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Diferentes investigaciones han propuesto que la práctica regular de la actividad física, especialmente el ejercicio aeróbico, se relaciona con beneficios cognitivos (Lautenschlager et al., 2008; Baker et al., 2010). Varios meta-análisis han informado que la actividad física se asocia con mejoras en la atención, velocidad de procesamiento, y la función ejecutiva en los adultos mayores con y sin discapacidades cognitivas (van Uffelen et al., 2008; Smith et al., 2010). Los movimientos empleados en Brain Gym® (BG) están diseñados para estimular la fluidez de comunicación entre las áreas intercerebrales. Este flujo de información debe liberarse debido a que para realizar cualquier acción, el cerebro debe funcionar coordinado, integrado y relajado. El programa BG asocia estas dificultades con bloqueos en el flujo de comunicación entre las dimensiones del cerebro, debido a la falta de conexiones neuronales. Objetivo: Analizar el efecto que un programa de ejercicios de Brain Gym® adaptados al medio acuático provoca en la función cognitiva y en el nivel de forma física de las personas mayores de 60 años.

Chemotherapy can cause vascular and metabolic liver injury in patients with liver metastases, but scarce data are available. We aimed to (i) describe the prevalence of porto-sinusoidal vascular disorder (PSVD) among patients undergoing resection for liver metastases; and (ii) assess whether liver (LSM) and spleen stiffness measurements could diagnose PSVD and predict postoperative complications. This is a prospective single-center study enrolling consecutive patients undergoing hepatic resection for metastases at a tertiary center. For each patient, we evaluated previous exposure to chemotherapy, comorbidities, elastography, type of surgery, histological features at the resection specimen, morbidity (post-hepatectomy liver failure and major complications according to Clavien-Dindo), and 90-day survival. Sixty-eight patients were included, of whom 60 (88%) had received chemotherapy. Twenty-nine (44%) patients had PSVD. Spleen stiffness measurements <21 kPa (negative predictive value 87%) and >40 kPa (positive predictive value 100%) could accurately diagnose PSVD. PSVD significantly increased the risk of post-hepatectomy liver failure (22% vs. 45%) and major complications (11% vs. 31%). Preoperative LSM was associated with postoperative morbidity. The cutoff LSMs <4.5 and >8 kPa predicted the risk of clinically significant post-hepatectomy liver failure (0%, 11%, and 33% in LSM <4.5, 4.5-8, and >8 kPa, respectively) and major complications (0%, 25%, 44% in LSM <4.5, 4.5-8, and >8 kPa, respectively). PSVD is very common among patients undergoing liver surgery for metastases, and it is associated with increased morbidity. LSM and spleen stiffness measurements can correctly identify patients with PSVD and those at risk of clinically relevant postoperative complications., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: The decision to accept or discard the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and 1-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium., Methods: The training set was n = 620 for DGF and n = 711 for 1y-tl, with validation sets n = 158 and n = 162, respectively. In Step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In Step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology., Results: Step 1 revealed an increased risk of DGF with increased cold ischaemia time (CIT), donor and recipient body mass index, dialysis vintage, number of HLA-DR mismatches or recipient cytomegalovirus immunoglobulin G positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c-statistics of 0.696 and 0.701, respectively). Risk of 1y-tl increased in recipients with CIT, sum of HLA-A, -B, -DR mismatches, and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set., Conclusion: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background and Objectives: The Esophageal Adenocarcinoma Study Group Europe (EACSGE) recently proposed a granular histologic classification of esophageal-esophago-gastric junctional adenocarcinomas (EA-EGJAs) based on the study of naïve surgically resected specimens that, when combined with the pTNM stage, is an efficient indicator of prognosis, molecular events, and response to treatment. In this study, we compared histologic classes of endoscopic biopsies taken before surgical resection with those of the surgical specimen, to evaluate the potential of the EACSGE classification at the initial diagnostic workup. Methods: A total of 106 EA-EGJA cases with available endoscopic biopsies and matched surgical resection specimens were retrieved from five Italian institutions. Histologic classification was performed on all specimens to identify well-differentiated glandular adenocarcinoma (WD-GAC), poorly differentiated glandular adenocarcinoma (PD-GAC), mucinous muconodular carcinoma (MMC), infiltrative mucinous carcinoma (IMC), diffuse desmoplastic carcinoma, diffuse anaplastic carcinoma (DAC), and mixed subtypes. Related risk subgroups (low-risk versus high-risk) were also assessed. The correlations of histologic classes and risk subgroups between diagnostic biopsies and surgical resection specimens were explored with Spearman's correlation test. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, true positives, true negatives, false positives, and false negatives were also calculated. Results: A strong positive correlation between biopsies and surgical specimens occurred for both histologic classes (coefficient: 0.75, p < 0.001) and risk subgroups (coefficient: 0.65, p < 0.001). The highest sensitivities and specificities were observed for MMC, IMC, and DAC (100% and 99% for all), followed by WD-GAC (sensitivity 91%, specificity 79%) and PD-GAC (sensitivity 722%, specificity 86%). The low-risk and high-risk groups presented a sensitivity and specificity of 89% and 76% (low-risk) and 76% and 89% (high-risk). Conclusions: The EACSGE histologic classification of EA-EGJAs and associated prognostic subgroups can be reliably assessed on pre-operative diagnostic biopsies. Further studies on larger and more representative cohorts of EA-EGJAs will allow us to validate our findings and confirm if the EA-EGJA biopsy histomorphology and clinical TNM staging will be as efficient as the surgical specimen histomorphology and pTNM in predicting patient prognoses and tailoring personalized therapeutic approaches.

