Biomedical subjects

R S Freedman

Publications and source records attributed to R S Freedman.

At least 91 records · Page 5Linked to original sources

PubMed1990

Comparison of recombinant-interleukin-2-activated peripheral blood and tumor-infiltrating lymphocytes of patients with epithelial ovarian carcinoma: cytotoxicity, growth kinetics and phenotype.

We have compared the growth and tumor-directed cytotoxic efficacy of recombinant-interleukin-2-(rIL-2)-activated peripheral blood (PBL) and tumor-infiltrating lymphocytes (TIL) from patients with epithelial ovarian carcinoma. These studies demonstrated that TIL and PBL displayed similar levels of cytotoxicity and a broad range of target cell killing, as exemplified by their reactivity against autologous and allogeneic ovarian tumors as well as against tumor cell lines. No specificity of autologous tumor cell killing was manifested by TIL. Even though TIL of some patients showed higher proliferative activity (especially at the later times in rIL-2 culture) this was not a general phenomenon. In fact, in one case TIL did not proliferate at all, and in the other case the PBL proliferated more actively. While the cultures were composed primarily of CD3+ lymphocytes, the major cytotoxic cells displayed the CD56+ and CD16+ phenotype. Addition of OKT3 mAb to rIL-2 cultures resulted in an increased proliferative index, but showed only a minor effect on the cytotoxic potential of cultured lymphocytes. The therapeutic potential of rIL-2-activated TIL and PBL is discussed.

Antigens, CD↗

PubMed1990

Inhibition of IL-2 receptor induction and IL-2 production in the human leukemic cell line Jurkat by a novel peptide inhibitor of protein kinase C.

We recently reported that the myristoylated peptide N-myristoyl-Lys-Arg-Thr-Leu-Arg (N-m-KRTLR) is a novel protein kinase C inhibitor. In this study, we investigated the biological effects of N-m-KRTLR using as an in vitro model the induction of the IL-2 receptor and IL-2 secretion by Jurkat cells in response to stimulation with 12-O tetradecanoylphorbol-13-acetate (TPA) plus phytohemagglutinin (PHA) and TPA plus OKT3 mAb. N-m-KRTLR significantly suppressed induction of the IL-2 receptor on the surface of the Jurkat cells by TPA plus either PHA or OKT3 mAb. Furthermore, N-m-KRTLR inhibited the production and release of IL-2 from cultured Jurkat cells stimulated with TPA plus either PHA or OKT3 mAb. Similarly, this peptide significantly inhibited the IL-2 production in normal human peripheral blood mononuclear cells in response to stimulation by TPA and PHA. In contrast, this peptide did not affect expression of the CD3 complex on the surface of the Jurkat cells either alone or in the presence of TPA or PHA. Furthermore, N-m-KRTLR did not interfere with the spontaneous proliferation of the Jurkat cells, and its effects on IL-2 secretion and IL-2 receptor expression in the Jurkat cells were evident without loss of cell viability. These results suggest that the novel protein kinase C inhibitor N-m-KRTLR may selectively inhibit certain activation pathways of Jurkat cells and indicate the usefulness of N-m-KRTLR in the analysis of discrete events in T cell activation.

Amino Acid Sequence↗

PubMed1990

Phase I evaluation of thio-TEPA in combination with cisplatin for advanced gynecologic malignancies.

