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Background and Aim: Recent researches have shown an altered gut microbiota in celiac disease (CD) patients compared with healthy controls (HCs). This study aims to evaluate the composition of the microbiota of CD children at onset and the relationship between bacterial abundances and symptoms. Methods: Celiac disease patients were consecutively enrolled at a pediatric unit referring for suspected CD. HCs were also included in the study. Stool and duodenal samples were collected and evaluated by a high taxonomic fingerprint microbiota array. Results: Thirty-seven subjects enrolled: 21 CD patients and 16 HCs. Fourteen subjects were male (38%). The mean age was 75months (standard deviation 31.5) for CD patients and 71months (standard deviation 34.9) for HCs. Duodenal microbiota of CD patients showed a dominance of Enterobacteriaceae and subdominance of Bacteroidetes/Streptococcus. Stool microbiota showed a lower abundance of Bacteroides–Prevotella (P=0.013), Akkermansia (P=0.002), and Staphylococcaceae (P=0.001) in CD patients compared with HC. At symptoms level, an increased mean relative abundance of Bacillaceae and Enterobaeriaceae in patients with abdominal pain (P=0.007 and P=0.010) was found. CD patients with diarrhea had reduced mean relative abundance of Clostridium cluster XIVa (P=0.044) and Akkermansia (P=0.033) and an increase in Bacillaceae (P=0.048) and Fusobacterium (P=0.048). Conclusions: Gut microbiota of CD children at disease onset is different from that of HC. Pro-inflammatory microbiota imbalances were associated with CD symptoms. Further studies are needed to assess whether dysbiosis is associated with CD early onset and symptoms.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and it is one of the main complications of cirrhosis and portal hypertension. Even in the presence of a well-established follow-up protocol for cirrhotic patients, to date poor data are available on predictive markers for primary HCC occurrence in the setting of compensated advanced chronic liver disease patients (cACLD). The gold standard method to evaluate the prognosis of patients with cACLD, beyond liver fibrosis assessed with histology, is the measurement of the hepatic venous pressure gradient (HVPG). An HVPG ≥10 mmHg has been related to an increased risk of HCC in cACLD patients. However, these methods are burdened by additional costs and risks for patients and are mostly available only in referral centers. In the last decade increasing research has focused on the evaluation of several, simple, non-invasive tests (NITs) as predictors of HCC development. We reviewed the currently available literature on biochemical and ultrasound-based scores developed for the non-invasive evaluation of liver fibrosis and portal hypertension in predicting primary HCC. We found that the most reliable methods to assess HCC risk were the liver stiffness measurement, the aspartate aminotransferase to platelet ratio index score and the fibrosis-4 index. Other promising NITs need further investigations and validation for different liver disease aetiologies.

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher's exact test, and logistic regression analyses to analyze the associations between the various FGFR3 alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3 GAs or high FGFR3 signature scores, or had lncRNA-FGFR3–active tumors. Despite an association of high FGFR3 gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3 expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time. Patient summary In patients with muscle-invasive bladder cancer treated within the PURE-01 trial, we analyzed the role of fibroblast growth factor receptor-3 (FGFR3) alterations, at the DNA and RNA levels, in association with the pathological response. We did not find any robust association, mainly when analyzing the landscape of alterations defining tumors with higher biological FGFR activity. Overall, FGFR3 activity and gene alterations did not provide sufficiently robust data to exclude patients whose tumors harbor these alterations from neoadjuvant immunotherapy trials.

Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise. Methods and results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3mm; malignant LCTs, mean 44mm) (P&nbsp

Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by 18[F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes. Background: Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by 18[F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes. Objective: To evaluate the role of PET/CT to visualize the immune-related adverse events (irAEs) following pembrolizumab. Design, setting, and participants: From February 2017 to August 2019, in 103 patients with nonmetastatic, clinical T2–4aN0M0 bladder cancer, PET/CT scan was performed before and after neoadjuvant pembrolizumab (N = 206 scans), before radical cystectomy. Intervention: PET/CT before and after neoadjuvant pembrolizumab, before radical cystectomy. Outcome measurements and statistical analysis: We analyzed the occurrence of irAEs, evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, against the development of inflammatory FDG uptake described at PET/CT (irAEs + PET/CT). Logistic regression analyses evaluated the association between irAEs + PET/CT and the pathological response to pembrolizumab. Kaplan-Meier curves tested their association with progression-free survival (PFS) after pembrolizumab and radical cystectomy. Results and limitations: Forty patients (39%) developed irAEs + PET/CT in several target organs. The most frequent target organs were the thyroid (N = 18), stomach (N = 14), mediastinal lymph nodes (N = 9), and lung (N = 5). These changes were clinically evident in 18 (45%) and were not associated with the pathological response, neither in terms of complete response (ypT0N0, p = 0.07) nor as downstaging to ypT≤1N0 disease (p = 0.1), although ypT0N0 responses were numerically more frequent in patients with irAEs+ PET/CT (47.5% vs 32%). Furthermore, irAE+ PET/CT events were associated with longer, not statistically significant, 24-mo PFS: 88.3% versus 76.5% (p = 0.5). Our results warrant further validation in larger datasets. Conclusions: We presented unique surrogate data of PET/CT that could help improve our understanding of nonclinically evident effects of ICI administration, especially in patients at the early disease stage. Patient summary: We evaluated the utility of PET/CT to visualize the occurrence of inflammatory changes after pembrolizumab in patients with localized bladder cancer without metastases. After immunotherapy, 39% of the patients developed 18[F] fluorodeoxyglucose uptake consistent of inflammatory changes. Overall, our data improve our knowledge on the effects induced by immunotherapy, which may have a clinical impact at longer follow-up. Take Home Message ● In the PURE-01 study, T2–4N0M0 muscle-invasive bladder cancer patients were staged with fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before and after pembrolizumab. ● PET/CT after pembrolizumab revealed inflammatory FDG uptake in 39% of patients, but only 45% of these cases of uptake corresponded to clinically evident adverse events. ● The development of inflammatory uptake was associated with a higher pathological complete response rate and longer progression-free survival, although these differences were not statistically significant.

