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Posts Tagged ‘Prostate biopsy’


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

 table 1

 * 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

table 2

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.

 Picture1

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:

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Figure 2b:

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Figure 2c:

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Figure 2d:

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Figure 2e:

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Figure 2f:

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Figure 2g:

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Figure 2h:

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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 23). 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:

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 Figure 3b: Patient 4:

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Figure 3c: Patient 4:

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Figure 3d: Patient 4:

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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:

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Figure 4b: Patient 3:

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Figure 4c: Patient 3:

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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:

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Figure 5b: Patient 13:

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Figure 5c: Patient 13:

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Figure 5d: Patient 13:

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Figure 5e: Patient 13:

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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.

 Picture6

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.

Picture7

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

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EARLY DETECTION OF PROSTATE CANCER: 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…..

 fig 1

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 above mentioned literature review was done using rigorous approach.

“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.

CONCLUSIONS: The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. The entire guideline is available at www.AUAnet.org/education/guidelines/prostate-cancer-detection.cfm.”

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

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

Imaging-biomarkers is Imaging-based tissue characterization

On the road to improve prostate biopsy

State of the art in oncologic imaging of Prostate

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

Today’s fundamental challenge in Prostate cancer screening

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Men With Prostate Cancer More Likely to Die from Other Causes

New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

New clinical results supports Imaging-guidance for targeted prostate biopsy

Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Prostate Cancer and Nanotecnology

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

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

Reporter: Dror Nir, PhD

This year’s AUA takes place in San Diego, USA.

Wednesday, May 08, 2013 10:30 AM-12:30 PM
SDCC: Room 8
Prostate Cancer: Detection & Screening (V)
Moderated Poster
Funding: none
2209: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies.
Oleg Apolikhin; Andrey Sivkov; Gennady Efremov; Nikolay Keshishev; Oleg Zhukov; Andrey Koryakin

Abstract: 2209
Introduction and Objectives
One of the biggest problems in the diagnosis of prostate cancer (PCa), which distinguishes it from many other solid tumors, is the difficulty of tumor imaging by means of standard visualization techniques. A transrectal ultrasound (TRUS) biopsy is mostly performed on the basis of risen PSA and is often blind – tissue specimens are taken from standard zones. Biopsy under MRI control is technically and logistically complicated and expensive, while TRUS can`t always differentiate the suspicious areas. A TRUS-based innovative technique, “Histoscanningâ€� is used in our centre for PCa identification and targeted biopsy.

Methods
Prior to template biopsy we have performed Histoscanning to 31 patients, with previous one to six negative TRUS biopsies and persistent clinical suspicion of PCa (elevated PSA, high-grade prostatic intraepithelial neoplasia (HPIN) in 4 cores or suspicious TRUS findings). Age range was 51 – 75, with PSA values 3,8 – 14,3 ng/ml. Prostate size range 22-67cc. Most of the patients (n-26) from this group received therapy with 5α-reductase inhibitors for 6 months or more. Depending on the gland size, 10-14 standardized cores were taken + 4 additional cores from the suspicious zones marked on Histoscanning report.

Results
Histopathology identified PCa in 13 out of 31 patients , adenocarcinomas with Gleason score ranging 6-8. In 11 patients with no signs of PCa we found HPIN or low-grade PIN. Comparing histology reports with Histoscanning mapping, in 8 PCa cases we found high correlation of this method with histopathological study on the amount and location of tumor lesions and in 5 cases Histoscanning showed greater spread of lesions, with good correlation of the tumor location.

Conclusions
Due to the effectiveness, ease of use and the short time required for data processing, Histoscanning is a promising method for more effective targeted biopsy of the prostate.

As a result of ongoing research, we aim to evaluate sensitivity and specificity of the method, fuse it with MRI, to create a 3D model for biopsy or surgery. In the future, this data could be used for decision making on the nerve-sparing prostatectomy and minimally invasive focal treatments such as cryoablation, high-intensity focused ultrasound, radiofrequency or laser ablation.

Date & Time: May 8, 2013 10:30 AM
Session Title: Prostate Cancer: Detection & Screening (V)
Sources of Funding: none

Personal note:

On the authors’ intention to fuse HistoScanning with MRI: The authors report a very compelling clinical benefit just from using HistoScanning for guiding their biopsies. HistoScanning itself results in a 3D mapping of the prostate and the suspicious locations inside.

3D mapping of the prostate by HistoScanning analysis following motorised TRUS. the colored locations represents tissue suspicious for being cancer.

3D mapping of the prostate by HistoScanning analysis following motorised TRUS. the colored locations represents tissue suspicious for being cancer.

