Posts Tagged ‘staging’

Examples of Surgical Procedures [4.4]

Writer and Curator: Larry H. Bernstein, MD, FCAP 

It is not possible to discuss surgical procedures without a firsthand knowledge of the principles of surgical, radiation and medical oncology and the current interdisciplinary approach to the care of the patient with cancer with respect to the type of cancer, the stage, the patient health status, the preoperative preparation, the assessment of treatment for cure or of palliation, and the postoperative plan for management of the patient.

Cancer surgery has evolved over the decades from a radical ‘one size fits all’ approach to a patient-specific, cancer-specific direction, which means that surgeons rely on their multidisciplinary partners in the assessment of patients. As surgeons are frequently the first specialists involved with most solid tumors, familiarity with pre-operative imaging, pathological biopsy and patient-selection, careful surgical technique and staging are fundamental to the surgeon’s armamentarium.

Surgical resection of cancers remains the cornerstone of treatment for many types of cancers. Historically, surgery was the only effective form of cancer treatment, but developments in radiation therapy and chemotherapy have demanded that surgeons work with the other disciplines of medicine in order to achieve best results for the patient with cancer.

This type of interaction between the medical disciplines together with the supportive care groups required by cancer patients is defined as multidisciplinary care. It is now widely recognized that for optimal treatment of cancer a multidisciplinary team with the surgeon as part of this team is essential.

Surgery is effective treatment for cancer if the disease is localized. Defining the extent of the cancer before surgery has become much more accurate with modern imaging methods including computed tomography (CT), positron emission tomography (PET) scanning and high resolution ultrasound. The exploratory operation to determine the extent of disease, or attempting a ‘curative’ resection when the disease has already spread beyond the bounds of a ‘surgical’ cure, is not part of the modern surgical treatment of cancer. Oncological trained surgeons are now distinguished from more general surgeons because of the particular needs of the cancer patients.

Clinical trials are required to evaluate new treatments and treatment combinations. The struggle against the scourge of cancer has seen an explosion in basic research directed towards cancer. This academic element to cancer care is a constant feature as all those involved in cancer care endeavor to advance the understanding of the management of cancer patients.

Three main questions to consider are implied from the preceding:

What is the type of cancer?

In most cases, this requires a tissue diagnosis. In modern oncology, it is unusual or inappropriate to start treatment based on clinical diagnosis alone without tissue diagnosis. Tissue diagnosis is also important to perform molecular studies to select appropriate targeted therapies.

What is the extent of the spread of the cancer?

This is answered by staging scans including CT scans, bone scans and PET scans.

Is it curable or not curable?

This depends on the type of cancer and the presence or absence of and the extent of metastasis.

For curable cancers, rate of cure is determined by prognostic factors (for example: tumor size and nodal status in breast cancer).

For incurable cancers, duration of survival is expressed in median survival rather than in absolute time frame.

Most solid tumors require adequate and site-specific imaging. This facilitates diagnosis and staging of the primary tumor and staging for distal metastases. Not all modalities are appropriate for all sites. For example mammography using the BIRADS system and ultrasound are used in breast cancers to assess a primary breast cancer. Meanwhile, an esophageal cancer requires a CT and a low rectal cancer will be best assessed with MRI or endorectal ultrasound, while a thyroid cancer is best evaluated with neck ultrasound.

One of the biggest challenges for the surgeon is to choose the correct surgery for the correct patient and with the tumor type and biology in mind. Although surgery removes a tumor and provides further pathological information to estimate prognosis and influence adjuvant therapies, the surgery cannot cause more morbidity than the cancer and must achieve surgical goals without compromising tumor biology.

The TNM staging system (American Joint Commission on Cancer AJCC) is devised for cancers to allow an assessment of T- tumor, N- nodal metastases and M- distal metastases. The goal of having a site-specific staging system is to estimate prognosis, facilitate treatment planning including the sequence of treatments and allow comparisons of treatment for different stages. Generally, a combination of different ‘T’, ‘N’, and ‘M’ allows the cancer to be grouped into stages. Stages I-IV usually depict a tumor in the following state: Stage 1- early and superficial cancer, Stage 2- locally advanced, Stage 3- regionally advanced with lymph node metastases and Stage 4- distant metastatic disease.

Despite suggestive imaging, a cancer is not diagnosed until histopathological biopsy. Biopsies where tissue (as opposed to cells) are provided to the pathologist increase the accuracy of the pre-operative diagnosis but may not always be feasible. Biopsies may be undertaken percutaneously — for example, a core biopsy of the breast, fine needle aspiration of thyroid or endoscopically such as in gastric cancer or colon cancer.

A biopsy should confirm the tumor type, grade, may show lymphovascular invasion and in some cases, special immunohistochemical stains may be performed to assess hormone receptor status such as in breast cancer or flow cytometry may be performed to assess subtypes such as in lymphoma. Staging may also require a biopsy of draining lymph nodes.

The aims of any cancer surgery are to remove the cancer with an adequate margin of normal tissue with minimal morbidity. Clear margins have an impact on local control.  Many solid tumors require removal of the draining lymph nodes for the purpose of staging and/or to achieve local control. Surgery has become more conservative with the advent of sentinel node biopsy, and is frequently used in breast cancer and melanoma. The sentinel node biopsy is a  staging tool to predict prognosis and influence use of adjuvant therapies. Surgery is performed for cure by removing the primary cancer and lymph nodes.

When tumors are locally advanced, a neoadjuvant approach with chemotherapy, radiotherapy or targeted therapies may be important to ‘control’ the growth of a tumor, down-stage a tumor to render it operable, or because the impact of systemic disease risk may outweigh those of local control. Similarly, patients with metastatic disease may still require surgery to prevent complications of the primary tumor, such as bowel obstruction from a colon cancer.

The preceding paragraphs define the discipline of surgical oncology. In summary, surgical oncology is the involvement of a specialty trained surgeon as part of a multidisciplinary team program, the use of appropriate surgery in an adequately staged patient and the involvement of the surgeon in academic programs particularly involved with clinical trials.

The use of effective techniques in the operating theater, the careful management of the patient undergoing surgery and supportive post-operative care are similar requirements to those of all other disciplines of surgery.

Communication with the patient and family, the obtaining of informed consent and the careful honest, realistic but where possible optimistic explanation of the results of surgery, are all matters of high importance to all surgical practice. However, the ability to talk sympathetically to cancer patients and their family is particularly important in the field of surgical oncology.

Multidisciplinary care

Surgeons need to understand the principles and practical consequences of the treatment offered by radiation oncologists, medical oncologists and the paramedical disciplines in order to be able to work in a team to treat cancer patients.

Principles of cancer surgery
Dr. Anita Skandarajah MBBS MD FRACS — Author
Cancer Council Australia Oncology Education Committee — Co-author

Principles of surgery for malignant disease


Surgical resection has the potential to cure early or localized cancers which have not metastasized. In general early cancers equate with curability. For example, a malignant polyp in the colon is usually curable by surgery. However, this does not always hold true. Small breast cancers may metastasize early with cure not inevitable from surgical excision alone. Screening for cancer to detect early asymptomatic cancers is now commonplace.

For screening to be effective, the test must be able to detect a common cancer at a stage when it can be cured by treatment. For screening to be effective it must be introduced on a population basis. The most effective screening program has been cervical screening where, since its introduction, there has been a substantial fall in mortality from cervical cancer in all age groups. Similar less dramatic effect is seen with breast cancer screening by mammography.

Surgeons are involved in screening programs performing endoscopies and biopsies (e.g. abnormal Barrett’s mucosa), excising polyps from the colons at colonoscopy and biopsying mammographically detected breast lesions.


A tissue diagnosis is essential prior to the creation of any management plan for a cancer patient. The consequences of many cancer treatments are so severe that only rarely can treatment be commenced without a pathological diagnosis. Tissue is obtained by fine needle aspiration, core biopsy or by excisional biopsy.