Background & Aims Hepatitis C virus (HCV) eradication with direct-acting antivirals (DAAs) reduces but does not eliminate the risk for hepatocellular carcinoma (HCC). The development of surveillance strategies for HCC after the sustained virologic response (SVR) is therefore warranted. We aimed to evaluate the role of spleen stiffness measurement (SSM) in the prediction of HCC risk in a cohort of patients with advanced chronic liver disease (ACLD) treated with DAAs. Methods This is a retrospective cohort study of 140 patients with HCV-related ACLD successfully treated with DAAs in our centre between 2015 and 2017. Patients with available liver stiffness (LSM) and SSM before treatment and 6 months after (SVR24) were included. A Cox regression model investigated the association between SSM and HCC development. Results During a median follow-up of 41.5 (IQR 32–49) months, 20 patients presented with HCC. SSM at SVR24 predicted HCC development in univariate and adjusted multivariate analysis (hazard ratio: 1.025; 95% CI: 1.001–1.050); the best cut-off was 42 kPa. Patients with LSM-SVR24 ≤10 kPa were at the lowest risk of HCC. In patients with LSM-SVR24 >10 kPa, HCC incidence was not further influenced by LSM values (10–20 kPa vs. >20 kPa), but only by SSM-SVR24 values (≤42 vs. >42 kPa). Conclusions Portal hypertension, as evaluated by SSM, plays a significant role in liver carcinogenesis after DAA treatment. We proposed a new algorithm based on post-treatment values of LSM and SSM for the stratification of HCC risk after SVR achievement. Lay summary Spleen stiffness predicts the development of hepatocellular carcinoma after viral eradication, especially in patients with post-treatment liver stiffness values >10 kPa. An algorithm based on liver and spleen stiffness can stratify for the risk of liver cancer development and guide the surveillance strategies after treatment with direct-acting antivirals., Graphical abstract, Highlights • Portal hypertension plays an important role in liver carcinogenesis after DAA treatment. • SSM is an independent predictor of HCC development after viral eradication, with a best cut-off of 42 kPa. • An algorithm based on LSM and SSM at SVR24 can be used to stratify for the risk of HCC and to guide surveillance.

PURPOSE: We evaluated the oncologic efficacy of early inguinal lymph-node dissection, observation or dynamic sentinel node biopsy followed by delayed or selective inguinal lymph-node dissection in cN0 patients with penile squamous cell carcinoma. MATERIALS AND METHODS: Between 1980 and 2017 (inclusive), 296 evaluable consecutive cN0 penile squamous cell carcinoma patients underwent early inguinal lymph-node dissection (16), observation (114) or dynamic sentinel node biopsy (166). Median followup was 50 months. Tumor stage, grade, lympho-vascular invasion and age were considered. Kaplan-Meier plots illustrated 5-year inguinal relapse-free and cancer specific survival rates. Multivariable Cox regression models tested the treatment effect. Analyses were repeated after inverse probability of treatment weighting adjustment. RESULTS: The 5-year inguinal relapse-free survival and cancer specific survival rates following early, observation and dynamic sentinel node biopsy inguinal lymph-node dissection were 100%, 87%, 89%, and 84%, 81%, 85%, respectively. The 5-year crude inguinal relapse-free survival and cancer specific survival rates were 90% and 93% in low-risk patients undergoing observation. Clavien grade 3 complications were 0.6 vs 12.5% in the dynamic sentinel node biopsy and early inguinal lymph-node dissection group, respectively. After inverse probability after treatment weighting adjustment, 5-year inguinal relapse and cancer specific survival were 90% vs 73% and 90% vs 77% following dynamic sentinel node biopsy and observation, respectively. At multivariable Cox regression model, patients undergoing dynamic sentinel node biopsy had significantly lower inguinal relapse (HR 0.4, 95% CI 0.2-0.85, p 0.02) and cancer specific mortality (HR 0.29, 95% CI 0.11-0.77; p=0.01) compared to those under observation. The low number of patients undergoing early inguinal lymph-node dissection made a reliable comparison with this group impractical. CONCLUSIONS: Selective inguinal lymph-node dissection following dynamic sentinel node biopsy significantly improved inguinal relapse and cancer specific mortality when compared with observation, providing evidence of efficacy of dynamic sentinel node biopsy in clinical stage N0 squamous cell carcinoma of the penis.

Portal hypertension is the main driver of complications in patients with advanced chronic liver disease (ACLD). In the last decade, many non-invasive tests, such us liver and spleen elastography, have been proposed and validated for the identification of patients with clinically significant portal hypertension (CSPH) and its complications, mainly hepatic decompensation and liver-related morbidity and mortality. Moreover, elastography accurately stratifies for the risk of HCC development, HCC recurrence and decompensation after liver surgery. Recent studies suggest a role of SSM in monitoring response to treatments and interventions in ACLD, such as viral eradication, non-selective beta-blockers and transjugular intrahepatic portosystemic shunt placement. However, one of the most indications to perform elastography in ACLD still remains the screening for esophageal varices. In fact, according to the Baveno VIconsensus, liver stiffness measurement (LSM) 20 kPa and platelet count 150,000/mm3 can safely identify patients at low risk of varices requiring treatment (VNT) and could therefore avoid invasive upper invasive endoscopy; LSM20-25 kPa can accurately rule-in CSPH in patients with viral etiology. Spleen stiffness measurement (SSM) is a direct surrogate of portal hypertension and has been demonstrated more accurate in predicting portal hypertension severity and VNT. Acombined model including Baveno VI Criteria and SSM (46 kPa) can significantly increase the number of spared endoscopies (40-50%), maintaining a low (5%) of missed VNT.

Non-selective β-blocker (NSBB) therapy is the treatment of choice for primary prophylaxis of cirrhotic patients with high-bleeding risk esophageal varices (HRV). The hemodynamic response to NSBB is assessed by the measurement of the hepatic venous pressure gradient (HVPG). Recently, liver and spleen stiffness measurements (LSM and SSM) were proposed as non-invasive surrogates of HVPG. We aimed to evaluate LSM and SSM changes for assessing hemodynamic response in these patients. Cirrhotic patients with HRV were prospectively enrolled and evaluated at our Department before starting NSBB and after 3 months. Correlation between changes (delta) of HVPG after NSBB treatment and those of LSM or SSM by transient elastography was performed. From the initial 59 patients considered for the study, 20 were finally included in the analysis. Fifteen (15) patients reached hemodynamic response to NSBB according to HVPG. Changes in LSM did not correlate with changes in HVPG (r = 0.107, p value = 0.655), unlike changes in SSM (r = 0.784, p value

Myoid gonadal stromal tumor represents a rare testicular neoplasm displaying smooth muscular and gonadal stromal differentiation. This entity has very few cases reported in the literature that describe heterogeneous clinical and pathological characteristics. Bayesian statistics provides a useful framework to combine information from diverse sources. We here presented a case series-the largest so far reported-of myoid gonadal stromal tumor (4 cases) with extensive morphologic, immunohistochemical, and molecular characterization, performed a systematic review of the literature (that identified 9 papers), and used a Bayesian data analysis to understand the characteristics of this disease. Our study collectively described 16 cases. This neoplasm is mainly found in adults (mean age about 40 years) and often has a size of about 3 cm. By morphology, the tumor can infiltrate testicular tubules and is composed of spindle cells; few mitoses can be seen (usually 2/10 HPF). Neoplastic cells are diffusely positive with α-smooth muscle actin with a tram-track staining pattern. S100 protein, FOXL2, and SF1 are also characteristically positive. Moreover, this neoplasm can display epithelial differentiation, in about half of the cases. In conclusion, we foresee the use of this statistical approach in pathology: our analysis allowed a more precise description of this rare entity.