Thirty-five patients with advanced gynecologic malignancies were entered into a phase I study evaluating thio-TEPA in combination with cisplatin (50 mg/m2) intravenously every 4 weeks. Thirty-four patients were evaluable for toxicity and response, and one was evaluable for toxicity only. Median age was 53 years (range 28-72), and performance status less than or equal to 2. Prior treatment included chemotherapy in 21 patients, radiation in 15, hormonal therapy in 3, and immunotherapy in 1. Thio-TEPA was given to three or more patients at each of the following dose levels: 15, 20, 25, 30, 40, 50, and 60 mg/m2. Thio-TEPA's primary toxicity was myelosuppression; at 50 mg/m2, grade 3 or 4 granulocytopenia occurred in 13 of 17 cycles, and grade 3 or 4 thrombocytopenia occurred in 8 of 17 cycles. The maximum tolerated dose (MTD) of thio-TEPA was 40 mg/m2; in 35 cycles at this dose, grade 3 or 4 granulocytopenia occurred in 19, and grade 3 or 4 thrombocytopenia occurred in 10 cycles; median granulocyte nadir was 1100 (range 110 to 3600) and median platelet nadir was 90,000 (range 10,000 to 289,000). Fifteen patients received three or more cycles at one dose level; cumulative myelosuppression was observed in 11. Two cases of partial alopecia occurred at 40 and 60 mg/m2 thio-TEPA. Responses were as follows: complete response, 5; partial response, 7; stable disease, 14; progressive disease, 8. In 16 patients with ovarian cancer (15 of whom had previously received cisplatin), there were 4 complete responses and 5 partial responses (overall response rate of 56%). The thio-TEPA dose recommended in combination with cisplatin (50 mg/m2) in phase II trials is 40 mg/m2. Cumulative hematologic toxicity may occur with this regimen.

Agranulocytosis↗

PubMed1989

OKT4 monoclonal antibody-induced activation of an autoreactive T-cell clone.

We report the presence of a CD4-mediated T-cell activation pathway on an autoreactive CD3+WT31+CD4+CD8- T-cell clone, designated 2F9, isolated from the peripheral blood of a patient with ovarian adenocarcinoma. The OKT4 mab modulated the CD4 antigen independently of the CD3 antigen or the alpha beta T-cell receptor. OKT4 mab immobilized on plastic or soluble OKT4 mab in the presence of feeder PBMC induced proliferation and IL-2 production by cells of the 2F9 clone. Mixtures of the OKT4 mab and the OKT3 or anti-WT31 mabs induced additive proliferative responses and IL-2 production. The OKT4 mab synergized with recombinant IL-2 in inducing proliferative responses. These results suggest the presence of activation pathway on 2F9 cells.

Adenocarcinoma↗

PubMed1989

Effect of virus-modified tumor cell extracts, autologous mononuclear cell infusions and interleukin-2 on oncolytic activity of effector cells of patients with advanced ovarian cancer.

We studied the biological responses of six ovarian cancer patients after intraperitoneal (i.p.) injections of virus-modified tumor cell extracts (VMTE) and autologous peripheral blood mononuclear cells, collected by leukapheresis after two injections of VMTE. VMTE was prepared from allogeneic ovarian cell lines, OV2774 and CaOV3, modified by influenza virus, A/PR8/34. A dose of 9 mg VMTE was given i.p. in total of 2-4 injections, and (1-9) x 10(8) autologous mononuclear cells were infused i.p., 24 h after the second VMTE injection, and 24 h and 72 h after the third VMTE injection. Both peripheral blood (PB) and peritoneal cavity (PC) effector cell cytotoxicity was significantly enhanced against the K562 cell line in the majority of patients, 24-48 h after the second and third VMTE injections. This was accompanied by a dramatic influx of neutrophils into PC (57-550-fold), increase in absolute numbers of lymphocytes, (including large granular lymphocytes) and monocytes, and resulted also in a significant decrease in the number of ascitic tumor cells (98% reduction). The infusion of autologous mononuclear cells did not appear to influence either cytotoxicity or cell infiltration of the peritoneal cavity. We also investigated the in vitro effect of recombinant interleukin-2 (IL-2) on effector cells from PB and PC from patients before and after VMTE treatment. Cytotoxicity of both of these compartments was significantly potentiated after culture with IL-2. In three out of five VMTE-treated patients, PC cytotoxicity was significantly higher after activation with IL-2 than that of patients before VMTE treatment. These data suggest that VMTE induces regional cellular immunity, which could be further potentiated by culture of PC effector cells with IL-2. Thus, combination of VMTE and IL-2 after regional administration could represent the effective therapy for patients with advanced ovarian cancer.

