CHEMICAL CONSEQUENCES OF THE C/O RATIO ON HOT JUPITERS: EXAMPLES FROM WASP-12b, COROT-2b, XO-1b, AND HD 189733b.

Motivated by recent spectroscopic evidence for carbon-rich atmospheres on some transiting exo-planets, we investigate the influence of the C/O ratio on the chemistry, composition, and spectra of extrasolar giant planets both from a thermochemical-equilibrium perspective and from consideration of disequilibrium processes like photochemistry and transport-induced quenching. We find that although CO is predicted to be a major atmospheric constituent on hot Jupiters for all C/O ratios, other oxygen-bearing molecules like H2O and CO2 are much more abundant when C/O < 1, whereas CH4, HCN, and C2H2 gain significantly in abundance when C/O > 1. Other notable species like N2 and NH3 that do not contain carbon or oxygen are relatively unaffected by the C/O ratio. Disequilibrium processes tend to enhance the abundance of CH4, NH3, HCN, and C2H2 over a wide range of C/O ratios. We compare the results of our models with secondary-eclipse photometric data from the Spitzer Space Telescope and conclude that (1) disequilibrium models with C/O ~ 1 are consistent with spectra of WASP-12b, XO-1b, and CoRoT-2b, confirming the possible carbon-rich nature of these planets, (2) spectra from HD 189733b are consistent with C/O ≲ 1, but as the assumed metallicity is increased above solar, the required C/O ratio must increase toward 1 to prevent too much H2O absorption, (3) species like HCN can have a significant influence on spectral behavior in the 3.6 and 8.0 µm Spitzer channels, potentially providing even more opacity than CH4 when C/O > 1, and (4) the very high CO2 abundance inferred for HD 189733b from near-infrared observations cannot be explained through equilibrium or disequilibrium chemistry in a hydrogen-dominated atmosphere. We discuss possible formation mechanisms for carbon-rich hot Jupiters, including scenarios in which the accretion of CO-rich, H2O-poor gas dominates the atmospheric envelope, and scenarios in which the planets accrete carbon-rich solids while migrating through disk regions inward of the snow line. The C/O ratio and bulk atmospheric metallicity provide important clues regarding the formation and evolution of the giant planets.

Immunobiology of gestational trophoblastic diseases.

Gestational trophoblastic diseases (GTDs) comprise a group of interrelated diseases characterized by development after gestation, widespread metastases, and high curability with chemotherapy. The good prognosis of GTDs is considered partly a result of the host immune response to paternal antigens expressed on trophoblastic cells. In this study, we review current understanding of the immunobiology of GTDs. First of all, we describe the microenvironment between trophoblastic cells and subpopulation of immune cells. Second, immunogenetics, immune microenvironment around abnormal trophoblast, and mechanism of GTDs escaping from maternal immune system surveillance were also discussed. Third, we propose the possible immunotherapy for persistent GTDs, particularly the vaccine designed on human chorionic gonadotrophin, which is generally accepted as a tumor marker for GTDs diagnosis. Due to the low incidence of GTDs and high response to chemotherapy, there have been few literatures about immunobiologic characteristics of GTDs compared with the other gynecologic malignancies, such as ovarian cancer, but the immunologic behavior of GTDs should be explored for further understanding of the etiology of these diseases and to help designing immunotherapeutic strategies for persistent GTDs.

Venous thromboembolism syndrome in gynecological cancer.

Venous thromboembolism (VTE) could be presented as an initial clinical feature in some cancer patients or a complication followed by various cancer treatments, which all indicates a poor outcome. This review focuses on elucidating the relationship of VTE and the main gynecological cancers including ovarian, endometrial, and cervical cancers. First, the general VTE information about gynecological cancer are introduced; second, the risk factors of VTE developing in gynecological cancer were discussed; third, we do a retrospective analysis on a novel treatment targeting coagulation cascade; and last, we analyze VTE as a remarkable complication followed by recombinant human erythropoietin and anti-vascular endothelial growth factor treatment in gynecological cancer patients. In summary, the interaction between the coagulation system and cancer progression is a novel promising area to be explored in the study of VTE in patients with gynecological cancer.

