Donald L. Morton

Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine.

A new polyvalent melanoma cell vaccine (MCV) was administered to 136 stage. IIIA and IV (American Joint Committee on Cancer) melanoma patients. Induction of cell-mediated and humoral immune responses to common melanoma-associated antigens present on autologous melanoma cells was observed in patients receiving the new MCV. This was accompanied by increased activation of tumor-infiltrating lymphocytes. Survival correlated significantly with delayed cutaneous hypersensitivity (p = 0.0066) and antibody responses to MCV (p = 0.0117). Of 40 patients with evaluable disease, nine (23%) had regressions (three complete). From our historical database of 126 stage IIIA and 1275 stage IV melanoma patients, there were no significant changes in the natural history of metastatic melanoma during the past 20 years. Univariate and multivariate analyses demonstrated prognostic significance for site of metastases (p = 0.0001) and immunotherapy with the new MCV (p = 0.0001). Overall our new MCV increased the median and 5-year survival of stage IIIA melanoma patients with regional soft tissue metastases twofold (p = 0.00024), and stage IV patients threefold (p = 0.0001) compared with previous immunotherapy and other treatments.

Factors prognostic for survival in patients with malignant melanoma spread to the regional lymph nodes.

To establish clinical and histologic determinants of survival, records of all UCLA patients with resectable melanoma metastatic to the lymph nodes during the years 1954-1976 were reviewed. These 150 patients were treated first with wide excision, lymphadenectomy, and with radiation/chemotherapy and/or additional surgery only if further recurrences developed. None received adjuvant immunotherapy or chemotherapy. In 97 of 139 patients with identified primary tumors, slides of the primary lesion were reviewed. Putative prognostic factors included age, sex, parity, site of primary tumor, presence of satellitosis, clinical status of nodes, histologic characteristics of primary lesion (Clarks level, thickness of tumor, presence/width of ulceration, and number of mitoses/HPF), time from biopsy of primary tumor to lymphadenectomy, and number of positive nodes. kaplan-Meier estimates of survival for the entire group at one, two, five, and ten years were 73, 55, 37, and 33%, respectively. Median follow-up period of survivors was four years. Univariate analyses using the log-rank test showed that thickness of the primary lesion (p less than 0.001), width of ulceration (p = 0.003), absence of ulceration (p = 0.024), and number of positive nodes (p = 0,.033) were prognostic for survival. In multivariate analysis by the Cox procedure, thickness of the primary (p = 0.001) and number of melanoma-containing nodes (p = 0.043) were prognostic for survival. Location of the primary tumor became marginally significant (p = 0.12) in the multrivariate model. These findings demonstrate the prognostic importance of characteristics of both the primary lesion and extent of regional dissemination. Future prospective randomized trials for (adjuvant) therapy of Stage II melanoma should be stratified by these variables.

Evidence for in vivo Reaction of Antibody and Complement to Surface Antigens of Human Cancer Cells

The immune adherence test was used to determine whether antibody and complement in cancer patients are fixed in vivo to tumor cells. Human erythrocytes adhered in vitro to the surface of human cancer cells obtained from autopsy and biopsy. Adherence was enhanced by further addition of the C2 and C3 components of complement, and was diminished by preliminary treatment with antibody to C3 (that is, to β1C-globulin). The results suggest that tumor associated membrane antigens form complexes in vivo with antibodies and complement.

Chromosomal abnormalities of a mediastinal embryonal cell carcinoma in a patient with 47,XXY Klinefelter syndrome: Evidence for the premeiotic origin of a germ cell tumor

Trypsin-Giemsa banding studies were performed on 30 tumor cells from an embryonal cell carcinoma originating in the mediastinum of an 18-year-old male with the Klinefelter syndrome (47,XXY). All tumor cells revealed an XXY chromosomal pattern with the addition of extra chromosomes. Electrophoretic patterns of the patients red blood cells and tumor cells were identical. These data suggest that this germ cell tumor originated from a primordial germ cell in which oncogenesis had occurred prior to meiotic division.

Breast cancers: estrogen and progesterone receptor status as a predictor of in vitro chemotherapeutic response.