Adjuvants, Immunologic↗

PubMed1989

Treatment of advanced epithelial ovarian cancer with cisplatin and cyclophosphamide.

Between June 1981 and June 1984, 50 patients with stage III or IV epithelial ovarian cancer underwent initial surgery followed by combination chemotherapy with cisplatin 50 mg/m2 iv and cyclophosphamide 500-1000 mg/m2 iv at 28-day intervals. No patients with borderline or well-differentiated tumors were included. If patients were clinically disease-free after 12 cycles of therapy, a second-look laparotomy was performed. A complete response was noted in 12 patients (24%), 11 of whom were surgically evaluated. A partial response was noted in 4 patients (8%), 3 of whom were surgically evaluated. Thirty-four patients (68%) had no response to therapy. The median progression-free survival (PFS) for the entire group was 19.8 months, with a median survival of 27 months. Patients with less than or equal to 2 cm residual disease had a superior median PFS (25.4 months vs 18 months) and median survival (29.4 months vs 19.5 months) to those patients with greater than 2 cm residual disease. Patients who underwent primary debulking had a longer median survival than patients who underwent "interval" debulking after two to four cycles of chemotherapy (29.2 months vs 17.3 months). Thirteen patients (26%) are alive without evidence of disease, 4 patients are alive with disease, and 33 patients are dead of disease. Toxicity was very moderate. In summary, the activity and toxicity of the combination of cisplatin and cyclophosphamide compare favorably to other cisplatin combination regimens.

Adult↗

PubMed1989

Treatment of advanced endometrial adenocarcinoma with cyclic sequential ethinyl estradiol and medroxyprogesterone acetate.

Fifteen patients with recurrent or progressive endometrial adenocarcinoma of moderate to poor histologic differentiation were entered in a phase II trial of sequentially administered oral ethinyl estradiol and medroxyprogesterone acetate. There were no significant clinical responses in 12 patients evaluated for response and four patients experienced thromboembolic complications. This cyclic treatment regimen is considered ineffective for this patient population at the dosages and schedules used.

Adenocarcinoma↗

PubMed1989

Randomized comparison of viral oncolysate plus radiation and radiation alone in uterine cervix carcinoma.

A randomized, controlled study was performed in patients with high-risk, untreated squamous cell carcinoma of the uterine cervix to evaluate the adjunctive use of viral oncolysate (VO) prepared from the SW756 cell line. Seventy-five patients were stratified by tumor volume and randomized to receive radiation therapy (RT) alone or RT plus intradermal immunization with VO. Fifty-one (68%) patients relapsed with a median survival (MS) of 29.1 months and a median progression-free interval (MPFI) of 18.0 months. No differences in MS or median PFI were observed by treatment arm or site of relapse, although a trend toward improved MS and median PFI in patients with small-volume primary lesions was suggested. Serum surface-binding antibody activity (greater than or equal to 1:8) to the SW756 cell line was detected in 14 of 41 unselected patients prior to therapy. Virus hemagglutination inhibitory activity (greater than or equal to 1:8) was detected in 37 of 41 patients before treatment. four-fold increases in titer were observed to the SW756 cell line in 83% and to influenza in 74% of patients tested after immunization. Preirradiation measurements of phytohemagglutinin-induced blastogenesis by the relative proliferation index (RPI) method in 39 patients revealed RPI values less than 0.58 in nine patients, eight of whom relapsed. At 3-6 months after the initiation of irradiation, 32 of 39 patients had values less than 0.58. Patients in the RT group with values less than 0.58 had significantly more relapses than those who received RT plus VO.

Adult↗

PubMed1989

Percutaneous drainage and feeding gastrostomies in 100 patients.

