key: cord-0019168-2kovhpaq authors: Faries, Mark B. title: Donald L. Morton Memorial Lecture: the legacy of Donald Morton: past, present and future date: 2021-07-18 journal: Clin Exp Metastasis DOI: 10.1007/s10585-021-10110-1 sha: 1cdfbbcab6a881b237f23ef733d52b052d8bf5b2 doc_id: 19168 cord_uid: 2kovhpaq Donald L. Morton, MD persevered against great odds throughout his life and career. Beginning in the humblest of circumstances, he worked his way to the highest echelon of academic surgery, revolutionized surgical treatment of melanoma with innovations that rippled through the rest of oncology. His research led to dramatically improved disease staging while also decreasing morbidity. He stood as a champion of immunotherapy for many years when few others believed it would ever work. His greatest professional legacy, and the achievement of which he was most proud, is in the accomplishments of those he trained over his many years in the field. It is a great honor to give the Donald L. Morton Memorial Lecture at the 8th International Symposium on Cancer Metastasis. Dr. Morton was a mentor to me and to innumerable others not only in surgical oncology, but in medicine more broadly. What he was able to accomplish, having been born into the humblest circumstances is truly remarkable. His achievements in oncology were far-reaching and include development of the sentinel lymph node biopsy technique, for which he is probably most well-known, as well as immunotherapy for cancer with both intralesional therapies and vaccine development. He was also a champion for surgical resection for patients with metastatic cancer. However, the professional achievement of which he was proudest was in the training of dozens of surgical oncologists through his career, who now carry his legacy forward into the future. Donald Morton was born September 12, 1934 in Richwood, West Virginia in a house build by his father in the middle of the Great Depression. Richwood is remarkably isolated, as a tiny community located in the interior of the Monongahela National Forest. He attended Berea College in Kentucky, which was available to him without tuition. His early success enabled him to transfer to the University of California Berkley and then to go on to medical school at the University of California San Francisco. He moved to the National Cancer Institute in 1969 to become head of the tumor immunology Section before taking a position on the faculty at UCLA where he was the Chief of Surgical Oncology and the Chief of General Surgery, where he founded the John Wayne Cancer Clinic together with the Wayne family in memory of their father. Dr. Morton moved his team to Santa Monica in 1991, where he remained for the rest of his career (Fig. 1) . He founded one of the earliest surgical oncology fellowship training programs, which was one of the first to be accredited as soon as accreditation was established. In addition to the many surgeons and oncologists who consider Dr. Morton a mentor, he directly trained dozens of surgical oncologists, many who went on to become leaders in academic surgery in their own right ( of Surgery there, he invited only two professional colleagues to speak at the ceremony that was held when he took the role, one of whom was Dr. Morton, which is a striking testament to the profound influence he had as a mentor. His pride in his trainees was always very evident, and he believed his accomplishments would be dwarfed by all that the next generation of surgeons, and the one after that would be able to do. Dr. Morton's own personal accomplishments, however, were considerable (Table 2 ). Sentinel lymph node biopsy is probably the most well-known of these. Although the concept of a sentinel lymph node had been discussed by others dating back over 100 years, Dr. Morton's transformational breakthrough came from an understanding that the sentinel lymph node was determined not by its anatomic location, but as its functional status as the first node to receive lymphatic drainage from the primary tumor site. This concept developed from the efforts he and his team were making in refining elective lymph node dissection. In the era in which entire nodal basins were dissected at the time of initial treatment, some primary tumor locations such as the central trunk, did not have a clear single basin to target. To make this process more rational, they developed lymphoscintigraphy using colloidal gold particles as tracers [1] . These were injected at the primary tumor site and the target basin was revealed though imaging. Over time, with refinements in tracers and imaging technology, it became apparent that tracer was distributed not to an entire nodal basin, but more focally to only a single or small number of nodes within the basin. This observation led Dr. Morton to test injection of vital blue dyes to visualize, dissect and remove individual first echelon draining nodes, which he called sentinel. The research, first presented at the Society of Surgical Oncology in 1990, demonstrated the pathologic status of the sentinel node was representative of the status of the basin and that patients with negative sentinel nodes could be spared dissection [2] . As was typical, Dr. Morton immediately designed a randomized clinical trial to test this new procedure and brought surgeons in from around the United States and the world to learn the technique and participate in the trial. This first Multicenter Selective Lymphadenectomy Trial (MSLT-I) confirmed the value of the technique in revolutionizing staging and improving outcomes, including the survival of those patients who had nodal metastases [3] . Even before the first trial was completed, the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) was being designed. This trial tested the role of completion lymph node dissection for patients with sentinel node metastases. Its findings, published after Dr. Morton's death, demonstrated that the sentinel node biopsy was the critical portion of initial treatment and that most patients could avoid nodal dissection safely, even with melanoma had spread to the sentinel node [4] . As a result of these trials, the standard of care for patients with melanoma now is radically different from what was the case before Dr. Morton's work and many thousands of patients have enjoyed the benefits of these advances. This is true not only for