Formal Degree Programs in Physiology Promote Careers of Clinical Scientists and Benefit Basic Science Departments.

Physiologists may play critical roles in the development of clinician-scientists, who aspire to an academic career. The complexity of contemporary biomedical science and economic matters regarding post-graduate education pose real conundrums. We report a more than 22-year follow-up of surgical trainees pursuing bench laboratory science in Physiology and in Surgery Departments within a single public medical school. The sources and resources include selection, funding, physiology classroom work, and laboratory studies with personal involvement by faculty that have seldom been recorded, especially with longer-term career outcomes. These selected Ph.D. candidates have subsequently pursued several lines of activity, many with distinguished careers and major influences upon future generations of academic surgeons.

EAES/SAGES evidence-based recommendations and expert consensus on optimization of perioperative care in older adults.

BACKGROUND: As the population ages, more older adults are presenting for surgery. Age-related declines in physiological reserve and functional capacity can result in frailty and poor outcomes after surgery. Hence, optimizing perioperative care in older patients is imperative. Enhanced Recovery After Surgery (ERAS) pathways and Minimally Invasive Surgery (MIS) may influence surgical outcomes, but current use and impact on older adults patients is unknown. The aim of this study was to provide evidence-based recommendations on perioperative care of older adults undergoing major abdominal surgery. METHODS: Expert consensus determined working definitions for key terms and metrics related to perioperative care. A systematic literature review and meta-analysis was performed using the PubMed, Embase, Cochrane Library, and Clinicaltrials.gov databases for 24 pre-defined key questions in the topic areas of prehabilitation, MIS, and ERAS in major abdominal surgery (colorectal, upper gastrointestinal (UGI), Hernia, and hepatopancreatic biliary (HPB)) to generate evidence-based recommendations following the GRADE methodology. RESULT: Older adults were defined as 65 years and older. Over 20,000 articles were initially retrieved from search parameters. Evidence synthesis was performed across the three topic areas from 172 studies, with meta-analyses conducted for MIS and ERAS topics. The use of MIS and ERAS was recommended for older adult patients particularly when undergoing colorectal surgery. Expert opinion recommended prehabilitation, cessation of smoking and alcohol, and correction of anemia in all colorectal, UGI, Hernia, and HPB procedures in older adults. All recommendations were conditional, with low to very low certainty of evidence, with the exception of ERAS program in colorectal surgery. CONCLUSIONS: MIS and ERAS are recommended in older adults undergoing major abdominal surgery, with evidence supporting use in colorectal surgery. Though expert opinion supported prehabilitation, there is insufficient evidence supporting use. This work has identified evidence gaps for further studies to optimize older adults undergoing major abdominal surgery.

Perioperative Pharmacologic Prophylaxis of Venous Thromboembolism: A Professional Liability Analysis.

BACKGROUND: Fear of medical liability is a major driver for broad administration of perioperative prophylactic anticoagulation, despite the persistently low rates of clinically symptomatic venous thromboembolism events (VTE) postoperatively. This study was undertaken to evaluate the medicolegal landscape of perioperative VTE and its pharmaceutical prophylaxis. METHODS: The Westlaw legal database was retrospectively searched for verdicts in medical professional liability cases in the United States between 2009 and 2020. One search strategy focused on perioperative VTE, and a second on claims of hemorrhagic complications in patients receiving perioperative anticoagulation. RESULTS: The search for VTE revealed 129 cases, and the search for hemorrhagic complications identified 24 cases. Almost half of the VTE cases were brought following orthopedic surgery (49%), and 29% following general surgery. The most common claims were failure to diagnose and treat during hospital stay or after discharge (74%), and failure to prescribe/administer anticoagulation (46%). Verdict for the health care professional (i.e., the defendant) was reached in 75% of cases. The median payout for patient verdicts was 1,213,644 USD (interquartile range 1,014,100; 150,000-7,700,000). Of hemorrhagic complication cases, 42% occurred in patients receiving VTE prophylaxis. In these cases, 82% resulted in a defendant verdict. CONCLUSIONS: Reasons for in-court medical professional liability claims involving perioperative VTE were mainly failure to diagnose VTE and rescue patients from complications postoperatively. The high rate of defendant verdicts supports the notion that decisions on VTE prophylaxis should not be influenced by fear of liability.

Optimizing the Combination of Immunotherapy and Trans-Arterial Locoregional Therapy for Stages B and C Hepatocellular Cancer.

