Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Multisession radiosurgery for intracranial meningioma treatment: study protocol of a single arm, monocenter, prospective trial.

BACKGROUND: Single session radiosurgery represents a widely accepted treatment for intracranial meningiomas. However, this approach could involve a high risk of treatment-related complications when applied to large volume lesions. In these cases and for those not suitable for surgical resection, radiosurgery in multisession setting could represents a viable option. The literature results are reassuring in terms of correlated adverse events as well as in terms of tumor control. However, no prospective long-term results are available. In this scenario, we design a prospective monocentric phase II study, in order to verify the safety of a multisession radiosurgery schedule delivering 25 Gy in 5 daily fractions. METHODS: Patients diagnosed with large and/or near to critical structures, intracranial meningiomas have been treated by means of multisession radiosurgery in both exclusive and postoperative settings. The primary study aim is safety that has been being prospectively scored based on international scales, including NCI Common Toxicity criteria, version 4.03, Barrow Neurological Institute pain intensity score, Barrow Neurological Institute facial numbness score and House-Brackmann Facial Nerve Grading System for qualitative analysis. Secondary aim is treatment efficacy in terms of local control that has been being assessed on volumetric analysis. DISCUSSION: This is the first prospective phase II trial on multisession radiosurgery for large and/or near to critical structures intracranial meningiomas. If positive results will be found, this study could represent the starting point for a phase III trial exploring the role of multisession radiosurgery in the exclusive and postoperative radiation therapy treatment of intracranial meningiomas. TRIAL REGISTRATION: Trial registration: clinicaltrials.gov platform (Multisession Radiosurgery in Large Meningiomas -MuRaLM- identifier NCT02974127). Registered: November 28, 2016. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02974127?term=radiosurgery&cond=Intracranial+Meningioma&draw=2&rank=1.

Diagnostic response to a cross-border challenge for the Swiss caprine arthritis encephalitis virus eradication program.

INTRODUCTION: Animal trading between countries with different small ruminant lentivirus infectious status is a potential danger for the reintroduction of eradicated genotypes. This was the case in 2017 with the importation of a large flock of seropositive goats into Switzerland. The handling of this case permitted us to test the preventive measures in place. The coordination between the local veterinarian and the cantonal and federal veterinary authorities worked efficiently and rapidly involved the national reference center in the investigations. This case posed a challenge for the reference center and enabled scrutiny of the applied diagnostic tests. ELISA and western blot provided consistent results and pointed to an unusually high infection rate in the flock. This was confirmed by the isolation of several viruses from different organs and cells, demonstrating that the spleen is particularly well suited for isolation of small ruminant lentiviruses. The SU5-ELISA, designed to predict the subtype of the infecting virus, correctly pointed to a B1 subtype as the infectious agent. We confirmed that with this test it is necessary to analyze a representative number of samples from a flock and not just individual sera to obtain reliable results. This analysis permitted us to identify particular amino acid residues in the SU5 peptides that may be crucial in determining the subtype specificity of antibody binding. Different gag-pol and env regions were amplified by PCR using primers designed for this purpose. The phylogenetic analysis revealed a surprisingly high heterogeneity of the sequences, pointing to multiple infections within single animals and the entire flock. In conclusion, this case showed that the defense of the CAEV negative status of the Swiss goat population with respect to the virulent, prototypic B1 subtype of small ruminant lentiviruses, requires, among other measures, a diagnostic facility capable of performing a thorough analysis of the collected samples.

