Effects of concentrated long-chain omega-3 polyunsaturated fatty acid supplementation before radical prostatectomy on prostate cancer proliferation, inflammation, and quality of life: study protocol for a phase IIb, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in north-American men. Few dietary or lifestyle interventions have been tested to prevent prostate cancer progression. Omega-3 fatty acid supplementation represents a promising intervention for prostate cancer patients. The aim of the study is to evaluate the effects of long-chain omega-3 polyunsaturated fatty acids (LCn3), more precisely eicosapentaenoic acid monoacylglyceride (MAG-EPA) supplementation, on prostate cancer proliferation, inflammation mediators and quality of life among men who will undergo radical prostatectomy. METHODS/DESIGN: We propose a phase IIb, randomized, double-blind placebo-controlled trial of MAG-EPA supplementation for 130 men who will undergo radical prostatectomy as treatment for a prostate cancer of Gleason score ≥ 7 in an academic cancer center in Quebec City. Participants will be randomized to 6 capsules of 625 mg of fish oil (MAG-EPA) per capsule containing 500 mg of EPA daily or to identically looking capsules of high oleic acid sunflower oil (HOSO) as placebo. The intervention begins 4 to 10 weeks prior to radical prostatectomy (baseline) and continues for one year after surgery. The primary endpoint is the proliferative index (Ki-67) measured in prostate cancer cells at radical prostatectomy. A secondary endpoint includes prostate tissue levels of inflammatory mediators (cytokines and proteins) at time of radical prostatectomy. Changes in blood levels of inflammatory mediators, relative to baseline levels, at time of radical prostatectomy and 12 months after radical prostatectomy will also be evaluated. Secondary endpoints also include important aspects of psychosocial functioning and quality of life such as depression, anxiety, sleep disturbances, fatigue, cognitive complaints and prostate cancer-specific quality of life domains. The changes in these outcomes, relative to baseline levels, will be evaluated at 3, 6, 9 and 12 months after radical prostatectomy. DISCUSSION: The results from this trial will provide crucial information to clarify the role of omega-3 supplementation on prostate cancer proliferation, inflammation and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02333435. Registered on December 17, 2014. Last updated September 6, 2016.

Dietary supplement use among cancer survivors of the NutriNet-Santé cohort study.

Dietary supplements (DS) may influence cancer prognosis. Their use in cancer patients has been described in the United States, but data are largely lacking in Europe and notably in France. The present study's objectives were (1) to assess DS use and its sociodemographic, lifestyle, and dietary correlates in a large sample of French cancer survivors; (2) to evaluate the involvement of physicians in such DS use; and (3) to assess the extent of potentially harmful practices. Data were collected by self-administered web-based questionnaires among participants of the NutriNet-Santé cohort. Data on DS use was available for 1081 cancer survivors. DS users were compared to non-users with unconditional logistic regressions. DS use was reported by 62% of women and 29% of men. Vitamins D, B6, C and Mg were the most frequently consumed nutrients. 14% of cancer survivors initiated DS use after diagnosis. For 35% of the DS consumed, subjects did not inform their attending physician. DS use was associated with a healthier lifestyle (normal weight, never smoking and better diet) and substantially contributed to nutrient intake. 18% of DS users had potentially harmful DS use practices, such as the simultaneous use of vitamin E and anticoagulant/antiplatelet agents, the use of ß-carotene and smoking or the use of phyto-oestrogens in hormone-dependent cancer patients. The present study suggests that DS use is widespread among cancer survivors, a large amount of that use is performed without any medical supervision and a substantial proportion of that use involves potentially harmful practices. Physicians should be encouraged to more routinely discuss DS use with their cancer patients.

Visual and automated assessment of matrix metalloproteinase-14 tissue expression for the evaluation of ovarian cancer prognosis.

