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Background. The response rate of metastatic renal cell cancer to cytotoxic therapy over the last 10 years has been 5.6%. Low dose continuous 5-fluorouracil (5-FU) has demonstrated efficacy in other cytotoxic refractory tumors, such as pancreas, colorectal, and recurrent breast. The Southwest Oncology Group undertook a Phase II trial of low dose, continuous 5-FU in metastatic renal cell cancer. Methods. Sixty-one patients were entered in the study to receive 300 mg 5-FU/m2/day for 7 days via a central venous catheter and external programmable pump. The pump was refilled every 7 days. Pyridoxine (50 mg, orally) was administered prophylactically three times a day. Results. A response of 5.2% (one complete response [CR] and two partial responses [PRs]) was achieved. The overall survival was 12 months. The duration of the CR is more than 30 months. Both PRs lasted 6 months. No survival advantage was noted with either prior nephrectomy or biologic therapy. The majority of toxicities were Grade 2: anemia, anorexia, diarrhea, nausea/vomiting, and stomatitis. No toxic deaths occurred. Conclusion. Low dose, continuous 5-FU demonstrated minimal activity in metastatic renal cancer.

Soft tissue sarcomas are generally resistant to most chemotherapeutic agents, and individuals with advanced disease have a poor prognosis. We evaluated amonafide, a new drug that has significant activity against several tumor cell lines, to determine its activity against sarcomas. Amonafide was administered to 18 patients with advanced soft tissue sarcoma (16 of whom had received prior chemotherapy) at a dose of 300 mg/m2 over 60 min daily for 5 days. Courses were repeated every 21 days. Toxicity was mild, but no responses were observed. We conclude that amonafide is not an active agent in previously treated, advanced soft tissue sarcomas in the dose and schedule utilized.

BACKGROUND Potential synergy between 5-fluorouracil (5-FU) and interferon alpha-2a (IFN-alpha-2a) has been demonstrated in the treatment of colorectal carcinoma. Continuous low-dose infusion of 5-FU may have superior response rates to bolus 5-FU in these malignancies. This report presents results of two Phase II trials using these principles in colorectal cancer. METHODS Forty-eight patients were entered onto two protocols; 18 were treated with 5-FU by a bolus infusion schedule with concurrent IFN-alpha-2a (Group 1). Thirty patients were treated with continuous low-dose 5-FU and IFN-alpha-2a thrice weekly (Group 2). RESULTS The overall response rates were 33% (95% confidence interval [CI], 16-68%) and 33% (95% CI, 17-53%), respectively, for Groups 1 and 2. In Group 2, in 16 previously untreated patients, there was a response rate of 56% (95% CI, 30-80%). The median survival was 11 months and 6 months for Groups 1 and 2, respectively. Toxicity in Group 1 was as expected, except the incidence of central nervous system toxicity was low, with only one patient requiring dose reduction because of cerebellar ataxia. The toxicity in Group 2 was substantial, with four patients being removed from study because of toxicity and all patients treated for more than 2 months requiring dose reductions. The most common (67%) toxicity was mucositis, with 33% of those patients classified as Grade III or IV (Southwest Oncology Group criteria). Other major toxicities were fatigue and hand/foot syndrome. CONCLUSIONS The first trial confirms previous response rate data for bolus injection 5-FU and IFN-alpha-2a. The second trial of low-dose continuous infusion 5-FU with IFN-alpha-2a demonstrates similar efficacy with substantially greater toxicity.

