Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non-small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations. METHODS: We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). RESULTS: From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/KRAS, 18 had STK11/TP53, and seven had STK11/KRAS/TP53. Patients with STK11/KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/TP53 (4.3 months; log-rank P = .043), and STK11/KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/TP53 (28.3 months; log-rank P < .001), and STK11/KRAS/TP53 (22 months; log-rank P = .025). CONCLUSION: Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.

The Severity of Herpes Zoster in Inflammatory Bowel Disease Patients Treated With Anti-TNF Agents.

Aim: There is a paucity of data on the clinical course and the factors affecting the clinical course of herpes zoster (HZ) in inflammatory bowel disease (IBD). Our aim was to determine the impact of anti-TNF therapy and other factors on the clinical course of HZ in IBD patients. Methods: We conducted a retrospective cohort study among a cohort of nation-wide Veterans Affairs patients with IBD who developed incident HZ. The exposed group consisted of eligible study patients who were actively exposed to anti-TNF alone or anti-TNF plus thiopurines at the time of HZ onset. The unexposed group consisted of patients who were only exposed to 5-ASA agents before the onset of HZ without any exposure to anti-TNF medications. The outcome of interest was the development of severe HZ that was defined by including various HZ complications. Results: A total of 295 patients were identified with an incident HZ flare during follow- up duration, and among them 69 met the definition of having a severe flare. In multivariable logistic regression analysis adjusting for sex, age at HZ flare onset, race, Charlson comorbidity score, and receipt of oral anti-HZ treatment, exposure to anti-TNF agent was not associated with an increased risk of severe HZ flare compared to exposure to mesalamine alone (adjusted relative risk (RR) 1.1, 95% confidence intervals (CI): 0.75-1.55). Among the covariates, receipt of oral anti-HZ treatment (adjusted RR 0.42, 95% CI: 0.29-0.61), advancing age at HZ onset (adjusted RR for each year increase in age 1.02, 95% CI: 1.00-1.04), and African-American race (adjusted RR with whites as reference 1.58, 95% CI: 1.02-2.44) were significantly associated with the risk of having severe HZ flare. Conclusion: Our study showed that among IBD patients who developed HZ, treatment with anti-TNF agents was not associated with increased risk of developing severe HZ as compared to patients treated with 5-ASA therapy only. 10.1093/ibd/izx115_video1izx115_Video_15786486963001.

Frequency of Surveillance and Impact of Surveillance Colonoscopies in Patients With Ulcerative Colitis Who Developed Colorectal Cancer.

BACKGROUND: The risk of developing colorectal cancer (CRC) in patients with chronic ulcerative colitis (UC) is increased. The aim of this study was to evaluate if patients who developed CRC in the setting of UC were undergoing guideline-recommended surveillance colonoscopies and to determine the impact of surveillance on the staging of CRC. PATIENTS AND METHODS: Data was obtained from the Veterans Affairs healthcare system to identify patients with UC and CRC. Stage 0 and I were considered early-stage CRC, whereas stage ≥ II were considered advanced-stage CRC. Patients were considered to have adequate surveillance if they had a colonoscopy within 2 years before developing CRC. We conducted a case-case analysis using multivariable logistic regression to estimate the odds ratio for presenting with advanced-stage CRC associated with lack of adequate surveillance. RESULTS: Of the 48 patients, the majority were white (70.8%) and male (100%). Sixty-nine percent of patients had inadequate surveillance. In multivariable analysis, prior adherence to CRC surveillance was associated with a decreased risk of presenting with advanced-stage CRC (vs. early-stage CRC) (adjusted odds ratio, 0.20; 95% confidence interval, 0.05-0.85; P = .029). CONCLUSION: The majority of patients who developed CRC in the setting of UC underwent inadequate surveillance, and they were more likely to present with advanced-stage CRC.

Efficacy of Peptide Receptor Radionuclide Therapy in a United States-Based Cohort of Metastatic Neuroendocrine Tumor Patients: Single-Institution Retrospective Analysis.

OBJECTIVES: The aim of this study was to analyze in a retrospective cohort study the outcomes of a United States-based group of metastatic neuroendocrine tumor (NET) patients who underwent peptide receptor radionuclide therapy (PRRT). METHODS: Twenty-eight patients from a single US NET Center were treated with PRRT. Toxicities were assessed using Common Terminology Criteria for Adverse Events version 4.03. Progression was determined by the Response Evaluation Criteria in Solid Tumors version 1.1. Univariate and multivariate Cox regression was performed to identify potential predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: The median age at NET diagnosis was 56 years, 50% of the patients were male, 46% of NET primaries were located in the pancreas, 71% of tumors were nonfunctional, 25% were World Health Organization (WHO) grade III, and 20% had at least a 25% hepatic tumor burden. Anemia (36%) was the most common post-PRRT toxicity, followed by leukopenia (31%), nephrotoxicity (27%), and thrombocytopenia (24%). Median PFS was 18 months, and median OS was 38 months. Having a WHO grade III NET and receiving systemic chemotherapy prior to PRRT were found to be to independent predictors of shorter PFS and OS. CONCLUSIONS: Peptide receptor radionuclide therapy is an effective therapy in a US population. Progression-free survival and OS were better in WHO grade I/II NETs and when PRRT was sequenced prior to systemic chemotherapy.