BackgroundIn the PURE-01 study (NCT02736266), we aimed to evaluate the ability to predict the pathologic complete response (pT0N0) after pembrolizumab by using clinical and tumor biomarkers.MethodsIn an open-label, single-arm, phase 2 study, 3 courses of 200 mg pembrolizumab preceding radical cystectomy were administered in patients with T2-4aN0M0 muscle-invasive bladder cancer. The analyses included a comprehensive genomic profiling and programmed cell-death-ligand-1 (PD-L1)–combined positive score assessment (CPS; Dako 22C3 antibody) of pre- and posttherapy samples. Multivariable logistic regression analyses evaluated baseline clinical T stage and tumor biomarkers in association with pT0N0 response. Corresponding coefficients were used to develop a calculator of pT0N0 response based on the tumor mutational burden (TMB), CPS, and the clinical T stage. Decision-curve analysis was also performed. All statistical tests were 2-sided.ResultsFrom February 2017 to June 2019, 112 patients with biomarker data were enrolled (105 with complete TMB and CPS data). Increasing TMB and CPS values featured a linear association with logistic pT0N0 probabilities (P = .02 and P = .004, respectively). For low TMB values (≤11 mut/Mb, median value, n = 53), pT0N0 probability was not associated with increasing CPS. Conversely, for high TMB values (>11 mut/Mb, n = 52), pT0N0 was statistically significantly associated with higher CPS (P = .004). The C index of the pT0N0 probability calculator was 0.77. On decision-curve analysis, the net benefit of the model was higher than the “treat-all” option within the clinically meaningful threshold probabilities of 40%-50%.ConclusionsThe study presents a composite biomarker-based pT0N0 probability calculator that reveals the complex interplay between TMB and CPS, added to the clinical T stage.

Background: In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients. Objective: To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0). Design, setting, and participants: Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist. Intervention: To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used. Outcome measurements and statistical analysis: The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen's kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps. Results and limitations: From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%). Conclusions: In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies. Patient summary: Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies. • In the PURE-01 study, multiparametric magnetic resonance imaging (mpMRI) of the bladder was used to stage and evaluate the response to pembrolizumab, before radical cystectomy. • Assessments of mpMRI sequence were externally reviewed, showing preliminary but promising reproducibility. • We proposed an mpMRI-based definition of complete response predicting the pathological complete response to pembrolizumab that was externally replicated.

Background Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited. Objective To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266). Design, setting, and participants In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH. Intervention Neoadjuvant pembrolizumab and RC. Outcome measurements and statistical analysis Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response. Results and limitations From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28–46) and the pT ≤ 1 rate was 55% (95% CI: 46–65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology. Conclusions The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes. Patient summary In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.

Background The prognostic role of spontaneous portosystemic shunts (SPSS) has been poorly investigated. Aims To evaluate the impact of the presence of SPSS, as well as their characteristics, on the risk of decompensation. Methods This is a retrospective cohort study of 235 advanced chronic liver disease (ACLD) patients with available imaging examination, transient elastography, and upper endoscopy. ACLD was defined as liver stiffness measurement (LSM) >10 kPa. Competitive risk analyses were performed to identify the factors associated with the main outcome. Results SPSS were reported in 141 (60%) of the patients. Non-viral etiology was independently associated with SPSS presence [Odds-Ratio (OR): 2.743;95%-Interval-of-Confidence (IC):1.129–6.664]. During a follow-up of 37 (20–63) months, SPSS were found predictors of any decompensation type [Subhazard Ratio (SHR):2.264; 95%-IC:1.259–4.071], independently from a history of decompensation or high-risk-varices presence. The risk of complications was higher in patients with large (SHR: 3.775; 95%-IC: 2.016–7.070) and multiple (SHR:3.832; 95%-IC: 2.004–7.330) shunts, and in those with gastrorenal shunts (SHR:2.636; 95%-IC:1.521–4.569). Conclusions The presence, size, and number of SPSS predict not only the risk of hepatic encephalopathy but that of any type of decompensation across all stages of cirrhosis. Future studies should explore the possibility of treating shunts to prevent decompensation.

PURPOSE The aim of the present study was to propose and validate a standardized CT protocol for evaluating all the types of portosystemic collaterals (P-SC), including gastroesophageal varices and spontaneous portosystemic shunts (SPSS), and to evaluate the prognostic role of portal hypertension CT features for the prediction of the hepatic decompensation risk in cirrhotic patients. METHODS A retrospective cohort study of 184 advanced chronic liver disease who underwent CT scan between January 2014 and December 2017. Patients with an interval��>��6��months between the imaging, elastometric, endoscopic and biochemical evaluation were excluded, as well as patients with previous transjugular intrahepatic portosystemic shunt (TIPS), liver transplantation (LT) or terminal medical conditions. Data on liver disease history, co-morbidities, endoscopic and radiologic findings were collected. The incidence of hepatic decompensation and other events, such as portal vein thrombosis, HCC, TIPS placement, LT, death, and its cause, were also recorded. The procedure was performed at baseline and after the administration of contrast agent using a multiphasic technique and bolus tracking. Two senior radiologists working in different centres and a non-expert radiologist reviewed all CT examinations, to evaluate both intra-observer and inter-observer variability of the CT protocol and to obtain an external validation. The radiological variables were evaluated using both univariate and adjusted multivariate competing risk regression models. RESULTS Both intra-observer and inter-observer agreement were excellent in detection and measurement of almost all types of P-SC. The presence of SPSS, a spleen diameter��>��16��cm, a portal vein diameter��>��17��mm and the presence of ascites resulted independent predictors of decompensation-free survival for cirrhotic patients and were incorporated in an easy-to-use score (AUROC��=��0.799, p-value��=��0.732) which can the risk of decompensation at 5��years, ranking it as low (11.3%), moderate (35.6%) or high (70.8%). CONCLUSIONS The CT protocol commonly performed during the HCC surveillance program for cirrhotic patients is valid for detecting all types of P-SC. The radiological score identified to predict the decompensation-free survival for cirrhotic patients could be an easy-to-use clinical tool.