BACKGROUND Etoposide may be schedule dependent in small cell lung cancer (SCLC), and some data suggest a benefit for increased dose intensity in this disease. This study attempted to optimize dose intensity using an outpatient program that included prolonged, oral etoposide administration. METHODS Cisplatin-etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV) were alternated at monthly intervals in patients with extensive SCLC. PE was given as cisplatin 50 mg/m2 on days 1 and 8 intravenously (i.v.) and etoposide 50 mg/m2/day for 14 days by mouth. CAV was administered as cyclophosphamide 60 mg/m2/day for 21 days orally, doxorubicin 20 mg/m2/week for three doses, and vincristine 2 mg i.v. on day 1 only. At the end of 4 months, responding patients received an additional course of PE alternating with CAV, and whole-brain irradiation (3000 cGy in 15 fractions) was delivered to clinical complete responders (CR). RESULTS Among 61 eligible patients, 4 achieved CR, and 11 had a partial remission, by strict Southwest Oncology Group criteria. An additional 20 patients demonstrated greater than 50% tumor shrinkage on one disease assessment but did not have confirming measurements at all sites 4 weeks later. The overall response rate was 57%, including the latter group. The toxicity was primarily hematologic, with three treatment-related deaths from neutropenic infection (5%). Grade 4 neutropenia (< 500/microliters) occurred in nine patients (15%) and Grade 4 thrombocytopenia (< 25,000/microliters), in three (5%). Analysis of the delivered dose intensity (in milligrams per square meter per week) as a function of that which was planned revealed a mean of 93% for all courses. CONCLUSIONS Although substitution of prolonged oral etoposide in PE and oral cyclophosphamide in CAV proved to be feasible, these results suggest no advantage over those from other reported series using these alternating regimens in which the agents are pulsed. Experience with alternating PE-CAV for extensive SCLC is reviewed.

PURPOSE To test the concept that cisplatin dose-intensity is important in the treatment of non-small-cell lung cancer (NSCLC), the Southwest Oncology Group (SWOG) performed a randomized trial comparing standard-dose cisplatin (SDCP) 50 mg/m2 days 1 and 8 on a 28-day cycle for eight cycles, high-dose cisplatin (HDCP) 100 mg/m2 days 1 and 8 for four cycles, and high-dose cisplatin plus mitomycin (HDCP-M) 8 mg/m2 day 1. To isolate the effects of dose-intensity versus total dose, the planned cumulative cisplatin dose was 800 mg/m2 in each arm. PATIENTS AND METHODS Between July 1988 and April 1990, 356 patients were enrolled and 323 were eligible and assessable. All patients had metastatic, measurable disease, were chemotherapy-naive, and had a performance status (PS) of 0 to 2. RESULTS Confirmed complete plus partial response rates were SDCP, 12%; HDCP, 14%; and HDCP-M, 27% (P < .05). Complete responses were uncommon (HDCP, 3%; HDCP-M, 4%) and were observed only in the high-dose arms. Progressive disease occurred more frequently in the SDCP arm (57%) compared with HDCP (38%) or HDCP-M (34%) (P < .05). However, there were no significant differences in median survival times (SDCP, 6.9 months; HDCP, 5.3 months; HDCP-M, 7.2 months; P = .53). The mean delivered dose-intensity for cisplatin was significantly greater in the high-dose arms: HDCP 41 mg/m2/wk and HDCP-M 39 mg/m2/wk, versus SDCP 23 mg/m2/wk (P = .05). The high-dose arms resulted in an increased incidence of ototoxicity, emesis, and myelosuppression, but similar degrees of renal toxicity and neuropathy compared with SDCP. CONCLUSION This study does not confirm evidence of a steep clinical dose-response curve for cisplatin in NSCLC at the cisplatin dose-intensities achieved. The addition of mitomycin increases the response rate, but does not improve survival. Continued evaluation of new agents in this disease is warranted.

Objectives: We sought to evaluate the effectiveness of HspE7, a recombinant fusion protein of Hsp65 from Mycobacterium bovis BCG and E7 protein from human papillomavirus 16, to improve the clinical course of pediatric patients with recurrent respiratory papillomatosis. Methods: An open-label, single-arm intervention study was conducted in 8 university-affiliated medical centers. Twenty-seven male and female patients with recurrent respiratory papillomatosis, ages 2 to 18 years, were enrolled and followed up to 60 weeks. Before enrollment, these patients required surgery on average every 55 days. After a baseline debulking surgery, the patients received HspE7 500 μg subcutaneously monthly, for 3 doses over 60 days. The primary end point was the length of the interval from the last surgery during the treatment period until the first debulking surgery in the posttreatment period, compared with the median intersurgical interval (ISI) of the 4 surgeries before the treatment. Results: The mean of the first posttreatment ISI increased 93% (from 55 days to 106 days; p < .02). The median ISI for all surgeries after treatment was similarly prolonged (mean, 107 days; p < .02), indicating a sustained treatment effect, and was associated with a significant decrease in the number of required surgeries (p < .003). Unexpectedly, the treatment effect was most striking in the 13 female patients, who had statistically significant increases in both the first posttreatment ISI (142%; p < .03) and the median ISI (147%; p < .03). The most common adverse events were mild-to-moderate injection site reactions. Conclusions: Treatment with HspE7 appears to significantly improve the clinical course in pediatric patients with RRP insofar as it reduces the frequency of required surgeries. These results warrant a confirmatory phase III trial.

