Tumor extent impacts survival benefit in minimally invasive colectomy for T4 colon cancer: A propensity matched national cohort analysis.

BACKGROUND: T4 colon cancers have been underrepresented in randomized trials comparing minimally invasive colectomy (MC) versus open colectomy (OC). Retrospective studies suggest improved survival with MC versus OC, but have not addressed the impact of tumor extent. METHODS: Using the National Cancer Database (NCDB), we analyzed patients undergoing colectomy for T4 colon adenocarcinoma from 2010 to 2014. Propensity score matching was performed between MC and OC patients. Tumor extent was defined by zones based on adjacent organ involvement. RESULTS: Of the 19 178 eligible patients, 6564 (34%) underwent MC. After matching, MC was associated with improved overall survival (hazard ratios: 0.71, 95% confidence interval: 0.67-0.76; median OS 59 vs. 42 months, p < 0.001). Compared to MC patients, those undergoing OC had: a higher margin positive rate (p = 0.009); lower median nodes examined (p < 0.001); a lower rate of adjuvant chemotherapy (p < 0.001); and a longer median time to chemotherapy (p < 0.001). Stratified survival analyses demonstrated that MC was associated with improved overall survival compared to OC in all zones except zone 3 and 4. CONCLUSIONS: Compared to OC, MC for T4 colon cancer is associated with improved oncologic outcomes when performed for zone 0-2 tumors. For, zone 3 and 4 tumors MC and OC have similar oncologic outcomes and patients should be cautiously selected.

Robotic versus laparoscopic gastrectomy for adenocarcinoma in the US: a propensity score-matching analysis of 11,173 patients on oncological adequacy.

INTRODUCTION: Surgery remains the cornerstone treatment for gastric cancer. Previous studies have reported better lymphadenectomy with minimally invasive approaches. There is a paucity of data comparing robotic and laparoscopic gastrectomy in the US. Herein, we examined whether oncological adequacy differs between laparoscopic and robotic approaches. METHODS: The National Cancer Database was utilized to identify patients who underwent gastrectomy for adenocarcinoma between 2010 and 2019. A propensity score-matching analysis between robotic gastrectomy (RG) versus laparoscopic gastrectomy (LG) was performed. The primary outcomes were lymphadenectomy ≥ 16 nodes and surgical margins. RESULTS: A total of 11,173 patients underwent minimally invasive surgery for gastric adenocarcinoma between 2010 and 2019. Of those 8320 underwent LG and 2853 RG. Comparing the unmatched cohorts, RG was associated with a higher rate of adequate lymphadenectomy (63.5% vs 57.1%, p < .0.0001), higher rate of negative margins (93.8% vs 91.9%, p < 0.001), lower rate of prolonged length of stay (26.0% vs 29.6%, p < .0.001), lower 90-day mortality (3.7% vs 5.0%, p < 0.0001), and a better 5-year overall survival (OS) (56% vs 54%, p = 0.03). A propensity score-matching cohort with a 1:1 ratio was created utilizing the variables associated with lymphadenectomy ≥ 16 nodes. The matched analysis revealed that the rate of adequate lymphadenectomy was significantly higher for RG compared to LG, 63.5% vs 60.4% (p = 0.01), respectively. There was no longer a significant difference between RG and LG regarding the rate of negative margins, prolonged length of stay, 90-day mortality, rate of receipt of postoperative chemotherapy, and OS. CONCLUSIONS: This propensity score-matching analysis with a large US cohort shows that RG was associated with a higher rate of adequate lymphadenectomy compared to LR. RG and LG had a similar rate of negative margins, prolonged length of stay, receipt of postoperative chemotherapy, 90-day mortality, and OS, suggesting that RG is a comparable surgical approach, if not superior to LG.

CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent.

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.

Trends and outcomes of minimally invasive surgery for gastrointestinal stromal tumors (GIST).

