Biological and Histological Assessment of the Hepatoportoenterostomy Role in Biliary Atresia as a Stand-Alone Procedure or as a Bridge toward Liver Transplantation.

Background and objectives: In patients with biliary atresia (BA), hepatoportoenterostomy (HPE) is still a valuable therapeutic tool for prolonged survival or a safer transition to liver transplantation. The main focus today is towards efficient screening programs, a faster diagnostic, and prompt treatment. However, the limited information on BA pathophysiology makes valuable any experience in disease management. This study aimed to analyze the evolution and survival of patients with BA referred for HPE (Kasai operation) in our department. Materials and Methods: A retrospective analysis was performed on fourteen patients with BA, diagnosed in the pediatric department and further referred for HPE in our surgical department between 2010 and 2016. After HPE, the need for transplantation was assessed according to patients cytomegalovirus (CMV) status, and histological and biochemical analysis. Follow-up results at 1-4 years and long term survival were assessed. Results: Mean age at surgery was 70 days. Surgery in patients younger than 60 days was correlated with survival. Jaundice's clearance rate at three months was 36%. Total and direct bilirubin values had a significant variation between patients with liver transplants and native liver (p = 0.02). CMV was positive in eight patients, half with transplant need and half with native liver survival. Smooth muscle actin (SMA) positivity was proof of advanced fibrosis. The overall survival rate was 79%, with 75% for native liver patients and an 83% survival rate for those with liver transplantation. Transplantation was performed in six patients (43%), with a mean of 10 months between HPE and transplantation. Transplanted patients had better survival. Complications were diagnosed in 63% of patients. The mean follow-up period was six years. Conclusions: HPE, even performed in advanced cirrhosis, allows a significant survival, and ensures an essential time gain for patients requiring liver transplantation. A younger age at surgery is correlated with a better outcome, despite early CMV infection.

Hepatoportoenterostomy in Selective Obstructive Cholestasis - An New Experimental Model in the Rat.

Biliary atresia is the most frequent cause for neonatal obstructive cholestasis. Hepatoportoenterostomy (HPE) is the only method allowing survival until liver transplantation. For a maximum rate of success, the HPE procedure has to be performed within the 60 days of life. We aimed to create an experimental model for relieving obstructive cholestasis. In 20 Wistar rats selective bile duct obstruction was induced by the microsurgical ligature of the bile ducts corresponding to the median and left lateral liver lobes. After four weeks surgical re-intervention was carried out and HPE was performed microsurgically on the hilum of the median and left lateral liver lobes. One week after HPE, the integrity of the anastomosis and the hepatic changes were assessed. The survival rate throughout the study was 90%. The surgical re-intervention revealed hepatic-hilum adhesions, with fibrosis. Microscopically, an initial fibrogenic repair was identified, equivalent of moderate cholestasis. After the HPE, there was no bile leak from the anastomosis and no biliary peritonitis. The evolution was marked by a reduction in food intake. The experimental model we propose for the HPE is reliable by using microsurgical techniques. Based on it, one can study the changes induced by the bile duct obstruction.

Cervical Exenteration - Guidelines and Surgical Technique Principles.

Introduction: Neoplastic invasion of the structures of the cervical region originating from a malignant tumour developed in one of the viscera of the throat may benefit from cervical exenteration. Defined as resection of the hypopharynx, cervical oesophagus, larynx and cervical trachea, exenteration has limited indications and is mandatorily accompanied by digestive tube reconstruction. The aim of this article is to highlight the indication, surgical strategy and important surgical stages illustrated by images from personal professional experience. MATERIALS AND METHOD: Pharyngo-laryngo-oesophageal en bloc resection and radical cervical lymphadenectomy were followed by reconstruction via free jejunal transfer or colic pedicle grafting. Between 2000 and 2018 we have performed cervical exenteration in 25 patients with tumours originating in the pharynx, larynx or cervical oesophagus. In the cases of 5 patients in whom we did not obtain the oncological safety margin for oesophageal cancer we performed transhiatal pharyngo-laryngo-oesophagectomy. In these patients, we performed reconstruction of the oesophagus with colonic graft. In 20 cases we performed jejunal autotransplant. Results: We recorded 4 perioperative deaths, due to major arterial vessel haemorrhage (1 case), after jejunal necrosis (2 cases), and mediastinitis after oesophageal striping and colonic graft necrosis (1 case). One patient presented tumour recurrence at the level of the tracheal stump. Survival rate varied between 6 months and 4 years for the group of patients who presented for postoperative follow-ups. Conclusions: Cervical exenteration remains an option for tumour recurrence after radiochemotherapy or for obstructive airway or digestive tract tumours. It can be burdened by complications difficult to treat. The surgical team has to adapt its initial surgical strategy to the reality of the surgical field, both in terms of exeresis and in terms of types of pharyngo-oesophageal reconstruction.

