Isaac D. Gukas

The effects of surgery on tumor growth: a century of investigations

A few clinical investigations suggest that while primary breast cancer surgical removal favorably modifies the natural history for some patients, it may also hasten the metastatic development for others. The concepts underlying this disease paradigm, i.e. tumor homeostasis, tumor dormancy and surgery-driven enhancement of metastasis development, have a long history that is reviewed. The review reveals the context in which these concepts were conceived and structured to explain experimental data and shows that they are not so new and far fetched. The idea that surgical cancer resection has both beneficial and adverse effects upon cancer spread and growth that result from the modulation of tumor dormancy by the resection should be considered a potentially fruitful working hypothesis.

Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer

To explain bimodal relapse patterns observed in breast cancer data, we have proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. The half‐lives of these states are 1 and 2 years respectively. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from early detection, through treatment and follow‐up, and consider how dormancy and surgery‐driven escape from dormancy would be observed. We examine mammography data, effectiveness of adjuvant chemotherapy, heterogeneity and aggressiveness, timing of surgery within the menstrual cycle and racial differences in outcome. Dormancy can be identified in these diverse data but most conspicuous is the sudden escape from dormancy following primary surgery. These quantitative findings provide linkage between experimental studies of tumor dormancy and clinical efforts to improve patient outcome.

Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth?

We review our work over the past 14 years that began when we were first confronted with bimodal relapse patterns in two breast cancer databases from different countries. These data were unexplainable with the accepted continuous tumor growth paradigm. To explain these data, we proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are apparently very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from a variety of historical, clinical, and scientific perspectives and consider how dormancy and surgery-driven escape from dormancy would be observed and what this would mean. Dormancy can be identified in these diverse data but most conspicuous is the sudden synchronized escape from dormancy following primary surgery. On the basis of our findings, we suggest a new paradigm for early stage breast cancer. We also suggest a new treatment that is meant to stabilize and preserve dormancy rather than attempt to kill all cancer cells as is the present strategy.

Reduction of breast cancer relapses with perioperative non-steroidal anti-inflammatory drugs: new findings and a review

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent.

Racial disparities in breast cancer outcome: insights into host-tumor interactions

Since the 1970s, overall age‐adjusted breast cancer mortality rates in the U.S. have been higher among African American (AA) women than among Caucasian American (CA) women. The racial disparity is not fully explainable based on socioeconomic factors. Suspected biologic factors underlying this trend may be interpreted by both epidemiologic and clinical perspectives. Descriptive epidemiologic studies suggest that breast cancer may be a mixture of at least 2 main diseases and/or causal pathways. The first breast cancer is early‐onset, with peak incidence near age 50 years and generally more aggressive outcome. The second breast cancer is late‐onset, with peak incidence near age 70 years and more indolent course. The early‐onset type of breast cancer is overrepresented among AA women compared with CA women. Clinical studies suggest that the course of breast cancer may be characterized by a common pathway through sequential dormant and active states eventually resulting in clustered appearance of clinical metastases. A balance between tumor and host traits influences the pace of the common pathway. Therefore, the recurrence risk profile of a single patient is seemingly determined by a specific mix of hierarchical prognostic factors, resulting from the unique genetic, environmental, or behavioral traits of that individual, which may be affected by race‐related factors. We suggest that the components of the AA versus CA disparity not attributable to socioeconomic factors are a particular case of the more general issue of host‐tumor interaction and that epidemiologic and clinical views are complementary; each is observing biologic parameters, which are not completely captured by the other. A ‘unifying hypothesis’ incorporating findings from genetics, epidemiology, and clinical studies should be aggressively pursued. Cancer 2007.

Global paradigm shift in medical education: issues of concern for Africa.

Introduction: When medical education became established in Africa, many curricula were adopted from the West so as to achieve comparable standards in training. Over the last half a century however, major global pedagogical shifts have occurred in medical education without African keeping pace. Methods: This article reviews key pedagogical changes and other innovations in medical education that have occurred over the last half a century as reported in the literature and identifies some of the issues that need to be addressed in Africa. Discussion and conclusion: Socioeconomic and political instability, failure to rapidly overcome the inertia for change by substituting the old curriculum with a more problem, system and student-based one and redefining the goals of medical education are some of the issues of concern for Africa, and its ability to keep up in the dynamic world of medical education. There are only few faculty and school managers with effective medical education backgrounds to initiate, evaluate and sustain these changes. African medical academics, national governments and the international community need to come together to assist Africa to rise up to these challenges to ensure attainment and sustenance of global standards in medical training.

Recurrence and mortality dynamics for breast cancer patients undergoing mastectomy according to estrogen receptor status: different mortality but similar recurrence.

