Study of the impact of ClinGen Revisions on ACMG/AMP variant semi-automatic classification for Rare Diseases diagnosis.

With the rapid development of massive sequencing technologies, the analysis of genetic variants for clinical diagnosis has exponentially escalated, particularly in the context of Rare Diseases (RDs). Diagnosing them involves identifying the genetic variants responsible for the underlying pathology development. In 2015, the American College of Medical Genetics (ACMG) established a set of recommendations to assess the evidence associated with each variant, aiming to achieve a standardized five tier classification.

Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report.

Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting the sense organs and the reproductive system.

MotSASi: Functional short linear motifs (SLiMs) prediction based on genomic single nucleotide variants and structural data.

Short linear motifs (SLiMs) are key to cell physiology mediating reversible protein-protein interactions. Precise identification of SLiMs remains a challenge, being the main drawback of most bioinformatic prediction tools, their low specificity (high number of false positives). An important, usually overlooked, aspect is the relation between SLiMs mutations and disease.

Diagnosis of Male Central Hypogonadism During Childhood.

The diagnosis of male central (or hypogonadotropic) hypogonadism, typically based on low luteinizing hormone (LH) and testosterone levels, is challenging during childhood since both hormones are physiologically low from the sixth month until the onset of puberty. Conversely, follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH), which show higher circulating levels during infancy and childhood, are not used as biomarkers for the condition. We report the case of a 7-year-old boy with a history of bilateral cryptorchidism who showed repeatedly low FSH and AMH serum levels during prepuberty.

AMH and AMHR2 Involvement in Congenital Disorders of Sex Development.

Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina.

Single hepatocellular carcinoma smaller than 2 cm: are ethanol injection and radiofrequency ablation equally effective?

Background/aim: The impact of radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) on survival in patients with small hepatocellular carcinoma (HCC) is unclear. We compared their efficacy in cirrhotics with single HCC ≤2 cm.

Patients And Methods: Two hundred forty-four cirrhotics with single HCC ≤2 cm treated with PEI (108 cases) or RFA (136 cases) were enrolled in the study.

Non-invasive score system for fibrosis in chronic hepatitis: proposal for a model based on biochemical, FibroScan and ultrasound data.

Background & Aims: We elaborate a non-invasive score system for liver fibrosis (NISF), exploring its diagnostic performance and comparing its accuracy to FibroScan in patients with chronic viral hepatitis (CH) and non-alcoholic fatty liver disease (NAFLD).

Methods: Clinical, biochemical, elastographic and ultrasound parameters derived from patients with CH (n = 83) or NAFLD (n = 58), undergoing liver biopsy for fibrosis assessment, were prospectively collected as potential predictors of fibrosis. Each parameter was evaluated for its correlation with the liver biopsy (Gold Standard).

Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey.

Background & Aims: The aim of this study was to compare liver resection and radiofrequency ablation in patients with single hepatocellular carcinoma ≤3 cm and compensated cirrhosis.

Methods: The study involved 544 Child-Pugh A cirrhotic patients (246 in the resection group and 298 in the radiofrequency group) observed in 15 Italian centers. Overall survival and tumor recurrence rates were analyzed using the Kaplan Meier method before and after propensity score matching.

Radiofrequency ablation: technical and clinical long-term outcomes for single hepatocellular carcinoma up to 30 mm.

Background And Aims: Western guidelines consider radiofrequency ablation (RF) as the standard treatment for 'very early' and 'early' hepatocellular carcinoma (HCC) in nonsurgical cirrhotic patients. RF has also been proposed as the first-line therapy for 'surgical' candidates with a single nodule of 20 mm or less. The aim of this monocentric cohort study was to evaluate the technical and clinical outcomes of RF in the treatment of cirrhotic patients with a single HCC of 30 mm or less.

Sorafenib in hepatocellular carcinoma: prospective study on adverse events, quality of life, and related feasibility under daily conditions.

Sorafenib is an oral multikinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). In two randomized trials, sorafenib was reported to be safe without a significant impact on quality of life (QoL). The aim of this study was to evaluate the occurrence of adverse events, QoL variations, and treatment discontinuations in HCC patients treated with sorafenib.

Long-term effectiveness of radiofrequency ablation for solitary small hepatocellular carcinoma: a retrospective analysis of 363 patients.

Background: Radiofrequency Ablation is the most widely performed percutaneous treatment for Hepatocellular Carcinoma. This multicentre study was aimed at assessing the complication, overall survival and disease-free survival rates in cirrhotic patients with single Hepatocellular Carcinoma nodule ≤3 cm undergoing Radiofrequency Ablation.

Methods: Data of 365 patients (59% males; mean age 67 ± 8 years), Child-Pugh A/B, with single Hepatocellular Carcinoma nodule ≤3 cm (tumours >2-3 cm = 127/236), showing complete necrosis after Radiofrequency Ablation between 1998 and 2010 in 7 Italian Centers were retrospectively reviewed.

Serum heat shock protein 27 levels in patients with hepatocellular carcinoma.

Levels of serum heat shock protein 27 (sHsp27) have been studied in numerous cancer types, but their potential relevance in patients with hepatocellular carcinoma (HCC) is undetermined. Our aim was to compare sHsp27 levels in patients with HCC and HCC-free controls. Specifically, we recruited 71 patients with HCC (80 % with early tumour), 80 patients with chronic liver disease (59 with liver cirrhosis and 21 with chronic active hepatitis) and 42 healthy subjects.