Although clinical observations have shown that estrogen receptor-positive (ER+) breast tumors are more responsive to hormonal therapy than ER-negative (ER-) tumors, it remains controversial whether ER status can predict chemotherapeutic response. To determine if there was any correlation between estrogen and progesterone values and in vitro chemosensitivity to various anticancer drugs, clonogenic (CA), estrogen (ERA), and progesterone (PRA) assays on breast cancers were performed on 100 patients. Clonogenic assays were performed using the double-layer soft agar technique with continuous drug exposures. ERAs and PRAs were performed using the charcoal-coated dextran method. Chemosensitivity was defined as 50% inhibition of colony formation. ERA was considered positive if greater than or equal to 5 fmole/mg cytosol and PRA positive if greater than or equal to 10 fmole/mg cytosol. Significant tumor growth (greater than 30 colonies/plate) was achieved in 81/100 assays. ERA and PRA values were not predictive of colony formation in vitro. Of all agents or combinations of agents tested (L-PAM, 5-FU, MTX, adriamycin, vinblastine, cis-plat, FAC, CMF), only the response to 5-FU correlated significantly with ERA. Eight of 11 (73%) of the ER- tumors were sensitive to 5-FU, whereas only 6/20 (30%) of ER+ tumors were sensitive (P less than 0.05). ER- tumors were also more likely to be sensitive to CMF (P = 0.09) and adriamycin (P = 0.07) than ER+ tumors. PRA values were not predictive of chemosensitivity, nor did combining PRA and ERA enhance the predictive value of ERA alone.

Tumor-associated antigens detected by autologous sera in urine of patients with solid neoplasms

Abstract Twenty-four-hour urine samples were procured from cancer patients and normal donors. The urine samples were processed and concentrated by centrifugation and ultrafiltration (10,000 MW cutoff). The processed urine samples were tested for the presence or absence of tumor-associated antigens by the complement-fixation assay. Autologous serum was used as the source of antibody. Ninety-two percent (55/60) of cancer patients were positive for the antigens in their urine. Within the cancer patient group, 86% (31/36) sarcoma patients, 100% (17/17) melanoma patients, and 100% (7/7) carcinoma patients were positive. In contrast, only 7% (2/27) normal donors were positive in this assay. Antibody activity of the sera reacting to the urine from cancer patients was removed by absorption with biopsied tumor specimens but not with normal skin or muscle suggesting that the antigens detected in urine of cancer patients were tumor associated.

A comparison of deep-heating electrode concepts for hyperthermia.

There is mounting evidence that localized hyperthermia produced by electromagnetic waves may be useful in the treatment of cancer, and many innovative devices have been designed for this purpose. Most applicators employed for deep heating operate in the frequency region of 10-100MHz to provide greatest depth of penetration. Two basic categories of launching devices exist: E-field and H-field. The E-field applicators include conductive plates and fringing field devices; either may be used individually or in a multiple feed system. The H-field applicators include cylindrical and planar devices configured to produce specific heating patterns. We have analyzed and compared the performance of each of these devices, particularly in terms of engineering principles, design characteristics and their ability to transfer potentially therapeutic energy safely and at depth.

Adjuvant Therapy Following Surgery for Primary Malignant Melanoma

Adjuvant therapy following surgical resection of primary malignant tumors has become an important consideration in the treatment of patients with cancer. Modern surgical and radiotherapeutic techniques have markedly reduced the incidence of tumor recurrence in the primary and regional sites; however, overall patient survival rates have not changed significantly over the past 20 years. This lack of improvement in survival rates does not indicate failure of primary treatment modalities; rather, it has emphasized the need for systemic therapy and it has altered our view of the role of surgery and other local treatments in cancer therapy.

Estimation in a Markov chain regression model with missing covariates

Markov chain proportional hazard regression model provides a powerful tool for analysis of multiple event times. We discuss estimation in absorbing Markov chains with missing covariates. We consider a MAR model assuming that the missing data mechanism depends on the observed covariates, as well as the number of events observed in a given time period, their types and times of their occurrence. For estimation purposes we use a piecewise constant intensity regression model.

Non-invasive thermochemotherapy for advanced brain tumors

Non-invasive hyperthermia by magnetic-loop induction has been safely used to treat patients with advanced tumors of extracranial sites. Both disease regression and disease stabilization have been observed. This technique was recently applied to brain tumors in an animal model, and its safety was again demonstrated. A trial of non-invasive localized hyperthermia combined with intravenous chemotherapy was carried out in 13 patients whose primary or metastatic brain tumors failed to respond to standard therapy. Patients underwent 35 thermochemotherapy sessions. The median, maximum temperature of normal brain after 1 hour of hyperthermia was 41.3°C (range 38.6-43.4°C); the median, maximum temperature of brain tumor was 42.5°C (range 38.8-46.3°C) (p<.01). The temperature of both the normal brain and the brain tumor were obtained during 26 treatments. Tumor temperature was greater than the normal brain temperature in 21/26 treatments. In 73% of the treatments, the measured tumor temperature reached at least 42° C, whereas the normal brain reached 42° C in only 23% of the treatments. These data demonstrate the ‘selective inability’ of brain tumor tissue to dissipate heat. Vital signs, intracranial pressure, and neurologic status were monitored throughout the hyperthermia treatments. No mortality or increase in chemotherapeutic toxicity could be attributed to the thermochemotherapy, and there were no local complications or permanent neurologic complications. We conclude that this new, non-invasive modality not only produced effective intracranial tumor heating, but could be performed safely with the proper precautions.