Harmsen, William S.

Abstract Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906–14. ©2016 AACR.

Purpose To describe outcomes of salvage radiotherapy (SRT) for men with detectable prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer and identify associations with outcomes. Patients and Methods A total of 1,106 patients received SRT between January 1987 and July 2013, with median follow-up 8.9 years. Outcomes were estimated using Kaplan-Meier for overall survival (OS) and cumulative incidence for biochemical recurrence (BcR), distant metastases (DM), and cause-specific mortality (CSM). Variable associations with outcomes used Cox or Fine-Gray methods, as appropriate. Multiple variable analyses used backward selection with P < .05 for retention. Results In multiple variable analyses, pathologic tumor stage, Gleason score, and pre-SRT PSA were associated with BcR, DM, CSM, and OS; androgen suppression and SRT doses > 68 Gy were associated with BcR; and age was associated with OS. Each pre-SRT PSA doubling increased significantly the relative risk of BcR (hazard ratio [HR], 1.30; P < .001), DM (HR, 1.32; P < .001), CSM (HR, 1.40; P < .001), and all-cause mortality (HR, 1.12; P = .02). Using a pre-SRT PSA cutoff ≤ 0.5 versus > 0.5 ng/mL, 5-year and 10-year cumulative incidences for BcR were 42% versus 56% and 60% versus 68% ( P < .001), DM 7% versus 14% and 13% versus 25% ( P < .001), CSM 1% versus 4% and 6% versus 13% ( P < .001), and OS of 94% versus 92% and 83% versus 73% ( P > .05). Conclusion SRT outcomes are in part affected by factors associated with prostatectomy findings but may be positively affected by using SRT at lower PSA levels, including reductions in BcR, DM, CSM, and all-cause mortality. These findings argue against prolonged monitoring of detectable postprostatectomy PSA levels that delay initiation of SRT.

Whether aspirin use is protective against cholangiocarcinoma (CCA) remains unclear. We determined the association between aspirin use and other risk factors for each CCA subtype individually. In a hospital‐based case‐control study, 2395 CCA cases (1169 intrahepatic, 995 perihilar, and 231 distal) seen at the Mayo Clinic, Rochester, MN, from 2000 through 2014 were enrolled. Controls selected from the Mayo Clinic Biobank were matched two to one with cases by age, sex, race, and residence (n = 4769). Associations between aspirin use, other risk factors, and CCA risk were determined. Aspirin was used by 591 (24.7%) CCA cases and 2129 (44.6%) controls. There was a significant inverse association of aspirin use with all CCA subtypes, with adjusted odds ratios (AORs) of 0.35 (95% confidence interval [CI], 0.29‐0.42), 0.34 (95% CI 0.27‐0.42), and 0.29 (95% CI 0.19‐0.44) for intrahepatic, perihilar, and distal CCA, respectively (P < 0.001 for all). Primary sclerosing cholangitis was more strongly associated with perihilar (AOR = 453, 95% CI 104‐999) than intrahepatic (AOR = 93.4, 95% CI 27.1‐322) or distal (AOR = 34.0, 95% CI 3.6‐323) CCA, whereas diabetes was more associated with distal (AOR = 4.2, 95% CI 2.5‐7.0) than perihilar (AOR = 2.9, 95% CI 2.2‐3.8) or intrahepatic (AOR = 2.5, 95% CI 2.0‐3.2) CCA. Cirrhosis not related to primary sclerosing cholangitis was associated with both intrahepatic and perihilar CCA, with similar AORs of 14. Isolated inflammatory bowel disease without primary sclerosing cholangitis was not associated with any CCA subtype. Conclusions: Aspirin use was significantly associated with a 2.7‐fold to 3.6‐fold decreased risk for the three CCA subtypes; our study demonstrates that individual risk factors confer risk of different CCA subtypes to different extents. (Hepatology 2016;64:785‐796)

AbstractBackgroundFactors predicting locoregional relapse after surgery for oropharyngeal squamous cell carcinoma (SCC) were identified in the pre‐human papillomavirus (HPV) era. We examined whether traditional indications for adjuvant radiotherapy (RT) or adjuvant chemoradiotherapy (CRT) still correlate with locoregional relapse in HPV‐positive patients after transoral robotic surgery (TORS).MethodsRetrospective review of oropharyngeal SCC cases identified patients with HPV‐positive tumors who did not receive adjuvant therapy after TORS despite intermediate or high‐risk features.ResultsMedian follow‐up was 26.7 months (range, 4.9–73.1 months). Five of 25 eligible patients (20%) relapsed at a median 4.8 months (range, 3.2–7.8 months). Two of 18 (11%) intermediate and 3 of 7 (43%) high‐risk patients relapsed. Kaplan–Meier 2‐year locoregional relapse‐free survival estimates for intermediate and high‐risk patients were 88% and 57% (p = .078), respectively.ConclusionTraditional indications for adjuvant RT or CRT were associated with high risk of locoregional relapse in HPV‐positive patients treated with TORS alone. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1674–E1679, 2016

AbstractGenetic risk factors for cholangiocarcinoma (CCA) remain poorly understood. We assessed the effect of single‐nucleotide polymorphisms (SNPs) of genes modulating inflammation or carcinogenesis on CCA risk and survival. We conducted a case‐control, candidate gene association study of 370 CCA patients and 740 age‐, sex‐, and residential area‐matched healthy controls. Eighteen functional or putatively functional SNPs in nine genes were genotyped. The log‐additive genotype effects of SNPs on CCA risk and survival were determined using logistic regression and the log‐rank test, respectively. Initial analysis identified significant associations between SNP rs2143417 and rs689466 in cyclooxygenase 2 (COX‐2) and CCA risk, after adjusting for multiple comparisons (cutoff of P = 0.0028). However, these findings were not replicated in another independent cohort of 212 CCA cases and 424 matched controls. No significant association was found between any SNP and survival of CCA patients. Although COX‐2 has been shown to contribute to cholangiocarcinogenesis, the COX‐2 SNPs tested were not associated with risk of CCA. This study shows a lack of association between variants of genes related to inflammation and carcinogenesis and CCA risk and survival. Other factors than these genetic variants may play more important roles in CCA risk and survival.

Abstract Background. The purpose of this study was to determine the risk of prosthetic joint infection (PJI) as a complication of routine genitourinary (GU) procedures in patients with total hip arthroplasty (THA) or total knee arthroplasty (TKA) and to study the impact of antibiotic prophylaxis administered prior to these procedures. Methods. We conducted a prospective, single-center, case-control study between December 1, 2001 and May 31, 2006. Case patients were hospitalized with total hip or knee PJI. Control subjects underwent a THA or TKA and were hospitalized during the same period on the same orthopedic floor without a PJI. Data regarding demographic features and potential risk factors were collected. The outcome measure was the odds ratio (OR) of PJI after GU procedures performed within 2 years of admission. Results. A total of 339 case patients and 339 control subjects were enrolled in the study. Of these, 52 cases (15%) and 55 controls (16%) had undergone a GU procedure in the preceding 2 years. There was no increased risk of PJI for patients undergoing a GU procedure with or without antibiotic prophylaxis (adjusted OR [aOR] = 1.0, 95% confidence interval [CI] = 0.2–4.5, P = .95 and aOR = 1.0, 95% CI = 0.6–1.7, P = .99, respectively). Results were similar in a subset of patients with a joint age less than 6 months, less than 1 year, or greater than 1 year. Conclusions. Genitourinary procedures were not risk factors for subsequent PJI. The use of antibiotic prophylaxis before GU procedures did not decrease the risk of subsequent PJI in our study.