What Happens After Discharge? A 2+ Year Follow-Up After Laparoscopic Subtotal Fenestrating and Reconstituting Cholecystectomy.

Laparoscopic subtotal cholecystectomy (LSC) is utilized to prevent complications in the difficult cholecystectomy. Medium-term outcomes are poorly studied for fenestrating and reconstituting operative techniques. A single-institution retrospective review was undertaken of all LSCs. A telephone survey was used to identify complications addressed at other institutions. We performed subgroup analyses by operative approach and of patients requiring postoperative endoscopic intervention (ERC). 28 patients met inclusion criteria. The median follow-up was 32.7 months. There were no bile duct injuries or reoperations. 21% of patients required a postoperative ERC and 50% were discharged home with a drain. Bile leaks were found to be more prevalent in the fenestrating LSC group (38% vs 0%, P = .003). The case series suggested more severe recurrent biliary disease in patients undergoing reconstituting LSC. Laparoscopic subtotal cholecystectomy appears to have satisfactory medium-term outcomes. The reconstituting LSC group trends toward more severe recurrent disease which warrants further investigation.

Joseph Murray: Pioneering Plastic Surgeon and Father of the First Organ Transplant.

Dr. Joseph Murray was a plastic surgeon who is best known for performing the first successful human organ transplant. After graduating from Harvard Medical School and completing a surgical internship at Peter Bent Brigham Hospital, Murray enlisted in the US Army Medical Corp and spent 5 years at Valley Forge General Hospital treating World War II soldiers injured in combat. He treated hundreds of burn victims with skin grafts and took an interest in the variable process of graft rejection based on both the patient's relation to the graft donor and the patient's level of immunocompetency. His work at Valley Forge set the stage for his research investigating the feasibility of kidney transplantation and immunosuppression. He went on to perform the first successful kidney transplant between identical twins in 1954, between fraternal twins in 1959, and between an unrelated donor and recipient in 1962. For his efforts, he was awarded the 1990 Nobel Prize in Medicine.

Warren B. Davis and the Birth of Plastic Surgery in Philadelphia: A Historical Vignette.

The field of plastic surgery, formally organized in 1931 with the founding of the American Society of Plastic and Reconstructive Surgery, was shaped in many ways by a small practice of Philadelphia physicians. At the center of the practice was Warren B. Davis, a Philadelphia otolaryngologist and plastics pioneer whose innovations in cleft palate surgery would lead to significant improvements in functional and cosmetic outcomes in his time. In addition to his own innovations, Davis was responsible for the training of John Reese, the inventor of the Reese dermatome that changed the face of burn medicine during World War II. Aside from his contributions to surgery and the founding of the American Society of Plastic and Reconstructive Surgery, Dr. Davis was also the founder and first editor of the Plastic and Reconstructive Surgery journal which to this day is the premiere, authoritative journal of plastic surgery. Lastly, Dr. Davis established a plastic surgical practice, now Jefferson Plastic Surgery. Unique in its longevity, this practice would continue to shape the field of plastic surgery and continues to improve lives today-109 years after its founding in 1913.

Implementation of a Structured Surgery Mentorship Program and Success in the Surgical Residency Match.

INTRODUCTION: General Surgery residency programs remain competitive, with over a quarter of US MD seniors failing to match into a categorical program each year. While previous literature has shown the role of mentorship in attracting medical students to surgery, there is a dearth of information demonstrating the role of mentorship in successfully matching those students to surgery programs. METHODS: We implemented a structured mentorship program for medical students interested in applying to general surgery or integrated plastics, vascular, or cardiothoracic residencies over the course of one year, consisting of seven standardized meetings and events spanning the students' MS3 and MS4 years. Following Match Day, we sent students a five-point Likert scale survey to assess the perceived utility of each event and solicited self-reported application information. RESULTS: Of the 22 students at a single institution who attended the structured mentorship program and applied to general surgery residency, 100% matched into a categorical program, significantly higher than the 73% national match rate of US MD seniors into general surgery (P < 0.01). There were no significant differences between the two cohorts in terms of United States Medical Licensing Examination board scores, Alpha Omega Alpha Honor Society status, or median number of publications, research experiences, work experiences, or volunteer experiences. Nineteen of the 22 students responded to the survey, yielding an 86% response rate. Ninety percent of the students attended at least six out of the seven events. Six out of the seven events had median helpfulness scores (out of five) that were significantly higher than a "neutral" baseline (P < 0.05). CONCLUSIONS: A structured mentorship program may play a useful role in successfully matching general surgery applicants to residencies and would be a simple and low-cost program to implement at other medical schools.

What We Owe the World Wars: Challenges That Fueled Surgical Innovation.

War has the unique ability to intensify obstacles that surgeons face daily in civilian hospitals. After a brief overview of the historical context of the first and second world wars, this article will focus on how those daily challenges, namely limited skill, bleeding, and infection, led to an era of surgical innovation and standardization of surgical education.

Evolving application of minimally invasive cancer operations at a tertiary cancer center.

