Reversible oxidation/reduction steps in the metabolic degradation of the glycerol side chain of the S1P1 modulator ponesimod.

1. Ponesimod is a selective modulator of the sphingosine 1-phosphate receptor 1 (S1P1) approved for the treatment of active relapsing forms of multiple sclerosis. The chemical structure of ponesimod contains a glycerol side chain which is the major target of drug metabolism in humans.2. The two major metabolic pathways give the acids M12 (-OCH2CH(OH)COOH) and M13 (-OCH2COOH). While the former results from oxidation of the terminal alcohol, the mechanism yielding the chain-shortened acid M13 is less obvious. A detailed mechanistic study with human liver microsomes and hepatocytes using ponesimod, M12 and some of the suspected intermediates revealed an unexpectedly complex pattern of enzyme-mediated and chemical reactions.3. Metabolic pathways for both acids were not independent and several of the transformations were reversible, depending on reaction conditions. Formation of M13 occurred either via initial oxidation of the secondary alcohol, or as a downstream process starting from M12.4. The phenol metabolite M32 was produced as part of several pathways. Control experiments at various pH values and in the absence of metabolising enzymes support the conclusion that its formation resulted from chemical degradation rather than from metabolic processes.

Long-term quality of life after hybrid robot-assisted and open Ivor Lewis esophagectomy for esophageal cancer in a single center: a comparative analysis.

PURPOSE: Due to improved survival of esophageal cancer patients, long-term quality of life (QoL) is increasingly gaining importance. The aim of this study is to compare QoL outcomes between open Ivor Lewis esophagectomy (Open-E) and a hybrid approach including laparotomy and a robot-assisted thoracic phase (hRob-E). Additionally, a standard group of healthy individuals serves as reference. METHODS: With a median follow-up of 36 months after hRob-E (n = 28) and 40 months after Open-E (n = 43), patients' QoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) and the EORTC Esophagus specific QoL questionnaire 18 (QLQ-OES18). RESULTS: Patients showed similar clinical-pathological characteristics, but hRob-E patients had significantly higher ASA scores at surgery (p < 0.001). Patients and healthy controls reported similar global health status and emotional and cognitive functions. However, physical functioning of Open-E patients was significantly reduced compared to healthy controls (p = 0.019). Operated patients reported reduced role and social functioning, fatigue, nausea and vomiting, dyspnea, and diarrhea. A trend towards a better pain score after hRob-E compared to Open-E emerged (p = 0.063). Regarding QLQ-OES18, hRob-E- and Open-E-treated patients similarly reported eating problems, reflux, and troubles swallowing saliva. CONCLUSIONS: The global health status is not impaired after esophagectomy. Despite higher ASA scores, QoL of hRob-E patients is similar to that of patients operated with Open-E. Moreover, patients after hRob-E appear to have a better score regarding physical functioning and a better pain profile than patients after Open-E, indicating a benefit of minimally invasive surgery.

The short- and long-term outcome after the surgical management of common bile duct stones in a tertiary referral hospital.

BACKGROUND: The removal of common bile duct stones by endoscopic retrograde cholangiopancreatography (ERCP) shows excellent results with low complication rates and is therefore considered a gold standard. However, in case of stones non-removable by ERCP, surgical extraction is needed. The surgical approach is still controversial and clinical guidelines are missing. This study aims to analyze the outcomes of patients treated with choledochotomy or hepaticojejunostomy for common bile duct stones. METHODS: All patients who underwent choledochotomy or hepaticojejunostomy for common bile duct stones at a tertiary referral hospital over 11 years were included. The analyzed data contains basic demographics, diagnostics, surgical parameters, length of hospitalization, and morbidity and mortality. RESULTS: Over the study period, 4375 patients underwent cholecystectomy, and 655 received an ERCP with stone extraction, with 48 of these patients receiving subsequent surgical treatment. ERCP was attempted in 23/30 (77%) of the choledochotomy patients pre/intraoperatively and 11/18 (56%) in hepaticojejunostomy patients. The 30-day major complication rate (Clavien-Dindo > II) was 1/30 (3%) in the choledochotomy group and 2/18 (11%) in the hepaticojejunostomy group. Complications after 30 days occurred in 3/30 (10%) patients and 2/18 (11%), respectively, and no mortality occurred. CONCLUSION: ERCP should still be considered the gold standard, although due to low short- and long-term morbidity rates, choledochotomy and hepaticojejunostomy represent effective surgical solutions for common bile duct stones.

