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Prior studies have demonstrated the efficacy of non-selective beta-blockers (NSBB) in preventing first variceal bleeding in patients with cirrhosis. However, little is known about the overall effectiveness of NSBB in routine clinical care.We conducted a retrospective cohort study of cirrhotic patients without prior bleeding who initiated a NSBB (propranolol, nadolol) at any Veterans Administration facility between 2008 and 2013. The primary outcome was variceal bleeding within 12 months. We conducted Cox-proportional hazards analyses to identify demographic, clinical, and NSBB-related (type of NSBB, mean dose, dose change, and heart rate response) factors associated with variceal bleeding.Of 5,775 patients, 678 (11.7%) developed variceal bleeding. Mean daily dose of NSBB was40 mg in 58.8%, 18.1% had either upward or downward titration in NSBB dose, and 9.8% had hemodynamic response. Patients who were younger, with ascites, greater medical comorbidity, and higher MELD (Model for end-stage liver disease) scores had a higher risk of variceal bleeding. Patients on a higher daily dose (60 vs.40 mg, adjusted hazard ratio (HR) 0.64; 95% confidence interval (CI): 0.51-0.81), who had either upward or downward dose titration (adjusted HR 0.69; 95% CI: 0.52-0.90 and 0.64; 95% CI 0.45-0.90, respectively), and those who achieved hemodynamic response (adjusted HR 0.75; 95% CI=0.57-1.0) had lower risk.Approximately 12% of patients bled while being on NSBB for primary prophylaxis. A higher NSBB dose and dose titration were protective; yet most patients did not have the NSBB dose titrated to the recommended levels. Our data highlight the need for careful monitoring of cirrhotic patients on NSBB.

Communication gaps in families with unexplained mismatch repair (MMR) deficiency (UMMRD) could negatively impact the screening behaviors of relatives of individual with UMMRD. We evaluated cancer risk perception, screening behaviors, and family communication among relatives of colorectal cancer (CRC) patients with UMMRD. Fifty-one family members of 17 probands with UMMRD completed a questionnaire about cancer risk perception, adherence to Lynch syndrome (LS) screening recommendations, and communication with relatives. Clinical data about the probands were obtained from medical records. Thirty-eight participants (78%) were worried from having cancer and twenty-one participants (42%) had undergone colonoscopy in the past 2 years, as recommended for LS families. In terms of screening for extracolonic cancers, only two eligible participants (3.9%) were screened for gastric, endometrial (10.0%), and ovarian (9.5%) cancers. Additionally, 5 participants (10%) underwent genetic counseling. Most participants were not told by anyone to be screened for extracolonic cancers (84, 85, and 95% for gastric, ovarian, and endometrial cancers, respectively). A minority of family members of CRC patients with UMMRD follow cancer screening as recommended for LS families. Health care providers should encourage patients with UMMRD to share information on LS-related cancers screening, especially extracolonic cancers, with their relatives.

BackgroundThe choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes.MethodsThe study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression.ResultsThe median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (

Metastatic colorectal cancer (mCRC) continues to show poor outcomes, with many patients exhausting effective standard-of-care therapy. To explore the current landscape of clinical trials for mCRC, we reviewed over 600 clinical trials that are currently ongoing for mCRC patients. Immunotherapeutic agents form approximately 39% (includes monoclonal antibodies, viruses, vaccines, and immunomodulators) of all agents and targeted therapy forms 45% (tyrosine kinase inhibitors, epigenetic modulators, and others) of all agents being investigated for mCRC.

e16074 Background: Differences in clinical outcomes for metastatic CRC (mCRC) have been reported across racial-ethnic groups, particularly between Hispanics (HA), non-Hispanic Blacks (NHB), and non-Hispanic Whites (NHW), with limited information available among Asian Americans (AA). We examined if there were differences in clinical outcomes by molecular drivers between these groups in a pooled analysis of two institutions serving ethnically diverse patient populations. Methods: We retrospectively examined 1927 mCRC patients from Montefiore Medical Center and the University of Texas MD Anderson Cancer Center. Mutations in KRAS, NRAS, and BRAF were determined by polymerase chain reaction or next generation sequencing. Mutations were then correlated with overall survival (OS). Results: Our patient population consisted of 1153 (61%) NHW, 314 (17%) HA, 320 (17%) NHB and 59 (3.1%) AA. Across subgroups, borderline significant difference in prevalence of BRAF mutation was observed (p = 0.04), with higher prevalence observed among NHW as compared to other groups. No differences were observed for KRAS and NRAS mutation prevalence. In univariate analysis, the median survival for BRAF MT tumors was 18.5 months vs 32 months for BRAF WT tumors (p < 0.0001). Similarly, median OS for KRAS WT, KRAS MT, NRAS WT and NRAS MT was 29.3, 27.4, 31 and 31.5 months respectively, with no differences between groups. In subgroup analysis by race/ethnicity, median OS in BRAF MT NHW was 19.98 months vs 33.48 in BRAF WT NHW (p < 0.0001). Similar trends were observed in HA and NHB. No differences in median OS were observed by KRAS or NRAS mutation status across racial-ethnic groups. Conclusions: This multi-institution study found no meaningful difference in the prevalence of molecular drivers across racial-ethnic groups. Additionally, in our subgroup analyses, OS based on the presence of a specific molecular driver mutation did not seem to vary by race. For example, RAS mutated and BRAF mutated patients showed similar OS across racial-ethnic groups. Our study demonstrates that reported differences in clinical outcomes by race and ethnicity in the literature are unlikely to be dependent on the difference in the presence of certain molecular drivers.

