Post-pregnancy recurrent biliary colic with intraoperative diagnosis of limy bile syndrome.

INTRODUCTION: Limy bile syndrome (LBS) is an unusual condition in which gallbladder and/or bile ducts are filled with paste-like radiopaque material with a high calcium carbonate content. It can be rarely associated with PTH disorder and hypercalcemia. PRESENTATION OF CASE: A 35-year-old woman presented with epigastric and right hypochondrium pain since a few hours. Similar attacks occurred in the past months soon after a pregnancy with vaginal delivery. Laboratory findings were not significant. The abdominal ultrasound highlighted a micro-lithiasis of gallbladder without complications. Considering the recurrent biliary attacks, laparoscopic cholecystectomy was performed with intraoperative diagnosis of LBS. A subsequent endocrinological screening highlighted a normocalcemic hyperparathyroidism associated with Vitamin D deficiency, likely related to the recent pregnancy and not to LBS. DISCUSSION: LBS is a rare condition with not clear etiology, frequently associated with cholelithiasis, of which it shares clinical presentation and potential complications. Diagnosis of LBS is based on abdominal X-ray/computed tomography scan, or it could be an intraoperative finding. The gold standard treatment is represented by laparoscopic cholecystectomy. The pregnancy with its related cholestatic phenotype could facilitate the LBS manifestation. An endocrinological screening should be performed to rule out a concomitant calcium metabolism disorder. CONCLUSION: Knowledge of this rare condition could help general surgeons handle it properly.

Anastomosis configuration and technique following ileocaecal resection for Crohn's disease: a multicentre study.

A limited ileocaecal resection is the most frequently performed procedure for ileocaecal CD and different anastomotic configurations and techniques have been described. This manuscript audited the different anastomotic techniques used in a national study and evaluated their influence on postoperative outcomes following ileocaecal resection for primary CD. This is a retrospective, multicentre, observational study promoted by the Italian Society of Colorectal Surgery (SICCR), including all adults undergoing elective ileocaecal resection for primary CD from June 2018 May 2019. Postoperative morbidity within 30 days of surgery was the primary endpoint. Postoperative length of hospital stay (LOS) and anastomotic leak rate were the secondary outcomes. 427 patients were included. The side to side anastomosis was the chosen configuration in 380 patients (89%). The stapled anastomotic (n = 286; 67%), techniques were preferred to hand-sewn (n = 141; 33%). Postoperative morbidity was 20.3% and anastomotic leak 3.7%. Anastomotic leak was independent of the type of anastomosis performed, while was associated with an ASA grade ≥ 3, presence of perianal disease and ileocolonic localization of disease. Four predictors of LOS were identified after multivariate analysis. The laparoscopic approach was the only associated with a reduced LOS (p = 0.017), while age, ASA grade ≥ 3 or administration of preoperative TPN were associated with increased LOS. The side to side was the most commonly used anastomotic configuration for ileocolic reconstruction following primary CD resection. There was no difference in postoperative morbidity according to anastomotic technique and configuration. Anastomotic leak was associated with ASA grade ≥ 3, a penetrating phenotype of disease and ileo-colonic distribution of CD.

Robotic versus laparoscopic right colectomy within a systematic ERAS protocol: a propensity-weighted analysis.

