Hereditary deficiency of the sixth component of complement in man. II. Studies of hemostasis.

Prompted by previous observations of defective blood clotting in rabbits deficient in the sixth component of complement (C6), an evaluation was made of the hemostatic functions of the homozygous proband of a newly recognized human kindred with hereditary C6 deficiency. This human subject, who had no clinical evidence of a bleeding disorder, exhibited a total lack of C6 by functional and immunoprecipitin assays of serum or plasma. Standard tests of hemostatic function were normal; however, when the whole blood clotting time was measured at 25 degrees C in plastic tubes, it was at the upper range of our normal values. In confirmation of this observation, prothrombin consumption, when performed at 37 degrees C in plastic tubes, was at the lower range of normal. Inulin and endotoxin, in concentrations shown to cause activation of human complement, had little or no effect on clotting times or prothrombin consumption of normal or C6-deficient human blood. These observations indicate that absence of C6 does not have a significant effect on hemostatic function in man. In the light of other investigations, the observed differences in clotting function between C6-deficient human blood and C6-deficient rabbit blood could be due to species differences governing the susceptibility of platelets to complement activation.

Radiation therapy salvage of Hodgkin's disease following chemotherapy failure.

Between 1972 and 1984, 17 patients with advanced Hodgkin's disease failing intensive combination chemotherapy in previously unirradiated nodal and/or pulmonary sites were treated with salvage radiotherapy. Treatment consisted of comprehensive wide field radiotherapy to all known areas of disease. Doses administered to these fields ranged from 1,700 to 5,000 rad, with only three patients (18%) receiving less than 3,000 rad to any field. With a median follow-up of over 4 years, 88% achieved a complete response, with median actuarial disease-free survival (DFS) of 19 months (range, 4 to 61+). Actuarial median survival was 64 months, with a range of 4 to 134+ months. Nine patients (53%) are currently alive with three (18%) in continuous complete remission (CR) for 24, 30, and 61 months. In addition, four patients relapsing after salvage radiotherapy are now in CR following additional therapy. Patients younger than 35 years of age had a significantly increased overall survival when compared with older patients (P less than .005). An initial complete response to chemotherapy lasting 12 or more months appeared to be a favorable prognostic factor, although small patient numbers preclude statistical significance. Comprehensive salvage radiotherapy is of significant benefit in patients with advanced Hodgkin's disease relapsing after combination chemotherapy in nodal and/or pulmonary sites.

Hyperthermia by magnetic induction: II. Clinical experience with concentric electrodes.

Thirty-one patients with visceral or extensive superficial malignant tumors of various histologies and sites have been evaluated for our hyperthermia protocols employing magnetic induction at 13.56 MHz with concentric electrodes associated with a commercially available device. Response data in patients completing combined hyperthermia and radiation treatment was difficult to analyze because of the short survival of these patients with advanced disease. Acute toxicity, however, was limited to 2/31 patients with minor skin blistering from excessive superficial heating. In this report we focus on clinical thermometric results. In 6/31 (19%) of patients, portions of the tumor achieved greater than or equal to 42.5 degrees C. In 3/31 (10%), nearly all the tumor achieved greater than or equal to 42.5 degrees C. Those tumors successfully heated to greater than or equal to 42.5 degrees C throughout were relatively superficial. In 22/31 (71%), temperature greater than or equal to 42.5 degrees C were not achieved at any measured site. Maximum applied power levels were limited by development of painful superficial hot spots in 21/31 (68%), by diffuse discomfort or systemic intolerance in 9/31 (29%), by maximum power output from the generator in 1/31, or by other factors in 2/31 patients. Some patients had both local and systemic discomfort that limited power levels. Based upon analysis of the thermometric results, we discuss the anatomic sites and tumor depths for which this technique is most applicable.

Treatment of advanced cancer of the cervix with transperineal interstitial irradiation.

A pilot study using transperineal interstitial implantation to the parametrium in patients with locally advanced carcinoma of the cervix or with distorted anatomy is presented. Twenty-one consecutive patients (2 cervical stump Stage IB, 3 Stage IIB, 15 Stage IIIB, 1 Stage IVA) received one (12) or two (9) implants following 40-45 Gy whole pelvis external irradiation. In addition 8 patients underwent staging laparotomies concurrently with the first implant procedure. Control of the pelvic tumor was accomplished in 18 of 21 patients (85%) with a mean follow-up of 26 months (range 15 to 48 months). Seven patients (33%) developed long term complications (fistula 3, superficial necrosis of the vagina 1, severe proctitis or cystitis 3). Six of the complications occurred in 8 patients (75%) who had radioactive sources placed on the surface of the vaginal obturator as a substitute for the lack of tandem. In contrast, only 1 in the remaining 13 patients (8%) who did not have obturator sources placed, developed long term complications.

External beam radiotherapy in cancer of the prostate. The University of Arizona experience.

