American Society of Anesthesiologists class and Charlson's comorbidity index as predictors of postoperative colorectal anastomotic leak: a single-institution experience.

BACKGROUND: The American Society of Anesthesiologists (ASA) physical status classification and Charlson comorbidity index (CCI) was adopted to assess patients' physical condition before surgery. Studies suggest that ASA score and CCI might be a prognostic criterion (indicator) for patient outcome. The aim of this study is to determine if ASA classification and CCI can determine the risk of anastomotic leaks (AL) in patients who underwent colorectal surgery. METHODS: A retrospective analysis of 505 consecutive colorectal resections with primary anastomoses between 2008 and 2012 was performed at a university hospital. ASA score, CCI, surgical procedure, length of stay, age, body mass index (BMI), comorbidities, and postoperative outcomes were analyzed. RESULTS: Two hundred sixty-five patients had an ASA score of I and II, 227 patients had an ASA score of III, and 13 patients had an ASA score of IV. A total of 19 patients had an anastomotic leak (ASA I-II: 5 patients, 1.9%; ASA III: 12 patients, 5.58%; ASA IV: 2 patients, 18.18%). A higher ASA score was significantly associated with AL on further analysis (OR: 2.99, 95% CI: 1.345-6.670, P = 0.007). When matched for age, BMI, and CCI on logistic regression analysis, increased ASA level was independently related to an increased likelihood of leak (OR(steroids) = 14.35, P < 0.01; OR(ASA_III v I-II) = 2.02, P = 0.18; OR(ASA_IVvI-II) = 8.45, P = 0.03). There were no statistically significant differences in means between the leak and no-leak patients with respect to age (60.69 versus 65.43, P = 0.17), BMI (28.03 versus 28.96, P = 0.46), and CCI (6.19 versus 7.58, P = 0.09). CONCLUSIONS: ASA score, but not CCI, is independently associated with anastomotic leak. Patients with a high ASA class should be closely followed postoperatively for AL after colorectal operations.

Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair (DDR) system in PDA cells has generated encouraging results. Ubiquitin-specific peptidase 11 (USP11), an enzyme that interacts with the DDR protein BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. A systematic high-throughput approach was used to biochemically screen 2,000 U.S. Food and Drug Administration (FDA)-approved compounds for inhibition of USP11 enzymatic activity. Six pharmacologically active small molecules that inhibit USP11 enzymatic activity were identified. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, impacted PDA cell survival with an IC50 of less than 10 nM. Importantly, across six different PDA cell lines, two with defects in the Fanconi anemia/BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40- to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. Interestingly, USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a preclinical model for the rapid discovery of FDA-approved compounds and identify USP11 as a target of mitoxantrone in PDA. IMPLICATIONS: This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA.

Technical skills acquisition in surgery-bound senior medical students: an evaluation of student assertiveness.

OBJECTIVE: To prepare students pursuing surgical careers, we devised a senior subinternship curriculum supplement that focused on the acquisition of technical skills required of surgical residents. We hypothesized that more assertive students, those that accomplished more of the curriculum, would perform better on a technical skills Objective Structured Clinical Examination (OSCE). DESIGN: Senior medical students rotating on their first general surgery subinternship were administered a 6-station OSCE on the first day of their subinternship and again during the final week of the month-long rotation. A self-directed, 38-task "scavenger hunt" representing common intern level clinical skills, procedures, and patient care activities was provided to each student. SETTING: The study was performed at Jefferson Medical College, a large, private medical school in Philadelphia, PA. PARTICIPANTS: Forty-nine senior students completed surgical subinternships between July 2009 and September 2010, and participated both in the pre-/post-OSCEs and the scavenger hunt. RESULTS: Students performed significantly better on the post-rotation OSCE than on the pre-rotation OSCE; 70.2% ± 8.1% vs. 60.4% ± 12.0%, p < 0.0001. Assertiveness scores from the "scavenger hunt" did not correlate with final OSCE scores (r = -0.328, p = 0.25), and were negatively correlated with the change between pre- and post-OSCE scores (r = -0.573, p < 0.04). Individual student assertiveness scores were determined by the number of tasks completed over the course of the rotation. CONCLUSIONS: As surgical education becomes more streamlined with evolving work hour restrictions, medical school education is playing an increasingly pivotal role in preparing students for internship. In our study, individual assertiveness in completing structured self-directed learning tasks did not directly predict the acquisition of proficiency in technical skills. We feel assertiveness is overshadowed by other factors that may carry more weight in terms of technical skills acquisition. Further studies are required to delineate these factors and ultimately enhance technical skills acquisition during medical school.

Molecular profiling of synchronous and metachronous cancers of the pancreas reveal molecular mimicry between samples from the same patient.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is rarely a survivable disease. In rare cases, separate synchronous tumors are discovered at the time of resection, while in others, patients present with a metachronous cancer after prior surgical resection. Studying molecular markers of synchronous and metachronous lesions may aid to clarify the biology of this often deadly disease. METHODS: Two patients presented with synchronous tumors (each one with a tumor in the pancreatic head/neck and the other in the tail, designated patients A and B). An additional patient (patient C) underwent an R0 resection for PDA of the head and recurred 1.5 y later with PDA in the tail. Genomic DNA was laser capture microdissected (LCM) from the tumor and molecular analysis was performed. K-ras status and loss of heterozygosity (LOH) were determined from multiple specimens for each case. RESULTS: All samples from each patient harbored identical K-ras mutations. In patient A, the tumor at the head of the pancreas had more clonal genetic instability as reflected by LOH analysis over multiple LCM samples. Patient B had more genetic instability in the tail lesion compared with the neck. Patient C had virtually the identical molecular profile in both tumors, supporting the notion that both tumors were related. CONCLUSION: We conclude that the synchronous and metachronous tumors likely are initiated from identical precursor lesions and/or events (i.e., K-ras mutations). Future studies will need to investigate if these tumors will respond similarly to adjuvant therapies targeted against the clonal molecular events in the tumor.

Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature.

BACKGROUND: Cystic fibrosis (CF) is the most commonly inherited lethal autosomal recessive genetic disease amongst Caucasians. CF results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with homozygous or compound heterozygous CFTR mutations have a risk of pancreatitis, but typically do not live long enough to develop pancreatic ductal adenocarcinoma (PDA), a disease that has an average age at diagnosis of 65 years. Little is known about the risk of the development of PDA in people who are heterozygous for mutations in the CFTR gene. PATIENTS AND METHODS: We report a case of a patient with PDA who underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. The patient is of Ashkenazi Jewish ethnicity and has a family history of CF, but no family history of PDA. We reviewed the English language literature for the prevalence of PDA in CF patients (and CFTR mutations in the setting of PDA) and their significance in terms of screening, and the use of this mutation as a biomarker for an increased risk of the development of PDA. CONCLUSION: We conclude that patients with CFTR mutations, who also have other risks for the development of PDA such as a family history of the disease, should undergo screening and be educated about their risks.