OBJECTIVE: Minimally invasive surgery (MIS) is increasingly being utilized for the resection of gastrointestinal cancers. National trends for perioperative and oncologic outcomes of MIS for gastrointestinal stromal tumors (GIST) are unknown. We hypothesized that with increased use of MIS, the perioperative outcomes and survival for GIST are preserved. METHODS: The National Cancer Database (2010-2016) was utilized to assess perioperative and oncologic outcomes for GIST of the stomach and small bowel. Kaplan-Meier method and log rank test were used to compare survival outcomes. RESULTS: Data from 8923 gastric and 3683 small bowel resections were analyzed. Over the study period, MIS became the prevalent modality for gastrectomies (2010: robotic: 2.4%, laparoscopic: 26.1%, open: 71.5% vs. 2016: robotic: 9.6%, laparoscopic: 48.8%, open: 41.6%; p < 0.001), with a smaller increase in enterectomies (2010: robotic: 1%, laparoscopic: 17.3%, open: 81.6% vs. 2016: robotic: 3.9%, laparoscopic: 27.2%, open: 68.9%; p < 0.001). Age and Charlson comorbidity index were similar among groups. MIS approaches were associated with fewer readmissions and lower 90 day mortality for gastrectomies and similar rates for enterectomies. MIS did not compromise patient survival even in patients who underwent neoadjuvant treatment or harbored tumors ≥ 10 cm. CONCLUSION: Minimally invasive surgery is increasingly being utilized for resection of gastric and small bowel GIST, with improved postoperative outcomes. In this retrospective review, overall survival after minimally invasive or open surgery was comparable, even in challenging scenarios of neoadjuvant treatment or large tumors (≥ 10 cm).

Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Liver Failure After Resection of Colorectal Liver Metastases.

BACKGROUND: Chemotherapy agents for metastatic colorectal cancer can cause liver injury, increasing the risk of post-hepatectomy liver failure after hepatectomy for metastases. The role of noninvasive fibrosis markers in this setting is not well established. AIMS: To evaluate the aspartate aminotransferase-to-platelet ratio index (APRI) as a predictor of postoperative liver failure. METHODS: The National Surgical Quality Improvement Program database was utilized to identify patients who received preoperative chemotherapy and underwent hepatectomy for colorectal metastases between 2015 and 2017. Concordance index analysis was conducted to determine APRI's contribution to the prediction of liver failure. The optimal cutoff value was defined and its ability to predict post-hepatectomy liver failure and perioperative bleeding were examined. RESULTS: A total of 2374 patients were identified and included in the analysis. APRI demonstrated to be a better predictor of postoperative liver failure than MELD score, with a statistically significant larger area under the curve. The optimal APRI cutoff value to predict liver failure was 0.365. The multivariable logistic regression showed that APRI ≥ 0.365 was independently associated with PHLF, odds ratio (OR) 2.51, 95% confidence interval (CI) 1.67-3.77, P < .0001. Likewise, APRI ≥ 0.365 was independently associated with perioperative bleeding complications requiring transfusions, OR 1.41, 95% CI 1.13-1.77, P = 0.002. MELD score was not statistically associated with PHLF or bleeding complications. CONCLUSIONS: APRI was independently associated with post-hepatectomy liver failure and perioperative bleeding requiring transfusions after resection of colorectal metastases in patients who received preoperative chemotherapy. Concordance index showed APRI to add significant contribution as a predictor of postoperative liver failure.

Minimally invasive vs open pancreatoduodenectomy on oncological adequacy: a propensity score-matched analysis.

