have seen an evolution in better image quality with more stable and reproducible results from these techniques.

One drawback of real time strain elastography is that there is a significant learning curve to be climbed before reproducible elastograms can be generated. The technique has to be performed by compressing and then decompressing the ultrasound probe to derive a measurement of tissue displacement.

Today there are ultrasound scanners on the market, which have the ability to produce elastograms without this “manual” assistance: this technique is called shear-wave elastography. While the ultrasound probe is being inserted transrectally, the “elastograms” are generated automatically by the calculation of shear wave velocity as the waves travel through the tissue being examined, thus providing measurements of tissue stiffness and not displacement measurements.

There are several different techniques for this type of elastography. The FibroScan system, which is not an ultrasound unit, uses shear waves (transient elastography) to evaluate the advancement of the stiffness of the liver. Another technique is Acoustic Radiation Force Impulse or ARF1 technique, also used for the liver. These non-real-time techniques only provide a shear wave velocity estimation for a single region of interest and are not currently used in prostate imaging.

A shear wave technology that provides specific quantification of tissue elasticity in real-time is ShearWave Elastography, developed by Super-Sonic Imagine. This technique measures elasticity in kilopascals and can provide visual representation of tissue stiffness over the entire region of interest in a color-coded map on the ultrasound screen. On a split screen the investigator can see the conventional ultrasound B-mode image and the color-coded elastogram at the same time. This enables an anatomical view of the prostate along with the elasticity image of the tissue to guide the biopsy needle.

In short, ShearWave Elastography (SWE) is a different elastography technique that can be used for several applications. It automatically generates a real-time, reproducible, fully quantifiable color-coded image of tissue elasticity.

QUANTIFICATION OF TISSUE STIFFNESS Such quantification can help to increase the chance that a targeted biopsy is positive for cancer.

It has been shown that elastography-targeted biopsies have an up to 4.7 times higher chance to be positive for cancer than a randomized biopsy [4J. Shear-Wave Elastography can not only visualize the tissue stiffness in color but also quantify (in kPa) the stiffness in real time, for several organs including the prostate. Correas et al, reported that with tissue stiffness higher than 45 to 50 kPa the chance of prostate cancer is very high in patients undergoing a prostate biopsy. The data from Gorreas et al showed a sensitivity of 80 % and a high negative predictive value of up to 9096. Another group (Barr et A) achieved a negative predictive value of up to 99.6% with a sensitivity of 96.2% and specificity of 962%. With a cut-off of 4D kPa the positive biopsy rate for the ShearWave Elastography targeted biopsy was 50%, whereas for randomized biopsy it was 20.8 95. In total 53 men were enrolled in this study.

Our group used SWE prior to radical prostatectomy to determine if the Shear-Wave Elastography threshold had a high accuracy using a cutoff >55 kPa. (Fig 1)

We then compared the ShearWave results with the final histopathological results. [Figure I], Our results showed the accuracy was around 78 % for all tumor foci We were also able to verify that ShearWave Elastography targeted biopsies were more likely to be positive compared to randomized biopsies. [Figures 2, 3]

CONCLUSION

SWE is a non-invasive method to visualize prostate cancer foci with high accuracy, in a user-friendly way. As Steven Kaplan puts it in an editorial comment in the Journal of Urology 2013: “Obviously, large-scale studies with multicenter corroboration need to be performed. Nevertheless, SWE is a potentially promising modality to increase our efficiency in evaluating prostate diseases:’

REFERENCES

Pallweln, L. et al-. Sonoelastography of the prostate: comparison with systematic biopsy findings in 492 patients. European journal of radiology, 2008. 65(2): p. 304-10.
Pallwein, L., et al., Comparison of sono-elastography guided biopsy with systematic biopsy: Impact on prostate cancer detecton. European radiology, 2007_ 17.(9) p. 2278-85.
Salomon, G., et al., Evaluation of prostate can cer detection with ultrasound real-time elas-tographyl a companion with step section pathological analysis after radical prostatectomy. European urology, 2008. 5446): p. 135462-
Aigner, F., at al., Value of real-time elastography targeted biopsy for prostate cancer detection in men with prostate specific antigen 125 ng/mi or greater and 4-00 ng/ml or Lass. The Journal of urology, 2010. 184{3): p. 813.7,

Other research papers related to the management of Prostate cancer and Elastography were published on this Scientific Web site:

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Today’s fundamental challenge in Prostate cancer screening

State of the art in oncologic imaging of Prostate.

