Search

Background: Surgical debulking of neuroendocrine tumor (NET) is used as a therapeutic approach for metastatic NETs in selected centers. Reported outcomes after parenchymal-sparing liver resections (PSR) in NET patients with high numbers of liver metastases are sparse. Methods: NET patients that underwent surgical debulking from 2019 to 2021 were reviewed. Trends in perioperative liver function was examined, as well as symptom response, complications, and progression free survival. Results: 1069 liver lesions (median=17) were debulked from 53 patients with a combination of PSR (45%) and ultrasound-guided microwave ablations (MWA) (55%). Post-operative transaminitis was proportional to the number of lesions debulked: Median POD1 AST was 681 IU/L for 1-15 lesions vs. 1396 IU/L for >15 lesions, p=0.01 (R2=0.271, pp=0.01 (R2=0.221, p9/L for 1-15 lesions vs. 109 x 109/L for >15 lesions, p=0.04; R2=0.163, p=0.003). Synthetic liver function measured by postoperative INR (median POD1 INR 1.3 vs 1.4, p=0.21) and total bilirubin (median POD 2 TB 1.35 vs 0.95 mg/dL; p=0.67) did not differ according to number of lesions debulked. 13% of patients sustained a Clavien-Dindo grade 3/4 complication which was not associated with the number of lesions targeted. All patients with preoperative symptoms had improvement after surgery. Median time to recurrence was 10.9 months. Conclusions: PSR with MWA for large numbers of NET liver metastases is safe and effective for symptom control and does not affect synthetic liver function. Transaminitis and thrombocytopenia are proportionate to the amount of liver lesions debulked.

Transarterial chemoembolization (TACE) is used to treat patients with unresectable hepatocellular carcinoma (HCC). We evaluated the clinical impact of a-fetoprotein (AFP) and circulating cell-free and tumor DNA (cfDNA and ctDNA) changes around the TACE procedure. Our prospective monocentric study enrolled consecutive patients treated with TACE, with samples collected at baseline (D - 1), Day 2 (D + 2) and 1 month (M + 1) after TACE. cfDNA was quantified by the fluorometric method, and ctDNA was quantified by digital polymerase chain reaction designed for two hotspot TERT mutations. Computerized tomography scans or magnetic resonance imaging were performed at M + 1 every 3 months following TACE and independently reviewed. The objective was to identify thresholds of cfDNA, ctDNA and AFP changes associated with progressive disease (PD) using receiver operating characteristic curves. Thirty-eight patients were included from March 2018 to March 2019. All markers significantly increased from D - 1 to D + 2 (P .005), and cfDNA and ctDNA significantly decreased from D + 2 to M + 1 (P .0001). The analysis of changes from D - 1 to M + 1 identified thresholds at +31.4% for cfDNA and 0% for ctDNA that were significantly associated with PD at M + 1 (44.4% [+31.4%] vs 3.8% [≤+31.4%] and 50.0% [0%] vs 5.0% [≤0%], respectively). No significant threshold was identified for AFP. Using a score combining cfDNA and ctDNA, the patients were classified into high- or low-risk PD groups at M + 1, with PD rates of 80.0% vs 4.3% (P = .001) and median progression-free survival times of 1.3 vs 10.3 months (P = .002). Our study suggests that cfDNA and ctDNA increases around the TACE procedure and are associated with therapeutic failure.

The proximate and ultimate mechanisms behind individual behavioural phenotypes are still only partially understood, with studies often focusing on a single or a few factor(s) that affect behaviour in a controlled environment. To understand the development and consequences of individual behavioural phenotypes in their complexity, a comprehensive approach is needed that analyses the effects of a broad spectrum of factors and their interactions on behaviour within the natural environment. We used focal observations to quantify four key behavioural components of Gala = pagos sea lion, Zalophus wollebaeki, pups under natural conditions: general social interactions, swimming, resting and social play behaviour. We then investigated the influence and interplay of age, sex, body condition, basal cortisol and testosterone levels, personality scores and the social environment on the observed behaviour. We identified significant correlations between all measured factors and behaviour. Complex interactions between testosterone, boldness and social play especially stand out, with the effect of boldness on social play being dependent on testosterone levels. We also demonstrate the importance of the early social environment, defined as local population density, for social play and, interestingly, time spent swimming. This could have consequences for the development of social and hunting skills, crucial for later stages of ontogeny. For this endangered pinniped, a decline in the diversity of social environments due to dwindling population numbers could lead to a decline in behavioural diversity and lower coping abilities towards future changes in their environment. Our study reveals important factors for the development of individual behavioural phenotypes of young Gala = pagos sea lions and elucidates some aspects of the architecture behind this individual variation in behaviour. (c) 2021 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.