Local Tumor Progression of Hepatocellular Carcinoma After Microwave Percutaneous Ablation: A Preliminary Report.

Background: Microwaves (MW) technology is an ablative treatment alternative to radiofrequency (RF) for early stages of hepatocellular carcinoma (HCC) in cirrhotic patients not suitable for surgical resection. It is well known that HCC lesions ≥ 30 mm treated by RF show a high rate of local tumor progression because of residual of unablated neoplastic tissue.

Methods: Aim of this study was to describe a limited experience of MW ablation (9 cirrhotic patients with medium size HCC: 11 lesions, 31 - 50 mm in diameter) treated from June 2009 to May 2010 by one of currently marketed western MW ablation systems and followed up for 2 years.

Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance.

Background: The aetiological factors of hepatocellular carcinoma may vary over time.

Aims: The study assessed the potential impact of the aetiological factors on the effectiveness of surveillance in real-world patients.

Methods: Multicentre, cross-sectional study enrolling consecutive hepatocellular carcinoma cases during a six month period.

Transcatheter arterial chemoembolization for hepatocellular carcinoma in cirrhosis: influence on portal hypertension.

Background: Transcatheter arterial chemoembolization (TACE) is a routine treatment for hepatocellular carcinoma in cirrhotic patients. Whether TACE influences the degree of portal hypertension remains uncertain. AIM AND PATIENTS: We retrospectively analyzed the clinical course of 283 TACE to investigate the incidence of variceal bleeding and ascites after the procedure.

Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis.

Background & Aims: Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM).

Methods: TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6 months of the liver biopsy.

[Bayesian approach for the cost-effectiveness evaluation of healthcare technologies].

The development of Bayesian statistical methods for the assessment of the cost-effectiveness of health care technologies is reviewed. Although many studies adopt a frequentist approach, several authors have advocated the use of Bayesian methods in health economics. Emphasis has been placed on the advantages of the Bayesian approach, which include: (i) the ability to make more intuitive and meaningful inferences; (ii) the ability to tackle complex problems, such as allowing for the inclusion of patients who generate no cost, thanks to the availability of powerful computational algorithms; (iii) the importance of a full use of quantitative and structural prior information to produce realistic inferences.

[Non-parametric methods for estimating confidence intervals around the incremental cost-effectiveness ratio].

In recent years, cost-effectiveness analysis has become a frequent component of randomized clinical trials. In statistical terms, the major efforts addressed the method for estimating the Incremental Cost Effectiveness Ratio (ICER) and its confidence interval both with parametric and non-parametric methods. The goal of the present work is to briefly present the main non-parametric methods, based on a bootstrap approach.

Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial.

Objective: To compare percutaneous ethanol injection (PEI), the standard approach which has been used for many years to treat early non-surgical hepatocellular carcinoma (HCC) in cirrhotic patients, and radiofrequency ablation (RFA), which has become an interesting alternative.

Material And Methods: A randomized trial was carried out on 139 cirrhotic patients in Child-Pugh classes A/B with 1-3 nodes of HCC (diameter 15-30 mm), for a total of 177 lesions. Patients were randomized to receive RFA (n=70) or PEI (n=69).

AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers.

Background/aims: The renin-angiotensin system plays an important role in hepatic fibrogenesis and in portal hypertension. To examine the long-term effects of Candesartan cilexetil, an angiotensin type 1 (AT1) receptor blocker, on portal-systemic haemodynamics and on liver fibrosis.

Methods: Forty-seven compensated Child A and Child B (8) cirrhotic patients were randomly assigned to receive Candesartan cilexetil, 8 mg/d (N.

Ectopic liver and hepatocarcinogenesis: report of three cases with four years' follow-up.

Hepatocellular carcinoma (HCC) may arise in ectopic livers, which are autonomous islands of normal liver parenchyma located in the abdomen or thorax. The majority of HCCs in ectopic livers are reported in oriental patients. We describe here three new cases of HCC in Caucasian patients.

Helicobacter pylori seroprevalence in patients with cirrhosis of the liver and hepatocellular carcinoma.

Background: Infection by Helicobacter hepaticus causes chronic hepatitis and hepatocellular carcinoma (HCC) in mice, and Helicobacter pylori (H. pylori) genomic sequences have been demonstrated in the liver of patients with HCC. H.

High-grade B-cell lymphoma arising in mucosa-associated lymphoid tissue of the duodenum.

Duodenal mucosa-associated lymphoid tissue lymphoma is a rare neoplasm. We report a case of a 70-year-old man with non-Hodgkin's lymphoma located in the descending duodenum that was not associated with Helicobacter pylori infection of the stomach. A surgical resection due to obstruction of the bowel lumen above the ligament of Treitz was performed.

Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.

Background & Aims: Nonalcoholic steatohepatitis (NASH) may progress to cirrhosis; whether NASH plays also a role in the development of hepatocellular carcinoma (HCC) is unknown.

Methods: Among 641 cirrhosis-associated HCCs, we retrospectively identified 44 patients with cryptogenic cirrhosis (CC). Of these, 23 were actively followed up and were compared in a case-control study with viral- and alcohol-associated HCC.