BACKGROUND: Patients and providers are increasingly interested in the utilization, safety, and efficacy of minimally invasive surgery (MIS). We reviewed 11 years of MIS resections (laparoscopic and robotic) for intra-abdominal malignancies. METHODS: Patients who underwent gastrectomy, distal pancreatectomy, hepatic resection, and colorectal resection between 2004 and 2014 were identified. Cases were categorized as open, laparoscopic, and robotic based on the initial operation approach. Diagnostic laparoscopies were excluded. RESULTS: Of the 10 039 patients who underwent the above procedures, between 2004 and 2014, 2832 (28%) were MIS. In 2004, 12% (100/826) of all resections were performed with MIS approaches, rising to 23% (192/821) of all resections by 2009 and 44% (484/1092) in 2014. The number of open resections has remained largely stable: 726 (88% of all resections) in 2004 and 608 (56% of all resections) in 2014. Initially, laparoscopy experienced incremental adoption. Robotic surgery was implemented in 2009 and is currently the dominant MIS approach, accounting for 76% (368/484) of all MIS resections in 2014. Overall mortality has remained less than 1%. CONCLUSIONS: While maintaining patient safety, utilization of MIS techniques has increased substantially since 2004, particularly for gastric and colorectal resections. Since 2009 robotic surgery is the predominant MIS approach.

MUC1 Promoter-Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer.

UNLABELLED: Mucin1 (MUC1) is overexpressed in pancreatic ductal adenocarcinoma (PDA) and is associated with tumor aggressiveness, suggesting that MUC1 is a promising therapeutic target for promoter-driven diphtheria toxin A (DTA). Endogenous MUC1 transcript levels were analyzed by quantitative PCR (qPCR) in multiple PDA cells (Capan1, HPAFII, Su.86.86, Capan2, Hs766T, MiaPaCa2, and Panc1). Expression levels were correlated with luciferase activity and cell death after transfection with MUC1 promoter-driven luciferase and DTA constructs. MUC1-positive (+) cells had significantly elevated MUC1 mRNA expression compared with MUC1-negative (-) cells. Luciferase activity was significantly higher in MUC1(+) cells when transfected with MUC1 promoter-driven luciferase and MUC1(+) cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter-driven DTA. IFNγ pretreatment enhanced MUC1 expression in MUC1(-) cells and induced sensitivity to MUC1-DTA therapy. Matched primary and metastatic tumor lesions from clinical specimens revealed similar MUC1 IHC labeling patterns, and a tissue microarray of human PDA biopsies revealed increased immunolabeling with a combination of MUC1 and mesothelin (MSLN) antibodies, compared with either antibody alone. Combining MUC1 with MSLN-targeted DTA enhanced drug efficacy in an in vitro model of heterogeneous PDA. These data demonstrate that MUC1 promoter-driven DTA preferentially kills MUC1-expressing PDA cells and drugs that enhance MUC1 expression sensitize PDA cells with low MUC1 expression. IMPLICATIONS: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter-driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs.

Incidence and severity of pancreatogenic diabetes after pancreatic resection.

BACKGROUND: While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized. METHODS: One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered. RESULTS: Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (p = 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM. CONCLUSIONS: The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM.

Grit: a marker of residents at risk for attrition?

BACKGROUND: Attrition from general surgery residency remains constant at approximately 20% despite nearly a decade of work-hour reform and studies aiming to identify common risk factors. High rates of attrition from training have a wide impact, from the overall quality of trainees produced to implications on public health and the broader surgical work force. We set out to evaluate a novel character trait, grit, defined as passion and perseverance for long-term goals, as a marker and potential risk factor for resident attrition. METHODS: Twelve Accreditation Council for Graduate Medical Education-approved general surgery residency programs participated in a prospective, multi-institutional, survey-based analysis of grit and attrition during the 2012-2013 academic year. Participating individuals were blinded with regards to the primary outcome of the study. Participating institutions were blinded to the responses of their trainees. Participating residency programs were located in a variety of settings, from university-based health systems to community hospitals. RESULTS: Sixty-eight percent (68%) of residents (180 of 265) at participating institutions completed the study. The primary end point for this study was attrition from residency as a function of grit. Secondary end points included an evaluation of the utility of the grit score in surgical residents, variability of grit according to postgraduate year, sex, measurements of resident satisfaction with current program, lifestyle, and career goals. Finally, the study included an analysis of key resident support strategies. The attrition rate across 12 institutions surveyed was approximately 2% (5 residents). Of those five, three participated in our study. All three had below-median levels of grit. Those residents with below-median grit were more likely to contemplate leaving surgical residency. Given the low attrition rate, no variable surveyed reached statistical significance in our analysis. Key support strategies for residents responding included family, friends outside of residency, co-residents, and formal mentorship through their particular residency. CONCLUSION: In this preliminary underpowered study, grit appears to be a promising marker and risk factor for attrition from surgical residency. In an effort to retain residents, programs should consider screening for grit in current residents and directing support to those residents with below-median values, with a focus on building family, friend, and formal mentor relationships.

Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer.

PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.

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.