SummaryBackgroundThe vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials.MethodsWe undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed).FindingsMajor vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37; p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253), but not major vascular events (1·44, 0·89–2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56–6·41; p=0·17), but not by naproxen (1·08, 0·48–2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17–2·81, p=0·0070; diclofenac 1·89, 1·16–3·09, p=0·0106; ibuprofen 3·97, 2·22–7·10, p<0·0001; and naproxen 4·22, 2·71–6·56, p<0·0001).InterpretationThe vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making.FundingUK Medical Research Council and British Heart Foundation.

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 69% (9/13) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

BACKGROUND Because low grade serous carcinoma of the ovary is relatively chemo resistant disease, this study evaluated Selumetinib (AZD6244), an inhibitor of mitogen-activated protein kinase kinase (MEK-1/2), and explored associations between RAS, and RAF family mutations with clinical outcome. METHODS Women with recurrent low-grade serous ovarian or peritoneal carcinoma were eligible and received Selumetinib at 100 mg. orally b.i.d. until progression or toxicity were enrolled in Gynecologic Oncology protocol 239(NCT00551070). This trial has been completed and we are reporting the results. The primary endpoint of this trial was to examine tumor response rate to Selumetinib. The study used all-treated patients to determine response rate and overall survival. FINDINGS Fifty-two patients were enrolled over two years. Eight patients (15.4%) had complete (1) or partial (7) responses, and 34 (65%) had stable disease. There were no treatment-related deaths. There were three observed grade 4 toxicities and 46 grade 3 toxicities that occurred in more than one patient. Observed grade 4 toxicities were cardiac (1), pain (1), and pulmonary (1). Grade 3 toxicities that occurred included gastrointestinal (13), dermatologic (9), and metabolic (7). CONCLUSIONS Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma. In exploratory analyses, response to Selumetinib did not appear to be related to RAS/RAF mutational status. The 63% disease control is encouraging and worthy of further evaluation of MEK inhibitors in this population. This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group.

Objectives To review the extent of health disparities in gynecologic cancer care and outcomes and to propose recommendations to help counteract the disparities. Methods We searched the electronic databases PubMed and the Cochrane Library. We included studies demonstrating quantifiable differences by race and ethnicity in the incidence, treatment, and survival of gynecologic cancers in the United States (US). Most studies relied on retrospective data. We focused on differences between Black and White women, because of the limited number of studies on non-Black women. Results White women have a higher incidence of ovarian cancer compared to Black women. However, the all-cause ovarian cancer mortality in Black women is 1.3 times higher than that of White women. Endometrial and cervical cancer mortality in Black women is twice that of White women. The etiology of these disparities is multifaceted. However, much of the evidence suggests that equal care leads to equal outcomes for Black women diagnosed with gynecologic cancers. Underlying molecular factors may play an additional role in aggressive tumor biology and endometrial cancer disparities. Conclusion Gynecologic cancer disparities exist between Black and White women. The literature is limited by the lack of large prospective trials and adequate numbers of non-Black racial and ethnic groups. We conclude with recommendations for continued research and a multifaceted approach to eliminate gynecologic cancer disparities.

BACKGROUND The objective of this study was to compare survival between patients with adenocarcinoma and patients with adenosquamous carcinoma of the cervix. METHODS Patients who were diagnosed with invasive cervical carcinoma from 1988 to 1999 were identified from the Automated Central Tumor Registry for the United States Military Health Care System. Clinical data, including race, age at diagnosis, histology, tumor grade, disease stage, lymph node status, treatment modality, and survival, were collected. Survival analysis was performed with Kaplan–Meier survival curves and compared using the log‐rank test. RESULTS A total of 273 women were identified, 185 women with a histologic diagnosis of adenocarcinoma (AC) and 88 women with a diagnosis of adenosquamous carcinoma (ASC). Among the women with ASC, only 5% had Grade 1 tumors, and 66% had Grade 3 tumors. By comparison, among the women with AC, 37% had Grade 1 tumors, and 26% had Grade 3 tumors (P < 0.001). There was no difference in the incidence of positive lymph nodes or in the number of patients who underwent radical hysterectomy as primary treatment between patients with ASC and patients with AC. More patients with ASC received radiation therapy (51% vs. 28%) or chemotherapy (29% vs. 12%) as treatment (P < 0.001). Patients who had tumors with ASC histology had a significantly decreased 5‐year survival rate compared with patients who had tumors with AC histology (65% vs. 83%; P < 0.002). When patients with early‐stage cervical carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage I) were examined separately, there was no statistically significant difference in the 5‐year survival rate (AC, 89%; ASC, 86%; P = 0.644). However, when patients with advanced‐stage disease (FIGO Stages II–IV) were analyzed, ASC was associated with a significant decrease in median and overall survival (P = 0.01). When the results were analyzed by grade, patients who had tumors with ASC histology had a shorter survival compared with patients who had AC histology of any grade; however, this was a significant difference only for patients with Grade 1 tumors: The 5‐year survival rate for patients with Grade 1 AC was 93%, compared with 50% for patients with Grade 1 ASC (P < 0.01). CONCLUSIONS ASC histology appears to be an independent predictor of poor outcome in women with cervical carcinoma compared with their counterparts who have pure AC. The significant decrease in survival was observed only in patients with advanced‐stage cervical carcinoma. This decreased survival may be related mainly to the grade of ASC. Cancer 2003;97:2196–202. Published 2003 American Cancer Society. DOI 10.1002/cncr.11371

PurposeSorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC).MethodsThis open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment.ResultsSeventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS.ConclusionSorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.

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Background Inorganic arsenic, a carcinogen at high exposure levels, is a major global health problem. Prospective studies on carcinogenic effects at low-moderate arsenic levels are lacking. Methods We evaluated the association between baseline arsenic exposure and cancer mortality in 3,932 American Indians 45–74 years from Arizona, Oklahoma and North/South Dakota who participated in the Strong Heart Study in 1989–1991 and were followed through 2008. We estimated inorganic arsenic exposure as the sum of inorganic and methylated species in urine. Cancer deaths (386 overall, 78 lung, 34 liver, 18 prostate, 26 kidney, 24 esophagus/stomach, 25 pancreas, 32 colon/rectal, 26 breast, 40 lymphatic/hematopoietic) were assessed by mortality surveillance reviews. We hypothesized an association with lung, liver, prostate and kidney cancer. Results Median (interquartile range) urine concentration for inorganic plus methylated arsenic species was 9.7 (5.8–15.6) μg/g creatinine. The adjusted hazard ratios (95% CI) comparing the 80th versus 20th percentiles of arsenic were 1.14 (0.92–1.41) for overall cancer, 1.56 (1.02–2.39) for lung cancer, 1.34 (0.66, 2.72) for liver cancer, 3.30 (1.28–8.48) for prostate cancer, and 0.44 (0.14, 1.14) for kidney cancer. The corresponding hazard ratios were 2.46 (1.09–5.58) for pancreatic cancer, and 0.46 (0.22–0.96) for lymphatic and hematopoietic cancers. Arsenic was not associated with cancers of the esophagus and stomach, colon and rectum, and breast. Conclusions Low to moderate exposure to inorganic arsenic was prospectively associated with increased mortality for cancers of the lung, prostate and pancreas. Impact These findings support the role of low-moderate arsenic exposure in lung, prostate and pancreas cancer development and can inform arsenic risk assessment.