Hepatocellular carcinoma (HCC), the most common primary hepatic malignancy worldwide, is the second leading cause of cancer-related death. Underlying liver dysfunction and advanced stage of disease require treatments to be optimally timed and implemented to minimize hepatic parenchymal damage while maximizing disease response and quality of life. Locoregional therapies (LRTs) such as trans-arterial chemo- and radio-embolization remain effective for intermediate liver-only and advanced HCC disease (i.e., Barcelona-Clinic liver cancer stages B and C) not amendable to primary resection or ablation. Additionally, these minimally invasive interventions have been shown to augment the immune system. This and the recent success of immune-oncologic treatments for HCC have generated interest in applying these therapies in combination with such locoregional interventions to improve patient outcomes and response rates. This report reviews the use of trans-arterial LRTs with immunotherapy for stages B and C HCC, potential biomarkers, and imaging methods for assessing the response and safety of such combinations.

Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma.

BACKGROUND: Colon cancer survival is dependent on metastatic potential and treatment. Large RNA-sequencing data sets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE: This study aimed to identify a highly specific biomarker for overall survival in colon adenocarcinoma by using an RNA-sequencing data set. DESIGN: Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n = 271) were downloaded from The Cancer Genome Atlas. A binomial regression model was used to calculate differential RNA expression between paired colon cancer and normal epithelium samples (n = 40). Highly differentially expressed RNAs were examined. SETTINGS: This study was conducted at the University of Louisville using data acquired by The Cancer Genome Atlas. PATIENTS: Patients from US accredited cancer centers between 1998 and 2013 were analyzed. MAIN OUTCOME MEASURES: The primary outcome measures were recurrence-free and overall survival. RESULTS: The median age was 66 years (147/271 men, 180/271 White patients). Thirty RNAs were differentially expressed in colon adenocarcinoma compared with paired normal epithelium, using a log-fold change cutoff of ±6. Using median expression as a cutoff, 4 RNAs were associated with worse overall survival: decreased ZG16 (log-rank = 0.023), aquaporin 8 (log-rank = 0.023), and SLC26A3 (log-rank = 0.098), and increased COL1A1 (log-rank = 0.105). On multivariable analysis, low aquaporin 8 expression (HR, 1.748; 95% CI, 1.016-3.008; p = 0.044) was a risk factor for worse overall survival. Our final aquaporin 8 model had an area under the curve of 0.85 for overall survival. On subgroup analysis, low aquaporin 8 was associated with worse overall survival in patients with high microsatellite instability and in patients with stage II disease. Low aquaporin 8 expression was associated with KRAS and BRAF mutations. Aquaporin 8 immunohistochemistry was optimized for clinical application. LIMITATIONS: This was a retrospective study. CONCLUSION: Aquaporin 8 is a water channel selectively expressed in normal colon tissue. Low aquaporin 8 expression is a risk factor for worse overall survival in patients who have colon cancer. Aquaporin 8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance. See Video Abstract at http://links.lww.com/DCR/B603. LA DISMINUCIN DE LA EXPRESIN TUMORAL DE LA ACUAPORINA DEL CANAL DE AGUA ESPECFICO DEL COLON SE ASOCIA CON UNA REDUCCIN DE LA SUPERVIVENCIA GENERAL EN EL ADENOCARCINOMA DE COLON: ANTECEDENTES:La supervivencia del cáncer de colon depende del potencial metastásico y del tratamiento. Grandes conjuntos de datos de secuenciación de ARN pueden ayudar a identificar biomarcadores específicos del cáncer de colon para mejorar los resultados de los pacientes.OBJETIVO:Identificar un biomarcador altamente específico para la supervivencia general en el adenocarcinoma de colon utilizando un conjunto de datos de secuenciación de ARN.DISEÑO:La secuenciación de ARN sin procesar y los datos clínicos para pacientes con adenocarcinoma de colon (n = 271) se descargaron de The Cancer Genome Atlas. Se utilizó un modelo de regresión binomial para calcular la expresión diferencial de ARN entre muestras de cáncer de colon emparejadas y muestras de epitelio normal (n = 40). Se examinaron los ARN expresados de forma altamente diferencial.ENTORNO CLINICO:Este estudio se realizó en la Universidad de Louisville utilizando datos adquiridos por The Cancer Genome Atlas.PACIENTES:Se analizaron pacientes de centros oncológicos acreditados en Estados Unidos entre 1998-2013.PRINCIPALES MEDIDAS DE VALORACION:Las principales medidas de valoración fueron la supervivencia general y libre de recurrencia.RESULTADOS:La mediana de edad fue de 66 años (147/271 hombres, 180/271 caucásicos). Treinta ARN se expresaron diferencialmente en el adenocarcinoma de colon en comparación con el epitelio normal emparejado, utilizando un límite de cambio logarítmico de ± 6. Utilizando la expresión mediana como punto de corte, cuatro ARN se asociaron con una peor supervivencia general: disminución de ZG16 (rango logarítmico = 0,023), acuaporina8 (rango logarítmico = 0,023) y SLC26A3 (rango logarítmico = 0,098) y aumento de COL1A1 (log -rango = 0,105). En el análisis multivariable, la baja expresión de acuaporina8 (HR = 1,748, IC del 95%: 1,016-3,008, p = 0,044) fue un factor de riesgo para una peor supervivencia global. Nuestro modelo de aquaporin8 final tuvo un AUC de 0,85 para la supervivencia global. En el análisis de subgrupos, la acuaporina8 baja se asoció con una peor supervivencia general en pacientes con MSI-H y en pacientes en estadio II. La baja expresión de acuaporina8 se asoció con mutaciones de KRAS y BRAF. La inmunohistoquímica de aquaporina8 se optimizó para su aplicación clínica.LIMITACIONES:Este fue un estudio retrospectivo.CONCLUSIÓN:La acuaporina8 es un canal de agua expresado selectivamente en el tejido normal del colon. La baja expresión de AQP8 es un factor de riesgo de peor supervivencia global en pacientes con cáncer de colon. La medición de aquaporina8 puede tener un papel como un biomarcador de pronóstico específico del colon y ayudar en la estratificación del riesgo del paciente para una mayor vigilancia. Consulte Video Resumen en http://links.lww.com/DCR/B603.