Several surgical teams have developed so-called minimally invasive esophagectomy techniques with the intention of decreasing post-operative complications. The goal of this report is to determine the feasibility, reproducibility, morbidity and mortality of esophagectomy and intrathoracic anastomosis via thoracoscopy.This retrospective series included 114 consecutive non-selected patients who underwent Lewis Santy type esophagectomy between 2016 and 2020. The procedure was performed via abdominal laparoscopy, thoracoscopy with the patient in a supine position, without selective intubation, with intra-thoracic semi-mechanical triangular esophagogastric anastomosis.Mean patient age was 62.8years. Conversion from laparoscopy to laparotomy was required in three patients (2.6%); no patient required conversion from thoracoscopy to thoracotomy. A semi-mechanical triangular esophagogastric anastomosis was successfully performed in all patients. Median duration of hospital stay was 16 (8-116) days. Mortality was 2.6%; 34 patients (29.8%) had major complications, 55 (48%) had a respiratory complication. The leakage rate was 12.3%; most were type I. Only 5.2% required an additional procedure. There was no mortality.The analysis of this consecutive series found that this operative technique was reproducible and reliable. These results need to be confirmed by other studies. Pulmonary morbidity was high and remains the main challenge in this type of surgery.

Pancreatic ductal adenocarcinoma (PDAC) is associated with increased venous thromboembolism (VTE). We sought to compare rates of bleeding complications and VTE in patients receiving extended postoperative thromboprophylaxis (EPT) to those who did not, and identify risk factors for VTE after pancreatectomy for PDAC.This is a retrospective review of pancreatectomies for PDAC. EPT was defined as 28 days of low molecular weight heparin. Multivariable analysis (MVA) was performed to identify independent risk factors of VTE.Of 269 patients included, 142 (52.8%) received EPT. Of those who received EPT, 7 (4.9%) suffered bleeding complications, compared to 6 (4.7%) of those who did not (p = 0.938). There was no significant difference in VTE rate at 90 days (2.8% vs. 2.4%, p = 0.728) or at 1 year (6.3% vs. 7.9%, p = 0.624). On MVA, risk factors for VTE included worse performance status, lower preoperative hematocrit, R1/R2 resection, and minimally invasive (MIS) approach. Among those who received EPT, there was no difference in VTE rate between MIS and open approach.EPT was not associated with a difference in VTE risk or bleeding complications. MIS approach was associated with a higher risk of VTE; however, this was significantly lower among those who received EPT.

Introduction Despite the increasing availability of early reperfusion, acute ischemic stroke (AIS) is still burdened by high mortality and long-time disability. Junctional protein associated with Coronary Artery Disease (JCAD) was associated to multiple cardiovascular disorders, but its role in AIS has not been investigated so far. Purpose To investigate the role of endothelial JCAD in the pathogenesis of AIS and its potential as a therapeutic target. Methods Cerebral ischemia was induced by transient Middle Cerebral Artery Occlusion (tMCAO) in mice with either global or endothelial-specific JCAD genetic deletion, and littermate controls. Stroke size was assessed ex-vivo by tetrazolium chloride staining 48 hours after reperfusion. For neurological assessment, RotaRod Test and Bederson score were recorded 24 and 48 hours after reperfusion. In vivo silencing of JCAD was achieved by intravenous injection of a JCAD small interfering RNA (siRNA) after tMCAO. In parallel, JCAD silencing was performed in vitro in human brain microvascular endothelial cells (HBMVECs) using siRNA transfection, followed by hypoxia/reoxygenation (H/R) injury. Cell death and trans-endothelial electrical resistance (TEER) were measured by LDH assay and electrical cell-substrate impedance sensing, respectively. Molecular mechanisms were investigated in vivo by immunohistochemistry and in vitro by Western blot, respectively. Lastly, JCAD plasma levels were measured by ELISA in two independent cohorts of patients with AIS. Results The expression of JCAD was up-regulated in the ipsilateral hemisphere of stroke in wild-type mice. Both global and endothelial-specific JCAD knockout mice displayed reduced stroke size after tMCAO and a significantly improved Bederson score. Similarly, mice with post-ischemic JCAD silencing had a reduced stroke size and a better motor performance at the RotaRod test (Figure 1). In vitro, JCAD-silenced HBMVECs showed a reduced cell death rate and a higher TEER after H/R injury, compared to controls. JCAD-silenced HBMVECs also had an increased phosphorylation of Akt. After treatment with the Akt/PI3K inhibitor Wortmannin, JCAD-silenced HBMVECs showed similar TEER and cell death rates to non-silenced cells, following H/R (Figure 2). Lastly, an increase of circulating levels of JCAD was observed in patients with AIS within 24 hours from symptoms onset. Furthermore, higher levels of JCAD at the time of hospitalization were associated with a higher risk of death within 90 days after the event. Conclusions JCAD expression is associated with a larger brain damage in mice in vivo and with a higher mortality in patients. In vitro results suggest that JCAD plays a pivotal role in regulating the integrity of endothelium after a H/R injury, inducing cellular death through the inhibition of the Akt/PI3K pathway. Thus, post-ischemic silencing of JCAD may represent a therapeutic strategy to improve the prognosis of patients with acute ischemic stroke. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation

Fat-level measurements used to indicate individual body condition and fitness are useful only when taken at a region along the body where fat responds to variations in caloric intake. Investigations to identify appropriate species-specific regions are limited, especially for cetaceans that have a specialized fat (blubber) that serves as an energy reserve and provides insulation. Over 18 mo, body mass of six pilot whales varied (range: 50-172 kg), and although caloric intake increased when water temperatures were lower, generally the best-fitting state-space model for length-adjusted mass was based on a single factor, caloric intake. After correcting for body length (range: 330-447 cm), the slope for blubber thickness and "blubber ring" thickness (average blubber thickness along a girth) in relation to body mass was positive and had a P value of

In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.

Vein grafts, the most commonly used conduits in multi-vessel coronary artery bypass grafting surgery, have high intermediate- and long-term failure rates. The abrupt and marked increase in hemodynamic loads on the vein graft is a known contributor to failure. Recent computational modeling suggests that veins can more successfully adapt to an increase in mechanical load if the rate of loading is gradual. Applying an external wrap or support at the time of surgery is one way to reduce the transmural load, and this approach has improved performance relative to an unsupported vein graft in several animal studies. Yet, a clinical trial in humans has shown benefits and drawbacks, and mechanisms by which an external wrap affects vein graft adaptation remain unknown. This study aims to elucidate such mechanisms using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, hemodynamics using computational fluid dynamics, structure using histology, and transcriptional changes using bulk RNA-sequencing in an ovine carotid-jugular interposition vein graft model, without and with an external biodegradable wrap that allows loads to increase gradually. We show that a biodegradable external wrap promotes luminal uniformity, physiological wall shear stress, and a consistent vein graft phenotype, namely, it prevents over-distension, over-thickening, intimal hyperplasia, and inflammation, and it preserves mechanotransduction. These mechanobiological insights into vein graft adaptation in the presence of an external support can inform computational growth and remodeling models of external support and facilitate design and manufacturing of next-generation external wrapping devices. STATEMENT OF SIGNIFICANCE: External mechanical support is emerging as a promising technology to prevent vein graft failure following coronary bypass graft surgery. While variants of this technology are currently under investigation in clinical trials, the fundamental mechanisms of adaptation remain poorly understood. We employ an ovine carotid-jugular interposition vein graft model, with and without an external biodegradable wrap to provide mechanical support, and probe vein graft adaptation using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, fluid flow using computational fluid dynamics, vascular composition and structure using histology, and transcriptional changes using bulk RNA sequencing. We show that the wrap mitigates vein graft failure by promoting multiple adaptive mechanisms (across biological scales).