Fusing ultrasound & MRI images is prone to image-registration errors (e.g. due to differences in the prostate’s shape-distortion by the probe) which are larger than the accuracy sought for when performing biopsy or nerve-sparing surgery. I recommend anyone who wishes to guide biopsies and treatment based on MRI and therefore is in need for good level of localized-MRI interpretation, to rely on dedicated MRI interpretation applications and not intra-modalities image fusion.

In addition, major benefits of using HistoScanning for managing prostate cancer patients are the accessibility; A urologist can perform himself, at any time he chooses and at any place, simplicity; it only requires routine TRUS, patient-friendly; it lasts less than a minute and does not require anesthesia and low-cost; it’s ultrasound! Mixing HistoScanning with MRI will certainly eliminate these.

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On the road to improve prostate biopsy

Author-Writer: Dror Nir, PhD

Urologists are in constant search for a method that will improve the outcome of prostate biopsy, particularly when it comes to ruling-in and ruling-out clinically significant prostate cancer. As stated in my recent post – State of the art in oncologic imaging of Prostate; “The disease’s staging and related prognosis are determined during diagnosis based on PSA level and the Gleason score of biopsy’s samples. Although prostate-specific antigen (PSA) screening resulted in the diagnosis of prostate cancer at earlier stages and with lower Gleason scores, it has also contributed to concerns about over-diagnosis, overtreatment of clinically insignificant disease, associated treatment-related toxicity, and escalating costs”. I already reported in the past on research conduc ted in this area; New clinical results supports Imaging-guidance for targeted prostate biopsy and Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention? Today I report on recent publication presenting the advantage of using targeted trans-perineal biopsy following HistoScanning imaging instead of systematic TRUS biopsies: Computer-aided (HistoScanning) Biopsies Versus Conventional Transrectal Ultrasound-guided Prostate Biopsies: Do Targeted Biopsy Schemes Improve the Cancer Detection Rate? (Moritz F. Hamann, Claudius Hamann, Eckhard Schenk, Amr Al-Najar, Carsten M. Naumann, and Klaus-Peter Jünemann, Urology, Volume 81, Issue 2, February 2013, Pages 370-375)

I have mentioned HistoScanning (ultrasound-based tissue characterization technology which I have invented and developed to a medical device) in many of my previous posts. HistoScanning for prostate is a specific HistoScanning application that is applied to the ultrasound’s raw signal (not the image) following a comprehensive scan of the prostate capturing its entire volume. The whole process takes about ten minutes and the output is a digital 3D map of the prostate gland where locations suspicious of presenting with prostate cancer are indicated.

HistoScanning report with 2, bilateral, basal lesions.

HistoScanning report with 2, bilateral, basal lesions.

 

The urologist translates such map into a “prostate regional biopsy scheme” when planning his biopsies and direct the needle, under ultrasound guidance, to these predefined suspicious locations.

 The systematic biopsy patterns targeted 7 sectors bilaterally: transition zone, apex, center, and base, each medially and laterally.

The systematic biopsy patterns targeted 7 sectors bilaterally: transition zone, apex, center, and base, each medially and laterally.

In that sense, the workflow is similar to using MRI for tumor detection and creating a tumor map for targeting the biopsy.

As reasoning for conducting the study the investigators argue that: “Exact staging of prostate cancer before treatment is essential for relevant therapeutic decision making. Current procedures, such as nerve-sparing prostatectomy and brachytherapy, as well as active surveillance and future focal treatment options, depend on the reliable identification of cancerous lesions within the prostate. Systematic prostate biopsies with at least 10 to 12 cores are the current standard method to detect and locate significant prostate cancer, as scientific evidence during the last decades has shown. Nevertheless, there are no homogeneous data concerning the required number of cores and the technical approach of prostate biopsy procedures. The unstable histologic results on active surveillance and the well-known discrepancy between transrectal diagnostics and radical prostatectomy specimens underline the neces­sity to develop reliable diagnostic tools for precise detection and localization of prostate cancer. Recent data on HistoScanning computer-aided ultra-sonography have shown favorable results. To generate a greater diagnostic yield than systematic needle biopsies, we integrated HistoScanning-guided targeted biopsies in our general prostate biopsy regimen. We report the cancer detection rate in a prospective series of 80 patients.”

The study’s objective was: “To define potential improvement in prostate cancer detection by application of a computer-aided, targeted, biopsy regimen using HistoScanning.”