BACKGROUND: The adoption of minimally invasive pancreatoduodenectomy (MIPD) has increased over the last decade. Most of the data on perioperative and oncological outcomes derives from single-center high-volume hospitals. The impact of MIPD on oncological outcomes in a multicenter setting is poorly understood. METHODS: The National Cancer Database was utilized to perform a propensity score matching analysis between MIPD vs open pancreatoduodenectomy (OPD). The primary outcomes were lymphadenectomy ≥ 15 nodes and surgical margins. Secondary outcomes were 90-day mortality, length of stay, and overall survival. RESULTS: A total of 10,246 patients underwent pancreatoduodenectomy for ductal adenocarcinoma between 2010 and 2016. Among these patients, 1739 underwent MIPD. A propensity score matching analysis with a 1:2 ratio showed that the rate of lymphadenectomy ≥ 15 nodes was significantly higher for MIPD compared to OPD, 68.4% vs 62.5% (P < .0001), respectively. There was no statistically significant difference in the rate of positive margins, 90-day mortality, and overall survival. OPD was associated with an increased rate of length of stay > 10 days, 36.6% vs 33% for MIPD (P < .01). Trend analysis for the patients who underwent MIPD revealed that the rate of adequate lymphadenectomy increased during the study period, 73.1% between 2015 and 2016 vs 63.2% between 2010 and 2012 (P < .001). In addition, the rate of conversion to OPD decreased over time, 29.3% between 2010 and 2012 vs 20.2% between 2015 and 2016 (P < .001). CONCLUSION: In this propensity score matching analysis, the MIPD approach was associated with a higher rate of adequate lymphadenectomy and a shorter length of stay compared to OPD. The surgical margins status, 90-day mortality, and overall survival were similar between the groups.

Epigenetic mapping of the somatotropic axis in Nile tilapia reveals differential DNA hydroxymethylation marks associated with growth.

In vertebrates, the somatotropic axis comprising the pituitary gland, liver and muscle plays a major role in myogenesis. Its output in terms of muscle growth is highly affected by nutritional and environmental cues, and thus likely epigenetically regulated. Hydroxymethylation is emerging as a DNA modification that modulates gene expression but a holistic characterization of the hydroxymethylome of the somatotropic axis has not been investigated to date. Using reduced representation 5-hydroxymethylcytosine profiling we demonstrate tissue-specific localization of 5-hydroxymethylcytosines at single nucleotide resolution. Their abundance within gene bodies and promoters of several growth-related genes supports their pertinent role in gene regulation. We propose that cytosine hydroxymethylation may contribute to the phenotypic plasticity of growth through epigenetic regulation of the somatotropic axis.

The impact of minimally invasive surgery and frailty on post-hepatectomy outcomes.

BACKGROUND: The impact of patient frailty on post-hepatectomy outcomes is not well studied. We hypothesized that patient frailty is a strong predictor of 30-day post-hepatectomy complications. METHODS: The liver-targeted National Surgical Quality Improvement Program (NSQIP) database for 2014-2019 was reviewed. A validated modified frailty index (mFI) was used. RESULTS: A total of 24,150 hepatectomies were reviewed. Worsening frailty was associated with increased incidence of Clavien-Dindo grade IV complications (mFI 0, 1, 2, 3, 4 was 3.9%, 6.3%, 10%, 8.1%, 50% respectively; p < 0.001). Minimally invasive hepatectomies had a lower rate of Clavien-Dindo grade IV complications for non-frail (Laparoscopic: 1%, Robotic: 2.6%, Open: 4.6%; p < 0.001) and frail patients (Laparoscopic: 3%, Robotic: 2.3%, Open: 7.7%; p < 0.001). Frail patients experienced higher incidence of post-hepatectomy liver failure (5.4% vs 4.1% for non-frail; p < 0.001) and grade C liver failure (28% vs 21.1% for non-frail; p = 0.03). Incorporating mFI to Albumin-Bilirubin score (ALBI) improved its ability to predict Clavien-Dindo grade IV complications (AUC improved from 0.609 to 0.647; p < 0.001) and 30-day mortality (AUC improved from 0.663 to 0.72; p < 0.001). CONCLUSION: Worsening frailty correlates with increased incidence of Clavien-Dindo grade IV complications post-hepatectomy, whereas minimally invasive approaches decrease this risk. Incorporating frailty assessment to ALBI improves its ability to predict major postoperative complications and 30-day mortality.