The purpose of this study was to evaluate whether the membrane type 1 matrix metalloproteinase-14 (or MT1-MMP) tissue expression, as assessed visually on digital slides and by digital image analysis, could predict outcomes in women with ovarian carcinoma. Tissue microarrays from a cohort of 211 ovarian carcinoma women who underwent a debulking surgery between 1993 and 2006 at the CHU de Québec (Canada) were immunostained for matrix metalloproteinase-14. The percentage of MMP-14 staining was assessed visually and with the Calopix software. Progression was evaluated using the CA-125 and/or the RECIST criteria according to the GCIG criteria. Dates of death were obtained by record linkage with the Québec mortality files. Adjusted hazard ratios of death and progression with their 95% confidence intervals were estimated using the Cox model. Comparisons between the two modalities of MMP-14 assessment were done using the box plots and the Kruskal-Wallis test. The highest levels of MMP-14 immunostaining were associated with nonserous histology, early FIGO stage, and low preoperative CA-125 levels (P<0.05). In bivariate analyses, the higher level of MMP-14 expression (>40% of MMP-14-positive cells) was inversely associated with progression using visual assessment (hazard ratio=0.39; 95% confidence interval: 0.18-0.82). A similar association was observed with the highest quartile of MMP-14-positive area assessed by digital image analysis (hazard ratio=0.48; 95% confidence interval: 0.28-0.82). After adjustment for standard prognostic factors, these associations were no longer significant in the ovarian carcinoma cohort. However, in women with serous carcinoma, the highest quartile of MMP-14-positive area was associated with progression (adjusted hazard ratio=0.48; 95% confidence interval: 0.24-0.99). There was no association with overall survival. The digital image analysis of MMP-14-positive area matched the visual assessment using three categories (>40% vs 21-40 vs <20%). Higher levels of MMP-14 immunostaining were associated with standard factors of better ovarian carcinoma prognosis. In women with serous carcinoma, high expression of MMP-14 was associated with lower progression.

Development and validation of an instrument assessing women's satisfaction with screening mammography in an organized breast cancer screening program.

BACKGROUND: The assessment of the quality of mammography services delivered in organized breast cancer screening programs should include measures centered on women's perceptions. The objective of this study was to develop and validate an instrument in French designed to evaluate the satisfaction of women having a screening mammography. METHODS: An instrument evaluating women's satisfaction with mammography services was developed using published research, the perceptions of screened women, the expertise of health professionals and a pilot study. Between November 9 and 21, 2011, the questionnaire was sent to 1500 consecutive women having had a screening mammography in eight radiologic facilities designated by the Québec Breast Cancer Screening Program, in Quebec City, Canada. Construct validity, convergent and discriminant validity, reliability and sensitivity of the instrument were examined. RESULTS: A total of 819 women (55%) participated in the validation study. The factor analysis retained four satisfaction dimensions: satisfaction with 1) the technician's skills (four items), 2) the physical environment (four items), 3) the staff's communication skills (three items) and 4) the information given by the program (3 items). The multitrait-scaling analysis showed good convergent and discriminant validity: scaling success was 100% for all subscales. All subscales had good internal consistency (Cronbach's alphas ≥ 0.86). The satisfaction scores were able to identify groups of women with lower levels of satisfaction, such as younger women or women with pain during breast compression. CONCLUSION: This brief satisfaction instrument, developed in French, showed good psychometric properties to evaluate satisfaction in women receiving mammographic services in an organized breast cancer screening program.

Genetic sequence variants in vitamin D metabolism pathway genes, serum vitamin D level and outcome in head and neck cancer patients.