INTRODUCTION: Le commerce d'animaux entre pays où le statut infectieux des lentivirus des petits ruminants est différent constitue un danger potentiel pour la réintroduction de génotypes éradiqués. Ce fut le cas en 2017 avec l'importation d'un grand troupeau de chèvres séropositives en Suisse. Le traitement de cette affaire nous a permis de tester les mesures préventives mises en place. La coordination entre le vétérinaire local et les autorités vétérinaires cantonales et fédérales a été efficace et a impliqué rapidement le centre de référence national dans les enquêtes. Ce cas a constitué un défi pour le centre de référence et a permis d'examiner de près les tests de diagnostic appliqués. Les tests ELISA et Western blot ont fourni des résultats cohérents et ont mis en évidence un taux d'infection anormalement élevé dans le troupeau. Cela a été confirmé par l'isolement de plusieurs virus provenant d'organes et de cellules différents, démontrant que la rate est particulièrement bien adaptée à l'isolement des lentivirus des petits ruminants. Le SU5-ELISA, conçu pour prédire le sous-type du virus infectant, désignait correctement un sous-type B1 en tant qu'agent infectieux. Nous avons confirmé qu'avec ce test, il était nécessaire d'analyser un nombre représentatif d'échantillons d'un troupeau et pas seulement des sérums individuels pour obtenir des résultats fiables. Cette analyse nous a permis d'identifier des résidus d'acides aminés particuliers dans les peptides SU5 qui pourraient jouer un rôle crucial dans la détermination de la spécificité de sous-type de la liaison à l'anticorps. Différentes régions gag-pol et env ont été amplifiées par PCR en utilisant des amorces conçues à cet effet. L'analyse phylogénétique a révélé une hétérogénéité étonnamment élevée des séquences, indiquant de multiples infections chez les animaux isolés et dans l'ensemble du troupeau. En conclusion, cette affaire a montré que la défense du statut négatif CAEV de la population de chèvres suisses vis-à-vis du virus virulent, sous-type B1 des lentivirus des petits ruminants, nécessite, entre autres mesures, un système de diagnostic capable d'effectuer une analyse approfondie des échantillons collectés.

In vitro assessment of radiobiology of meningioma: A pilot study.

BACKGROUND: Meningioma are the second most common brain tumors in adults and can cause significant morbidity and mortality. The scarcity of in vitro and in vivo models represents the major obstacle to understand the molecular basis of meningioma tumorigenesis. The main aim of this study was to assess a method for radiobiology of meningioma cells colture by means of well-known meningioma lines. NEW METHOD: We carried out a protocol of cells culture for irradiation of meningioma cells. We used the immortalized cell lines IOMM-Lee and CH-157 to study their radiation-reponse by means of clonogenic assays and to evaluate their proliferation and apoptosis. We irradiated the cells with different total doses using two different linear accelerators. RESULTS: We observed a more radiation resistance of the IOMM-Lee than the CH-157. Indeed, the cellular death of CH-157 was obtained at a very low dose irradiation. Moreover, we showed a dose-response effect due to the early and late apoptosis, in fact the rate of apoptotic cells is greater than that of the necrotic cells at any dose of irradiation and at any time of analysis. COMPARISON WITH EXISTING METHODS: There is not a standardized method for radiobiology of meningioma experiments. CONCLUSIONS: Our method of cells culture appears suitable for radiosensitivity studies on meningioma. We can confirm that the response to radiotherapy depends not only on irradiation features, but also on tumor radiosensitivity.

Diagnosis of Mesiodistal Vertical Root Fractures in Teeth with Metal Posts: Influence of Applying Filters in Cone-beam Computed Tomography Images at Different Resolutions.

