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Simple Summary: Colorectal cancer is one of the most significant causes of cancer mortality worldwide. Patients stratification is central to improve clinical practice and the Consensus Molecular Subtypes (CMS) have been validated as a useful tool to predict both prognosis and treatment response. This is the first study describing that microRNA profiling can define colorectal cancer CMS subtypes as well as mRNA profiling. MicroRNAs small size facilitates its analysis in serum facilitating a real-time analysis of the disease course. Three microRNA subtypes are identified: miR-LS is associated with the low-stroma/CMS2-subtype; miR-MI with the mucinous-MSI/CMS1-subtype and miR-HS with the high-stroma/CMS4-subtype. MicroRNA novel subtypes and association to the CMS classification were externally validated using TGCA data. Analyzing both mRNAs and miRs in the same population enabled identification of miR target genes and altered biological pathways. A miR-mRNA interaction screening and regulatory network selected major miR targets and was functionally validated for the miR30b/SCL6A4 pair. Colorectal cancer consensus molecular subtypes (CMSs) are widely accepted and constitutes the basis for patient stratification to improve clinical practice. We aimed to find whether miRNAs could reproduce molecular subtypes, and to identify miRNA targets associated to the High-stroma/CMS4 subtype. The expression of 939 miRNAs was analyzed in tumors classified in CMS. TALASSO was used to find gene-miRNA interactions. A miR-mRNA regulatory network was constructed using Cytoscape. Candidate gene-miR interactions were validated in 293T cells. Hierarchical-Clustering identified three miRNA tumor subtypes (miR-LS; miR-MI; and miR-HS) which were significantly associated (p < 0.001) to the reported mRNA subtypes. miR-LS correlated with the low-stroma/CMS2; miR-MI with the mucinous-MSI/CMS1 and miR-HS with high-stroma/CMS4. MicroRNA tumor subtypes and association to CMSs were validated with TCGA datasets. TALASSO identified 1462 interactions (p < 0.05) out of 21,615 found between 176 miRs and 788 genes. Based on the regulatory network, 88 miR-mRNA interactions were selected as candidates. This network was functionally validated for the pair miR-30b/SLC6A6. We found that miR-30b overexpression silenced 3′-UTR-SLC6A6-driven luciferase expression in 293T-cells; mutation of the target sequence in the 3′-UTR-SLC6A6 prevented the miR-30b inhibitory effect. In conclusion CRC subtype classification using a miR-signature might facilitate a real-time analysis of the disease course and treatment response. [ABSTRACT FROM AUTHOR]

Registry data on invasive cervical cancers (n = 1,274) from four major hospitals (1984‐2012) were analysed to determine their value for informing local service delivery in Australia. The methodology comprised disease‐specific survival analyses using Kaplan‐Meier product‐limit estimates and Cox proportional hazards models and treatment analyses using logistic regression. Five‐ and 10‐year survivals were 72% and 68%, respectively, equating with relative survival estimates for Australia and the USA. Most common treatments were surgery and radiotherapy. Systemic therapies increased in recent years, generally with radiotherapy, but were less common for residents from less accessible areas. Surgery was more common for younger women and early‐stage disease, and radiotherapy for older women and regional and more advanced disease. The proportion of glandular cancers increased in‐step with national trends. Little evidence of variation in risk‐adjusted survival presented over time or by Local Health District. The study illustrates the value of local registry data for describing local treatment and outcomes. They show the lower use of systemic therapies among residents of less accessible areas which warrants further investigation. Risk‐adjusted treatment and outcomes did not vary by socio‐economic status, suggesting equity in service delivery. These data are important for local evaluation and were not available from other sources. [ABSTRACT FROM AUTHOR]