Assessment of the patient

An important early part of the assessment of a patient with cancer is to determine the psychological and physical fitness of the patient. An idea of the ‘health’ of the patient can be gained from a simple clinical assessment, the Eastern Cooperative Oncology Group (ECOG) status. Patients who are ECOG 3 or lower will usually have a poor outcome from any treatment including major surgery.

All patients undergoing major surgery need assessment of the clinical status including, where appropriate, tests of cardiac function, for example scans and angiography if indicated, respiratory status by lung function tests and renal function tests including creatinine clearance.

Staging of malignant disease

Accurate staging of the extent of disease is of great importance in formulating a treatment plan. Clinical stage is that defined by clinical examination and imaging of the patient. It is often not accurate but with the use of high quality CT and PET scanning the accuracy is improved. Pathological staging is that defined after excisional surgery by the anatomical pathologist. It is accurate in defining the extent of disease associated with a primary tumor. The staging system is varied according to the primary site of the tumor.

Rectal cancers have a long-standing clinical and pathological staging system known as the Cuthbert-Dukes staging system. Dukes A is local disease in the rectum not invading muscularis propria; Dukes B, the tumour has extended through the wall of the bowel; and Dukes C, where there is lymph node involvement. Dukes D is when distant metastases are present. The Dukes system is commonly used alongside the TNM system.

Methods of clinical staging include radiological methods such as CT, MRI and ultrasound. Within the area of nuclear medicine are PET scanning and nuclear scanning generally (e.g. bone scanning). Laparoscopy is an added staging method which detects intra-abdominal tumors.

Decision about treatment at the multidisciplinary conference

Armed with information about the diagnosis of the cancer, the extent of the disease, that is the clinical stage of the disease and the fitness of the patient, decisions can be made about the most appropriate treatment program. Ideally consultation with a multidisciplinary team occurs at this stage, however if the decision regarding surgery is straightforward, the multidisciplinary conference usually occurs after the surgery when a pathological stage has been determined. However many cancers require down-staging with radiotherapy or chemotherapy prior to surgery, and multidisciplinary consultations early are important to facilitate this process.

The provision of written information to the patient and family, with careful and repeated discussions, is necessary to ensure that the patient can give informed consent to any treatment plan offered. Patients have the right to refuse all or some of the treatment plan and they are encouraged to be part of the decision making process.

At this stage discussions regarding involvement in research projects, use of resected tissues and involvement in clinical trials need to be commenced.

Principles of operative surgical oncology

The technical issues in surgical oncology are not different from other surgical intervention. Open surgery, laparoscopic surgery, robotic surgery, ablative interventions and other technical interventions all have a place in modern surgical oncology. However some important oncological principles exist which must be followed by the surgeon for a satisfactory outcome.

Definition of curative surgery

Despite modern staging methods, occult tumor spread is still discovered by the surgeon, for example small-volume peritoneal disease or unsuspected nodal disease. Frozen section examination of the disease is necessary to confirm the diagnosis. So-called curative surgery is only performed when a total excision of the tumor is possible. The primary tumor and the associated lymph node drainage fields are excised in continuity. A measure of the adequacy of the oncological surgical operation is demonstrated by the findings on pathological examination of the specimen. The operative specimens need to be correctly orientated by the surgeon to allow the pathologist to carefully examine and interpret the specimen given to him. The key issues are:

  • whether the margins of the specimen removed are clear of tumor
  • the total number of lymph nodes excised together with the number of involved lymph nodes.
  • Standards exist for the adequacy of the surgical excision to be assessed in many tumors.

Palliative surgery

Here the operation is performed to overcome some symptom-producing consequence of the tumor either by resection or bypass. This is to remove a potentially symptomatic lesion even though a cure is known to be impossible.
Examples include the following:

In case of pyloric obstruction from an advanced cancer of the stomach, a gastrojejunostomy will provide good palliation of vomiting.

Resection of a bleeding cancer of the colon is justified even in the presence of metastases.

Many other examples exist. ‘Tailoring’ this type of surgery to the needs of the patient without undue morbidity or loss of quality of life is an important role for an oncological surgeon.

Margins of surgical excision

The degree to which normal tissues should be removed with the primary tumor is a subject constantly being researched. A universal rule is not possible to formulate. In general a margin of 2-5 cm is suggested. Particular examples follow:

For excision of melanomas the depth of excision is more important than the extent of surrounding skin. A margin of 2 cm usually suffices in contrast to the 5 cm previously practiced.

However for esophageal resection the majority of the esophagus needs to be resected because the tumor does spread up and down in the submucosal plane.

Soft tissue sarcomas may spread along aponeurotic planes so that complete excision requires the resection of the entire muscle group and fascial compartment to encompass this type of spread.

The recognition that spread of rectal cancer occurs into perirectal tissues has led to the use of the total mesorectal excision of the rectum to improve the completeness of resection.

The principle of complete local excision with an adequate margin is paramount in surgical oncology and it needs to be achieved in different ways depending on the type of tumor being resected.

Lymph node resection

Traditionally the draining lymph nodes from a primary tumor are excised with the local lesion. The main benefit of this removal is increased staging information, which will affect the decisions regarding post-operative adjuvant therapy. In some situations there may be a survival benefit from removal of early-involved lymph nodes. However prophylactic excision of uninvolved nodes does not provide a survival advantage to the patient and exposes the patient to increased morbidity from the node removal. An example is the prophylactic removal of groin lymph nodes (radical groin dissection), when these glands are not involved. This operation is nowadays not performed when the glands are clinically not involved as randomized controlled trials have shown that survival rates have not improved but the morbidity from the operation is significant. Poor skin healing and swelling of the affected leg are two such complications.


It is necessary to undertake rehabilitation of the cancer patient who has undergone major a resection. This usually involves the allied health disciplines, part of the oncology team. The type and duration of the process will vary according to the type of tumor and surgery performed.

Follow-up of patient after initial treatment

A program of follow-up is required for cancer patients after their initial treatment. This is for two main reasons. This is to observe the patient and investigate when appropriate to detect recurrent disease, which can then be treated effectively. By definition this is only likely to be useful to the patient when strong effective postoperative therapies are available which will have a real impact on the control of cancer.


The principles of surgical oncology can be applied to many of the systemic practices of surgery. In simple terms the surgeon operating on cancer patients in the 21st century must have some understanding of the malignant process, be prepared to work as part of a team and offer multidisciplinary care, communicate well with a very concerned sometimes desperate group of patients, operate with a high level of skill and perform an adequate cancer operation, help the patient rehabilitate from the treatment and finally be prepared to be involved in the advancing area of surgical science as applied to cancer patients. As God knows, surgeons cannot cure all cancers on their own.

Principles of Surgical Oncology    (Apr 08, 2009) Lawrence D. Wagman, MD, FACS

Surgical oncology, as its name suggests, is the specific application of surgical principles to the oncologic setting. These principles adapt standard surgical approaches to the unique situations that arise when treating cancer patients.

The surgical oncologist must be knowledgeable about all of the available surgical and adjuvant therapies, both standard and experimental, for a particular cancer. This enables the surgeon not only to explain the various treatment options to the patient but also to facilitate and avoid interfering with future therapeutic options.

Invasive diagnostic modalities

As the surgeon approaches the patient with a solid malignancy or abnormal nodal disease or the rare individual with a tissue-based manifestation of a leukemia, selection of a diagnostic approach that will have a high likelihood of a specific, accurate diagnosis is paramount. The advent of high-quality invasive diagnostic approaches guided by radiologic imaging modalities has limited the open surgical approach to those situations where the disease is inaccessible, a significant amount of tissue is required for diagnosis, or a percutaneous approach is too dangerous (due, for example, to a bleeding diathesis, critical intervening structures, or the potential for unacceptable complications, such as pneumothorax).

