BCG immunotherapy for recurrent malignant melanoma

Summary A study was made of immunologic parameters obtained from patients with stage IIIB malignant melanoma who were treated with BCG. Patients with the longest disease-free interval and survival times were those who had small initial skin test reactions and developed larger reactions during the course of BCG treatment. Of these patients, those with less than five involved nodes had the longest disease-free interval and survival times. Patients who had increases in skin test reactivity generally showed these increases by the first visit after initiation of BCG therapy.     

Hypertonicity primes malignant melanoma cells for apoptosis

The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na⁺ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.     

Adjuvant BCG immunotherapy for malignant melanoma.

A total of 199 patients with stage I malignant melanoma at Clark''s level 3 to 5 of invasion were entered into a prospectively controlled randomized clinical trial that attempted to assess the value of local and systemic immunotherapy with BCG (bacille Calmette-Guérin) after surgery. The patients were randomly assigned, with stratification by Clark''s level, to receive either routine follow-up or immunotherapy with BCG, administered intradermally with a Heaf gun around the site of wide excision and then given orally for 2 years. Intradermal administration of BCG was repeated after 1 year''s oral therapy with BCG. Of the 99 patients in the treatment group 66 had Clark''s level 3, 28 had level 4, and 5 had level 5 invasion. Of the 100 patients in the control group, 61 had level 3, 36 had level 4, and 3 had level 5 invasion. Other prognostic factors, such as sex, depth of invasion, histologic features, site of disease and type of surgery, were evenly distributed. There were 57 recurrences of the melanoma, 24 in the treatment group and 33 in the control group. However, this trend was not statistically significant (p = 0.194). The suggestion that BCG may reduce the likelihood of local/regional recurrence has not been confirmed with longer follow-up. There were 13 such recurrences in the BCG group, compared with 21 in the control group; the proportions of patients in each group who had such a recurrence were not significantly different. Of the 199 patients 41 died, 24 in the control group and 17 in the treatment group; again, this difference was not significant. While there may be minor activity in selected patients, there appeared to be no benefit from this form of adjuvant BCG therapy in patients with malignant melanoma.     

Congenital malignant melanoma.

The diagnosis and management of a 3-day-old infant with an exophytic pigmented growth on her back and chest are discussed. At 3 days of age, the child underwent a complete surgical excision of this lesion with immediate coverage by partial-thickness skin grafts. Pathologically, the lesion proved to be a thoracolumbar congenital melanocytic nevus with multiple focal areas of malignant melanoma. The child is now 3 years past surgery and shows no evidence of recurrence or distant metastases. The importance of this case lies in the presence of overt malignant melanoma at birth within a giant congenital nevocytic nevus.     

Immuno-diagnosis of malignant melanoma

The diagnosis of malignant melanoma must be followed by treatment shown to be effective. Therefore a correct diagnosis, including staging, that will permit a meaningful prognosis and treatment, is essential. The usefulness and great specificity of immunological methods is based on the detection of antigens characteristic of neoplastic and reactive cells. In cases of malignant melanoma, immunohistochemistry has limited practical value in the routine diagnosis of melanocytic lesions. The method may be important, however, in the differential diagnosis of, for example, malignant melanoma vs. non-melanocytic anaplastic neoplasia, malignant vs. benign melanocytic lesions, etc. Recent advances in relating the immunostaining of antigens to the development of tumor cells, such as proliferation and apoptosis, metastatic potential, etc. have given considerable importance to the immunomorphological evaluation of malignant melanomas. Likewise, immunotherapy requires the immunophenotyping of the reactive cells of the immune system.     

GC subtypes and malignant melanoma

Using polyacrylamide gel isoelectric focusing (PAGIF), group-specific component (GC) subtypes were determined for 64 malignant melanoma patients and 208 controls residing in Victoria, Australia. No association was found, confirming the results of earlier studies.     

Anti-tyrosinase antibodies in malignant melanoma

 Anti-tyrosinase antibodies were measured by enzyme-linked immunosorbent assay in sera of patients with malignant melanoma with either metastatic disease or no evidence of disease, in patients with melanoma and associated hypopigmentation (MAH), in patients with vitiligo and in healthy volunteers. The mean relative absorbance (A _rel) was calculated by dividing the absorbance of each sample by the mean value for the control group. Using this method, the A _rel of the control group was 1.000(SE 0.083). A _rel of patients with metastatic disease (1.516; SE 0.225) was significantly higher (P = 0.03) than the value for the controls, but insignificantly higher than that for patients with no evidence of disease (1.216; SE 0.148). Patients with no evidence of disease, in whom the primary lesion originated in the lower limb, had a significantly higher (P = 0.01) A _rel than the healthy volunteers. Patients with metastatic disease showed higher A _rel if their primary lesions were confined to the area of the head and neck or to the lower limb. Patients with vitiligo had higher A _rel values for their anti-tyrosinase antibody than any of the other groups. However, those with melanoma and MAH (vitiligo-like) had the same A _rel of anti-tyrosinase antibodies as the controls or the patients with metastatic melanoma. This observation reflected the possible absorption of anti-tyrosinase antibodies to melanoma antigens, and pointed to the participation of anti-tyrosinase antibodies in the destruction of normal melanocytes in patients with melanoma, as part of the immune reaction towards this disease. Received: 4 January 1996 / Accepted: 11 April 1996