Background Potential benefits of screening mammography among women ages 75 years and older remain unclear. Methods We evaluated 10-year cumulative incidence of breast cancer and death from breast cancer and other causes by Charlson Comorbidity Index (CCI) and age in the Medicare-linked Breast Cancer Surveillance Consortium (1999–2010) cohort of 222 088 women with no less than 1 screening mammogram between ages 66 and 94 years. Results During median follow-up of 107 months, 7583 were diagnosed with invasive breast cancer and 1742 with ductal carcinoma in situ; 471 died from breast cancer and 42 229 from other causes. The 10-year cumulative incidence of invasive breast cancer did not change with increasing CCI but decreased slightly with age: ages 66–74 years (CCI0 = 4.0% [95% CI = 3.9% to 4.2%] vs CCI ≥ 2 = 3.9% [95% CI = 3.5% to 4.3%]); ages 75–84 years (CCI0 = 3.7% [95% CI = 3.5% to 3.9%] vs CCI ≥ 2 = 3.4% [95% CI = 2.9% to 3.9%]); and ages 85–94 years (CCI0 = 2.7% [95% CI = 2.3% to 3.1%] vs CCI ≥ 2 = 2.1% [95% CI = 1.3% to 3.0%]). The 10-year cumulative incidence of other-cause death increased with increasing CCI and age: ages 66–74 years (CCI0 = 10.4% [95% CI = 10.3 to 10.7%] vs CCI ≥ 2 = 43.4% [95% CI = 42.2% to 44.4%]), ages 75–84 years (CCI0 = 29.8% [95% CI = 29.3% to 30.2%] vs CCI ≥ 2 = 61.7% [95% CI = 60.2% to 63.3%]), and ages 85 to 94 years (CCI0 = 60.3% [95% CI = 59.1% to 61.5%] vs CCI ≥ 2 = 84.8% [95% CI = 82.5% to 86.9%]). The 10-year cumulative incidence of breast cancer death was small and did not vary by age: ages 66–74 years = 0.2% (95% CI = 0.2% to 0.3%), ages 75–84 years = 0.29% (95% CI = 0.25% to 0.34%), and ages 85 to 94 years = 0.3% (95% CI = 0.2% to 0.4%). Conclusions Cumulative incidence of other-cause death was many times higher than breast cancer incidence and death, depending on comorbidity and age. Hence, older women with increased comorbidity may experience diminished benefit from continued screening.

Additional file 2. Table summarizing CIMP methodologies.

Background Accurate childhood cancer burden data are crucial for resource planning and health policy prioritisation. Model-based estimates are necessary because cancer surveillance data are scarce or non-existent in many countries. Although global incidence and mortality estimates are available, there are no previous analyses of the global burden of childhood cancer represented in disability-adjusted life-years (DALYs). Methods Using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 methodology, childhood (ages 0–19 years) cancer mortality was estimated by use of vital registration system data, verbal autopsy data, and population-based cancer registry incidence data, which were transformed to mortality estimates through modelled mortality-to-incidence ratios (MIRs). Childhood cancer incidence was estimated using the mortality estimates and corresponding MIRs. Prevalence estimates were calculated by using MIR to model survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated by multiplying age-specific cancer deaths by the difference between the age of death and a reference life expectancy. DALYs were calculated as the sum of YLLs and YLDs. Final point estimates are reported with 95% uncertainty intervals. Findings Globally, in 2017, there were 11·5 million (95% uncertainty interval 10·6–12·3) DALYs due to childhood cancer, 97·3% (97·3–97·3) of which were attributable to YLLs and 2·7% (2·7–2·7) of which were attributable to YLDs. Childhood cancer was the sixth leading cause of total cancer burden globally and the ninth leading cause of childhood disease burden globally. 82·2% (82·1–82·2) of global childhood cancer DALYs occurred in low, low-middle, or middle Socio-demographic Index locations, whereas 50·3% (50·3–50·3) of adult cancer DALYs occurred in these same locations. Cancers that are uncategorised in the current GBD framework comprised 26·5% (26·5–26·5) of global childhood cancer DALYs. Interpretation The GBD 2017 results call attention to the substantial burden of childhood cancer globally, which disproportionately affects populations in resource-limited settings. The use of DALY-based estimates is crucial in demonstrating that childhood cancer burden represents an important global cancer and child health concern. The work in this paper was supported by the Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities (ALSAC), and St Baldrick's Foundation