Lymph node biopsy

The usual indication for biopsy of the lymph node is to establish the diagnosis of lymphoma or metastatic carcinoma. Each situation should be approached in a different manner.

Lymphoma The initial diagnosis of lymphoma should be made on a completely excised node that has been minimally manipulated to ensure that there is little crush damage. When primary lymphoma is suspected, the use of needle aspiration does not consistently allow for the complete analyses described above and can lead to incomplete or inaccurate diagnosis and treatment delays.

Carcinoma The diagnosis of metastatic carcinoma often requires less tissue than is needed for lymphoma. Fine-needle aspiration (FNA), core biopsy, or subtotal removal of a single node will be adequate in this situation. The use of immunocytochemical analyses can be successful in defining the primary site, even on small amounts of tissue.

Head and neck adenopathy The head and neck region is a common site of palpable adenopathy that poses a significant diagnostic dilemma. Nodal zones in this area serve as the harbinger of lymphoma (particularly Hodgkin lymphoma) and as sites of metastasis from the mucosal surfaces of the upper digestive tract; nasopharynx; thyroid; lungs; and, occasionally, intra-abdominal sites, such as the stomach, liver, and pancreas. The surgical oncologist must consider the most likely source of the disease prior to performing the biopsy. FNA or core biopsy becomes a valuable tool in this situation, as the tissue sample is usually adequate for basic analysis (cytologic or histologic), and special studies (eg, immunocytochemical analyses) can be performed as needed.

Biopsy of a tissue-based mass

Several principles must be considered when approaching the seemingly simple task of taking a tissue biopsy. As each of the biopsy methods has unique risks, yields, and costs, the initial choice can be a critical factor in the timeliness and expense of the diagnostic process.

Mass in the digestive tract In the digestive tract, biopsy of a lesion should include a representative amount of tissue taken preferably from the periphery of the lesion, where the maximum amount of viable malignant cells will be present. The biopsy must be of adequate depth to determine penetration of the tumors. This is particularly true for carcinomas of the oral cavity, pharynx, and larynx.

Breast mass Although previously a common procedure, an open surgical biopsy of the breast is rarely indicated today. Palpable breast masses that are highly suspicious (as indicated by physical findings and mammography) can be diagnosed as malignant with close to 100% accuracy with FNA. However, because the distinction between invasive and noninvasive diseases is often required prior to the initiation of treatment, a core biopsy, performed either under image guidance (ultrasonography or mammography) or directly for palpable lesions, is the method of choice.

An excellent example of the interdependence of the method of tissue diagnosis and therapeutic options is the patient with a moderate-sized breast tumor considering breast conservation who chooses preoperative chemotherapy for downsizing of the breast lesion. The core biopsy method establishes the histologic diagnosis, provides adequate tissue for analyses of hormone-receptor levels and other risk factors, causes little or no cosmetic damage, does not perturb sentinel node analyses, and does not require extended healing prior to the initiation of therapy. In addition, a small radio-opaque clip can be placed in the tumor to guide the surgical extirpation. This step is important because excellent treatment responses can make it difficult for the surgeon to localize the original tumor site.

Mass in the trunk or extremities For soft-tissue or bony masses of the trunk or extremities, the biopsy technique should be selected on the basis of the planned subsequent tumor resection. The incision should be made along anatomic lines in the trunk or along the long axis of the extremity. When a sarcoma is suspected, FNA can establish the diagnosis of malignancy, but a core biopsy will likely be required to determine the histologic type and plan neoadjuvant therapy.

Specific Surgical References

Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data
AJ Breugom, M Swets, Jean-François Bosset, L Collette, ..CJH van de Velde
Lancet (Oncology) 2015; 16: 200-207.

Background The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. Methods We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomized, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. Findings We analyzed data from four eligible trials, including data from 1196 patients with TNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumor located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0·97, 95% CI 0·81–1·17; p=0·775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0·91, 95% CI 0·77–1·07; p=0·230) or distant recurrences (0·94, 0·78–1·14; p=0·523) compared with observation. However, in subgroup analyses, patients with a tumor 10–15 cm from the anal verge had improved disease-free survival (0·59, 0·40–0·85; p=0·005, p interaction=0·107) and fewer distant recurrences (0·61, 0·40–0·94; p=0·025, p interaction=0·126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Interpretation Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumor 10–15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted.

Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial
IH Kunkler, LJ Williams, WJL Jack, DA Cameron, JM Dixon, et al.
Lancet Oncol 2015; 16: 266–73

Background For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years. Methods Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1–T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumor histology or lympho-vascular invasion, but not both, were permitted), who had had breast conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomized controlled trial at 76 centers in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40–50 Gy in 15–25 fractions) or no radiotherapy by computer-generated permuted block randomization, stratified by center, with a block size of four. The primary endpoint was ipsilateral breast tumor recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomized patient. Analyses were done by intention to treat. The trial is registered on, number ISRCTN95889329.n Findings 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84–6·05), ipsilateral breast tumor recurrence was 1·3% (95% CI 0·2–2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4–5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumor recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99–13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8–96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer. Interpretation Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomization. However, the 5-year rate of ipsilateral breast tumor recurrence is probably low enough for omission of radiotherapy to be considered for some patients.
Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: a retrospective, population-based study   CA Bertelsen, AU Neuenschwander, JE Jansen, M Wilhelmsen, et al.
Lancet Oncol 2015; 16: 161–68

Background Application of the principles of total mesorectal excision to colon cancer by undertaking complete mesocolic excision (CME) has been proposed to improve oncological outcomes. We aimed to investigate whether implementation of CME improved disease-free survival compared with conventional colon resection. Methods Data for all patients who underwent elective resection for Union for International Cancer Control (UICC) stage I–III colon adenocarcinomas in the Capital Region of Denmark between June 1, 2008, and Dec 31, 2011, were retrieved for this population-based study. The CME group consisted of patients who underwent CME surgery in a centre validated to perform such surgery; the control group consisted of patients undergoing conventional colon resection in three other hospitals. Data were collected from the Danish Colorectal Cancer Group (DCCG) database and medical charts. Patients were excluded if they had stage IV disease, metachronous colorectal cancer, rectal cancer (≤15 cm from anal verge) in the absence of synchronous colon adenocarcinoma, tumor of the appendix, or R2 resections. Survival data were collected on Nov 13, 2014, from the DCCG database, which is continuously updated by the National Central Office of Civil Registration. Findings The CME group consisted of 364 patients and the non-CME group consisted of 1031 patients. For all patients, 4-year disease-free survival was 85·8% (95% CI 81·4–90·1) after CME and 75·9% (72·2–79·7) after non-CME surgery (log-rank p=0·0010). 4-year disease-free survival for patients with UICC stage I disease in the CME group was 100% compared with 89·8% (83·1–96·6) in the non-CME group (log-rank p=0·046). For patients with UICC stage II disease, 4-year disease-free survival was 91·9% (95% CI 87·2–96·6) in the CME group compared with 77·9% (71·6–84·1) in the non-CME group (log-rank p=0·0033), and for patients with UICC stage III disease, it was 73·5% (63·6–83·5) in the CME group compared with 67·5% (61·8–73·2) in the non-CME group (log-rank p=0·13). Multivariable Cox regression showed that CME surgery was a significant, independent predictive factor for higher disease-free survival for all patients (hazard ratio 0·59, 95% CI 0·42–0·83), and also for patients with UICC stage II (0·44, 0·23–0·86) and stage III disease (0·64, 0·42–1·00). After propensity score matching, disease-free survival was signifi cantly higher after CME, irrespective of UICC stage, with 4-year disease-free survival of 85·8% (95% CI 81·4–90·1) after CME and 73·4% (66·2–80·6) after non-CME (log-rank p=0·0014). Interpretation Our data indicate that CME surgery is associated with better disease-free survival than is conventional colon cancer resection for patients with stage I–III colon adenocarcinoma. Implementation of CME surgery might improve outcomes for patients with colon cancer.

Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know
I Opitza, R Bueno, E Lim, H Pass, U Pastorino, M Boeri, G Rocco, et al.
European J Cardio-Thor Surg 46(2014):602–606

Today, molecular-profile-directed therapy is a guiding principle of modern thoracic oncology. The knowledge of new biomolecular technology applied to the diagnosis, prognosis, and treatment of lung cancer and mesothelioma should be part of the 21st century thoracic surgeons’ professional competence. The European Society of Thoracic Surgeons (ESTS) Biology Club aims at providing a comprehensive insight into the basic biology of the diseases we are treating. During the 2013 ESTS Annual Meeting, different experts of the field presented the current knowledge about diagnostic and prognostic biomarkers in malignant pleural mesothelioma including new perspectives as well as the role and potential application of microRNA and genomic sequencing for lung cancer, which are summarized in the present article.


Principles of Surgical Therapy in Oncology
Michael S. Sabel, Kathleen M. Diehl, and Alfred E. Chang
With the expansion of the multidisciplinary approach to cancer, the role of the surgeon has changed significantly. In addition to the well-established curative role, surgeons are often asked to obtain tissue for diagnosis and staging, debulk tumors as part of multimodality therapy, palliate incurable patients, or prevent cancer by the surgical removal of nonessential organs. As the management of cancer is altered by new discoveries in genetics, molecular biology, immunology, and improved therapeutics, so too will the functions of the surgical oncologist change. With our increased understanding of the genetic predisposition to cancer, the surgeon is increasingly being asked to remove healthy organs to prevent malignancy. However, as other effective methods of prevention are developed, such as chemoprevention or gene therapy, this role will certainly diminish. Improving imaging technologies may have diminished the need for surgical intervention for staging (such as in Hodgkin’s lymphoma), but the expanded use of neoadjuvant therapies often requires interventions to accurately assess response to therapy. In addition, harvesting tumors may become increasingly important for molecular staging as well as identifying molecular targets for specific therapies. It is therefore imperative for surgical oncologists to remain up-to-date on the newest approaches to cancer therapy, both multidisciplinary and experimental, and be prepared to adapt to the changing requirements for surgery.

The major objective for surgery of the primary cancer is to achieve optimal local control of the lesion. Local control is defined as the elimination of the neoplastic process and establishing a milieu in which local tumor recurrence is minimized. Historically, this was achieved with radical extirpative surgeries that shaped the surgical oncologists’ major objective, namely, avoiding a local recurrence. Before William Halsted’s description of the radical mastectomy, surgical

treatment of breast cancer resulted in a dismal local control rate of less than 30%. The reason why Halsted’s procedure was adopted as a standard approach was because he achieved greater than 90% local control, despite the fact that the overall survival of his patients was not improved.4 The latter was due to the locally advanced stage of the patients who were treated in those days. This consideration ushered in the concept of en bloc removal of adjacent tissue when removing a primary cancer. Halsted’s mastectomy involved the removal of adjacent skin (often necessitating a skin graft), underlying pectoral muscles, and axillary lymph nodes (Figure 4.1). One of the major principles of surgical therapy of the primary tumor is to obtain adequate negative margins around the primary tumor, which could mean different operative approaches depending on the tumor type and its local involvement with adjacent structures. For example, the removal of a primary colon cancer that involves an adjacent loop of small bowel or bladder requires the en bloc resection of the primary tumor along with removal of the involved segment of small bowel and bladder wall. This approach avoids violation of the primary tumor margins that could lead to tumor spillage and possible implantation of malignant cells in the surrounding normal tissues. Aside from biopsies of the primary tumor, the lesion should not be entered during a definitive resection. In fact, any biopsy tract or incision that was performed before the tumor resection should be included in the procedure to reduce the risk of local recurrence (Figure 4.2). The risk of local recurrence for all solid malignancies is clearly increased if negative margins are not achieved. The adequacy of the negative margin has been defined for most tumor types either from retrospective clinical experience or prospective clinical trials. For example, a 5-cm margin is an adequate bowel margin for primary colon cancers that has been established from clinical experience. Likewise, it is accepted that a 2-cm distal margin for rectal cancers results in adequate local control. Through several prospective, randomized clinical trials, the margins of excision for primary cutaneous melanomas differ according to the thickness of the primary (see Chapter 60). It was a commonly held notion that the development of a local recurrence would in itself result in metastatic disease with decreased overall survival. However, this has not been borne out in the context of prospective trials as described here. The emergence of multimodal therapy has dramatically affected the surgical approach to many primary cancers, especially when surgical resection of the tumor is combined with radiotherapy. Local control is significantly improved after surgical resection of breast, rectal, sarcoma, head and neck, and pancreatic primary cancers. In fact, the addition of radiation therapy as an adjunctive therapy has allowed for less-radical procedures to be performed with an improvement in the quality of life of patients. A prime example of this is in breast cancer. Several clinical trials have demonstrated that the overall survival of patients with invasive breast cancer was comparable if treated by mastectomy versus lumpectomy plus adjuvant radiotherapy.

The regional lymph nodes represent the most prevalent site of metastasis for solid tumors. Because of this, the involvement of the regional lymph nodes represents an important prognostic factor in the staging of the cancer patient. For this reason, the removal of the regional lymph nodes is often performed at the time of resection of the primary cancer. Besides staging information, a regional lymphadenectomy provides regional control of the cancer. Examples of this are patients with melanoma who have tumor metastatic to lymph nodes. It is well documented that the removal of these regional lymph nodes can result in long-term survival benefit in approximately 20% to 40% of individuals depending upon the extent of nodal involvement. Hence, the removal of regional lymph nodes can be therapeutic. The controversies regarding regional lymphadenectomy for solid malignancies have related to the timing of the procedure as well as the extent of the procedure. For some visceral solid tumors such as gastric and pancreatic cancers, the extent of lymphadenectomy at the time of primary tumor resection has been hypothesized to be important in optimizing local and regional control and has an impact on improving overall survival. This concept has not been borne out in prospective randomized trials of gastric cancer in which the extent of lymphadenectomy has been examined.

Based on these trials, the more-extended lymphadenectomy appears to result in more accurate staging of patients at a cost of increased morbidity. For nonvisceral solid tumors such as melanoma, breast cancers, and head and neck squamous cancers, the elective removal of regional lymph nodes at the time of primary tumor resection has been postulated to result in better survival outcomes compared to taking the wait-and-watch approach. The latter involves performing a lymphadenectomy only when the patient relapses in a nodal basin that would then necessitate a therapeutic lymph node dissection. In prospective randomized clinical studies evaluating elective versus therapeutic lymph node dissection in various tumor types, there was no survival advantage for performing elective lymph node dissections (Table 4.2). It is apparent from these controversies that the initial removal of regional lymph nodes is most important for its staging impact, rather than its therapeutic effect. The introduction of selective lymphadenectomy based upon the concept of the sentinel lymph node has dramatically improved our ability to stage the regional lymph nodes of certain cancers. This is reviewed in more detail in the Diagnosis and Staging section of this chapter.