(Cancer Sci 2010; 101: 826–830)

Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer

BackgroundWomen with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing.ResultsThe therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems.ConclusionWe propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that develops, as happens in most cancer therapies.

Breast Cancer in Nigeria: Is Non‐Adherence to Chemotherapy Schedules a Major Factor in the Reported Poor Treatment Outcome?

To the Editor: Mortality from breast cancer has been declining steadily in many countries. This has been attributed to early detection, accurate diagnosis and prompt treatment (1,2). This is not the case in most developing countries. Breast cancer is now the leading female malignancy in Nigeria and the leading cause of cancer mortality among women seen in many centers across the country (3). The patients are young; they present late and have an overall poor survival. Various reports from Nigeria have shown a high incidence of tumors with unfavorable histopathological and molecular characteristics (4–6). Although a number of studies have attributed the poor treatment outcome to tumor biology, late presentation and poor knowledge of breast cancer (7), to the best of our knowledge, none has examined the phenomenon of non-adherence to therapeutic regimes and its possible effects on treatment outcome. This study examines the reasons for, and the frequency of occurrence of non-adherence to chemotherapeutic regimes among Nigerian women diagnosed with breast cancer. We also suggest ways to address the problem. A retrospective review of the case notes of patients who have been diagnosed with breast cancer and placed on cyclical chemotherapy regimes between January 1996 and December 2005 was carried out. We were specifically interested in the number of treatment cycles missed or delayed. We were also interested in the reasons why they were missed or delayed. The specific drug combinations were not analyzed, but the most commonly used regime in this centre is a course of six cycles of Cyclophosphamide, Methothrexate and 5-Fluorouracil (CMF). Modified radical mastectomy, axillary sampling and simple mastectomy are the commonest surgical procedures for confirmed breast cancer in the centre. A total of 188 cases were reviewed. Their ages ranged between 27 and 81 years with a mean of 49 (SD 10.3) years. One hundred and five (56%) of them were less than 50 years of age, and only 22 (11.7%) were aged above 65 years (elderly). One hundred and sixty-three (86%) of them presented with late stage (stages 3 & 4) disease. A total of 152 patients (80%) reported non-adherence to treatment at one stage or the other. There was no significant association between age or stage at presentation and non-adherence to treatment (v = 4.390, p = 0.624 and v = 5.465, p = 0.141, respectively). The reasons for non-adherence were available in only 110 patients. Among these patients, 21% received less than 75% while 55% received 50% or less of the expected cycles. About 52% of all patients who failed to take five or all of the six cycle of treatment did so because they could not afford the drugs. Paradoxically, 16% of all non-adherences to the regime was due to patients’ feeling well and did not think it important to continue the schedule. This was seen mostly commonly after the third cycle. Most of these patients however, returned and continued the cycle. About 13% of the patients opted out of treatment regime in order to attend faith ⁄ spiritual healing. About 10% experienced severe adverse effects of drug treatment like severe diarrhea, vomiting, and neutropenia. These patients either withdrew themselves from further treatment or their physician officially delayed their treatment. Other reasons for non-adherence to treatment include hospital staff strikes, unavailability of the drugs to buy, patients forgetting treatment cycle and lack of transportation to the treatment centre. These account for about 19% of non-adherence to treatment. Adequate adjuvant chemotherapy unequivocally improves outcome for breast cancer patients (8). This Address correspondence and reprint requests to: Isaac D. Gukas, BM; Bch, FMCS, MRCSEd, PhD, MA (Higher Education Practice), School of Medicine, Health Policy and Practice, Biomedical Research Centre (BMRC), University of East Anglia, Norwich NR4 7TJ, UK, or e-mail: i.gukas@uea. ac.uk.

Medical Students' Perceptions of Peer Feedback on an Anatomy Student-Selected Study Module

Objective: The study aimed to determine student views of peer feedback on their student-selected study (SSS) module. Methods: A questionnaire was developed to study perceptions of three groups of medical students (N = 42) towards feedback received from peers about their anatomy SSS presentation. Results: Most students felt comfortable receiving and giving feedback. They also felt that received feedback was fair, adequate and helpful, and that receiving feedback made them reflect. Slightly more students reported inadequate feedback from their peers about the presentations’ content, compared to other aspects, due to their peers’ relative lack of knowledge about their ‘specialized’ subject. Students would be reluctant to give feedback if anonymity was removed. Conclusion: The attitudes of medical students towards peer feedback were largely positive. We advocate further studies to evaluate quality of feedback, and the role of anonymity in peer feedback, and its effect on group dynamics and cohesion.