Michael J. Mastrangelo

Primary malignant melanoma of the urinary bladder

A melanin‐synthesizing tumor of the urinary bladder was studied by light and electron microscopy. Careful clinical evaluation did not reveal evidence for a primary melanoma elsewhere in the patient. The clinical presentation, course of the disease, and demonstration of melanocytes in the bladder epithelium and malignant melanocytes comprising the tumor by light and electron microscopy indicated that the neoplasm was a primary malignant melanoma arising in the bladder.

Current Concepts of the Biology of Human Cutaneous Malignant Melanoma

Publisher Summary Malignant melanoma is an uncommon tumor derived from pigment synthesizing cells; it is seen in all races of man and in many mammals as well as lower animals. The inductive circumstances operative in this tumor must be widespread in nature and, in part, are heritable cellular susceptibilities to neoplastic transformation. The established lesions of melanoma, both primary and metastatic, are associated with various immunologic phenomena. Apparently tumor-specific melanoma antigens have been demonstrated; patients may generate humoral and cellular immunologic responses to these antigens and, to some extent, the neoplastic systems may be manipulated by immunologic means. The meaning of “competence for metastasis” can be understood at a cellular level, and, if this is understood, then the control of the disease can be rationally approached. It seems reasonable that the disorderly life form that is cancer is probably illustrated rather completely by malignant melanoma, the one complete neoplastic system that forms and evolves on the body surface, where it may be studied with precision.

A clinical, histologic, and immunologic study of a case of metastatic malignant melanoma undergoing spontaneous remission

A patient with biopsy‐proven dermal recurrent malignant melanoma who refused therapy, and who was observed to undergo clinical regression during the period of November 1972 through June 1974 was studied to define the histologic features of spontaneous remission, and to evaluate the immune response as measured by in vitro assays of lymphocyte cytotoxicity and serum effects during the course of regression. Biopsy of regressed areas showed the following histologic features: 1) absence of malignant melanoma cells in basal layers of epidermis with relative increase in basal layer clear cells; 2) dermal inflammatory reaction with lymphocytic infiltrate, melanophages, and degenerate malignant melanocytes; and 3) dermal reactive vascular proliferation and interstitial edema progressing to reparative dermal fibrosis. Using a microcytotoxicity assay with two established allogeneic melanoma cell cultures as target cells, a statistically significant (p < 0.01) increase in lymphocyte cytotoxicity values was observed over the clinical time course of regression. No significant serum cytotoxic or serum blocking effects were detectable. These findings are consistent with an immunologic basis for the spontaneous remission of the dermal melanoma metastases present in this patient.

An effective low‐dose intermittent cyclophosphamide, methotrexate, and 5‐fluorouracil treatment regimen for metastatic breast cancer

A low‐dose, three‐drug regimen, C.M.F. (cyclophosphamide 50 mg, p.o., days 1–14; methotrexate, 25 mg, and 5‐fluorouracil, 500 mg, i.v., days 1 and 8; cycled every 28 days) was used in 46 consecutive chemotherapy‐eligible women (41 previously hormonally treated) with recurrent breast cancer. Thirteen percent of the patients had complete regressions (C.R.); 33% had partial regressions (P.R.); 26% stabilized; and 28% progressed. In evaluating response by sites of metastases, lymph nodes (30%), lung nodules (22%), and subcutaneous deposits (2/3) had the highest incidence of C.R.; 46–71% of patients with lymph node, lung, subcutaneous, liver, breast, or peritoneal disease showed C.R. or P.R. Skin and pleural disease responded in 30% of patients whereas no patients had radiographic healing of bony metastases. The toxicity was minimal: 7% gastrointestinal, 26% marrow‐suppressive, and 7% infectious. This low‐dose C.M.F. regimen resulted in regression rates similar to higher dose C.M.F. protocols, which use approximately twice these drug dosages with commensurate toxicity.

Intralesional BCG in the treatment of metastatic malignant melanoma.

The therapeutic efficacy of intralesional BCG (Bacillus Calmette‐Guerin; one immunizing dose every 2 weeks for a minimum of five treatments) was studied in 19 melanoma patients. Of 15 patients evaluable for response, five experienced significant objective improvement (two complete and three partial remissions). Objective improvement was limited to those patients with dermal metastatic disease. In vitro cytotoxicity in the presence of patients serum bore, on average, a relationship to the clinical disease. In certain individual cases, serum blocking and/or lymphocyte stimulation may have had prognostic significance.

A phase III comparison of methyl-CCNU + vincristine with or without BCG + allogeneic tumor cells in metastatic melanoma

SummarySixty-two patients with metastatic malignant melanoma were randomized to treatment with either (a) methyl-CCNU (200 mg/m2, PO every 8 weeks) plus vincristine (2 mg IV every 4 weeks), or (b) the same chemotherapy plus intradermal (ID) injections of irradiated (15,000 rads) allogeneic (fresh-frozen) melanoma cells (1–2×108) admixed with BCG (Glaxo, 2–4.5×106 organisms) every 2 weeks. Treatment cycles were repeated every 8 weeks until tumor progression. Seven (2 CR, 5 PR) objective remissions were noted among 31 patients (22.5%) treated with chemotherapy alone, whereas six (3 CR, 3 PR) objective remissions were noted among 31 patients (19%) treated with chemoimmunotherapy (P>0.05). The medians for remission duration (6 months) and survival (6.5 months) in the chemotherapy group did not differ significantly from the medians for remission duration (8 months) and survival (8 months) in the chemoimmunotherapy group. The patients manifested no unexpected toxicity. Hematologic toxicity was experienced by patients on both regimens; however, those receiving chemoimmunotherapy rebounded more quickly.

CHAPTER 12 – In Situ Immune Modulation Using Recombinant Vaccinia Virus Vectors: Preclinical Studies to Clinical Implementation

This chapter discusses an approach to immunologically based gene therapy logically designed from the requirements to generate a productive cellular immune response. The approach has been translated to clinical trials, with positive antitumor activity seen in a number of patients. The chapter hypothesizes that in situ tumor transfection with cytokine genes provides a logical extension of the vaccine strategies. By incorporating genes selected based on their known contribution to the generation of systemic immune responses, the ability to optimize the generation of an antitumor response can be anticipated. In addition to this logical in vivo vaccine design, this methodology allows the generation of a single reagent in a bottle that can be used in any tumor type provided it is accessible to injection. This can preclude the need to have sufficient autologous tumor for harvest and subsequent vaccine production and thus overcome the significant limitation of the in vitro transfectants for tumor transfection and selection in the lab.