Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies.

Fifty-four patients with advanced malignancies were treated on this phase I trial of coumarin and cimetidine. The dose of coumarin was escalated, with three patients treated at each dose level, while the cimetidine dose was held constant at 300 mg four times daily. Patients received coumarin alone as a single daily oral dose for 14 days; on day 15, cimetidine was added and both drugs were continued until progression of disease. This trial was initiated with patients receiving coumarin at 400 mg daily and closed at 7 g daily with four of five patients on this dose experiencing nausea and vomiting. Treatment was generally well tolerated over a wide range of coumarin doses. Symptomatic side effects were few, mild, and usually self limited. Side effects included insomnia, nausea, vomiting, diarrhea, and dizziness. Two patients withdrew from therapy because of daily nausea and vomiting. Typically, nausea, vomiting, and dizziness occurred 2.5-3 hours after a dose of coumarin. In most patients, these side effects abated spontaneously with continuation of therapy. There was no significant hematologic or renal toxicity. Hepatotoxicity occurred in only one patient and was manifested by asymptomatic abnormal elevations of serum hepatic transaminases. This toxicity was reversible upon interruption of therapy. Objective tumor regressions were observed in six patients with renal cell carcinoma. Responses occurred at coumarin doses ranging from 600 mg to 5 g daily. Coumarin is a relatively nontoxic, oral, outpatient therapy that warrants further investigations for the treatment of human malignancies. Because of its low toxicity, there is potential for combining coumarin with chemotherapeutic and/or biological agents in an attempt to improve on efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunosurgical treatment of stage I malignant melanoma

Summary We treated thirty seven patients suffering from a clinical stage I malignant melanoma by immunosurgery and observed them for a three-year period ending December 1975. Prior to surgery the tumor was submitted to the application of DNCB. Patients were divided between those who had or had not been subjected to biopsy before starting treatment. Accordingly, 23 patients treated by immunosurgery as the first treatment, were called the primitive treatment group and 14 patients subjected to a previous biopsy, the secondary treatment group. In the primitive treatment group, all 23 patients survived without any sign of recurrence. Relapse was observed in 4 out of 14 patients of the biopsy group. Extensive histological investigations have been made by light and electron microscopes. The tumors were infiltrated and disrupted by a large number of mononucleated cells. The majority of infiltrating cells were small lymphocytes. True lymphatic follicles have been observed in the skin around the melanoma.     

Combined interferon and vinblastine treatment of advanced melanoma: evaluation of the treatment results and the effects of the treatment on immunological functions

Summary Thirteen patients with metastatic malignant melanoma received interferon -2a (Roferon-A) and vinblastine. The interferon dosage was increased from 3×10⁶ IU to 9×10⁶ IU daily in 10 weeks and thereafter 9×10⁶ IU was administered three times weekly intrasmuscularly. Vinblastine (0.075–0.15 mg/kg) was given every third week intravenously. One of the ten evaluable patients had partial remission (PR) (11%) for 10 months. The diseases was stabilized (NC) in three patients (30%) for 3, 6 and 9 months. Progression (PD) occurred in six patients. The treatment time varied from 5 weeks to 44 weeks. The median survial time from the beginning of this combination treatment was 5 months. The most common side-effects were fever, fatigue, loss of taste, weight loss and neutropenia.The mitogen response to phytohemagglutinin and purified protein derivative of tuberculin decreased in all patients. The response to concanavalin A decreased less and began to increase again in the patients with PR and NC. The natural killer cell activity in PD patients decreased more than in the patients with PR and NC. The ratio of T4/T8-positive cells was restored in PR + NC patients but rose in PD patients indicating a difference in the immunomodulatory effect of the combination or of the advanced disease itself on T-cell function in PD patients.This combination of daily interferon and vinblastine did not prove to be effective in melanoma. The depression of immunological functions, which was more marked in patients with PD, might indicate that vinblastine in this combination counteracts the immunostimulatory effect of interferon.     

Characteristics of malignant melanoma cells in the treatment with fast neutrons

The radioresistance of malignant melanoma cells has been explained by the wide shoulder of the dose-cell-survival curve of the cells exposed to photon beams. Fast neutrons, 30 MeV d-Be, were used to treat patients who had malignant melanoma in order to confirm the biological effects of high linear energy transfer (LET) radiation for tumor control. Seventy-two patients suffering from malignant melanoma participated in the clinical trials with fast neutrons between November 1975 and December 1986. Of 72 patients, 45 had melanoma of the skin, 20 had melanoma of the head and neck, and seven had choroidal melanoma. Five-year survival rate of the patients who had previously untreated melanoma of the skin was 61% and for patients who received postoperative irradiation, it was 35.7% whereas no patients who had recurrent tumor survived over 4 years. Of 22 patients who had melanoma of the skin, stage I, local control in four cases was achieved by irradiation alone, whereas local control was achieved in 17 of 18 patients who required salvage surgery after fast-neutron therapy. The results of pathological studies performed with specimens obtained from salvage surgery have shown that melanoma cells growing in intradermal tissue are radio-resistant, compared with cells growing in intraepidermal tissue. This might suggest that melanoma cells acquire radioresistance when the connective tissue is involved. Five-year survival rate of the patients who had locally advanced melanoma of the head and neck, previously untreated, was 15.4%. Radiation therapy with accelerated protons was suitable for patients suffering from choroidal melanoma.     