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities.

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been extensively applied to quantitatively translate invitro data, predict the invivo performance, and ultimately support waivers of invivo clinical studies. In the area of biopharmaceutics and within the context of model-informed drug discovery and development (MID3), there is a rapidly growing interest in applying verified and validated mechanistic PBPK models to waive invivo clinical studies. However, the regulatory acceptance of PBPK analyses for biopharmaceutics and oral drug absorption applications, which is also referred to variously as "PBPK absorption modeling" [Zhang et al. CPT: Pharmacometrics Syst. Pharmacol. 2017, 6, 492], "physiologically based absorption modeling", or "physiologically based biopharmaceutics modeling" (PBBM), remains rather low [Kesisoglou et al. J. Pharm. Sci. 2016, 105, 2723] [Heimbach et al. AAPS J. 2019, 21, 29]. Despite considerable progress in the understanding of gastrointestinal (GI) physiology, invitro biopharmaceutic and in silico tools, PBPK models for oral absorption often suffer from an incomplete understanding of the physiology, overparameterization, and insufficient model validation and/or platform verification, all of which can represent limitations to their translatability and predictive performance. The complex interactions of drug substances and (bioenabling) formulations with the highly dynamic and heterogeneous environment of the GI tract in different age, ethnic, and genetic groups as well as disease states have not been yet fully elucidated, and they deserve further research. Along with advancements in the understanding of GI physiology and refinement of current or development of fully mechanistic in silico tools, we strongly believe that harmonization, interdisciplinary interaction, and enhancement of the translational link between invitro, in silico, and invivo will determine the future of PBBM. This Perspective provides an overview of the current status of PBBM, reflects on challenges and knowledge gaps, and discusses future opportunities around PBPK/PD models for oral absorption of small and large molecules to waive invivo clinical studies.

National postoperative and oncologic outcomes after pelvic exenteration for T4b rectal cancer.

BACKGROUND AND OBJECTIVES: Studies reporting outcomes after pelvic exenteration for rectal cancer are limited. The objective of this study was to evaluate early postoperative and oncologic outcomes in a national multi-institutional cohort. METHODS: Using the National Cancer Database (NCDB), which collects data from over 1500 commission on cancer (CoC)-accredited hospitals, we analyzed patients undergoing pelvic exenteration for T4b rectal adenocarcinoma. RESULTS: There were 1367 pelvic exenterations performed in 552 hospitals. Median age was 60 years, the majority of patients (n = 831; 60.8%) were female. Neoadjuvant radiation was used only in 57%; 24.3% of resections had positive margins. Following exenteration, 30-day mortality rate, 90-day mortality rate, and readmission rates were: 1.8%, 4.4%, and 7.4%. Age ≥ 60 years and higher Charlson-Deyo comorbidity index were independently associated with increased 90-day mortality (P < .001). Overall survival (OS) was 50 months. After adjustment of significant covariates, negative margin status (adjusted HR, 0.6, 95% CI, 0.5-0.8; P < .001) and receipt of perioperative radiation or chemoradiation (adjusted HR, 0.5; 95% CI, 0.4-0.6; P < .001) were significantly associated with decreased risk of death. Only 71% of the patients received perioperative radiation. CONCLUSIONS: Pelvic exenterations are being performed safely in Coc-accredited hospitals. However, up to one fourth of patients undergo resections with positive margins or are subject to underutilization of perioperative radiation therapy. Increased use of radiation may increase negative margin resections and improve patient outcomes.

Trends and outcomes of robotic surgery for gastrointestinal (GI) cancers in the USA: maintaining perioperative and oncologic safety.