Patients with measurable metastatic or recurrent squamous carcinoma of the uterine cervix who had failed prior surgery or radiation therapy were enrolled on this randomized phase II study. Twenty-seven eligible patients were assigned to receive didemnin B at either 2.6 mg/m2 iv every 28 days (sixteen patients) or at 5.6 mg/m2 (eleven patients). Sixteen patients were assigned to receive 12 mg/m2/day iv trimetrexate for 5 days, repeated every 21 days. Toxicity for didemnin B was characterized by nausea and vomiting (78% of patients), anemia (59%), mild diarrhea (11%), and episodic hypersensitivity (three patients). Toxicity for trimetrexate included nausea and vomiting (69%), leukopenia (51%), mild thrombocytopenia (38%), anemia (63%), and diarrhea (31%). No antitumor responses were observed for either agent. Neither trimetrexate nor didemnin B at these doses and schedules is recommended for the treatment of advanced squamous carcinoma of the uterine cervix.

Fifty evaluable patients with advanced colorectal cancer, but without prior chemotherapy or immunotherapy, were randomized to one of two schedules of recombinant gamma-interferon (rGIFN). Twenty-four evaluable patients received rGIFN as a 2-h intravenous infusion daily x 5 every other week at a starting dose of 4.0 x 10(6) IU/m2/day (arm I). Twenty-six evaluable patients received rGIFN as a 24-h continuous intravenous infusion daily x 5 every month at a starting dose of 2.6 x 10(6) IU/m2/day (arm II). Toxicities on both schedules included flu-like symptoms, fevers/rigors, nausea/vomiting, hypotension, leukopenia, hepatotoxicity, nephrotoxicity, diarrhea, anemia, confusion, and ileus. Toxicity appeared to be more severe on arm I. No antitumor responses were observed, with 95% confidence intervals of 0 to 14% for arm I and 0 to 13% for arm II.

Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days. Eight patients responded objectively and six patients (6%) had a complete response. The median duration of complete response was 11 months. Patients achieving complete response had only cutaneous, nodal, or pulmonary disease; some had extensive prior therapy; some could tolerate no more than three million units per day. Few patients could tolerate the target dose of 36 million units daily for 70 days. Limiting toxicity was primarily fatigue. Interferon in tolerable doses is effective in a small subset of patients with melanoma. Comparison of published trials of dacarbazine and recombinant alpha interferon indicates the two drugs have similar activity.

Lethally irradiated rhesus monkeys were used for bone marrow allografting and autografting. Monkeys receiving allogeneic bone marrow developed acute graft-versus-host reaction (GVHR) and had a mean survival time of 9.1 days as compared to autografted monkeys which survived above 500 days. Treatment with antilymphocyte sera (ALS) before allografting modified the GVHR and extended the survival time to an average of 43 days. Histologically, such animals showed evidence of "chronic" GVHR and septicemia secondary to a lack in lymphoreticular recovery. Subsequently, severe GI-tract infections followed which usually served as portal of entry for septicemia.

