Is there an association between a history of military service and cancer diagnosis? Results from a US national-level study of self-reported outcomes.

PURPOSE: To examine cancer prevalence in men with and without military service history, using national-level self-reported outcomes. METHODS: A cross-sectional survey-based US study, including men aged 18 and above from the Health Information National Trends Survey database between 2011 and 2014. The primary endpoint was self-reported cancer prevalence. Multivariable logistic regression analyses assessed the association of various covariates with the prevalence of cancer. RESULTS: A total of 4,527 men were analyzed, with 1,352 (29.9%) reporting a history of military service. Compared to men with no military service history, men with a military service history were older (median of 65 [IQR 56, 74] vs. 53 [IQR 41, 62] years, p < 0.0001), more commonly Caucasian (71.4% vs. 61.4%, p < 0.0001), born in the US (95.6% vs. 79.5%, p < 0.0001), attained higher education level and annual household income (p < 0.0001), and consisted of more smokers(58.3% vs. 44.5%, p < 0.0001). The age-adjusted comparison demonstrated a higher cancer prevalence in men with military service history (20.5% vs. 7.6%, p < 0.0001). Specifically, genitourinary, dermatological, gastrointestinal, and hematological cancers were generally more prevalent. Adjusting for all available confounders, multivariable models showed that military service history was associated with 1.56 (95% CI 1.20-2.03), and 1.57 (95% CI 1.07-2.31) increased odds of having any cancer, and specifically genitourinary cancer, respectively. CONCLUSIONS: Further research is needed to ascertain whether the association between military service and increased cancer diagnosis results from better screening programs or increased exposure to risk factors during military service.

The association between physician trust and smoking cessation: Implications for motivational interviewing.

Although the relationship between cigarette smoking and increased risk of malignancy has been well established, smoking remains a major public health threat in the United States. Therefore, we examined the relationship between a person's level of trust in cancer information from their physician and the likelihood of quitting smoking in order to better understand the doctor-patient relationship in the context of smoking cessation. The Health Information Nation Trends Survey (2011-2015) was used to identify smokers (n = 2186). Multivariable logistic regression was used to assess the relationship between trust in physicians, the internet, and family members on smoking cessation, accounting for demographic variables. Smokers reported a significantly higher level of trust in cancer information from their physician than cancer information from the internet or family members. However, no significant association between level of trust in cancer information from their physician and wanting to quit smoking was observed (ptrend = 0.55). There was also no association between level of trust in the internet or family and quitting smoking (ptrend = 0.52 and ptrend = 0.83, respectively). These results were confirmed by multivariate analysis. Smoking cessation is not associated with the level of trust an individual has in cancer information from their physician, the internet, or from family members. These findings may impact the utility of standardized information campaigns.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review.

Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs' role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects.

Mystery in the mediastinum: Rare case of indolent primary thoracic amyloids.

A 53-year-old African American male smoker presented with epigastric pain, tarry stools, and laboratory results indicative of acute pancreatitis. Chest X-ray showed a right perihilar mass with pleural effusion. Computed tomography scan showed multiple large right paratracheal and hilar nodes with internal calcification. The patient underwent a fiberoptic bronchoscopy with biopsies which were negative for malignancy. Mediastinoscopy was performed and revealed amyloidosis. Evaluation for multiple myeloma showed elevated kappa and lambda light chains and diffuse polyclonal gammopathy, but there was no monoclonal spike on serum protein electrophoresis. Bone marrow and abdominal fat pad were negative for amyloid, and the patient continues to lack chronic underlying systemic disease with no symptoms on cardiac or pulmonary examination.

Upgrading on radical prostatectomy specimens of very low- and low-risk prostate cancer patients on active surveillance: A population-level analysis.

INTRODUCTION: A proportion of prostate cancer (PCa) patients initially managed with active surveillance (AS) are upgraded to a higher Gleason score (GS) at the time of radical prostatectomy (RP). Our objective was to determine predictors of upgrading on RP specimens using a national database. METHODS: The Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting database was used to identify AS patients diagnosed with very low- or low-risk PCa who underwent delayed RP between 2010 and 2015. The primary outcome was upgrading to GS 7 disease or worse. Logistic regression analyses were used to evaluate demographic and oncological predictors of upgrading on final specimen. RESULTS: A total of 3775 men underwent RP after a period of AS, 3541 (93.8%) of whom were cT2a; 792 (21.0%) patients were upgraded on RP specimen, with 85.4%, 10.6%, and 3.4% upgraded to GS 7(3+4), 7(4+3), and 8 diseases, respectively. On multivariable analysis, higher prostate-specific antigen (PSA) at diagnosis (5-10 vs. 0-2 ng/ml, odd ratio [OR] 2.59, p<0.001) and percent core involvement (80-100% vs. 0-20%, OR 2.52, p=0.003) were significant predictors of upgrading on final RP specimen, whereas higher socioeconomic status predicted lower odds of upgrading (highest vs. lowest quartile OR 0.75, p=0.013). CONCLUSIONS: Higher baseline PSA and percent positive cores involvement are associated with significantly increased risk of upgrading on RP after AS, whereas higher socioeconomic status predicts lower odds of such events. These results may help identify patients at increased risk of adverse pathology on final specimen who may benefit from earlier definitive treatment.

Pathologic upgrading in favorable intermediate risk active surveillance patients: Clinical heterogeneity and implications for active surveillance decision.