Neopterin as an indicator of immune activation and prognosis in patients with gynecological malignancies.

Malignant tumors may contribute to host response that involves both the adaptive and innate immune systems. Among other biochemical indicators of systemic immune and inflammatory activity, activation of macrophages by interferon-gamma induces a marked increase in the production of neopterin. Neopterin production by activated macrophages is also associated with tryptophan degradation. In addition to tumors of other primary locations, increased urinary and serum neopterin concentrations have been reported in patients with gynecological cancers, including epithelial ovarian carcinoma, cervical carcinoma, endometrial carcinoma, uterine sarcomas, and vulvar carcinoma, but not in women with benign neoplasms or precancerous disorders. Increased neopterin concentrations have been associated with poor prognosis. Elevated levels of neopterin have also been observed in the tumor microenvironment. Systemic (urinary or serum) or local (ascitic fluid) neopterin concentrations increased after therapeutic administration of cytokines. Elevated neopterin concentrations have been associated with anemia of chronic disease and increased urinary zinc loss in patients with gynecological malignancy. Elevated neopterin has also been connected with depressed function of peripheral blood lymphocytes and a decrease in CD4+ T-cell numbers.

Retrospective review: re-treatment of patients with ovarian cancer with carboplatin after platinum resistance.

The objective of the analysis was to determine the effectiveness of re-treating patients with ovarian cancer, primary peritoneal cancer, and fallopian tube cancer with carboplatin after being deemed platinum resistant. From a database period January 1, 1996, to December 12, 2002, 34 patients were identified who received nonplatinum agents before resuming treatment with carboplatin. The median age was 65 years, and a median of two nonplatinum chemotherapy (range 1-5) prior to re-treatment with carboplatin was received. The median platinum-free interval from the time platinum was last received to re-treatment with carboplatin was 15.2 months (95% confidence interval [CI] 12.6-17.9; range 6.2-47.0). A median number of four cycles of carboplatin (range 1-11) was received. Two patients (5.9%) achieved partial response, while 21 patients (61.7%) achieved stable disease. The median time to progression for these 23 patients after re-treatment with carboplatin was 5.7 months (95% CI 5.2-6.3; range 1.8-15.3). Twenty-seven patients have died, and all patients have progressed. Seven patients are still receiving salvage therapy. The median overall survival from the time deemed to be platinum resistant is 23.2 months (95% CI 20.1-26.4). Patients who have been deemed platinum resistant may still benefit from platinum re-treatment after an interval of treatment with nonplatinum agents.

Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation.

The purpose of this study was to identify characteristics significant to survival and progression-free survival in patients with advanced ovarian cancer receiving high-dose chemotherapy. In all, 96 patients received autologous stem cell transplantation. Regimens included paclitaxel with carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa (CBT). At the time of transplantation, 43% of patients were in clinical CR, 34% were in clinical PR, 18% had progressive disease and 5% had stable disease. There were no treatment-related deaths. The 6-year survival by Kaplan-Meier was 38%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% with a PFS of 29%. On univariate analysis, the CBT regimen, clear cell histology and disease status other than CR prior to treatment were statistically significant adverse prognostic factors. This analysis has demonstrated that patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology. The TMC combination appeared to be superior to the PC and CBT combinations. Comparative studies of different consolidation approaches will be necessary to determine if autologous transplantation is the preferred treatment for this patient population.

Phenotype and antitumor activity of ascitic fluid monocytes in patients with ovarian carcinoma.