It has been shown with glucose 6-phosphate dehydrogenase (G-6-PD) mosaicism that Ph1-positive chronic myelogenous leukemia (CML) is a clonal disease that involves multipotent hematopoietic stem cells. We now report G-6-PD studies of a 79-yr-old woman with Ph1-negative CML. Equal amounts of B and A-type activities were found in nonhematopoietic tissues, indicating that the patient was heterozygous for G-6-PD. In contrast, only A-type G-6-PD was found in marrow cells, blood erythrocytes, leukocytes, and platelets and in granulocyte-monocyte and eosinophil colonies grown from blood mononuclear cells. Unlike most cases of PH1-positive CML, colony growth in this patient increased during blastic transformation and the colonies contained only immature monocytic cells. The data indicate that in this patient, Ph1-negative CML is similar to the Ph1-positive form of the disease in involvement of multipotent stem cells and probable clonal origin, but the two disorders differ in the rapidity with which they enter blastic transformation and in the pattern of granulocyte-monocyte colony growth at that time.

Plasma perfusion over filters containing staphylococcal protein A (SPA) was used to treat 11 patients with adenocarcinoma who developed a hemolytic uremic syndrome. Immunoperfusion resulted in complete clearance of pretreatment elevated levels of circulating immune complexes in eight of the 11 patients with normalization of complement values depressed at the start of the therapy in seven. A significant rise in platelets and erythrocyte counts was achieved in nine patients, and stabilization of progressive renal impairment was achieved in six. The response was incomplete and short lived in three patients with clinically evident tumor recurrence, whereas long-term control of the syndrome was demonstrated in seven patients in complete tumor remission (no recurrence with median follow-up of 9 months). SPA immunoperfusion appears to be an effective form of therapy for this otherwise fatal syndrome.

The lymphocytotoxicity of 116 rhesus monkey alloantisera was evaluated in 92 unrelated rhesus monkeys and in 33 pedigreed rhesus families. The study was conducted using a standard complement-dependent microcytotoxocity assay. A computer-assisted chi2 analysis of the reactivity of these sera in unrelated monkeys generated 23 groups of highly correlated antisera. The two-locus model of the mammalian major histocompatibility complex was assumed for the monkey, and genetic criteria for RhL-A antigens were determined before study. Seventeen groups of antisera which had met these predetermined criteria in a previous study using a different random population of monkeys were confirmed in the present analysis. The remaining six groups also met these predetermined criteria, although the genetic data for two were incomplete. Of the 23 antigens defined, 12 appeared to be products of the A locus and 11 of the B locus. Nineteen were similar or identical to antigens previously described by us or by Balner and coworkers in The Netherlands. Two groups have not been previously described. A frequency analysis indicated that these 23 antigens represented approximately 75% of the total expression of the RhL-A-A and RhL-A-B loci.

Cytotoxic lymphocytes produced by in vitro sensitization to H-2 alloantigens may be adsorbed efficiently and specifically on monolayers of spleen lymphocytes attached to poly- l -lysine-coated polystyrene. Greater than 16-fold median reduction in activity resulted from adsorption to the target-type monolayer while adsorption to the attacker-type monolayer resulted in a less than two-fold median reduction. Since this reduction could have resulted from competitive inhibition by detached monolayer cells rather than from sticking of the cytotoxic cells to the monolayer, experiments were performed to distinguish between these possibilities. The inhibitory properties of a nonadherent population were tested directly by addition to a different attacker-target combination in which its killing properties were irrelevant but in which the H-2 genotype of detached monolayer cells was appropriate to cause competitive inhibition. No significant inhibition was observed; and this indicated that reduction of activity in an adsorbed population results from removal of the cytotoxic cells and not from inhibition by detached monolayer cells competing with the labeled targets for attackers.

Gastric carcinoma, despite a decreasing incidence in the United States over the past 40 years, is the seventh most common cause of cancer death in this country and remains a significant worldwide problem. The 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin (FAM) chemotherapy regimen, which was initially reported by Georgetown in 1979, has become a standard for advanced gastric carcinoma with response rates in the 40% range. The FAM regimen as well as subsequent trials conducted at Georgetown and our current approach to management of this tumor are discussed. Despite a decade of intensive clinical research, we have not identified a modification or innovation that is superior to the original FAM.