Percutaneous gastrostomy was performed in 100 cancer patients. In 67 patients with bowel obstruction, the procedure was performed for gastric drainage with 24-28-F Malecot catheters inserted in one sitting. The remaining 33 patients had supragastric obstructions or fistulas and required 10-14-F pigtail catheters for feeding purposes. Average postgastrostomy hospitalization was 3.6 days. Drainage gastrostomies were ready for use immediately after the procedure, whereas use of feeding gastrostomies started on average within 2 days of tube insertion. There were no major complications or deaths related to the procedure. Percutaneous gastrostomy is a simple and safe procedure even when large-caliber catheters are used, and it does not require gastric fixation to the abdominal wall to prevent spillage into the peritoneum.

Adult↗

PubMed1989

Lymphokine activity in malignant effusions after intracavitary viral oncolysate.

Six patient with malignant effusions (five with ascites and one with malignant pleural effusion) due to refractory ovarian carcinomatosis, received intracavitary injections of ovarian viral oncolysate (VO). Measurements were made of the intracavitary activities of T cell growth factor (TCGF-IL-2) and B cell growth factor 12-kD (BCGF) and these were correlated with the clinical activity and cytologic changes in the malignant effusions. Both BCGF and IL-2 activities were demonstrated in malignant effusions prior to therapy although these were relatively higher for BCGF. Increases in the activities of both lymphokines were observed in the post VO treatment samples ranging from 4.1% to 45.0% for BCGF and 4.8% - 33.9% for IL-2. One patient who exhibited marked clinical improvement accompanied by mononuclear cell infiltrates and diminution of ascitic fluid malignant cells, also had elevation of lymphokine activities after repeated VO injections. These data provide further support for the role of VO as inducers of regional immunity.

Ascitic Fluid↗

PubMed1988

Recombinant IL-2-activated NK cells mediate LAK activity against ovarian cancer.

We investigated the ability of endogenous and recombinant interleukin-2 (IL-2)-stimulated NK cells from normal donors and ovarian cancer patients to mediate lysis of ovarian tumors, and found that peripheral blood (PB) mononuclear cells of normal donors or cancer patients did not display tumoricidal activity against ovarian cell line or fresh ovarian tumors. In addition, ovarian cancer patients displayed a defect in NK-cell activity against the highly NK-sensitive target, K-562. However, lytic activity against ovarian tumors (including cultured and primary tumors) was induced and that against K-562 was potentiated in PB of normal donors and PB and peritoneal cavity of ovarian cancer patients after enrichment of LGL on Percoll density gradient or after stimulation of effector cells with recombinant IL-2 in vitro. The IL-2-generated cytotoxic cells in PB were characterized as NK cells displaying CD16+, NKH1 (Leu-19)+, CD3- and CD5- phenotype, while those in the peritoneal cavity were predominantly CD16-, NKH1+, CD3- and CD5-. Studies on the mechanism of IL-2-dependent generation of cytotoxicity showed that such an effect was mediated via recruitment of tumor-binding cells as well as by an increase in the frequency of cytotoxic cells.

Cytotoxicity, Immunologic↗

PubMed1988

Viral oncolysates in patients with advanced ovarian cancer.

Viral oncolysates (VO) derived from two cultured ovarian carcinoma cell lines infected with influenza A/PR8/34 were administered intraperitoneally (IP) to 40 patients with advanced ovarian carcinoma, including 31 with late-onset ascites and 5 with pleural effusions. PR8 virus-specific antigens and ovarian tumor-associated antigens have been demonstrated on two oncolysates designated OVO1 and OVO2. Thirty-five patients received 9 mg of a 1:1 mixture of OVO1 and OVO2, 5 patients received one or the other. During the first month three IP schedules were evaluated, i.e., single, biweekly, and weekly, which were followed by monthly injections. Intrapleural (IP1) injections of a 3.0-mg 1:1 mixture of OV1 and OV2 were administered to 3 patients concurrently with initial IP injections and to 2 patients following later development of pleural effusions. In 7 patients ascites disappeared; in 5 of these the number of cytologically detected malignant cells was markedly reduced, in 1 pleural effusion disappeared, and in 3 tumor masses were reduced. Tumor masses shrank also in 2 patients without ascites. Tumor reduction conformed to standard response criteria in 2 of the 5 patients. Response duration in the 9 responding patients lasted from 3 to 19 months and survival durations 4 to 42 months. Disease symptoms in 7 patients improved noticeably. Two of the 9 responders later developed unilateral pleural effusions that responded for 7 and 15+ months to a single IP1 injection. Seventeen patients experienced one or more treatment side effects including fever, nausea or anorexia, malaise, abdominal pain, and arthralgia, but in only 2 patients, both on the weekly schedule, was toxicity severe enough to require treatment withdrawal. Humoral responses to viral and tumor cell-surface antigens were frequently observed in patients demonstrating clinical activity.

Adult↗

PubMed1988

Hyperfractionated split-course whole abdominal radiotherapy for ovarian carcinoma: tolerance and toxicity.

Whole abdominal irradiation after chemotherapy and second look laparotomy for advanced ovarian carcinoma is poorly tolerated because of hematologic toxicity that frequently necessitates interruption or abandonment of treatment. A new treatment strategy using a hyperfractionated split course schedule to deliver a total of 30 Gy in 30 fractions over 6 weeks was designed in an attempt to overcome this problem, while not compromising the tolerance of late reacting normal tissues. Of 23 patients treated between August 1984 and June 1986, only one failed to complete therapy as scheduled. Six patients with gross residual disease also received a limited field boost of 15 Gy in 15 fractions after completion of treatment to the whole abdomen. None of these six patients achieved disease control, and five required surgery for intestinal obstruction with pathologic evidence of radiation bowel injury. Of the 17 patients who received no boost, five developed gut obstructions associated with tumor recurrence and not attributable to irradiation. We conclude that whole abdominal irradiation using the hyperfractionated split course schedule without a boost is safe and feasible but its therapeutic efficacy appears confined to subsets of patients with no visible residual disease at the time of second look laparotomy, or in whom all visible residual tumor can be resected.

Adult↗

PubMed1987

High-dose doxorubicin infusion therapy for disseminated mixed mesodermal sarcoma of the uterus.

Fifteen patients with metastatic mixed mesodermal sarcoma of the uterus received high dose doxorubicin infusion therapy. For 12 patients, the initial dose was 90 mg/m2; the other three patients' starting doses were 50, 75, and 75 mg/m2 respectively. Twelve patients received doxorubicin as firstline chemotherapy, with a cumulative dose of 90 mg/m2 to 675 mg/m2 (median = 495 mg/m2). Three patients treated secondarily received cumulative doses of 90, 205, and 425 mg/m2. Of nine patients who had measurable disease, none had an objective response. The median survival of the 15 patients was 11.3 months, with a range of 0.5 to 51+ months. Two patients died of neutropenia related sepsis. Cardiotoxicity occurred in two patients. Eleven patients are dead of disease, and two patients are alive without evidence of disease at 49, and 51 months. Extending the doxorubicin dosage to its tolerable limits did not appear to result in improved efficacy in patients with metastatic mixed mesodermal uterine sarcomas. Future clinical trials should concentrate on doxorubicin-containing combination regimens and Phase II single agent studies.

Adult↗

PubMed1987

Nature of cervical involvement in endometrial carcinoma.

In patients with endometrial carcinoma the prognostic significance of clinical and histopathologic variants of cervical involvement is unknown. Fifty-eight patients with endometrial carcinoma and cervical involvement diagnosed by gross examination or endocervical curettage are reviewed. Three clinicopathologic groups were identified: gross cervical involvement (10 patients), occult stromal invasion (25), and no evidence of stromal invasion (23). There were no differences in clinical, pathologic, surgical, or therapeutic characteristics. There was no significant difference in actuarial 5-year survival rates between patients with gross cervical involvement (70%) and occult disease (65%). There was also no significant difference in survival rates among patients with occult cervical stromal invasion (67%). The presence of cervical involvement in endometrial carcinoma is an important prognostic factor. However, the extent of cervical involvement does not appear to be of significant prognostic value.