Materials and Methods: “The data were collected prospectively from 80 men who consecutively underwent a systematic 14-core prostate biopsy supplemented by targeted transrectal and perineal ultrasound-guided biopsies. All biopsies were performed between March 2011 and September 2011. Indications for prostate biopsy were suspicious findings at the digital rectal examination (DRE), or serum prostate-specific antigen (PSA) level >10 ng/mL, or both. In case of elevated serum PSA levels >4 ng/mL a PSA-velocity of >0.75 ng/mL p.a. and free-to-total PSA ratio <15% were seen as the indication for prostate biopsies. Thirty-six patients had undergone a previous transrectal prostate biopsy. All patients were informed of the mode of the extended prostate biopsy scheme and its potential complications. All patients provided written informed consent for the procedure.After indication and before starting the biopsy procedure, all patients underwent a standardized 3-dimensional (3D) transrectal ultrasound (TRUS) with an end-fire array of a BK 8818 probe. Computer-aided analysis of the raw (radio-frequency) back-scatter data was performed by using the Conformite Europeene-marked and commercially available HistoScanning device, admitted for medical use in the Euro­pean Union (software version 2.1, Advanced Medical Diag­nostics, Belgium).”

“Each patient was diagnosed preoperatively by HistoScanning, defining a maximum of 3 suspicious areas. These areas were biopsied, both transrectally and via the perineum, with a maximum of 3 cores per location.”

Results: “We detected prostatitis in 30 patients (37.5%), premalignant lesions in 10 (12.5%), and prostate cancer in 28 (35%). The transrectal technique was used to detect 78.6% of all cancers using 14 cores by systematic biopsy. With a maximum of 9 targeted cores, 82.1% of all cancers were detected with the targeted perineal approach and 53.6% were detected with the targeted transrectal approach. Although our data did not show significant difference in the performance of targeted transperineal compared with systematic transrectal biopsies, the detection rate of targeted transrectal biopsies was significantly lower.”

 table

Conclusion: “The presented targeted biopsy scheme achieved an overall detection rate of 85% of prostate-specific antigen–relevant pathologic lesions within the prostate. Thus, the presented procedure shows an improved detection rate compared with standard systematic prostate biopsies, and the number of cores required is reduced. Furthermore, the perineal HistoScanning-aided approach seems to be superior to the transrectal approach with respect to the prostate cancer detection rate. The presented procedure might be a step toward reliable ultrasound-based tissue characterization and toward fulfilling the requirements of novel therapeutic strategies.”

 

The authors’ included an elaborated discussion on the background to their study and its results. This discussion is important for understanding the limitation of the study results and for putting the authors conclusion into balanced context: “When other solid-organ cancer guidelines are compared with prostate cancer guidelines, the common methods of prostate cancer detection are unmasked as an outmoded concept because cancer detection is based on chance as a result of a blinded, subjective examination. A systematic biopsy with at least 10 to 12 cores is considered the standard procedure in prostate cancer diagnostics to date. 1,2 The continuous increase in the number of biopsy cores taken over the last years has predictably improved the detection rate, but several studies report detection rates of only 30% to 40% even in repeated biopsies. 5,9 It is noteworthy that the recommendations must be seen as a compromise bbetween the cancer detection rate and the invasiveness of the surgical procedure. Modern diagnostic procedures, including magnetic resonance imaging, elastography, computerized analysis of TRUS/artificial neuronal network analysis, and HistoScanning, try to overcome this principle of approach.7,10,11 The current therapeutic concepts and further currently evolving therapy strategies depend on sophisticated prostate cancer diagnostics. It is more important than ever to look for ways to detect and locate the cancer before subjecting patients to more or less invasive procedures as the indication for surgical treatment or prostate-preserving (focal) tumor therapy. The results of magnetic resonance imaging for prostate cancer detection are very promising so far and show a sensitivity of up to 80%. Elastography has also shown promising capabilities for cancer detection, with a recent review article reporting that several studies show 74% to 75% sensitivity.11 HistoScanning has shown 93% sensitivity in detecting and locating prostate cancer. 12 As a matter of principle, our study is unable to report on the accuracy or sensitivity of prostate cancer detection because the exact number of cancer lesions in our patients collective remains incomputable. Integration of HistoScanning for guided, targeted biopsies helped us achieve a prostate cancer detection rate of 35%. These data are lower than results from current publications on initial prostate biopsies but higher than those of repeated biopsy protocols.4,5,13 Given that tumors looked for during initial biopsies are usually large and easy to detect, we believe that this finding is caused by the smaller overall risk of cancer in a repeated biopsy setting, as was the case in 37.5% of our patients (0.61 biopsies per patient). Overall, HistoScanning seems to improve selective targeting of suspicious prostate lesions. Taking into account all malignant, premalignant, and atypical histologic findings, including prostate cancer, atypical small acinar proliferations, and high-grade prostatic intraepithelial  eoplasia, the detection rate of relevant prostatic lesions by specimens from perineal-targeted biopsies rises to 47.5% and 85%, including prostatitis, respectively. Apart from the high quality of the HistoScanning tissue analysis, we believe in a significant effect of the technical approach used to perform the biopsy. As our data show, prostate cancer detection rates from specimens obtained from perineal-targeted biopsies differed significantly from the transrectal-targeted biopsy regimen, a difference that occurred independently from previous tissue analysis because both targeted approaches are aligned to the same scanning process. Compared with the transrectal approach, the perineal biopsy technique might reduce variables that can influence the needle placement. Furthermore, longitudinal biopsy punches following the axis of the prostate seem to allow more accurate sampling of the anterior part. Theoretically, because previous studies reported inhomogeneous results comparing transrectal and transperineal prostate biopsies.3,4,13 The use of a 14-gauge needle in perineal biopsies might be responsible for a systematic bias because it possibly yields more tissue than transrectal cores. Despite this potential advantage, systematic transrectal biopsies do not reflect a significant difference in the detection rate. Nevertheless, due to the individual setting, our study is unable to report standardized results on the accuracy of comparing transrectal and transperineal needle placement. Template-guided mapping biopsies have recently attracted attention because of the high rate of cancer detection as initial (75%) and even repeat biopsy procedures (46%). 14 It notably increases the ability to locate and differentiate cancer foci within the prostatic gland, implicating mapping biopsies for active surveillance or focal treatment purposes regardless of the considerable surgical trauma generated by the use of extended biopsy protocols. A reduction of tissue trauma by generating a greater diagnostic yield would be a favorable methodologic aspect as initiated by our study. Regarding cancer detection, the presented data show no significant differences between the perineal-targeted and transrectal-targeted systematic biopsy regimen, but even though considerably fewer tissue samples (14 vs 9 cores; -35%) were taken from selected prostate areas, we detected no significant limitations by the perineal approach. These data are even more encouraging when bearing in mind that the number of samples represents a crucial factor in prostate cancer detection rates, as recently reported. A critical issue in the present study is in the implementation of the modified biopsy procedures. Although the surgeons at our center are experienced in using TRUS, our data show a learning curve during the first 80 procedures. In addition, the overlaying of the HistoScanning image analysis to the B-mode grey-scale live ultrasound picture is done by the surgeon performing the biopsy. This process implies a bias in individual interpretation of the TRUS picture and manual needle guidance. The online fusion of HistoScanning with the ultrasound image presumably would increase the handling accuracy. Further methodologic limitations lie in the heterogeneous and small collective of patients that were included in the study. With regard to the reasonably high number of previous negative biopsy specimens, patient selection can affect the hit rate of positive biopsy specimens. This circumstance might make the cancer detection frequency with HistoScanning look relatively small in this particular study compared with other diagnostic methods in patients undergoing an initial biopsy, but this is due to the daily routine in an academic referral center.

