Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

Severe craniosynostosis in an infant with deletion 22q11.2 syndrome.

We report a male infant with 22q11.2 deletion syndrome and very severe multi-sutural craniosynostosis associated with increased intracranial pressure, marked displacement of brain structures, and extensive erosion of the skull. While uni- or bi-sultural craniosynostosis is a recognized (though relatively uncommon) feature of 22q11 deletion syndrome, a severe multi-sutural presentation of this nature has never been reported. SNP Microarray was otherwise normal and the patient did not have common mutations in FGFR2, FGFR3, or TWIST associated with craniosynostosis. While markedly variable expressivity is an acknowledged feature of deletion 22q11 syndrome, herein we also consider and discuss the possibility that this infant may have been additionally affected with an undiagnosed single gene disorder.

Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.

Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.

Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients.

Ascites from ovarian cancer patients contain potent growth-promoting activity toward human ovarian cancer cells both in vitro and in vivo. This activity is associated with rapid increases in cytosolic free calcium ([Ca2+]i) as a consequence of phosphoinositide hydrolysis. In this study, we describe the purification, characterization, and identification of an ovarian cancer activating factor (OCAF) from ascites of ovarian cancer patients. We have isolated OCAF by a combination of solvent extraction, silica gel chromatography, and TLC. Mass spectral analysis, phospholipase sensitivity, and gas chromatographic behavior of purified OCAF indicate that OCAF is composed of various species of lysophosphatidic acid (LPA), including LPAs with polyunsaturated fatty acyl chains (linoleic, arachidonic, and docosahexaenoic acids). However, OCAF is more potent than sn-1 palmitoyl, oleoyl, or stearoyl LPA in increasing [Ca2+]i in ovarian cancer cells. The ability of OCAF to alter [Ca2+]i is sensitive to the effects of lipoxidase, whereas the activity of sn-1 oleoyl, stearoyl, or palmitoyl LPA is not, suggesting that polyunsaturated bonds in the fatty acyl chain of OCAF may account for its increased ability to activate ovarian cancer cells. Furthermore, a sn-2 linoleoyl LPA generated by phospholipase A1 treatment of synthetic phosphatidic acid is much more active than are sn-1 palmitoyl, stearoyl, or oleoyl LPA in increasing [Ca2+]i in ovarian cancer cells. Taken together, these data suggest that the ability of OCAF to increase cellular calcium may reside in the structure and/or location of the fatty acyl chain of LPA. Purified OCAF, at concentrations similar to those present in ascites from ovarian cancer patients, was sufficient to induce proliferation of ovarian cancer cells, as indicated by thymidine incorporation, reduction of 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, or colony formation. However, even at optimal concentrations of OCAF, proliferation was lower than that induced by FCS or ascites from ovarian cancer patients, indicating that, although OCAF may be a major regulator of ovarian cancer cells in vivo, it is not the sole mediator present in ascites, and it likely functions in concert with other growth factor activities.

Villoglandular adenocarcinoma of the cervix: a case report.

BACKGROUND: Villoglandular adenocarcinoma of the cervix is a rare neoplasm associated with a favorable outcome and has not been described as a complication of pregnancy. CASE: A gravida at 20 weeks' gestation was found to have a bulky stage-IB adenocarcinoma of the cervix. She was delivered at 32 weeks' gestation by cesarean, then a radical hysterectomy and pelvic and periaortic lymphadenectomies were performed. Pathology revealed a deeply invasive, grade 1 villoglandular adenocarcinoma confined to the cervix. The patient remains free of disease at 14 months follow-up. CONCLUSION: Villoglandular adenocarcinoma of the cervix has a favorable prognosis and can be managed conservatively, even when complicated by pregnancy.

Chemotherapy-induced apoptosis in epithelial ovarian cancers.