One of the earliest examples of surgical prophylaxis is the recommendation for total proctocolectomy for subsets of patients with chronic ulcerative colitis. Patients with pancolitis, onset of disease at a young age, and a long duration of colitis are at high risk of developing colorectal cancer.36 Other clinical diseases of the large intestine also illustrate the role of proctocolectomy in cancer prevention. Familial adenomatous polyposis coli (FAP) syndrome, defined by the diffuse involvement of the colon and rectum with adenomatous polyps often in the second or third decade of life, almost always predisposes to colorectal cancer if the large intestine is left in place. However, the role of screening and prophylactic proctocolectomy changed dramatically with the identification of the gene responsible for FAP, the adenomatous polyposis coli (APC) gene, located on the long arm of chromosome 5 (5q21).37 Now, children of families in which an APC mutation has been identified can have genetic testing before polyps become evident. Carriers can have screening and surgical resection once polyps appear, usually in the late teens or early twenties. Although not ideal, the palatability of proctocolectomy in this population was furthered with the description of the total abdominal colectomy, mucosal proctectomy, and ileoanal pouch anastomosis.38

Another example of prophylactic surgery is the bilateral mastectomy for women at high risk of developing breast cancer. Before the identification of the BRCA genes, prophylactic mastectomies were typically reserved as an option for women with lobular carcinoma in situ (LCIS). However, with the identification of BRCA1 and BRCA2, the role of prophylactic mastectomies has been greatly expanded. For women with BRCA1 or BRCA2 mutations, the lifetime probability of breast cancer is between 40% and 85%.41–43 Because mastectomy cannot remove all breast tissue, women can expect a 90% to 94% risk reduction with prophylactic surgery.44 Schrag et al. calculated the estimated gain in life expectancy after prophylactic surgery versus no operation in women with either a BRCA1 or BRCA2 mutation and found a 30-year-old woman would be expected to gain 2.9 to 5.3 years of life, depending on her family history.45 However, potential benefits of prophylactic mastectomy must be weighed against quality of life issues and the morbidity of the surgery.46 In addition, other methods for prophylaxis, such as tamoxifen chemoprevention or bilateral oophorectomy, must be considered. Along with the increased risk of breast cancer with BRCA1/2 mutations, the risk of ovarian cancer is also increased. Bilateral oophorectomy after childbearing is complete not only reduces the risk of ovarian cancer47 but may also decrease the risk of breast cancer.48 A detailed discussion must be held with each patient considering bilateral mastectomies regarding the risks and benefits, the knowns and unknowns. It is becoming increasingly important that today’s surgical oncologist have a clear understanding of genetics and inherited risk.

Increased genetic knowledge has also changed our approach to thyroid cancer. Medullary thyroid cancer (MTC) is a wellestablished component of multiple endocrine neoplasia syndrome type 2a (MEN 2a) or type 2b (MEN 2b). Previously, family members at risk for MEN 2 underwent annual screening for elevated calcitonin levels; however, this only detected MTC after it developed. In 1993 it was identified that mutations in the RET proto-oncogene were present in almost all cases of MEN 2a and 2b. Now family members of MEN patients can be screened for the presence of a RET mutation. Those without the mutation need not undergo additional screening, whereas those with the mutation should undergo total thyroidectomy at a young age (6 years for MEN 2a, infancy for MEN 2b).49

The readers are reminded that older or elderly patients will increasingly make up the population of patients with cancer. Currently 60% of all malignancies, and 70% of all cancer deaths, occur in people over the age of 65.58 In addition to the previously mentioned considerations, assessment of the older patient should include evaluation of activities of daily living, depression, cognitive function, current medications and potential medication interactions, and available social support.59–62

  1. Lewison EF. Breast Cancer and Its Diagnosis and Treatment. Baltimore: Williams & Wilkins, 1955.
  2. Rutledge RH. Theodore Billroth: a century later. Surgery (St. Louis) 1995;118:36–43.
  3. Weir R. Resection of the large intestine for carcinoma. Ann Surg 1886;1886(3):469–489.
  4. Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Ann Surg 1894;320(13):497–555.
  5. Clark JG. A more radical method for performing hysterectomy for cancer of the cervix. Johns Hopkins Bull 1895;6:121.
  6. Crile G. Excision of cancer of the head and neck. JAMA 1906; XLVII:1780.
  7. Miles WE. A method for performing abdominoperineal excision for carcinoma of the rectum and terminal portion of the pelvic colon. Lancet 1908;2:1812–1813.
  8. Krakoff IH. Progress and prospects in cancer treatment: the Karnofsky legacy. J Clin Oncol 1994;12:432–438.
  9. Farber S, Diamond LK, Mercer RD, et al. Temporary regressions in acute leukemia in children produced by folic acid antagonist, aminopteroyl-glutamic acid. N Engl J Med 1948;238: 693.
  10. Huggins CB, Hodges CV. Studies on prostatic cancer: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293–297.
  11. Lawrence W Jr, Wilson RE, Shingleton WW, et al. Surgical oncology in university departments of surgery in the United States. Arch Surg 1986;121:1088–1093.
  12. Fisher B, Remond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822–828.

Quality of surgery: has the time come for colon cancer?
Lancet (Oncology)   Feb 2015; 16

Major improvements in outcomes for rectal cancer have occurred in the 30 years since the introduction of total mesorectal excision and multidisciplinary treatment.1 This situation should continue to improve with more radical surgery for low rectal cancer. Pioneering work by leaders of rectal cancer surgery was initially ignored and it took the independent reproduction of the improved outcomes in single hospital and small regional studies before large-scale regional and national training programs led to major reductions in local recurrence, significant improvements in survival, and major financial savings occurred around the world. Colon cancer accounts for around 70% of bowel cancer and although survival has improved, it has not been to the same extent as that for rectal cancer, with substantial variation remaining between hospitals for operative cases. Historical reports have shown significantly improved survival in colon cancer following surgical standardization,2–4 and excellent results from Japan have largely been ignored.5 The rectal cancer story is repeating itself. Colonic cancer resection in western countries is unfortunately still viewed as a routine procedure with little concern surrounding these major variations in outcome. Indeed the focus has been on laparoscopic surgery rather than optimisation of the surgery. In The Lancet Oncology, a paper by Claus Anders Bertelsen and colleagues,6 and the debate it should generate, is a key step to reproduce the benefits of optimum rectal cancer surgery in colonic cancer, and hints at what could be achievable by the routine adoption of high-quality surgery. In this detailed report, the researchers show that implementation of complete mesocolic excision (CME) with central vascular ligation (CVL) results in a major improvement in survival. By simply visiting and adopting the methods of expert surgeons in Erlangen, led by Werner Hohenberger,4 and by quality controlling their surgery through mesocolic grading, routine specimen photography, and internal and external pathology audit,7 the researchers have independently reproduced results from Erlangen and Japan. The improvement in outcome described could be attributable to two specific variables; first, CME, which comprises the intact removal of the mesocolon and its lymphatic drainage within embryological planes. This procedure should be routine; it does not increase risks to the patient and might seem obvious since careful dissection following anatomical planes is a basic principle of surgery and such planes were described in the early 20th century, but on close scrutiny surgical planes are very variable and must be improved.8,9 Second, but more controversially, is the role of CVL. This procedure entails more radical central dissection, with potential risk to major vessels, nerves, and organs such as the pancreas. In Erlangen, Japan, and now in Hillerød, such surgery seems to be safe, but several important questions remain. How much benefit does it convey in addition to mesocolic surgery? What is the learning curve and is this achievable for all surgeons? Can it be safely achieved laparoscopically? Is the same benefi t derived for all stages of disease?

Radiation therapy in the locoregional treatment of triple-negative breast cancer
Meena S Moran
Lancet Oncol 2015; 16: e113–22

This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks (relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for postmastectomy radiation, and accelerated delivery methods for TNBC should be off ered on clinical trials. Preliminary data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard locoregional management principles should be adhered to.


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The importance of spatially-localized and quantified image interpretation in cancer management

Writer & reporter: Dror Nir, PhD

I became involved in the development of quantified imaging-based tissue characterization more than a decade ago. From the start, it was clear to me that what clinicians needs will not be answered by just identifying whether a certain organ harbors cancer. If imaging devices are to play a significant role in future medicine, as a complementary source of information to bio-markers and gene sequencing the minimum value expected of them is accurate directing of biopsy needles and treatment tools to the malignant locations in the organ.  Therefore, the design goal of the first Prostate-HistoScanning (“PHS”) version I went into the trouble of characterizing localized volume of tissue at the level of approximately 0.1cc (1x1x1 mm). Thanks to that, the imaging-interpretation overlay of PHS localizes the suspicious lesions with accuracy of 5mm within the prostate gland; Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(™).

