Loss of ovarian function promotes angiogenesis in human ovarian carcinoma

We show here that elevated levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), as found in menopause or after ovariectomy, promote growth of human ovarian carcinoma by induction of tumor angiogenesis. Human epithelial ovarian cancer tumors progressed faster in ovariectomized mice. This induced growth could be attributed to the elevated levels of gonadotropins associated with loss of ovarian function because direct administration of gonadotropins also was effective in promoting tumor progression in vivo. On the other hand, gonadotropins had no direct effect on the proliferation of human ovarian cancer cells in vitro. Using MRI, we demonstrated that ovariectomy significantly (P < 0.02) induces neovascularization of human ovarian carcinoma spheroids implanted in nude mice. Moreover, conditioned medium of gonadotropin-treated human ovarian carcinoma cells showed increased mitogenic activity to bovine endothelial cells, and this activity could be blocked by neutralizing antibodies against luteinizing hormone and against vascular endothelial growth factor. Accordingly, gonadotropin stimulation resulted in a dose-dependent-induced expression of vascular endothelial growth factor in monolayer culture as well as in the outer proliferating cells of human ovarian cancer spheroids. These results demonstrate the significance of the elevated levels of gonadotropins, as found in menopause and in all ovarian cancer patients, on the progression of ovarian cancer and could explain the protective effect of estrogen replacement therapy. Based on these results, we suggest that hormonal therapy aimed at lowering the circulating levels of gonadotropins may possibly prolong remission in ovarian cancer by extending tumor dormancy.     

Serum copper level in ovarian carcinoma

Serum copper levels (SCL) were determined before any diagnostic procedure was performed or treatment given in 40 women admitted for the investigation of a pelvic mass and, later, in those patients with ovarian carcinoma after chemotherapy and before a second-look operation was performed. Patients with ovarian carcinoma were found to have significantly higher SCL than patients with benign ovarian lesions. A SCL of 150 micrograms/dl clearly separated patients with a pelvic mass on the basis of ovarian carcinoma and those with benign noninflammatory pelvic lesions. The same SCL of 150 micrograms/dl separated patients with ovarian carcinoma that responded to chemotherapy and those with residual disease. It is suggested that SCL be included as a member of the screening panel of biologic tumor markers in general and in ovarian carcinoma in particular.     

Fast neutron radiotherapy for locally advanced prostate cancer. Update of a past trial and future research directions

Between June, 1977, and April, 1983, the Radiation Therapy Oncology Group (RTOG) sponsored a phase III study comparing fast neutron radiotherapy as part of a mixed beam (neutron/photon) regimen with conventional photon (x-ray) radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate. A total of 91 analyzable patients were entered into the study with the two treatment groups balanced in regard to all major prognostic variables. The current analysis is for a median follow-up of 6.7 years (range 3.4-9.0 yrs.). The results are statistically significant in favor of the mixed-beam group of all parameters mentioned. At five years the freedom from local/regional relapse rate is 81 percent on the mixed-beam arm compared with 60 percent on the photon arm. The actuarial overall survival rate at five years is 70 percent on the mixed beam compared with 56 percent on the conventional photon arm. The determinantal survival at five years (which excluded death due to intercurrent disease in patients clinically free of cancer) was 82 percent on the mixed-beam arm compared with 61 percent on the photon arm. The type of therapy appeared to be the most important predictor of both local tumor control and patient survival in a step-wise Cox analysis. There was no difference in the treatment-related morbidity for the two patient groups. Mixed-beam therapy may be superior to standard photon radiotherapy for treatment of locally advanced prostate cancer.     

Phase II Radiation Therapy Oncology Group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: results of RTOG 9710

PURPOSE: The aim of this study was to determine whether recombinant human interferon beta-1a (rhIFN-beta), when given after radiation therapy, improves survival in glioblastoma. METHODS AND MATERIALS: After surgery, 109 patients with newly diagnosed supratentorial glioblastoma were enrolled and treated with radiation therapy (60 Gy). A total of 55 patients remained stable after radiation and were treated with rhIFN-beta (6 MU/day i.m., 3 times/week). Outcomes were compared with the Radiation Therapy Oncology Group glioma historical database. RESULTS: RhIFN-beta was well tolerated, with 1 Grade 4 toxicity and 8 other patients experiencing Grade 3 toxicity. Median survival time (MST) of the 55 rhIFN-beta-treated patients was 13.4 months. MST for the 34 rhIFN-beta-treated in RPA Classes III and IV was 16.9 vs. 12.4 months for historical controls (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 0.89-1.81). There was also a trend toward improved survival across all RPA Classes comparing the 55 rhIFN-beta treated patients and 1,658 historical controls (HR = 1.24, 95% CI = 0.94-1.63). The high rate of early failures (54/109) after radiation and before initiation of rhIFN-beta was likely caused by stricter interpretation of early radiographic changes in the current study. Matched-pair and intent-to-treat analyses performed to try to address this bias showed no difference in survival between study patients and controls. CONCLUSION: RhIFN-beta given after conventional radiation therapy was well tolerated, with a trend toward survival benefit in patients who remained stable after radiation therapy. These data suggest that rhIFN-beta warrants further evaluation in additional studies, possibly in combination with current temozolomide-based regimens.     