Diagnosis of pernicious anemia and the risk of pancreatic cancer.

OBJECTIVES: A number of studies have demonstrated a trophic effect of gastrin on pancreatic cancer cells in vitro. Pernicious anemia (PA) is a clinical condition characterized by chronic hypergastrinemia. The aim of this study was to determine if PA is a risk factor for pancreatic cancer. METHODS: This study is a retrospective cohort study using The Health Improvement Network database, which contains comprehensive health information on 7.5 million patients in the United Kingdom from 1993 to 2009. All patients with PA in the study cohort were identified and composed of the exposed group. Each exposed patient was matched on practice site, sex, and age with up to 4 unexposed patients without PA. The outcome was incident pancreatic cancer. The hazard ratio and 95% confidence intervals were estimated using multivariable Cox regression analysis. RESULTS: We identified 15,324 patients with PA and 55,094 unexposed patients. Mean follow-up time was similar between groups (exposed 4.31 [SD, 3.38] years, unexposed 4.63 [SD, 3.44] years). The multivariable adjusted hazard ratio for pancreatic cancer associated with PA was 1.16 (95% confidence interval, 0.77-1.76; P = 0.47). CONCLUSIONS: There is no significant association between PA and the risk of pancreatic cancer.

Angiotensin-converting enzyme inhibitor therapy and colorectal cancer risk.

BACKGROUND: Laboratory data suggest a role of angiotensin II in the pathogenesis of colorectal cancer (CRC). Whether angiotensin converting enzyme inhibitor (ACE-I) and/or angiotensin receptor blocker (ARB) use reduces the risk of colorectal neoplasia remains unclear. Given their widespread use, we sought to determine whether exposure to these agents would have a secondary benefit on CRC incidence. METHODS: A nested case-control study was conducted using EPIC's General Practice Research Database (1987-2002). The study cohort consisted of hypertensive patients. Case patients were those diagnosed with CRC after the diagnosis of hypertension. Each case patient was matched to up to 10 control subjects on age, sex, and both calendar year and duration of follow-up using incidence density sampling. The association between CRC and ACE-I/ARB exposure was assessed with conditional logistic regression. All statistical tests were two-sided. RESULTS: Two thousand eight-hundred forty-seven case patients were matched with 28239 control subjects. The adjusted odds ratios (ORs) of CRC were 0.84 (95% confidence interval [CI] = 0.72 to 0.98; P = .03) for or more years of ACE-I/ARB therapy and 0.75 (95% CI = 0.58 to 0.97; P = .03) for 5 or more years of exposure. The strength of this association increased with high-dose exposure (OR = 0.53; 95% CI = 0.35 to 0.79; P = .003 for ≥3 years of high-dose exposure). Among patients receiving antihypertensive medications, the association with long-term therapy was no longer statistically significant for ≥5 years), but the benefit of high-dose therapy remained (OR = 0.59; 95% CI = 0.39 to 0.89; P = .01 for ≥3 years of high-dose exposure). CONCLUSIONS: Long-term/high dose exposure to ACE-Is/ARBs may be associated with a decreased incidence of CRC.

Metformin and survival in pancreatic cancer: a retrospective cohort study.

OBJECTIVES: Our aim was to determine the effect of metformin exposure on survival in patients with advanced pancreatic adenocarcinoma (PAC). METHODS: A retrospective cohort study was conducted using The Health Improvement Network, a primary care electronic medical record database from the United Kingdom (2003-2010). The study cohort included all subjects with a diagnostic code for incident PAC and a preexisting diagnosis of type 2 diabetes mellitus. Subjects were classified as exposed if they were prescribed metformin around the time of PAC diagnosis (between 6 months prior and 1 month after). A secondary analysis was performed only on exposed subjects without prior (ie, 6 months before PAC diagnosis) exposure to metformin. The primary outcome was overall survival. The analysis was performed using univariate and multivariable Cox proportional hazards models. RESULTS: The study included 516 subjects with preexisting type 2 diabetes mellitus and PAC, 247 of which were exposed to metformin. In univariate and multivariable analysis, there was no difference in survival between those exposed and those unexposed to metformin in the primary analysis (hazards ratio, 1.11 [0.89-1.38], P = 0.367) or the secondary analysis (hazards ratio, 1.09 [0.80-1.47], P = 0.585). CONCLUSIONS: Metformin use is not associated with improved survival in subjects with advanced PAC.