OBJECTIVE: To determine whether chemotherapy drugs elicit programmed cell death (apoptosis) in ovarian cancer cells. METHODS: Monolayers of immortalized ovarian cancer cell lines and primary ovarian cancer cells obtained from ascites were grown in the presence of cisplatin, 4-hydroxyperoxy-cyclophosphamide (the active metabolite of cyclophosphamide) or paclitaxel. Next, DNA was extracted from the cells and subjected to electrophoresis to determine if DNA laddering characteristic of apoptosis was present. RESULTS: In three of six immortalized cell lines (OVCA 420, 429, and 433), apoptosis was not seen in response to any of the three drugs. In contrast, in OVCAR-3 and OVCA 432, DNA laddering consistent with apoptosis was observed in response to all three drugs. In the DOV 13 cell line, apoptosis was seen only with 4-hydroxyperoxycyclophosphamide. Among three primary ovarian cancers, cisplatin elicited apoptosis in one case. Both cell lines with mutant p53 genes (OVCAR-3 and OVCA 432) underwent apoptosis in response to all three drugs, whereas among three cell lines known to have normal p53 genes, one underwent apoptosis in response to 4-hydroxyperoxycyclophosphamide and two were unaffected. CONCLUSION: Ovarian cancer cell death in response to commonly used chemotherapeutic drugs involves the induction of a genetically programmed sequence of events (apoptosis) rather than simply necrosis.

Gynecologic cancers metastatic to the breast.

BACKGROUND: We report a series of gynecologic cancers metastatic to the breast, illustrating the diagnostic and prognostic implications of this rare event. STUDY DESIGN: By reviewing the gynecologic oncology data base, we identified 10 women with gynecologic cancer metastatic to the breast who were treated at Indiana University School of Medicine between August 1978 and February 1995. Medical records were reviewed for pertinent data concerning the presentation, evaluation, and treatment of the primary gynecologic malignancy and the metastatic breast tumor. RESULTS: The mean patient age was 56.8 years (range, 30-80 years). The most common gynecologic malignancy was ovarian cancer (five patients), followed by cervical cancer (two patients) and cancers of the vagina, endometrium, or peritoneum (one patient each). A palpable solitary breast mass was found in 8 of 10 patients (80%), and the upper outer quadrant of the breast was the most common site of tumor involvement. One woman presented with examination findings resembling inflammatory breast cancer, and one patient presented with multiple firm subcutaneous nodules. Despite further treatment, which in all cases consisted of systemic chemotherapy, 83% of the patients died with a breast metastasis within 1 year of presentation. CONCLUSIONS: Secondary breast malignancy should be suspected in any patient with a breast tumor and a known history of gynecologic cancer. A breast metastasis implies widespread tumor dissemination and a poor prognosis. Radical breast surgery should be avoided.

Replantation of an entire scalp and ear by microvascular anastomoses of only 1 artery and 1 vein.

We present a successful microvascular replantation of a scalp and ear, where almost the entire scalp and right ear survived on 1 artery and 1 vein.

Evaluation of cisplatin and cyclosporin A in recurrent platinum-resistant ovarian cancer: a phase II study of the gynecologic oncology group.

OBJECTIVE: The objective of this study was to study the effectiveness of cyclosporin A and cisplatin in patients with recurrent epithelial ovarian cancer. METHODS. Twenty-six patients with measurable recurrent epithelial ovarian cancer, considered to be resistant to cisplatin, received cisplatin in combination with cyclosporin A. Patients received 75 mg/m2 cisplatin every 3 weeks and two cyclosporin A injections over 2 h each, 24 h apart, at a dose of 4 mg/kg each. RESULTS: Only a single patient had a complete response, with two experiencing a partial response to cyclosporin A/cisplatin combination. Hematologic toxicity in this study was modest. No patient developed grade 4 renal toxicity. CONCLUSION: These data indicate minimal activity of the combination of cyclosporin A and cisplatin in ovarian cancer patients with recurrent measurable disease previously treated with cisplatin and thought to be resistant to this chemotherapeutic agent.

Levels of soluble interleukin-2 receptor-alpha are elevated in serum and ascitic fluid from epithelial ovarian cancer patients.

OBJECTIVE: The purpose of the study was to determine whether ovarian cancer patients have activated lymphocytes as indicated by the presence of soluble interleukin-2 receptor-alpha and to compare soluble interleukin-2 receptor-alpha with other markers in ovarian cancer. STUDY DESIGN: Ascites and serum from patients with advanced active ovarian cancer was tested for the presence of elevated levels of soluble interleukin-2 receptor-alpha and compared with normal controls. Levels of soluble interleukin-2 receptor-alpha were also compared with levels of CA 125 and macrophage colony-stimulating factor in the same patients, to evaluate the correlation between different markers. RESULTS: Elevated levels of soluble interleukin-2 receptor-alpha were detected in 86 of 86 (100%) ascites samples and 67 of 85 (79%) serum samples from patients with advanced epithelial ovarian cancer. In contrast, only 12 of 25 (48%) benign ascites samples and one of 88 (1%) serum samples from controls had elevated levels. There was no obvious correlation between levels of soluble interleukin-2 receptor-alpha and levels of CA 125; however, levels of soluble interleukin-2 receptor-alpha did correlate with levels of macrophage colony-stimulating factor. Concurrent measurement of serum-soluble interleukin-2 alpha and CA 125 levels detected 100% of patients with epithelial ovarian cancer. CONCLUSION: The detection of elevated levels of soluble interleukin-2 receptor-alpha in serum and ascites indicates the presence of activated lymphocytes in patients with epithelial ovarian cancer. Ascites and serum levels of soluble interleukin-2 receptor-alpha are elevated in patients with advanced ovarian cancer and warrant assessment as a potential complementary marker to CA 125 for early detection of ovarian cancer and management of patients with advanced ovarian cancer.

The biology of ovarian cancer.

Recent studies have begun to elucidate the molecular events involved in the development of ovarian cancer. First, it has been shown that epithelial ovarian cells both produce and have receptors for many peptide growth factors. It is possible that these growth factors may participate in autocrine and paracrine growth-regulatory pathways in these cells. Increased activity of stimulatory factors, eg, transforming growth factor-alpha, or decreased activity of inhibitor factors, eg, transforming growth factor-beta, may facilitate malignant transformation. In addition, it has been shown that ovarian cancer cells often have acquired the ability to degrade extracellular matrix and invade the underlying tissues. Finally, alterations in several oncogenes and tumor-suppressor genes, including HER2/neu, c-myc, and p53, have been found in ovarian cancers. Although exciting insights into the molecular pathology of ovarian cancer have been gained, we remain far from a comprehensive understanding of the biology of this highly lethal disease.

Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study.

Objective. The goal of this study was to estimate the antitumor activity and toxicity of recombinant human interleukin-12 (rhIL-12) in patients with recurrent or refractory epithelial ovarian cancer. Methods. From December 1997 to March 1999, patients with recurrent or refractory epithelial ovarian cancer were entered on a Gynecologic Oncology Group phase II study of intravenous rhIL-12. All patients had measurable disease, had a performance status of 0-2, and had failed first-line platinum-based chemotherapy regimen. Eligible patients received rhIL-12, 250 ng/kg IV bolus, as a single dose on Day 1 followed by a 2-week rest period, with subsequent cycles administered daily for 5 days followed by a 16-day rest period per cycle, until disease progression or adverse effects prohibited further therapy. Results. Twenty-eight patients were entered and evaluable for toxicity, while 26 were evaluable for response. The median age was 59.5 years (range: 45-77). The median number of cycles was 2 (range: 1-9). There were no complete responders; however, one patient (3.8%) was a partial responder and 13 patients (50%) had stable disease. Grade 4 myelotoxicity occurred in 21% of patients. Two patients experienced capillary leak syndrome: one grade 2 and one grade 4. Conclusion. As a single agent, rhIL-12 is tolerable and shows a low response rate in recurrent epithelial cancer with measurable disease.

Effect of carbon dioxide on human ovarian carcinoma cell growth.

OBJECTIVE: Laparoscopy may be associated with increased risk of ovarian carcinoma wound metastases. This study was designed to determine whether carbon dioxide exposure increases the growth of human ovarian cancer cells in vitro. STUDY DESIGN: Immortalized ovarian epithelial carcinoma cell (SKOV-3 cell line) cultures were exposed to carbon dioxide, nitrous oxide, or culture media with decreased pH for up to 3 hours. Cell growth was determined with the use of a spectrophotometric assay, and the results were compared with control cells by paired t tests and linear regressions analysis. RESULTS: Carbon dioxide exposure increased SKOV-3 cell growth by 52% after 4 days in culture. The increased cell growth had a linear relationship to the length of carbon dioxide exposure. Cells that were exposed to either nitrous oxide or media with pH 6.3 showed a trend toward decreased growth. CONCLUSION: Carbon dioxide exposure increases the in vitro growth of human ovarian carcinoma cells by an effect that is independent of the carbon dioxide-related decrease in the culture media pH.

Cervical primitive neuroectodermal tumor.

BACKGROUND: Primitive neuroectodermal tumors (PNETs) are rare and potentially aggressive malignancies. CASE: A 24-year-old woman in her eighth week of pregnancy presented with a cervical mass. Tissue biopsy demonstrated poorly differentiated carcinosarcoma with neuroendocrine features. Immunohistochemical studies confirmed the diagnosis of PNET. Treatment included alternating courses of cyclophosphamide, adriamycin, vincristine (CAV) and ifosfamide, etoposide (IE). A radical hysterectomy with bilateral ovarian transposition and periaortic lymphadenectomy was performed with postoperative chemotherapy and radiotherapy. The patient remains disease free 2 years from therapy. CONCLUSION: This is a rare case of cervical PNET occurring in a pregnant patient. A review of the literature indicates that cervical PNET is distinguishable from uterine PNET. This tumor affects younger women and may have a different histogenesis. Pregnancy should not delay diagnosis of this potentially aggressive tumor.

DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells.

OBJECTIVE: The aim of this study was to investigate whether expression of the enzymes that catalyze cytosine CpG island methylation, DNA methyltransferases, DNMT1, DNMT3a, and DNMT3b is altered in human ovarian cancer. Aberrations in DNA methylation are common in cancer and have important roles in tumor initiation and progression. Tumors that display frequent and concurrent inactivation of multiple genes by methylation are designated as having a CpG Island methylator phenotype, or CIMP. To date, colon, gastric, and most recently ovarian cancers meet the CIMP criteria for cancer. We hypothesized that altered expression of DNA methyltransferases can result in hypermethylation events seen in CIMP cancers. METHODS: DNMT1, DNMT3a, and DNMT3b mRNA levels in eight ovarian cancer cells lines (Hey, HeyA8, HeyC2, OVCAR-3, SK-OV-3, PA-1, A2780, and A2780-P5) were compared to DNMT expression in normal ovarian surface epithelial cells using semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: In HeyA8 and HeyC2 ovarian cancer cells, DNMT1 expression levels were up to threefold higher (P < 0.05) than in normal ovarian surface epithelial cells. SK-OV-3 and PA-1 displayed increased DNMT3b expression (P < 0.05) compared to normal ovarian surface epithelial cells. Transcript levels for DNMT3a, however, were similar in cancer and normal ovarian cells. CONCLUSIONS: We observed differential expression of the DNMT genes in some ovarian cancer cell lines and conclude that alterations in DNMT expression might contribute to the CIMP phenotype in ovarian cancer. However, based on the lack of aberrant DNMT expression in some of the cancer cell lines examined, we further suggest that another mechanism(s), in addition to DNMT overexpression, accounts for methylation anomalies commonly observed in ovarian cancer.

A phase II trial of pyrazoloacridine (PZA) in squamous carcinoma of the cervix--a Gynecologic Oncology Group Study.