Systematic identification of novel cancer genes through analysis of deep shRNA perturbation screens.

Systematic perturbation screens provide comprehensive resources for the elucidation of cancer driver genes. The perturbation of many genes in relatively few cell lines in such functional screens necessitates the development of specialized computational tools with sufficient statistical power. Here we developed APSiC (Analysis of Perturbation Screens for identifying novel Cancer genes) to identify genetic drivers and effectors in perturbation screens even with few samples. Applying APSiC to the shRNA screen Project DRIVE, APSiC identified well-known and novel putative mutational and amplified cancer genes across all cancer types and in specific cancer types. Additionally, APSiC discovered tumor-promoting and tumor-suppressive effectors, respectively, for individual cancer types, including genes involved in cell cycle control, Wnt/ß-catenin and hippo signalling pathways. We functionally demonstrated that LRRC4B, a putative novel tumor-suppressive effector, suppresses proliferation by delaying cell cycle and modulates apoptosis in breast cancer. We demonstrate APSiC is a robust statistical framework for discovery of novel cancer genes through analysis of large-scale perturbation screens. The analysis of DRIVE using APSiC is provided as a web portal and represents a valuable resource for the discovery of novel cancer genes.

Continuously sutured versus linear-stapled anastomosis in robot-assisted hybrid Ivor Lewis esophageal surgery following neoadjuvant chemoradiotherapy: a single-center cohort study.

BACKGROUND: Esophageal cancer surgery is technically highly demanding. During the past decade robot-assisted surgery has successfully been introduced in esophageal cancer treatment. Various techniques are being evaluated in different centers. In particular, advantages and disadvantages of continuously sutured (COSU) or linear-stapled (LIST) gastroesophageal anastomoses are debated. Here, we comparatively analyzed perioperative morbidities and short-term outcomes in patients undergoing hybrid robot-assisted esophageal surgery following neoadjuvant chemoradiotherapy (nCRT), with COSU or LIST anastomoses in a single center. METHODS: Following standardized, effective, nCRT, 53 patients underwent a hybrid Ivor Lewis robot-assisted esophagectomy with COSU (n = 32) or LIST (n = 21) gastroesophageal anastomoses. Study endpoints were intra- and postoperative complications, in-hospital morbidity and mortality. Duration of operation, intensive care unit (ICU) and overall hospital stay were also evaluated. Furthermore, rates of rehospitalization, endoscopies, anastomotic stenosis and recurrence were assessed in a 90-day follow-up. RESULTS: Demographics, ASA scores and tumor characteristics were comparable in the two groups. Median duration of operation was similar in patients with COSU and LIST anastomosis (467 vs. 453 min, IQR 420-521 vs. 416-469, p = 0.0611). Major complications were observed in 4/32 (12.5%) and 4/21 (19%) patients with COSU or LIST anastomosis, respectively (p = 0.697). Anastomotic leakage was observed in 3/32 (9.3%) and 2/21 (9.5%) (p = 1.0) patients with COSU or LIST anastomosis, respectively. Pleural empyema occurred in 1/32 (3.1%) and 2/21 (9.5%) (p = 0.555) patients, respectively. Mortality was similar in the two groups (1/32, 3.1% and 1/21, 4.7%, p = 1.0). Median ICU stay did not differ in patients with COSU or LIST anastomosis (p = 0.255), whereas a slightly, but significantly (p = 0.0393) shorter overall hospital stay was observed for COSU, as compared to LIST cohort (median: 20 vs. 21 days, IQR 17-22 vs. 18-28). CONCLUSIONS: COSU is not inferior to LIST in the performance of gastroesophageal anastomosis in hybrid Ivor Lewis operations following nCRT.

Robot-assisted vs. laparoscopic repair of complete upside-down stomach hiatal hernia (the RATHER-study): a prospective comparative single center study.