Twenty-one patients with metastatic colorectal cancer were treated with high-dose intravenous interferon alpha-2 (30-50 X 10(6) units/m2) administered daily for 5 consecutive days. Courses of therapy were repeated every 2 to 3 weeks. No tumor responses were seen among 15 evaluable patients. In two subjects, disease remained stable for 3 and 7 months, respectively. Toxicity was substantial and a de-escalation of dose was frequently required. Fevers, gastrointestinal symptoms, fatigue, leukopenia, and elevated serum transaminases were common. High-dose interferon was found to be ineffective in the treatment of metastatic colorectal cancer. A daily dose of 50 X 10(6) units/m2 was greater than the maximum tolerated dose in this group of patients.

Appendiceal vasculitis and splenosis in a young woman provided pathologic evidence that a systemic necrotizing vasculitis preceded the onset of hairy cell leukemia by at least six years. As in other patients who have had both diseases, florid polyarteritis nodosa developed during the course of the malignancy. However, the antecedent vasculitis, as well as the coincidence of these rare diseases, indicate that systemic vasculitis does not necessarily result from hairy cell leukemia as previously reported and suggest that the two diseases might share a common pathogenesis or predisposing factor.

Statistical analysis of paired observations indicated that RhLA-A,B disparate teeth caused the accelerated rejection of tooth-donor skin grafts placed 21 to 24 mo after tooth allotransplantation, but not at 30 to 34 mo. Teeth transplanted between matched monkeys did not cause the accelerated rejection of skin grafts.

The mechanism of the lytic event in cell-mediated lympholysis is as yet incompletely understood. Two major hypotheses have been proposed: (1) lysis is a nonspecific result of the intimacy created between killer and target by specific antigen-receptor binding, and (2) lysis is effected by the killer cell receptor itself or by a closely linked cell surface component. Two populations of cytotoxic effector cells were coincubated, one relevantly sensitized to the second and the second irrelevantly sensitized to a third party; in some experiments the third party cells were also added. If target cell lysis occurred because of killer-target intimacy, the relevantly sensitized killers should have been lysed when incubated with cytotoxic targets. Relevantly sensitized killers were not lysed when coincubated with either cytotoxic targets alone or with cytotoxic targets and their appropriate third party targets. These findings suggest that the lytic event in cell-mediated lympholysis is accomplished by the receptor itself, or by a geographically closely linked cell surface component.

That viral hepatitis may be transmitted by whole blood or plasma is well known. The assumption has often been made that persons suffering from clinically inapparent infection are transient carriers of the virus and are infectious for only short periods of time. The existence of long-term asymptomatic carriers of the virus of hepatitis has been demonstrated recently by Neefe and his coworkers and by Stokes and his associates. In the study of Neefe and his collaborators, 14 cases of viral hepatitis occurring in recipients of 1 to 3 blood transfusions were reported. In each instance, at least 1 donor for each of the 14 patients was found to have 1 or more abnormal hepatic tests when recalled and examined following the onset of viral hepatitis in the recipient of this blood. Blood serum from 5 of these 6 suspected carriers transmitted viral hepatitis to volunteers. The results of this study were sufficiently striking to suggest a search for hepatic tests that might be found useful in detecting donors who are carriers of viral hepatitis. The present paper deals with the incidence of abnormal hepatic tests in a large series of blood donors selected at random at this hospital.

Available information concerning the etiology and epidemiology of viral hepatitis, including both infectious hepatitis and homologous serum hepatitis, is reviewed and evaluated. The clinical manifestations of the disease are considered primarily in respect to those infections which present problems in diagnosis and/or which deviate from the usual course of prompt and spontaneous recovery. These include fatal hepatitis, recurrent and/or relapsing hepatitis, prolonged hepatitis, chronic hepatitis, the carrier state and certain other post-hepatitis states of uncertain relationship. Some of the problems in diagnosis and changing concepts in treatment are presented. An attempt is made to evaluate the present status of the multiple problems associated with the prevention and control of viral hepatitis, particularly in respect to those infections acquired from blood and its derivatives.

Viral hepatitis is a disease of relatively long duration and high morbidity.The course of the uncomplicated forms of this disease varies greatly from that of the complicated varieties; however, the initial symptoms of fatal viral hepatitis often do not differ from those of a mild infection. No specific cultural or serologic tests for viral hepatitis are available; properly selected hepatic tests constitute the most valuable nonspecific diagnostic aids. The prognosis for the average infection is excellent.The incidence of complications may vary with the virus concerned and with the age, sex and over-all condition of the patient.