melanoma, but also for patients with breast cancer after the technique was brought to that malignancy by Dr. Morton's colleague (and mentee), Armando Giuliano. Dr. Morton was also an early and vocal champion of immunotherapy for cancer [5] . For much of his career, he worked tirelessly on developing a vaccine for melanoma. This vaccine was an allogeneic, whole-cell vaccine administered with Bacille Calmette-Guerin (BCG) as an immune adjuvant. Unfortunately, at about the same time Dr. Morton was working to open clinical studies of his melanoma cell vaccine at the National Cancer Institute, controversy was swirling around an oncologist in New York named Chester Southam who had injected patients with varying quantities of cancer cells into patients, reportedly without their fully informed consent. According to Dr. Morton's recollection, in the context of that controversy, the Institutional Review Board at the NCI was initially unwilling to allow him to begin his trials injecting irradiated melanoma as a vaccine, even with informed patients. At about that time, though, a patient presented to him with extensive in-transit melanoma metastases in her arm whose treatment allowed proof of principle. Her contralateral arm had been paralyzed by polio, and she was not willing to undergo an amputation of her fully functional arm as treatment. Dr. Morton realized there was no need to inject melanoma cells, as the patient's tumor cells were already present, but that provision of immune stimulation to those sites with BCG might accomplish the same end. He injected BCG into several of the metastases, recreating the conditions he had planned to use for his vaccine protocol. After a series of injections, the patient went on to a complete clinical response and remained free of evidence of disease for many years thereafter. Although BCG has now been eclipsed by modern checkpoint inhibitors and First report of detection of occult tumor cells in regional lymph nodes by immunohistochemistry 1992 Technical details of intraoperative lymphatic mapping for early stage melanoma [2] Seminal report of sentinel lymph node biopsy technique in mela- Completion dissection or observation for sentinel-node metastasis in melanoma [4] Initial report from the second MSLT study cytokines, as a proof of concept it helped keep the hope of an effective immune therapy alive while research continued. It may still be used in selected cases even today [6] (Fig. 2) . Metastasectomy for melanoma was also a concept Dr. Morton felt strongly about [7] . He was often quoted as saying that "Overall data suggest initial treatment of choice for Stage IV metastatic melanoma to single or multiple sites should be surgery, followed by surgery, followed by surgery again." A recent review of resection for stage IV melanoma reaffirms his earlier observations that patients who can have complete resection of metastases, even in advanced stage disease, can enjoy long-term survival if they are properly selected [8] . This appears to still be true in the era of modern, effective systemic therapies. The advent of those therapies, though, has made treatment decisions more complex, as there are patients who become candidates for resection after an initial period of systemic therapy, and others form whom surgery, though possible at the time of diagnosis, may be better served with an initial period of medical treatment. However, the principal that surgery can add to the care of patients even after hematogenous dissemination remains an important one to preserve as melanoma care evolves. As a member of the group of surgeons trained by Dr. Morton, I remain committed to carrying the discoveries he made further into the future. He remained eternally optimistic and was never discouraged even in the face of initial failure. His presentation of the sentinel node technique to the Society of Surgical Oncology was followed by almost 2 years of failed efforts to gain acceptance of the manuscript related to that work for publication. Eventually it was published and went on to become one of the most highly cited papers in oncology [9] . Similarly, when the randomized Phase 3 trials evaluating his vaccine failed to show a survival benefit in the vaccine arm. He immediately saw the glass as half full, since the survivals in both the vaccine and placebo groups was over 40% at 5-years, which for Stage IV melanoma was unheard of at the time [10] . Rather than being defeated, he began designing the next clinical trial to determine whether the favorable outcomes were due to trial selection, surgical therapy or adjuvant BCG injections, which both groups had received. In closing, I would like to again express my gratitude for the opportunity to deliver the Morton Lecture. I know that his legacy will continue through generations of surgeons and oncologists well into the future. Fig. 2 Intralesional immunotherapy with Bacille Calmette-Guerin. The patient is a 66-yearold woman with innumerable dermal in-transit metastases in her thigh, buttock and hip. A Sensitization to BCG followed by intralesional injections into a subset of the lesions (B) led to complete regression of injected and non-injected lesions over 12 weeks, with only pigment remaining (C). She remained without evidence of disease at her last follow up 3 years later A rational approach to the surgical management of melanoma Technical details of intraoperative lymphatic mapping for early stage melanoma Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-1, an interanational multicenter trial Completion dissection or observation for sentinel-node metastasis in melanoma BCG immunotherapy of malignant melanoma: summary of a seven-year experience Combined intralesional Bacille Calmette-Guerin (BCG) and topical imiquimod for in-transit melanoma Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) Impact of effective systemic therapy on metastasectomy in stage IV melanoma: a matched-pair analysis In memoriam: Donald L. Morton, MD (1934-2014): an icon in surgical oncology: past president, society of surgical oncology (1992-1993) and associate editor, annals of surgical oncology An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after compete resection of melanoma metastatic to regional or distant sites Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations The author has no conflicts of interest relevant to this material.