Interferon-gamma increases monocyte PD-L1 but does not diminish T-cell activation.

Immune dysfunction can occur during sepsis or following major trauma. Decreased monocyte HLA-DR expression and cytokine responses are associated with mortality. Recent studies have shown that adaptive immune system defects can also occur in such patients, characterised by increased PD-L1 expression and associated T-cell anergy. The aim of this study was to determine the effects of an immune adjuvant, interferon-gamma, on monocyte PD-L1 expression and T-cell activation in an ex-vivo human whole blood model of infection. We found that with interferon-gamma treatment, monocytes had increased HLA-DR expression and augmented TNF-α production in response to LPS stimulation, with a decrease in IL-10 levels. Both LPS and interferon-gamma increased the level of monocyte PD-L1 expression, and that a combination of both agents synergistically stimulated a further increase in PD-L1 levels as measured by flow cytometry. However, despite elevated PD-L1 expression, both CD4 and CD8 T-cell activation was not diminished by the addition of interferon-gamma treatment. These findings suggest that PD-L1 may not be a reliable marker for T-cell anergy, and that interferon-gamma remains an adjuvant of interest that can improve the monocyte inflammatory response while preserving T-cell activation.

Does preoperative pharmacologic prophylaxis reduce the rate of venous thromboembolism in pancreatectomy patients?

BACKGROUND: Whether the risk of venous thromboembolism (VTE) may be reduced by preoperative administration of prophylactic heparin is unknown. We hypothesized that timing of heparin administration does not significantly alter the incidence of VTE in pancreatic surgery. METHODS: An analysis was conducted using data from Massachusetts General Hospital's National Surgical Quality Improvement Program from 2012 to 2017. All patients admitted for elective pancreatic resection were included. The primary outcome was development of VTE. Multivariable regression was performed, adjusting for patient demographics and various clinical factors. RESULTS: In total, 1448 patients were analyzed, of whom 1062 received preoperative heparin (73.3%). Overall, 36 (2.5%) patients developed VTE. On unadjusted analysis, there was no statistically significant difference between patients who received preoperative heparin compared with those who did not (2.6% vs. 1.3%, respectively; p = 0.079). On adjusted analysis, there was an association with increased VTE rates among patients who received preoperative heparin (OR 2.93, 95% CI 1.10-7.81; p = 0.031). CONCLUSION: There was an association between preoperative heparin administration and increased incidence of VTE on adjusted analysis, possibly reflecting appropriate surgical judgment in patient selection for prophylaxis. These data question the inclusion of preoperative VTE pharmacologic prophylaxis as a reliable quality indicator.