Background The survival of patients with metastatic colorectal cancer (mCRC) is influenced by the genetic and epigenetic changes that might influence the patient experience of symptom burden. Understanding the association of molecular changes with the symptom burden could help clinicians gain insight into the molecular basis of symptom burden and improve treatment tolerance. To date, no studies have compared the patient-reported symptom burden with these molecular subsets among patients with mCRC. Patients and Methods We recruited patients with mCRC that was refractory to ≥ 1 line of therapy who had been enrolled in the Assessment of Targeted Therapies Against Colorectal Cancer trial at The University of Texas MD Anderson Cancer Center. All patients completed a baseline gastrointestinal symptom inventory (MD Anderson Symptom Inventory, gastrointestinal). The symptom burden across key demographic variables and molecular changes, including CRC-associated mutations, microsatellite instability (MSI) status, and the CpG island methylator phenotype (CIMP) were compared using χ2 tests. Association of the symptom burden with overall survival was examined using Cox regression models. Results Patients with an MSI-high (MSI-H) phenotype reported greater pain (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.61-5.84), fatigue (OR, 2.78; 95% CI, 1.41-5.49), sleep (OR, 2.52; 95% CI, 1.32-4.08); and drowsiness (OR, 2.51; 95% CI, 1.32-4.78) compared with microsatellite stable patients. Patients with an MSI-H phenotype also had greater odds of overall symptom burden (OR, 2.48; 95% CI, 1.29-4.74) compared with microsatellite stable patients. The CIMP-high patients experienced greater odds of pain compared with the CIMP-negative patients (OR, 1.72; 95% CI, 1.06-2.80). A greater overall symptom burden was associated with poor overall survival (hazard ratio, 1.42; 95% CI, 0.98-2.06]), although the difference was not significant (P = .06). Conclusion Correlation of MSI-H–associated tumor features with the symptom burden could help provide a better understanding of underlying mechanisms associated with our findings.

Background Cachexia is a multisystem syndrome characterized by weight loss, anorexia, loss of muscle mass, systemic inflammation, insulin resistance, and functional decline. Management of cachexia involves addressing multiple underlying biological mechanisms. Previous review on pharmacological management of cancer cachexia identified progestins and corticosteroids as effective agents for treatment of cachexia. However, to date no consensus exists on a single effective or standard treatment for management of cachexia. The aim of this systematic review is to determine the effectiveness of pharmacological treatments used to manage cachexia among adult cancer patients. Methods We performed literature searches of PubMed (NLM), Embase (Ovid), and Medline(Ovid) to identify clinical trials focused on pharmacological management of cancer cachexia among adult cancer patients from 2004 to 2018. Three reviewers screened a random selection of abstracts to measure for interrater reliability. After this step, each screener screened two-thirds of all abstracts and 177 studies were identified for full text review. The primary outcome was impact of pharmacological management on change in either weight or lean body mass in cancer patients. Results We identified 19 articles (representing 20 RCTs) that focused on pharmacological management of cancer cachexia. Agents showing promising results included Anamorelin and Enobosarm. Anamorelin at 50 or 100 mg per day for 12 weeks showed a consistent benefit across all studies and resulted in significant improvement in weight as compared to baseline among cancer patients. Enobosarm at 1 and 3 mg per day was also effective in improving lean body mass and QOL symptoms among advancer stage cancer patients. Finally, use of combination agents provide evidence for targeting multiple pathways underlying cachexia mechanism to achieve maximum benefit. No agents showed functional improvement in cancer patients. Conclusion Anamorelin as a single agent shows promising results in improving cachexia related weight loss among cancer patients. Further research on combination therapies may be helpful to address critical gaps in cachexia management. Electronic supplementary material The online version of this article (10.1186/s12885-018-5080-4) contains supplementary material, which is available to authorized users.

OBJECTIVE: The association of caffeine intake with testosterone remains unclear. We evaluated the association of caffeine intake with serum testosterone among American men and determined whether this association varied by race/ethnicity and measurements of adiposity. METHODS: Data were analyzed for 2581 men (≥20 years old) who participated in the cycles of the NHANES 1999-2004 and 2011-2012, a cross-sectional study. Testosterone (ng/mL) was measured by immunoassay among men who participated in the morning examination session. We analyzed 24-h dietary recall data to estimate caffeine intake (mg/day). Multivariable weighted linear regression models were conducted. RESULTS: We identified no linear relationship between caffeine intake and testosterone levels in the total population, but there was a non-linear association (pnonlinearity

Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; P = 0.023 and

Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS.

Summary of Databases Searched. (DOCX 33 kb)

Impact on pharmacological agents on cachexia associated biomarkers. (DOCX 19 kb)

SummaryBackground Testosterone deficiency (TD, total testosterone ≤ 350 ng/dL [12.15 nmol/L]) and obesity epidemic are growing in parallel in the United States. Yet the sequelae of TD and obesity on the risk of mortality remains unclear. Objective To investigate whether the co-occurrence of TD and overall obesity (body mass index ≥ 30 kg/m2), and abdominal obesity (waist circumference ≥ 102 cm), is associated with a risk of all-cause mortality in American men. Design The data were obtained from the NHANES 1999-2004 and the Linked Mortality File (December 31, 2011). A total of 948 participants aged ≥ 20 years old with endogenous sex hormones and adiposity measurements data were included in this study. Results Over a median of 9.5 y of follow-up, 142 men died of any cause in this cohort. Multivariable analysis showed a 2.60 fold increased risk of death among men with TD compared with men without TD (Hazard Ratio [HR] = 2.60; 95% confidence interval [CI] = 1.20 – 5.80). No evidence for interaction between TD and overall or abdominal obesity with risk of death (Pinteraction ≥ 0.80). However, only after comparing men with TD and abdominal obesity with men without TD and no abdominal obesity, we found a 3.30 fold increased risk of death (HR = 3.30, 95% CI = 1.21 – 8.71). Conclusion Men with co-occurrence of TD and abdominal obesity have a higher risk of mortality. The effect of co-occurrence of TD and abdominal obesity should be further explored with a larger and longer follow-up time study. This article is protected by copyright. All rights reserved.

// Amir Mehrvarz Sarshekeh 1 , Shailesh Advani 1 , Daniel M. Halperin 1 , Claudius Conrad 2 , Chan Shen 3 , James C. Yao 1 and Arvind Dasari 1 1 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3 Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence to: Arvind Dasari, email: adasari@mdanderson.org Keywords: appendix, neuroendocrine, right hemicolectomy, survival, tumor size Received: May 09, 2017 Accepted: June 30, 2017 Published: August 19, 2017 ABSTRACT Background: Appendiceal neuroendocrine neoplasms are most often diagnosed incidentally during appendectomy. The need for subsequent right hemicolectomy (RHC) is determined based on the risk of regional lymph node (LN) involvement. Tumor size has historically been used as an indicator of this risk, but controversy remains regarding its cut off. Furthermore, the impact of RHC on survival is unclear. Methods: We used the SEER database to identify patients diagnosed with appendiceal neuroendocrine tumors. Results: Of 1731 patients, 38.0% had well-differentiated neuroendocrine tumors (WDNETs), 60.8% had mixed histology tumors (MHTs), and 1.2% had poorly differentiated neuroendocrine carcinomas (PDNECs). In patients with WDNETs and MHTs who had adequate lymphadenectomy, higher rates of LN involvement were noted for tumors size 11–20 mm than ≤10 mm (56.8% vs. 11.6%, p

215 Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p< .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p< .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p < .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.

ObjectivePrevious studies identified several factors associated with cervical cancer screening. However, many of them used samples from the general population and limited studies focused on women with high-risk health behaviours. We aimed to disentangle the association of cervical cancer screening with healthcare access and HIV testing among women at a high risk of HIV infection.DesignNationwide cross-sectional survey in the USA.Setting2016 Behavioral Risk Factor Surveillance System.Participants3448 women with a history of high-risk behaviours associated with HIV infectionExposure and outcomeClinical check-up, having personal healthcare provider, health coverage and HIV testing history were treated as exposures. Appropriate cervical cancer screening, which was defined according to 2016 US Preventive Services Task Force guideline, was treated as the outcome of interest.Data analysisMultivariable logistic regression model was performed to evaluate associations of healthcare access and HIV testing with the uptake of cervical cancer screening; adjusted odds ratio (aOR) and 95% CI were reported. We further investigated if educational attainment modified associations identified in the primary multivariable model.ResultsA total of 2911 (84.4%) high-risk women in our sample underwent cervical cancer screening. In the multivariable model, delayed clinical check-up (≥5 years ago vs within the past year: aOR: 0.19, 95% CI: 0.14 to 0.26), having no health insurance (aOR: 0.60, 95% CI: 0.46 to 0.79) and no history of HIV testing (no testing vs testing within the past year: aOR: 0.46, 95% CI: 0.35 to 0.61) were inversely associated with cervical cancer screening utilisation.ConclusionFactors reflecting healthcare access, specifically clinical check-up and health coverage, as well as history of HIV testing were associated with cervical cancer screening in this population-based study of high-risk women. Targeted interventions are warranted to further increase cervical cancer screening among women at high risk of HIV infection.

Background: The interplay between metabolic syndrome (MetS) and race/ethnicity on prostate specific antigen (PSA) still remains unclear. The three major definitions of MetS (National Cholesterol Education Program [ATP III], International Diabetes Federation [IDF], and World Health Organization [WHO]) differ in number and type of components, which are linked to race/ethnicity. We proposed to investigate the associations of three major definitions of metabolic syndrome with PSA levels, and to determine whether these associations vary by race and ethnicity. Methods: We used measurements of serum PSA levels (ng/mL) in 3528 adult men >40 years from the National Health and Nutrition Examination Survey 2001–2006. MetS was defined using ATP III, IDF, and WHO criteria. Racial/ethnic groups included non-Hispanic blacks (NHBs), non-Hispanic whites (NHWs), and Mexican Americans (MAs). We computed geometric mean PSA levels from weighted multiple linear regression models. Results: Men classified with MetS-ATP ...

3577 Background: Transforming growth factor- β pathway (TGF-β) has an established role in promoting growth, invasion, metastasis as well as epithelial to mesenchymal (EMT) transition. Among 4 different described molecular subtypes of colorectal cancer (CRC), consensus molecular subtype 4 (CMS4) comprises up to 25% of CRC pts, distinguished by activation of this pathway, and is associated with higher relapse rate and poor prognosis. Recently, it has also been proposed that TGF-β activation drives immune evasion in murine models, but these findings have not been clinically validated. Methods: Using multi-gene RNA expression profiling, fresh-frozen paraffin-embedded samples of 35 patients with CRC were analyzed to determine TGF-β and EMT expression levels. Multiplexed IHC staining was performed on FFPE tumor blocks by using the Opal 7-Color fIHC Kit and the stained slides were scanned by a Vectra multispectral microscope (PerkinElmer) to measure infiltration of immune cells (i.e., T lymphocytes, cytotoxic T lymphocytes (CTL), T cell antigen-experienced, macrophages, etc.) in the tumor, stroma, and both components. TGF-β and EMT expression levels – as continuous variables - were compared with the infiltration of various immune cells using Spearman’s rank correlation analysis. Results: Among 35 pts, 28 pts had non-CMS1/MSS CRC. TGF-β RNA expression in the tumor microenvironment of these samples was inversely associated with the infiltration of CTL into the tumor (r=-0.43, p= 0.022). In contrast, there was no association of TGF-β with non-cytotoxic T-cells or macrophage infiltration. The tumor and stromal CTL infiltration differed substantially by CMS ( p=0.04, p=0.02, respectively) with tumor infiltration lowest in CMS4 (n=7). Consistent with this, EMT gene signature, which includes TGF-β expression, showed a similar inverse correlation with CTL infiltration (r=-0.48, p=0.009). Conclusions: TGF-β and EMT gene signatures have important roles in the exclusion of CTL in the tumor microenvironment of CRC pts. Inhibiting TGF-β pathway can potentially increase the intratumoral infiltration of CTL, which is a necessary (but not sufficient) step for immunotherapy response in MSS CRC. Clinical trials evaluating this hypothesis are currently ongoing (NCT03436563).

Phthalates are endocrine-disrupting compounds detectable in more than 75% of the U.S. population with differential distributions across racial and ethnic groups, and they have been linked with reduced levels of serum testosterone. This study aims to investigate the associations of phthalate metabolites with erectile dysfunction (ED) and to determine whether these associations vary by race/ethnicity among men in the United States. Analyzed data for 12 phthalate metabolites from 3,746 men (≥20 years old), who participated in the National Health and Nutrition Examination Survey 2001-2004 cross-sectional study, were included. Metabolites included MBP, MCHP, MEP, MEHP, MiNP, MBzP, MMP, MCPP, MEHHP, MEOHP, MiBP, and MECPP. Racial/ethnic groups included non-Hispanic Blacks ( n = 770), non-Hispanic Whites ( n = 2,147), and Mexican Americans ( n = 829). ED was assessed by a single question during a self-paced, computer-assisted self-interview. In racial/ethnic stratified analyses, there were higher MBP and MBzP concentrations that had a strong-dose response association with lower prevalence odds of ED among Mexican Americans, ptrend < .01, and ptrend = .03, respectively. Similarly, a significant inverse association between MEHHP and likelihood of ED among non-Hispanic Black men ( ptrend < .04) was observed. Furthermore, significant inverse associations between higher concentrations of phthalates and ED were identified only in minority populations. Further investigations, particularly prospective studies, are warranted to determine the role of phthalates on the biological mechanism(s) associated with ED. A focus may be placed on testosterone levels which are suggested to be affected by phthalates, and also low levels of testosterone are suggested to increase the risk of ED.

10520Background: Despite the high levels of point mutations, rearrangements, and other genomic instability events such as kataegis and chromothripsis, immune checkpoint inhibitors have shown limite...

11522Background: Osteosarcoma (OS) is characterized by genomic complexity and significant genetic heterogeneity. However, it is unknown whether relapse and metastatic samples incur additional insul...

e22169Background: Cancer cachexia affects many cancer patients, especially in the setting of advanced disease. Despite advancements in treatment strategies, no standard treatment or guidelines exis...

Background and Aims It is not possible to accurately count adenomas in many patients with familial adenomatous polyposis (FAP). Nevertheless, polyp counts are critical in evaluating each patient's response to interventions. However, the U.S. Food and Drug Administration no longer recognizes the decrease in polyp burden as a sufficient chemoprevention trial treatment endpoint requiring a measure of "clinical benefit." To develop endpoints for future industry-sponsored chemopreventive trials, the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) developed an FAP staging and intervention classification scheme for lower-GI tract polyposis. Methods Twenty-four colonoscopy or sigmoidoscopy videos were reviewed by 26 clinicians familiar with diagnosis and treatment of FAP. The reviewers independently assigned a stage to a case by using the proposed system and chose a stage-specific intervention for each case. Our endpoint was the degree of concordance among reviewers staging and intervention assessments. Results The staging and intervention ratings of the 26 reviewers were highly concordant (ρ = 0.710; 95% credible interval, 0.651-0.759). Sixty-two percent of reviewers agreed on the FAP stage, and 90% of scores were within ±1 stage of the mode. Sixty percent of reviewers agreed on the intervention, and 86% chose an intervention within ±1 level of the mode. Conclusions The proposed FAP colon polyposis staging system and stage-specific intervention are based on a high degree of agreement on the part of experts in the review of individual cases of polyposis. Therefore, reliable and clinically relevant means for measuring trial outcomes can be developed. Outlier cases showing wide scatter in stage assignment call for individualized attention and may be inappropriate for enrollment in clinical trials for this reason.

640 Background: In advanced gastrointestinal (GI) malignancies, genetic profiling is often performed with the goal of facilitating enrollment of patients into clinical trials. While multigene genetic profiling has become the standard of care in many practices, the data on success rate of identifying actionable genomic alterations remain limited. In this study, we aimed to characterize the rate of actionable mutations using larger ( > 150 genes) and smaller ( < 150 genes) panels across different GI malignancies. Methods: We reviewed all reports of formalin-fixed paraffin-embedded clinical specimens sent for next-generation sequencing (NGS-using assays of at least 45 genes) for patients with advanced GI malignancies between 2012-2017 at MD Anderson Cancer Center. Actionable mutations were defined as those matching or informing the use of targeted therapies available in clinical trials, or FDA-approved. These were determined by a precision oncology support team (pct.mdanderson.org), using available literature and functional genomic screens. Novel actionable mutations were defined as those not used in current testing guidelines for GI malignancies. Results: Out of 11968 detected mutations, 3832(32.0%) were deemed to be actionable mutations and the remainder were either in non-actionable genes, deemed benign, or variants of unknown significance. Therefore, 1987 (65.1%) of assays had actionable mutations. When limited to novel actionable mutations, the rate fell to 21.5% (659/3052). Compared to CRC, other GI malignancies were 1.65 times more likely to have a novel actionable mutation (95% CI 1.35-2.00, p< .001). The use of larger and smaller panels did not differ in detecting novel actionable mutations, but larger panels resulted in a 3.5-fold higher number of mutations not deemed clinically actionable. Conclusions: Despite incorporation of NGS in oncology practice for GI malignancies, the success rate of detecting novel actionable mutations beyond those in the current guidelines remains low. Using assays with larger gene numbers does not seem to improve this detection rate. Future studies are required to evaluate the success rate of clinical interventions when actionable alterations are present.

619 Background: The benefits of matching targeted treatments to aberrations identified by molecular profiling (MP) is unclear. Outcomes in phase 1 settings have been traditionally reported across tumor histologies. We report outcomes based on a metastatic colorectal cancer (mCRC) population. Methods: Patients (pts) with mCRC receiving at least one dose of treatment on a phase 1 study were annotated for variants detected by MP. A precision oncology decision support (PODS) team determined variant function and actionability. A matched therapy (MT) was defined as allocation to a novel agent that targeted the aberration or predicted pathway deemed actionable by PODS. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HR). Results: A total of 370 patients enrolled onto 467 phase 1 trials were identified from January 2012 to April 2017. 106 enrolments were assigned to MT. Pts with microsatellite instability-high (MSI-H), BRAFV600E, PIK3CA mutation were more likely to be assigned a MT, while left-sided tumors and RAS mutant patients were less likely to be treated with a MT. Molecularly-targeted regimens (MTR) were utilized more frequently in MT while immune-targeting MTR was more common in non-MT. BRAFV600E mutations and HER2 amplification/overexpression made up 44.3% of MT. There was a significant difference in PFS between the MT vs non-MT group (HR 0.65, 95% CI 0.51-0.83, p = 0.016) in univariate analysis. The 6-month PFS probability was 31% (95% CI; 23-41%) versus 13% (95% CI; 10-17%) respectively. Other significant factors in univariate analysis associated with longer PFS were MSI-H, BRAFV600E and use of a regimen containing cytotoxic chemotherapy while RAS mutations were associated with shorter PFS. In multivariate analysis, after correcting for mutation status, allocation to a MT was associated with improved PFS (HR = 0.72, 95% CI 0.50-0.99, p = 0.043). Conclusions: Matching clinical trial enrollment to MP based on dedicated decision support is associated with improved outcomes in mCRC patients. The MT strategy is still hampered by a limited number of actionable variants, and is driven by a small number of active MTs.

1575 Background: Lung cancer is the leading cause of cancer-related mortality linked with smoking, though only 6-18% of heavy smokers die of lung cancer. We hypothesized that major stressful life events are a risk factor for developing lung cancer. Methods: In our matched case-control study, cases (CA) were lung cancer patients diagnosed within past 12 months. Controls (CO) were patients without a prior history of malignancy. CA and CO were matched for age, gender and smoking status. Smokers had at least 10 packs/years history of smoking. Data was collected using standardized research questionnaire on 11 major stressful life events using Holmes and Rahe stress scale. The primary endpoint was odds of having a major stressful life event. A sample of 360 patients (120 CA and 240 CO), was needed to achieve 80% power to detect an odds ratio (OR) of 2.00 using Chi-Square test with a P = 0.05 significance. The study was IRB approved at each institution. Results: Between May 2015 and December 2016, 324 patients were enrolled (23 were excluded due to prior cancer history or incomplete information). 301 (CA = 102; CO = 199) were included in the final analysis. The two groups were well matched in median age (CA = 64.4 years; CO = 63.9years), gender (CA-Male = 48%; CO-Male = 49.2%) and smoking status (ever smoker, CA = 86%; CO = 85%). There was no difference in lifetime stressful life event between CA and CO (95% vs 93.9% P = 0.68%). However, CA were significantly more likely to have had a major stressful life event within the past 5 years than controls (CA = 77.4% vs CO = 65.8%, P = 0.03, (OR = 1.78). Serious life-threatening illness of an immediate family member (P = 0.04) and retirement (P = 0.07) within the past 5 years were noticeably more common among CA. Holmes-Rahe stress score in the last 5 years was higher in men (86.3 vs 63.3, P = 0.07) and those > 65 years old (82.4 vs 57.2,P = 0.04) as compared with CO and in those with squamous histology than with adenocarcinoma (115.6 vs 63.4, P = 0.005). Conclusions: Patients with lung cancer (CA) were significantly more likely to have had a major stressful life event within the past 5 years than the matched controls (CO), especially in older men with squamous histology. Major stressful life events should be considered a risk factor for developing lung cancer.

