Citations

SummaryBackgroundUp to 80% of patients with Crohn's disease require an abdominal operation in their lifetime. As the use of vedolizumab is increasing for the treatment of Crohn's disease, it is important to understand its potential association with post‐operative complications.AimWe sought to compare 30‐day postoperative infectious complication rate among vedolizumab‐treated Crohn's disease patients vs those who had received TNFα inhibitors or no biologic therapy.MethodsA retrospective review of all Crohn's disease patients who received vedolizumab within 12 weeks of a major abdominal or pelvic operation was performed. Two control cohorts consisted of Crohn's disease patients treated with TNFα inhibitors or no biologic therapy.ResultsOne hundred Crohn's disease patients received vedolizumab within 12 weeks of an abdominal operation. Vedolizumab‐treated patients underwent an equivalent rate of laparoscopic surgery (P = .25), had fewer anastomoses performed (P = .0002), and had equally frequent diversion in the setting of anastomoses (P = .47). Thirty‐two vedolizumab‐treated patients experienced postoperative infectious complications (32%), 26 of which were surgical site infections (26%). The vedolizumab‐treated group experienced no difference in nonsurgical site infections (6% vs 5% anti‐TNFα and 2% nonbiologic; P = .34), but significantly higher rates of surgical site infections (26% vs 8% and 11%; P < .001). On univariate and multivariate analysis, exposure to vedolizumab remained a significant predictor of postoperative surgical site infection (P < .001 and P = .002).ConclusionsTwenty‐six per cent of Crohn's disease patients who received vedolizumab within 12 weeks prior to a major abdominal operation experienced a 30‐day postoperative surgical site infection, significantly higher than that of patients receiving TNFα inhibitors or no biologic therapy. Vedolizumab within 12 weeks of surgery remained a predictor of 30‐day postoperative surgical site infection on multivariable analysis. While vedolizumab‐treated Crohn's disease patients may be a sicker cohort of patients, it is important to consider these findings with regard to preoperative counselling, operative timing and primary closure of wounds.

Abstract Aims: Androgen-targeted therapies (ATTs) are the mainstay treatment for metastatic prostate cancer (PCa). However, ATTs promote adaptation of tumour cells and lead to castration resistant disease (CRPC). We have recently identified the cell surface receptor, Neuropilin-1 (NRP1) as increased during EMT and in CRPC. However, the role of NRP1 in the prostate epithelium is poorly understood. This study aims to determine whether the inhibition of NRP1 will be a feasible therapeutic strategy for blocking PCa metastasis and therapy resistance. Methods: qPCR and western blotting were used to assess NRP1 expression in PCa cell lines. NRP1 expression in CRPC was assessed using a murine LNCaP xenograft model of castration. NRP1 was knocked down with shRNA sequences from the pLKO.1 lentiviral construct. For metastasis assays, PC3 cells were microinjected into the zebrafish yolk sac and metastatic dissemination imaged 5 days later. NRP1 expression in radical prostatectomy (RP) samples from Mayo Clinic (545 patients) and Johns Hopkins Medical Institutions (JHMI; 188 patients) cohorts was quantified by Affymetrix exon arrays and multivariable analysis performed. Wound scratch migration and invasion assays were performed with the WoundMaker™ tool and IncuCyte™ FLR imaging systems. Results: NRP1 levels were elevated in humanCRPC xenografts, metastatic and castrate resistant clinical PCa samples (p &lt;0.0001), and PCa cell lines. NRP1 suppression significantly reduced metastasis of human xenografts in zebrafish and the migratory and invasive behaviour of metastatic PCa cells (p=0.0002). Multivariable analysis identified NRP1 as a significant independent prognostic indicator of metastasis and prostate cancer specific mortality in two large clinical cohorts (Mayo Clinic and JHMI; p=0.008/0.048 and 0.013/0,034 respectively). We show that NRP1 knockdown promotes E-Cadherin expression and loss of vimentin in mesenchymal PCa cells. Conclusion: These results will provide the preclinical data necessary to rationalise the use of anti-NRP1 directed adjuvant therapies for clinical use in PCa patients receiving ATTs, and will pave the way for larger scale preclinical and clinical trials in the PCa setting. Citation Format: Marianna Volpert, Brian Tse, Ellca Ratther, Nataly Stylianou, Mannan Nouri, Melanie Lehman, Stephen McPherson, Mani Roshan-Moniri, Mandeep Takhar, Nicholas Erho, Mohamed Alshalafa, Elai Davicioni, Robert Jenkins, Ashley Ross, Jeffrey Karnes, Robert Den, Ladan Fazli, Martin Gleave, Elizabeth Williams, Paul Rennie, Ralph Buttyan, Pamela Russell, Colleen Nelson, Brett Hollier. Neuropilin-1 is up-regulated in the adaptive response of prostate tumors to androgen targeted therapies and is prognostic of metastatic progression and patient mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4908. doi:10.1158/1538-7445.AM2017-4908