The purpose of this study is to compare the early postoperative and pathological outcomes of robotic right colectomy (RRC) to those of laparoscopic right colectomy (LRC) with intracorporeal anastomosis (IA) within the systematic application of an enhanced recovery after surgery (ERAS) program. A single-institution prospective database of patients who underwent elective RRC or LRC with IA for neoplastic lesions between April 2010 and June 2018 was retrospectively reviewed. The patients' demographic characteristics, and perioperative and pathological outcomes were analyzed. Propensity-weighted analysis was employed to address potential selection biases of treatment allocation. A total of 216 patients (46 RRC, 170 LRC) were included. RRC demonstrated a significantly longer operative time (mean 242.43 min, SD 47.51) compared to LRC (mean 187.60 min, SD 56.60) (p = 0.001), confirmed by the propensity-weighted analysis (Coefficient 50.65; p < 0.001). Conversion rate between the two groups was comparable (p = 0.99). Median length of hospital stay (LOS) was the same in the RRC and the LRC group (4 days, p = 0.35). Readmission rate within 30 days in the RRC and LRC group was 2.2% and 2.4%, respectively (p = 0.99). Overall 30-day morbidity and 30-day mortality was 32.6% versus 27.1% (p = 0.46), and 0% versus 1.2% (p = 0.99) in the robotic and laparoscopic groups, respectively. No difference was found in the number of harvested lymph nodes (p = 0.75). In an ERAS environment, without the bias of mixed techniques of anastomosis, RRC had similar postoperative and pathological outcomes compared to the laparoscopic approach, but was associated with a longer operative time.

Management and 1-year outcomes of anastomotic leakage after elective colorectal surgery.

PURPOSE: To analyze different types of management and one-year outcomes of anastomotic leakage (AL) after elective colorectal resection. METHODS: All patients with anastomotic leakage after elective colorectal surgery with anastomosis (76/1,546; 4.9%), with the exclusion of cases with proximal diverting stoma, were followed-up for at least one year. Primary endpoints were as follows: composite outcome of one-year mortality and/or unplanned intensive care unit (ICU) admission and additional morbidity rates. Secondary endpoints were as follows: length of stay (LOS), one-year persistent stoma rate, and rate of return to intended oncologic therapy (RIOT). RESULTS: One-year mortality rate was 10.5% and unplanned ICU admission rate was 30.3%. Risk factors of the composite outcome included age (aOR = 1.08 per 1-year increase, p = 0.002) and anastomotic breakdown with end stoma at reoperation (aOR = 2.77, p = 0.007). Additional morbidity rate was 52.6%: risk factors included open versus laparoscopic reoperation (aOR = 4.38, p = 0.03) and ICU admission (aOR = 3.63, p = 0.05). Median (IQR) overall LOS was 20 days (14-26), higher in the subgroup of patients reoperated without stoma. At 1 year, a stoma persisted in 32.0% of patients, higher in the open (41.2%) versus laparoscopic (12.5%) reoperation group (p = 0.04). Only 4 out of 18 patients (22.2%) were able to RIOT. CONCLUSION: Mortality and/or unplanned ICU admission rates after AL are influenced by increasing age and by anastomotic breakdown at reoperation; additional morbidity rates are influenced by unplanned ICU admission and by laparoscopic approach to reoperation, the latter also reducing permanent stoma and failure to RIOT rates. TRIAL REGISTRATION: ClinicalTrials.gov # NCT03560180.

Design, Synthesis, and Biological Evaluation of a Series of Oxazolone Carboxamides as a Novel Class of Acid Ceramidase Inhibitors.

Acid ceramidase (AC) is a cysteine hydrolase that plays a crucial role in the metabolism of lysosomal ceramides, important members of the sphingolipid family, a diversified class of bioactive molecules that mediate many biological processes ranging from cell structural integrity, signaling, and cell proliferation to cell death. In the effort to expand the structural diversity of the existing collection of AC inhibitors, a novel class of substituted oxazol-2-one-3-carboxamides were designed and synthesized. Herein, we present the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 8a and 2-oxo-5-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 12a, which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo-N-pentyl-oxazole-3-carboxamide 32b as a potent AC inhibitor with optimal physicochemical and metabolic properties, showing target engagement in human neuroblastoma SH-SY5Y cells and a desirable pharmacokinetic profile in mice, following intravenous and oral administration. 32b enriches the arsenal of promising lead compounds that may therefore act as useful pharmacological tools for investigating the potential therapeutic effects of AC inhibition in relevant sphingolipid-mediated disorders.

Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors.

Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg-1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.

European association for endoscopic surgery (EAES) consensus statement on single-incision endoscopic surgery.