Monocytes/macrophages (MO/MA) represent a major leukocyte population in the peritoneal cavity of patients with epithelial ovarian cancer (EOC). We examined the phenotypic characteristics and antitumor cell activity of ascitic MO in patients with EOC. MO/MA phenotype was compared with MO in peripheral blood by two- and three-color flow cytometry. Cytotoxic/cytostatic effects of different cytokines on cultured EOC cells were measured by initial labeling or uptake inhibition of [methyl-3H] thymidine. Malignant ascites had higher proportion of MO/MA with the CD14brightCD16+ phenotype than peripheral blood. Cell surface antigen expression of activation and differentiation in peripheral blood and ascites, including CD38, CD40, CD64, and CD86, was higher on CD14brightCD16- and CD14brightCD16+ than on CD14dimCD16- cells. HLA-DR expression was higher on ascitic MO/MA than peripheral blood MO. Significant cytotoxic/cytostatic activity was elicited by treating ascitic MO/MA with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), but not with interleukin-12, paclitaxel, granulocyte-monocyte colony-stimulating factor (GM-CSF), or tumor necrosis factor-alpha (TNF-alpha). Soluble CD40Lt did not enhance MO/MA cytotoxic activity, and inhibited IFN-gamma or IL-2 induced cytoxicity. We conclude that MO/MA from ascites have elevated proportions of CD14brightCD16+ cells, showing phenotypic features of activation. IFN-gamma induces the cytotoxic and cytostatic activity of MO/MA that is inhibited by CD40Lt.

Thiotepa in combination with cisplatin for primary epithelial ovarian cancer: a phase II study.

The objectives of this phase II protocol were: 1) to determine the clinical activity of thiotepa combined with cisplatin in suboptimally debulked advanced epithelial ovarian carcinoma as first-line chemotherapy, 2) to determine by surgery the response after 6 courses of chemotherapy, and 3) to identify the regimen's qualitative and quantitative toxicities. Patients with FIGO stage IIIC or IV epithelial ovarian cancer were eligible to receive cisplatin (50 mg/m2) followed by thiotepa (40 mg/m2) on an every 4-week schedule. Patients showing no evidence of disease after six cycles of chemotherapy underwent surgical reassessment. Thirty-one patients were evaluable for toxicity and response. Myelosuppression was the major toxicity and hematologic toxicities prompted all dose reductions. No growth factor support was given in this trial. Thirty-nine percent of patients (12/31) had a clinical complete response. Of these, 16% (5/31) had complete pathologic response and 19% (6/31) had partial pathologic response. One long-term survivor declined reassessment laparotomy. Including the 16% of patients with a partial response, the overall response rate was 55% (17/31). Five patients are currently alive 8 years after enrollment. Median survival was 16.8 months for all patients, 21.5 months for patients with partial response, and 60.8 months for patients with complete pathologic response. A normalization or >50% decrease in CA125 level occurred in 93% of patients. This study indicates that first-line treatment with thiotepa and cisplatin produces significant long-term responses when tumors are sensitive. Such treatment is a reasonable option when paclitaxel is not available.

Activity of ALRT 1550, a new retinoid, with interferon-gamma on ovarian cancer cell lines.

Retinoids have been shown to be effective regulators of cell proliferation and differentiation in many human cancers. The major biologic activity of the retinoids is mediated by two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). ALRT 1550 is one of the most potent RAR selective retinoids discovered to date, with 10-100 times more activity than ATRA in competitive binding and cotransfection assays and 300 times more inhibiting activity against proliferation of cervical carcinoma cell. To evaluate the role of ALRT 1550 in ovarian cancer, the growth inhibitory activity of ALRT 1550 was determined in the ATRA-resistant ovarian cancer cell line SKOV-3 and ovarian cancer cell line 2774 after exposure to concentrations of 0.1, 1, 2.5, 5, and 10 microM for 7 days. SKOV-3 showed 51%, 53%, and 68% cell growth inhibition after treatment with ALRT 1550 at concentrations of 2.5, 5, and 10 microM, respectively, and the 2774 cell line showed 46% inhibition after treatment at 10 microM. Because interferon (IFN)-gamma was found to synergistically amplify the growth inhibition of retinoids in cultured breast cancer cells, we investigated the combination of ALRT 1550 with IFN-gamma in two ovarian cancer cell lines. ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 500 U/ml inhibited cell growth of SKOV-3 by as much as 81% (CI = 1.88). This is a 28% greater effect than with ALRT alone. Cell line 2774 showed a 69% cell growth inhibitory effect with ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 1000 U/ml (CI = 1.03). ALRT 1550 and IFN-gamma may act synergistically in the SKOV-3 ovarian cancer cell line and additively in the 2774 cell line. In conclusion, ALRT 1550 may be a promising drug with a high biologic modulating activity against ovarian cancer. In combination with IFN-gamma, additive and perhaps synergistic effects may be seen in some ovarian cancer cell lines. Combining these two biologic modifiers for the treatment of ovarian cancer may lower the effective dose of the retinoids, thus decreasing their side effects.

