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As of August 1984, 115 women with advanced breast cancer have been randomized to receive a combination of either cyclophosphamide, Novantrone (mitoxantrone) and 5-fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil (CAF). Seventy-one percent of all patients were post-menopausal and 44% of CNF patients and 57% of CAF patients were estrogen receptor (ER) negative. Slightly over 30% of all patients had received hormonal therapy or chemotherapy in an adjuvant setting. Hematologic toxicity was similar in regard to platelet counts but slightly lower nadirs were experienced with CNF therapy than with CAF. However, there were fewer dosage decreases with CNF. Significantly less nausea and vomiting were observed with the CNF regimen compared to CAF. Moreover, alopecia was reduced appreciably in patients who received CNF. The response rate to CNF for the first 38 eligible and evaluable patients was 42%, and for 53 eligible and evaluable patients who received CAF the response rate was 45%, a non-significant difference. Median response durations were similar also, 140 days for CNF and 168 days for the CAF regimen. Time to treatment failure was similar for both regimens. CNF is an effective regimen for patients with advanced breast cancer, with less toxicity than CAF.

Patients with regional metastases of malignant melanoma (75 with Stage IIIA soft tissue metastases, 124 with Stage IIIB nodal metastases and 75 with Stage IIIAB soft tissue and nodal metastases) treated by regional perfusion between 1957 and 1982 were retrospectively studied to identify prognostic factors relating to survival. In patients with Stage IIIB disease, the melanoma specific cumulative survival rates at five years was 72 per cent for one, 33 per cent for two to three and 20 per cent for four or more positive lymph nodes. In patients with Stage IIIAB disease, those with one node had a better survival rate at five years than those with multiple nodes (45 versus 25 per cent). In patients with Stage IIIA melanoma, two groups were identified based upon the results of prior treatment--those with and without prophylactic lymph node dissection (PLND) at the time of primary therapy. The factors associated with decreased survival rates in patients with PLND were: 1, increasing age; 2, presence of subcutaneous or both subcutaneous and dermal metastases, and 3, treatment at normothermic temperatures or earlier date of treatment. No significant factors were found in the group without PLND; however, the survival time was similar to that for patients with Stage IIIAB and one positive node (45 per cent at five years). Knowledge of these factors is important in assessing the prognosis and establishing randomization criteria for prospective studies evaluating various forms of therapy.

Thirty-eight cases of lentigo maligna and 22 cases of lentigo maligna melanoma, were reviewed in order to compare cure rates of various methods of treatment. Surgical excision resulted in the best cure rate (91%); destructive modalities were less successful (45%). All lesions treated with 5% 5-fluorouracil recurred.

The original work with chemotherapy by regional perfusion began at Tulane University in 1957 [1, 2]. Based on previous work using indwelling arterial catheters to deliver chemotherapy directly into tumor bearing regions [3–5], the use of an extracorporeal oxygenated circuit was adapted to maintain and deliver a concentrated chemotherapeutic agent to the isolated tumor bearing region, obtaining a prolonged high dose tumor exposure with minimal systemic effects. Drug dosages were limited only by local tissue tolerance. The technique was applied in a variety of tumor types, and to most areas of the body, but the most dramatic responses were seen in melanoma of the extremities, for which no good systemic agents existed at that time. Objective responses were seen in more than half of the melanoma patients following limb perfusions, a response rate still unequalled by any systemic agent or combination of agents.

Macrophages require a plasma component, designated "recognition factor" (RF), for the expression of optimal function. The RF activity was profoundly depleted in plasma from patients with malignant disease, and the degree of depletion and the severity of the malignant state seemed to be related. Since experiments demonstrated that an active RF significantly inhibited tumor growth, clinical studies were initiated to investigate the influence of intratumor administration of an active RF fraction. Glucan, a potent macrophage activator, was also employed alone or combined with RF. These studies were undertaken to enhance the recognition of malignant cells by macrophages and to mobilize and activate macrophages intralesionally. The initial 9 patients studied had malignant melanoma, adenosquamous carcinoma of the lung, or carcinoma of the breast. Control and experimental lesions were injected; subsequently biopsies were performed at varying intervals for histologic evaluation. Always when glucan or glucan and RF fraction were administered intralesionally, the size of the lesion was strikingly reduced in as short a period as 5 days. This reduction was associated with necrosis of the tumor and a monocytic infiltrate. In small lesions, resolution was complete, whereas in large lesions, resolution was partial. The amount of glucan injected and the quantity of residual tumor appeared to be related. The induced necrosis of the tumor nodule was associated with an increase in plasma levels of circulating RF activity.

