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.

NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup.

To explain a bimodal relapse hazard among early stage breast cancer patients treated by mastectomy we postulated that relapses within 4 years of surgery resulted from something that happened at about the time of surgery to provoke sudden exits from dormant phases to active growth. Relapses at 10 months appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. Another relapse mode with peak about 30 months corresponded to sudden growth from a single cell. Late relapses were not synchronized to surgery. This hypothesis could explain a wide variety of breast cancer observations. We have been looking for new data that might provide more insight concerning the various relapse modes. Retrospective data reported in June 2010 study of 327 consecutive patients compared various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Follow-up was average 27.3 months with range 13-44 months. Updated hazard as of September 2011 for this series is now presented. NSAID ketorolac, a common analgesic used in surgery, is associated with far superior disease-free survival in the first few years after surgery. The expected prominent early relapse events are all but absent. In the 9-18 month period, there is fivefold reduction in relapses. If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate most early relapses. Transient systemic inflammation accompanying surgery could be part of the metastatic tumor seeding process and could have been effectively blocked by perioperative anti-inflammatory agents. In addition, antiangiogenic properties of NSAIDs could also play a role. Triple negative breast cancer may be the ideal group with which to test perioperative ketorolac to prevent early relapses.

Promising development from translational or perhaps anti-translational research in breast cancer.

BACKGROUND: A great deal of the public's money has been spent on cancer research but demonstrable benefits to patients have not been proportionate. We are a group of scientists and physicians who several decades ago were confronted with bimodal relapse patterns among early stage breast cancer patients who were treated by mastectomy. Since the bimodal pattern was not explainable with the then well-accepted continuous growth model, we proposed that metastatic disease was mostly inactive before surgery but was driven into growth somehow by surgery. Most relapses in breast cancer would fall into the surgery-induced growth category thus it was highly important to understand the ramifications of this process and how it may be curtailed. With this hypothesis, we have been able to explain a wide variety of clinical observations including why mammography is less effective for women age 40-49 than it is for women age 50-59, why adjuvant chemotherapy is most effective for premenopausal women with positive lymph nodes, and why there is a racial disparity in outcome. METHODS: We have been diligently looking for new clinical or laboratory information that could provide a connection or correlation between the bimodal relapse pattern and some clinical factor or interventional action and perhaps lead us towards methods to prevent surgery-initiated tumor activity. RESULTS: A recent development occurred when a retrospective study appeared in an anesthesiology journal that suggested the perioperative NSAID analgesic ketorolac seems to reduce early relapses following mastectomy. Collaborating with these anesthesiologists to understand this effect, we independently re-examined and updated their data and, in search of a mechanism, focused in on the transient systemic inflammation that follows surgery to remove a primary tumor. We have arrived at several possible explanations ranging from mechanical to biological that suggest the relapses avoided in the early years do not show up later. CONCLUSIONS: We present the possibility that a nontoxic and low cost intervention could prevent early relapses. It may be that preventing systemic inflammation post surgery will prevent early relapses. This could be controlled by the surgical anesthesiologist's choice of analgesic drugs. This development needs to be confirmed in a randomized controlled clinical trial and we have identified triple negative breast cancer as the ideal subset with which to test this. If successful, this would be relatively easy to implement in developing as well as developed countries and would be an important translational result.

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) The purpose was to ascertain whether the recurrence risk patterns for patients with estrogen receptor (ER)-positive (P) and ER-negative (N) breast cancer support the ER-related clinical divergence suggested by the observed different mortality patterns and gene expression profiles. Both recurrence and death were considered in a series of 771 patients undergoing mastectomy. ER status was available for 539 patients. The hazard rates for recurrence and mortality throughout 15 years of follow-up were assessed. The recurrence dynamics displays a bimodal pattern for both ERP and ERN tumors with comparable peak timings. The two curves cross during the 3rd year. By contrast, the mortality dynamics are definitely different for ERP and ERN tumors: during the early follow-up period ERN patients have their highest mortality risk, while ERP patients have their lowest mortality risk. The two curves cross during the 5th year. In spite of the different mortality dynamics, the recurrence dynamics do not demonstrate a major distinction in timing between ERP and ERN breast cancers, suggesting that the metastasis development process following mastectomy is apparently similar for both ER categories. The observed differences in the mortality risk are plausibly attributable to ER-related factors influencing the clinical course from recurrence to death. These clinical findings apparently contradict the occurrence of two different types of breast cancer, notwithstanding the distinct epidemiological, clinical, and molecular features linked to ERP and ERN tumors, although ER levels may concur to establish the event risk levels.