From AUA2013: “HistoScanning”- aided template biopsies for patients with previous negative TRUS biopsies

On the road to improve prostate biopsy

Protected: Flywheel iNO, Three Novel Adult Patient Inhaled Nitric Oxide Product Concepts by Justin D. Pearlman MD ME PhD FACC

Posted in Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Nitric Oxide in Health and Disease, Technology Transfer: Biotech and Pharmaceutical, tagged Heart Failure, Hypertension, nitric oxide, Nitric oxide synthase, Pulmonary hypertension, Torr on June 3, 2013|

http://pharmaceuticalintelligence.com/2013/05/21/early-detection-of-prostate-cancer-aua-guideline/

In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, tagged Cancer - General, Conditions and Diseases, evidence based medicine, Prostate cancer, Prostate cancer screening, Prostate-specific antigen, PSA on May 23, 2013| 1 Comment »

In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Larry H. Bernstein, MD, FCAP, Author and Curator
Dror Nir, PhD, Curator
Aviva Lec-Ari, PhD, RN, Curator

There have been two important articles in the last several days giving perspectives on the current and evolving status of current and evolving diagnosis of prostate cancer (PCA) by experts Dror Nir, PhD and Aviva Lev-Ari, PhD, RN, Editor-in-Chief, http://Pharmaceuticalintelligence.com

The first article reviews the recent published update on PCA screening and diagnosis, as determined by review of the literature by an Expert Panel, in order to determine what is the current validated Evidence-Based Medicine Practice Guideline for American Urological Surgeons.

The method of review is rigorously laid out and follows the accepted standard for publication. The emphasis in the study lies in the reliance on prostate specific abtigen (PSA), which has undergone an evolutioary improvement sine 1999, although substantiation of a benefit could not be trusted until almost a decade later. The problem the is notable is the absence of discussion of improvements in cancer imaging that has also evolved in that time period, and continues to evolve with molecular probes.

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Author-Writer: Dror Nir, PhD

When reviewing the DETECTION OF PROSTATE CANCER section on the AUA website , The first thing that catches one’s attention is the image below; clearly showing two “guys” exploring with interest what could be a CT or MRI image….

But, if you bother to read the review underneath this image regarding EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE produced by an independent group that was commissioned by the AUA to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening; Panel Members: H. Ballentine Carter, Peter C. Albertsen, Michael J. Barry, Ruth Etzioni, Stephen J. Freedland, Kirsten Lynn Greene, Lars Holmberg, Philip Kantoff, Badrinath R. Konety, Mohammad Hassan Murad, David F. Penson and Anthony L. Zietman – You are bound to be left with a strong feeling that something is wrong!

“The AUA commissioned an independent group to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening. The protocol of the systematic review was developed a priori by the expert panel. The search strategy was developed and executed by reference librarians and methodologists and spanned across multiple databases including Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials and Scopus. Controlled vocabulary supplemented with keywords was used to search for the relevant concepts of prostate cancer, screening and detection. The search focused on DRE, serum biomarkers (PSA, PSA Isoforms, PSA kinetics, free PSA, complexed PSA, proPSA, prostate health index, PSA velocity, PSA doubling time), urine biomarkers (PCA3, TMPRSS2:ERG fusion), imaging (TRUS, MRI, MRS, MR-TRUS fusion), genetics (SNPs), shared-decision making and prostate biopsy. The expert panel manually identified additional references that met the same search criteria”

While reading through the document, I was looking for the findings related to the roll of imaging in prostate cancer screening; see highlighted above. The only thing I found: “With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests.”

This must mean that: Notwithstanding hundreds of men-years and tens of millions of dollars which were invested in studies aiming to assess the contribution of imaging to prostate cancer management, no convincing evidence to include imaging in the screening progress was found by a group of top-experts in a thorough and rigorously managed literature survey! And it actually lead the AUA to declare that “Nothing new in the last 20 years”…..

My interpretation of this: It says-it-all on the quality of the clinical studies that were conducted during these years, aiming to develop an improved prostate cancer workflow based on imaging. I hope that whoever reads this post will agree that this is a point worth considering!

