Tungsten-anisole complex provides 3,6-substituted cyclohexenes for highly diversified chemical libraries.

Medicinal chemists use vast combinatorial molecular libraries to develop leads for new pharmaceuticals. The syntheses of these compounds typically rely on coupling molecular fragments through atoms with planar (sp2) geometry. These so-called flat molecules often lack the protein binding site specificity needed to be an effective drug. Here, we demonstrate a coupling strategy in which a cyclohexene is used as a linker to connect two diverse molecular fragments while forming two new tetrahedral (sp3) stereocenters. These connections are made with the aid of a tungsten complex that activates anisole toward an unusual double protonation, followed by sequential nucleophilic additions. As a result, either cis- or trans-disubstituted cyclohexenes can be prepared with a range of chemical diversity unparalleled by other dearomatization methods.

Risk factors for failure to rescue after hepatectomy in a high-volume UK tertiary referral center.

BACKGROUND: Mortality after severe complications after hepatectomy (failure to rescue) is strongly linked to center volume. The aim of this study was to evaluate the risk factors for failure to rescue after hepatectomy in a high-volume center. METHODS: Retrospective study of 1,826 consecutive patients who underwent hepatectomy from 2011 to 2018. The primary outcome was a 90-day failure to rescue, defined as death within 90 days posthepatectomy after a severe (Clavien-Dindo grade 3+) complication. Risk factors for 90-day failure to rescue were evaluated using a multivariable binary logistic regression model. RESULTS: The cohort had a median age of 65.3 years, and 56.6% of patients were male. The commonest indication for hepatectomy was colorectal metastasis (58.9%), and 46.9% of patients underwent major or extra-major hepatectomy. Severe complications developed in 209 patients (11.4%), for whom the 30- and 90-day failure to rescue rates were 17.0% and 35.4%, respectively. On multivariable analysis, increasing age (P = .006) and modified Frailty Index (P = .044), complication type (medical or combined medical/surgical versus surgical; P < .001), and body mass index (P = .018) were found to be significant independent predictors of 90-day failure to rescue. CONCLUSION: Older and frail patients who experience medical complications are particularly at risk of failure to rescue after hepatectomy. These results may inform preoperative counseling and may help to identify candidates for prehabilitation. Further study is needed to assess whether failure to rescue rates could be reduced by perioperative interventions.

Minimally Invasive versus Open Distal Pancreatectomy in the 2020s: Recent Institutional Experience and a Narrative Review of Current Evidence.

(1) Background: Distal pancreatectomy is a standard treatment for tumours of the pancreatic body and tail. Minimally invasive techniques for all types of pancreatic tumours (benign and malignant) are being established, while concerns regarding oncological safety, cost effectiveness and learning curves are being explored with prospective studies. This paper presents our unit's data in the context of the above concerns and provides a relevant narrative review of the current literature. (2) Methods: Data were collected retrospectively between 2014 and 2021 for all adult patients who underwent elective distal pancreatectomy in our tertiary care referral HPB Unit. Data on demographics, underlying pathology, perioperative variables and post-operative complications were collected and reported using descriptive statistics. On review of the Miami guidelines, four important but less validated areas regarding distal pancreatectomy are presented in light of the current evidence; these are recent randomised controlled trials, oncological safety, cost effectiveness and learning curves in minimally invasive distal pancreatectomy (MIDP). (3) Results: 207 patients underwent distal pancreatectomy in total from 2014-2021, with 114 and 93 patients undergoing open and minimally invasive techniques, respectively. 44 patients were operated on for PDAC in the open vs. 17 in the minimally invasive group. The operative time was 212 min for the open and 248 min for the minimally invasive group. The incidence of pancreatic fistula was higher in the minimally invasive group vs. the open group (16% vs. 4%). (4) Conclusions: Our unit's data conform with the published literature, including three randomised control trials. These published studies will not only pave the way for establishing minimally invasive techniques for suitable patients, but also define their limitations and indications. Future studies will inform us about the oncological safety, cost effectiveness, overall survival and learning curves regarding patients undergoing minimally invasive distal pancreatectomy.

Use of Near-Infrared Fluorescence Techniques in Minimally Invasive Surgery for Colorectal Liver Metastases.