OBJECTIVE: Minimally invasive surgery (MIS) continues to gain traction as a feasible approach for the operative management of gastrointestinal (GI) malignancies. The aim of this study is to quantify national trends, perioperative and oncologic outcomes of MIS for the most common GI malignancies including the esophagus, stomach, pancreas, colon, and rectum. We hypothesize that with more widespread use of MIS techniques, perioperative outcomes and oncologic resection quality will remain preserved. METHODS: The National Cancer Database (2010-2014) was utilized to assess perioperative outcomes and pathologic quality of MIS (robotic and laparoscopic) compared to open, in patients who underwent resection for cancers of the esophagus, stomach, pancreas, colon, and rectum. Multilevel logistic regression models were constructed to identify independent factors associated with postoperative and long-term outcomes. RESULTS: Data from 11,023 esophageal, 30,664 gastric, 30,689 pancreas, 260,669 colon, and 52,239 rectal resections were analyzed. Although laparoscopy is the most prevalent MIS approach, the number of robotic resections increased nearly fourfold from 2010 to 2014 in all organ sites (increase by factor: esophagus: 3.8, stomach: 4.4, pancreas: 4.4, colon: 3.8 and rectum: 4). The number of laparoscopic resections increased at a slower rate (factor: 1.3-1.9), whereas the number of open resections decreased (factor: 0.67-0.77). Patients who underwent robotic-assisted resections were younger for stomach and colorectal resections and with lower Charlson Comorbidity Index across all sites. Patients who underwent robotic or laparoscopic resections had shorter hospitalizations, fewer readmissions (with the exception of rectal resections) and lower postoperative mortality at 90 days. Robotic-assisted resections had comparable negative margin resections and number of lymph nodes to laparoscopic and open resections across all sites. CONCLUSION: The utilization of robotic-assisted resections of GI cancers is rapidly increasing with more frequent use in younger and healthier patients. This study demonstrates that with the rising utilization of robotic-assisted resections, perioperative outcomes and oncologic safety have not been compromised.

Bile Leak Reduction with Laparoscopic Versus Open Liver Resection: A Multi-institutional Propensity Score-Adjusted Multivariable Regression Analysis.

INTRODUCTION: The reported rate of postoperative bile leak is variable between 3 and 33%. Recent data would suggest a minimally invasive approach to liver surgery has decreased this incidence. METHODS: This multi-institutional case-control study utilized databases from three high-volume surgeons. All consecutive open and minimally invasive liver resection cases were analyzed in a propensity score-adjusted multivariable regression. A p value < 0.05 was considered significant. RESULTS: In 1388 consecutive liver resections, the average age was 56.9 ± 14.0 years, 730 (52.59%) were male gender, and 599 (43.16%) underwent minimally invasive liver resection. Thirty-nine (2.81%) in the series were identified with post-resection bile duct leaks. Leaks were associated with major resections and increased blood loss (p < 0.05). Propensity score-adjusted multivariable regression identified minimally invasive liver resection significantly and independently reduced the odds of bile duct leak (OR 0.48, p = 0.046) even controlling for BMI, ASA, cirrhosis, major resection, and resection year. CONCLUSIONS: Our data suggest the incidence of bile leaks in a large-volume center series is far less than previously reported and that a minimally invasive approach to liver resection reduces the incidence of postoperative bile leak.

Pharmacological interventions for heart failure in people with chronic kidney disease.

BACKGROUND: Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD. OBJECTIVES: This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration. DATA COLLECTION AND ANALYSIS: Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta-analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence. MAIN RESULTS: One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies. AUTHORS' CONCLUSIONS: The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.

Translucency of Zirconia Ceramics before and after Artificial Aging.