For those who do not want to bother reading the whole AUA guidelines document here is a peer reviewed summary:

“Early Detection of Prostate Cancer: AUA Guideline; Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, Holmberg L, Kantoff P, Konety BR, Murad MH, Penson DF, Zietman AL; Journal of Urology (May 2013)”

It says:

“A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age<40; 40 to 54; 55 to 69; ≥70).

RESULTS: With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.

Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/05/21/prostate-cancer-molecular-diagnostic-market-the-players-are-sri-intl-genomic-health-wcleveland-clinic-myriad-genetics-wucsf-genomedx-and-biotheranostics/

On February 6, 2013 we reported that DR. MARK RUBIN, LEADING PROSTATE CANCER AND GENOMICS EXPERT, TO LEAD CUTTING-EDGE CENTER FOR TARGETED, INDIVIDUALIZED PATIENT CARE BASED ON EACH PATIENT’S GENETICS

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute

On May 16, 2013 we reported a major breakthrough in the Prostate Cancer Screening

A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

After nearly a decade, my collaborators and I have found the first marker that specifically identifies the approximately six to eight percent of prostate cancers that are considered “aggressive,” meaning they will migrate to other parts of the body, at which point they are very difficult to treat. Although we have confirmed this marker, there is much to be done before a clinical application can be developed.

http://pharmaceuticalintelligence.com/2013/05/16/a-blood-test-to-identify-aggressive-prostate-cancer-a-discovery-sri-international-menlo-park-ca/

Prostate Cancer MDx Competition Heating Up; New Data from Genomic Health, Myriad

May 15, 2013 By Turna Ray

Life sciences companies are gearing up for battle to capture the profitable prostate cancer molecular diagnostic market.

Genomic Health and Myriad Genetics both made presentations to the investment community last week about their genomic tests that gauge a man’s risk of prostate cancer aggressiveness. As part of its annual investor day, Myriad discussed new data on its Prolaris test, which analyzes the expression level of 46 cell cycle progression genes and stratifies men’s risk of biochemical recurrence of prostate cancer. If the test reports low gene expression, then the patient is at low risk of disease progression, while high gene expression is associated with disease progression.

Meanwhile, around the same time last week, Genomic Health launched its Oncotype DX prostate cancer test and presented data from the first validation study involving the diagnostic. The Oncotype DX prostate cancer test analyzes the expression of 17 genes within four biological pathways to gauge prostate cancer aggressiveness. The test reports a genomic prostate score from 0 to 100; the lower the score the more certain a patient can be that they can avoid treatment and continue with active surveillance. Prostate cancer patients who are deemed to be at very low risk, low risk, or intermediate risk of progressing are eligible to be tested with the Oncotype Dx test. If, based on standard clinical measures, a person’s prostate cancer is considered high risk, then he is not a candidate for Genomic Health’s test.

These molecular tests are entering the market at a time when currently available tools aren’t specific enough to distinguish between men who have an aggressive form of prostate cancer and therefore, need invasive treatments, and those that are low risk and can do well with active surveillance. According to an NIH estimate, in 2010, the annual medical costs associated with prostate cancer in the US were $12 billion.

It is estimated that each year 23 million men undergo testing for prostate specific antigen, a protein produced by the prostate gland that increases when a man has prostate cancer. Additionally, one million men get a prostate biopsy annually, while 240,000 men end up with a diagnosis for prostate cancer, and around 30,000 die from the disease. Although most of the men diagnosed with prostate cancer end up receiving surgery or radiation treatment, as many as half of these men will probably not progress, and their disease isn’t life threatening.

While PSA testing has been shown to reduce prostate cancer deaths, a man’s PSA level may be increased for reasons other than cancer. As such, broadly screening men for PSA has been controversial in the healthcare community since the test isn’t specific enough to gauge which men are at low risk of developing aggressive prostate cancer and can forgo unnecessary treatments that can have significant side effects.

Both Myriad and Genomic Health are hoping their tests will further refine prostate cancer diagnosis and help doctors gain more confidence in determining which of their patients have aggressive disease and which are at low risk.

Myriad’s advantage

In this highly competitive space, Myriad has the first mover advantage, having launched Prolaris three years ago. The company has published four studies involving the test and conducted a number of trials analyzing around 3,000 patient samples.