Remembrances from an early follower and leader of the Association for Academic Surgery.

This reflection retraces the evolution of early followers and leaders. Social change and early contributions set the stage for the current Association for Academic Surgery. Perhaps the most important contribution was Dr. George Zuidema's theme of inclusiveness. AAS was a decade ahead of its time in that regard.

Warming to 39°C but Not to 37°C Ameliorates the Effects on the Monocyte Response by Hypothermia.

OBJECTIVE: To investigate whether warming to normal body temperature or to febrile range temperature (39°C) is able to reverse the detrimental effects of hypothermia. BACKGROUND: Unintentional intraoperative hypothermia is a well-described risk factor for surgical site infections but also sepsis. We have previously shown that hypothermia prolongs the proinflammatory response whereas normothermia and especially febrile range temperature enhance the anti-inflammatory response. METHODS: Primary human monocytes were isolated from healthy volunteers. After stimulation with LPS (Lipopolysaccharide), the monocytes were exposed to 32°C for 3  hours or 6  hours and then warmed at either 37°C or 39°C for the remaining 33  hours or 36  hours, respectively. Tumor necrosis factor α, interleukin 10, and the expression of miR-155 and miR-101 were assessed at 24  hours and 36  hours. RESULTS: Warming to 37°C does not normalize monocyte cytokine secretion within 36  hours, whereas warming to 39°C partially reverses the effects of hypothermia on monocyte function. Both miR-155 and miR-101 were suppressed after the warming episode. However, 39°C had a stronger suppressive effect than 37°C. The duration of hypothermia and the warming temperature seem to be critical for a full reversibility of the effects of hypothermia. CONCLUSION: Warming to normal body temperature (37°C) does not restore normal monocyte function in vitro. These data suggest that hypothermic patients should be warmed to febrile range temperatures. Furthermore, febrile range temperatures should be investigated as a means to modulate the inflammatory response in patients with systemic infections.

MicroRNA-155 potentiates the inflammatory response in hypothermia by suppressing IL-10 production.

Therapeutic hypothermia is commonly used to improve neurological outcomes in patients after cardiac arrest. However, therapeutic hypothermia increases sepsis risk and unintentional hypothermia in surgical patients increases infectious complications. Nonetheless, the molecular mechanisms by which hypothermia dysregulates innate immunity are incompletely understood. We found that exposure of human monocytes to cold (32°C) potentiated LPS-induced production of TNF and IL-6, while blunting IL-10 production. This dysregulation was associated with increased expression of microRNA-155 (miR-155), which potentiates Toll-like receptor (TLR) signaling by negatively regulating Ship1 and Socs1. Indeed, Ship1 and Socs1 were suppressed at 32°C and miR-155 antagomirs increased Ship1 and Socs1 and reversed the alterations in cytokine production in cold-exposed monocytes. In contrast, miR-155 mimics phenocopied the effects of cold exposure, reducing Ship1 and Socs1 and altering TNF and IL-10 production. In a murine model of LPS-induced peritonitis, cold exposure potentiated hypothermia and decreased survival (10 vs. 50%; P < 0.05), effects that were associated with increased miR-155, suppression of Ship1 and Socs1, and alterations in TNF and IL-10. Importantly, miR-155-deficiency reduced hypothermia and improved survival (78 vs. 32%, P < 0.05), which was associated with increased Ship1, Socs1, and IL-10. These results establish a causal role of miR-155 in the dysregulation of the inflammatory response to hypothermia.

Transient receptor potential ion channels: powerful regulators of cell function.

OBJECTIVE: This article reviews the current understanding of transient receptor potential ion channels (TRP channels) in health and disease. BACKGROUND: Transient receptor potential ion channels are a group of 27 channels that are expressed in all tissues. These channels play important roles in surgically important problems, such as chronic pain, susceptibility to infection, hypothermia, and some cancers. METHODS: A literature search was performed. This review focuses on the role of TRP channels in a few surgically important disease processes, such as pain, inflammation, airway diseases, and malignant melanomas. In addition, we discuss some of the structural properties that are important for the activation of TRP channels. RESULTS: TRPA1 and TRPV1 are expressed on pain fibers and play an important role in the development of chronic pain, such as chemotherapy-related neuropathic pain. Deletion of TRPA1 and TRPV1 suppresses the development of chronic pain, and blockers of TRPA1 and TRPV1 show promise as a new class of painkillers. Furthermore, several TRP channels are expressed on immune cells. Macrophages express at least 3 different TRP channels, and the properly balanced activation of all these channels together allows normal macrophage function. Deletion of any of these channels results in impaired macrophage function and increased susceptibility to infection. Because several of these TRP channels on macrophages are temperature sensitive, they may comprise the link for hypothermia-related infectious complications in trauma, and to a lesser degree, in elective surgical patients. CONCLUSIONS: Transient receptor potential ion channels are involved in several surgically important disease processes. Activation or blockade of these channels offers new therapeutic opportunities. Pharmacologic activation or blockade of TRP channels may offer new treatment options in surgical patients for the management of pain and infections.

A proposal for enhancing the general surgical workforce and access to surgical care.

OBJECTIVE(S): The goals of this focused meeting were to verify and clarify the causes and extent of the general surgery (GS) workforce shortfalls. We also sought to define workable solutions within the existing framework of medical accreditation and certification. BACKGROUND: Numerous peer-reviewed and lay reports describe a current and worsening availability of GS services, affecting rural areas as well as large cities, academia, and the military. METHOD: Primary recommendations were broadly agreed upon by attendee surgeons who were selected from numerous different professional scenarios and included 2 nonmedical observers. RECOMMENDATIONS: (1) enhance the number of GS trainees and the breadth of training, (2) incorporate more flexibility and breadth in residency, (3) minimally invasive surgery should largely return to GS, (4) broader use of community hospitals in these efforts, (5) publicize loan forgiveness and improved visa status for international medical graduates going into GS, and (6) select candidates with a bias toward a general surgical career. CONCLUSION: These methods are promising approaches to this serious deficiency but will require regular reporting and publicity for the recording of actual increases in GS output.

Is there a role for bowel preparation and oral or parenteral antibiotics in infection control in contemporary colon surgery?

The numbers of unanswered questions are many. Can intraoperative application, such as topical antimicrobial use in pulsed lavage, reduce the microbial burden on the wound interface before closure? Can closed suction drains within the closed surgical incision reduce infection rates, especially in patients with a large body mass index? What is the role of delayed primary closure or secondary closure in the wound where obvious contamination has occurred, or in the circumstance of emergent colonic resection where considerable contamination is encountered from preexistent perforation? Should immediate negative-pressure wound dressings be applied in the open contaminated wound? These and many other questions still confront the surgeon in the challenge of the surgical wound in major colorectal surgery.

Anal squamous cell carcinoma incidentally found at hemorrhoidectomy.

BACKGROUND: Anal squamous cell carcinoma incidence is increasing nationally and, more so, in Kentucky. Squamous cell carcinoma of the anus unexpectedly identified at hemorrhoidectomy pathologic evaluation is not uncommon. We hypothesized this is occurring more frequently and sought to evaluate its impact on outcomes. METHODS: The Kentucky Cancer Registry, a premier population database, was queried for all squamous cell carcinoma of the anus cases between 2007 and 2016. Hemorrhoidal squamous cell carcinoma of the anus patients were compared with nonhemorrhoidal squamous cell carcinomas of the anus. Patient demographics, treatments, and outcomes were analyzed. RESULTS: Of the 722 squamous cell carcinoma of the anus cases identified, 3.05% (n = 22) were within hemorrhoidectomy specimens. Demographics were similar between hemorrhoidal squamous cell carcinoma of the anus versus nonhemorrhoidal squamous cell carcinoma of the anus. Chemoradiation was the most common treatment strategy among all patients, and there were similar rates of disease, persistence, recurrence, and survival between hemorrhoidal and nonhemorrhoidal squamous cell carcinoma. Stage I disease was more common in the hemorrhoid group compared with the nonhemorrhoid group (63% vs 27%, P < .01). CONCLUSION: Hemorrhoidal squamous cell carcinoma of the anus comprised 3.05% of our population-based cohort. Hemorrhoidal squamous cell carcinomas of the anus were more likely to receive chemoradiation compared with local excision, but there were similar oncologic outcomes. We postulate that some individuals may receive overtreatment with chemoradiation owing to imprecise labeling of hemorrhoid specimens. For this reason, we advocate for separate submission of each hemorrhoid specimen.