Verbal and nonverbal indices of learning during problem-based learning (PBL) among first year medical students and the threshold for tutor intervention.

BACKGROUND: During problem-based learning (PBL), students brainstorm on a problem, generate hypotheses and formulate learning objectives. Certain verbal and non-verbal expressions are used by students in response to specific learning issues. AIMS: This study examines the use of these expressions as indices of the learning taking place and the tutors' threshold to intervene. METHODS: Common verbal expressions used by students during PBL were identified and scored on a Likert scale to indicate the learning taking place. These expressions were categorised into the following groups of learning interactions: exploratory questioning, cumulative reasoning and handling conflicts relating to learning. The tutor's threshold for intervention was also scored on a Likert scale. Means for each learning interaction and observed non-verbal expressions were used to construct bar charts for comparison. RESULTS: When the learning interactions involve exploratory questioning or cumulative reasoning, students tend to score high on learning and tutors have high threshold for intervention. When the learning interactions involve handling conflicts relating to knowledge, students score high on learning, but teachers have a low threshold for intervention. CONCLUSION: Verbal and non-verbal expressions from students during PBL are useful indices of learning and can be used to help tutors decide when and when not to intervene.

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.

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

BACKGROUND: Women 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. RESULTS: The 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. CONCLUSION: We 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.

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.

A comparison of clinicopathological features and molecular markers in british and nigerian women with breast cancer.

BACKGROUND: Some studies have suggested that breast cancer in black women is more aggressive than in white women. This study's aim was to look for evidence of differences in tumour biology between the two cohorts. METHODS: This study compared the stage, grade and pathological expression of five immunohistochemical markers (oestrogen receptor [ER], progesterone receptor [PR], ERBB2, P53 and cyclin D1 [CCND1]) in tumour biopsies from age-matched cohorts of patients from Nigeria and England. Sixty-eight suitable samples from Nigerian (n = 34) and British (n = 34) breast cancer patients were retrieved from histology tissue banks. RESULTS: There were significant differences between the two cohorts in the expression of ER and CCND1; and stark differences in the clinical stage at presentation. But no significant differences were observed for tumour grade. CONCLUSION: There was a significantly, low ER expression in the Nigerian cases which also predicts a poor response to hormonal therapy as well as a poorer prognosis. Differences in clinical stage at presentation will most likely influence prognosis between Nigerian and British women with breast cancer.

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.

Enhanced surgery-induced angiogenesis among premenopausal women might partially explain excess breast cancer mortality of blacks compared to whites: an hypothesis.

There is excess breast cancer mortality for African-Americans (AA) compared to European-Americans (EA) of 1.5-2.2 fold that first appeared in 1970s and has been worsening since. This disparity may not be explained solely by reduced access to medical care. We proposed that surgery to remove a primary tumor induces angiogenesis of distant dormant micrometastases in 20% of premenopausal node-positive patients. This hypothesis helps explain the reduced benefit of mammography for women aged 40-49. Interestingly, for AA the average age at diagnosis is 46 while for EA it is 57. The resultant increased proportion of AA premenopausal breast cancer suggests a possible explanation for the AA/EA excess mortality. Early detection, which began in the 1970s, is more effective in postmenopausal women than in premenopausal women. Since AA breast cancer is mostly premenopausal and EA breast cancer is mostly postmenopausal, it might be anticipated that starting in the 1970s because of surgery-induced early mortality, outcome would be superior for EA compared to AA.

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.

A comparison of the pattern of occurrence of breast cancer in Nigerian and British women.

Studies have suggested a predominance of premenopausal breast cancer in black compared to white women. The aim of the study was to compare the age specific incidence of breast cancer in Nigerian and British women. The mean age at presentation was 43.1 and 64 years for Jos (Nigeria) and Norfolk (United Kingdom), respectively. The age specific incidence rates were higher in women above 50 years compared to women less than 50 years of age in both populations. The odds of having breast cancer for women aged less than 50 years is 3.0 times higher in Norfolk (95% Confidence Interval 2.0-4.4) than Jos and 9.0 times higher for women over 50 years of age in Norfolk (95% Confidence Interval 5.3-18.3) than Jos. The age specific incidence rates are higher for postmenopausal women in both populations; with higher rates for all age groups in the United Kingdom population.