Although some studies have reported associations between serum vitamin D level and prognosis in several cancers, others have found associations between genetic sequence variants (GSVs) in the vitamin D metabolism pathway genes and outcomes in various cancers including head and neck cancer (HNC). We comprehensively evaluated the association and interaction of GSVs in vitamin D metabolism pathway genes and their regulatory effects on circulatory serum vitamin D level in HNC outcome. We systemically evaluated the association of 89 tagging and candidate-based GSVs in six major vitamin D metabolism pathway genes (VDR, GC, CYP24A1, CYP27A1, CYP27B1 and CYP2R1) and the circulating serum vitamin D level with overall survival (OS) and second primary cancer (SPC) in 522 Stages I-II radiation-treated patients with HNC. For OS: median follow-up time was 8 years; for SPC, 4.4 years. The most common subsite was the larynx (84%). Three hundred and twelve patients were alive at the end of follow-up for OS. SPCs were diagnosed in 108 patients and were primarily of lung (46%). Serum vitamin D levels were significantly lower in patients carrying the minor alleles of GC:rs4588 and CYP2R1:rs10500804. CYP24A1:rs2296241 was significantly associated with OS and CYP2R1:rs1993116 was with SPC. These two GSVs remained significantly associated after adjusting for serum vitamin D level and important clinical factors. GSVs in the vitamin D metabolism pathway genes were associated with disease outcomes in HNC patients; however, these GSVs are different from those affecting serum vitamin D levels.

A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer.

OBJECTIVES: A two-stage, single-arm, phase II study was conducted to assess the effectiveness and safety of an epigallocatechin gallate (EGCG)-enriched tea drink, the double-brewed green tea (DBGT), as a maintenance treatment in women with advanced stage serous or endometrioid ovarian cancer (clinicaltrials.gov, NCT00721890). METHODS: Eligible women had FIGO stage III-IV serous or endometrioid ovarian cancer. They had to undergo complete response after debulking surgery followed by 6 to 8 cycles of platinum/taxane chemotherapy at the Centre Hospitalier Universitaire de Québec. They all had to drink the DBGT, 500 mL daily until recurrence or during a follow-up of 18 months. The primary endpoint was the absence of recurrence at 18 months. Statistical analyses were done according to the principle of intention to treat. Using a two-stage design, the first stage consisted of 16 enrolled patients. At the end of the follow-up, if 7 or fewer patients were free of recurrence, the trial stopped. Otherwise, accrual would continue to a total of 46 patients. RESULTS: During the first stage of the study, only 5 of the 16 women remained free of recurrence 18 months after complete response. Accordingly, the clinical trial was terminated. Women's adherence to DBGT was high (median daily intake during intervention, 98.1%, interquartile range: 89.7-100%), but 6 women discontinued the intervention before the end of their follow-up. No severe toxicity was reported. CONCLUSIONS: DBGT supplementation does not appear to be a promising maintenance intervention in women with advanced stage ovarian cancer after standard treatment.

Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers.

BACKGROUND: Secondary primary cancers (SPCs), a major cause of morbidity and mortality in head and neck cancers (HNCs), are commonly associated with field cancerization. We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC. METHODS: Germline DNA from 531 stage I-II radiation-treated HNC patients (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention clinical trial) were genotyped, and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: The majority of SPCs were of lung and HNCs. Median follow-up time was 5 years. SPCs were diagnosed in 21% of patients. The 5-year SPC-free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) sequence variant, DNMT3B:C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32-3.78; P = .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P = .003). CONCLUSIONS: A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at-risk individuals with HNCs.

Green tea for ovarian cancer prevention and treatment: a systematic review of the in vitro, in vivo and epidemiological studies.

OBJECTIVE: This systematic review was conducted to examine the effects of green tea or green tea components on the prevention and progression of epithelial ovarian cancer. METHODS: Using Medline, EMBASE and SciVerse (last researched: July 2011), we retrieved 22 articles including 5 epidemiological studies. RESULTS: In epithelial ovarian cancer cell lines, green tea and green tea components have been shown to downregulate the expression of proteins involved in inflammation, cell signalization, cell motility and angiogenesis. Green tea and green tea components would induce apoptosis and could potentiate the effects of cisplatin, a chemotherapeutic agent. In human observational studies, significant associations between green tea intake and both decreased ovarian cancer occurrence and better prognosis were reported. CONCLUSIONS: Available literature suggests potential molecular targets for green tea in ovarian cancer treatment and also provides data supporting the clinical evaluation of the role of green tea or green tea components in ovarian cancer prevention and treatment.