Immunology of the peritoneal cavity: relevance for host-tumor relation.

The peritoneal membrane, formed by a single layer of mesothelial cells, lines the largest cavity of the human body. Anatomic structures of the peritoneal cavity, along with resident leukocyte populations, play an important role in the defense against microorganisms invading by breaching the gut integrity or ascending through the female genital tract. Local immune mechanisms in the peritoneal cavity are also important in patients undergoing peritoneal dialysis and in women with endometriosis. There is now extensive evidence demonstrating the significance of peritoneal immune mechanisms in the control of metastatic spread. Leukocytes belonging to both the innate and adaptive immune systems are present in the peritoneal cavity of normal subjects as well as in patients with intra-abdominal cancer. There is now increased understanding of the mechanisms that not only allow the tumor cells to escape the detection and destruction by the host immune system, but also to use the inflammatory mechanisms to promote tumor growth and spread inside the peritoneal cavity. Malignant ascites represents a model for the study of the interaction between tumor cells and the host immune system as well for the analysis of the tumor microenviroment. The peritoneal immune system may be stimulated by intraperitoneal administration of biologic agents. This peritoneal immunotherapy may be used for palliation of malignant ascites, or as a consolidation strategy in patients with minimal residual disease.

Maturation of dendritic cells from ovarian cancer patients.

PURPOSE: Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system. We have shown that DC, defined as LN-DR+ leukocytes from the ascites of patients with ovarian or peritoneal carcinoma, have the cell surface characteristics of immature cells. Moreover, p70 interleukin-12 has not been detected in the ascites of ovarian cancer patients in vivo. In the current study, we examined the effects of in vitro treatment of DC from peripheral blood and ascites samples of patients with ovarian cancer with either cytokines or proteolytic enzymes (polyenzyme preparation). METHODS: Mononuclear leukocytes from the ascites of 15 patients or peripheral blood from 9 patients with epithelial ovarian cancer were cultured with tissue culture medium containing either papain, trypsin and chymotrypsin for 5-7 days or recombinant human granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha and interleukin-4 (complete medium) or tissue culture medium alone. RESULTS: Phenotypic analysis of DC obtained on days 5-7 of the culture showed higher proportions of CD83+, CD40+ and CD80+ cells when cultured with cytokines or enzymes as compared with DC cultured with medium alone. Stimulation of allogeneic T cells was detected by the mixed leukocyte reaction (MLR) and higher concentrations of IL-12 were detected after growing these cells in the presence of cytokines or enzymes as compared to tissue culture medium alone. CONCLUSION: Our studies demonstrate for the first time that DC obtained from the peritoneal cavity and peripheral blood of ovarian cancer patients after culturing in the presence of a polyenzyme preparation, will undergo maturation. Further studies are warranted to determine whether polyenzyme preparations facilitate DC maturation in vivo.

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.

OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.

Diffuse large B-cell non-Hodgkin's lymphoma presenting as a vaginal mass in a patient with a history of intestinal mucosa-associated lymphoid tissue (MALT) lymphoma.

Vaginal involvement in non-Hodgkin's lymphoma is uncommon and is often secondary to disseminated disease. Primary disease at this site is quite rare. We present here an unusual case of a patient who developed a diffuse large B-cell lymphoma presenting as a vaginal mass after having been treated for primary intestinal mucosa-associated lymphoid tissue (MALT) lymphoma 4 years earlier. Combined chemotherapy and radiation therapy for the intestinal MALT lymphoma produced complete remission that lasted for 2 years. Chemotherapy given for the diffuse large B-cell lymphoma with secondary vaginal involvement produced a second complete remission. The second remission was consolidated with high-dose chemotherapy and autologous bone marrow transplantation. Although the patient died from complications related to the transplant procedure, the disease was in complete remission at the time of her death. Given the rarity of primary intestinal MALT lymphoma and primary vaginal lymphoma, no standard treatment has been established. Treatment options have included chemotherapy, radiation therapy, or surgery, given alone or in combination.