The role of surgery in the treatment of malignant melanoma

Surgical interventions have important role in the treatment of all stages of malignant melanoma. Surgery is the primary treatment of localized cutaneous melanoma. Excision of the primary tumor makes it possible to set up the histological diagnosis and to determine pathological prognostic factors. Appropriate surgical margin is important for local disease control. Sentinel lymph node biopsy with detailed histological examination has gained prominent importance for correct histological staging and for determining adjuvant oncological treatment. Surgery is the primary treatment of isolated regional metastases. Surgical methods also have a role in the palliative management of distant metastatic melanoma. In the present review the most important issues of the surgical treatment of malignant melanoma have been discussed in detail.     

Herpes zoster: treatment with cimetidine.

The active phase of herpes zoster can be predicted from the length of time it takes for all the vesicles to erupt. A case is reported in which cimetidine therapy appeared to reduce the expected length of the active phase from 35 days or longer to 10 days.     

Experience with malignant melanoma of the head and neck

Data on 127 patients with malignant melanoma who had a minimum 5-year follow-up have been analyzed. A good, though not yet significant, correlation appears to exist between length of survival and the diameter and the thickness of the primary lesion, the level of the tumor invasion, and the type of melanoma. A further analysis of patients with Stage I disease lends support to the use of "prophylactic" node dissection when the primary lesions penetrate to levels 4 or 5, or when they are 1.5 mm or greater in thickness. Our current overall approach to the management of malignant melanoma of the head and neck is outlined.     

Intermittent treatment of duodenal ulcer with cimetidine.

Intermittent treatment with short courses of cimetidine given only when symptoms recurred was assessed in patients with duodenal ulcer as an alternative to maintenance treatment. Their progress was followed up for up to 22 months. Gastroscopy was carried out in most attacks to confirm recurrence of the ulcer and subsequent healing. Out of 125 patients treated, 83 relapsed, of whom 21 defaulted. After retreatment 36 patients relapsed again. The pattern of relapse and remission for the group as a whole was similar after both courses of treatment, indicating an unchanged natural history. Nevertheless, wide variation occurred in individual patients, so that the pattern of relapse could not be predicted by the duration of the initial remission. Most patients had one or two or rarely three symptomatic relapses a year, which were rapidly treated successfully with cimetidine. Therefore, unless the necessity for long-term maintenance treatment is established, intermittent treatment provides an adequate alternative in most patients with duodenal ulcer.     

Treatment of advanced melanoma with laser immunotherapy and ipilimumab

Immunotherapy has become a promising modality for melanoma, especially using checkpoint inhibitors, which revive suppressed T cells against the cancer. Such inhibitors should work better when combined with other treatments which could increase the number and quality of anti‐tumor T cells. We treated one patient with advanced (stage IV) melanoma, using the combination of laser immunotherapy (LIT), a novel immunological approach for metastatic cancers that has been shown to stimulate adaptive immunity, and ipilimumab. The patient was treated with LIT, followed with one course of ipilimumab 3 months after the beginning of LIT. After LIT treatment, all treated cutaneous melanoma in head and neck cleared completely. After the application of ipilimumab, all the tumor nodules in the lungs decreased. The patient had remained tumor free for one year. While anecdotal, the responses seen in this patient support the hypothesis that laser immunotherapy increases the number and quality of anti‐tumor T cells so that ipilimumab and other checkpoint inhibitors are more effective in enhancing the therapeutic effects. Picture : Schematic of treatment using laser immunotherapy and ipilimumab on a stage IV melanoma patient.     

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.     

Cellular immunecompetence in patients with malignant melanoma

Summary The nonspecific immunecompetence of the peripheral blood lymphocytes of 29 patients with malignant melanoma and one with the benign condition of Riehl's melanosis was tested by means of a local xenogeneic graft-versus-host reaction and the E rosette test. The lymphocytes of 20 normal donors served as controls. Impairment of cellular immunecompetence was found in patients with invasive multiple primaries and those with invasive nodular malignant melanoma. Functional activity of T lymphocytes was normal in most of the patients who had an invasive melanoma with adjacent intraepidermal component of Hutchinson melanotic freckle or superficial spreading. In three cases with superficial spreading in which there had been an impairment of T cell function before removal of the tumor, there was an improvement following surgery. There was a clear correlation between the patient's cell-mediated immune response and the pathological type of the tumor, but not with the depth of invasion. It is suggested that cellular immunecompetence is a valuable parameter in the prognosis and treatment of malignant melanoma and should be measured in all patients with this type of tumor.     

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.