Human epididymis protein 4 (HE4) and ovarian cancer prognosis.

OBJECTIVE: A cohort study was conducted to evaluate whether preoperative plasma HE4 levels could predict the occurrence of death (primary endpoint) and progression (secondary endpoint) in women with ovarian cancer (OC). METHODS: Between 1998 and 2006, we recruited 136 women newly diagnosed with OC of any FIGO stage at the University Hospital, CHUQ-L'Hôtel-Dieu de Québec, Canada. HE4 was measured using the Abbott's ARCHITECT HE4 assay. Dates of death were obtained by record linkage with the Québec mortality files. Progression was evaluated using the CA-125 or the RECIST criteria, as recommended by the Gynecology Cancer Intergroup. Adjusted hazard ratios (HR) of death and progression, as well as their 95% confidence intervals (CI), were estimated using the Cox proportional hazard regression model. RESULTS: Preoperative levels of HE4 were strongly associated with all OC standard prognostic factors. HE4 levels increased significantly with age (p=0.02), FIGO stage (p<0.0001), grade (p=0.005), preoperative CA-125 levels (p<0.0001), and residual tumor (p<0.0001). HE4 levels above the median value (394 pmol/L) were significantly associated with mortality (HR=2.17; 95% CI: 1.42-3.32) and progression (HR=1.81; 95% CI: 1.21-2.72). After adjustment for the FIGO stage, which was the only factor significantly associated with prognosis in multivariate analyses, the association of HE4 with death remained statistically significant (HR=1.67; 95% CI: 1.08-2.59). However, the association with progression was no longer significant (HR=1.32; 95% CI: 0.87-1.99). CONCLUSION: These results show that preoperative the plasma level of HE4 is a marker of OC aggressiveness and a predictor of death.

Factors associated with weight loss during radiotherapy in patients with stage I or II head and neck cancer.

BACKGROUND: The purpose of the study was to identify factors associated with weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer. METHODS: This study was conducted as part of a phase III chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Patients' characteristics, dietary intake, health-related quality of life (HRQOL), tumor characteristic, treatment characteristics, and acute adverse effects of RT were evaluated at baseline and during RT. Factors independently associated with weight loss during RT were identified using the multiple linear regression (P ≤ 0.05). RESULTS: The mean weight loss during RT was 2.2 kg (standard deviation, 3.4). In bivariate analyses, the occurrence of adverse effects of RT and most of the HRQOL dimensions evaluated during RT were correlated with weight loss. In the multivariate analysis, eight factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P < 0.001), TNM stage II disease (P = 0.01), higher pre-RT body weight (P < 0.001), dysphagia before RT (P < 0.005), higher mucosa adverse effect of RT (P = 0.03), lower dietary energy intake during RT (P < 0.001), lower score of the digestive dimension on the Head and Neck Radiotherapy Questionnaire (P < 0.001) and a higher score of the constipation symptom on the EORTC QLQ-C30 during RT (P = 0.02). CONCLUSIONS: The results underline the importance of maintaining energy intake in early stage HN cancer patients during RT and the importance of preventing and treating adverse effects.

Dietary vitamin D intake and serum 25-hydroxyvitamin D level in relation to disease outcomes in head and neck cancer patients.