Despite high mortality rates from gastric cancer, surgical management remains critical for curative potential. Optimal outcomes of gastric cancer resection depend on a multitude of variables, including the extent of resection, scope of lymphadenectomy, method of reconstruction, and potential for a minimally invasive approach. Laparoscopic gastrectomy, compared with open gastrectomy, has been analyzed in numerous randomized control trials. Generally, those trials demonstrated statistically similar postoperative complication rates, mortality, and oncologic outcomes between the two approaches. Although laparoscopic gastrectomy requires longer operative times, significant improvements in estimated blood loss, postoperative length of stay, and return of bowel function have been noted in patients who undergo laparoscopic gastrectomy. These short-term benefits, along with equivalent oncologic results, have influenced national guidelines in both Eastern and Western countries to recommend laparoscopy, especially for early stage disease. Although robotic gastrectomy has not been as widely validated in effective trials, studies have reported equivalent oncologic outcomes and similar or improved postoperative complication and recovery rates after robotic gastrectomy compared with open gastrectomy. Comparing the two minimally invasive gastrectomy approaches, robotic surgery was associated with improved estimated blood loss, incidence of pancreatic sequela, and lymph node harvests in some studies, whereas laparoscopy resulted in lower operative times and hospital costs. Ultimately, when applying outcomes from the literature to clinical patient care decisions, it is imperative to recognize these studies' range of inclusion criteria, delineating between patients originating from Eastern or Western countries, the use of neoadjuvant chemotherapy, the volume of surgeon experience, and the extent of gastrectomy, among others.

The growth in minimally invasive pancreatic surgery (MIPS) has been accompanied by a recent surge in evidence-based data available to analyze patient outcomes. A small complement of randomized control trials as well as a multitude of observational studies have demonstrated both consistent similarities and differences between MIPS and the open approach, although abundant questions remain. This review highlights the available literature and emphasizes key factors for evaluating laparoscopic and robotic pancreatic surgery.

Foraging strategies are of great ecological interest, as they have a strong impact on the fitness of an individual and can affect its ability to cope with a changing environment. Recent studies on foraging strategies show a higher complexity than previously thought due to intraspecific variability. To reliably identify foraging strategies and describe the different foraging niches they allow individual animals to realize, high-resolution multivariate approaches which consider individual variation are required. Here we dive into the foraging strategies of Galápagos sea lions (Zalophus wollebaeki), a tropical predator confronted with substantial annual variation in sea surface temperature. This affects prey abundance, and El Niño events, expected to become more frequent and severe with climate change, are known to have dramatic effects on sea lions. This study used high-resolution measures of depth, GPS position and acceleration collected from 39 lactating sea lion females to analyze their foraging strategies at an unprecedented level of detail using a novel combination of automated broken stick algorithm, hierarchical cluster analysis and individually fitted multivariate hidden Markov models. We found three distinct foraging strategies (pelagic, benthic, and night divers), which differed in their horizontal, vertical and temporal distribution, most likely corresponding to different prey species, and allowed us to formulate hypotheses with regard to adaptive values under different environmental scenarios. We demonstrate the advantages of our multivariate approach and inclusion of individual variation to reliably gain a deeper understanding of the adaptive value and ecological relevance of foraging strategies of marine predators in dynamic environments. Supplementary Information The online version contains supplementary material available at 10.1007/s00442-021-04850-w.

Facing persistent shortages of qualified nurses, Baystate Health partnered with a staffing firm to bring 30 RNs from 10 countries to western Massachusetts. Nurses had passed the licensure exam, demonstrated command of English, and held valid green cards, giving them permanent US residency status. Baystate focused on diversity and inclusion implications, anticipating potential roadblocks to success, and maximizing the value of the international nurses. Prior to the international nurses’ arrival, existing staff were informed and surveyed on their perceptions; based on those perceptions, targeted cross-cultural training was developed and delivered. The effectiveness of the program is being assessed before expansion.

Resume La pandemie due au COVID-19 modifie l’organisation des soins et change la realisation de la chirurgie digestive. Les priorites sanitaires et les circuits de soins sont modifies. La chirurgie d’urgence reste prioritaire. Les interventions pour chirurgie fonctionnelles sont a reporter. La chirurgie par laparoscopie doit suivre des regles strictes pour ne pas exposer les professionnels a un surrisque. Le questionnement principal concerne la chirurgie oncologique, operer ou reporter ? Il existe probablement un sur risque operatoire induit par la pandemie qui doit etre mis en balance avec le retard de prise en charge chirurgical. Pour chaque type de cancer, colon, pancreas, œsogastrique, hepatocarcinome, la morbi-mortalite est rappelee et mise en parallele avec le risque oncologique lie au retard a la chirurgie et/ou au temps de doublement de la tumeur. Cette comparaison permet de proposer des strategies, ainsi pour les cancers coliques (T1-2, N0), il est souhaitable de retarder la chirurgie. Pour les lesions coliques avancees, il semble prudent de recommander une chimiotherapie neo adjuvante et d’attendre. Pour les cancers du rectum T3-4 et/ou N+, une radio-chimiotherapie est indiquee, une radiotherapie courte devra etre discutee (suivie d’une periode d’attente) afin de reduire le temps d’exposition a l’hopital et d’eviter les infections. La majorite des chirurgies complexes a forte morbi-mortalite, œsogastrique, hepatique ou pancreatique doivent sans doute le plus souvent etre reportee.