Researchers from UCSF and Myriad recently published the fourth validation study in the Journal of Clinical Oncology, which analyzed samples from 400 men who had undergone a radical prostatectomy. In the published study, researchers reported that 100 percent of the men whom Prolaris deemed to be at “low risk” of progression did not experience a recurrence within the five years the study was ongoing. Meanwhile, 50 percent of those the test deemed to be a “high risk” did experience recurrence during that time (PGx Reporter 3/6/2013).

New competition

Like Myriad’s BRACAnalysis test, which comprises more than 80 percent of its product revenues, Genomic Health’s Oncotype DX breast cancer recurrence tests is bringing in the majority of its product revenues. However, the company believes that its newly launched Oncotype DX prostate cancer test stands to be its largest market opportunity to date.

Last week, researchers from University of California, San Francisco, presented data from the first validation study involving the Oncotype DX prostate cancer test. The study involved nearly 400 prostate cancer patients considered low or intermediate risk by standard methods such as Gleason score and showed that when the Oncotype DX score was used in conjunction with other measures, investigators identified more patients as having very low risk disease who were appropriate for active surveillance than when they diagnosed patients without the test score.

More than one third of patients classified as low risk by standard measures in the study were deemed to be “very low risk” by Oncotype DX and therefore could choose active surveillance. Meanwhile, 10 percent of patients in the study were found by clinical measures to be at very low risk or low risk, but the Oncotype DX test deemed them as having aggressive disease that needed treatment.

Matthew Cooperberg of UCSF, who presented data from this validation study at the American Urological Association’s annual meeting last week, highlighted this feature of the Oncotype DX prostate cancer test to investors during a conference call last week. He noted that the test not only gauges which low-risk patients can confidently remain with active surveillance, but it also finds those patients who didn’t receive an accurate risk assessment based on standard clinical measures. “It’s also equally important that we identify the man who frankly should not be on active surveillance, because they’re out there,” he said.

Genomic Health has aligned its test with guidelines from the National Comprehensive Cancer Network, which has expressed concern about over-diagnosis and over-treatment in prostate cancer patients. In 2010, NCCN guidelines established a new “very low risk” category for men with clinically insignificant prostate cancer and recommended that men who fall into this category and have a life expectancy of more than 20 years should only be followed with active surveillance. In 2011, NCCN made the active surveillance criteria more stringent for men in the “very low risk” category.

In order to develop the prostate cancer test, Genomic Health collaborated with the Cleveland Clinic on six feasibility studies and selected the gene expression panel after analyzing 700 genes on tissue samples from 700 patients. The commercial test analyzes the expression of 17 genes across four biological

I am quite surprised that nothing is said about the current status of PSA for Pca, which is far advanced today, and it also needs attention. We are in the old SUFI tale about the blind men who grasped the trunk, or the tail, etc., and called it the elephant.

Robustness of ProsVue™ linear slope for prognostic identification of patients at reduced risk for prostate cancer recurrence: Simulation studies on effects of analytical imprecision and sampling time variation

Mark J. Sarno, Charles S. Davis

Clinical Biochemistry Nov 2012; 45 (16–17): 1479-1484

Highlights

► We simulate effects of analytical and sampling time variation on ProsVue slope.

► Classification switching is minimal in both stable disease and recurrence.

► We provide a framework for assessment of assays using rate of change principles

Objective

The ProsVue assay measures serum total prostate-specific antigen (PSA) over three time points post-radical prostatectomy and calculates rate of change expressed as linear slope. Slopes ≤ 2.0 pg/ml/month are associated with reduced risk for prostate cancer recurrence. However, an indicator based on measurement at multiple time points, calculation of slope, and relation of slope to a binary cutoff may be subject to effects of analytical imprecision and sampling time variation. We performed simulation studies to determine the presence and magnitude of such effects.

Design and methods

Using data from a two-site precision study and a multicenter clinical trial of 304 men, we performed simulation studies to assess whether analytical imprecision and sampling time variation can drive misclassifications or classification switching of patients with stable disease or recurrence.

Results

Analytical imprecision related to expected PSA values in a stable disease population results in ≤ 1.2% misclassifications. For populations with recurrent disease, an analysis taking into account correlation between sampling time points demonstrates that classification switching across the 2.0 pg/ml/month cutoff occurs at a rate ≤ 11%. In the narrow region of overlap between populations, classification switching maximizes at 12.3%. Lastly, sampling time variation across a wide range of scenarios results in 99.7% retention of proper classification for stable disease patients with linear slopes up to the 75th percentile of the distribution.

Conclusions

These results demonstrate the robustness of the ProsVue assay and the linear slope indicator. Further, these simulation studies provide a potential framework for evaluation of future assays that rely on the rate of change principle.

As the reviewer of this paper for Clinical Biochemistry, I have never encountered such a beautiful and rigorous evaluation that is described in the outline below:

Article Outline

1. Introduction

2. Materials and Methods

2.1. Source data

2.2. Simulation 1 – Effects of analytical imprecision in patients with stable disease

2.3. Simulations 2 and 3 – Effects of analytical imprecision in patients with PCa recurrence

2.4. Simulations 4 and 5 – Simulations in highest tertile of stable disease slopes and lowest tertile of recurrent slopes

2.5. Simulation 6 – Effects of sampling time variation

2.6. Software

3. Results

3.1. Source data for simulations

3.2. Simulation 1 – Effects of analytical imprecision in patients with stable disease

3.3. Simulations 2 and 3 – Effects of analytical imprecision in patients with PCa recurrence

3.4. Simulations 4 and 5 — Simulations in highest tertile of stable disease slopes and lowest tertile of recurrent slopes

3.5. Simulation 6 – Effects of sampling time variation

4. Discussion

5. Conclusions

References

This article is followed by another in the Urology journal.

NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy.

Moul JW, Lilja H, Semmes OJ, Lance RS, Vessella RL, Fleisher M, Mazzola C, Sarno MJ, Stevens B, Klem RE, McDermed JE, Triebell MT, Adams TH.

Division of Urologic Surgery and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina 27710, USA. judd.moul@duke.edu

Urology. 2012 Dec;80(6):1319-25. http://dx.doi.org/10.1016/j.urology.2012.06.080. Epub 2012 Oct 26.

OBJECTIVE:

To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤ 2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer.

MATERIALS AND METHODS:

From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses.

RESULTS:

The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤ 2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤ 2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥ 7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004).

CONCLUSION:

Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤ 2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.

Urology. 2012 Dec;80(6):1325-6; author reply 1326-7. http://dx.doi.org/10.1016/j.urology.2012.06.081. Epub 2012 Oct 26. Collins S.

Editorial comment.

NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy. [Urology. 2012]

Why NADiA ProsVue? IRIS INTERNATIONAL

http://www.irispermed.com/patients/why-nadia-prosvue

Some patients who had surgery to remove the prostate may be at higher risk for recurrence. Determining the risk of recurrence is critical for these patients and their physicians in order to make the most informed decision possible about future medical management.

Physicians use post-surgical risk assessment to review a variety of parameters to help determine if the patient might develop recurrent disease. Risk factors may include:

The size and proximity of the tumor at the time of surgery (whether it has grown through the prostate walls):

Through imaging tests, physicians can determine how far cancerous tissue may have spread, with indicators such as

extracapsular extensions (ECE, beyond the prostatic capsule) and
seminal vesicle invasion (SVI, presence in the walls of the vesicles surrounding the prostate).
The presence of cancer cells at the edge of the removed tumor (known as positive margins) or in the lymph nodes outside the prostate.
A high preoperative PSA level (> 20 ng/mL).
The tumor’s Gleason Score (if it is at least 8 or higher).

However, current risk assessment relies on subjective and imprecise information. This uncertainty can have a dramatic impact on a patient’s personal experience after prostatectomy.

The newly available NADiA ProsVue test may help provide a more clear and accurate prediction of a patient’s true risk for clinical recurrence.
The NADiA ProsVue test measures

the rate of change of PSA at extremely low levels over time, which can help quickly and accurately identify patients
who are at reduced risk for clinical recurrence.

In conjunction with other information, NADiA ProsVue may allow some men to avoid unnecessary treatments and anxiety after prostatectomy.

NADiA ProsVue is an in-vitro diagnostic assay for determining

rate of change of serum total prostate specific antigen (tPSA) over a period of time (slope, pg/mL per month).

The NADiA ProsVue assay is performed for patients having less than 0.1 ng/mL serum tPSA values (determined by standard-of-care assays that are FDA approved/cleared) in the first sample collected more than 6 weeks after radical prostatectomy.

What is NADiA?

NADiA stands for Nucleic Acid Detection immunoassay. Immuno-PCR, first described by Sano and Cantor in 1992 involves combining protein antigen detection by immunoassay with the detection sensitivity and precision of real-time polymerase chain reaction (qPCR). This amplified DNA-immunoassay approach is similar to that of an enzyme immunoassay, involving antibody binding reactions and intermediate washing steps. The enzyme label is replaced by a strand of DNA and detected by exponential amplification using qPCR.

http://www.irispermed.com/images/pictures/thumbnails/thumb_NADiA_Technology1.jpg

NADiA employs a soluble (reporter) monoclonal antibody (MAb) labeled with an assay-specific double-stranded DNA sequence.

The presence of this DNA label does not interfere with MAb binding, nor
does the MAb interfere with DNA label amplification and detection.
The second (capturing) MAb specific for another site on the target protein (antigen)
is coated onto paramagnetic microparticles.

The reporter MAb-DNA conjugate is reacted with sample in a microtiter plate format to form a first immune complex with the target antigen. The immune complex is then captured onto paramagnetic particles coated with the second capture MAb, forming an insoluble sandwich immune complex. The microparticles are washed by several cycles of magnetic capture and re-suspension to remove excess reporter MAb-DNA conjugate.
The specifically bound DNA label is then detected by subjecting

suspended particles to qPCR conditions and monitoring the generations of amplicon in real time.

What are possible clinical applications?

Proteins play a crucial role in all biological functions. Identifying and measuring the quantity of specific proteins is fundamental to understanding the cause and evolution of many human disease processes.
There are hundreds of thousands of proteins in the human body, but the vast majority are present at extremely low concentrations. For example, only ten (10) proteins make up 90% of the mass of plasma proteins found in human serum. Twelve (12) proteins make up another 9% of the mass. The remaining proteins comprise the final 1%. Advancing medicine through the study of proteins (known as proteomics) requires powerful and sensitive tools.
http://www.irispermed.com/images/pictures/Protein_Slide_2.png

NADiA combines the specificity of an immunoassay with the detection sensitivity of qPCR and can assist efforts to provide clinical insight into many human diseases. Any disease process involving proteins below the detection limits of today’s enzyme immunoassays (EIA) is a potential target for NADiA.

NADiA ProsVue is the first of a line of assays designed to advance human healthcare in the areas of oncology and infectious disease.

http://www.irispermed.com/images/pictures/Major_Plasma_Proteins.jpg

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION

DECISION SUMMARY

A. 510(k) Number:

k101185

B. Purpose for Submission:

New device

C. Measurand:

Total Prostate specific antigen (tPSA)

D. Type of Test:

Quantitative, Immuno-PCR (Polymerase Chain Reaction)

E. Applicant:

Iris Molecular Diagnostics

F. Proprietary and Established Names:

NADiA® ProsVue™

Intended Use:

NADiA® ProsVue™ is an in-vitro diagnostic assay for determining rate of change of serum total prostate specific antigen over a period of time (slope, pg/mL per month). The NADiA® ProsVue™ assay is performed for patients having less than 0.1 ng/mL serum total PSA values (determined by standard-of-care assays that are FDA approved/cleared) in the first sample collected more than 6 weeks after radical prostatectomy. ProsVue™ slope is indicated for use as a prognostic marker in conjunction with clinical evaluation as an aid in identifying those patients at reduced risk for recurrence of prostate cancer for the eight year period following prostatectomy.

The NADiA® ProsVue™ assay is not intended for the diagnosis or for the monitoring of prostate cancer.

†”Recurrence” is defined as clinical recurrence, not biochemical recurrence, and was documented by positive imaging, positive biopsy, or death due to prostate cancer.

U.S. FDA approves NADiA ProsVue prognostic test for prostate cancer

Posted on September 23, 2011 by Sitemaster

According to a media release issued

Moul et al. have now conducted a retrospective, multi-center clinical trial to further evaluate the potential prognostic value of ProsVue slope at a decision threshold of 2 pg/ml/month. (One nanogram or 1 ng = 1,000 picograms or 1,000 pg.)

The retrospective analysis was based on data from 392 prostate cancer patients who had been given radical prostatectomies between November 1991 and August 2001. To be eligible for this study, all of the following data had to be available from individual patients:

A first post-surgical PSA level of <100 pg/ml (i.e., < 0.1 ng/ml)
Full pathologic and radiographic data
Three frozen serum samples drawn between 6 weeks and 19.4 months post-surgery.
Patients were not eligible if they had received adjuvant radiotherapy and/or hormone therapy after surgery and prior to completion of the three post-surgical blood draws.