Clinical and biological effects of intraperitoneal injections of recombinant interferon-gamma and recombinant interleukin 2 with or without tumor-infiltrating lymphocytes in patients with ovarian or peritoneal carcinoma.

To identify strategies that enhance tumor-specific immunity in patients with ovarian carcinoma, 22 patients received four to six doses of i.p. recombinant IFN-gamma (rIFN-gamma), 200 microg/m2 on days 1, 3, 5, 8, 10, and 12, and i.p. recombinant interleukin 2 (rIL-2), either 6.0 x 10(5) IU/m2 (group A) or 1.0 x 10(5) IU/m2 (group B), on days 9, 10, and 11. Two patients in group A also received T-cell lines expanded from peritoneal tumor-infiltrating lymphocytes (TILs) obtained after i.p. rIFN-gamma/rIL-2 administration. Toxicity was manageable and included five nonhematological grade 3 or 4 events in 22 patients (23%). A patient had normalization of CA-125 values and a progression-free interval of 18 months, after receiving i.p. rIFN-gamma/rIL-2 without TILs. Another patient who received i.p. rIFN-gamma/rIL-2 plus TILs had stabilization of ascites and intra-abdominal tumors and >50% reduction in serum CA-125 values over 6 months. A third patient who received i.p. rIFN-gamma/rIL-2 had stabilization of intra-abdominal tumors and ascites accompanied by CA-125 values of 50 to 100 units over 6 months. T-cell lines for adoptive immunotherapy were developed for only 3 of 20 patients who were treated with rIFN-gamma/rIL-2. Large numbers of CD3- CD56+ adherent cells were expanded in rIL-2 in the remaining patients, precluding the development of T-cell lines. i.p. rIFN-gamma, either alone or followed by rIL-2, increased proportions of human leukocyte antigen (HLA) class I+ and class II+ tumor cells and increased HLA class I staining intensity on peritoneal carcinoma cells. i.p. rIFN-gamma plus rIL-2 also enhanced cytotoxic activity against Daudi and K562 cells and against allogeneic ovarian tumor cells. Increased cytotoxic activity was associated with an increase in the proportion of CD56+ cells. IFN-gamma and IL-2 transcripts were expressed more frequently after rIFN-gamma and rIL-2 treatment. In addition, the proportions of CD45RA+ (naive lymphocytes) were increased, and CD8+ DR+ lymphocytes were increased relative to CD8+ CD69+ cells, which were decreased. IL-10 concentrations in peritoneal fluids were increased after treatment with rIFN-gamma and the higher rIL-2 dosing (group A) but not in those treated with rIFN-gamma and the lower rIL-2 dosing (group B). These results demonstrated that patients with ovarian carcinoma can tolerate treatment with rIFN-gamma and rIL-2 and that rIFN-gamma alone or rIFN-gamma combined with rIL-2 enhances the expression of HLA class I and class II antigens on ovarian tumor cells, although immunosuppressive cytokines, such as transforming growth factor-beta and IL-10, may persist. Treatment with rIFN-gamma/rIL-2 i.p. did not facilitate the production of TIL-derived T-cell lines ex vivo.

Anomalies of the TGF-beta postreceptor signaling pathway in ovarian cancer cell lines.

Transforming growth factor-beta (TGF-beta) can cause cell cycle arrest, terminal differentiation, or apoptosis in most normal epithelial cells, whereas most malignant cell lines are resistant to TGF-beta. Mechanisms of resistance to TGF-beta caused by modulation of cell cycle regulators and/or inactivation of components of the TGF-beta signaling transduction pathway such as C-myc and Smad4 have been demonstrated in human pancreatic cancer and squamous cell carcinoma cell lines. But, this has not been shown in ovarian cancer. To investigate the potential association between loss of sensitivity to TGF-beta and expression status of transforming growth factor receptor II (T beta RII), Smad4, CDC25A and C-myc in fourteen cell lines derived from ovarian cancer, the expression levels of these genes were examined by semi-quantitative RT-PCR. Normal ovarian surface tissues were used as controls. Expression of T beta RII was detectable in all of fourteen cell lines. Expression of Smad4 was decreased in ten cell lines and nine cell lines overexpressed CDC25A, compared to normal controls. CDC25A gene was overexpressed in 88% (8/9) of tumorigenic cell lines as determined by xenografts in nude mice, and only in 20% (1/5) of non-tumorigenic cell lines (P < 0.05). C-myc was not overexpressed in any of these cell lines. The loss of sensitivity to TGF-beta of cell lines derived from ovarian cancers may be related to (1) a decreased expression of Smad4, which mediates TGF-beta induced growth inhibition; and/or (2) an overexpression of CDC25A. This overexpression correlates with increased tumorigenicity of ovarian cancer cell lines. The loss of sensitivity to TGF-beta is not associated with a lack of T beta RII.

