Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements.

The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.

Multi-disciplinary assessment of the entrustable professional activities of surgery residents.

Purpose: Medicine is practiced in a collaborative and interdisciplinary manner. However, medical training and assessment remain largely isolated in traditional departmental silos. Two Entrustable Professional Activities (EPAs) developed by the American Board of Surgery are multidisciplinary in nature and offer a unique opportunity to study interdisciplinary assessment. Methods: EPA microassessments were collected from Surgery and Emergency Medicine (EM) faculty between July 2018 and May 2020. Differences in feedback provided by faculty were assessed using natural language processing (NLP) techniques, (1) automated algorithms; and (2) topic modeling. Summative content analysis was used to identify themes in text feedback. We developed automated coding algorithms for these themes using regular expressions. Topic modeling was performed using latent Dirichlet allocation. Results: 549 assessments were collected for two EPAs: 198 for GS Consultation and 351 for Trauma. 27 EM and 27 Surgery faculty provided assessments for 71 residents. EM faculty were significantly more likely than Surgery faculty to submit feedback coded as Communication, Demeanor, and Timeliness, (all chi-square test p-values < 0.01). No significant differences were found for Clinical Performance, Skill Level, or Areas for Improvement. Similarly, topic modeling indicated that assessments submitted by EM faculty focused on communication, timeliness, and interpersonal skills, while those submitted by Surgery faculty focused on the residents' abilities to effectively gather information and correctly diagnose the underlying pathology. Conclusions: Feedback from EM and Surgery faculty differed significantly based on NLP analyses. EPA assessments should stem from multiple sources to avoid assessment gaps and represent a more holistic picture of performance.

Considering immunomodulatory therapies in the septic patient: should apoptosis be a potential therapeutic target?

Treatment of sepsis and septic shock remains a clinical conundrum. Recent prospective trials with anti-cytokine and anti-inflammatory therapies have shown only modest clinical benefit. The successful treatment of the patient with sepsis syndrome will likely require multi-modal therapies aimed at several of the immunological and physiological disturbances which are occurring simultaneously. Recent studies in experimental animals and critically ill patients have suggested that increased apoptosis of lymphoid organs and some parenchymal tissues may contribute to the immune suppression, anergy and organ system dysfunction. Therapies aimed at inhibiting lymphoid cell apoptosis may contribute to improved outcome, and should be considered in the treatment of hospitalized patients with sepsis syndromes. Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis may be an appropriate therapeutic target for the septic patient.

Application of gene therapy to acute inflammatory diseases.

The application of gene therapy to acute inflammation has not received as much research attention as has the treatment of genetically-based diseases, cancer, and viral infections. However, gene therapy as a drug delivery system offers several theoretical and practical advantages over current protein delivery systems. These include the ability to target therapies to individual tissues or cell types, to locally produce proteins that can act intracellularly or in an autocrine, juxtacrine, or paracrine fashion, and to sustain new protein synthesis for periods up to several weeks after a single administration. Although retrovirus, herpes simplex, and adeno-associated virus have been proposed for gene therapy in cancer and in genetic diseases, nonviral and adenovirus approaches appear most applicable as drug delivery systems due to their rapid onset and short duration of transgene expression. The relative modest transduction efficiencies obtained at present with nonviral approaches, and the inherent inflammatory properties of first-generation adenovirus constructs, however, have limited their usefulness to date. The present review discusses the theoretical and practical benefits of specific gene therapy approaches for the treatment of acute inflammatory diseases, as well as our experiences with liposome:plasmid DNA and adenovirus-based approaches. Although a number of technical and theoretical hurdles remain before it can be evaluated in humans with acute inflammation, gene therapy offers a novel approach for the treatment of acute inflammation, and will likely enter the armamentarium of critical care physicians in the near future.

Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Relationship with body weight change.

We investigated the long-term effects of physiological levels of leptin produced by gene therapy on body weight (BW) and expression of genes that encode orexigenic and anorexigenic peptides in the hypothalamus. Recombinant adeno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic vector, encoding leptin (betaOb) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-betaOb (6x10(9) particles) was ineffective, the middle dose (6x10(10) particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6x10(11) particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-betaOb doses that either curbed BW without affecting food consumption or evoked BW loss and reduced food intake, decreased the expression of genes encoding the orexigenic peptides, neuropeptide Y and agouti-related peptide in the ARC, and the two doses were equally effective. Concomitantly, the expression of genes encoding the anorexigenic peptide, alpha-melanocyte stimulating hormone and cocaine-and-amphetamine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of delivering biologically active leptin for extended periods by an iv injection of rAAV-betaOb and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on anorexigenic signaling in the hypothalamus. This intricate dynamic interplay induced by leptin regulates BW with or without an effect on food intake in leptin-deficient ob/ob mice. Further, these results suggest that gene therapy is an effective mode of delivery to the hypothalamus of those therapeutic proteins that cross the blood-brain barrier to ameliorate neuroendocrine disorders.