Objective: To compare all-cause mortality between women who underwent fertility-sparing surgery with those who underwent conventional surgery for stage I ovarian cancer.Methods: In a cohort study using the National Cancer Database, we identified women younger than 40 years diagnosed with stage IA and unilateral IC epithelial ovarian cancer between 2004 and 2012. Fertility-sparing surgery was defined as conservation of one ovary and the uterus. The primary outcome was time from diagnosis to death. We used propensity score methods to assemble a cohort of women who underwent fertility-sparing or conventional surgery but were otherwise similar on observed covariates and conducted survival analyses using the Kaplan-Meier method and Cox proportional hazard models.Results: We identified 1,726 women with stage IA and unilateral IC epithelial ovarian cancer of whom 825 (47.8%) underwent fertility-sparing surgery. Fertility-sparing surgery was associated with younger age, residence in the northeastern and western United States, and serous or mucinous histology (P<.05 for all). Propensity score matching yielded a cohort of 904 women who were balanced on observed covariates. We observed 30 deaths among women who underwent fertility-sparing surgery and 37 deaths among propensity-matched women who underwent conventional surgery after a median follow-up of 63 months. Fertility-sparing surgery was not associated with hazard of death (hazard ratio 0.80, 95% confidence interval [CI] 0.49-1.29, P=.36). The probability of survival 10 years after diagnosis was 88.5% (95% CI 82.4-92.6) in the fertility-sparing group and 88.9% (95% CI 84.9-92.0) in the conventional surgery group. In patients with high-risk features such as clear cell histology, grade 3, or stage IC, 10-year survival was 80.5% (95% CI 68.5-88.3) among women who underwent fertility-sparing surgery and 83.4% (95% 76.0-88.7) among those who had conventional surgery (hazard ratio 0.86, 95% CI 0.49-1.53, P=.61).Conclusion: Compared with conventional surgery, fertility-sparing surgery was not associated with increased risk of death in young women with stage I epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: To identify predictors of ovarian conservation at hysterectomy and to examine the association of ovarian conservation and survival of young women with early-stage cervical cancer.Methods: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Program to identify hysterectomy-based surgically treated patients with stage I cervical cancer diagnosed between 1983 and 2012 (N=16,511). Multivariable models were used to identify independent factors associated with ovarian conservation. Among the subgroup of 9,419 women younger than 50 years of age with stage I disease, survival outcomes and causes of death were examined for 3,908 (41.5%) women who underwent ovarian conservation at hysterectomy without radiotherapy.Results: On multivariable analysis, age younger than 50 years, stage IA disease, and squamous histology were independent factors associated with ovarian conservation (all, P<.001). Among 5,526 women younger than 50 years of age with stage IA disease who underwent hysterectomy without radiotherapy, overall survival was significantly higher in patients undergoing ovarian conservation than in those undergoing oophorectomy (20-year rate, 93.5% compared with 86.8%, P<.001); cervical cancer-specific survival was similar between the patients who underwent ovarian conservation and those who underwent oophorectomy (98.8% compared with 97.8%, P=.12). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.63, 95% confidence interval [CI] 0.49-0.82, P=.001) and was independently associated with lower cumulative risks of death resulting from cardiovascular disease (20-year cumulative rate, 1.2% compared with 3.3%, adjusted hazard ratio 0.47, 95% CI 0.26-0.86, P=.014) and other chronic disease (0.5% compared with 1.4%, adjusted hazard ratio 0.24, 95% CI 0.09-0.65, P=.005) compared with oophorectomy. Both cervical cancer-specific survival (20-year rate, 93.1% compared with 92.0%, P=.37) and overall survival (86.7% compared with 84.6%, P=.12) were similar between ovarian conservation and oophorectomy among 3,893 women younger than 50 years of age with stage IB disease who underwent hysterectomy without radiotherapy.Conclusion: Among young women with stage IA cervical cancer, ovarian conservation at hysterectomy is associated with decreased all-cause mortality including death resulting from cardiovascular disease and other chronic diseases. [ABSTRACT FROM AUTHOR]

Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) <0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cost-effectiveness of the multivariate index assay (MIA) for use in triaging women with an adnexal mass relative to modified American College of Obstetricians and Gynecologists (mACOG) referral guidelines and CA-125 testing alone.Methods: The MIA triage algorithm was based on qualitative serum testing of five biomarkers: transthyretin, apolipoprotein, A-1, 2-microglobulin, transferrin, and CA-125. An economic analysis was developed to evaluate the clinical and cost implications of adopting MIA in clinical practice versus the mACOG referral guidelines and CA-125 alone, over a lifetime horizon, from the perspective of the public payer. Clinical parameters used to characterize patients' disease status, quality of life, and treatment decisions were estimated using the results of published studies; costs were approximated using reimbursement rates from CMS fee schedules. Model endpoints included overall survival (OS), costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The cost-effectiveness threshold was set to $50,000 per QALY. One-way sensitivity analysis was performed to assess uncertainty of individual parameters included in the analysis. All costs were reported in 2014 US dollars.Results: Use of MIA was cost-effective, resulting in fewer re-operations and pre-treatment CT scans. Overall MIA resulted in an ICER of $35,094/QALY gained. MIA was also cost-saving and QALY-increasing compared to use of CA-125 alone with an ICER of $12,189/QALY gained. One-way sensitivity analysis showed the ICER was most affected by the following parameters: (1) sensitivity of MIA; (2) sensitivity of mACOG; and (3) percentage of patients, not referred to a gynecologic oncologist, who were correctly diagnosed with advanced epithelial ovarian cancer (EOC).Conclusion: Use of MIA is a more cost-effective triage strategy than mACOG or CA-125. It is expected to increase the percentage of women with ovarian cancer that are referred to gynecologic oncologists, which is shown to improve clinical outcomes. Limitations include the use of assumptions when published data was unavailable, and the use of multiple sources for survival data. [ABSTRACT FROM AUTHOR]