BACKGROUND: Complete upside-down stomach (cUDS) hernias are a subgroup of large hiatal hernias characterized by high risk of life-threatening complications and technically challenging surgical repair including complex mediastinal dissection. In a prospective, comparative clinical study, we evaluated intra- and postoperative outcomes, quality of life and symptomatic recurrence rates in patients with cUDS undergoing robot-assisted, as compared to standard laparoscopic repair (the RATHER-study). METHODS: All patients with cUDS herniation requiring elective surgery in our institution between July 2015 and June 2019 were evaluated. Patients undergoing primary open surgery or additional associated procedures were not considered. Primary endpoints were intra- and postoperative complications, 30-day morbidity, and mortality. During the 8-53 months follow-up period, patients were contacted by telephone to assess symptoms associated to recurrence, whereas quality of life was evaluated utilizing the Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) questionnaire. RESULTS: A total of 55 patients were included. 36 operations were performed with robot-assisted (Rob-G), and 19 with standard laparoscopic (Lap-G) technique. Patients characteristics were similar in both groups. Median operation time was 232 min. (IQR: 145-420) in robot-assisted vs. 163 min. (IQR:112-280) in laparoscopic surgery (p < 0.001). Intraoperative complications occurred in 5/36 (12.5%) cases in the Rob-G group and in 5/19 (26%) cases in the Lap-G group (p = 0.28). No conversion was necessary in either group. Minor postoperative complications occurred in 13/36 (36%) Rob-G patients and 4/19 (21%) Lap-G patients (p = 0.36). Mortality or major complications did not occur in either group. Two asymptomatic recurrences were observed in the Rob-G group only. No patient required revision surgery. Finally, all patients expressed satisfaction for treatment outcome, as indicated by similar GERD-HRQL scores. CONCLUSION: While robot-assisted surgery provides additional precision, enhanced visualization, and greater feasibility in cUDS hiatal hernia repair, its clinical outcome is at least equal to that obtained by standard laparoscopic surgery.

Laparoscopic versus robotic-assisted, left-sided colectomies: intra- and postoperative outcomes of 683 patients.

BACKGROUND: Robotic-assisted colorectal surgery has gained more and more popularity over the last years. It seems to be advantageous to laparoscopic surgery in selected situations, especially in confined regions like a narrow male pelvis in rectal surgery. Whether robotic-assisted, left-sided colectomies can serve as safe training operations for less frequent, low anterior resections for rectal cancer is still under debate. Therefore, the aim of this study was to evaluate intra- and postoperative results of robotic-assisted laparoscopy (RAL) compared to laparoscopic (LSC) surgery in left-sided colectomies. METHODS: Between June 2015 and December 2019, 683 patients undergoing minimally invasive left-sided colectomies in two Swiss, high-volume colorectal centers were included. Intra- and postoperative outcome parameters were collected and analyzed. RESULTS: A total of 179 patients undergoing RAL and 504 patients undergoing LSC were analyzed. Baseline characteristics showed similar results. Intraoperative complications occurred in 0.6% of RAL and 2.0% of LSC patients (p = 0.193). Differences in postoperative complications graded Dindo ≥ 3 were not statistically significant (RAL 3.9% vs. LSC 6.3%, p = 0.227). Occurrence of anastomotic leakages showed no statistically significant difference [RAL n = 2 (1.1%), LSC n = 8 (1.6%), p = 0.653]. Length of hospital stay was similar in both groups. Conversions to open surgery were significantly higher in the LSC group (6.2% vs.1.7%, p = 0.018), while stoma formation was similar in both groups [RAL n = 1 (0.6%), LSC n = 5 (1.0%), p = 0.594]. Operative time was longer in the RAL group (300 vs. 210.0 min, p < 0.001). CONCLUSION: Robotic-assisted, left-sided colectomies are safe and feasible compared to laparoscopic resections. Intra- and postoperative complications are similar in both groups. Most notably, the rate of anastomotic leakages is similar. Compared to laparoscopic resections, the analyzed robotic-assisted resections have longer operative times but less conversion rates. Further prospective studies are needed to confirm the safety of robotic-assisted, left-sided colectomies as training procedures for low anterior resections.

From open Ivor Lewis esophagectomy to a hybrid robotic-assisted thoracoscopic approach: a single-center experience over two decades.