PURPOSE: The Gynecologic Oncology Group performed a Phase II study to determine the response rate of Pyrazoloacridine (PZA) in patients with advanced, persistent or recurrent squamous carcinoma of the cervix. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over three hours every three weeks. RESULTS: Among 21 evaluable patients, there were no complete and one (4.2%) partial response. The major toxicities were hematologic. CONCLUSION: PZA at the dose and schedule employed has insignificant activity in this population.

Trisomy 21 associated with ovarian dysgerminoma.

A 13-year-old G(0)P(0) white female with trisomy 21 presented with a complex pelvic mass. She underwent resection of the mass and complete staging for what was found to be a stage IIIC completely resected dysgerminoma. She was treated with three cycles of bleomycin, etoposide, and cisplatin chemotherapy and remains free of disease 1 year later. This association is presented as a rare case that may illustrate the relative increase in germ cell neoplasms in female patients with Down's syndrome. While the association of seminoma with Down's syndrome has been documented in a number of cases in males, the female counterpart of this tumor, dysgerminoma, in trisomy 21 has been reported quite infrequently. The potential for germ cell tumors in both male and female trisomy 21 is therefore illustrated.

FIGO stage IIIC endometrial carcinoma with metastases confined to pelvic lymph nodes: analysis of treatment outcomes, prognostic variables, and failure patterns following adjuvant radiation therapy.

OBJECTIVES: This study was undertaken to evaluate the prognostic significance of isolated positive pelvic lymph nodes on survival and to analyze other prognostic variables, overall survival, and failure patterns in surgically staged endometrial carcinoma patients with positive pelvic lymph nodes and negative para-aortic lymph nodes following radiation therapy (RT). METHODS: Between January 1, 1987, and December 31, 1997, 782 women underwent primary treatment for uterine cancer at Indiana University Medical Center. Through a review of the medical records, we identified 58 patients with pathologic stage IIIA, 27 patients with pathologic stage IIIB, and 77 patients with pathologic stage IIIC endometrial carcinoma. Patients with pathologically positive or unsampled para-aortic lymph nodes and patients who received preoperative radiation therapy were excluded, leaving a study group of 17 patients with nodal metastases confined to pelvic lymph nodes. Thirteen patients received adjuvant pelvic RT using AP-PA or four-field technique. A median dose of 5040 cGy was delivered. Four patients received whole abdominal irradiation (WAI) delivering a median dose of 3000 cGy. Two patients received vaginal cuff boosts of 1000 and 3560 cGy to 0.5 cm from the vaginal surface mucosa via Cs-137 brachytherapy. Two patients also received adjuvant chemotherapy (cis-platinum and doxorubicin) and/or hormonal therapy (megestrol acetate). Disease-free and overall survivals were estimated using the Kaplan-Meier method of statistical analysis and prognostic variables were analyzed using the log-rank test. RESULTS: With a median follow-up of 51 months the actuarial 5-year disease-free survival was 81% and the actuarial 2-year and 5-year overall survival rates were 81 and 72%, respectively. Univariate analysis revealed that positive peritoneal cytology in conjunction with positive pelvic lymph nodes imparts a greater risk of recurrence and decreased overall survival. There were no pelvic and/or upper abdominal failures, but there were recurrences in the para-aortic lymph nodes (two patients) and distantly (two patients). CONCLUSION: Surgery followed by postoperative pelvic RT is a viable treatment option for pathologically staged stage IIIC endometrial carcinoma with disease confined to the pelvic lymph nodes. Failures in the para-aortic region suggest a possible role for extended-field RT. Patients with positive peritoneal cytology in conjunction with nodal metastasis fared poorly with pelvic RT. Studies evaluating the efficacy of WAI are ongoing. Finally, substages within FIGO stage IIIC are recommended in an effort to better understand and define treatment strategies which might be appropriate for these patients.

Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian stromal malignancies. METHODS: Patients with incompletely resected Stages II-IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2 x 9 weeks for a maximum dose of