For completeness of this reporting and before stating my own conclusion I bring here below two comments that were made, one by Dr. Stephen Jones of Glickman Urological and Kidney Institute, Cleveland, Ohio and the reply by the first author:

COMMENT

The promise of image-guided diagnosis and management of prostate cancer has been frustratingly elusive. Early pioneers of prostate ultrasound imaging reported that hyperechoic lesionswere indicative of malignancy, but it rapidly became clear that the opposite was actually more realistic. Even so, these hypoechoic lesions were soon shown to be poor indicators of prostate cancer. Thus, the value of visual abnormalities on grey-scale prostate ultrasound imaging remains essentially negligible with current technology. As a result, a number of alternative imaging modalities have been developed and introduced with great excitement. Typically, images in the publications showcase an apparently obvious cancer standing out in contrast to adjacent benign tissues. Unfortunately, the data still reveal minimal value from most of these technologies, and those reported in this article are similarly disappointing. HistoScanning demonstrated interesting color images, but coupled with a transperineal-targeted biopsy found exactly one more case of prostate cancer than did the current standard of care—the 14-core extended transrectal biopsy. This “difference” is actually statistically identical (P >.99). Exactly the same number of patients (n¼ 4) was found exclusively by both transperineal HistoScan-targeted biopsy as with standard transrectal biopsy, and when targeted using the transrectal approach, the technology actually missed almost half of the cancers that were identified overall. Furthermore, these data do not support the suggestion that 9 cores are less morbid or traumatic than 14 cores, and the literature is replete with reports demonstrating this is simply not true. This is especially misleading when those 9 cores come at the cost, morbidity, time, and complexity of an operation such as this performed under general anesthesia. So the real question remains whether HistoScanning or any emerging technology to image the prostate—improves visualization of prostate cancer. Although magnetic resonance imaging is beginning to show notable promise, the clinical value of most other modalities remains mostly anecdotal. As one whose desire for a solution remains frustratingly unfulfilled, I hope that some imaging technique will demonstrate clinical value during my career. J. Stephen Jones, M.D., Department of Regional Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, Ohio