I then started a more ambitious research aiming to explore the feasibility of identifying sub-structures within the cancer lesion itself. The preliminary results of this exploration were so promising that it surprised not only the clinicians I was working with but also myself. It seems, that using quality ultrasound, one can find Imaging-Biomarkers that allows differentiation of inside structures of a cancerous lesions. Unfortunately, for everyone involved in this work, including me, this scientific effort was interrupted by financial constrains before reaching maturity.

My short introduction was made to explain why I find the publication below important enough to post and bring to your attention.

I hope for your agreement on the matter.

Quantitative Imaging in Cancer Evolution and Ecology

Robert A. Gatenby, MD, Olya Grove, PhD and Robert J. Gillies, PhD

From the Departments of Radiology and Cancer Imaging and Metabolism, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612. Address correspondence to  R.A.G. (e-mail:


Cancer therapy, even when highly targeted, typically fails because of the remarkable capacity of malignant cells to evolve effective adaptations. These evolutionary dynamics are both a cause and a consequence of cancer system heterogeneity at many scales, ranging from genetic properties of individual cells to large-scale imaging features. Tumors of the same organ and cell type can have remarkably diverse appearances in different patients. Furthermore, even within a single tumor, marked variations in imaging features, such as necrosis or contrast enhancement, are common. Similar spatial variations recently have been reported in genetic profiles. Radiologic heterogeneity within tumors is usually governed by variations in blood flow, whereas genetic heterogeneity is typically ascribed to random mutations. However, evolution within tumors, as in all living systems, is subject to Darwinian principles; thus, it is governed by predictable and reproducible interactions between environmental selection forces and cell phenotype (not genotype). This link between regional variations in environmental properties and cellular adaptive strategies may permit clinical imaging to be used to assess and monitor intratumoral evolution in individual patients. This approach is enabled by new methods that extract, report, and analyze quantitative, reproducible, and mineable clinical imaging data. However, most current quantitative metrics lack spatialness, expressing quantitative radiologic features as a single value for a region of interest encompassing the whole tumor. In contrast, spatially explicit image analysis recognizes that tumors are heterogeneous but not well mixed and defines regionally distinct habitats, some of which appear to harbor tumor populations that are more aggressive and less treatable than others. By identifying regional variations in key environmental selection forces and evidence of cellular adaptation, clinical imaging can enable us to define intratumoral Darwinian dynamics before and during therapy. Advances in image analysis will place clinical imaging in an increasingly central role in the development of evolution-based patient-specific cancer therapy.

© RSNA, 2013



Cancers are heterogeneous across a wide range of temporal and spatial scales. Morphologic heterogeneity between and within cancers is readily apparent in clinical imaging, and subjective descriptors of these differences, such as necrotic, spiculated, and enhancing, are common in the radiology lexicon. In the past several years, radiology research has increasingly focused on quantifying these imaging variations in an effort to understand their clinical and biologic implications (1,2). In parallel, technical advances now permit extensive molecular characterization of tumor cells in individual patients. This has led to increasing emphasis on personalized cancer therapy, in which treatment is based on the presence of specific molecular targets (3). However, recent studies (4,5) have shown that multiple genetic subpopulations coexist within cancers, reflecting extensive intratumoral somatic evolution. This heterogeneity is a clear barrier to therapy based on molecular targets, since the identified targets do not always represent the entire population of tumor cells in a patient (6,7). It is ironic that cancer, a disease extensively and primarily analyzed genetically, is also the most genetically flexible of all diseases and, therefore, least amenable to such an approach.

Genetic variations in tumors are typically ascribed to a mutator phenotype that generates new clones, some of which expand into large populations (8). However, although identification of genotypes is of substantial interest, it is insufficient for complete characterization of tumor dynamics because evolution is governed by the interactions of environmental selection forces with the phenotypic, not genotypic, properties of populations as shown, for example, by evolutionary convergence to identical phenotypes among cave fish even when they are from different species (911). This connection between tissue selection forces and cellular properties has the potential to provide a strong bridge between medical imaging and the cellular and molecular properties of cancers.

We postulate that differences within tumors at different spatial scales (ie, at the radiologic, cellular, and molecular [genetic] levels) are related. Tumor characteristics observable at clinical imaging reflect molecular-, cellular-, and tissue-level dynamics; thus, they may be useful in understanding the underlying evolving biology in individual patients. A challenge is that such mapping across spatial and temporal scales requires not only objective reproducible metrics for imaging features but also a theoretical construct that bridges those scales (Fig 1).


Figure 1a: Computed tomographic (CT) scan of right upper lobe lung cancer in a 50-year-old woman.


Figure 1b: Isoattenuation map shows regional heterogeneity at the tissue scale (measured in centimeters).


Figure 1c & 1d: (c, d)Whole-slide digital images (original magnification, ×3) of a histologic slice of the same tumor at the mesoscopic scale (measured in millimeters) (c) coupled with a masked image of regional morphologic differences showing spatial heterogeneity (d). 


Figure 1e: Subsegment of the whole slide image shows the microscopic scale (measured in micrometers) (original magnification, ×50).


Figure 1f: Pattern recognition masked image shows regional heterogeneity. In a, the CT image of non–small cell lung cancer can be analyzed to display gradients of attenuation, which reveals heterogeneous and spatially distinct environments (b). Histologic images in the same patient (c, e) reveal heterogeneities in tissue structure and density on the same scale as seen in the CT images. These images can be analyzed at much higher definition to identify differences in morphologies of individual cells (3), and these analyses reveal clusters of cells with similar morphologic features (d, f). An important goal of radiomics is to bridge radiologic data with cellular and molecular characteristics observed microscopically.

To promote the development and implementation of quantitative imaging methods, protocols, and software tools, the National Cancer Institute has established the Quantitative Imaging Network. One goal of this program is to identify reproducible quantifiable imaging features of tumors that will permit data mining and explicit examination of links between the imaging findings and the underlying molecular and cellular characteristics of the tumors. In the quest for more personalized cancer treatments, these quantitative radiologic features potentially represent nondestructive temporally and spatially variable predictive and prognostic biomarkers that readily can be obtained in each patient before, during, and after therapy.

Quantitative imaging requires computational technologies that can be used to reliably extract mineable data from radiographic images. This feature information can then be correlated with molecular and cellular properties by using bioinformatics methods. Most existing methods are agnostic and focus on statistical descriptions of existing data, without presupposing the existence of specific relationships. Although this is a valid approach, a more profound understanding of quantitative imaging information may be obtained with a theoretical hypothesis-driven framework. Such models use links between observable tumor characteristics and microenvironmental selection factors to make testable predictions about emergent phenotypes. One such theoretical framework is the developing paradigm of cancer as an ecologic and evolutionary process.

For decades, landscape ecologists have studied the effects of heterogeneity in physical features on interactions between populations of organisms and their environments, often by using observation and quantification of images at various scales (1214). We propose that analytic models of this type can easily be applied to radiologic studies of cancer to uncover underlying molecular, cellular, and microenvironmental drivers of tumor behavior and specifically, tumor adaptations and responses to therapy (15).

In this article, we review recent developments in quantitative imaging metrics and discuss how they correlate with underlying genetic data and clinical outcomes. We then introduce the concept of using ecology and evolutionary models for spatially explicit image analysis as an exciting potential avenue of investigation.


Quantitative Imaging and Radiomics

In patients with cancer, quantitative measurements are commonly limited to measurement of tumor size with one-dimensional (Response Evaluation Criteria in Solid Tumors [or RECIST]) or two-dimensional (World Health Organization) long-axis measurements (16). These measures do not reflect the complexity of tumor morphology or behavior, and in many cases, changes in these measures are not predictive of therapeutic benefit (17). In contrast, radiomics (18) is a high-throughput process in which a large number of shape, edge, and texture imaging features are extracted, quantified, and stored in databases in an objective, reproducible, and mineable form (Figs 12). Once transformed into a quantitative form, radiologic tumor properties can be linked to underlying genetic alterations (the field is called radiogenomics) (1921) and to medical outcomes (2227). Researchers are currently working to develop both a standardized lexicon to describe tumor features (28,29) and a standard method to convert these descriptors into quantitative mineable data (30,31) (Fig 3).