Background: Sorafenib is the gold standard therapy for the advanced hepatocellular carcinoma (HCC). No scoring/staging is universally accepted to predict the survival of these patients. Aims: To evaluate the accuracy of the available prognostic models for HCC to predict the survival of advanced HCC patients treated with Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. Methods: The performance of several prognostic scores was assessed through a Cox regression-model evaluating the C-index and the Akaike Information Criterion (AIC). Results: Data of 1129 patients were analyzed. The mean age of patients was 61.6 years, and 80.8% were male. During a median follow-up period of 13 months, 789 patients died. The median period of Sorafenib administration was 4 months. All the prognostic scores were able to predict the overall survival (p

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm worldwide. Recurrence of HCC after resection or loco-regional therapies represents an important clinical issue as it affects up to 70% of patients. This can be divided into early or late, if it occurs within or after 24 months after treatment, respectively. While the predictive factors for early recurrence are mainly related to tumour biology (local invasion and intrahepatic metastases), late recurrences are mainly related to de novo tumour formation. Thus, it is important to recognize these factors prior to any treatment in each patient, in order to optimize the treatment strategy and follow-up after treatment. The aim of this review is to summarize the current evidence available regarding predictive factors for the recurrence of HCC, according to the different therapeutic strategies available. In particular, we will discuss the role of new ultrasound-based techniques and biological features, such as tumor-related and circulating biomarkers, in predicting HCC recurrence. Recent advances in imaging-related parameters in computed-tomography scans and magnetic resonance imaging will also be discussed.

Summary The authors summarize their personal interactions with someone for whom they had unbounded admiration, Dr. Juan Rosai. This varied from daily review of cases, to sharing the platform at meetings, being under his tutelage as an author, and co-directing postgraduate courses. These all highlighted the remarkable knowledge of medicine Dr. Rosai had, imparting as he did diagnostic pearls and remarks on the literature including the history of our discipline, often laced with a well-honed sense of humor. The contributions he made to the pathology of the testis are then considered beginning with his role in highlighting a tumor, at the time not particularly well publicized, spermatocytic seminoma. He wrote two major papers on it, one on standard clinical and pathologic aspects, and one on its ultrastructure. The first was associated with his diligent investigation of a prior paper reporting an unusually high number of malignant examples of this tumor but on review that was explained by their representing malignant lymphoma. The organizational skills of Dr. Rosai, and attention to detail, were second to none and shown perhaps most notably with his organizing many courses, but they were also illustrated early in his career when he moderated a symposium on germ cell tumors of the testis which laid the framework for the classification and nomenclature of premalignant lesions. Finally, his almost career-long interest in the entity he codiscovered, Rosai-Dorfman disease, was associated with his reporting testicular involvement by that disorder in his later years. This giant figure in pathology will stand forever in the top tier with other greats who have contributed to the field.

Introduction: Pelvic schwannomas are rare, mostly benign tumors. They are usually asymptomatic until their massive growth compresses adjacent organs. We describe the case of a 53-year-old man with a pelvic schwannoma who initially complained of constipation and urinary retention. Areas Covered: We analyzed the clinical presentation, histopathology, diagnostic imaging tools, and the treatment options for pelvic schwannomas, compared with the few other cases reported in the literature. Expert Commentary: Pelvic schwannomas are masses that can grow to considerable size, producing symptoms over time. Due to their size and localization, surgery, although difficult, is the only available treatment.

Background: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). Objective: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC. Design, setting, and participants: We analyzed the expression data from patients with T2–4aN0M0 MIBC enrolled in the PURE-01 study (N = 84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N = 140). Intervention: Neoadjuvant pembrolizumab or NAC and RC. Outcome measurements and statistical analysis: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage. Results and limitations: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p = 0.02) in PURE-01, but not in the NAC cohort (p = 0.7). Hallmark signatures for interferon gamma (IFNγ; p = 0.004) and IFNα response (p = 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p = 0.9 and IFNα: p = 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up. Conclusions: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection. Patient summary: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC. By using gene expression profiling of transurethral bladder tumor resection samples from patients with muscle-invasive bladder cancer (MIBC), we reported a significant association between pre-existing immune gene expression and response to neoadjuvant pembrolizumab, but not to neoadjuvant chemotherapy. Different outcomes were also obtained according to the molecular subtype. Gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.

Background & Aims Hepatocellular carcinoma (HCC) is a frequent complication of liver disease. When feasible, hepatic resection is the first-choice therapy. However, tumor recurrence complicates at least 2/3 hepatic resections at 5 years. Early recurrences are mainly tumor or treatment-related, but predictors of late recurrences are undefined. We aimed to evaluate the factors related to HCC recurrence after curative resection, with liver and spleen stiffness measurement (LSM and SSM) as markers of severity and duration of the underlying liver disease. Methods We enrolled patients with chronic liver disease and primary HCC suitable for hepatic resection. We followed up patients for at least 30 months or until HCC recurrence. We performed uni- and multivariate analyses to evaluate the predictive role of tumor characteristics, laboratory data, LSM and SSM for both early and late recurrence of HCC. Results We prospectively enrolled 175 patients. Early HCC recurrence at multivariate analysis was associated with viral etiology, HCC grading (3 or 4), resection margins Conclusions SSM seems to be the only predictor of late HCC recurrence, since it is directly correlated with the degree of liver disease and portal hypertension, both of which are involved in carcinogenesis. Lay summary The main result of this study is that spleen stiffness measurement, evaluated by transient elastography, seems to be the only predictor of the late recurrence of hepatocellular carcinoma, defined as recurrence after 24 months from liver resection. Indeed, spleen stiffness measurement is directly correlated with the degree of liver disease and portal hypertension, which are both involved in carcinogenesis.