REPLY

In accordance with your comprehensive notes, we have to search for diagnostic improvement and underline the need further investigations in the field of prostate cancer diagnostics and staging. Minimally invasive techniques, focal and targeted therapy modalities, and low-risk cancer surveillance probably are future treatment modalities for prostate malignancies that progressively challenge common diagnostic pathways. Sophisticated therapy strategies will require reliable staging results. The constant increase of cores taken during systematic prostate biopsy apparently will not overcome the well-known diagnostic uncertainties. Consequently, imaging techniques and methods of biopsy targeting will gain in importance. Clearly, the presented data do not show significant improvement in the overall detection rate of prostate cancer in our patient cohort. Further, the maximum number of 9 biopsy cores must be attributed to the initial study design and will undergo further investigation; however, the results rather support the study approach than reduce its validity. Considering the indeterminate number of cancers, the proof of superiority remains incomputable. Compared with the current standard of care of 12 to 14 cores, we detected no significant limitations, although perineal-targeted biopsies took significantly fewer cores (3-9 cores [35%]). Maintaining the detection rate unchanged and focusing on 1 to 3 preselected suspicious index lesions display a proof of principle rather than disappointing results. In line with future treatment options mentioned above, any less invasive, focused diagnostic procedure represents an encouraging advance compared with the common and recommended practice of a nonselective, systematic biopsy of the prostate to harbor cancerous tissue. Moritz F. Hamann, M.D., Department of Urology and Pediatric Urology, University of SchleswigeHolstein, Campus Kiel, Kiel, Germany

As mentioned by the authors, further improvement of the outcome of HistoScanning-based targeted biopsies of prostate is expected when an implementation of image-fusion application between the “off-line” generated 3D tumor map and the real-time ultrasound guiding the needle will be available; similar to the results presented already when using ultrasound-MRI image fusion applications for prostate biopsy. Of course, the ultimate biopsy workflow (which I am currently engaged in developing) that urologist are asking for is the one comprised of real-time ultrasound-based tissue characterization and real-time ultrasound guidance of the needle to the lesion.

References

1. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61-71.

2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Available at http://www.nccn.org 2011 Accessed May 2011.

3. Abdollah F, Novara G, Briganti A, et al. Trans-rectal versus transperineal saturation re-biopsy of the prostate: is there a difference in cancer detection rate? Urology. 2011;77:921-925.

4. Hara R, Yoshimasa J, Tomohiro F, et al. Optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. Urology. 2008;71:191-195.

5. Patel AR, Jones JS. Optimal biopsy strategies for the diagnosis and staging of prostate cancer. Curr Opin Urol. 2009;19:232-237.

6. Al Otaibi M, Ross P, Fahmy N, et al. Role of repeated biopsy of the prostate in predicting disease progression in patients with prostate cancer on active surveillance. Cancer. 2008;113:286-292.

7. Braeckman J, Autier P, Garbar C, et al. Computer-aided ultrasonography (HistoScanning): a novel technology for locating and characterizing prostate cancer. BJU Int. 2008;101:293-298.

8. Braeckman J, Autier P, Soviany C, et al. The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers. BJU Int. 2008;102:1560-1565.

9. Presti JC Jr, O’Dowd G, Miller C, et al. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a community multi-practice study. J Urol. 2003;169:125-129.

10. Turkbey B, Mani H, Shah V, et al. Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds. J Urol. 2011;186: 1818-1824.

11. Trabulsi EJ, Sackett D, Gomella L, et al. Enhanced transrectal ultrasound modalities in the diagnosis of prostate cancer. Urology. 2010;76:1025-1033.

12. Simmons LA, Autier P, Zat_ura F, et al. Detection, localisation and characterisation of prostate cancer by Prostate HistoScanning. BJU Int. 2012;110:28-35.

13. Emiliozzi P, Corsetti A, Tassi B, et al. Best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. Urology. 2003;61:961-966.

14. Taira AV, Merrick GS, Galbreath RW, et al. Performance of transperineal template-guided mapping biopsy in detecting prostate cancer in the initial and repeat biopsy setting. Prostate Cancer Prostatic Dis. 2010;13:71-77.

 

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

Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Prostate Cancer and Nanotecnology

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

Today’s fundamental challenge in Prostate cancer screening

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Men With Prostate Cancer More Likely to Die from Other Causes

New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

New clinical results supports Imaging-guidance for targeted prostate biopsy

 

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The unfortunate ending of the Tower of Babel construction project and its effect on modern imaging-based cancer patients’ management


The story of the city of Babel is recorded in the book of Genesis 11 1-9. At that time, everyone on earth spoke the same language.