Between 1973 and 1979, 218 patients with adenocarcinoma of the prostate stage A2 through D1 were treated with primary external beam radiotherapy. The majority of the patients (211) received 6000-7000 rad to the prostate using a small (160) or large (58) volume technique. With a minimum follow-up of 36 months and a maximum of 120 months, the control rates of the local tumor were 96%, 95%, 88% and 81% for stage A2, B, C and D1. The corresponding 5-year survivals were 100%, 82%, 60% and 42%. Mild to severe complications were documented in 35 cases (16%). The frequency and severity of the complications correlated with the size of the irradiated volume and history of previous surgery. The use of large fields, to encompass the regional lymphatics, is not associated with improved survival.

Adjuvant treatment of node-positive breast cancer with adriamycin-cyclophosphamide with or without radiation therapy: interim results of an ongoing clinical trial.

During 1974-1980, 138 women with node-positive stage II breast cancer were treated with either eight courses of adriamycin-cyclophosphamide (AC) chemotherapy (82 patients) or AC chemotherapy plus comprehensive regional radiotherapy (56 patients). The overall relapse-free survival of the treated patients was significantly superior (P less than 0.001) to a comparable group of women who underwent surgery alone. This effect of adjuvant therapy was clearly manifest in all groups of patients irrespective of nodal involvement or menopausal status. To date, relapse-free survival for patients receiving AC compared to AC plus radiotherapy is not different (P = 0.7). In summary, wer have demonstrated that a brief 6-month course of adjuvant chemotherapy with AC can significantly reduce the recurrence rate in women with stage II breast cancer.

Comprehensive radiotherapy for advanced Hodgkin's disease refractory to chemotherapy.

Seven patients with advanced nodular sclerosing Hodgkin's disease who relapsed after initial intensive combination chemotherapy were selected for individualized pathologic restaging and comprehensive radiotherapy. One patient failed to respond completely to mantle-field irradiation and no further staging or radiotherapy was undertaken. Six other patients underwent staging laparotomy and received total nodal irradiation including prophylactic lung irradiation (5 cases) and hepatic irradiation (3 cases). Irradiation was well tolerated. Complete remission was achieved by 5 patients and 2 continue in remission 29+ and 32+ months after beginning of irradiation. Five of the 7 patients remain alive. This study indicates that comprehensive irradiation is a relatively well tolerated and effective treatment for carefully selected patients with advanced Hodgkin's disease who have relapsed after combination chemotherapy. For selected patients, pathologic restaging and comprehensive radiotherapy can be considered as an alternative to further chemotherapy.

Combination chemotherapy of metastatic malignant schwannoma with vincristine, adriamycin, cyclophosphamide, and imidazole carboxamide: a case report.

This report describes a patient with a 15-year history of schwannoma (peripheral nerve sheath sarcoma) who developed extensive pulmonary metastases associated with hypoxemia. Treatment with chemotherapy consisting of cyclophosphamide, vincristine, Adriamycin, and imidazole carboxamide resulted in a complete remission lasting 17+ months. Malignant schwannoma should probably be regarded as a drug sensitive neoplasm.

Prospects for hyperthermia in human cancer therapy. Part I: hyperthermic effects in man and spontaneous animal tumors.

Systemic hyperthermia in man may occur by accident, as in heat stroke or malignant hyperthermia during general anesthesia, or it may be therapeutically induced (fever therapy). The latter has been used infrequently since the advent of antibiotics, except recently for treatment of cancer. Local or regional heating combined with x irradiation for human cancer therapy has been sporadically reported for over 60 years, but has not found its place in clinical medicine possibly due to technical limitations in heat production and dosimetry. Preliminary results are reported for treatment of spontaneous animal tumors with radiofrequency current fields and x irradiation.

Hereditary C6 deficiency in man.

An 18-year-old black female (D.B.) in good general health was found to have no hemolytic activity in serum CH50 titrations. Functional assays yielded normal values for all C components except C6. C6 was not detectable in plasma or serum by two different functional assays nor by antigenic analysis using monospecific anti-C6 antibody. Hemolytic activity was restored by addition of functionally pure C6. By specific functional assay, both parents and 5 of 6 available sibs had approximately half-normal serum C6 levels and 1 sib was normal. Biologic properties of D.B. serum include: a) absent bactericidal activity against S. typhi 0 901 with or without added rabbit antibody; b) normal generation of chemotactic activity for human neutrophils in the presence of endotoxin or aggregated IgG; c) ability to sensitize appropriate cells for immune adherence of agglutination by anti-C3 Coombs serum; and d) inability to lyse PNH red cells in either acid hemolysis or "sugar water" tests. An extensive clotting workup by standard methods was within normal limits. These studies document for the first time a human kindred with C6 deficiency. This defect exhibits a classic mendelian autosomal inheritance, with all 3 genotypes being recognizable. Unlike the C6-deficient rabbits studied by others, the homozygous C6-deficient human exhibits chemotactic and coagulation functions within the range of normal.