Background: Physicians’ lack of comfort and skill in communicating about hospice care results in deficits and delays in hospice referrals. Preclinical exposure to hospice may lay a foundation to improve medical students’ knowledge and comfort with hospice care. Objective: To understand how preclinical medical student (MS)-2s respond both educationally and emotionally to a required hospice care experience (HCE). Design: Accompanied by hospice clinicians, MS-2s spent 3 hours seeing inpatient or home hospice patients followed by a 1-hour debriefing. Students submitted written reflections to e-mailed educational and emotional prompts. Setting/patients: Two hundred and two MS-2s from 2 academic cohorts completed the HCE at 1 of 2 hospice sites. Measurements: Written reflective responses were analyzed qualitatively, where salient themes extracted and responses were coded. Results: Ninety-two students submitted 175 responses to Prompt #1 (educational impact) and 85 students entered 85 responses to prompt #2 (emotional impact) of the HCE. Eleven themes were identified for prompt #1, most frequently focusing on hospice services and goals and hospice providers’ attitudes and skills. Prompt #2 elicited a diverse spectrum of emotional responses, spanning positive and negative emotions. Most often, students reported “no specified emotional reaction,” “sad/depressed,” “difficult /challenging,” “heartened/encouraged,” and “mixed emotions.” Conclusion: In an HCE, preclinical students reported learning core aspects of hospice care and experiencing a broad spectrum of emotional responses. These findings may assist educators in the planning of HCEs for preclinical students, including debriefing sessions with skilled clinicians and opportunities for triggered reflection.

ObjectiveTo study the relationship between serum hydroxychloroquine (HCQ) concentrations and flares of systemic lupus erythematosus (SLE) in a longitudinal cohort of patients.MethodsPatients who fulfilled ≥4 American College of Rheumatology classification criteria for SLE and had been treated with HCQ for >6 months were studied. Blood was assayed for HCQ levels by tandem mass spectrometry. Patients were serially assessed for disease activity, using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and flares (SELENA flares instrument). Comparison of the mean summated SLEDAI scores over time and rates of flares in groups with different HCQ levels was performed by the Kruskal‐Wallis test.ResultsA total of 276 SLE patients were studied (93% women, mean ± SD age 41.0 ± 13.8 years). The proportion of patients with HCQ levels <10 (total noncompliance), 10–500 (subtherapeutic), and >500 ng/ml (therapeutic) was 11%, 77%, and 12%, respectively. HCQ levels correlated significantly with the prescribed dose but not with body weight or renal function. The prescribed HCQ dose also correlated significantly with baseline SLEDAI scores, indicating that higher doses were used for more active manifestations. After a mean ± SD observation period of 32.5 ± 5.5 months, the mean summated SLEDAI score and the incidence of SLE flares was not statistically different among patients with different baseline HCQ levels. In a subgroup of 73 patients with serologic and clinical remission and having therapeutic HCQ levels, a trend of lower disease activity and fewer incidences of flares was observed.ConclusionNoncompliance and subtherapeutic serum HCQ levels were seen frequently in these SLE patients, which was partly due to the low prescribed dose. In patients in remission, higher HCQ concentrations were associated with a trend showing fewer flares over time.

ABSTRACT Among 177 carbapenemase-producing Gram-negative bacilli (108 KPC, 32 NDM, 11 IMP, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 4 VIM, and 3 SME producers), aztreonam-avibactam was active against all isolates except two NDM producers with elevated MICs of 8/4 and 16/4 mg/liter; ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%) but not metallo-β-lactamase producers. Among older and contemporary antimicrobials, the most active were colistin, tigecycline, and fosfomycin, with overall susceptibilities of 88%, 79%, and 78%, respectively.

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. Some epidemiologic data have indicated differences in DLBCL incidence rates and subtype distributions between Eastern Asian and Western countries. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. In order to evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 × 10-10). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 × 10-6), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009). Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations. Citation Format: Nathaniel Rothman, Bryan A. Bassig, James R. Cerhan, Wing-Yan Au, Hee Nam Kim, Suleeporn Sangrajrang, Wei Hu, Jovic Tse, Sonja Berndt, Tongzhang Zheng, Heping Zhang, Pattarapong Pornsopone, Je-Jung Lee, Hyeoung-Joon Kim, Christine F. Skibola, Joseph Vijai, Laurie Burdette, Meredith Yeager, Paul Brennan, Min-Ho Shin, Raymond Liang, Stephen Chanock, Qing Lan. Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations. [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 4626. doi:10.1158/1538-7445.AM2015-4626

Context and Objective:Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management.Design and Patients:Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line, and five Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene.Results:Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors.Conclusion:Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of MEN1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis, and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.

AbstractObjectivesDiffuse large B‐cell lymphoma (DLBCL) is an aggressive subtype of non‐Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large‐scale genome‐wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome‐wide significance, and two SNPs that showed a suggestive association with DLBCL risk.MethodsTo evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand.ResultsThree of the five genome‐wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome‐wide significance in our data (per allele OR = 2.04, 95% CI = 1.63–2.56; ptrend = 3.9 × 10−10). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19–1.52; ptrend = 2.1 × 10−6), which was the second strongest finding in the GWAS, and with HLA‐B rs2523607 (per allele OR = 3.05, 95% CI = 1.32–7.05; ptrend = 0.009).ConclusionsOur study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations.