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.

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.

Long non-coding RNA ZFAS1 is a major regulator of epithelial-mesenchymal transition through miR-200/ZEB1/E-cadherin, vimentin signaling in colon adenocarcinoma.

Colon adenocarcinoma is a common cause of cancer-related deaths worldwide. Epithelial-mesenchymal transition is a major regulator of cancer metastasis, and increased understanding of this process is essential to improve patient outcomes. Long non-coding RNA (lncRNA) are important regulators of carcinogenesis. To identify lncRNAs associated with colon carcinogenesis, we performed an exploratory differential gene expression analysis comparing paired colon adenocarcinoma and normal colon epithelium using an RNA-sequencing data set. This analysis identified lncRNA ZFAS1 as significantly increased in colon cancer compared to normal colon epithelium. This finding was validated in an institutional cohort using laser capture microdissection. ZFAS1 was also found to be principally located in the cellular cytoplasm. ZFAS1 knockdown was associated with decreased cellular proliferation, migration, and invasion in two colon cancer cell lines (HT29 and SW480). MicroRNA-200b and microRNA-200c (miR-200b and miR-200c) are experimentally validated targets of ZFAS1, and this interaction was confirmed using reciprocal gene knockdown. ZFAS1 knockdown regulated ZEB1 gene expression and downstream targets E-cadherin and vimentin. Knockdown of miR-200b or miR-200c reversed the effect of ZFAS1 knockdown in the ZEB1/E-cadherin, vimentin signaling cascade, and the effects of cellular migration and invasion, but not cellular proliferation. ZFAS1 knockdown was also associated with decreased tumor growth in an in vivo mouse model. These results demonstrate the critical importance of ZFAS1 as a regulator of the miR-200/ZEB1/E-cadherin, vimentin signaling cascade.

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.

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.

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.

The role and function of IκKα/ß in monocyte impairment.

Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/ß, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/ß complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naïve monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/ß with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1ß, TNF-ß, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/ß activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/ß activation, and that IκKα/ß is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/ß function to restore monocyte function in this clinically important problem.

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.

Temporal expression of circulating miRNA after severe injury.

BACKGROUND: Severe injury can lead to immune dysfunction and predispose patients to infection and death. Micro-RNAs regulate gene expression and may act as biomarkers for susceptibility to infection. The aim of this study was to examine the temporal and differential expression of previously identified dysregulated micro-RNAs in patients with severe injury. METHODS: Fourteen severely injured patients requiring transfusion were enrolled prospectively in this study approved by our institutional review board. Inclusion criteria consisted of adult patients deemed clinically to be in hemorrhagic shock necessitating transfusion in the acute phase of their injury care. Peripheral blood samples were obtained after admission to the surgical intensive care unit and again at 6, 12, 24, and 48 hours after admission. The samples obtained at arrival to the intensive care unit and 24 and 48 hours later were analyzed in this data set. Fourteen healthy volunteers served as controls. The 10 dysregulated micro-RNAs identified in a prior study at the 12-hour time point and important genes in innate immunity were measured using quantitative reverse transcription-polymerase chain reaction. RESULTS: The participants were 21-77 years old (median, 42), 78% were male, and their Injury Severity Score ranged from 11 to 43 (median, 27); 11 had blunt and 3 had penetrating injuries. Three were intubated and 5 had received blood products before arrival at the hospital. Base deficit on hospital admission was 3-20 (median, 9). All patients required blood transfusion secondary to blood loss sustained during injury. Eleven of the 14 patients went directly to the operating room from the emergency department for control of the source of hemorrhage. Survival to discharge was 93%. Seven patients developed infection. Compared with healthy controls, miR-106a was downregulated at all time points compared with controls (P < .05). miR-618 was upregulated in initial blood draws (P < .05) and at 24 and 48 hours (P < .06). Tumor necrosis factor α and human leukocyte antigen-DR (HLA-DR) were downregulated, and interleukin-10 and PD-L1 were upregulated (P < .05). In patients who developed infection, miR-106a levels appeared more downregulated than those who did not develop infection. CONCLUSION: miR-106a was downregulated in trauma patients after major injury for up to 48 hours after intensive care unit admission. Tumor necrosis factor α and interleukin-10 are targeted by miR-106a, which are regulators of the immune response. Manipulation of micro-RNA expression may be a therapeutic target for immune dysfunction.

Early Impact of Medicaid Expansion and Quality of Breast Cancer Care in Kentucky.

BACKGROUND: In January 2014, Kentucky expanded Medicaid coverage to include all individuals and families with incomes up to 33% above the federal poverty line. This study evaluated the early impact of Medicaid expansion on some aspects of the quality of breast cancer care in Kentucky. STUDY DESIGN: The Kentucky Cancer Registry was queried for all women aged 20 to 64 years diagnosed with breast cancer between 2011 and 2016. Demographic, tumor, and treatment characteristics were assessed for each year during this interval. To evaluate the association between Medicaid expansion and these parameters, these variables, along with quality metrics deriving from said variables, were compared for the years 2011 to 2013 (pre) and the years 2014 to 2016 (post). RESULTS: Of 13,625 women with breast cancer, 11,915 (59.5%) were diagnosed and treated from 2011 to 2013, and 8,127 (40.5%) were diagnosed and treated from 2014 to 2016. After Medicaid expansion, fewer patients were uninsured (3.7% post vs 1.0% pre) and more were covered by Medicaid (15.9% post vs 10.9% pre) (p < 0.001). There was increased diagnosis of early stage (I and II) breast cancer (p = 0.002) and an increasing proportion of women undergoing breast-conservation therapy (p < 0.001). Time from diagnosis to operation increased (p < 0.001), time from operation to chemotherapy remained unchanged (p = 0.26) and time from operation to radiation decreased (p < 0.001). CONCLUSIONS: The expansion of Kentucky Medicaid in 2014 has been associated with earlier diagnosis and somewhat improved quality of breast cancer care, despite a stable disease incidence. Additional improvements in treatment expediency will require improvements in patient outreach and healthcare infrastructure.

The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes.

This study focuses on impaired monocyte function, which occurs in some patients after trauma, major elective surgery, or sepsis. This monocyte impairment increases the risk of secondary infection and death. We aimed to determine the influence IκK-16 had on monocytes using an ex-vivo model of human monocyte impairment. We included the effects of the well-studied comparators interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on impaired monocytes. Primary human monocytes were stimulated with 10ng/mL of lipopolysaccharide (LPS) for 16h and then challenged with 100ng/mL LPS to assess the monocyte inflammatory response. Treatment regimens, consisting of either IκK-16, IFN-γ, or GM-CSF, were administered to impaired monocytes near the time of initial LPS stimulation. Stimulation with 10ng/mL LPS initially promoted a pro-inflammatory response but subsequently impaired production of both tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) and decreased HLA-DR expression. IκK-16 treatment attenuated TNF-α production and programmed death-ligand 1 (PD-L1) expression and increased IL-10 and CD14 expression. IFN-γ treatment increased TNF-α production as well as PD-L1 and HLA-DR expression. In conclusion, limiting early inflammation with IκK-16 suppresses TNF-α production and PD-L1 expression but enhances IL-10 production and preserves CD14 expression for potential future exposure to infective stimuli.