INTRODUCTION: Current guidelines support active surveillance (AS) for select patients with favorable intermediate risk (FIR) prostate cancer (CaP). A significant proportion of FIR CaP patients undergoing surgical treatment are found to have evidence of adverse pathology. Our objective was to determine the incidence and predictors of pathologic upgrading in FIR AS patients undergoing radical prostatectomy. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting (WW) database was used to identify men younger than 80 years with National Comprehensive Cancer Network FIR CaP initially opting for AS and/or WW between 2010 and 2015 and subsequently underwent radical prostatectomy at least one year following diagnosis. Patients were assigned into one of three subgroups based on their intermediate risk factor: Gleason Score 7(3 + 4) (Group 1), prostate specific antigen level of 10-20 ng/ml (Group 2), and cT2b-c (Group 3). Pathologic upgrading was present in Group 1 if pathologic GS was 7 (4 + 3) or worse. For patients in Groups 2 and 3, upgrading occurred if pathologic GS was 7 (3 + 4) or worse. Oncologic and sociodemographic predictors of pathologic upgrading were evaluated univariable and multivariable logistic regression analysis. RESULTS: 18,760 patients were identified. Pathologic upgrading occurred in 138 (13.3%), 59 (25.0%), and 8,011 (45.8%) patients in groups 1, 2, and 3 respectively. Pathologic downgrading occurred in 226 (21.7%) patients in group 1. Significant predictors of pathologic upgrading on multivariable analysis included older age at diagnosis: 70 to 79 vs. 40 to 49 years (Groups 1 and 3, P < 0.05), a more recent diagnosis: 2014 to2015 vs. 2010-2011 (Groups 2 and 3, P < 0.005), higher volume disease: 37.5% to 49.9% vs. 0% to 12.4% (Groups 2 and 3, P < 0.005), and clinically palpable disease (Groups 1 and 2, P < 0.05). Additional risk factors for upgrading included uninsured or Medicaid status, diagnosis in a Western region (Group 2), African American ethnicity and higher socioeconomic status (Group 3) CONCLUSIONS: FIR CaP is a clinically heterogeneous risk group with incidence of pathologic upgrading ranging from 13.3% in those with GS 7 (3 + 4) to 45.8% in those with cT2b-c disease. Risk of pathologic upgrading in FIR CaP patients initially managed with AS and/or WW is significantly associated with multiple patient-level oncologic and sociodemographic variables.

Influence of Sociodemographic Factors on Definitive Intervention Among Low-risk Active Surveillance Patients.

OBJECTIVES: To investigate sociodemographic factors influencing decision of initially active surveillance (AS) prostate cancer (CaP) patients to opt for definitive therapy, and, specifically, choice of radical prostatectomy (RP) versus radiation therapy (XRT). METHODS: The Surveillance, Epidemiology, and End Results (SEER) Prostate with Watchful Waiting database was used to identify AS patients diagnosed with NCCN low-risk CaP between 2010 and 2015. We sought to determine predictors of treatment type using multivariable logistic regression analyses. RESULTS: Out of 32,874 men included, 21,255 (64.7%) underwent delayed treatment, with 3,751 (17.6%) and 17,463 (82.2%) opting for RP and XRT, respectively. Patients who were married (Odds Ratio [OR]: 1.18, P <.001), insured (OR 2.94, P <.001), of higher socioeconomic status (OR 1.67 for highest vs lowest, P <.01), and residing in a Southeastern or Midwestern region (ORs 1.26 and 1.22 vs Northeast, respectively, P <.01) were significantly more likely to undergo definitive intervention. A significant interaction between patient race and marital/socioeconomic statuses on the decision-making process was identified. Decision for XRT (vs RP) was more likely in older (OR 11.6 for 70-79 vs 50-59 years, P <.01), unmarried (OR 1.89, P <.01), African American (OR 1.41, P .018), and higher socioeconomic status (OR 1.54 for highest versus lowest quartile, P <.01) patients. CONCLUSION: The majority of patients initially treated with AS underwent delayed treatment. After accounting for pathologic characteristics, the interaction of sociodemographic factors including race, socioeconomic status, marital status, insurance status, and region of residence are significantly associated with the likelihood of undergoing definitive therapy.

MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL.

BACKGROUND: While aberrant DNA methylation is a characteristic feature of tumor cells, our knowledge of how these DNA methylation patterns are established and maintained is limited. DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases (TETs) function has been found altered in a variety of cancer types. RESULTS: Here, we report that in T cell acute lymphoblastic leukemia (T-ALL) the MYC oncogene controls the expression of TET1 and TET2 to maintain 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) patterns, which is associated with tumor cell-specific gene expression. We found that cellular senescence and tumor regression upon MYC inactivation in T-ALL was associated with genome-wide changes in 5mC and 5hmC patterns. Correlating with the changes in DNA (hydroxy)methylation, we found that T-ALL overexpress TET1, while suppressing TET2 in a MYC-dependent fashion. Consequently, MYC inactivation led to an inverse expression pattern, decreasing TET1, while increasing TET2 levels. Knockdown of TET1 or ectopic expression of TET2 in T-ALL was associated with genome-wide changes in 5mC and 5hmC enrichment and decreased cell proliferation, suggesting a tumor promoting function of TET1, and a tumor suppressing role for TET2. Among the genes and pathways controlled by TET1, we found ribosomal biogenesis and translational control of protein synthesis highly enriched. CONCLUSIONS: Our finding that MYC directly deregulates the expression of TET1 and TET2 in T-ALL provides novel evidence that MYC controls DNA (hydroxy)methylation in a genome-wide fashion. It reveals a coordinated interplay between the components of the DNA (de)methylating machinery that contribute to MYC-driven tumor maintenance, highlighting the potential of specific TET enzymes for therapeutic strategies.

Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition.

Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.

DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma.

Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt's lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EµSRα-tTA;tet-o-MYC) and human Burkitt's lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt's lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.