Summary It seems clear from the data presented that routine use of ACTH and cortisone is not indicated in any form of liver disease. The results to date with this therapy are unpredictable. From the present experience it seems likely that ACTH and/or cortisone are indicated in patients with acute hepatic disease of viral origin where jaundice is deep and sustained for several weeks. One can expect a rapid diminution of serum bilirubin in these patients. A trial of corticosteroid therapy is probably also indicated in patients with acute hepatitis who have suffered a spontaneous relapse of their disease. In the usual patient with viral hepatitis who remains jaundiced for 3 to 5 weeks, on the other hand, ACTH will probably not prove to be useful unless further studies demonstrate a significant shortening of the convalescent period by corticosteroids. The regular return of well-being and appetite and the continued improvement of liver function which have resulted from the use of ACTH and cortisone in certain cases of chronic viral hepatitis would seem to make a trial of these substances desirable, particularly in those cases where conservative therapy has failed. It should be remembered, however, that the sodium and water retention which result from the use of corticosteroids may complicate management to such a degree that one may be forced to withdraw the medication. Similarly in hepatic cirrhosis one may expect improvement of hepatic function under certain circumstances. In addition to the salt and water retention, the possibility of precipitating bleeding from esophageal varices should be considered. If it can be shown that the administration of large amounts of potassium will prevent sodium and water retention in patients with chronic liver disease, additional, perhaps more vigorous, trials of ACTH and cortisone will be warranted. A sudden withdrawal of corticosteroids may precipitate a relapse in any form of liver disease. On the other hand, administration of these substances has caused no demonstrable harm as far as the liver disease itself is concerned. The evidence favoring the use of ACTH and cortisone in hepatic coma has not been convincing. In view of the otherwise poor prognosis, however, the use of ACTH and cortisone as an adjunct to other measures may be indicated.

(1) Flocculation of cephalin-cholesterol emulsions by blood serum is markedly influenced by the amount of light to which the serum-saline-antigen suspensions are exposed. Protection from bright light, natural and artificial, has eliminated many falsely positive reactions. (2) Other factors that appear to influence the cephalin flocculation procedure have been briefly mentioned. Misses Dorothy Feinberg, Arvilla Howley and Mary Lanning contributed helpful technical assistance.

The immunologic and pharmacologic effects of free doxorubicin and of doxorubicin entrapped in liposomes were compared in mice at a dose of 20 mg/kg. Liposomes for encapsulation of doxorubicin were prepared by using 39.35 mumol drug, 19.65 mumol cardiolipin, 100 mumol phosphatidylcholine, 68.4 mumol cholesterol, and 38.9 mumol stearylamine. Pharmacologic disposition studies after a dose of 20 mg/kg demonstrated 7- to 10-fold higher drug concentrations in the spleen at all time points following administration of doxorubicin entrapped in cardiolipin liposomes than after the free drug. The levels in liver were 4- to 5-fold higher with liposomal drug, whereas the cardiac uptake with liposomal doxorubicin was significantly lower than with free drug. Mice were sacrificed on days 1, 8, 15, and 22 after drug administration and spleen cells were isolated for studies of sensitization to alloantigens for cell-mediated cytolysis and of proliferation in response to mitogens. Mice treated with free doxorubicin demonstrated a decrease of more than 50 fold (compared with saline control) in allospecific cytotoxic activity on day 15; normal levels were recovered by day 22. The animals treated with doxorubicin encapsulated in liposomes showed a similar but not more pronounced fall to low levels. The total lytic activity per spleen after free drug or drug encapsulated in liposomes was markedly reduced at day 8, but this activity was fully recovered by day 15 in animals receiving liposomal doxorubicin; in those receiving free drug it had not recovered fully even at day 22. The proliferative response to concanavalin A was affected by the two forms of doxorubicin in a pattern very similar to the cytotoxic response. The proliferative response to lipopolysaccharide was markedly depressed by doxorubicin delivered in either form, and the kinetics were not altered by the mode of administration. The concentration of doxorubicin in spleen was markedly increased with liposomal delivery, but did not result in greater toxicity than that of free drug according to the immunologic parameters evaluated.