Low pretreatment vitamin D status has been associated with worsened disease outcomes in patients with cancer at various sites. Its prognostic significance in head and neck cancer (HNC) patients has not been studied. Patients with HNC who participated in a randomized trial were evaluated for: (i) total intake of vitamin D from diet and supplements using a validated food frequency questionnaire (all trial participants, n = 540) and (ii) pretreatment serum 25-hydroxyvitamin D through a radioimmunoassay (n = 522). The association of dietary/serum measures of vitamin D status with HNC recurrence, second primary cancer (SPC) incidence, and overall mortality was evaluated using multivariate Cox proportional hazard models. There was no significant association between dietary or serum vitamin D measures and the three HNC outcomes. The hazard ratios (HRs) comparing the highest with the lowest quartile of dietary/supplemental vitamin D intake were 1.10 (95% confidence interval (CI): 0.66-1.84) for recurrence, 1.05 (95% CI: 0.63-1.74) for SPC, and 1.27 (95% CI: 0.87-1.84) for overall mortality. HRs comparing the uppermost to the lowest quartile of serum 25-hydroxyvitamin D levels were 1.12 (95% CI: 0.65-1.93) for recurrence, 0.72 (95% CI: 0.40-1.30) for SPC, and 0.85 (95% CI: 0.57-1.28) for overall mortality. There was no effect modification by cancer stage, season of initial treatment, or trial arm. Among patients with HNC, vitamin D status before treatment does not influence disease outcomes. Our results contrast with those from most published studies, which suggest prognostic significance of vitamin D status in cancer patients at least in subgroups.

Impact of a meaning-centered intervention on job satisfaction and on quality of life among palliative care nurses.

OBJECTIVE: Palliative care (PC) nurses experience several recurrent organizational, professional, and individual challenges. To address existential and emotional demands, the meaning-centered intervention was recently developed. The intervention applied didactic and process-oriented strategies, including guided reflections, experiential exercises, and education based on themes of Viktor Frankl's logotherapy. The objective of this study was to test its efficiency to improve job satisfaction and quality of life in PC nurses from three regional districts in Quebec Province, Canada. METHODS: A randomized waiting-list group design was conducted, intervention group (n=56) versus waiting-list group (n=53). Job satisfaction, perception of benefits of working in PC, and spiritual and emotional quality of life were measured at pre-, posttest, and 3-month follow-up. RESULTS: The PC nurses in the experimental group reported more perceived benefits of working in PC after the intervention and at follow-up. Spiritual and emotional quality of life remained, however, unaffected by the intervention. CONCLUSIONS: To explain null findings, theoretical and methodological challenges, related to existential interventions, such as choice of outcomes, and selection bias (participants recruited were healthy workers) are discussed. Future directions and strategies to deal with those issues are proposed.

Prognostic significance of cyclooxygenase-2 overexpression in glottic cancer.

PURPOSE: Cyclooxygenase-2 (COX-2) overexpression has been associated with a poor prognosis in many cancers. However, the role of COX-2 overexpression in head and neck cancers remains undetermined. The objective of this study was to evaluate whether COX-2 is a prognostic factor in glottic cancer. EXPERIMENTAL DESIGN: This study was part of a phase III placebo-controlled randomized trial evaluating the efficacy of alpha-tocopherol in reducing second primary cancers (SPC) in head and neck cancer patients. Immunohistochemical analyses were conducted on pretreatment biopsies of 301 patients with early-stage glottic cancer treated by radiotherapy. The median value of 50% of positive tumor cells was the cutoff point used to define COX-2 overexpression. Outcomes considered in the statistical analysis were recurrence, SPC, and death. The Cox proportional hazards model was used to estimate the hazard ratios (HR) and their 95% confidence intervals (95% CI). RESULTS: The HR associated with COX-2 overexpression was 0.94 (95% CI, 0.55-1.62) for recurrence. The HR associated with SPC was 2.63 (95% CI, 1.32-5.23) for the first 3.5 years of follow-up and 0.55 (95% CI, 0.22-1.32) for the following 3.5 years. The HR associated with COX-2 overexpression was 1.57 (95% CI, 1.01-2.45) for overall mortality. CONCLUSIONS: COX-2 overexpression in glottic cancer was associated with increased overall mortality and an increased risk of SPC during the early follow-up period. Future studies are needed to explain observed effects on SPC. COX-2 expression may prove helpful in defining an individual patient's prognosis.

Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.

BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit. STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

A randomized controlled trial to test the efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity in patients with head and neck cancer.

BACKGROUND: Cisplatin-induced hearing loss is frequent and severe. Antioxidants such as sodium thiosulfate (STS) can neutralize the effects of cisplatin. The objective of the trial was to test the efficacy of trans-tympanic injections of a STS gel to prevent cisplatin-induced ototoxicity. METHODS: Eligible participants were newly diagnosed patients with stage III or IV squamous cell carcinoma of the mouth, oropharynx, hypopharynx, or larynx and scheduled to be treated by concurrent chemoradiation (CCR). Patients with asymmetric hearing were not eligible. The planed treatment included cisplatin 100 mg/m2 at days 1, 22 and 43. A baseline pre-treatment complete audiometric evaluation (pure tone at frequencies ranging from 0.5 to 14 kHz, bone conduction at 0.5-4 kHz and DPOAEs) was performed. Adverse effects were noted according to CTCAE. On the day before the beginning of CCR, eligible and consenting patients were randomized to receive a trans-tympanic injection of the gel either in the left ear or in the right ear. A final post-treatment complete audiometric evaluation was scheduled to be performed 1 month after the end of CCR by audiologists kept blind to the ear assignment. For the main outcome, the permanent threshold shift (PTS) in decibel (dB) was calculated as the difference between the final and baseline measures at all pure tone frequencies at 0.5-14 kHz for each patient and for each ear. The main outcome was assessed blindly in a mixed linear model with the PTS as the dependent variable and intervention, frequency, their interaction and radiation dose to the cochlea as independent variables. RESULTS: Between January 2015 and April 2016, 13 patients were randomized. The trial was stopped in June 2016 for poor accrual. The average loss of hearing over all frequencies was 1.3 dB less for treated ears compared to control ears. Although not statistically (p = 0.61) nor clinically significant, the difference was in favor of the treated ears for all frequencies between 3 and 10 kHz. CONCLUSIONS: Our trial suggests that STS deposited on the round window was safe for the middle and inner ears. More work is needed to improve the efficacy of trans-tympanic injections of cisplatin antidotes. TRIAL REGISTRATION: ClinicalTrials.gov, NTC02281006 , Registered 3 November 2014.

Performance of preoperative plasma tumor markers HE4 and CA125 in predicting ovarian cancer mortality in women with epithelial ovarian cancer.

Clinical utility of new biomarkers often requires the identification of their optimal threshold. This external validation study was conducted to assess the performance of the preoperative plasma tumor markers HE4 and CA125 optimal cut-offs to predict cancer mortality in women with epithelial ovarian cancer (EOC). Participating women had upfront debulking surgery in the University Hospital of Quebec City (Canada) between 1998 and 2013. A total of 136 women participated in the training cohort (cohort 1) and 177 in the validation cohort (cohort 2). Preoperative plasma HE4 and CA125 levels were measured by Elecsys. Optimal thresholds were identified in the cohort 1 using time-dependent receiver operating characteristic (ROC) curves. Multivariate Cox models were used to validate the biomarkers using their optimal cut-offs in the cohort 2. The likelihood ratio (LR) test was done to test whether the biomarkers added prognostic information beyond that provided by standard prognostic factors. The Areas Under the Curves (AUC) for HE4 and CA125 were respectively 64.2 (95% CI: 54.7-73.6) and 63.1 (95%CI: 53.6-72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA125. Preoperative plasma HE4 (≥277 pmol/L) was significantly associated with EOC mortality (adjusted hazard ratio (aHR): 1.90; 95% CI:1.09-3.29). The prognostic effect of HE4 was strongest in the subgroup of women with serous ovarian cancer (aHR: 2.42; 95% CI: 1.25-4.68). Using a multivariate model including all standard prognostic factors, this association was maintained (aHR: 2.21; 95% CI: 1.15-4.23). In addition, preoperative plasma HE4 added prediction for death over the standard prognostic markers in women with serous tumors (p-value for LR-test: 0.01). Preoperative CA125 was not associated with cancer mortality, both in women with EOC and in those with serous tumors. Preoperative HE4 is a promising prognostic biomarker in EOC, especially in serous tumor.

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer.

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI - encoding Complement Factor I - and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2-3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2-3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17-4.53) and death (adjusted HR: 3.42; 95% CI: 1.72-6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.

Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients.

There has been concern that the efficacy of radiation therapy may be reduced when patients smoke or take antioxidant vitamins during treatment. Cancer prevention trials with beta carotene supplements documented adverse effects only among smokers. We conducted a randomized trial with alpha tocopherol (400 IU/day) and beta carotene (30 mg/day) supplements among 540 head and neck cancer (HNC) patients treated by radiation therapy. We examined whether smoking during radiation therapy modified the effects of the supplementation on HNC recurrence and on mortality. During the follow-up, 119 patients had a HNC recurrence and 179 died. Cox models were used to test the interaction between smoking and supplementation and to estimate the hazard ratios (HR) for HNC recurrence and death associated with the supplementation. Cigarette smoking either before or after radiation therapy did not modify the effects of the supplementation. In contrast, the interactions between supplementation and cigarette smoking during radiation therapy were statistically significant for HNC recurrence (p = 0.03), all-cause mortality (p = 0.02) and mortality from the initial HNC (p = 0.04). Among cigarette smokers, the HR were 2.41 (95% CI: 1.25-4.64) for recurrence, 2.26 (95% CI: 1.29-3.97) for all-cause mortality and 3.38 (95% CI: 1.11-10.34) for HNC mortality. All corresponding HR among nonsmokers were close to 1. These results could best be explained by the hypothesis that the combined exposures reduced the efficacy of radiation therapy. Particular attention should be devoted to prevent patients from both smoking and taking antioxidant supplements during radiation therapy.

Genetic polymorphisms and head and neck cancer outcomes: a review.

Head and neck cancer (HNC) patients have variable prognoses even within the same clinical stage and while receiving similar treatments. The number of studies of genetic polymorphisms as prognostic factors of HNC outcomes is growing. Candidate polymorphisms have been evaluated in DNA repair, cell cycle, xenobiotic metabolism, and growth factor pathways. Polymorphisms of XRCC1, FGFR, and CCND1 have been consistently associated with HNC survival in at least two studies, whereas most of the other polymorphisms have either conflicting data or were from single studies. Heterogeneity and lack of description of patient populations and lack of accounting for multiple comparisons were common problems in a significant proportion of studies. Despite a large number of exploratory studies, large replication studies in well-characterized HNC populations are warranted.

Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas.

Using the DNA microarray technology, we have identified genes that are differentially expressed in chemosensitive and chemoresistant ovarian serous papillary carcinomas and could potentially distinguish ovarian cancer patients based on their response to chemotherapy. The present study aims to evaluate the clinical usefulness of overexpression of selected genes by immunohistochemistry. Our cohort included 158 women who were operated on and received chemotherapy for an advanced serous papillary ovarian carcinoma (FIGO stages III and IV). The end point used in this study was progression-free survival. Immunohistochemistry was performed on microarray blocks containing all 158 cases. Twelve commercially available antibodies were selected. Of them, 10 corresponded to differentially expressed genes in our micro-array study and p53 and Ki67 were included. Antibodies were obtained for the following selected genes: GSTA1, MMP1, FOSB, CTSL2, HSP10, CD36, CXCL2, RBBP7, Siva, and PTGDS. Cox proportional hazards models, adjusted for standard risk factors, were used to estimate the associations between the markers and progression-free survival. No association was found between mRNA level and protein expression by immunohistochemistry. In multivariate analyses, patients whose tumors overexpressed HSP10 had a lower risk of progression than those with low expression (HR: 0.6; CI: 0.42-0.87; P=0.007). High level of proliferation (Ki67) tended to be associated with a lower risk of progression (HR: 0.72; CI: 0.51-1.03; P=0.07) whereas MMP1 overexpression tended to be associated with a higher risk of progression (HR: 1.61; CI: 0.94-2.79; P=0.08). Our study shows that gene expression analysis coupled with immunohistochemistry allowed the identification of HSP10 as an independent factor of progression-free survival.