PURPOSE: Robotic-assisted procedures are increasingly used in esophageal cancer surgery. We compared postoperative complications and early oncological outcomes following hybrid robotic-assisted thoracoscopic esophagectomy (Rob-E) and open Ivor Lewis esophagectomy (Open-E), performed in a single mid-volume center, in the context of evolving preoperative patient and tumor characteristics over two decades. METHODS: We evaluated prospectively collected data from a single center from 1999 to 2020 including 321 patients that underwent Ivor Lewis esophagectomy, 76 underwent Rob-E, and 245 Open-E. To compare perioperative outcomes, a 1:1 case-matched analysis was performed. Endpoints included postoperative morbidity and 30-day mortality. RESULTS: Preoperative characteristics revealed increased rates of adenocarcinomas and wider use of neoadjuvant treatment over time. A larger number of patients with higher ASA grades were operated with Rob-E. In case-matched cohorts, there were no differences in the overall morbidity (69.7% in Rob-E, 60.5% in Open-E, p value 0.307), highest Clavien-Dindo grade per patient (43.4% vs. 38.2% grade I or II, p value 0.321), comprehensive complication index (median 20.9 in both groups, p value 0.401), and 30-day mortality (2.6% in Rob-E, 3.9% in Open-E, p value 1.000). Similar median numbers of lymph nodes were harvested (24.5 in Rob-E, 23 in Open-E, p value 0.204), and comparable rates of R0-status (96.1% vs. 93.4%, p value 0.463) and distribution of postoperative UICC stages (overall p value 0.616) were observed. CONCLUSIONS: Our study demonstrates similar postoperative complications and early oncological outcomes after Rob-E and Open-E. However, the selection criteria for Rob-E appeared to be less restrictive than those of Open-E surgery.

Trends in pancreatic surgery in Switzerland: a survey and nationwide analysis over two decades.

BACKGROUND: Centralisation of highly specialised medicine (HSM) has changed practice and outcome in pancreatic surgery (PS) also in Switzerland. Fewer hospitals are allowed to perform pancreatic surgery according to nationally defined cut-offs. OBJECTIVE: We aimed to examine trends in PS in Switzerland. First, to assess opinions and expected trends among Swiss pancreatic surgeons in regard of PS practice and second, to assess the evolution of PS performance in Switzerland by a nationwide retrospective analysis. METHODS: First, a 26-item survey among all surgeons who performed PS in 2016 in Switzerland was performed. Then, nationwide data from 1998 to 2018 from all hospitals performing PS was analysed including centre volume, perioperative morbidity and mortality, surgical indications and utilisation of minimally invasive pancreatic surgery (MIPS). The national cut-off for regulatory accredited volume centres (AVC) was ≥ 12. Additionally, an international benchmark definition for high volume (≥ 20 surgeries/year) was used. RESULTS: Among 25 surgeons from 15 centres (response rate 51%), the survey revealed agreement that centralisation is important to improve perioperative outcomes. Respondents agreed on a minimum case load per surgeon or centre. Within the nationwide database, 8534 pancreatic resections were identified. Most resections were performed for pancreatic ductal adenocarcinoma (58.9%). There was a significant trend towards centralisation of PS with fewer non-accredited volume centres (nAVC) (36 in 1998 and 17 in 2018, p < 0.001) and more AVC (2 in 1998 and 18 in 2018, p < 0.001). A significantly higher adjusted mortality after pancreatoduodenectomy (PD) was observed in low-volume compared to high-volume hospitals (OR 1.45 [95% CI 1.15-1.84], p = 0.002) and a similar trend compared among AVC and nAVC (OR 1.25 [95% CI 0.98-1.60], p = 0.072), while mortality after distal pancreatectomy (DP) was not influenced by centre volume. CONCLUSIONS: Over the last two decades, centralisation of PS towards higher-volume centres was observed in Switzerland with a decrease of mortality after PD and low mortality after DP. Further centralisation is supported by most pancreatic surgeons. However, the ideal metric and outcome measures for the allocation of highly specialised medicine need further discussion to allow a fair and outcome-focused allocation.