Introduction: Lymphoepithelial carcinoma (LEC) of the salivary glands is extremely rare worldwide, with studies limited to small case reports and case series from endemic areas (Southern China, Arctic Inuits) and strong association to Epstein Barr Virus (EBV). Studies on non-endemic regions are even more limited given the reality of only sporadic cases in these areas. Using the National Cancer Database (NCDB), we present the largest study on salivary LEC from a non-endemic region, the United States.Methods: A retrospective review of the NCDB from 1998-2012 for LEC of the major salivary glands was performed. Demographic and clinical variables were extracted for analysis. Multivariate COX regression was used to assess predictors of survival.Results: Two hundred and thirty-eight cases were identified (0.66% of all salivary cancers). Median age at diagnosis was 62 with peak incidence in ages 50-70. Most patients were Caucasian (81.2%), without gender preference. Regional metastasis was common (45.1%) and did not significantly impact survival. Distant metastasis was rare (2%). Overall survival (OS) at 5- and 10 years was 77% and 56%. Surgery and radiotherapy significantly showed better survival outcomes than surgery alone (p<0.001). Age >62, advanced stage, and dual modality therapy were significant predictors of survival in multivariate analysis.Conclusion: Lymphoepithelial carcinoma in the US mostly affects an older, Caucasian demographic. Regional metastasis is common and survival is fair at 5- and 10 years. Surgery and radiation are recommended for early and advanced disease stages. Age, stage, and therapy are significant predictors of survival outcomes. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.Methods: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.Results: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).Conclusions: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention. [ABSTRACT FROM AUTHOR]

Simple Summary: Human papillomavirus (HPV) is recognized as a significant risk factor for head and neck cancers worldwide, and it is the most common cause of oropharyngeal cancers in the United States. Here, we review the incidence and pathogenesis of HPV-related cancers, the development and approval of HPV prophylactic vaccines, and the use and effectiveness of HPV vaccines around the world. Furthermore, we discuss advances in the development of HPV therapeutic vaccines as well as its associated challenges. The rising incidence of oropharyngeal squamous cell cancers (OPSCC) in the United States is largely attributed to HPV. Prophylactic HPV vaccines have demonstrated effectiveness against oral infection of HPV 16 and HPV 18. We review the global epidemiology and biology of HPV-related cancers as well as the development of HPV vaccines and their use worldwide. We also review the various strategies and challenges in development of therapeutic HPV vaccines. [ABSTRACT FROM AUTHOR]

Molecular testing of pulmonary adenocarcinomas for EGFR and KRAS mutations is becoming more common as tyrosine kinase inhibitor therapy is used for EGFR-mutated adenocarcinomas. Adenosquamous carcinomas represent a hybrid carcinoma, and there is no literature addressing the frequency of EGFR and KRAS mutations in this subset of lung carcinomas in Western populations. For this study, 23 adenosquamous carcinomas were microdissected with the glandular and squamous components analyzed for EGFR and KRAS mutations and EGFR amplification. In 3 cases (13%), there were EGFR mutations, with 2 having the identical mutation in the glandular and squamous elements. In 3 cases (13%), there were KRAS mutations in both histologic elements. Great heterogeneity existed in the rates of EGFR amplification in the 2 histologic components. Amplification was most common in both glandular and squamous components (11/23 [48%]). EGFR mutations occur in adenosquamous carcinoma in the same percentages as in conventional adenocarcinoma in the Western population. KRAS mutations are less common. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate accuracy of the referring diagnoses of retinoblastoma to a tertiary cancer referral center. Methods: Retrospective chart review of 352 retinoblastoma-related patients seen by the ophthalmic oncology service during a 4-year period from January 1, 2004 to October 21, 2008. Of these, 111 were referred with a suspicion of new retinoblastoma and were included in the study. Fundus photographs, gender, family history of retinoblastoma, initial symptoms, age, initial and referring physicians'' specialty (eg, pediatrician, general ophthalmologist, retinal specialist) and their suspected diagnoses were recorded. The main outcome measure was accuracy of diagnosis given by referring providers. Results: Of 111 patients, 62% had retinoblastoma and 38% did not. Persistent fetal vasculature (PFV) and Coats'' Disease were the most common simulating lesions accounting for 31% and 29% of the simulating lesions respectively. Other simulating lesions included infrequent cases of rare conditions such as primary ocular teratoma, a retinal pigment epithelial tumor, and astrocytic hamartoma. Conclusions: Retinoblastoma continues to present a diagnostic dilemma. There has been limited improvement in the rate of correct diagnosis in the United States in the last 15 years. There has however been a change in the composition of misdiagnosed lesions with rare conditions accounting for more than 1/3 of cases. Attention to age, family history, laterality and presenting signs such as globe size can aid diagnosis of retinoblastoma. [ABSTRACT FROM AUTHOR]