Prospective evaluation of the giant prosthetic reinforcement of the visceral sac for recurrent and complex bilateral inguinal hernias.

BACKGROUND: Recurrent and complex bilateral inguinal hernias are associated with a high recurrence rate. This study evaluates prospectively the efficacy and safety of giant prosthetic reinforcement of the visceral sac (GPRVS) in a group of patients at high risk for recurrence. METHODS: Sixty-four patients with 124 inguinal hernias (60 bilateral and 4 unilateral) underwent repair using a large polyester mesh based on Stoppa's preperitoneal technique. Mean age was 61 years (63 men and 1 woman), and 69% had one or more comorbid medical conditions. RESULTS: Factors predicating a high risk for recurrence included large hernia size (> or =5 cm; 31%, 20 of 64), failure of one or more previous repairs (39%, 25 of 64), and chronic obstructive pulmonary disease (28%, 18 of 64). Mean operative time was 115 minutes (range 45 to 235). Mean length of stay was 3+/-3 days. There were 2 major and 15 minor complications, no mesh infections, and no death. Follow-up was obtained in 95% (61 of 64). After a mean follow-up of 24 months, the recurrence rate was 1% (1 of 124) per inguinal hernia repaired or 2% (1 of 64) per patient. CONCLUSION: GPRVS is a safe and effective addition to the surgeon's armamentarium to treat selected patients with recurrent or complex bilateral inguinal hernias.

Institutional validation of breast cancer treatment guidelines.

Several groups have developed clinical guidelines for the management of breast cancer, yet little data exist regarding their validation. Therefore, we examined the effect of published National Comprehensive Cancer Network (NCCN) guidelines for invasive breast cancer on survival, quality of life (QOL), and hospital cost. From 260 consecutive breast cancer patients, 129 patients were identified for analysis: 93 patients (72%) were treated according to the guidelines (NCCN+), while the treatment of 36 patients (28%), with a similar stage distribution, deviated from the guidelines (NCCN-). Patients were excluded from analysis with a diagnosis of carcinoma in situ, inflammatory cancer, stage IV disease, and comorbid conditions that affected treatment. The 5-year survival was 87.6% for the NCCN+ patients versus 83.3% for NCCN- patients (P = 0.319 by Kaplan-Meier). Twelve QOL parameters were evaluated using a Likert-type scale (1 = severe and 5 = none). NCCN+ patients had a cumulative QOL score of 4.18 +/- 0.08 versus 4.24 +/- 0.14 for NCCN- patients (P = 0.745). Treatment-related costs were $20,300 +/- 1800 for NCCN+ patients versus $59,700 +/- 25,200 for NCCN- patients (P = 0.016 by t test). Although deviation from NCCN breast cancer guidelines had no effect on perceived quality of life or survival, there was a significant decrease in cost in the NCCN+ group. These findings suggest that adherence to NCCN guidelines can significantly reduce the cost of breast cancer care without adversely affecting either survival or quality of life.

TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung.

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors. Absence of TNF-alpha or the p55 receptor significantly attenuated the Ab response to both adenovirus and beta-galactosidase. Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.

Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis.

Sepsis remains a significant clinical conundrum, and recent clinical trials with anticytokine therapies have produced disappointing results. Animal studies have suggested that increased lymphocyte apoptosis may contribute to sepsis-induced mortality. We report here that inhibition of thymocyte apoptosis by targeted adenovirus-induced thymic expression of human IL-10 reduced blood bacteremia and prevented mortality in sepsis. In contrast, systemic administration of an adenovirus expressing IL-10 was without any protective effect. Improvements in survival were associated with increases in Bcl-2 expression and reductions in caspase-3 activity and thymocyte apoptosis. These studies demonstrate that thymic apoptosis plays a critical role in the pathogenesis of sepsis and identifies a gene therapy approach for its therapeutic intervention.

Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy.

IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.

Adenoviral delivery of human and viral IL-10 in murine sepsis.

Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.