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0 X 10(6) IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table. Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.

Chemotherapy with 5-fluorouracil, doxorubicin, and mitomycin-C was administered to 17 patients with locally advanced pancreatic cancer. The median survival for these patients was 8 months. With a multiaxial retrospective analysis, the overall survival of this study group appears to be least equivalent to that reported with 6,000 photon rad alone or of neutrons, and compares favorably to that achieved with combined 6,000 photo rad plus 5-fluorouracil. Of 15 relapses, only 4 had presented with evidence of disseminated disease. Based upon this analysis we recommend additional studies of combination chemotherapy with radiation therapy in future prospective randomized trials.

The lymphocytotoxic activity of 144 rhesus allonantisera was evaluated in 112 unrelated rhesus monkeys and 33 pedigreed rhesus families. This study was conducted using a standard complement-dependent microcytotoxicity assay. A computer-assisted chi2 analysis of the reactivity of these sera in the unrelated monkeys generated 23 groups of highly correlated antisera. The two-locus model of the mammalian major histocompatibility complex was assumed for the monkey, and genetic criteria for RhLA antigens were determined prior to study. Seventeen groups of antisera met these predetermined criteria. Six were products of the B locus and 11 were products of the A locus. Sixteen were similar or identical to antigens previously described by us or by Balner and coworkers in The Netherlands. One has not been previously described. A frequency analysis indicated that these 17 antigens represented approximately 74% of the total expression of these two loci.

SUMMARY Kaposi's sarcoma is associated with an increased frequency of HLA-DR5. The hypothesized model of a susceptibility gene in linkage disequilibrium with DR5 may be tested by haplotype analysis in familial Kaposi's sarcoma. Our finding of no common haplotype among afflicted members of a family provides evidence against the hypothesized linkage.

Two rhesus (Macaca mulatta) monkey lymphocyte-defined (LD) antigens have been identified using two typing cells as stiumlators in a one-way mixed leukocyte culture (MLC) assay. An analysis of the genetic behavior of these LD antigens in six rhesus monkey families revealed that both antigens were linked with RhLA. One probable recombinant indicated that the LD locus lies outside the two known RhLA-SD loci and the locus which controls the serum protein, properdin B(Bf). These two antigens, LD1 and LD2, had observed gene frequencies of 0.07 and 0.25, respectively. Neither of these two new LD antigens was significantly associated with any serologically defined (SD) antigen.

Publisher Summary This chapter describes the natural killer activity in cloned Interleukin-2 (IL-2) dependent allospecific lymphoid populations. Natural killer cells have been defined by their capacity to lyse certain allogeneic tumor targets without priming or prior exposure. A recognition and binding event is involved, and it appears that at least several widely distributed specificities may be involved in the recognition. In a study described in the chapter, interleukin-2 was generated in cultures of rat spleen cells stimulated with Concanavalin A. The supernatants were harvested at 24–48 h, filtered, and frozen. Aliquots were concentrated by ultrafiltration, assayed for activity against a standard IL-2 dependent cell line, and used at the defined optimally supportive strength. B6 possesses one such determinant not possessed by bm1 and this determinant is expressed on bm11 but not bm8. The allogeneic specificity displayed by these clones is very precise and must detect the strong specificity previously deduced by other methods. It was observed that five of seven clones also lysed the NK-susceptible target YAC-1. The feeders or IL-2 were not responsible for the NK activity, because all clones were maintained in an identical fashion: H44 and the negative clones showed no activity against YAC-1.