INTRODUCTION: The aim of this article was to evaluate the influence of applying filters in cone-beam computed tomography (CBCT) images at different resolutions. These CBCT images were obtained for diagnosing mesiodistal vertical root fractures (VRFs) in teeth with metal posts. METHODS: Forty teeth were treated endodontically, and 20 received metal posts. Ten teeth without posts and 10 teeth with posts were subjected to VRF in the mesiodistal direction. The sample was submitted to periapical radiographs and CBCT exams with a voxel of 0.25 and 0.30 mm. To reduce the influence of the metal artifact in the CT images, the teeth were evaluated with and without the application of filters ("Sharpen" and "Hard"). The images were evaluated by 2 radiologists who identified the presence of VRF. Accuracy values (receiver operating characteristic curves) for the different variables were compared by using analysis of variance and t test. RESULTS: No difference was observed between images with and without filter application (P > .05). Images obtained with a 0.25-mm voxel were more accurate (P < .05). The presence of the metal post reduced the accuracy of the diagnosis of VRF (P < .05), and the CBCT images showed superior results compared with periapical radiographs (P < .05). CONCLUSIONS: The presence of a metal post and the voxel size significantly interfere with the diagnosis of VRF. Despite the formation of metal artifacts associated with metallic cores, applying filters did not improve the diagnosis. For mesiodistal VRF, the CBCT images are superior to the periapical radiographs.

Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C.

BACKGROUND: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival. AIM: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. METHODS: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. RESULTS: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008). CONCLUSIONS: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.

Infections and organ transplantation: new challenges for prevention and treatment of hepatitis C virus.

Hepatitis C virus infection is a widespread condition, affecting about 170 million people worldwide. It is associated with the progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Therefore, antiviral treatment appears to be recommended for patients infected with HCV. This article reviewed recent evidence on antiviral therapy for HCV-infected patients.

Risk factors in liver retransplantation: a single-center experience.

Liver retransplantation (Re-OLT) is one of the most debated issues in medicine over the past decade. Re-OLT, currently is accepted for patients with irreversible failure of a hepatic graft caused by primary nonfunction (PNF), hyperacute/chronic rejection, or hepatic artery thrombosis (HAT); whereas it is still controversial for patients with recurrent viral disease, in particular hepatitis C virus (HCV) cirrhosis. Patient and graft survival rates are lower than those observed after primary liver transplantation (OLT). The aim of the present study was to analyze the risk factors that adversely affect survival after Re-OLT in a single center. Medical data were collected for 23 patients who underwent Re-OLT from November 2002 to December 2008 including six men and seven women of mean age of 51.3 years. The most frequent indications for Re-OLT were: PNF (69.5%; 16/23), HCV recurrence (8.6%; 2/23), or HAT (8.6%; 2/23). Mean Model for End-Stage Liver Disease (MELD) at Re-OLT was 27.7 (range = 9-40). After a mean follow-up of 37.4 ± 30 (standard deviation) months, 43% (10/23) of patients had died, including 70% within the first 2 months after Re-OLT. Sepsis represented the commonest cause of death (40%). Re-OLT was performed for PNF among 90% of succumbing patients. As regards dead patients, 4/10 were HCV(+) whose causes of death were sepsis (n=2), alcoholic cirrhosis (n=2), and undetermined (n=1). Comparing patients who died after liver Re-OLT versus alive patients, we did not find any significant difference in terms of mean MELD (28.6 vs 27; P=NS), MELD > 25 (60% vs 61.5%, P=NS), donor age > 60 years (30% vs 15.3%, P=NS), HCV(+) (40% vs 62%, P = NS), or time interval from OLT to Re-OLT (12.2 vs 777.7 days, P=NS). Patient survivals after Re-OLT were 67% at 3 years and 50% at 5 years, which were lower than those of first transplantations, as reported by other European and International Centers. Forty percent of deaths after Re-OLT occurred among HCV(+) recipients, but for reasons unrelated to HCV infection.

Fibrosis progression and the pros and cons of antiviral therapy for hepatitis C virus recurrence after liver transplantation: a review.

The progression of fibrosis due to hepatitis C virus (HCV) recurrence after liver transplantation (OLT) is faster than in the pretransplant setting, leading to histologically documented cirrhosis within 5 years in 25% to 30% of cases. Whether it is associated with biliary complications or previous alcohol abuse, recurrent HCV is the main cause of graft failure and death after OLT. The most important donor risk factor for HCV recurrence is advanced donor age. The disease's course is even more aggressive if it is associated with anti-HCV positivity or graft steatosis. The type of calcineurin inhibitor does not seem to influence HCV recurrence. Avoiding or slowly tapering steroids has been associated with less disease recurrence, while steroid pulses to treat acute rejection episodes have been associated with a worse progression of fibrosis. Antiviral therapy (AT) is not always recommended in OLT patients, but is of some benefit. Fibrosis has been shown to ameliorate in sustained virological responders to AT and to progress significantly more in nonresponders. Using long-term maintenance, AT has recently been shown to increase the probability of biochemical and histological responses, regardless of the timing of the HCV recurrence. In conclusion, the donor- recipient match should be assessed to limit HCV recurrences and their severity; AT is recommended to reduce or reverse the progression of fibrosis.

The impact of hepatitis C and biliary complications on patient and graft survival following liver transplantation.

Recurrent hepatitis C (HCV) and biliary complications (BC) are major causes of post liver transplant morbidity and mortality. The impact of these complications may be additive or synergistic. We performed a retrospective cohort study to analyze the effects of HCV and BC on all patients transplanted at two institutions over 6 years. BC was defined by imaging findings in the setting of abnormal liver function tests that required intervention. The primary outcomes were graft and patient survival over a mean 3.4 years. 709 patients (619 deceased, 90 living donor) were included, 337 with HCV and 372 without. BC was diagnosed more frequently in patients with HCV, 26% versus 18% (p = 0.008). One-year and overall patient and graft survival were significantly lower in patients with HCV, but BC impacted only 1-year graft survival. The combination of BC and HCV had no additional impact on survival or fibrosis rates on 1-year protocol biopsies. Multivariate analysis revealed HCV (HR 2.1) and HCC (HR 1.9) to be independent predictors of mortality. Since BC are diagnosed more frequently in HCV patients and only affect early graft loss, it is likely that recurrent HCV rather than BC accounts for the majority of adverse graft outcomes.

HCV histological recurrence and survival following liver transplantation in patients with and without hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatitis C virus (HCV)-related cirrhosis is one of the leading indication for liver transplantation (LT) and a major risk factor for the development of hepatocellular carcinoma (HCC). HCV recurrence after LT is universal. This study evaluated HCV recurrence and survival in patients transplanted for HCV and HCC. METHODS: We evaluated all adults transplanted for HCV cirrhosis between January 1999 and December 2006, HCC was diagnosed on the explant and HCV recurrence confirmed on protocol liver biopsies performed at 6 months and yearly after LT. The sustained viral response (SVR) was defined as HCV-RNA undetectable at 6 months after therapy discontinuation. The patient survival rates were assessed with Kaplan-Meier curves and the chi-square test was used when appropriate. RESULTS: Two hundred sixteen patients underwent LT for HCV including 153 men and 63 women of mean age 54 years with a mean follow-up of 35 months. There were 71 (33%) HCC(+) patients. At 1, 3, and 5 years from LT severe fibrosis (Scheuer 3-4) due to the HCV recurrence was reported in 18%, 14%, and 11% for HCC(+) and 14%, 16%, and 28% for HCC(-) patients respectively (P=NS). HCC recurred only in 3 (4%) patients at a mean follow-up of 3 years. Patients who received antiviral treatment after LT were 10% HCC(+) and 12% HCC(-) patients (P=NS). SVR was seen in 3/7 (43%) of HCC(+) and in 10/18 (55%) of HCC(-) patients (P=NS). At 1, 3, and 5 years the patient survivals was 91%, 86%, and 86% for HCC(+) and 94%, 86%, and 83% for HCC(-) patients, respectively (P=NS). CONCLUSIONS: Severe fibrosis due to HCV recurrence, which increases over time, involves one third of transplanted patients at 5 years after LT. The long-term survival was identical among HCC(+) compared to HCC(-) recipients. The recurrence of HCC was negligible and did not affect patient survival.