International audience; Introduction - Patients treated for malignancy are considered at risk of severe COVID-19. This exceptional pandemic has affected countries on every level, particularly health systems which are experiencing saturation. Like many countries, France is currently greatly exposed, and a complete reorganization of hospitals is ongoing. We propose here adaptations of diagnostic procedures, therapies and care strategies for patients treated for digestive cancer during the COVID-19 epidemic. Methods - French societies of gastroenterology and gastrointestinal (GI) oncology carried out this study to answer two main questions that have arisen (i) how can we limit high-risk situations for GI-cancer patients and (ii) how can we limit contact between patients and care centers to decrease patients' risk of contamination while continuing to treat their cancer. All recommendations are graded as experts' agreement according to the level of evidence found in the literature until March 2020. Results - A proposal to adapt treatment strategies was made for the main GI oncology situations. Considering the level of evidence and the heterogeneous progression of the COVID-19 epidemic, all proposals need to be considered by a multidisciplinary team and implemented with patient consent. Conclusion - COVID-19 epidemic may significantly affect patients treated for digestive malignancies. Healthcare teams need to consider adapting treatment sequences when feasible and according to the epidemic situation.

International audience; Purpose of review The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives.Recent findings Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin at least 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC.Summary After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit patients with PDAC. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients.

International audience; Background: Spontaneous rupture of hepatocellular carcinoma (HCC) remains a life-threatening complication, with a reported mortality rate of between 16 and 30% and an incidence rate of approximately 3% in Europe. Survival data and risk factors after ruptured HCC are lacking, especially for peritoneal metastasis (PM).Objectives: The aims of this study were to evaluate the pattern of recurrence and mortality after hepatectomy for ruptured HCC, and to focus on PM.Methods: We retrospectively reviewed the files of patients admitted to 14 French surgical centers for spontaneous rupture of HCC between May 2000 and May 2012.Results: Overall, 135 patients were included in this study. The median disease-free survival and overall survival (OS) rates were 16.1 (11.0-21.1) and 28.7 (26.0-31.5) months, respectively, and the median follow-up period was 29 months. At last follow-up, recurrences were observed in 65.1% of patients (n = 88). The overall rate of PM following ruptured HCC was 12% (n = 16). Surgical management of PM was performed for six patients, with a median OS of 36.6 months. An α-fetoprotein level > 30 ng/mL (p = 0.0009), tumor size at rupture > 70 mm (p = 0.0009), and vascular involvement (p < 0.0001) were found to be independently associated with an increased likelihood of recurrence. No risk factor for PM was observed.Conclusion: This large-cohort French study confirmed that 12% of patients had PM after ruptured HCC. A curative approach may be an option for highly selected patients with exclusive PD because of the survival benefit it could provide.

SummaryThe E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.

Mitochondrial transport relies on a motor-adaptor complex containing Miro1, a mitochondrial outer membrane protein with two GTPase domains, as well as TRAK1/2, kinesin-1, and dynein. Using a peroxisome-directed Miro1, we quantified the ability of GTPase mutations to influence peroxisomal recruitment of complex components. Miro1 whose N-GTPase is locked in the GDP-state doesn’t recruit TRAK1/2, kinesin or P135 to peroxisomes whereas the GTP-state does. Miro1 C-GTPase mutations have little influence on complex recruitment. Though Miro2 is thought to support mitochondrial motility, peroxisome-directed Miro2 did not recruit the other complex components regardless of the state of its GTPase domains. Neurons expressing peroxisomal Miro1 with the GTP-state form of the N-GTPase had markedly increased peroxisomal transport to growth cones while the GDP-state caused their retention in the soma. Thus, the N-GTPase of Miro1 is critical for regulating Miro1’s interaction with the other components of the motor-adaptor complex and thereby for regulating mitochondrial motility.SummaryA Miro-containing complex mediates mitochondrial motility. Relocalizing Miro1 and 2 to peroxisomes and systematically manipulating each GTPase domain of Miro revealed the importance of the N-terminal GTPase domain of Miro1 for governing interaction with TRAK proteins, motors, and transport.