PURPOSE: The aging of zirconia ceramics (Y-TZP) is associated with tetragonal to monoclinic phase transformation. This change in microstructure may affect the optical properties of the ceramic. This study examines the effect of aging on the translucency of different zirconia materials. MATERIALS AND METHODS: 120 disc-shaped specimens were fabricated from four zirconia materials: Cercon ht white, BruxZir Solid Zirconia, Zenostar T0, Lava Plus (n = 30 per group). Accelerated aging was performed in a steam autoclave (134°C, 0.2 MPa, 5 hours). CIELab coordinates (L*, a*, b*) and luminous reflectance (Y) were measured with a spectrophotometer before and after aging. Contrast ratio (CR) and translucency parameter (TP) were calculated from the L*, a*, b*, and Y tristimulus values. The general linear model (Bonferroni adjusted) was used to compare both parameters before and after aging, as well as between the different zirconia materials (p ≤ 0.05). RESULTS: CR and TP differed significantly before and after aging in all groups tested. Before aging, Zenostar T showed the highest and Lava Plus showed the lowest translucency. After aging, Cercon ht and Zenostar T showed the highest and BruxZir and Lava Plus the lowest translucency. CONCLUSIONS: Aging reduced the translucency in all specimens tested. Furthermore, translucency differed between the zirconia brands tested. Nevertheless, the differences were below the detectability threshold of the human eye. The aging process can influence the translucency and thus the esthetic outcome of zirconia restorations; however, the changes in translucency were minimal and probably undetectable by the human eye.

National Trends and Outcomes in Dialysis-Requiring Acute Kidney Injury in Heart Failure: 2002-2013.

BACKGROUND: Dialysis-requiring acute kidney injury (D-AKI) is a serious complication in hospitalized heart failure (HF) patients. However, data on national trends are lacking after 2002. METHODS: We used the Nationwide Inpatient Sample (2002-2013) to identify HF hospitalizations with and without D-AKI. We analyzed trends in incidence, in-hospital mortality, length of stay (LoS), and cost. We calculated adjusted odds ratios (aORs) for predictors of D-AKI and for outcomes including in-hospital mortality and adverse discharge (discharge to skilled nursing facilities, nursing homes, etc). RESULTS: We identified 11,205,743 HF hospitalizations. Across 2002-2013, the incidence of D-AKI doubled from 0.51% to 1.09%. We found male sex, younger age, African-American and Hispanic race, and various comorbidities and procedures, such as sepsis and mechanical ventilation, to be independent predictors of D-AKI in HF hospitalizations. D-AKI was associated with higher odds of in-hospital mortality (aOR 2.49, 95% confidence interval [CI] 2.36-2.63; P < .01) and adverse discharge (aOR 2.04, 95% CI 1.95-2.13; P < .01). In-hospital mortality and attributable risk of mortality due to D-AKI decreased across 2002-2013. LoS and cost also decreased across this period. CONCLUSIONS: The incidence of D-AKI in HF hospitalizations doubled across 2002-2013. Despite declining in-hospital mortality, LoS, and cost, D-AKI was associated with worse outcomes.

Primary liver sarcomas in the modern era: Resection or transplantation?

BACKGROUND AND OBJECTIVES: Primary liver sarcomas (PLS) are rare. Published series are limited by small numbers of patients. METHODS: We reviewed the National Cancer Database (2004-2014) for patients who underwent surgical resection of PLS. RESULTS: Of 237 patients identified, the majority were female (60.8%), with median age of 52 years. Histologies were: epithelioid hemangioendothelioma (n = 67), angiosarcoma (n = 64), leiomyosarcoma (n = 33), embryonal rhabdomyosarcoma (n = 31), carcinosarcoma (n = 16), giant cell sarcoma (n = 14), spindle cell sarcoma (n = 12). Ninety-seven (40.9%) patients underwent lobectomies or extended lobectomies, 41 patients (17.3%) underwent transplantation. Surgical margins were negative in 82.9%. Tumors were well differentiated in 11.3%. Histology type correlated with outcome with the best prognosis for epithelioid hemangioendothelioma (OS: not reached, similar for resection and transplantation) and the worst for angiosarcoma (OS:16.6 mo with resection; 6 mo with transplantation; P = 0.04). Resections with microscopically negative margins were associated with improved survival (58.7 vs 11.3 mo for positive margins; P < 0.001). Chemotherapy and radiation therapy were used in a minority of patients (32.9% and 4.3% respectively) with no improvement in outcomes. CONCLUSIONS: Both hepatic resection and liver transplantation can be associated with long term survival for selected primary liver sarcomas such as epitheliod hemangioendotheliomas. Histology type and the ability to resect the tumor with negative margins correlate with outcomes and the decision to operate should be carefully weighed for subtypes with particularly dismal prognosis such as angiosarcomas.