Adult↗

PubMed1987

Lewis and related tumor-associated determinants on ovarian carcinoma.

Monoclonal antibodies that defined blood group and related determinants bind to sections of fixed tissues from epithelial ovarian carcinoma in immunoperoxidase assays. Seventy-eight carcinomas and 27 normal tube and ovarian tissues were examined. Lewis (Le)a and Leb determinants were expressed on 58% of the serous carcinomas, on 60% of the endometrioid tumors, and on 78% of the mucinous carcinomas. Sialylated Lea, gastrointestinal cancer-associated antigen (GICA), and lacto-N-fucopentaose (LNF) III, another Le-related determinant, have a similar distribution pattern. Of 10 normal ovaries and fallopian tubes tested from patients without cancer, one reacted with anti-Lea, anti-Leb, or anti-LNF III monoclonal antibodies. Anti-GICA antibodies reacted with tissue from one patient. Le and Le-related antigenic determinants could be useful markers for ovarian cancer.

Antibodies, Monoclonal↗

PubMed1987

Cervical carcinoma DNA content, S-fraction, and malignancy grading. II. Comparison with clinical staging.

In an attempt to achieve more biologically meaningful subclassification of squamous cell cervical cancers and ultimately more reliable prediction of tumor behavior, we have studied the tumor pretreatment DNA content (i.e., DNA index), cell-cycle S-fraction, and histomorphologic malignancy grading properties for tumors having similar and different clinical staging. The tumor DNA index, %S-phase cells, and average malignancy grades were statistically tested against known clinical predictive variables for 90 primary squamous cell carcinomas of the uterine cervix studied prior to radiotherapy. We observed that the biological and morphological tumor properties of cervical cancers broadly overlapped between different stages of disease and for other clinical criteria including the gross morphology, lymph node status, and intravenous positivity. No significant differences were detected in the DNA indices, %S, or malignancy grades between the stages of disease or the other clinical criteria. It was concluded that: the gross clinical staging criteria inadequately reflected the tumor biological properties; and that the possibility exists for refining prognosis by use of the biological and morphological noncodependent tumor parameters to supplement staging criteria; and the use of cell-cycle cytokinetic and malignancy grading criteria in addition to tumor DNA index is superior to DNA index (or DNA content) alone for identifying biologically different cervical cancers.

Carcinoma, Squamous Cell↗

PubMed1987

Methylprednisolone in cis-platinum induced nausea and emesis: a placebo-controlled trial.

In a double-blind, placebo-controlled trial, the antiemetic efficacy of a total of 1-2 g methylprednisolone sodium succinate (MPSS) alone versus placebo was evaluated over the first three courses of chemotherapy in a group of 27 women receiving moderate to high-dose cis-platinum (50-118 mg/m2) for ovarian or cervical carcinomas. Antiemetic protection was classified as total (no emesis), major (one or two bouts), minor (three to five bouts), or minimal (six or more bouts). Total or major protection occurred in 10/26 (38.5%) of the MPSS cycles and in 6/24 (25%) of the placebo cycles (NS). A significant number of placebo patients (7/14 placebo versus 1/13 MPSS, P = 0.02) dropped out of the study due to lack of efficacy. Patient evaluations completed 24 hr before and after each course of chemotherapy indicated no treatment effect on pain, appetite, nausea, drowsiness, anxiety, sense of well-being, or sleep. Physician and patient global evaluations of antiemetic efficacy favored treatment with MPSS. Evidence of the efficacy of single-drug MPSS antiemetic therapy during non-cis-platinum or low-dose cis-platinum (less than 50 mg/m2) chemotherapy can be found in the literature. The results of this study, however, do not support the use of MPSS alone with high-dose cis-platinum chemotherapy.

Adult↗