From 1957 through 1977, a total of 714 patients with malignant melanoma were treated by chemotherapy administered by isolated regional perfusion of the limbs, and 56 patients were treated by intra-arterial infusion. Excisional surgery and adjunctive perfusion in 286 patients with stage I disease resulted in cumulative survival rates of 87% at 5 years and 75% at 10 and 15 years. With recurrent or metastatic regional disease treated by perfusion alone or in combination with surgical excision, the survival rates were 36%, 34%, and 31% at 5, 10, and 15 years, respectively. Even in the least favorable group, those with nodal and soft tissue involvement, the survival rates were 27% at 5 years and 22.5% at 10 and 15 years. Analysis of 121 patients with stage I melanoma according to level of dermal invasion showed recurrence in 2 of 42 (4%) patients with level III lesions, 11 of 75 (15%) with level IV tumors, and 2 of 4 (50%) with level V lesions. Recurrence rates by pathologic type were 2 of 49 (4%) patients with superficial spreading melanoma, 6 of 30 (20%) with nodular melanoma, and 5 of 14 (36%) with acral lentiginous melanoma, the latter including subungual, plantar, or palmar lesions. Chemotherapy by intra-arterial infusion is a technique useful in treating regional disease not amenable to isolation-perfusion. Of 36 patients having measurable lesions, there were 4 complete responses. Objective responses occurred in 50–80% of patients treated, depending on the agent used. As an adjunct to surgical treatment, chemotherapy by isolation-perfusion offers improved survival rates without prolonged treatment or the risks associated with systemic chemotherapy. As primary therapy for advanced regional disease, chemotherapy by perfusion produces survival rates superior to those obtained by surgery alone or systemic chemotherapy.

Eight chimpanzees were immunized, each with a single melanoma cell line. It was found that the serum of only one of the eight chimpanzees showed immunofluorescence with four of the five melanoma cell lines at the membrane surface; but it showed no fluorescence with normal skin fibroblasts, WI-38 cells, HeLa cells, human or monkey kidney cells. With appropriate absorption studies it was found that the antiserum was specific to melanoma cell lines. Trypsinated cells showed bright patchy membrane fluorescence, whereas non-trypsinated cells showed bright full ring fluorescence. The chimpanzee's antibody was C'-fixing IgG. It was concluded that the immunized chimpanzee produced antibody to surface antigen(s) common to four of the five melanoma cell lines tested.

Since 1957, 822 patients with invasive malignant melanoma of the limbs were treated by regional perfusion at the Tulane Medical Center. Between 1958 and 1982, there were 32 patients with regional metastatic melanoma from an unknown primary site involving either the upper limb and axillary lymph nodes or lower limb and femoral or inguinal lymph nodes. This group represents 3.5% of patients with regional melanomas treated during this period. There were 16 patients with upper limb regional metastases and 14 patients with lower limb metastases. Sixteen patients had stage IIIB disease (ie, regional lymph node metastases), ten had stage IIIA disease (ie, satellitosis), and four had stage IIIAB disease. Six patients had a history of a suggestive limb lesion that had completely regressed and showed no residual tumor on biopsy. All 30 patients were treated by regional isolated perfusion and regional lymph node dissection, with surgical excision of in-transit disease when possible. The cumulative five-year survival for all patients is 50%. Interestingly, the patients with a history of a lesion that regressed had 85% cumulative five-year survival, and the patients with stage IIIB disease did almost as well, with 62% surviving for five years.

The original work with chemotherapy by regional perfusion began at Tulane University in 1957 (Creech et al. 1958; Ryan et al. 1958). Based on previous work using indwelling arterial catheters to deliver chemotherapy directly into tumor-bearing regions (Bierman et al. 1950; Klopp et al. 1950; Sullivan et al. 1953), the use of an extracorporeal oxygenated circuit was adapted to maintain and deliver a chemotherapeutic agent to the isolated tumor-bearing region, obtaining high-dose tumor exposure, with minimal systemic effects. Drug dosages were limited only by the local tissue tolerance. The technique was applied to a variety of tumor types, and in most areas of the body, but the most dramatic responses were seen in melanoma of the extremities, for which no good systemic agents existed at that time. Objective responses were seen in more than 50% of melanoma patients following limb perfusions, a response rate still unequaled by any systemic agent or combination of agents.