Little evidence is available regarding the risk of hepatic decompensation (HD) after direct-acting antivirals (DAAs) in patients with advanced chronic liver disease. Our aim was to assess the risk of decompensation and the prognostic role of noninvasive tests, such as liver (LSM) and spleen (SSM) stiffness measurements, in the prediction of decompensation after sustained virologic response (SVR) by DAAs.A cohort study involving 146 cirrhotic patients treated with DAAs in our tertiary center with LSM and SSM available both before and six months after treatment (SVR24). A historical cohort of 92 consecutive cirrhotic patients with active HCV was used as a control group. A propensity score inverse probability weighting method was used to account for differences between the groups. Time-dependent models for the prediction of decompensation were applied to account for changes in noninvasive tests after therapy.The decompensation incidence in the DAA cohort was 7.07 (4.56-10.96) per 100 person-years (PYs), which was significantly lower than in the active HCV cohort. The DAA therapy was an independent protective factor for HD development (SHR: 0.071, 95 %-CI: 0.015-0.332). SSM ≥ 54 kPa was independently associated with decompensation despite SVR achievement (SHR: 4.169, 95 %-CI: 1.050-16.559), alongside with a history of decompensation (SHR: 7.956, 95 %-CI: 2.556-24.762). SSM reduction 10 % also predicted the risk of decompensation after SVR24.The risk of decompensation was markedly reduced after DAA therapy, but it was not eliminated. Paired SSM values stratified the risk of decompensation after SVR better than other noninvasive tests.ZIEL: Über das Risiko einer hepatischen Dekompensation (HD) nach direkt antiviral wirksamen Substanzen (DAA) bei Patienten mit fortgeschrittener chronischer Lebererkrankung gibt es nur wenig Evidenz. Unser Ziel war es, das Risiko einer Dekompensation und den prognostischen Wert nichtinvasiver Tests wie Messungen der Lebersteifigkeit (LSM) und Milzsteifigkeit (SSM) zur Vorhersage einer Dekompensation nach anhaltendem virologischem Ansprechen (SVR) unter DAA zu bewerten.Kohortenstudie mit 146 Zirrhose-Patienten, die in unserem Tertiärzentrum mit DAAs behandelt wurden, wobei LSM und SSM sowohl vor als auch 6 Monate nach der Behandlung verfügbar waren (SVR24). Eine historische Kohorte von 92 konsekutiven zirrhotischen Patienten mit aktiver HCV wurde als Kontrollgruppe verwendet. Um die Unterschiede zwischen den Gruppen zu berücksichtigen, wurde die Propensity-Score-Methode („inverse probability weighting“) verwendet. Zeitabhängige Modelle zur Prädiktion der Dekompensation wurden angewandt, um Veränderungen in den nichtinvasiven Tests nach Therapie zu berücksichtigen.Die Dekompensations-Inzidenz in der DAA-Kohorte betrug 7,07 (4,56–10,96) pro 100 Personenjahre (PYs), was signifikant niedriger war als in der aktiven HCV-Kohorte. Die DAA-Therapie war ein unabhängiger protektiver Faktor für die Entwicklung einer HD (SHR: 0,071; 95 %-KI 0,015–0,332). SSM ≥ 54kPa war trotz erfolgreichem SVR unabhängig mit Dekompensation assoziiert (SHR: 4,169; 95 %-KI 1,050–16,559), zusammen mit früher aufgetretener Dekompensation (SHR: 7,956; 95 %-KI 2,556–24,762). Eine SSM-Reduktion 10 % sagte auch das Risiko einer Dekompensation nach SVR24 voraus.Das Risiko einer Dekompensation war nach DAA-Therapie deutlich reduziert, aber nicht eliminiert. Gepaarte SSM-Werte stratifizierten das Risiko einer Dekompensation nach SVR besser als andere nichtinvasive Tests.

Background: Sarcopenia, defined as low muscle mass with reduced function, is frequently encountered in cirrhotic patients and is a major predictor of adverse events, including post-liver transplant (LT) outcome. Objectives: This study assessed the impact of sarcopenia using computed tomography (CT)-based measurements on post-LT mortality and complications. Methods: From January 2008 to June 2016, 646 adult patients underwent 613 LTs at our institution. We analyzed the postoperative outcome of 287 patients who had pathologically proven cirrhosis on the explanted liver and who had performed a CT examination three months before LT. Psoas muscle density (PMD) was detected for every patient using standard instruments present in the radiological workstation and was related to postoperative survival rates and complications. Statistical analysis was carried out using the appropriate tests. Results: Postoperative mortality was 6.3%. At least one grade III-IV postoperative complication was experienced by 121 patients. Respiratory and infective complications occurred in 30 and 32 patients, respectively. Also, PMD was an independent predictor of postoperative mortality (P = 0.021), respiratory complications (P = 0.015), and infections (P = 0.010). The ROC analysis identified a PMD ≤ 43.72 HU as the best cutoff value for predicting 90-day mortality after LT. Conclusions: Psoas muscle density accurately predicted post-LT mortality and complications. Its ease and low-cost determination can allow widespread use of this parameter to improve clinical care and help with the decision to give these patients some priority on the transplant waiting list.

Simple Summary Active surveillance (AS) has evolved as an alternative to radical treatment for potentially indolent prostate cancer. However, current selection criteria for entering AS are suboptimal, and a significant percentage of patients discontinue AS because of disease reclassification. Hence, there is an unmet need for novel biomarkers for the accurate identification of high-risk PCa and the unequivocal classification of indolent disease. Circulating biomarkers, including microRNAs identified through liquid biopsies, represent a valuable approach to improve on currently available clinicopathological risk-stratification tools. In an attempt to identify specific microRNA signatures as potential circulating biomarkers, the authors performed an unprecedented analysis of the global microRNA profile in plasma samples from AS patients and identified and validated a three-microRNA signature able to predict patient reclassification. The addition of the three-microRNA signature was able to improve the performance of currently available clinicopathological variables, thus showing potential for the refinement of AS patients’ selection. Abstract Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts (training, testing and validation sets). A three-miRNA signature (miR-511-5p, miR-598-3p and miR-199a-5p) was found to predict reclassification in all patient cohorts (training set: AUC 0.74, 95% CI 0.60–0.87, testing set: AUC 0.65, 95% CI 0.51–0.80, validation set: AUC 0.68, 95% CI 0.56–0.80). Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only (AUC 0.70, 95% CI 0.61–0.78 vs. 0.76, 95% CI 0.68–0.84). Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS.

Sarcopenia is gaining attention as a negative prognostic factor in different fields of medicine, including chronic liver failure. However, the assessment of sarcopenia in patients with liver diseases is often neglected due to unawareness of reliable tools and methods and thus is limited to research studies. Cross-sectional imaging is a diffuse diagnostic tool and is commonly performed in patients with chronic liver failure. The last advancements in radiology image analysis using dedicated software allow an easy and standardized method to assess skeletal muscle volume. Several measures can be obtained from cross-sectional imaging analysis to evaluate sarcopenia in patients affected by chronic liver disease. We aimed to review the recent advances in imaging-based sarcopenia assessment, in particular in patients with chronic liver diseases. As a result, we found that the skeletal muscle index (SMI) seems to be a reliable method to assess sarcopenia in cirrhotic patients. Even if further studies are needed to validate proper cut-offs for each clinical endpoint, physicians are invited to consider the assessment of sarcopenia in the work-up of patients with chronic liver disease.

Neuroendocrine carcinomas (NECs) of the urinary bladder are very rare and can be observed in the context of mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs), most frequently in association with urothelial carcinoma. Small cell NECs are far more common than large cell NECs (LCNECs), which are exceedingly rare. We describe a primary MiNEN of the urinary bladder, composed of a LCNEC and of an adenocarcinoma, in which the neuroendocrine component reached complete pathological regression after neoadjuvant M-VAC chemotherapy, whereas the non-neuroendocrine component of the tumor progressed to metastatic disease. Compared to mixed neuroendocrine/non-neuroendocrine neoplasms described in the literature until now, this appears to be a unique case that expands the spectrum of neuroendocrine neoplasia of the urinary bladder.