Picture: Pieter Bruegel the Elder: The Tower of Babel_(Vienna)

It is probably safe to assume that medical practitioners at that time were reporting the status of their patients in a standard manner. Although not mentioned, one might imagine that, at that time, ultrasound or MRI scans were also reported in a standard and transferrable manner. The people of Babel noticed the potential in uniform communication and tried to build a tower so high that it would  reach the gods. Unfortunately, God did not like that, so he went down (in person) and confounded people’s speech, so that they could not understand each another. Genesis 11:7–8.

This must be the explanation for our inability to come to a consensus on reporting of patients’ imaging-outcome. Progress in development of efficient imaging protocols and in clinical management of patients is withheld due to high variability and subjectivity of clinicians’ approach to this issue.

Clearly, a justification could be found for not reaching a consensus on imaging protocols: since the way imaging is performed affects the outcome, (i.e. the image and its interpretation) it takes a long process of trial-and-error to come up with the best protocol.  But, one might wonder, wouldn’t the search for the ultimate protocol converge faster if all practitioners around the world, who are conducting hundreds of clinical studies related to imaging-based management of cancer patients, report their results in a standardized and comparable manner?

Is there a reason for not reaching a consensus on imaging reporting? And I’m not referring only to intra-modality consensus, e.g. standardizing all MRI reports. I’m referring also to inter-modality consensus to enable comparison and matching of reports generated from scans of the same organ by different modalities, e.g. MRI, CT and ultrasound.

As developer of new imaging-based technologies, my personal contribution to promoting standardized and objective reporting was the implementation of preset reporting as part of the prostate-HistoScanning product design. For use-cases, as demonstrated below, in which prostate cancer patients were also scanned by MRI a dedicated reporting scheme enabled matching of the HistoScanning scan results with the prostate’s MRI results.

The MRI reporting scheme used as a reference is one of the schemes offered in a report by Miss Louise Dickinson on the following European consensus meeting : Magnetic Resonance Imaging for the Detection, Localisation, and Characterisation of Prostate Cancer: Recommendations from a European Consensus Meeting, Louise Dickinson a,b,c,*, Hashim U. Ahmed a,b, Clare Allen d, Jelle O. Barentsz e, Brendan Careyf, Jurgen J. Futterer e, Stijn W. Heijmink e, Peter J. Hoskin g, Alex Kirkham d, Anwar R. Padhani h, Raj Persad i, Philippe Puech j, Shonit Punwani d, Aslam S. Sohaib k, Bertrand Tomball,Arnauld Villers m, Jan van der Meulen c,n, Mark Emberton a,b,c,

http://www.europeanurology.com/article/S0302-2838(10)01187-5

Image of MRI reporting scheme taken from the report by Miss Louise Dickinson

The corresponding HistoScanning report is following the same prostate segmentation and the same analysis plans:


Preset reporting enabling matching of HistoScanning and MRI reporting of the same case.

It is my wish that already in the near-future, the main radiology societies (RSNA, ESR, etc..) will join together to build the clinical Imaging’s “Tower of Babel” to effectively address the issue of standardizing reporting of imaging procedures. This time it will not be destroyed…:-)

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Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?


Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

Author: Dror Nir, PhD

 

Advances in techniques for cancer lesions’ detection and localisation [1-6] opened the road to methods of localised (“focused”) cancer treatment [7-10].  An obvious challenge on the road is reassuring that the imaging-guided treatment device indeed treats the region of interest and preferably, only it.

A step in that direction was taken by a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans [7]. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment. Eight eligible patients were recruited.

 

The setup

 

Treatment protocol

 

The result

 

“There was excellent agreement between the zone targeted for treatment and the zone of thermal injury, with a targeting accuracy of ±2.6 mm. In addition, the temporal evolution of heating was very consistent across all patients, in part because of the ability of the system to adapt to changes in perfusion or absorption properties according to the temperature measurements along the target boundary.”

 

Technological problems to be resolved in the future:

“Future device designs could incorporate urinary drainage during the procedure, given the accumulation of urine in the bladder during treatment.”

“Sufficient temperature resolution could be achieved only by using 10-mm-thick sections. Our numeric studies suggest that 5-mm-thick sections are necessary for optimal three-dimensional conformal heating and are achievable by using endorectal imaging coils or by performing the treatment with a 3.0-T platform.”

Major limitation: “One of the limitations of the study was the inability to evaluate the efficacy of this treatment; however, because this represents, to our knowledge, the first use of this technology in human prostate, feasibility and safety were emphasized. In addition, the ability to target the entire prostate gland was not assessed, again for safety considerations. We have not attempted to evaluate the effectiveness of this treatment for eradicating cancer or achieving durable biochemical non-evidence of disease status.”