Figure 2: Contrast-enhanced CT scans show non–small cell lung cancer (left) and corresponding cluster map (right). Subregions within the tumor are identified by clustering pixels based on the attenuation of pixels and their cumulative standard deviation across the region. While the entire region of interest of the tumor, lacking the spatial information, yields a weighted mean attenuation of 859.5 HU with a large and skewed standard deviation of 243.64 HU, the identified subregions have vastly different statistics. Mean attenuation was 438.9 HU ± 45 in the blue subregion, 210.91 HU ± 79 in the yellow subregion, and 1077.6 HU ± 18 in the red subregion.



Figure 3: Chart shows the five processes in radiomics.

Several recent articles underscore the potential power of feature analysis. After manually extracting more than 100 CT image features, Segal and colleagues found that a subset of 14 features predicted 80% of the gene expression pattern in patients with hepatocellular carcinoma (21). A similar extraction of features from contrast agent–enhanced magnetic resonance (MR) images of glioblastoma was used to predict immunohistochemically identified protein expression patterns (22). Other radiomic features, such as texture, can be used to predict response to therapy in patients with renal cancer (32) and prognosis in those with metastatic colon cancer (33).

These pioneering studies were relatively small because the image analysis was performed manually, and the studies were consequently underpowered. Thus, recent work in radiomics has focused on technical developments that permit automated extraction of image features with the potential for high throughput. Such methods, which rely heavily on novel machine learning algorithms, can more completely cover the range of quantitative features that can describe tumor heterogeneity, such as texture, shape, or margin gradients or, importantly, different environments, or niches, within the tumors.

Generally speaking, texture in a biomedical image is quantified by identifying repeating patterns. Texture analyses fall into two broad categories based on the concepts of first- and second-order spatial statistics. First-order statistics are computed by using individual pixel values, and no relationships between neighboring pixels are assumed or evaluated. Texture analysis methods based on first-order statistics usually involve calculating cumulative statistics of pixel values and their histograms across the region of interest. Second-order statistics, on the other hand, are used to evaluate the likelihood of observing spatially correlated pixels (34). Hence, second-order texture analyses focus on the detection and quantification of nonrandom distributions of pixels throughout the region of interest.

The technical developments that permit second-order texture analysis in tumors by using regional enhancement patterns on dynamic contrast-enhanced MR images were reviewed recently (35). One such technique that is used to measure heterogeneity of contrast enhancement uses the Factor Analysis of Medical Image Sequences (or FAMIS) algorithm, which divides tumors into regions based on their patterns of enhancement (36). Factor Analysis of Medical Image Sequences–based analyses yielded better prognostic information when compared with region of interest–based methods in numerous cancer types (1921,3739), and they were a precursor to the Food and Drug Administration–approved three-time-point method (40). A number of additional promising methods have been developed. Rose and colleagues showed that a structured fractal-based approach to texture analysis improved differentiation between low- and high-grade brain cancers by orders of magnitude (41). Ahmed and colleagues used gray level co-occurrence matrix analyses of dynamic contrast-enhanced images to distinguish benign from malignant breast masses with high diagnostic accuracy (area under the receiver operating characteristic curve, 0.92) (26). Others have shown that Minkowski functional structured methods that convolve images with differently kernelled masks can be used to distinguish subtle differences in contrast enhancement patterns and can enable significant differentiation between treatment groups (42).

It is not surprising that analyses of heterogeneity in enhancement patterns can improve diagnosis and prognosis, as this heterogeneity is fundamentally based on perfusion deficits, which generate significant microenvironmental selection pressures. However, texture analysis is not limited to enhancement patterns. For example, measures of heterogeneity in diffusion-weighted MR images can reveal differences in cellular density in tumors, which can be matched to histologic findings (43). Measures of heterogeneity in T1- and T2-weighted images can be used to distinguish benign from malignant soft-tissue masses (23). CT-based texture features have been shown to be highly significant independent predictors of survival in patients with non–small cell lung cancer (24).

Texture analyses can also be applied to positron emission tomographic (PET) data, where they can provide information about metabolic heterogeneity (25,26). In a recent study, Nair and colleagues identified 14 quantitative PET imaging features that correlated with gene expression (19). This led to an association of metagene clusters to imaging features and yielded prognostic models with hazard ratios near 6. In a study of esophageal cancer, in which 38 quantitative features describing fluorodeoxyglucose uptake were extracted, measures of metabolic heterogeneity at baseline enabled prediction of response with significantly higher sensitivity than any whole region of interest standardized uptake value measurement (22). It is also notable that these extensive texture-based features are generally more reproducible than simple measures of the standardized uptake value (27), which can be highly variable in a clinical setting (44).


Spatially Explicit Analysis of Tumor Heterogeneity

Although radiomic analyses have shown high prognostic power, they are not inherently spatially explicit. Quantitative border, shape, and texture features are typically generated over a region of interest that comprises the entire tumor (45). This approach implicitly assumes that tumors are heterogeneous but well mixed. However, spatially explicit subregions of cancers are readily apparent on contrast-enhanced MR or CT images, as perfusion can vary markedly within the tumor, even over short distances, with changes in tumor cell density and necrosis.

An example is shown in Figure 2, which shows a contrast-enhanced CT scan of non–small cell lung cancer. Note that there are many subregions within this tumor that can be identified with attenuation gradient (attenuation per centimeter) edge detection algorithms. Each subregion has a characteristic quantitative attenuation, with a narrow standard deviation, whereas the mean attenuation over the entire region of interest is a weighted average of the values across all subregions, with a correspondingly large and skewed distribution. We contend that these subregions represent distinct habitats within the tumor, each with a distinct set of environmental selection forces.

These observations, along with the recent identification of regional variations in the genetic properties of tumor cells, indicate the need to abandon the conceptual model of cancers as bounded organlike structures. Rather than a single self-organized system, cancers represent a patchwork of habitats, each with a unique set of environmental selection forces and cellular evolution strategies. For example, regions of the tumor that are poorly perfused can be populated by only those cells that are well adapted to low-oxygen, low-glucose, and high-acid environmental conditions. Such adaptive responses to regional heterogeneity result in microenvironmental selection and hence, emergence of genetic variations within tumors. The concept of adaptive response is an important departure from the traditional view that genetic heterogeneity is the product of increased random mutations, which implies that molecular heterogeneity is fundamentally unpredictable and, therefore, chaotic. The Darwinian model proposes that genetic heterogeneity is the result of a predictable and reproducible selection of successful adaptive strategies to local microenvironmental conditions.

Current cross-sectional imaging modalities can be used to identify regional variations in selection forces by using contrast-enhanced, cell density–based, or metabolic features. Clinical imaging can also be used to identify evidence of cellular adaptation. For example, if a region of low perfusion on a contrast-enhanced study is necrotic, then an adaptive population is absent or minimal. However, if the poorly perfused area is cellular, then there is presumptive evidence of an adapted proliferating population. While the specific genetic properties of this population cannot be determined, the phenotype of the adaptive strategy is predictable since the environmental conditions are more or less known. Thus, standard medical images can be used to infer specific emergent phenotypes and, with ongoing research, these phenotypes can be associated with underlying genetic changes.