Introduction Advances in neoadjuvant therapy for patients with localized, nonmetastatic, upper tract urothelial carcinoma (UTUC) is needed. Patients and methods PURE-02 was a feasibility study enrolling individuals with UTUC, at clinical stage N0M0, with high-risk features according to the modified European Association of Urology definition, based on the presence of either: high-grade disease, multifocality, tumor size ≥2 cm, and/or hydronephrosis. The treatment consisted of 3 courses of 200 mg pembrolizumab, intravenously, every 3 weeks, followed by radical nephroureterectomy (RNU). The endpoints were to assess the safety, pathological responses, and biomarkers. Results Ten patients were enrolled between August 2018 and November 2020, 9 (90%) completed the neoadjuvant course. One treatment-related death occurred as a complication of severe myocarditis, myasthenia gravis, hepatitis and myositis. One (14.3%) patient achieved a clinical complete response and refused to undergo RNU. Two (20%) had disease progression and received subsequent chemotherapy, prior to RNU. Overall, 7 patients underwent RNU: one (14.3%) achieved an ypT1N0 response, although this patient was reported to have a cT1 tumor at baseline imaging. The remaining patients were nonresponders. Circulating tumor DNA assay did not identify patients likely to achieve a complete pathologic response. Conclusion Single-agent neoadjuvant pembrolizumab did not appear to be a promising treatment strategy for patients with biomarker-unselected, high-risk localized UTUC.

Patients with cirrhosis show an increased susceptibility to infection due to disease-related immune-dysfunction. Bacterial infection therefore represents a common, often detrimental event in patients with advanced liver disease, since it can worsen portal hypertension and impair the function of hepatic and extra-hepatic organs. Among pharmacological strategies to prevent infection, antibiotic prophylaxis remains the first-choice, especially in high-risk groups, such as patients with acute variceal bleeding, low ascitic fluid proteins, and prior episodes of spontaneous bacterial peritonitis. Nevertheless, antibiotic prophylaxis has to deal with the changing bacterial epidemiology in cirrhosis, with increased rates of gram-positive bacteria and multidrug resistant rods, warnings about quinolones-related side effects, and low prescription adherence. Short-term antibiotic prophylaxis is applied in many other settings during hospitalization, such as before interventional or surgical procedures, but often without knowledge of local bacterial epidemiology and without strict adherence to antimicrobial stewardship. This paper offers a detailed overview on the application of antibiotic prophylaxis in cirrhosis, according to the current evidence.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy. Materials and methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics. Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/< 5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance. Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians. (C) 2020 Elsevier Inc. All rights reserved.

Introduction: Sarcopenia is defined as loss of skeletal muscle mass, strength, and function, and it is associated with increased morbidity and mortality in patients with chronic liver disease. Areas covered: The aim of this review is to provide a detailed report on the pathophysiological mechanisms underlying sarcopenia in cirrhotic patients, the several imaging methods available for the assessment of sarcopenia and the clinical studies evaluating the prognostic role of sarcopenia presence in cirrhotic patients. Expert opinion: Sarcopenia pathogenesis is complex and multifaceted, as chronic catabolic conditions, increased energy expenditure, reduced appetite, side effects of multiple therapies, alterations in circulating levels of hormones, low protein synthesis, presence of ascites or portosystemic shunts are all factors contributing to muscle atrophy in cirrhotic patients. Computed tomography scan is the most validated method to evaluate muscle mass and quality. Sarcopenia is associated with a higher rate waitlist mortality, hepatic encephalopathy, and lower quality of life in patients with liver cirrhosis. Future studies should make an effort to unify and validate liver disease-specific cutoffs for the definition of sarcopenia.

Background: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised. Objective: To develop consensus statements for all domains of DAT. Design, setting, and participants: A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed. Results and limitations: A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion. Conclusions: Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials. Patient summary: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers. (C) 2019 Published by Elsevier B.V. on behalf of European Association of Urology.

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Background ECCO Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give oncology teams, patients, policymakers and managers an overview of essential care throughout the patient journey. Prostate cancer Prostate cancer is the second most common male cancer and has a wide variation in outcomes in Europe. It has complex diagnosis and treatment challenges, and is a major healthcare burden. Care must only be a carried out in prostate/urology cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

AIM To investigate changes in spleen stiffness measurements (SSMs) and other non-invasive tests (NITs) after treatment with direct-acting antivirals (DAAs) and identify predictors of SSM change after sustained virological response (SVR). METHODS We retrospectively analysed 146 advanced-chronic liver disease (ACLD) patients treated with DAA with available paired SSM at baseline and SVR24. Liver stiffness (LSM), spleen diameter (SD), platelet count (PLT) and liver stiffness-spleen diameter to platelet ratio score(LSPS) were also investigated. LSM ≥ 21 kPa was used as a cut-off to rule-in clinically significant portal hypertension (CSPH). SSM reduction > 20% from baseline was defined as significant. RESULTS SSM significantly decreased at SVR24, in both patients with and without CSPH; in 44.8% of cases, SSM reduction was > 20%. LSPS significantly improved in the entire cohort at SVR24; SD and PLT changed significantly only in patients without CSPH. LSM significantly decreased in 65.7% of patients and also in 2/3 patients in whom SSM did not decrease. The independent predictor of decreased SSM was median relative change of LSM. CSPH persisted in 54.4% patients after SVR. Delta LSM and baseline SSM were independent factors associated with CSPH persistence. CONCLUSION SSM and other NITs significantly decrease after SVR, although differently according to the patient’s clinical condition. SSM faithfully reflects changes in portal hypertension and could represent a useful NIT for the follow-up of these patients.

Purpose: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients’ response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery. Methods: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation. Results: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score. Conclusions: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.

open 13 no Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complication affecting patients undergoing hematopoietic stem cell transplantation (HSCT). The survival rate is higher when specific therapy is initiated early; thus, improving early, noninvasive diagnosis of VOD/SOS is an important need. In an adult population undergoing HSCT, we aimed to assess the role of liver stiffness measurement (LSM), evaluated by transient elastography (TE), for diagnosing VOD/SOS. Between April 2016 and March 2018, 78 consecutive adult patients with indications for allogeneic HSCT were prospectively included. LSM was performed before HSCT and at days +9/10, +15/17, and +22/24 post-HSCT. New European Society for Blood and Marrow Transplantation criteria were used to establish VOD/SOS diagnosis. Four patients developed VOD/SOS (5.1%) during the study period, with a median time of +17 days post-HSCT. A sudden increase in LSM compared with previously assessed values and pre-HSCT values, was seen in all patients who developed VOD/SOS. LSM increases occurred from 2 to 12 days before clinical SOS/VOD appearance. The VOD/SOS diagnostic performance of increased LSM over pre-HSCT assessment showed an area under the receiver operating characteristic curve of 0.997 (sensitivity 75%; specificity 98.7%). LSM gradually decreased following successful VOD/SOS-specific treatment. Interestingly, LSM values did not increase significantly in patients experiencing hepatobiliary complications (according to the Common Terminology Criteria) other than VOD/SOS. LSM by TE can be considered a promising method to perform an early, preclinical diagnosis and follow-up of VOD/SOS. open open Antonio, Colecchia; Federico, Ravaioli; Mariarosaria, Sessa; Vanessa, Alemanni Luigina; Elton, Dajti; Giovanni, Marasco; Amanda, Vestito; Maurizio, Zagari Rocco; Barbato, Francesco; Mario, Arpinati; Michele, Cavo; Davide, Festi; Francesca, Bonifazi Antonio, Colecchia; Federico, Ravaioli; Mariarosaria, Sessa; Vanessa, Alemanni Luigina; Elton, Dajti; Giovanni, Marasco; Amanda, Vestito; Maurizio, Zagari Rocco; Barbato, Francesco; Mario, Arpinati; Michele, Cavo; Davide, Festi; Francesca, Bonifazi

