Christie Y. Jeon

Diabetes, pancreatic cancer, and metformin therapy

Pancreatic cancer carries a poor prognosis as most patients present with advanced disease and preferred chemotherapy regimens offer only modest effects on survival. Risk factors include smoking, obesity, heavy alcohol, and chronic pancreatitis. Pancreatic cancer has a complex relationship with diabetes, as diabetes can be both a risk factor for pancreatic cancer and a result of pancreatic cancer. Insulin, insulin-like growth factor-1 (IGF-1), and certain hormones play an important role in promoting neoplasia in diabetics. Metformin appears to reduce risk for pancreatic cancer and improve survival in diabetics with pancreatic cancer primarily by decreasing insulin/IGF signaling, disrupting mitochondrial respiration, and inhibiting the mammalian target of rapamycin (mTOR) pathway. Other potential anti-tumorigenic effects of metformin include the ability to downregulate specificity protein transcription factors and associated genes, alter microRNAs, decrease cancer stem cell proliferation, and reduce DNA damage and inflammation. Here, we review the most recent knowledge on risk factors and treatment of pancreatic cancer and the relationship between diabetes, pancreatic cancer, and metformin as a potential therapy.

Incidence of Oropharyngeal Cancer Among Elderly Patients in the United States.

ImportancenAn escalating incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been reported predominantly among middle-aged adults. However, HPV infection is believed to occur many years before cancer develops, and tissue studies suggest that HPV DNA is found in the majority of OPSCC diagnosed in patients 65 years or older.nnnObjectivenTo update the trends in OPSCC incidence using US cancer registry data, with an emphasis on age-specific trends.nnnDesign, Setting, and ParticipantsnData from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2012) were queried to compare changes in incidence and survival trends in OPSCC with selected tobacco-related cancers (larynx, oral cavity, hypopharynx, lung) and an HPV-related cancer (anus). A total of 40u202f264 patients who received a diagnosis of OPSCC from 2000 to 2012 were included. Elderly patients were defined as those 65 years or older.nnnMain Outcomes and MeasuresnThe annual percentage change in OPSCC incidence from 2000 to 2012, stratified according to age group.nnnResultsnAmong the 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012, 13 313 (33.1%) were aged 65 years or older and 80.3% were male. Significant increases in the age-adjusted incidence of OPSCC were observed during the study period for both younger adults aged 45 to 64 years (annual percentage change [APC], 2.31; 95% CI, 1.76-2.86; Pu2009<u2009.001) and patients 65 years or older (APC, 2.92; 95% CI, 2.32-3.51; Pu2009<u2009.001). These changes were driven predominantly by base-of-tongue and tonsil cancers in men. Concomitantly, the incidence of tobacco-associated head and neck cancers decreased for elderly patients (larynx: APC, -1.54; 95% CI, -2.00 to -1.08; Pu2009<u2009.001; oral cavity: APC, -1.23; 95% CI, -1.84 to -0.62; Pu2009=u2009.001; hypopharynx: APC, -2.44; 95% CI, -3.01 to -1.86; Pu2009<u2009.001), whereas the incidence of anal cancer significantly increased (APC, 4.42; 95% CI, 3.28 to 5.57; Pu2009<u2009.001). Furthermore, improved overall and cause-specific survival over time were observed for both younger and elderly patients with OPSCC. Nevertheless, absolute cause-specific survival remained worse for elderly patients (3-year CSS, 60.8%; 95% CI, 59.6%-61.9%) in comparison with those aged 45 to 64 years (75.7%; 95% CI, 75.1%-76.4%; Pu2009<u2009.001).nnnConclusions and RelevancenThe incidence of OPSCC is increasing among elderly patients in the United States, likely driven by HPV-associated cancers. Given the unique challenges related to treating elderly patients with OPSCC, their limited enrollment in clinical trials, and the aging US population, clinical studies investigating improved therapeutic strategies for elderly patients with HPV-positive OPSCC should be performed.

Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection

Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus–infected patients who are treatment‐naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real‐world experience. Using data from real‐world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut für Interdisziplinäre Medizin), Burmans Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta‐analysis of six additional real‐world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow‐up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment‐eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta‐analysis of six additional real‐world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98‐1.00). Conclusion: An 8‐week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094‐1103)

Statin use and survival in elderly patients with endometrial cancer

BACKGROUNDnEndometrial cancer is the most common gynecologic cancer in the United States. Statins have demonstrated anti-cancer effects in other tumor types, such as the breast and lung cancers.nnnAIMnThe objective of our study was to determine the association between statin use and endometrial cancer survival in a nationally-representative elderly population with endometrial cancer in the U.S.nnnMETHODSnWe employed the linked Surveillance, Epidemiology and End Results registries and Medicare claims files to collect data from 2987 patients who were diagnosed with endometrial cancer between 2007 and 2009 and who received a hysterectomy. The association between statin use and overall survival was examined using Cox regression models adjusting for follow-up time, age, race, neighborhood income, cancer stage, tumor grade, hysterectomy type, chemotherapy, radiation, impaired glucose tolerance, obesity, dyslipidemia and diabetes.nnnRESULTSnThe mortality rate was lower in statin users compared to non-users for both type I (4.6 vs. 5.7 deaths/100 person-years, p=0.08) and type II (11.2 vs. 16.5 deaths/100 person-years, p=0.01) cancer types. However, after adjustment for the time from surgery to statin use and confounding, statin use after a hysterectomy was not significantly associated with a reduction in hazard of death for both type I (hazard ratio [HR] 0.92, 95%CI 0.70,1.2) and type II (HR=0.92, 95%CI 0.65, 1.29, p=0.62) endometrial cancer patients.nnnCONCLUSIONnAccounting for all confounders and biases considered, statin use on or after a hysterectomy was not associated with survival in those with type I or type II disease.

Obesity is independently associated with infection in hospitalised patients with end-stage liver disease.

Infection is the most common cause of mortality in end‐stage liver disease (ESLD). The impact of obesity on infection risk in ESLD is not established.

Digoxin therapy is not associated with improved survival in epithelial ovarian cancer: A SEER-Medicare database analysis

OBJECTIVESnBoth in vitro and clinical trial data suggest that cardiac glycosides demonstrate a synergistic anti-tumor effect when administered with platinum chemotherapy. Epidemiologic studies have also demonstrated improved cancer survival in colorectal, breast, head and neck and hepatocellular carcinoma patients on digoxin therapy at the time of cancer treatment. We sought to determine whether digoxin improves survival in epithelial ovarian cancer patients treated with platinum.nnnMETHODSnSurveillance, Epidemiology and End-Results (SEER) tumor registries program data on ovarian cancer patients diagnosed in 2007-2009 were linked to Medicare claims data to capture platinum administration, digoxin use and cardiac comorbidities. We analyzed 762 patients who underwent cancer-directed surgery and received platinum chemotherapy. Patients were considered digoxin users during platinum administration if a prescription was filled within 6months of cancer diagnosis. Cox proportional hazards regression models were used to determine the impact of digoxin use on overall survival (OS).nnnRESULTSnAmong 762 epithelial ovarian cancer patients treated with surgery and platinum chemotherapy, 53 (7%) used digoxin ever and 38 (5%) used digoxin specifically during platinum administration. Adjusting for age, heart disease and Charlson comorbidity score, digoxin use was not associated with OS (HR=1.29, 95% CI 0.81, 2.06).nnnCONCLUSIONSnIn this SEER-Medicare database analysis, digoxin use during chemotherapy was not associated with improved OS outcomes in patients with epithelial ovarian cancer treated with surgery and platinum chemotherapy. These conclusions are limited, however, by a small sample size and bias intrinsic to claims-based data and should be further evaluated in a larger cohort.

Polymorphisms of peroxisome proliferator-activated receptors and survival of lung cancer and upper aero-digestive tract cancers

BACKGROUNDnPeroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in several biological processes such as inflammation, cancer growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer outcomes. Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers.nnnMETHODSn1212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) were followed for a median duration of 11 years. We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman - rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG - and investigated their associations with lung and UADT cancer survival using Cox regression. A semi-Bayesian shrinkage approach was used to reduce the potential for false positive findings when examining multiple associations.nnnRESULTSnThe variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR]=0.63, 95% confidence interval [CI]=0.42, 0.96) and UADT cancers (aHR=0.51, 95% CI=0.27, 0.99). Use of the semi-Bayesian shrinkage approach yielded a posterior aHR for lung cancer of 0.66 (95% posterior limits=0.44, 0.98) and a posterior aHR for UADT cancers of 0.58 (95% posterior limits=0.33, 1.03).nnnCONCLUSIONnOur findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants.