This area of investigation will likely be challenging. As noted earlier, the most obvious spatially heterogeneous imaging feature in tumors is perfusion heterogeneity on contrast-enhanced CT or MR images. It generally has been assumed that the links between contrast enhancement, blood flow, perfusion, and tumor cell characteristics are straightforward. That is, tumor regions with decreased blood flow will exhibit low perfusion, low cell density, and high necrosis. In reality, however, the dynamics are actually much more complex. As shown in Figure 4, when using multiple superimposed sequences from MR imaging of malignant gliomas, regions of tumor that are poorly perfused on contrast-enhanced T1-weighted images may exhibit areas of low or high water content on T2-weighted images and low or high diffusion on diffusion-weighted images. Thus, high or low cell densities can coexist in poorly perfused volumes, creating perfusion-diffusion mismatches. Regions with poor perfusion with high cell density are of particular clinical interest because they represent a cell population that is apparently adapted to microenvironmental conditions associated with poor perfusion. The associated hypoxia, acidosis, and nutrient deprivation select for cells that are resistant to apoptosis and thus are likely to be resistant to therapy (46,47).


Figure 4: Left: Contrast-enhanced T1 image from subject TCGA-02-0034 in The Cancer Genome Atlas–Glioblastoma Multiforme repository of MR volumes of glioblastoma multiforme cases. Right: Spatial distribution of MR imaging–defined habitats within the tumor. The blue region (low T1 postgadolinium, low fluid-attenuated inversion recovery) is particularly notable because it presumably represents a habitat with low blood flow but high cell density, indicating a population presumably adapted to hypoxic acidic conditions.

Furthermore, other selection forces not related to perfusion are likely to be present within tumors. For example, evolutionary models suggest that cancer cells, even in stable microenvironments, tend to speciate into “engineers” that maximize tumor cell growth by promoting angiogenesis and “pioneers” that proliferate by invading normal issue and co-opting the blood supply. These invasive tumor phenotypes can exist only at the tumor edge, where movement into a normal tissue microenvironment can be rewarded by increased proliferation. This evolutionary dynamic may contribute to distinct differences between the tumor edges and the tumor cores, which frequently can be seen at analysis of cross-sectional images (Fig 5).


Figure 5a: CT images obtained with conventional entropy filtering in two patients with non–small cell lung cancer with no apparent textural differences show similar entropy values across all sections. 


Figure 5b: Contour plots obtained after the CT scans were convolved with the entropy filter. Further subdividing each section in the tumor stack into tumor edge and core regions (dotted black contour) reveals varying textural behavior across sections. Two distinct patterns have emerged, and preliminary analysis shows that the change of mean entropy value between core and edge regions correlates negatively with survival.

Interpretation of the subsegmentation of tumors will require computational models to understand and predict the complex nonlinear dynamics that lead to heterogeneous combinations of radiographic features. We have exploited ecologic methods and models to investigate regional variations in cancer environmental and cellular properties that lead to specific imaging characteristics. Conceptually, this approach assumes that regional variations in tumors can be viewed as a coalition of distinct ecologic communities or habitats of cells in which the environment is governed, at least to first order, by variations in vascular density and blood flow. The environmental conditions that result from alterations in blood flow, such as hypoxia, acidosis, immune response, growth factors, and glucose, represent evolutionary selection forces that give rise to local-regional phenotypic adaptations. Phenotypic alterations can result from epigenetic, genetic, or chromosomal rearrangements, and these in turn will affect prognosis and response to therapy. Changes in habitats or the relative abundance of specific ecologic communities over time and in response to therapy may be a valuable metric with which to measure treatment efficacy and emergence of resistant populations.


Emerging Strategies for Tumor Habitat Characterization

A method for converting images to spatially explicit tumor habitats is shown in Figure 4. Here, three-dimensional MR imaging data sets from a glioblastoma are segmented. Each voxel in the tumor is defined by a scale that includes its image intensity in different sequences. In this case, the imaging sets are from (a) a contrast-enhanced T1 sequence, (b) a fast spin-echo T2 sequence, and (c) a fluid-attenuated inversion-recovery (or FLAIR) sequence. Voxels in each sequence can be defined as high or low based on their value compared with the mean signal value. By using just two sequences, a contrast-enhanced T1 sequence and a fluid-attenuated inversion-recovery sequence, we can define four habitats: high or low postgadolinium T1 divided into high or low fluid-attenuated inversion recovery. When these voxel habitats are projected into the tumor volume, we find they cluster into spatially distinct regions. These habitats can be evaluated both in terms of their relative contributions to the total tumor volume and in terms of their interactions with each other, based on the imaging characteristics at the interfaces between regions. Similar spatially explicit analysis can be performed with CT scans (Fig 5).

Analysis of spatial patterns in cross-sectional images will ultimately require methods that bridge spatial scales from microns to millimeters. One possible method is a general class of numeric tools that is already widely used in terrestrial and marine ecology research to link species occurrence or abundance with environmental parameters. Species distribution models (4851) are used to gain ecologic and evolutionary insights and to predict distributions of species or morphs across landscapes, sometimes extrapolating in space and time. They can easily be used to link the environmental selection forces in MR imaging-defined habitats to the evolutionary dynamics of cancer cells.


Imaging can have an enormous role in the development and implementation of patient-specific therapies in cancer. The achievement of this goal will require new methods that expand and ultimately replace the current subjective qualitative assessments of tumor characteristics. The need for quantitative imaging has been clearly recognized by the National Cancer Institute and has resulted in formation of the Quantitative Imaging Network. A critical objective of this imaging consortium is to use objective, reproducible, and quantitative feature metrics extracted from clinical images to develop patient-specific imaging-based prognostic models and personalized cancer therapies.

It is increasingly clear that tumors are not homogeneous organlike systems. Rather, they contain regional coalitions of ecologic communities that consist of evolving cancer, stroma, and immune cell populations. The clinical consequence of such niche variations is that spatial and temporal variations of tumor phenotypes will inevitably evolve and present substantial challenges to targeted therapies. Hence, future research in cancer imaging will likely focus on spatially explicit analysis of tumor regions.

Clinical imaging can readily characterize regional variations in blood flow, cell density, and necrosis. When viewed in a Darwinian evolutionary context, these features reflect regional variations in environmental selection forces and can, at least in principle, be used to predict the likely adaptive strategies of the local cancer population. Hence, analyses of radiologic data can be used to inform evolutionary models and then can be mapped to regional population dynamics. Ecologic and evolutionary principles may provide a theoretical framework to link imaging to the cellular and molecular features of cancer cells and ultimately lead to a more comprehensive understanding of specific cancer biology in individual patients.



  • • Marked heterogeneity in genetic properties of different cells in the same tumor is typical and reflects ongoing intratumoral evolution.
  • • Evolution within tumors is governed by Darwinian dynamics, with identifiable environmental selection forces that interact with phenotypic (not genotypic) properties of tumor cells in a predictable and reproducible manner; clinical imaging is uniquely suited to measure temporal and spatial heterogeneity within tumors that is both a cause and a consequence of this evolution.
  • • Subjective radiologic descriptors of cancers are inadequate to capture this heterogeneity and must be replaced by quantitative metrics that enable statistical comparisons between features describing intratumoral heterogeneity and clinical outcomes and molecular properties.
  • • Spatially explicit mapping of tumor regions, for example by superimposing multiple imaging sequences, may permit patient-specific characterization of intratumoral evolution and ecology, leading to patient- and tumor-specific therapies.
  • • We summarize current information on quantitative analysis of radiologic images and propose future quantitative imaging must become spatially explicit to identify intratumoral habitats before and during therapy.

Disclosures of Conflicts of Interest: R.A.G. No relevant conflicts of interest to disclose. O.G. No relevant conflicts of interest to disclose.R.J.G. No relevant conflicts of interest to disclose.



The authors thank Mark Lloyd, MS; Joel Brown, PhD; Dmitry Goldgoff, PhD; and Larry Hall, PhD, for their input to image analysis and for their lively and informative discussions.


  • Received December 18, 2012; revision requested February 5, 2013; revision received March 11; accepted April 9; final version accepted April 29.
  • Funding: This research was supported by the National Institutes of Health (grants U54CA143970-01, U01CA143062; R01CA077575, andR01CA170595).


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