OBJECTIVE: Mediastinal extragonadal germ-cell tumors (MEGCTs) are rare neoplasms with a multifaceted clinical behavior. This paper is devoted to review their main characteristics, including histological patterns and different factors of aggressiveness in MEGCTs. Proper understanding of the latter can help to better stratify patients’ prognoses and improve clinical management. BACKGROUND: Different theories exist on the origin of MEGCTs, including primordial germ cells deposition during embryogenesis. MEGCTs predominantly affects young males and aggressiveness follows the ability of local and systemic spread of each germ-cell neoplasia subtype, as well as their distinct responsiveness to therapy. Indeed, non-seminomatous MEGCTs have a worse prognosis. Unfortunately, they are also more frequent than seminomas in the mediastinum. Regardless of histological type, local aggressiveness can follow tumoral expansion with compression on or infiltration of mediastinal structures. Chemotherapy can be effective in reducing neoplastic volume, but different levels of sensitivity can be found in different MGCTs. In particular, a chemo-resistant teratoma component of a mixed MEGCTs can undergo a paradoxical enlargement after chemotherapy, while other components of the tumor regress. This is reflected by a concomitant normalization of serum tumoral markers and cardiopulmonary deterioration due to compression. Such clinical phenomenon, called growing-teratoma syndrome (GTS), requires a prompt surgical approach. METHODS: A literature research of pertinent epidemiological, pathological and clinical articles was conducted. CONCLUSION: The mediastinum can harbor different kinds of neoplasia, including GCTs. The full spectrum of MEGCTs includes a variety of tumors with different clinical behaviors. Aggressiveness follows the inherent ability of local and systemic spread of each neoplastic type, as well as their distinct responsiveness to therapy.

Background: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients. Patients and Methods: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival. Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT=0.19 (0.18-0.20); RES=0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT=0.58 (0.55-0.61); SOR=0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage. Conclusion: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage.

Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors with high morbidity and mortality that have remained mostly unchanged over the past decades. The epidermal growth factor receptor (EGFR) is often overexpressed and activated in these tumors and strongly contributes to their pathogenesis. Still, EGFR-targeted therapies such as monoclonal antibodies and kinase inhibitors have demonstrated only limited improvements in the clinical outcome of this disease. Here, we take advantage of the extraordinary affinity of EGF for its cognate receptor to specifically target magnetite-containing nanoparticles to HNSCC cells and mediate, in vitro, their cellular upload. On the basis of this, we show efficient accumulation, in vivo, of such nanoparticles in subcutaneous xenograft tumor tissues in sufficient amounts to be able to mediate visualization by magnetic resonance imaging. Overall, our EGF-coated nanosystem may warrant, in the near future, novel and very efficient theranostic approaches to HNSCC.

We demonstrate in 351 diabetic patients with steatosis that NAFLD fibrosis score (NFS), a rapid and affordable score to diagnose hepatic fibrosis, identifies patients at higher risk of advanced fibrosis and vascular diabetic complications (especially peripheral neuropathy), pointing NFS as a first-line vascular and hepatic screening in diabetic patients. (C) 2020 Elsevier Inc. All rights reserved.

The clinical usefulness of pancreatic elastography (PE) in the assessment of the pancreatic texture before pancreatic resection still remains uncertain. The aims are: to evaluate the value of pancreatic stiffness in both healthy volunteers and patients affected by pancreatic tumor; to evaluate the ability of PE in predicting clinically relevant postoperative pancreatic fistula (CR-POPF). Pancreatic stiffness of healthy subjects was compared with those of pancreatic tumors measuring shear wave velocity (SWV). In the last group, the ability of preoperative SWV in predicting CR-POPF was evaluated using linear regression. Ninety subjects were consecutively enrolled. No difference was found in SWV in the two groups (1.33 ± 0.31 vs 1.26 ± 0.30, p = 0.337). Multivariate analyses showed that male gender was associated with a softer pancreas (OR 0.74, CI 0.55–0.98, p = 0.035). In the 45 patients suitable for a secondary endpoint, the presence of soft pancreas assessed by surgeon’s palpation (OR 61.21; CI 2.14– > 1000; p = 0.016) and preoperative risk score (OR 1.72; CI 1.01–2.96; p = 0.049) was predictors of CR-POPF. SWV showed a trend in predicting CR-POPF. The pancreatic stiffness far to the pancreatic neoplasm is the same as healthy controls. SWV showed a trend in predicting CR-POPF but the clinical utility is limited.

Objectives Ultrasound (US) elastography has been proposed for the non-invasive prediction of clinically relevant pancreatic fistula (CR-POPF) in patients undergoing pancreatic resection. We aimed to perform a systematic review with meta-analysis to assess the diagnostic value of US elastography in predicting CR-POPF. Methods MEDLINE via PubMed, Ovid Embase, Scopus, and Cochrane Library databases, and abstracts of international conference proceedings were searched up to April 20, 2020. Studies assessing the performance of abdominal US elastography in predicting CR-POPF in patients undergoing pancreatic resection were included. The quality of the studies was assessed using Quality Assessment of Diagnostic Accuracy Studies. Results Five studies, including 247 patients who underwent partial pancreatic resection of whom 72 patients experiencing CR-POPF, were selected. All studies performed US elastography in different pancreatic sites. The pooled mean strain value was lower in pancreatic segments of patients experiencing CR-POPF than in those without, with a pooled weighted mean difference of -0.187 (95% confidence intervals, -0.303 to -0.071; P = 0.002). There was low heterogeneity between studies (I = 7.6%), and all studies were at "high risk" or "unclear risk" of bias. Conclusions This study provides evidence that US elastography values are statistically significantly lower in patients experiencing CR-POPF.