BACKGROUND: Laparoscopic surgery changed the management of numerous surgical conditions. It was associated with many advantages over open surgery, such as decreased postoperative pain, faster recovery, shorter hospital stay and excellent cosmesis. Since two decades single-incision endoscopic surgery (SIES) was introduced to the surgical community. SIES could possibly result in even better postoperative outcomes than multi-port laparoscopic surgery, especially concerning cosmetic outcomes and pain. However, the single-incision surgical procedure is associated with quite some challenges. METHODS: An expert panel of surgeons has been selected and invited to participate in the preparation of the material for a consensus meeting on the topic SIES, which was held during the EAES congress in Frankfurt, June 16, 2017. The material presented during the consensus meeting was based on evidence identified through a systematic search of literature according to a pre-specified protocol. Three main topics with respect to SIES have been identified by the panel: (1) General, (2) Organ specific, (3) New development. Within each of these topics, subcategories have been defined. Evidence was graded according to the Oxford 2011 Levels of Evidence. Recommendations were made according to the GRADE criteria. RESULTS: In general, there is a lack of high level evidence and a lack of long-term follow-up in the field of single-incision endoscopic surgery. In selected patients, the single-incision approach seems to be safe and effective in terms of perioperative morbidity. Satisfaction with cosmesis has been established to be the main advantage of the single-incision approach. Less pain after single-incision approach compared to conventional laparoscopy seems to be considered an advantage, although it has not been consistently demonstrated across studies. CONCLUSIONS: Considering the increased direct costs (devices, instruments and operating time) of the SIES procedure and the prolonged learning curve, wider acceptance of the procedure should be supported only after demonstration of clear benefits.

Safety of single-incision robotic cholecystectomy for benign gallbladder disease: a systematic review.

BACKGROUND: Multiport laparoscopic cholecystectomy (MLC) is the gold standard technique for cholecystectomy. In order to reduce postoperative pain and improve cosmetic results, the application of the single-incision laparoscopic cholecystectomy (SILC) technique was introduced, leading surgeons to face important challenges. Robotic technology has been proposed to overcome some of these limitations. The purpose of this review is to assess the safety of single-incision robotic cholecystectomy (SIRC) for benign disease. METHODS: An Embase and Pubmed literature search was performed in February 2017. Randomized controlled trial and prospective observational studies were selected and assessed using PRISMA recommendations. Primary outcome was overall postoperative complication rate. Secondary outcomes were postoperative bile leak rate, total conversion rate, operative time, wound complication rate, postoperative hospital stay, and port site hernia rate. The outcomes were analyzed in Forest plots based on fixed and random effects model. Heterogeneity was assessed using the I2 statistic. RESULTS: A total of 13 studies provided data about 1010 patients who underwent to SIRC for benign disease of gallbladder. Overall postoperative complications rate was 11.6% but only 4/1010 (0.4%) patients required further surgery. A postoperative bile leak was reported in 3/950 patients (0.3%). Conversion occurred in 4.2% of patients. Mean operative time was 86.7 min including an average of 42 min should be added as for robotic console time. Wound complications occurred in 3.7% of patients. Median postoperative hospital stay was 1 day. Port site hernia at the latest follow-up available was reported in 5.2% of patients. CONCLUSIONS: The use of the Da Vinci robot in single-port cholecystectomy seems to have similar results in terms of incidence and grade of complications compared to standard laparoscopy. In addition, it seems affected by the same limitations of single-port surgery, consisting of an increased operative time and incidence of port site hernia.

Preparation and In Vivo Use of an Activity-based Probe for N-acylethanolamine Acid Amidase.