A pilot study of cis-diamminedichloroplatinum and radiation therapy in patients with high grade astrocytomas

A pilot study was performed combining cis-diamminedichloroplatinum (CDDP) and radiation therapy to treat patients with high-grade astrocytomas. CDDP at a dose of 40 mg/m2/week intravenously was given during the course of cranial irradiation. Following irradiation, CDDP was given every three weeks on a schedule of 35-40 mg/m2/day for three days until toxicity became unacceptable or until tumor progression occurred. Radiation therapy consisted of 6 000 rads over a seven week period or 5 000 rads followed by an additional 1 500 rads to the tumor site. Patients were followed by computerized axial tomography (CT) scan and neurologic examination. Thirty patients were entered onto the study; 22 were considered evaluable. The median survival was 53 weeks and the median time to progression was 21 weeks. Toxicity was generally tolerable; however, ototoxicity may be enhanced by this treatment. CDDP combined with cranial irradiation is tolerable and feasible, although close follow-up is recommended in case CDDP has to be temporarily interrupted.     

Fast neutron therapy for locally advanced head and neck tumors

Between October 1972 and April 1979, 187 patients with locally advanced head and neck tumors were treated with 50 MeV_d→Be neutrons or with conventional treatment in the M. D. Anderson Hospital-Texas A & M University variable energy cyclotron (MDAH-TAMVEC) program. Of these, 114 patients were treated in pilot studies and 73 in a randomized clinical trial. In the pilot studies, 49 patients were treated with neutrons alone, 25 with mixed-beam irradiation (two neutron and three photon fractions per week), and 40 with conventional treatment (surgery, photons, or combined surgery and photons). There was no appreciable difference among patients in these studies with regard to local tenor control or servival. However, the patients in the conventional-treatment pilot study had less advanced disease than those in either of the other studies. The complication rates in the neutrons-only and conventional-treatment studies were significantly greater than the complication rate observed in the mixed-beam pilot study. In the randomized clinical trial, 41 patients were treated with mixed-beam irradiation and 32 with photon irradiation. The preliminary results of this trial show a slight superiority with mixed-beam irradiation. In the mixed-beam group, 61% had local tumor control, 7% developed major complications, and 4996 were alive at the time of analysis; whereas in the photon group, 47% had local tumor control, 3% developed major complications, and 25% were alive at the time of analysis.     

Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumor angiogenesis

Maintaining homogeneous perfusion in tissues undergoing remodeling and vascular expansion requires tight orchestration of the signals leading to endothelial sprouting and subsequent recruitment of perivascular contractile cells and vascular maturation. This regulation, however, is frequently disrupted in tumors. We previously demonstrated the role of tumor-associated myofibroblasts in vascularization and exit from dormancy of human ovarian carcinoma xenografts in nude mice. The aim of this work was to determine the contribution of stroma- and tumor cell-derived angiogenic growth factors to the heterogeneity of vascular permeability and maturation in MLS human ovarian carcinoma tumors. We show by RT-PCR and by in situ hybridization that VEGF was expressed by the tumor cells, while angiopoietin-1 and -2 were expressed only by the infiltrating host stroma cells. Vascular maturation was detected in vivo by vasoreactivity to hypercapnia, measured by BOLD contrast MRI and validated by immunostaining of histologic sections to alpha-smooth muscle actin. Vascular permeability was measured in vivo by dynamic contrast-enhanced MRI using albumin-based contrast material and validated in histologic sections by fluorescent staining of the biotinylated contrast material. MRI as well as histologic correlation maps between vascular maturation and vascular permeability revealed a wide range of vascular phenotypes, in which the distribution of vascular maturation and vasoreactivity did not overlap spatially with reduced permeability. The large heterogeneity in the degree of vascular maturation and permeability is consistent with the differential expression pattern of VEGF and angiopoietins during tumor angiogenesis.