Publisher Summary This chapter discusses the phase I trial of immunomodulatory activities of human leukocyte interferon in advanced cancer patients. In a study described in the chapter, twenty-two patients with advanced malignancy were treated in a phase I trial of (Meloy) human leukocyte interferon (IFN-α). 40 ml of venous blood were collected in heparinized vacutainers, washed, diluted, and layered on Ficoll–Hypaque gradients to obtain the mononuclear fraction. Mononuclear cells suspended in RPMI+20% fetal calf serum (1–2 × 106/ml) were layered onto plastic tissue culture flasks previously coated with murine sarcoma line TU5 microexudate. After 45 min of incubation at 37°C, nonadherent cells were decanted and further eluted with 5× washing and resuspension in RPMI+10% FCS. Nonadherent cells were counted and used as effector cells in natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) assays. Adherent cells were eluted from microexudate coated flasks by 10 min incubation in 10mM EDTA in PBS. These were washed, counted, and used as effector cells in the monocyte-mediated cytotoxicity (MMC) assay. Collected cells were 90% viable, 90% latex positive, and 90% nonspecific esterase positive. The results of this study suggested that a single dose of IFN between 10–40 × 106 IU/M2 results in enhancement of natural cytolysis in as many as half of patients.

Excerpt The apparent initiation of chronic liver disease by acute illnesses presumed to be acute viral hepatitis now has been observed sufficiently often to warrant serious consideration of this in...

• Fifteen recipients acquired viral hepatitis after a single blood transfusion. Tests for hepatic function—serum bilirubin, thymol turbidity, thymol flocculation, cephalin-cholesterol flocculation, zinc turbidity, urine urobilinogen, and sulfobromophthalein retention—had all given normal results in three of the donors. Twenty donors were examined repeatedly during periods up to four years after giving blood. One had consistently abnormal hepatic tests, yet his blood serum did not induce hepatitis in volunteers. Throughout the retesting period, each donor generally had consistently normal or abnormal results in the various tests. One donor developed clinical hepatitis seven months after donating blood that was believed to have caused hepatitis in a recipient and four and one-half months after his serum had caused hepatitis in volunteers; his blood still infected volunteers six months after his own clinical recovery. At present the six tests enumerated are insufficient either to detect carriers with certainty or to pronounce a prospective donor safe.

During the past few years the incidence of infectious (epidemic) hepatitis has increased to such an extent that the disease has become one of the most serious medical problems of the present war. The development of effective methods for its prevention and control has been prevented by the lack of definite knowledge concerning the sources of the causative agent and the factors involved in its transmission. However, recent investigations 1 have shown that the causative agent is excreted in the feces of infected persons. This has suggested that feces may be a common source of the agent and that anything subject to fecal contamination may be a potential means of transmission of the disease. More recently, evidence has been obtained that the agent from feces may be transmitted by drinking water. 2 It has seemed important, therefore, to determine the effect on the hepatitis agent of methods commonly used for

Antigenic differences between certain strains of infectious (epidemic) hepatitis virus (IH) of relatively short incubation (about eighteen to forty days) and certain strains of serum hepatitis virus (SH) of relatively long incubation (about sixty to one hundred and fifty days) 1 have been conclusively demonstrated. The data of Oliphant, 2 suggesting immunologic similarities in such viruses, could well be explained by the facts that: (1) the virus, designated by Oliphant as that of epidemic hepatitis, had a long incubation period (about seventy-five days), (2) thus, it actually may have been a strain of serum hepatitis virus, SH, rather than one of epidemic hepatitis, IH, and (3) a cross immunity with his designated serum hepatitis virus, SH, therefore would not have been surprising. The confusion concerning the origin of such strains of hepatitis virus can best be clarified by study of their immunologic behavior in experimental subjects. It thus would appear

The control of infectious (epidemic) hepatitis, the only pandemic disease of the present war, has been seriously handicapped by the lack of any conclusive evidence concerning its method or methods of transmission. In our recent report on the prevention and attenuation of infectious hepatitis by gamma globulin 1 there was brief mention of the epidemic in which the globulin was tested. The epidemiologic factors involved in that epidemic also were investigated, and subsequently transmission experiments in human volunteers, using materials obtained from the patients and the camp, were conducted in order to supplement and confirm the epidemiologic observations. The results of these investigations have provided information concerning the sources of the causative agent and at least one of the methods responsible for its transmission. I. THE EPIDEMIC The Camp.— The epidemic occurred in a summer camp for boys and girls located in an isolated area in the Pocono Mountains near