From laparoscopic to robotic-assisted Heller myotomy for achalasia in a single high-volume visceral surgery center: postoperative outcomes and quality of life.

BACKGROUND: Laparoscopic (LSC) Heller myotomy (HM) is considered the standard procedure for the treatment of achalasia. Robotic platforms, established over the last years, provide important advantages to surgeons, such as binocular 3-dimensional vision and improvement of fine motor control. However, whether perioperative outcomes and long-term results of robotic-assisted laparoscopic (RAL) HM are similar or even superior to LSC technique, especially concerning long-term follow-up, is still debated. Therefore, the aim of the present study was to evaluate intra- and postoperative results as well as long-term quality of life after RAL compared to LSC surgery for achalasia in a single high-volume visceral surgery center. METHODS: Between August 2007 and April 2020, 43 patients undergoing minimally invasive HM for achalasia in a single high-volume Swiss visceral surgery center, were included in the present study. Intra- and postoperative outcome parameters were collected and evaluated, and a long-term follow-up was performed using the gastroesophageal-reflux disease health-related quality of life (GERD-Hr-QuoL) questionnaire. RESULTS: A total of 11 patients undergoing RAL and 32 undergoing LSC HM were analyzed. Baseline demographics and clinical characteristics were similar. A trend (p = 0.052) towards a higher number of patients with ASA III score treated with RAL was detectable. Operation time was marginally, but significantly, shorter in LSC (140 min, IQR: 136-150) than in RAL (150 min, IQR: 150-187, p = 0.047). Postoperative complications graded Clavien-Dindo ≥ 3 were only observed in one patient in each group. Length of hospital stay was similar in both groups (LSC: 11 days, IQR: 10-13 vs. RAL: 11 days, IQR: 10-14, p = 0.712). Long-term follow-up (LSC: median 89 months, vs. RAL: median 28 months, p = 0.001) showed comparable results and patients from both groups expressed similar levels of satisfaction (p = 0.181). CONCLUSIONS: LSC and RAL HM show similar peri- and postoperative results and a high quality of life, even in long-term (> 24 months) follow-up. Prospective, randomized, controlled multicenter trials are needed to overcome difficulties associated to small sample sizes in a rare condition and to confirm the equality or demonstrate the superiority of robotic-assisted procedures for achalasia. Meanwhile, the choice of the treatment technique could be left to the operating surgeon's preferences.

Persistent acute cholecystitis after cholecystostomy - increased mortality due to treatment approach?

BACKGROUND: Percutaneous cholecystostomy (PC) is a treatment option for acute cholecystitis (AC) in cases where cholecystectomy (CCY) is not feasible due to limited health conditions. The use of PC remains questionable. The aim was to retrospectively analyse the outcome of patients after PC. METHODS: All patients who underwent PC for AC at a tertiary referral hospital over 10 years were included. Descriptive statistics, analysed mortality with and without CCY after PC, and a multivariable logistic regression for potential confounder and a landmark sensitivity analysis for immortal time bias were used. RESULTS: Of 158 patients, 79 were treated with PC alone and 79 had PC with subsequent CCY. Without CCY, 48% (38 patients) died compared to 9% with CCY. In the multivariable analysis CCY was associated with 85% lower risk of mortality. The landmark analysis was compatible with the main analyses. Direct PC-complications occurred in 17% patients. Histologically, 22/75 (29%) specimens showed chronic cholecystitis, and 76% AC. CONCLUSION: Due to the high mortality rate of PC alone, performing up-front CCY is proposed. PC represents no definitive treatment for AC and should remain a short-term solution because of the persistent inflammatory focus. According to these findings, almost all specimens showed persistent inflammation.

MAP17 Expression in Colorectal Cancer Is a Prognostic Factor for Disease Recurrence and Dismal Prognosis Already in Early Stage Disease.