Burden of present-on-admission infections and health care-associated infections, by race and ethnicity

BACKGROUNDnIn the United States incidence of sepsis and pneumonia differ by race, but it is unclear whether this is due to intrinsic factors or health care factors.nnnMETHODSnWe conducted a study of 52,006 patients hospitalized during 2006-2008 at a referral hospital in upper Manhattan. We examined how the prevalence of present-on-admission and health care-associated infection compared between non-Hispanic blacks, Hispanics, and non-Hispanic whites adjusting for sociodemographic factors, admission through the emergency department, and comorbid conditions.nnnRESULTSnNon-Hispanic blacks had 1.59-fold (95% confidence interval [CI], 1.29-1.96) and 1.55-fold (95% CI, 1.35-1.77) risk of community-acquired bloodstream infection and urinary tract infection compared with non-Hispanic whites. Hispanic patients had 1.31-fold (95% CI, 1.15-1.49) risk of presenting with community-acquired urinary tract infection compared with non-Hispanic whites. Controlling for admission through the emergency department, comorbidity, and neighborhood income attenuated the differences in prevalence of infections.nnnCONCLUSIONSnWe found that health disparities in present-on-admission infections might be largely explained by potential lack of ambulatory care, socioeconomic factors, and comorbidity.

Abstract 2173: Survival time in pancreatic cancer patients with metabolic syndrome varies by use of insulin and statins

Background: Insulin-sensitizing drugs (i.e. metformin) and lipid-lowering agents (i.e. statins) demonstrate pleiotropic effects against cancer cell lines and show potential as therapeutic adjuvants for cancer patients. Our objective was to examine the association of specific classes of diabetes drugs and statins on survival time among pancreatic cancer patients with metabolic syndrome. Methods: Linked Surveillance, Epidemiology and End Results (SEER) cancer registry and Medicare claims data were used identify pancreatic cancer patients diagnosed in 2008-2009 with the following: resection of the pancreas, metabolic syndrome prior to cancer diagnosis, continual enrollment in Medicare Parts A, B, and D. Metabolic syndrome was defined as having 3 out of the 4 conditions: hyperglycemia, dyslipidemia, obesity, or hypertension. Exposure to diabetes drugs and statins 12 months prior to resection of cancer was assessed in the prescription drug event database and categorized as insulin/sulfonylureas vs. metformin/thiazolidinediones (TZD) vs. none; and as no statin vs. lipophilic statin vs. hydrophilic statin. We employed Cox regression adjusting for age, sex, race, stage at diagnosis and chemotherapy, to estimate the impact of individual drug classes on survival with pancreatic cancer. Results: We analyzed data on 263 pancreatic cancer cases with metabolic syndrome. Users of insulin/sulfonylureas demonstrated shorter survival by 6 months and had higher hazard of death (HR=1.43, 95%CI (1.05, 1.95)) compared to non-users. In contrast, users of hydrophilic statins experienced longer survival by 9 months and showed lower hazard of death compared to those who did not use statin (HR = 0.67, 95%CI (0.46, 0.96)) (Table). Conclusion : Insulin/sulfonylureas use is associated with shorter survival, while hydrophilic statin use was associated with longer survival in pancreatic patients with metabolic syndrome. Table. Relative hazard of death in pancreatic cancer patients by diabetes drugs and statin Citation Format: Christie Y. Jeon, Stephen J. Pandol, Marc T. Goodman. Survival time in pancreatic cancer patients with metabolic syndrome varies by use of insulin and statins. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2173. doi:10.1158/1538-7445.AM2014-2173

The Association of Recently Diagnosed Diabetes and Long-term Diabetes With Survival in Pancreatic Cancer Patients : A Pooled Analysis

Objectives It is unclear whether long-standing diabetes or new-onset pancreatogenic diabetes contributes to poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Methods We investigated the influence of diabetes diagnosed shortly before PDAC and long-term diabetes on overall survival in 2792 PDAC patients who had participated in 3 PDAC case-control studies in the Pancreatic Cancer Case-Control Consortium. There were 300 patients with long-term diabetes of more than 3 years duration (11%) and 418 patients with recently diagnosed diabetes of 3-year duration or less (15%). We performed Cox regression to determine the association of long-term diabetes and recently diagnosed diabetes with overall survival, adjusting for study site, age, sex, race, stage of disease, surgery, chemotherapy, smoking history, and body mass index at diagnosis. Results In the overall population, neither long-term diabetes (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.97–1.26) nor recently diagnosed diabetes (HR, 1.06; 95% CI, 0.94–1.18) was associated with shorter survival. When stratified by stage of disease, long-term diabetes was associated with 42% increase in rate of death in persons with resectable PDAC (HR, 1.42; 95% CI, 1.13–1.78), whereas it was not associated with survival in PDAC patients with more advanced disease. Conclusion Long-term diabetes was associated with increased rate of death in patients with resectable PDAC.