Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells ...preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.
Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest ...effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics FIGO stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin AUC 5 or 6 and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months 95% CI 43·2–45·9 in the standard chemotherapy group vs 45·5 months 44·2–46·7 in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months 95% CI 32·0–37·0 with standard chemotherapy vs 39·3 months 37·0–41·7 with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months 95% CI 48·3–51·1) in the standard chemotherapy group vs 48·4 months 47·0–49·9 in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.
A Phase 3 Trial of Bevacizumab in Ovarian Cancer Perren, Timothy J; Swart, Ann Marie; Pfisterer, Jacobus ...
New England journal of medicine/The New England journal of medicine,
12/2011, Letnik:
365, Številka:
26
Journal Article
Recenzirano
Odprti dostop
The addition of bevacizumab to chemotherapy (15 mg/kg for six cycles) followed by extended therapy with bevacizumab every 3 weeks for a total of 15 months of treatment improved progression-free ...survival by 4 months in incompletely resected stage III or IV ovarian cancer.
Ovarian cancer is the fourth most common cause of cancer-related deaths in women, with an estimated 200,000 cases and 125,000 deaths occurring annually worldwide. For the past decade, the standard treatment for women with advanced ovarian cancer has been surgery and platinum-based chemotherapy. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug failed to affect either progression-free survival or overall survival and resulted in an increase in toxic effects.
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Although intraperitoneal chemotherapy has extended overall survival by 12 to 17 months, it is an option only for women with advanced ovarian cancer who have a . . .
Abstract Objectives Recent literature has highlighted histological types of ovarian carcinoma as distinct diseases, each with unique clinical and molecular features. Historically, the diagnosis of ...ovarian clear cell carcinoma (CCC) has been of concern to both patients and physicians due to reports that CCC is associated with a worse prognosis than the more common serous type of ovarian carcinoma (HGSC). This review discusses the unique features of ovarian CCC. Methods In June of 2010, a group of researchers and clinicians convened in Vancouver to review and discuss the clinical, pathological, molecular, and treatment-related features of CCC. Results CCC is the second most common type of ovarian epithelial cancer, representing 5–25% of ovarian carcinomas. It is characterised by its association with endometriosis, and frequent mutations of ARID1A and PIK3CA. Low-stage CCC appears to have a better outcome than stage matched HGSC, while the opposite is true for high-stage disease, suggesting that the current standard treatments applied to HGSC are ineffective for CCC. Conclusions Ovarian CCC is highly distinct from HGSC, and a clearer understanding of the basic biology of this disease is needed. Alternative therapies should be explored: irradiation and targeting disease-specific molecular markers should be examined in greater detail. Finally, novel approaches to clinical trial design are needed due to the smaller numbers of patients affected.
AIMThis executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in ...adult and pediatric patients as well as supporting documentation to encourage their use.
METHODSA comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases.
STRUCTUREMany recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.
This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in ...adult and pediatric patients as well as supporting documentation to encourage their use.
A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases.
Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.
The prevalence of BRCA(1/2) mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA(1/2) changes, given the ...sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.
In 235 unselected ovarian cancers, BRCA(1/2) was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA(1/2) transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA(1/2) mutations, germline DNA was sequenced.
Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA(1/2) mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA(1/2) mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio HR = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA(1/2) deficiency, defined as BRCA(1/2) mutations or expression loss (in 24 13.3% BRCA(1/2)-wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses.
BRCA(1/2) somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.
Irritable bowel syndrome (IBS) is a heterogeneous disorder affecting 12% of the population worldwide. Several studies identify IBS as a sequela of infectious gastroenteritis (IGE) with reported ...prevalence ranging from 4% to 31% and relative risk from 2.5 to 11.9. This meta-analysis was conducted to explore the differences between reported rates and provide a pooled estimate of risk for postinfectious irritable bowel syndrome (PI-IBS).
Electronic databases (MEDLINE, OLDMEDLINE, EMBASE, Cochrane database of clinical trials) and pertinent reference lists (including other review articles).
Data were abstracted from included studies by two independent investigators; study quality, heterogeneity, and publication bias were assessed; sensitivity analysis was performed; and a summative effect estimate was calculated for risk of PI-IBS.
Eight studies were included for analysis and all reported elevated risk of IBS following IGE. Median prevalence of IBS in the IGE groups was 9.8% (IQR 4.0-13.3) and 1.2% in control groups (IQR 0.4-1.8) (sign-rank test, p= 0.01). The pooled odds ratio was 7.3 (95% CI, 4.7-11.1) without significant heterogeneity (chi2 heterogeneity statistic, p= 0.41). Subgroup analysis revealed an association between PI-IBS risk and IGE definition used.
This study provides supporting evidence for PI-IBS as a sequela of IGE and a pooled risk estimate revealing a sevenfold increase in the odds of developing IBS following IGE. The results suggest that the long-term benefit of reduced PI-IBS may be gained from primary prevention of IGE.
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