The results of this retrospective study showed that:

The average (median) PSA levels of the 392 patients was 6.3 ng/ml (range, 0 to 60.6 ng/ml)
The average (median) post-surgical Gleason score was 7.0 (range, 4 to 10).

73 patients had received neoadjuvant hormone therapy prior to their surgery.

The pathologic stages of the patients were

pT0-2, n = 228

pT3, n = 147

pT4, n = 17

116 patients had positive margins and 8 had positive lymph nodes.

The three post-surgical PSA values were based on serum drawn

after median times of 4.9, 8.6, and 12.8 months and showed median values of 10.7, 23.0 and 50.7 pg/ml, respectively.

The sensitivity, specificity, PPV and NPV for a 2 pg/mL/month ProsVue slope were 75.0, 96.6, 81.4, and 95.2, respectively.

At a median follow-up of 10.5 years, 14 patients had died of prostate cancer and 40 had died overall.

The authors conclude the the ProsVue test “provides information previously unknown” in patients in the first year post-surgery, and that a ProsVue slope of ≤ 2 pg/mL/month in that first year is highly associated with a lack of evidence of progression in long-term follow-up.

In theory, the ProsVue test may have some clinical value in the identification of patients who do not need long-term oncologic follow-up and in predicting the need for adjuvant radiation therapy. However, additional prospective studies will be necessary before this can be confirmed, and the practical clinical value of such a test would depend on whether it is significantly more accurate that data currently available from ultrasensitive PSA testing.

Additional information is available in a media release from the developer of the ProsVue test (IRIS International). According to that media release, the developer has submitted data to the FDA requesting approval to market this test.

The centers involved in this study included Duke University, Memorial Sloan-Kettering Cancer Center, Eastern Virginia Medical Center, and the University of Washington — all of which are highly reputable institutions.

NADiA ProsVue results are calculated as the linear slope of three NADiA ProsVue total PSA test results obtained on three serum samples collected between six weeks and 20 months post-radical prostatectomy.

http://www.irispermed.com/images/pictures/NADiA_ProsVue_Timeline.jpg

by IRIS International, the U.S. Food & Drug Administration (FDA) has approved the company’s NADiA® ProsVue™ test as a prognostic marker that can “aid in identifying” men at reduced risk for recurrence of prostate cancer in the first 8 years after a prostatectomy

NADiA ProsVue: A prognostic test for identifying men at a reduced risk for prostate cancer recurrence following radical prostatectomy

J. Moul2, R. Lance1, J. Alter3, M. Sarno3, J. McDermed3
1 Eastern Virginia Medical School, Norfolk, USA
2 Duke Prostate Center, Durham, USA
3 Iris Molecular Diagnostics, Carlsbad, USA

Introduction: Clinical recurrence after radical prostatectomy (RP) is difficult to predict since established factors do not reliably stratify risk. We validated a pre-specified hypothesis that a post-RP NADiA® PSA slope cutpoint of ≤2.0 pg/mL/month (mo) identifies men at reduced risk of clinical recurrence as determined by positive biopsy, imaging or prostate cancer death. This study aimed to compare the prognostic strength of the ProsVue slope cutpoint vs. surgical margin status to identify men at very low risk of post-RP clinical recurrence.
Methods: From a cohort of 304 men, surgical margin data was available for 234 men. PSA was measured with a Nucleic Acid Detection Immunoassay (NADiA®) having a limit of quantification of 0.00065 ng (0.65 pg) per mL. Least-squares linear PSA slope (ProsVue™) was calculated using 3 serum samples drawn 1.5-20 mo post-RP. Recurrence risk using a 2.0 pg/mL/mo ProsVue cutpoint and surgical margin status were compared by two survival methods, univariate Cox proportional hazards regression analysis (table) and Kaplan-Meier plots (figure).
Results: ProsVue slope ≤2.0 pg/mL/mo was significantly associated with a reduced risk of clinical recurrence by univariate Cox analysis (HR 18.3, 95% CI, 10.6–31.8, P < 0.0001). A negative surgical margin was less significantly associated with a reduced risk of recurrence (HR 3.3, 95% CI 2.0–5.4). Median time to recurrence for men with ProsVue slope ≤2.0 pg/mL/mo and those with negative margins exceeded 17.6 years (yrs). However, median time to recurrence in men with ProsVue slope >2.0 pg/mL/mo was shorter compared to those with positive margins.