References

  1. SIMMONS (L.A.M.), AUTIER (P.), ZATURA (F.), BRAECKMAN (J.G.), PELTIER (A.), ROMICS (I.), STENZL (A.), TREURNICHT (K.), WALKER (T.), NIR (D.), MOORE (C.M.), EMBERTON (M.). Detection, localisation and characterisation of prostate cancer by Prostate HistoScanning.. British Journal of Urology International (BJUI). Issue 1 (July). Vol. 110, Page(s): 28-35
  2. WILKINSON (L.S.), COLEMAN (C.), SKIPPAGE (P.), GIVEN-WILSON (R.), THOMAS (V.). Breast HistoScanning: The development of a novel technique to improve tissue characterization during breast ultrasound. European Congress of Radiology (ECR), A.4030, C-0596, 03-07/03/2011.
  3. Hebert Alberto Vargas, MD, Tobias Franiel, MD,Yousef Mazaheri, PhD, Junting Zheng, MS, Chaya Moskowitz, PhD, Kazuma Udo, MD, James Eastham, MD and Hedvig Hricak, MD, PhD, Dr(hc) Diffusion-weighted Endorectal MR Imaging at 3 T for Prostate Cancer: Tumor Detection and Assessment of Aggressiveness. June 2011 Radiology, 259,775-784.
  4. Wendie A. Berg, Kathleen S. Madsen, Kathy Schilling, Marie Tartar, Etta D. Pisano, Linda Hovanessian Larsen, Deepa Narayanan, Al Ozonoff, Joel P. Miller, and Judith E. Kalinyak Breast Cancer: Comparative Effectiveness of Positron Emission Mammography and MR Imaging in Presurgical Planning for the Ipsilateral Breast Radiology January 2011 258:1 59-72.
  5. Anwar R. Padhani, Dow-Mu Koh, and David J. Collins Reviews and Commentary – State of the Art: Whole-Body Diffusion-weighted MR Imaging in Cancer: Current Status and Research Directions Radiology December 2011 261:3 700-718
  6. Eggener S, Salomon G, Scardino PT, De la Rosette J, Polascik TJ, Brewster S. Focal therapy for prostate cancer: possibilities and limitations. Eur Urol 2010;58(1):57–64).
  7. Rajiv Chopra, PhD, Alexandra Colquhoun, MD, Mathieu Burtnyk, PhD, William A. N’djin, PhD, Ilya Kobelevskiy, MSc, Aaron Boyes, BSc, Kashif Siddiqui, MD, Harry Foster, MD, Linda Sugar, MD, Masoom A. Haider, MD, Michael Bronskill, PhD and Laurence Klotz, MD. MR Imaging–controlled Transurethral Ultrasound Therapy for Conformal Treatment of Prostate Tissue: Initial Feasibility in Humans. October 2012 Radiology, 265,303-313.
  8. Black, Peter McL. M.D., Ph.D.; Alexander, Eben III M.D.; Martin, Claudia M.D.; Moriarty, Thomas M.D., Ph.D.; Nabavi, Arya M.D.; Wong, Terence Z. M.D., Ph.D.; Schwartz, Richard B. M.D., Ph.D.; Jolesz, Ferenc M.D.  Craniotomy for Tumor Treatment in an Intraoperative Magnetic Resonance Imaging Unit. Neurosurgery: September 1999 – Volume 45 – Issue 3 – p 423
  9. Medel, Ricky MD,  Monteith, Stephen J. MD, Elias, W. Jeffrey MD, Eames, Matthew PhD, Snell, John PhD, Sheehan, Jason P. MD, PhD, Wintermark, Max MD, MAS, Jolesz, Ferenc A. MD, Kassell, Neal F. MD. Neurosurgery: Magnetic Resonance–Guided Focused Ultrasound Surgery: Part 2: A Review of Current and Future Applications. October 2012 – Volume 71 – Issue 4 – p 755–763
  10. Bruno Quesson PhD, Jacco A. de Zwart PhD, Chrit T.W. Moonen PhD. Magnetic resonance temperature imaging for guidance of thermotherapy. Journal of Magnetic Resonance Imaging, Special Issue: Interventional MRI, Part 1, Volume 12, Issue 4, pages 525–533, October 2000

Writer: Dror Nir, PhD

 

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Author and Curator: Dror Nir, PhD

Radiology congresses are all about imaging in medicine. Interestingly, radiology originates from radiation. It was the discovery of X-ray radiation at the beginning of the 20th century that opened the road to “seeing” the inside of the human body without harming it (at that time that meant cutting into the body).

Radiology meetings are about sharing experience and knowhow on imaging-based management patients. The main topic is always image-interpretation: the bottom line of clinical radiology! This year’s European Congress of Radiology (ECR) dedicated few of its sessions to recent developments in image-interpretation tools. I chose to discuss the one that I consider contributing the most to the future of cancer patients’ management.