Intraperitoneal radioimmunotherapy with human monoclonal IGM in nude mice with peritoneal carcinomatosis.

UNLABELLED: In an effort to improve loco-regional control of ovarian cancer, intraperitoneal (i.p.) administration of an yttrium-90 (90Y) labeled human IgM was studied in a nude mouse model of the disease. METHODS: Athymic nude mice bearing i.p. nodules of SKOV3 NMP2, a human ovarian carcinoma cell line, received single (50-400 microCi) or fractionated (150-510 microCi) administrations of 90Y-labeled 2B12. Untreated mice and mice treated with unlabeled immunoconjugate served as controls. Mice were monitored for weight loss, blood counts and survival. RESULTS: Mice that received at least 300 microCi of 90Y-labeled 2B12 in a single administration lost more than 10% of their body weight with some early deaths, both of which were prevented with fractionated administration. Granulocytes and lymphocytes declined with treatment while red blood cell counts were relatively stable. Untreated mice and mice treated with unlabeled immunoconjugate had a median survival time of 20 and 17 days respectively. Treatment with 90Y-labeled 2B12 increased median survival by 11-12 days per 100 microCi for single (50-300 microCi) and fractionated administrations (150-510 microCi). The highest fractionated activity produced over three logs of tumor cell kill without significant toxicity. CONCLUSION: Intraperitoneal RIT with 90Y-labeled 2B12 appears to be an attractive modality to treat peritoneal carcinomatosis and warrants further development.

Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer.

BACKGROUND: Thrombocytopenia is a significant problem in the treatment of cancer. OBJECTIVE: To assess the clinical safety of therapy with recombinant human thrombopoietin (rhTPO) and its ability to ameliorate chemotherapy-induced severe thrombocytopenia. DESIGN: Phase I/II clinical cohort study. SETTING: The University of Texas M.D. Anderson Cancer Center, Houston, Texas. PATIENTS: 29 patients with gynecologic cancer. INTERVENTION: Recombinant human thrombopoietin was given before chemotherapy and after a second cycle of carboplatin therapy. MEASUREMENTS: Peripheral blood counts and platelet transfusions. RESULTS: Administration of rhTPO after chemotherapy significantly reduced the degree and duration of thrombocytopenia and enhanced platelet recovery. In patients who received the optimal biological dose of rhTPO (1.2 microg/kg of body weight) in cycle 2 (carboplatin plus rhTPO), the mean platelet count nadir was higher (44x10(9) cells/L and 20x10(9) cells/L; P = 0.002) and the duration of thrombocytopenia was shorter (days with a platelet count <20x10(9) cells/L, 1 and 4 [P = 0.002]; days with a platelet count <50x10(9) cells/L, 4 and 7 [P = 0.006]) than in cycle 1 (carboplatin only). The need for platelet transfusion in this group was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = 0.013). CONCLUSIONS: Therapy with rhTPO seems to be safe and may attenuate chemotherapy-induced severe thrombocytopenia and reduce the need for platelet transfusions.

Growth inhibitory effects and radiosensitization induced by fatty aromatic acids on human cervical cancer cells.