3506Background: CRCs originating in the right colon (RC) have features distinct from those in the rectum/left colon, including more frequent CpG island methylator phenotype (CIMP-High) and BRAF mut...

Background: Asian Indians represent one of the fastest growing immigrant groups in the United States; a population that grew from less than 0.5% in 1960 to almost 5% in 2011; and is expected to exceed 40 million by the year 2050 comprising of 10% of the total U.S. population then. Cancer is one of the leading causes of death among this population. Non-adherence to screening recommendations remains a concern as cancer is often detected at a later stage. Purpose: To examine specific factors associated with cancer screening practices among Asian Indians in the Greater Houston area. Methods: The data analyzed were from the South Asian Health Needs Assessment (SAHNA) project, a community survey carried out in 2013-2014 by the Indian American Cancer Network (IACAN), in collaboration with MD Anderson Cancer Center. Participants included 1525 self-identified Asian Indians, 18 years or older, living in the Greater Houston area. We used logistic regression models to examine associations between various factors including demographic characteristics, perceived risk for cancer and knowledge regarding cancer screening for their association with multiple cancer screening practices. The screening outcomes analyzed were as follows: if participants ever had a mammogram or clinical breast exam and if had them within past 1 year for breast cancer; if they ever had a pap test or had it in past 3 years for cervical cancer; if ever had a prostate specific antigen (PSA) test for prostate cancer; and ever had colonoscopy for colorectal cancer screening. Age and gender specific recommendations for various cancer screenings were considered in creating sub-groups to analyze. Results: The average participant age was 47 years (range = 18-87 years), of which 52% were males, 82% were married, 48% had yearly income of >100,000$, 83% had at least 4 years of college education, and 88% had some form of health insurance. 85% women greater than 40 years of age had ever had a mammogram, and 70% of those had mammogram in last year, whereas, 75% of all women ever had a clinical breast exam and 73% of those had clinical breast exam within last year. 80% of all women had ever had a pap test and 85% of those had it in past 3 years. Among men older than 40 years of age, 31% had a PSA screening. Among both women and men above 50 years of age, 42% ever had either a colonoscopy or sigmoidoscopy. Of all the factors studied, participant age, marital status, income, education, and insurance status had significant associations with at least one or more cancer screening behaviors. Whereas, contrary to expectations, according to behavioral theory proposed by the Health Belief Model, perceived risk for cancer and knowledge regarding screening practices were not associated with any of the cancer screening behaviors. Conclusion: For the Asian Indian community in this study, demographic characteristics were associated with adherence to various cancer screening practices more than their personal perceptions and knowledge. Therefore, outreach efforts to increase cancer screening practices should be targeted towards the younger age group, unmarried/single, with low income, less education and those lacking health insurance. Further studies are recommended to examine the role of perceived risk and knowledge with cancer screening practices, among the growing Asian Indian community in the US. Citation Format: Pragati Advani, Shailesh Advani, Beverly Gor, Dorai Vaithianathan, Kabad Kanchan, Mala Pande. Factors associated with cancer screening practices among Asian Indians. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B63.

Background: Colorectal cancer morbidity and mortality rates vary by race and ethnicity. The combined contribution of genetics and environment to response to chemotherapy, progression-free and overall survival in colorectal cancer patients is unclear, but CpG island hypermethylation (CIMP), a discrete molecular subtype of colorectal cancer, is associated with inflammation and environmental exposures. Hence our main objective is to assess correlation between various modifiable risk factors and CIMP status among metastatic colorectal cancer patients. Methods: We characterized CIMP methylation (MINT1, MINT2, MINT31, p14, p16, and MLH1) in 229 metastatic colorectal cancer patients using PCR amplification of bisulfite treated DNA followed by pyrosequencing. The number of methylated probes were averaged to obtain the% methylation with CIMP-High (CIMP-H) being defined as ≥40% of probes methylated. Associations of demographic and clinical characteristics, including BMI, diabetes, obesity, physical activity, smoking and drinking status, as well as presence or absence of other molecular alterations (BRAF, KRAS, NRAS, PIK3CA and PTEN loss) with overall survival were assessed in multivariable-adjusted Cox proportional hazards models. Results: When treating methylation as a continuous variable, patients with BRAF mutation had higher methylation as compared to participants with BRAF wildtype (40.6% vs 20.5%, p = 0.001). White, non-Hispanic (WNH) patients had greater degree of tumor methylation (24.8%) as compared to other racial categories (p = 0.02). When classified as a categorical variable, moderate to vigorous physical activity was associated with higher rate of having any methylated probes, as compared to sedentary patients (p = 0.02). CIMP status was not associated with OS in these patients in multivariable-adjusted Cox models. However when stratified by CIMP status. When stratified by CIMP status; among patients with 0-40% methylation, KRAS mutation was associated with poor OS(HR = 3.19, p = 0.006) and diabetes was protective (HR = .14, p = 0.025). Among patients with high methylation(41-100%) methylation, obesity was associated with poor OS (HR = 5.20, p = 0.038) and former smoking was associated with poor OS(HR = 2.92, p = 0.05). When stratified by KRAS mutation status, among patients with KRAS wildtype, obesity was associated with poor OS(HR = 2.86, p = 0.019) and among patients with KRAS mutation, diabetes was protective (HR = 0.18, p = 0.033) Conclusion and Impact: CpG island methylator phenotype was associated with unique clinicopathologic characteristics. Methylation, as assessed by the 6-gene CIMP panel, was not associated with worse outcomes after correcting for the KRAS mutations, a well-established genetic marker of poor prognosis. Hypermethylation did appear to modulate outcomes in obese patients with hypermethylated tumors. Citation Format: Shailesh M. Advani, Michael Sangmin Lee, Michael James Overman, David Fogelman, Bryan K. Kee, Shanequa D. Manuel, Jennifer Davis, Van Karlyle Morris, Callisia Nathelee Clarke, Carrie R. Daniel, David G. Menter, Stanley R. Hamilton, Dipen Maheshbhai Maru, Scott Kopetz. Correlation of CpG island methylation with clinical and pathologic characteristics in metastatic colorectal cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2015-4763