Interim data from the PURE-01 study, using pembrolizumab before radical cystectomy in muscle-invasive bladder cancer (MIBC), suggested that multiparametric magnetic resonance imaging (mpMRI) was able to predict the pathologic response. Owing to the availability of novel effective therapies in MIBC, the possibility to assess tumor response easily has become exceedingly important. The primary objective of the present study was to evaluate the association between individual and combined MRI sequences, and the pathologic response in the final PURE-01 population. Images were internally evaluated and the diagnostic performance was analyzed for separate sequences, along with their combination. From February 2017 to December 2019, 143 patients were enrolled in PURE-01, and 123 with suitable paired imaging assessments before and after pembrolizumab tests (N = 246 mpMRI in total) were analyzed in relation to the pathologic response. The area under the curve (AUC) of the combination of all sequences to predict ypT0ypN0 response was 0.74. By excluding dynamic contrast enhancement (DCE) assessment, the AUC was 0.74. When looking at ypT1/a/is ypN0 response, the AUC was 0.87 in both cases. Without DCE, 95% of patients with no evidence of disease resulted in ypT1/a/is ypN0 and 65% ypT0ypN0 responders. In conclusion, the final results confirmed the reliability of mpMRI and suggested the opportunity to avoid intravenous gadolinium contrast to personalize bladder-sparing strategies in radiologically complete responders. Patient summary We evaluated the reliability of multiparametric bladder magnetic resonance imaging to predict the pathologic response to pembrolizumab administered before radical cystectomy in muscle-invasive bladder cancer. We observed that this radiologic examination is promising in the attempt to identify opportunities to spare the bladder in selected, radiologically defined complete responders. We also observed that the use of intravenous gadolinium contrast can be avoided in future studies. ClinicalTrials.gov, number NCT02736266.

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.

Changes in body composition are associated with poor outcomes in cancer patients including hepatocellular carcinoma (HCC). Sarcopenia, defined as the loss of skeletal muscle mass, quality and function, has been associated with a higher rate of complications and recurrences in patients with cirrhosis and HCC. The assessment of patient general status before HCC treatment, including the presence of sarcopenia, is a key-point for achieving therapy tolerability and to avoid short- and long-term complications leading to poor patients’ survival. Thus, we aimed to review the current literature evaluating the role of sarcopenia assessment related to HCC treatments and to critically provide the clinicians with the most recent and valuable evidence. As a result, sarcopenia can be predictive of poor outcomes in patients undergoing liver resection, transplantation and systemic therapies, offering the chance to clinicians to improve the muscular status of these patients, especially those with high-grade sarcopenia at high risk of mortality. Further studies are needed to clarify the predictive value of sarcopenia in other HCC treatment settings and to evaluate its role as an additional staging tool for identifying the most appropriate treatment. Besides, interventional studies aiming at increasing the skeletal muscle mass for reducing complications and increasing the survival in patients with HCC are needed.

Background Pembrolizumab is a new standard of care for patients with platinum-treated, metastatic urothelial carcinoma (UC). Nab-paclitaxel is active in advanced UC. In the PEANUT study ( NCT03464734 ) we investigated their combination in advanced UC. Patients and methods PEANUT was an open-label, single-arm, phase II trial that included patients who had failed one or two chemotherapy regimens, including platinum chemotherapy. Biomarker analyses focused on programmed cell-death ligand-1 combined positive score (CPS) and comprehensive genomic profiling on tumor samples and circulating tumor DNA. Patients received 200 mg pembrolizumab on day 1 (D1), and 125 mg/m2 nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) according to RECIST (v1.1). The assumption was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results Between January 2019 and January 2020, the PEANUT study enrolled 70 patients: 24% had failed two prior systemic therapies; 31% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1; and 28.6% had liver metastases. After a median follow-up of 9.8 months, 40 patients have relapsed (57.1%). The median PFS was 5.9 months [95% confidence interval (CI) 3.1–11.5]. The confirmed objective response rate (ORR) was 38.6% (95% CI 27–51) with 17 partial responses and 10 complete responses (14.3%). The median duration of response was not reached. Five patients (7.1%) had ongoing responses lasting >12 months. The most common any-grade treatment-related adverse events included alopecia (71.4%), neutropenia (32.9%), and peripheral neuropathy (34.3%). Neither tumor mutational burden nor CPS was significantly associated with PFS at univariable analyses. The single-arm design of the trial was the major limitation. Conclusions Pembrolizumab combined with nab-paclitaxel, as second- and third-line chemoimmunotherapy for metastatic UC, showed a favorable safety profile, durable PFS, and a clinically meaningful ORR in these preliminary analyses. This combination warrants additional randomized studies in earlier disease stages. ClinicalTrials.gov number ClinicalTrials.gov NCT03464734 ; https://clinicaltrials.gov/ct2/show/NCT03464734 .

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely associated, and liver fibrosis has been related to macrovascular complications. We examined whether liver fibrosis, diagnosed by FibroScan® , correlates with chronic vascular complications in a cohort of T2DM. METHODS: We recruited 394 outpatients with T2DM attending five Italian diabetes centres who underwent liver ultrasonography (US), FibroScan® and extensive evaluation of macrovascular and microvascular diabetic complications. RESULTS: Steatosis by US was present in 89%. Almost all patients (96%) were on hypoglycaemic drugs, 58% had at least one chronic vascular complication, 19% a macrovascular complication (prior myocardial infarction and/or ischaemic stroke) and 33% a microvascular one (26% chronic kidney disease [CKD]; 16% retinopathy; 6% neuropathy). In all, 171 (72%) patients had CAP ≥ 248dB/m (ie hepatic steatosis), whereas 83 (21%) patients had LSM ≥ 7.0/6.2 kPa (M/XL probes) (significant liver fibrosis). CAP was not associated with any macro/microvascular complications, whereas LSM ≥ 7.0/6.2 kPa was independently associated with prior cardiovascular disease (adjusted OR 3.3, 95%CI 1.2-8.8; P = .02) and presence of microvascular complications (adjusted OR 4.2, 95%CI 1.5-11.4; P = .005), mainly CKD (adjusted OR 3.6, 95%CI 1.3-10.1; P = .01) and retinopathy (adjusted OR 3.7, CI 95% 1.2-11.9; P = .02). Neither diabetes duration nor haemoglobin A1c differed according to CAP or LSM values. CONCLUSION: Significant fibrosis, detected by FibroScan® , is independently associated with increased prevalence of macrovascular and microvascular complications, thus opening a new scenario in the use of this tool for a comprehensive evaluation of hepatic and vascular complications in patients with T2DM

Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) is a rare complication characterized by hepatomegaly, right-upper quadrant pain, jaundice, and ascites, occurring after high-dose chemotherapy, hematopoietic stem cell transplantation (HSCT) and, less commonly, other conditions. We review pathogenesis, clinical appearance and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD occurring post-HSCT. The injury of the sinusoidal endothelial cells with loss of wall integrity and sinusoidal obstruction is the basis of development of postsinusoidal portal hypertension responsible for clinical syndrome. Risk factors associated with the onset of VOD and diagnostic tools have been recently updated both in the pediatric and adult settings and here are reported. Treatment includes supportive care, intensive management, and specific drug therapy with defibrotide. Because of its severity, particularly in VOD with associated multiorgan disease, prophylaxis approaches are under investigation. During the last years, decreased mortality associated to VOD/SOS has been reported being it attributable to a better intensive and multidisciplinary approach.