Evidences have been reported that phenylacetic (PA) and phenylbutyric (PB) fatty aromatic acids can exert tumor growth inhibition in vitro and in vivo. Moreover, clinical trials also showed some activity for these drugs to modulate the expression of genes implicated in tumor growth, metastasis, immunogenicity, and to potentiate the efficacy of cytotoxic agents. The aim of the study was to examine the effects of PA and PB on the growth as well as sensitization to cisplatin and radiation in human cervical cancer cells. The effects of PA and PB on the proliferative activity and apoptosis induction in cervical tumor tissue was investigated. Both PA and PB exhibited a time- and dose-dependent antiproliferative activity in SW756 and ME180 cell lines: after 72-h treatment, the IC50 (concentration able to inhibit 50% of cell growth) of PB was 1.9 +/- 0.2 mM and 1.5 +/- 0.2 mM in SW756 and ME180 cells, respectively, while the IC50 of PA was 13.0 +/- 1.7 mM and 10.0 +/- 1.2 mM in SW756 and ME180 cells, respectively. In tumor tissue biopsies obtained from patients affected by squamous cervical cancer, both drugs resulted in a marked reduction of the percentage of bromodeoxyuridine-labeled cells compared with untreated samples [19.0 +/- 1.63% in untreated tissues with respect to 1.30 +/- 0.54% and 4.20 +/- 2.50% of stained cells after treatment with PA (30 mM) (P < 0.0001) and PB (5 mM) (P < 0.0001), respectively]. Moreover, analysis of the staining with M30 monoclonal antibody revealed that PA (30 mM) and PB (5 mM) were able to produce a marked increase in the number of stained apoptotic nuclei with respect to untreated samples. Finally, PB and PA were shown to enhance the sensitivity of SW756 to radiation and to exert an additive effect when combined with cisplatin. A significant reduction of the processed form of p21ras and rhoB proteins in the membrane fraction of cells exposed to PA and PB was observed. When farnesol, which is able to circumvent the enzymatic step inhibited by PA and PB, was added to the medium only a partial reversal of the growth inhibition and potentiation of sensitivity to radiation induced by PA and PB were found. In conclusion, the growth inhibitory properties of fatty aromatic acids suggest that these molecules could represent the prototype of a new class of compounds with some therapeutic potential in cervical cancer.

Expression of costimulatory molecules CD80 and CD86 and their receptors CD28, CTLA-4 on malignant ascites CD3+ tumour-infiltrating lymphocytes (TIL) from patients with ovarian and other types of peritoneal carcinomatosis.

Costimulation of T lymphocytes by the leucocyte surface molecules CD80 and CD86 expressed on antigen-presenting cells (APC) is required for the development of T cell responses. The CD28 and CTLA-4 molecules on T cells serve as receptors for the CD80 and CD86 costimulatory antigens. We have examined the frequency of expression of CD80 (B7.1), CD86 (B7.2), CD28 and CTLA-4 surface antigens on TIL isolated from malignant ascites or peritoneal washings of 26 patients with ovarian carcinoma and five patients with non-ovarian peritoneal carcinomatosis. Expression of CD80 and CD86 antigen was detected by reverse transcription-polymerase chain reaction (RT-PCR), and by FACS analysis. Significantly higher proportions of intraperitoneal CD3+ cells expressed CD86 antigen than the CD80 antigen (14 +/- 9% versus 3 +/- 3%, P < 0.05). Moreover, CD3+CD86+ cells were significantly more frequent in the peritoneal fluid (14 +/- 9%) than in the peripheral blood (3 +/- 0.4%, P < 0.05) of ovarian patients or normal controls (3 +/- 1%). CTLA-4 and CD28 antigen were expressed, respectively, on 9 +/- 4% and 86 +/- 14% of ascitic CD3+ cells of ovarian cancer patients. Both CD80 and CD86 antigens were expressed primarily on HLA-DR+ ascites TIL and were present in a very low proportion of HLA-DR- ascites TIL. These HLA-DR+ cells may represent a population of lymphocytes that have been activated in vivo, and function as APC. An anti-CD86 MoAb or a combination of anti-CD86 and anti-CD80 MoAbs significantly inhibited the proliferation of cultured intraperitoneal TIL. We have shown that in addition to CD28 and CTLA-4, CD3+ intraperitoneal TIL express the costimulatory molecules CD80 and CD86. The expression of these molecules on T cells could be dependent upon certain factors in the tumour microenvironment that could determine the outcome of in vivo immune responses.