Robotic total pancreatectomy with splenectomy: technique and outcomes.

BACKGROUND: Robotic total pancreatectomy (TP) represents a minimally invasive approach to a major intra-abdominal operation. Its utility, technique, and outcomes are evolving. METHODS: In this video, we describe a systematic approach to a robotic total pancreatectomy performed for multifocal intraductal papillary mucinous neoplasm (IPMN). Additionally, we reviewed the National Cancer Database (NCDB) to examine the outcomes of robotic TP compared to laparoscopic and open TP between 2010 and 2014. RESULTS: The patient is a 61-year-old female who was diagnosed with multifocal IPMN. A total of 6 robotic ports were placed and the da Vinci Xi robotic system was used with the patient supine. The approach entailed as follows: (1) Diagnostic laparoscopy; (2) Entry into the lesser sac; (3) Division of the short gastric vessels; (4) Exposure and dissection of the inferior pancreas border; (5) Dissection and transection of the splenic artery; (6) Mobilization of the pancreas tail/spleen; (7) Exposure of the splenic vein-superior mesenteric vein confluence; (8) Kocher maneuver; (9) Release of the ligament of Treitz and transection of the proximal jejunum; (10) Transection of the distal stomach; (11) Portal lymphadenectomy; (12) Dissection and transection of the gastroduodenal artery; (13) Superior mesenteric vein exposure/dissection of the uncinate process; (14) Hepaticojejunostomy; (15) Cholecystectomy; and (16) Gastrojejunostomy. NCDB database review of 73 patients who underwent robotic TP revealed similar rates of margin negative resections and retrieved lymph nodes between robotic, laparoscopic, and open TP, whereas robotic and laparoscopic TP were associated with shorter in-hospital stay and reduced mortality at 30 and 90 days compared to open TP. Overall median survival of pancreatic adenocarcinoma patients who underwent TP was similar between robotic, laparoscopic, and open approaches. CONCLUSION: Robotic total pancreatectomy with splenectomy offers a minimally invasive approach to a major abdominal operation and is feasible in a stepwise, reproducible technique. It is associated with improved postoperative outcomes and equivalent oncologic outcomes compared to open TP.

Frailty Correlates with Postoperative Mortality and Major Morbidity After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Frailty is increasingly being recognized as a powerful predictor of postoperative outcomes for cancer patients. This study examined the role of the modified frailty index (MFI) in predicting outcomes for patients undergoing cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Data from National Surgical Quality Improvement Program (NSQIP) patients who underwent CRS/HIPEC between 2005 and 2014 were reviewed. The MFI, validated for use in NSQIP, was used to determine correlation between frailty and postoperative outcomes. RESULTS: The analysis included 1171 patients. The patients were divided into three groups: non-frail (MFI 0), mildly frail (MFI 1 or 2), or severely frail (MFI ≥ 3). More than 90% of patients had an MFI of 0 or 1. The MFI was 0 for 716 patients (61.1%), 1 for 373 patients (31.9%), 2 for 76 patients (6.5%), 3 for 5 patients (0.4%), and 4 for 1 patient (0.1%). Overall, grade 4 Clavien morbidity was observed in 99 patients (8.5%) and mortality in 26 patients (2.2%). For non-frail, mildly frail, and severely frail patients, worsening frailty correlated respectively with increases in grade 4 Clavien morbidity (6.7% vs. 10.9% vs. 33.3%; p = 0.004) and mortality (1.3% vs. 3.3% vs. 33.3%; p < 0.001). In the multivariate analysis, which included age of 70 years or older and albumin level of 3 or lower, frailty was the only factor that correlated with postoperative mortality: non-frail:reference, mildly frail [odds ratio (OR) 2.76, 95% confidence interval (CI) 1.14-6.73; p = 0.025], severely frail (OR 29.1, 95% CI 4-210.87; p = 0.01), age of 70 years or older (OR 1.16, 95% CI 0.34-3.93; p = 0.81), and albumin level of 3 or lower (OR 2.42, 95% CI 0.84-6.98; p = 0.1). CONCLUSIONS: Frailty is a strong predictor of major grade 4 morbidity and mortality after CRS/HIPEC. Severe frailty should be a relative contraindication to CRS/HIPEC. Frailty correlates should be a selection factor in the evaluation of all candidates for CRS/HIPEC.