Extension of Hepatic Resection Ameliorates Survival in Patients with Type IIIa or IIIb Klatskin Tumors Despite Surgical Complications.

Background: Major hepatectomies for hilar cholangiocarcinoma (HC) are associated with high rates of morbidity and mortality. We aimed to evaluate how and if surgical complications related to extended hepatectomies for HC type III and IV according to Bismuth-Corlette classification influence patients long-term survival. Methods: The files of all patients with major hepatectomy for HC and postoperative complications were retrospectively reviewed. Only patients with a complete postoperative follow up have be taken into account for the study. Postoperative morbidity and mortality, length of hospital stay (LOS) as well as overall survival (OS) and disease free survival (DFS) were recorded. Results: Five patients have been found to respond to all inclusion criteria. Three of them required re-operation with one in hospital death. Two patients are still alive and two other died because of the tumor recurrence with a DFS of 36 and 49 months respectively. The actuarial mean OS for the group was 30 months and the actuarial DFS was 26 months. Conclusions: In patients with HC, extensive resections bring a clearly benefit in terms of survival, even though there is an increase in postoperative morbidity and mortality. However, postoperative complications, if managed susccesfully do not interfere with the long-term survival.

Mathematical model of GAL regulon dynamics in Saccharomyces cerevisiae.

Genetic switches are prevalent in nature and provide cells with a strategy to adapt to changing environments. The GAL switch is an intriguing example which is not understood in all detail. The GAL switch allows organisms to metabolize galactose, and controls whether the machinery responsible for the galactose metabolism is turned on or off. Currently, it is not known exactly how the galactose signal is sensed by the transcriptional machinery. Here we utilize quantitative tools to understand the S. cerevisiae cell response to galactose challenge, and to analyze the plausible molecular mechanisms underlying its operation. We work at a population level to develop a dynamic model based on the interplay of the key regulatory proteins Gal4p, Gal80p, and Gal3p. To our knowledge, the model presented here is the first to reproduce qualitatively the bistable network behavior found experimentally. Given the current understanding of the GAL circuit induction (Wightman et al., 2008; Jiang et al., 2009), we propose that the most likely in vivo mechanism leading to the transcriptional activation of the GAL genes is the physical interaction between galactose-activated Gal3p and Gal80p, with the complex Gal3p-Gal80p remaining bound at the GAL promoters. Our mathematical model is in agreement with the flow cytometry profiles of wild type, gal3Δ and gal80Δ mutant strains from Acar et al. (2005), and involves a fraction of actively transcribing cells with the same qualitative features as in the data set collected by Acar et al. (2010). Furthermore, the computational modeling provides an explanation for the contradictory results obtained by independent laboratories when tackling experimentally the issue of binary versus graded response to galactose induction.

Wilkie's syndrome as a cause of anxiety-depressive disorder: A case report and review of literature.

BACKGROUND: Superior mesenteric artery syndrome is a disease with a complex diagnosis, and it is associated with complications that make it even harder to identify. Currently, a frequent association with psychiatric disorders has been noted. Despite numerous case reports and case series, the variability of the disease has not allowed the development of protocols regarding diagnosis and management. CASE SUMMARY: A 33-year-old woman presented with abdominal pain, nausea, and bile vomiting over the last 15 mo, associated with a 15-kg weight loss over the last three months. After the onset of the symptoms, the patient was diagnosed with anxiety-depressive disorder and treated appropriately. Standard examinations excluded an organic cause, and the cause of the symptoms was considered psychogenic. The persistence of symptoms, even under treatment, prompted a computer tomography angiography examination of the abdomen and pelvis. The examination identified emergence at a sharp angle of 13.7° of the superior mesenteric artery, with a reduced distance between the artery and the anterior wall of the aorta up to a maximum of 8 mm. A diagnosis of aortomesenteric clamp was established. Surgical treatment by laparoscopic duodenojejunostomy was performed. Postoperative evolution was marked by a patent anastomosis at 1 mo, with a 10-kg weight gain and improvement of the associated anxiety. CONCLUSION: This case report underlines two major aspects. One aspect refers to the predisposition of patients with superior mesenteric artery syndrome to develop psychiatric disorders, with an excellent outcome when proper treatment is administered. The second aspect underlines the key role of a multidisciplinary approach and follow-up.