Colorectal liver metastases (CRLM) afflict a significant proportion of patients with colorectal cancer (CRC), ranging from 25% to 30% of patients throughout the course of the disease. In recent years, there has been a surge of interest in the application of near-infrared fluorescence (NIRF) imaging as an intraoperative imaging technique for liver surgery. The utilisation of NIRF-guided liver surgery, facilitated by the administration of fluorescent dye indocyanine green (ICG), has gained traction in numerous medical institutions worldwide. This innovative approach aims to enhance lesion differentiation and provide valuable guidance for surgical margins. The use of ICG, particularly in minimally invasive surgery, has the potential to improve lesion detection rates, increase the likelihood of achieving R0 resection, and enable anatomically guided resections. However, it is important to acknowledge the limitations of ICG, such as its low specificity. Consequently, there has been a growing demand for the development of tumour-specific fluorescent probes and the advancement of camera systems, which are expected to address these concerns and further refine the accuracy and reliability of intraoperative fluorescence imaging in liver surgery. While NIRF imaging has been extensively studied in patients with CRLM, it is worth noting that a significant proportion of published research has predominantly focused on the detection of hepatocellular carcinoma (HCC). In this study, we present a comprehensive literature review of the existing literature pertaining to intraoperative fluorescence imaging in minimally invasive surgery for CRLM. Moreover, our analysis places specific emphasis on the techniques employed in liver resection using ICG, with a focus on tumour detection in minimal invasive surgery (MIS). Additionally, we delve into recent developments in this field and offer insights into future perspectives for further advancements.

Detection of Colorectal Liver Metastases Using Near-Infrared Fluorescence Imaging During Hepatectomy: Prospective Single Centre UK Study.

INTRODUCTION: Small superficial colorectal liver metastases (CLM) may be difficult to localise intraoperatively, especially during minimally invasive hepatectomy due to reduced tactile feedback and limitations of ultrasound (US). Near-infrared (NIRF) fluorescence imaging is an emerging technology that permits detection of liver tumours after systemic injection of indocyanine green (ICG). Our aim was to report our experience using NIRF to detect CLM. PATIENTS AND METHODS: Patients with small, superficial resectable CLM received a 10-mg IV bolus of ICG the day before hepatectomy. All patients underwent preoperative liver-specific MRI. CLM were localised intraoperatively using a combination of white light/ultrasound (WL-US) and NIRF. Sensitivity and specificity of NIRF were compared with WL-US. RESULTS: Between March 2019 and July 2021, NIRF was utilised in 15 patients who underwent hepatectomy (laparoscopic 13, open 2). Thirty-two lesions were detected by MRI (including 3 disappearing CLM), of which 2 were ICG-negative and not resected (1 haemangioma, 1 disappearing CLM). Of 30 resected lesions, the median tumour diameter was 11 mm (range 2-25), median distance from liver surface was 4.5 mm (range 0-20) and all were confirmed CLM on histology (R0 resection rate 71%). Twenty-three of thirty (77%) and twenty-seven of thirty (90%) resected CLM were detected by WL-US and NIRF, respectively. Of 7/30 (23%) resected CLM that were WL-US negative, 5 were ICG-positive. Two resected 'disappearing' CLM were ICG-positive, one of which contained viable cancer cells. Overall, NIRF influenced the operative strategy in 6 patients (43%). CONCLUSION: Near-infrared fluorescence imaging allows detection of small, superficial colorectal liver metastases that are missed by conventional techniques and warrants further study.

Requirement of preoperative blood typing for cholecystectomy and appendectomy: a systematic review.

PURPOSE: Blood typing, or group and save (G&S) testing, is commonly performed prior to cholecystectomy and appendectomy in many hospitals. In order to determine whether G&S testing is required prior to these procedures, we set out to evaluate the relevant literature and associated rates of perioperative blood transfusion. METHODS: Studies from January 1990 to June 2021 assessing the requirement of preoperative G&S testing for elective or emergency cholecystectomy and appendectomy were retrieved from MEDLINE, EMBASE and CINAHL databases. The search was performed on 6th July 2021 (PROSPERO registration number CRD42021267967). Number of patients, co-morbidities, operation performed, number of patients that underwent preoperative G&S testing, perioperative transfusion rates and financial costs were extracted. RESULTS: We initially screened 194 studies of which 15 retrospective studies, a total of 477,437 patients, specifically met the inclusion criteria. Ten studies reported on cholecystectomy, two studies on appendectomy and three studies included both procedures. Where reported, a total of 177,539/469,342 (37.8%) patients underwent preoperative G&S testing with a perioperative transfusion rate of 2.1% (range 0.0 to 2.1%). The main preoperative risk factors associated with perioperative blood transfusion identified include cardiovascular co-morbidity, coagulopathy, anaemia and haematological malignancy. All 15 studies concluded that routine G&S is not warranted. CONCLUSION: The current evidence suggests that G&S is not necessarily required for all patients undergoing cholecystectomy or appendectomy. Having a targeted G&S approach would reduce delays in elective and emergency lists, reduce the burden on the blood transfusion service and have financial implications.