BACKGROUND: Disease recurrence in colorectal cancer constitutes a major cause of significant cancer-associated morbidity and mortality. MAP17 is a small protein, and its overexpression in malignant tumors has been correlated with aggressive tumor phenotypes. The aim of the present study was to investigate the expression patterns of MAP17 in colorectal cancer specimens and to assess its clinical significance. PATIENTS AND METHODS: Surgical specimens of 111 patients with primary resectable colorectal cancer constituted the study population. Expression of MAP17 was assessed by immunohistochemistry, and the results were correlated with clinical and survival data. RESULTS: MAP17 was expressed in cancer cells and endothelial cells of tumor blood vessels. Expression of MAP17 more than 10% was correlated with advanced disease stage (p < 0.001), higher T classification (p = 0.007), the presence of lymph node metastasis (p < 0.001), vascular (p = 0.013) and perineural invasion (p = 0.012). Patients exhibiting MAP17 expression of more than 30% in cancer cells compared to those expressing MAP17 less than 10% demonstrated a significantly worse 3-year progression-free survival (35.2 vs. 91%, p < 0.001) and 5-year overall survival (40.8 vs. 91%, p < 0.001). Cox regression analysis confirmed MAP17 expression of more than 30% as a prognostic marker of progression free survival (HR 0.136, 95% CI = 0.056-0.329, p < 0.001) and overall survival (HR 0.144 [95% CI) = 0.049-0.419, p < 0.001) independent of other clinicopathological characteristics. Statistically significantly worse 3-year progression-free survival and 5-year overall survival was demonstrated in the subgroup analysis of patients with early stage cancer only and high expression of MAP17. CONCLUSIONS: High MAP17 expression in patients with colorectal cancer is a significant risk factor for cancer-associated morbidity and mortality already in early stage disease.

Nestin and CD34 expression in colorectal cancer predicts improved overall survival.

BACKGROUND: Nestin, a class VI intermediate filament protein of the cytoskeleton, and CD34, a transmembrane phosphoglycoprotein, are markers of progenitor cells. This study aimed to evaluate their expression and clinical significance in colorectal cancer. METHODS: A clinically annotated tissue microarray, including 599 patients with colorectal cancer, was analyzed by immunohistochemistry. Furthermore, nestin and CD34 correlations with HIF-1a and a panel of cytokines and chemokines were assessed using quantitative reverse transcription PCR and The Cancer Genome Atlas dataset. RESULTS: Expression of nestin and CD34 was observed only in the tumor stroma. Patients displaying high expression of nestin and CD34 demonstrated higher rates of T1 and T2 tumors (p = .020), lower vascular invasion (p < .001) and improved 5-year overall survival (65%; 95% CI = 55-73 vs 45%; 95% CI = 37-53) after adjusting for clinicopathological characteristics (HR: 0.67; 95% CI = 0.46-0.96). A moderate to strong correlation (r = 0.37-0.78, p < .03) of nestin and CD34 was demonstrated for the following markers; HIF-1α, CD4, CD8, FOXP3, IRF1, GATA3, CCL2, CCL3, CXCL12 and CCL21. CONCLUSIONS: Combined expression of nestin and CD34 expression is associated with better overall survival possibly by modulating a favorable immune response.

Role of lymphadenectomy in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) remains one of the most devastating malignant diseases, predicted to become the second leading cause of cancer-related death by 2030. Despite advances in surgical techniques and in systemic therapy, the 5-year relative survival remains a grim 9% for all stages combined. The extent of lymphadenectomy has been discussed intensively for decades, given that even in early stages of PC, lymph node (LN) metastasis can be detected in approximately 80%. PURPOSE: The primary objective of this review was to provide an overview of the current literature evaluating the role of lymphadenectomy in resected PC. For this, we evaluated randomized controlled studies (RCTs) assessing the impact of extent of lymphadenectomy on OS and studies evaluating the prognostic impact of anatomical site of LN metastasis and the impact of the number of resected LNs on OS. CONCLUSIONS: Lymphadenectomy plays an essential part in the multimodal treatment algorithm of PC and is an additional therapeutic tool to increase the chance for surgical radicality and to ensure correct staging for optimal oncological therapy. Based on the literature from the last decades, standard lymphadenectomy with resection of at least ≥ 15 LNs is associated with an acceptable postoperative complication risk and should be recommended to obtain local radicality and accurate staging of the disease. Although radical surgery including appropriate lymphadenectomy of regional LNs remains the only chance for long-term tumor control, future studies specifically assessing the impact of neoadjuvant therapy on extraregional LNs are warranted.