In the refresher course dedicated to computer application the discussion was aimed at understanding the question “How do image processing and CAD impact radiological daily practice?” Experts’ reviews gave the audience some background information on the following subjects:

  1. A.     The link between image reconstruction and image analysis.
  2. B.     Semantic web technologies for sharing and reusing imaging-related information
  3. C.     Image processing and CAD: workflow in clinical practice.

I find item A to be a fundamental education item. Not once did I hear a radiologist saying: “I know this is the lesion because it’s different on the image”.  Being aware of the computational concepts behind image rendering, even if it is at a very high level and lacking deep understanding of the computational processes,  will contribute to more balanced interpretations.

Item B is addressing the dream of investigators worldwide. Imagine that we could perform a web search and find educating, curated materials linking visuals and related clinical information, including standardized pathology reporting. We would only need to remember that search engines used certain search methods and agree, worldwide, on the method and language to be used when describing things. Having such tools is a pre-requisite to successful pharmaceutical and bio-tech development.

I find item C strongly linked to A, as all methods for better image interpretation must fit into a workflow. This is a design goal that is not trivial to achieve. To understand what I mean by that, try to think about how you could integrate the following examples in your daily workflow: i.e. what kind of expertise is needed for execution, how much time it will take, do you have the infrastructure?

In the rest of this post, I would like to highlight, through examples that were discussed during ECR 2012, the aspect of improving cancer patients’ clinical assessment by using information fusion to support better image interpretation.

  • Adding up quantitative information from MR spectroscopy (quantifies biochemical property of a target lesion) and Dynamic Contrast Enhanced MR imaging (highlights lesion vasculature).

Image provided by: Dr. Pascal Baltzer, director of mammography at the centre for radiology at Friedrich Schiller University in Jena, Germany

  • Registration of images generated by different imaging modalities (Multi-modal imaging registration).

The following examples: Fig 2 demonstrates registration of a mammography image of a breast lesion to an MRI image of this lesion. Fig3 demonstrates registration of an ultrasound image of a breast lesion scanned by an Automatic Breast Ultrasound (ABUS) system and an MRI image of the same lesion.

Images provided by members of the HAMAM project (an EU, FP7 funded research project: Highly Accurate Breast Cancer Diagnosis through Integration of Biological Knowledge, Novel Imaging Modalities, and Modelling): http://www.hamam-project.org

 

 Multi-modality image registration is usually based on the alignment of image-features apparent in the scanned regions. For ABUS-MRI matching these were: the location of the nipple and the breast thickness; the posterior of the nipple in both modalities; the medial-lateral distance of the nipple to the breast edge on ultrasound; and an approximation of the rib­cage using a cylinder on the MRI. A mean accuracy of 14mm was achieved.

Also from the HAMAM project, registration of ABUS image to a mammography image:

registration of ABUS image to a mammography image, Image provided by members of the HAMAM project (an EU, FP7 funded research project: Highly Accurate Breast Cancer Diagnosis through Integration of Biological Knowledge, Novel Imaging Modalities, and Modelling): http://www.hamam-project.org

  • Automatic segmentation of suspicious regions of interest seen in breast MRI images

Segmentation of suspicious the lesions on the image is the preliminary step in tumor evaluation; e.g. finding its size and location. Since lesions have different signal/image character­istics to the rest of the breast tissue, it gives hope for the development of computerized segmentation techniques. If successful, such techniques bear the promise of enhancing standardization in the reporting of lesions size and location: Very important information for the success of the treatment step.

Roberta Fusco of the National Cancer Institute of Naples Pascal Foundation, Naples/IT suggested the following automatic method for suspi­cious ROI selection within the breast using dynamic-derived information from DCE-MRI data.

 

Automatic segmentation of suspicious ROI in breast MRI images, image provided by Roberta Fusco of the National Cancer Institute of Naples Pascal Foundation, Naples/IT

 

 Her algorithm includes three steps (Figure 2): (i) breast mask extraction by means of automatic intensity threshold estimation (Otsu Thresh-holding) on the par­ametric map obtained through the sum of intensity differences (SOD) calculated pixel by pixel; (ii) hole-filling and leakage repair by means of morphological operators: closing is required to fill the holes on the boundaries of breast mask, filling is required to fill the holes within the breasts, erosion is required to reduce the dilation obtained by the closing operation; (iii) suspicious ROIs extraction: a pixel is assigned to a suspicious ROI if it satisfies two conditions: the maximum of its normalized time-intensity curve should be greater than 0.3 and the maximum signal intensity should be reached before the end of the scan time. The first condition assures that the pixels within the ROI have a significant contrast agent uptake (thus excluding type I and type II curves) and the second condition is required for the time-intensity pattern to be of type IV or V (thus excluding type III curves).

Written by: Dror Nir, PhD

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