Difficulties in diagnosing anorectal melanoma: A case report and review of the literature.

BACKGROUND: Anorectal melanoma is a tumour that is difficult to identify due to its rarity and variability of presentation. Insufficient data published in the literature do not allow for diagnostic and treatment guidelines to be established. Anorectal melanoma has the worst prognosis among mucosal melanomas and is frequently misdiagnosed by standard identification methods. CASE SUMMARY: A 66-year-old woman presented with intermittent anal bleeding, pain, and tenesmus in the past month, with no associated weight loss. Colonoscopy revealed a cauliflower-like tumour with a diameter of 1.5 cm, with exulcerated areas and an adherent clot but without obstruction. Biopsy results identified an inflammatory rectal polyp with nonspecific chronic rectitis. Tumour markers CA 19-9 and CEA were within the normal range. After 6 mo, due to the persistence of symptoms, a pelvic magnetic resonance imaging scan was performed. A lesion measuring 2.8 cm × 2.7 cm × 2.1 cm was identified at the anorectal junction, along with two adjacent lymphadenopathies. No distant metastases were detected. Immunohistochemistry was performed on the second set of biopsies, and a diagnosis of anorectal melanoma was established. Surgical treatment by abdominoperineal resection was performed. Evolution was marked by the appearance of lung metastases at 1 mo postoperatively, detected on a positron emission tomography-computer tomography scan, and perineal recurrence after 5 mo. After molecular testing, the patient was included in an immunotherapy trial. CONCLUSION: This case highlights the difficulty of establishing a definitive early diagnosis of anorectal melanoma, the importance of performing histological analysis on a well-represented biopsy specimen, and the poor prognosis, even with radical surgery.

Understanding cyclical thrombocytopenia: a mathematical modeling approach.

Cyclical thrombocytopenia (CT) is a rare hematological disease characterized by periodic oscillations in the platelet count. Although first reported in 1936, the pathogenesis and an effective therapy remain to be identified. Since besides fluctuations in platelet levels the patients hematological profile have been consistently normal, a destabilization of a peripheral control mechanism might play an important role in the genesis of this disorder. In this paper, we investigate through computer simulations the mechanisms underlying the platelet oscillations observed in CT. First, we collected the data published in the last 40 years and quantified the significance of the platelet fluctuations using Lomb-Scargle periodograms. Our analysis reveals that the incidence of the statistically significant periodic data is equally distributed in men and women. The mathematical model proposed in this paper captures the essential features of hematopoiesis and successfully duplicates the characteristics of CT. With the same parameter changes, the model is able to fit the platelet counts and to qualitatively reproduce the TPO oscillations (when data is available). Our results indicate that a variation in the megakaryocyte maturity, a slower relative growth rate of megakaryocytes, as well as an increased random destruction of platelets are the critical elements generating the platelet oscillations in CT.

Expression of TLR4 protein is reduced in chronic renal failure: evidence from an experimental model of nephron reduction.

Toll-like receptor 4 (TLR4) signaling is involved in various acute and chronic renal lesions and contributes to inflammation and fibrosis in several organs; the latter are important determinants to the progression of chronic kidney disease (CKD). We aimed to assess TLR4 expression in progressive CKD and relate it to severity of kidney damage, using an experimental nephron reduction model. Male Wistar rats were subjected to subtotal nephrectomy using the ligation technique, after 12 weeks of observation, serum creatinine and proteinuria were determined, animals were sacrificed, glomerulosclerosis and interstitial scarring were quantified histologically, and TLR4 expression was assessed by immunohistochemistry. Sham-operated rats served as controls. Case animals had significantly higher creatinine, proteinuria, glomerulosclerosis and tubulointerstitial involvement. TLR4 expression was prominent in proximal tubes, less staining was observed on infiltrating inflammatory cells. Percentage of TLR4-positive tubes was reduced in the subtotal nephrectomy animals, when compared to controls (0.67±0.09 versus 0.79±0.07, p=0.003). Percentage of TLR4-positive tubes correlated inversely to markers of kidney damage: to proteinuria (r=-0.55, p=0.02), serum creatinine (r=-0.53, p=0.01); percentage of glomeruli with glomerulosclerosis (r=-0.54, p=0.01) and tubulointerstitial score (r=-0.36, p=0.01). As TLR4 staining appears in tubular casts only in nephrectomy animals, shedding from damaged tubular cells is a very likely explanation for the reduced TLR4 expression in the kidneys of subjects with experimental nephron reduction.