Robotic Total Pelvic Exenteration: Video-Illustrated Technique.

BACKGROUND: Robotic-assisted total pelvic exenteration (TPE) can offer a minimally invasive approach to a major multi-organ operation. METHODS: In this video, we summarize a stepwise approach to robotic TPE in a 70 year-old female Jehovah's witness with a history of cervical cancer post-chemoradiation and radical hysterectomy who experienced local recurrence at the vaginal cuff involving the rectum and bladder. RESULTS: The patient was placed in the lithotomy position. A total of six robotic ports were used and the da Vinci Si robotic system was docked between the legs. We proceeded as follows: (1) the abdomen and pelvis were thoroughly explored for evidence of metastatic disease; (2) the pelvic sidewalls were mobilized and bilateral ureters identified; (3) the mesorectal plane was dissected to the level of the levators; (4) the lateral and anterior pelvic structures were completely mobilized, and parametrial tissues were mobilized to the pelvic wall; (5) the bladder was separated from the pubis symphysis, the space of Retzius entered, and the bladder and proximal urethra freed; (6) a perineal incision was made around the vagina, perineal body, and anus, which were excised; (7) an Alloderm mesh secured the pelvic floor, and an omental J flap was mobilized; and (8) a 6 cm incision was utilized for creation of an ileal conduit and a permanent-end colostomy. Final pathology was consistent with recurrent cervical squamous cell carcinoma invading into the vaginal, bladder, and rectal walls. Surgical margins and seven lymph nodes were negative for carcinoma. CONCLUSION: Robotic-assisted TPE is technically feasible in a Jehovah's witness under a multidisciplinary surgical team, even in the setting of prior radical hysterectomy and irradiated tissue.

Interval between cytoreductions as a marker of tumor biology in selecting patients for repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND AND OBJECTIVES: Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for recurrence of peritoneal surface malignancies is safe and effective. Patient selection and factors associated with a favorable outcome are still evolving. METHODS: A prospectively maintained institutional database consisting of 1314 CRS/HIPEC procedures performed between February 1993 and December 2015 was reviewed. Clinicopathologic data from 103 patients and 112 (8.5%) repeat CRS/HIPEC procedures were retrospectively analyzed. RESULTS: Primary tumors were appendiceal for 60 patients (58.3%), mesothelioma for 14 (13.6%), colorectal for 9 (8.7%), ovarian for 8 (7.8%). R0/R1 resection was achieved in 46 (46.5%) patients. The time interval between the initial and the repeat CRS/HIPEC was <1 year for 21 (20.4%), 1-2 years for 40 (38.8%), and >2 years for 42 patients (40.8%). Overall median survival was 4.3 years and correlated with the time interval (1.3 years for <1 years, 3.7 years for 1-2 years, and 7 years for >2 years; P < 0.001). In multivariate analysis, the R status (P = 0.005) and a time interval of more than 2 years (P = 0.0002) were strongly associated with survival with each additional month between the surgeries conferring a 2.6% reduction in the risk of death. CONCLUSIONS: The current series validates time interval between cytoreductions as a major surrogate of tumor biology in selection of patients with recurrent peritoneal surface malignancies for repeat CRS/HIPEC. Complete repeat cytoreduction more than 2 years from the initial surgery is associated with a favorable outcome.