Normothermic Machine Perfusion-Improving the Supply of Transplantable Livers for High-Risk Recipients.

The effectiveness of liver transplantation to cure numerous diseases, alleviate suffering, and improve patient survival has led to an ever increasing demand. Improvements in preoperative management, surgical technique, and postoperative care have allowed increasingly complicated and high-risk patients to be safely transplanted. As a result, many patients are safely transplanted in the modern era that would have been considered untransplantable in times gone by. Despite this, more gains are possible as the science behind transplantation is increasingly understood. Normothermic machine perfusion of liver grafts builds on these gains further by increasing the safe use of grafts with suboptimal features, through objective assessment of both hepatocyte and cholangiocyte function. This technology can minimize cold ischemia, but prolong total preservation time, with particular benefits for suboptimal grafts and surgically challenging recipients. In addition to more physiological and favorable preservation conditions for grafts with risk factors for poor outcome, the extended preservation time benefits operative logistics by allowing a careful explant and complicated vascular reconstruction when presented with challenging surgical scenarios. This technology represents a significant advancement in graft preservation techniques and the transplant community must continue to incorporate this technology to ensure the benefits of liver transplant are maximized.

Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer.

HIV Envelope (Env) is the main vaccine target for induction of neutralizing antibodies. Stabilizing Env into native-like trimer (NLT) conformations is required for recombinant protein immunogens to induce autologous neutralizing antibodies(nAbs) against difficult to neutralize HIV strains (tier-2) in rabbits and non-human primates. Immunizations of mice with NLTs have generally failed to induce tier-2 nAbs. Here, we show that DNA-encoded NLTs fold properly in vivo and induce autologous tier-2 nAbs in mice. DNA-encoded NLTs also uniquely induce both CD4 + and CD8 + T-cell responses as compared to corresponding protein immunizations. Murine neutralizing antibodies are identified with an advanced sequencing technology. The structure of an Env-Ab (C05) complex, as determined by cryo-EM, identifies a previously undescribed neutralizing Env C3/V5 epitope. Beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines.

Meta-analysis of transanal vs laparoscopic total mesorectal excision of low rectal cancer: Importance of appropriate patient selection.

BACKGROUND: Achieving a clear resection margins for low rectal cancer is technically challenging. Transanal approach to total mesorectal excision (TME) was introduced in order to address the challenges associated with the laparoscopic approach in treating low rectal cancers. However, previous meta-analyses have included mixed population with mid and low rectal tumours when comparing both approaches which has made the interpretation of the real differences between two approaches in treating low rectal cancer difficult. AIM: To investigate the outcomes of transanal TME (TaTME) and laparoscopic TME (LaTME) in patients with low rectal cancer. METHODS: A comprehensive systematic review of comparative studies was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. Intraoperative and postoperative complications, anastomotic leak, R0 resection, completeness of mesorectal excision, circumferential resection margin (CRM), distal resection margin (DRM), harvested lymph nodes, and operation time were the investigated outcome measures. RESULTS: We included twelve comparative studies enrolling 969 patients comparing TaTME (n = 969) and LaTME (n = 476) in patients with low rectal tumours. TaTME was associated with significantly lower risk of postoperative complications (OR: 0.74, P = 0.04), anastomotic leak (OR: 0.59, P = 0.02), and conversion to an open procedure (OR: 0.29, P = 0.002) in comparison with LaTME. Moreover, the rate of R0 resection was significantly higher in the TaTME group (OR: 1.96, P = 0.03). Nevertheless, TaTME and LaTME were comparable in terms of rate of intraoperative complications (OR: 1.87; P = 0.23), completeness of mesoractal excision (OR: 1.57, P = 0.15), harvested lymph nodes (MD: -0.05, P = 0.96), DRM (MD: -0.94; P = 0.17), CRM (MD: 1.08, P = 0.17), positive CRM (OR: 0.64, P = 0.11) and procedure time (MD: -6.99 min, P = 0.45). CONCLUSION: Our findings indicated that for low rectal tumours, TaTME is associated with better clinical and short term oncological outcomes compared to LaTME. More randomised controlled trials are required to confirm these findings and to evaluate long term oncological and functional outcomes.