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overview Michael Retsky’s formal education is in experimental physics. He has PhD in physics from University of Chicago that was awarded in 1974. His thesis project was to build a 100 kV scanning transmission electron microscope that could resolve single atoms and use the device to measure elastic cross-sections of individual silver, mercury and uranium atoms. His main contribution to microscope technology was to build power supplies for the high voltage and lens current that were stable to 1 part per million per hour, ten-fold better than anything else in the world. M Retsky and J Wall. One ampere current supply stable to one part per million per hour. Review of Scientific Instruments 43:384, 1972. M Retsky, Observed single atom elastic cross sections in a scanning electron microscope. Optik 41(2):127-124, 1974. While working at Hewlett-Packard in Colorado Springs in early 1980s, what began as an informal side project to help a friend whose wife was diagnosed with gastric lymphoma, he gradually made a career change over a 5 year period into cancer research. Retsky compliments H-P for allowing him to do cancer research and use their computers over the weekend as long as he got his work done. He left HP and became Prof of Biology at University of Colorado – Colorado Springs and visiting Prof at University of Texas – San Antonio. His first publication (Speer et al Cancer Research 1984) predicted cancer growth was intermittent with periods of temporary dormancy. Computer simulation of published clinical data was the basis for this finding. This was revolutionary since if true it would predict adjuvant chemotherapy after removal of a primary tumor should be administered as an intermittent protocol rather than maximum tolerated therapy for six or so months after surgery as widely practiced. As an ironic test of his confidence in the computer simulation, in 1994 Retsky was diagnosed with stage IIIc colon cancer. Surgery was routine anastomosis and recovery was uneventful. As might be expected, he decided against conventional adjuvant chemotherapy and instead chose a low dose, long term therapy using the mainstay colon cancer drug 5-fluoruracil. The drug was administered 5 hours each night using an infusion pump. This therapy was designed by William Hrushesky, MD. It had been used in late stage disease but had never been used as adjuvant chemotherapy. Retsky was on Judah Folkman’s staff at Harvard Medical School in 1996 or 1997 when he had been on the low dose - long term therapy for about 2 years. He asked Judah Folkman if this type of therapy had been tested as an anti-angiogenic. Folkman brought lab researcher Tim Browder into the room and it was determined that 5-FU had been tested but only as bolus, not low dose & long term. Retsky told them that 5-FU has half life of 20 minutes in the body if given as bolus and would be hard to imagine how it could be antiangiogenic if given that way. Browder eventually tested it in mice and to great surprise found it was antiangiogenic if administered continually at low dose for extended times. After much difficulty since the finding was unexpected, this was published as Browder et al, Cancer Research 2000. As of Nov 2017 this paper has been cited over 1100 times. See ProPublica 2014 by Jake Bernstein. Missing in Action - (Media links) The therapy was termed metronomic chemotherapy by D. Hanahan who was well known at the Folkman lab. Folkman and Browder are now deceased and Retsky (the cancer patient) is the only one left alive to tell this story. Based on calculations Retsky stayed on the therapy for a total of 2.5 years. Retsky M, Metronomic Chemotherapy was Originally Designed and first used in 1994 for Early Stage Cancer - why is it Taking so Long to Proceed? Journal of Bioequivalence and Bioavailability, May 2011, Editorial http://www.omicsonline.org/0975-0851/JBB-Editorial6.pdf MW Retsky; How long should adjuvant chemotherapy be given in early stage colon cancer? Clinical and Experimental Pathology. 3:1 2013. Open Access Journals | http://www.omicsonline.org/2161-0681/2161-0681-3-136.digital/2161-0681-3-136.html Retsky was very active as a patient-advocate. He is a founder of the Colon Cancer Alliance and was on the board of Directors for over 10 years. Retsky recently resigned from honorary faculty at University College London. His recent research is shown in this following abstract that was presented in London in June 2017: A bimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We are studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group (Forget et al, Aneth Analg 2010) suggested a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with 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. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) 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. 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. We suggest this would be most effective for triple negative breast cancer and be especially valuable in low and middle income countries. Similar bimodal patterns have been identified in other cancers suggesting a general effect. This research has been published a number of times and most recently issued in a book published July 2017 by Springer-Nature and edited by Retsky and long term colleague Romano Demicheli. (Perioperative Inflammation as Triggering Origin of Metastasis Development). An update review is under preparation and publication is expected by Summer 2019. A major development was reported by Krall et al in Science Translational Medicine in April 2018. See media links USA Today and WBUR Boston. They developed an animal model that shows inflammation from surgery can initiate exit from dormancy. This can be controlled with an NSAID. This is considered supportive evidence for the effect we propose in the Springer-Nature 2017 book. A paper (Retsky et al Breast Cancer Research and Treatment 2004 https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/pmc/articles/PMC468653/ that explains why adjuvant chemotherapy in breast cancer is mostly effective for premenopausal node positive patients has been downloaded 24,000 times. Current interest is planning and fund raising to conduct a clinical trial of perioperative NSAID for triple negative breast cancer at Beth Israel Deaconess Medical Center (Harvard) with Dr. Ted James, Chief of Breast Surgical Oncology. If this works as well as we expect, we will transfer the technology to Nigeria with full resources to treat patients. Retsky has visited Nigeria 3 times in the past 3 years. Refer to Chapter 6 in the Springer-Nature book that was written by our Nigerian colleagues.
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  • Computer Simulation
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.