Purpose: Regular NSAID (Non-Steroidal Anti-Inflammatory Drug) use results in an overall reduction in colorectal cancer (CRC) risk; however, this reduction may vary among molecularly defined subsets of CRC. Characterization of patients by regular NSAID use and molecular subtype will provide unique insight into the biology of NSAID-based CRC prevention. Methods: A sample of patients was selected from the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) protocol, which is designed to molecularly profile tumors of patients with refractory metastatic CRC. Demographic data and NSAID use were collected from a risk-factor survey. Demographic characteristics were compared between 106 non-NSAID users, 75 regular aspirin users and 78 regular non-aspirin NSAID users. Chi-square analysis was used to compare categorical variables and ANOVA was used for continuous variables. Logistic regression was used to assess predictors of aspirin or non-aspirin NSAID use compared to non-use. Results: Preliminary results indicate that aspirin users tend to be older, male and more frequently engage in vigorous physical activity compared to non-users and users of non-aspirin NSAIDs (Table I). In univariate analyses, patients who are older or engage in more frequent vigorous physical activity are at increased odds of using aspirin. When controlling for other variables, only age at diagnosis predicts aspirin use. Table 1.Description and AssociationsNo NSAID useAspirin useNon-Aspirin usep valueN1067578Age at Stage IV Diagnosis, Mean (SE)55.2 (1.0)59.5 (1.1)53.1 (1.3)0.0006Gender, N (%)11884810.0251Male72 (61.0)59 (72.8)44 (52.4)Female46 (39.0)22 (27.2)40 (47.6)Vigorous Physical Activity, N (%)11780840.0214Little or none50 (42.7)18 (22.5)34 (40.5)Once/week10 (8.6)14 (17.5)13 (15.5)Twice/week or more57 (48.7)48 (60.0)37 (44.1)Logistic RegressionUnadjusted Odds of Aspirin UseAdjusted Odds of Aspirin Use*OR (95% CI)p valueOR (95% CI)p valueAge at Stage IV Diagnosis1.047 (1.013, 1.081)0.00571.049 (1.014, 1.085)0.0055Gender (Female)0.584 (0.316, 1.078)0.08550.701 (0.356, 1.379)0.3032Vigorous Physical Activity (overall effect)0.00850.0486Little or none (Ref)1.001.00Once/week3.889 (1.468, 10.300)0.03692.481 (0.892, 6.906)0.2997Twice/week or more2.339 (1.207, 4.533)0.58952.305 (1.137, 4.673)0.2662*Each variable is adjusted for the other variables in the table Conclusions: These preliminary data indicate that we will be able to distinguish aspirin users from non-NSAID users in a sample of late-stage CRC patients. Going forward, we will combine these demographic data with tumor molecular classification to determine the subtypes of CRC that are more or less prevalent in aspirin/NSAID users. Use of NSAIDs and overall survival will also be evaluated among different molecular subtypes of CRC. This data, combined with analysis of risk factors for each molecular subtype will provide unique insight into the biology of NSAID-based CRC prevention. Citation Format: Jennifer S. Davis, Shailesh Advani, Emilyn Banfield, Michael Overman, Zhi-Qin Jiang, Shanequa Manuel, Carrie Daniel, Shine Chang, Scott Kopetz. Demographics of colorectal cancer patients vary by aspirin use. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3704. doi:10.1158/1538-7445.AM2015-3704

3633 Background: Deranged epigenetic regulation is thought to play an important role in pathogenesis and behavior of metastatic colorectal cancer (mCRC). The CpG island methylator phenotype (CIMP) is associated with distinct tumor biology, which may have differential sensitivity to targeted drug therapy. We hypothesized that methylation status affects susceptibility to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs). Methods: 195 mCRC patients initially tested as KRAS wild-type had tumor tissue successfully tested for CIMP status via bisulfite pyrosequencing and PCR amplification of MINT1, MINT2, and MINT31 loci and promoter sequences of p14, p16, and hMLH1. Next generation sequencing for KRAS, BRAF, and NRAS mutations was done. The duration of the first anti-EGFR mAb treatment and reason for cessation was retrospectively determined, and log-rank test was used for comparisons of progression-free survival (PFS). Cox regression analysis was performed. Results: 162 patients received...