Activity-based protein profiling (ABPP) is a method for the identification of an enzyme of interest in a complex proteome through the use of a chemical probe that targets the enzyme's active sites. A reporter tag introduced into the probe allows for the detection of the labeled enzyme by in-gel fluorescence scanning, protein blot, fluorescence microscopy, or liquid chromatography-mass spectrometry. Here, we describe the preparation and use of the compound ARN14686, a click chemistry activity-based probe (CC-ABP) that selectively recognizes the enzyme N-acylethanolamine acid amidase (NAAA). NAAA is a cysteine hydrolase that promotes inflammation by deactivating endogenous peroxisome proliferator-activated receptor (PPAR)-alpha agonists such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). NAAA is synthesized as an inactive full-length proenzyme, which is activated by autoproteolysis in the acidic pH of the lysosome. Localization studies have shown that NAAA is predominantly expressed in macrophages and other monocyte-derived cells, as well as in B-lymphocytes. We provide examples of how ARN14686 can be used to detect and quantify active NAAA ex vivo in rodent tissues by protein blot and fluorescence microscopy.

Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis.

Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.

Efficacy and safety of laparo-endoscopic resections of colorectal neoplasia: A systematic review.

OBJECTIVE: The purpose of this review is to assess the efficacy and safety of laparo-endoscopic local resections for colorectal lesions not suitable for endoscopic resection. SUMMARY BACKGROUND DATA: The combined laparo-endoscopic approach has been proposed for large colorectal lesions unsuitable for endoscopic resection, in order to reduce morbidity of common laparoscopic resection. However, data on the efficacy and safety of laparo-endoscopic local resections are still controversial. METHODS: An Embase search of papers published during the period 1985-2014 was performed. Published studies that evaluated laparo-endoscopic resections for colorectal lesions were assessed using PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) recommendations by two authors. Forest plots on primary (per-lesion rate of further surgery, including surgery for complications and surgery for oncologic radical treatment) and secondary outcomes were produced based on fixed and random effects models. Heterogeneity was assessed using the I (2) statistic. Risk for within-study bias was ascertained with QUADAS (Quality Assessment of Diagnostic Accuracy Studies) system. RESULTS: A total of 11 studies provided data on 707 lesions treated with a combined laparo-endoscopic approach. A variety of techniques were reported. The overall per-lesion rate of further surgery was 9.5%, while per-lesion rate of further surgery for oncologic treatment was 7.9%, per-lesion rate of further surgery for complications treatment was 3.5%, incidence of adenocarcinoma was 10.5%, incidence of overall complications was 7.9%, incidence of conversion to open surgery 4.3% and incidence of recurrence was 5.4%. CONCLUSIONS: Despite laparo-endoscopic approach ensures limited invasiveness, it is affected by a consistent rate of complications and oncologic inadequacy that often requires further surgical treatment.

Transanal endoscopic microsurgery after endoscopic resection of malignant rectal polyps: a useful technique for indication to radical treatment.

BACKGROUND: Management of malignant rectal polyps (MRPs) after endoscopic polypectomy (EP) is still debated. It is sometimes difficult to decide whether to simply follow-up (FU) or to treat such a removed lesion. Transanal endoscopic microsurgery (TEM) could have a role both in T staging and in treating MRPs after EP. METHODS: Patients who underwent a full-thickness TEM within 3 months after an EP between January 2008 and October 2012 were retrospectively analyzed. If post-TEM histology showed locally advanced rectal cancer, patients underwent a total mesorectal excision (TME) within 4-6 weeks. Patients without malignant disease or pT1sm1 cancers at post-TEM histology were followed up every 3 months for 2 years with clinical examination, flexible rectal endoscopy, and neoplastic markers monitoring. RESULTS: A total of 39 patients were included. Post-EP histology was adenocarcinoma in 27/39 cases (69.2 %) and adenoma in 12/39. Mean operative time was 64.2 min; no 30-day mortality occurred; 30-day morbidity was 2.7 % (rectal bleeding in 1/39 cases). Post-TEM histology showed a T2 cancer in 5/39 patients, four with and one without a previous cancer diagnosis, who were further treated by TME (four RARs and one APR) and are disease free with a mean FU of 24.2 months. Post-TEM histology showed adenoma in 10/39 cases and fibrosis in 24/39. These patients are disease free with a mean FU of 13 months. CONCLUSIONS: A full-thickness TEM after EP of MRPs can establish the presence of residual malignant disease and its depth of invasion, precisely defining the indication to TME. In event of benign post-EP histology, TEM must be performed in presence of macroscopic residual disease, in order to obtain an RO resection and finally exclude cancer, while, in absence of macroscopic residual disease, only close FU is required.