Antisera to common human melanoma antigens were obtained from melanoma patients receiving autologous immunization with their own irradiated cultured melanoma cells and Bacillus Calmette-Guérin. The antibody thus derived was used to detect common antigens on the plasma membrane of three different human melanoma cell lines by membrane immunofluorescence. The antigen-antibody complexes on the surface of melanoma cells would move to a pole (capping) and would subsequently be extruded into the extracellular milieu at room temperature. Approximately 25 to 30% of viable cells were positive by immunofluorescence. However, when the cells were fixed with methanol, 60 to 70% of cells demonstrated membrane binding. Capping was inhibited at 0 degrees or when the cells were pretreated with vinblastine sulfate. It can be concluded that common tumor antigens exist on the surface of viable human melanoma cells and that the redistribution of antigen-antibody complexes is an active process. The extrusion of antigen-antibody complexes in vitro may represent a mechanism of antigenic modulation in vivo and could indicate a basic method of tumor survival since presumably the antigen-denuded cell is viable and capable of replication but not of recognition by subsequent effector immune events.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

• A 6-year-old girl with unresectable and metastatic neuroblastoma had a complete remission with irradiation to the primary tumor and systemic administration of cyclophosphamide. The patient was disease-free for 16 years but had an explosive recurrence of tumor six weeks after a hysterectomy. Although no clear cause-and-effect relationship exists between the surgery and the recurrence, this case illustrates that a recurrence is possible after a long disease-free interval. Diagnostic and therapeutic procedures in such patients should be undertaken with caution. ( Arch Surg 1981;116:474-475)

When a single focus of metastatic carcinoma is discovered for which no primary tumor can be found, the prognosis is extremely poor. In 75 per cent of these patients, the primary tumor will never become apparent. An analysis of fifty-three cases indicates that considerable palliation and some permanent cures may be achieved by the proper selection of patients for treatment. External radiation for undifferentiated carcinoma and external radiation followed by extirpation of the involved lymph node chain for epidermoid carcinoma offer the best hope for prolonged survival. If the patient survives one year, his chances for prolonged survival are good.

Introduction Tetanus, although less common today than in former years, remains a challenge to the medical profession. The case fatality rate for tetanus is generally regarded to approximate 50%, and the organismClostridium tetani, an anaerobic, Gram-positive rod which forms spores, is universal in distribution, particularly in soil and feces. The case fatality rates observed in various studies of tetanus conducted at the Charity Hospital of Louisiana at New Orleans have declined since 1906 but still remain alarmingly high (Table 1). The present review of experiences at this same institution from 1957 through 1961 was undertaken to bring attention to continuing problems in diagnosis and treatment of this preventable infection. Of the 80 patients with tetanus seen at Charity Hospital during this five-year period, 65 had traumatic tetanus and 15 had tetanus neonatorum (Table 2). Their ages ranged from the newborn period to 84 years. Prophylaxis. —Tetanus rarely occurs in

Publisher Summary This chapter focuses on cancer chemotherapy by perfusion. Perfusion has been employed in the treatment of cases that are inoperable because of local extension of the tumor, or when the patient has refused radical and deforming extirpative operations. Techniques of regional perfusion are based on the concept that various anatomic regions can be isolated from the remainder of the circulation, supplied with a separate, extraneous system for pumping and oxygenating the blood, and can be maintained for varying periods of time under abnormal conditions without significant systemic effect. By altering the character and temperature of the perfusing medium, the normal biochemical environment of a tumor may be selectively altered. The techniques of perfusion discussed in the chapter include lower extremity perfusion, upper extremity perfusion, pelvic perfusion, brain perfusion, perfusion of oropharyngeal area, and total body perfusion. The chapter also discusses the escape of agent from the perfusion circuit. A standard technique has been developed for determining the dose of a chemotherapeutic agent to be administered by perfusion. The effect upon normal tissues in a perfused region depends upon the amount of an agent used. The pathologic changes occurring in perfused malignant tissues vary widely. In addition to the problems which may follow any major surgical procedure, perfusion techniques give rise to special problems that call for close attention during the period after treatment. The most common complication of cancer chemotherapy by perfusion is depression of hematopoiesis. Morbidity from cancer chemotherapy by perfusion is greater than what would be expected to occur after similar surgical procedures without chemotherapy.

Review of six years' experience with regional perfusion in the treatment of melanoma of the limbs reveals a four-year cure rate of 44%. Six of 12 patients treated five years ago have no evidence of malignant disease. Nine of 20 patients with satellitosis or clinically positive inguinal nodes treated four years ago are apparently free of melanoma.