NADiA ProsVue Prostate-specific Antigen Slope Is an Independent Prognostic Marker for Identifying Men at Reduced Risk of Clinical Recurrence of Prostate Cancer After Radical Prostatectomy

Judd W. Moul, Hans Lilja, O. John Semmes, Raymond S. Lance, Robert L. Vessella, Martin Fleisher, Clarisse Mazzola, Mark J. Sarno, Barbara Stevens, Robert E. Klem, Jonathan E. McDermed, Melissa T. Triebell, Thomas H. Adams
Urology Dec 2012; 80(6): 1319-1327,

Objective
To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer.
Materials and Methods
From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses.
Results
The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004).
Conclusion
Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.

Fifth–Generation Digital Immunoassay for Prostate Specific Antigen by Single Molecule Array Technology.

D.H. Wilson, D.W. Hanlon, G.K. Provuncher, L. Chang, L. Song, P.P. Patel, E.P. Ferrell, H. Lepor,A.W. Partin, D.W. Chan, L.J. Sokoll, C.D. Cheli, R.P. Thiel, D.R. Fournier, and D.C. Duffy
http://dx.doi.org/10.1373/clinchem.2011.169540

Measurement of prostate specific antigen (PSA) in prostate cancer patients following radical prostatectomy (RP) has been hindered by the limit of quantification of available assays. Because radical prostatectomy removes the tissue responsible for PSA production, postsurgical PSA is typically undetectable with current assay methods. Evidence suggests, however, that more sensitive determination of PSA status following RP could improve assessment of patient prognosis and response to treatment and better target secondary therapy for those who may benefit most. We developed an investigational digital immunoassay with a 2–logs–lower limit of quantification than current ultrasensitive third–generation PSA assays. We developed reagents for a bead–based ELISA for use with high–density arrays of femtolitervolume wells. Anti–PSA capture beads with immunocomplexes and associated enzyme labels were singulated within the wells of the arrays and interrogated for the presence of enzymatic product. We characterized analytical performance, compared its accuracy with a commercially available test, and analyzed longitudinal serum samples from a pilot study of 33 RP patients. The assay exhibited a functional sensitivity (20% interassay CV) <0.05 pg/mL, total imprecision <10% from 1 to 50 pg/mL, and excellent agreement with the comparator method. All RP samples were well within the assay measurement capability. PSA concentrations following surgery were found to be predictive of prostate cancer recurrence risk over 5 years. The robust 2–log improvement in limit of quantification relative to current ultrasensitive assays and the validated analytical performance of the assay allow for accurate assessment of PSA status after RP.

EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE
Dror Nir, PhD
http://pharmaceuticalintelligence.com/2013/05/21/early-detectio…-aua-guideline
Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics
Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/05/21/prostate-cance…iotheranostics/

EARLY DETECTION OF PROSTATE CANCER: American Urological Association (AUA) GUIDELINE (pharmaceuticalintelligence.com)
From AUA2013: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies (pharmaceuticalintelligence.com)
FDA Approves a New Drug for Prostate Cancer (cancerwhattodoorsay.wordpress.com)
Clinical trial tests targeting prostate cancer treatment (sys-con.com)
Routine PSA Tests No Longer Recommended – American Urological Association (medicalnewstoday.com)
Clinical trial tests targeting prostate cancer treatment (hormonetherapymiami.wordpress.com)
AUA Releases New Clinical Guideline On Prostate Cancer Screening (medicalnewstoday.com)

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A, Richie J, deKernion J, Walsh P, Scardino P, Lange P, Subong E, Parson R, Gasior G, Loveland K, Southwick P (1998). “Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial”. JAMA 279 (19) : 1542–7. doi:10.1001/jama.279.19.1542. PMID 9605898. (Photo credit: Wikipedia)

English: Human prostate specific antigen (PSA/KLK3) with bound substrate from complex with antibody (PDB id: 2ZCK) (Photo credit: Wikipedia)

Table 1. Side-effects and effects on recovery of treatments for newly diagnosed prostate cancer. The Prostate Brachytherapy Advisory Group: http://www.prostatebrachytherapyinfo.net (Photo credit: Wikipedia)