Which treatment for large rectal adenoma? Preoperative assessment and therapeutic strategy.

In the present review the authors discuss the standard ways of preoperative work-up for a suspected large rectal non-invasive lesion, comparing East and West different attitudes both in staging and treatment. Looking at the literature and analyzing recent personal data, neither pit-pattern classification, nor EUS, nor biopsy histology, nor lifting sign verification, nor digital examination allow a specificity of more than three fourth of such cases. The authors disquisition about which optimal treatment excludes a role for EMR for the impossibility to obtain a single en-bloc specimen, minimum requirement for a correct lateral and vertical margin assessment. For the same reason ESD should be preferred, although a recent meta-analysis of the literature defined that one fourth of patients undergoing ESD for a preoperatively assessed non-invasive large rectal lesion fail to receive an R0 en-bloc resection. This forces about 10% of patients treated by flexible endoscopy to undergo abdominal surgery, which is about fourfold higher than TEM. While awaiting further implementation of modern technologies both to improve staging and to reduce invasiveness, a full-thickness excision of the rectal wall by TEM still represents the standard treatment even for suspected benign diseases.

Identification and characterization of carprofen as a multitarget fatty acid amide hydrolase/cyclooxygenase inhibitor.

Pain and inflammation are major therapeutic areas for drug discovery. Current drugs for these pathologies have limited efficacy, however, and often cause a number of unwanted side effects. In the present study, we identify the nonsteroidal anti-inflammatory drug carprofen as a multitarget-directed ligand that simultaneously inhibits cyclooxygenase-1 (COX-1), COX-2, and fatty acid amide hydrolase (FAAH). Additionally, we synthesized and tested several derivatives of carprofen, sharing this multitarget activity. This may result in improved analgesic efficacy and reduced side effects (Naidu et al. J. Pharmacol. Exp. Ther.2009, 329, 48-56; Fowler, C. J.; et al. J. Enzyme Inhib. Med. Chem.2012, in press; Sasso et al. Pharmacol. Res.2012, 65, 553). The new compounds are among the most potent multitarget FAAH/COX inhibitors reported so far in the literature and thus may represent promising starting points for the discovery of new analgesic and anti-inflammatory drugs.

Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus.

OBJECTIVES: To progress the anti-varicella-zoster-virus (VZV) aryl bicyclic nucleoside analogues (BCNAs) to the point of Phase 1 clinical trial for herpes zoster. METHODS: A new chromatography-free synthetic access to the lead anti-VZV aryl BCNAs is reported. The anti-VZV activity of lead Cf1743 was evaluated in monolayer cell cultures and organotypic epithelial raft cultures of primary human keratinocytes. Oral dosing in rodents and preliminary pharmacokinetics assessment was made, followed by an exploration of alternative formulations and the preparation of pro-drugs. We also studied uptake into cells of both parent drug and pro-drug using fluorescent microscopy and biological assays. RESULTS: Cf1743 proved to be significantly more potent than all reference anti-VZV compounds as measured either by inhibition of infectious virus particles and/or by viral DNA load. However, the very low water solubility of this compound gave poor oral bioavailability (approximately 14%). A Captisol admixture and the 5'-monophosphate pro-drug of Cf1743 greatly boosted water solubility but did not significantly improve oral bioavailability. The most promising pro-drug to emerge was the HCl salt of the 5'-valyl ester, designated as FV-100. Its uptake into cells studied using fluorescent microscopy and biological assays indicated that the compound is taken up by the cells after a short period of incubation and limited exposure to drug in vivo may have beneficial effects. CONCLUSIONS: On the basis of its favourable antiviral and pharmacokinetic properties, FV-100 is now being pursued as the clinical BCNA candidate for the treatment of VZV shingles.