[Pancreatic arteriovenous malformations†: from pathophysiology to therapy]. / Malformations artérioveineuses pancréatiques†: de la physiopathologie à la prise en charge.

Pancreatic arteriovenous malformations are rare conditions, mostly asymptomatic and increasingly diagnosed incidentally. Once symptomatic, patients can present with non specific abdominal pain, potentially life-threatening gastrointestinal bleeding, acute pancreatitis or portal hypertension. The aim of this article is to present the pathophysiology underlying this type of vascular malformation, to discuss its diagnostic modalities and the therapeutic options described to date in the literature.

Les malformations artérioveineuses pancréatiques sont rares, asymptomatiques dans la majorité des cas et de plus en plus souvent découvertes de manière fortuite. Elles peuvent toutefois être à l'origine de douleurs abdominales peu spécifiques, de saignements gastro-intestinaux potentiellement sévères, d'une pancréatite ou d'une hypertension portale. L'objectif de cet article est de présenter la physiopathologie sous-tendant ce type de malformation vasculaire, d'en discuter les modalités diagnostiques ainsi que les possibilités thérapeutiques décrites à ce jour dans la littérature.

Gut microbiota modulate T cell trafficking into human colorectal cancer.

OBJECTIVE: Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. DESIGN: Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. RESULTS: CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. CONCLUSIONS: Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

S1P1 Modulator-Induced G αi Signaling and ß-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count In Vivo.

S1P1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P1 receptor modulator library was screened for compounds with clear potency differences in ß-arrestin recruitment and G protein alpha i subunit (G αi) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P1 modulators with apparent pathway selectivity for ß-arrestin recruitment. The most differentiated compound, D3-2, displayed a 180-fold higher potency in the ß-arrestin recruitment assay (EC50 0.9 nM) compared with the G αi-activation assay (167 nM), whereas ponesimod, a S1P1 modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC50 1.5 and 1.1 nM, respectively). Using these novel compounds as pharmacological tools, we showed that although a high potency in ß-arrestin recruitment is required to fully internalize S1P1 receptors, the potency in inducing G αi signaling determines the rate of receptor internalization in vitro. In contrast to ponesimod, the compound D3-2 did not reduce the number or circulating lymphocytes in rats despite high plasma exposures. Thus, for rapid and maximal S1P1 receptor internalization a high potency in both G αi signaling and ß-arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo.

The Discovery of Macitentan - A Standard Medicinal Chemistry Program?

A plethora of properties are typically studied during a medicinal chemistry program and many of these parameters may shape the cascade of compound selection. Given the task to discover a molecule with a profile superior to that of the dual endothelin receptor antagonist bosentan, we tailored our compound profiling cascade to the specific properties that were not optimal in bosentan, namely in vivo efficacy and safety. Contrary to conventional thinking, we therefore focused on corresponding in vivo experiments. In the following, we highlight and illustrate some key learnings of our approach that led to the discovery of macitentan (1), an orally available potent dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension.

From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.

The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several endothelin receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH). This digest highlights the medicinal chemistry of the pyrimidine based ERAs 6 and 43 and describes the story that started with bosentan and culminated in macitentan (43). A condensed overview of the competitive landscape in the field of ERAs puts the different strategies and tactics applied by the medicinal chemists involved in this endeavor into perspective.

The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog.

1. The metabolism of the endothelin receptor antagonist macitentan has been characterized in bile duct-cannulated rats and dogs. 2. In both species, macitentan was metabolized along five primary pathways, i.e. conjugation with glucose (M9), oxidative depropylation (M6), aliphatic hydroxylation (M7), oxidative cleavage of the ethylene glycol linker (M4) and hydrolysis of the sulfamide moiety (M3). Most of the primary metabolites underwent subsequent biotransformation including conjugation with glucuronic acid or glucose, hydrolysis of the sulfamide group or secondary oxidation of the ethylene glycol moiety. 3. Though there were species differences in their relative importance, all metabolic pathways were present in rat and dog. The depropylated M6 was the only metabolite present in plasma of both species. 4. Metabolism was a prerequisite for macitentan excretion as relevant amounts of parent drug were neither detected in bile nor urine. Biliary excretion was the major elimination pathway, while renal elimination was of little importance.