Transplantation of an organ from a donor carries an unavoidable risk of tumor transmission. The need to extend the donor pool increases the use of organs from donors with malignancies and potential disease transmission is a constant tension influencing donor suitability decisions. Current classification systems for the assessment of donor malignancy transmission risk have evolved from reports of potential transmission events in recipients to national donation and transplant surveillance agencies. Although the risk of malignancy transmission is very low in the general transplant setting it must constantly be balanced with the transplant benefits. Guidelines are mainly based on large registries and sparse case reports of transmission, so they cannot cover all the possible situations. For this reason, in 2004 in Italy, the National Transplant Center gave rise to the Second Opinion Service, charged by the Ministry of Health, by structuring expertise in diagnostic oncology and risk transmission and making it available to the Italian Transplant Centers. In this paper the registry of the Italian Oncological Second Opinion was reviewed, from 2016 to 2018, to detail the most frequent and problematic neoplastic topics addressed, those are separately reported and discussed. Furthermore, a review of the most recent strategies and risk stratification is provided, according to the most recent literature evidence and to the European Guidelines., Competing Interests: Declaration of Competing Interest I, Antonia D’Errico, on behalf of all Authors, declare that there are no conflicts of interest to be disclosed concerning the manuscript “Donors Risk Assessment in Transplantation: from the Guidelines to their Real-World Application”., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

FGFR inhibitors have been developed to inhibit FGFR activation and signal transduction; notwithstanding, currently the selection of intrahepatic cholangiocarcinoma (iCCA) patients for these drugs only relies on the detection of FGFR2 genetic alterations (GAs) in tumor tissues or circulating tumor DNAs, without concomitant assessment of FGFR2 signalling status. Accordingly, we performed multi-omic analyses of FGFR2 genes and FGFR2 signalling molecules in the tissue samples from 36 iCCA naïve patients. Gain-of-function FGFR2 GAs were detected in 7 patients, including missense mutations (n = 3; p.F276C, p.C382R and p.Y375C), translocations (n = 1) and copy number gain (n = 4; CNV ≥ 4). In contrast, among 29 patients with wild-type FGFR2, 4 cases showed activation of FGFR2 signalling, as they expressed the FGFR2 ligand FGF10 and phosphorylated FGFR2/FRS2α proteins; the remaining 25 cases resulted negative for activated FGFR2 signalling, as they lacked FGFR2 (n = 8) or phosphorylated FRS2α (n = 17) expression. Overall, we found that activation of FGFR2 signalling occurs not only in iCCA naïve patients with FGFR2 GAs, but also in a subgroup carrying wild-type FGFR2. This last finding entails that also this setting of patients could benefit from FGFR targeted therapies, widening indication of these drugs for iCCA patients beyond current approval. Future clinical studies are therefore encouraged to confirm this hypothesis., (© 2024. The Author(s).)

Alterations in microRNA (miRNA) expression have been reported in different cancers. We assessed the expression of 754 oncology-related miRNAs in esophageal adenocarcinoma (EAC) samples and evaluated their correlations with clinical parameters. We found that miR-221 and 483-3p were consistently upregulated in EAC patients vs. controls (Wilcoxon signed-rank test: miR-221 p < 0.0001; miR-483-3p p < 0.0001). Kaplan-Meier analysis showed worse cancer-related survival among all EAC patients expressing high miR-221 or miR-483-3p levels (log-rank p = 0.0025 and p = 0.0235, respectively). Higher miR-221 or miR-483-3p levels also correlated with advanced tumor stages (Mann-Whitney p = 0.0195 and p = 0.0085, respectively), and overexpression of miR-221 was associated with worse survival in low-risk EAC patients. Moreover, a significantly worse outcome was associated with the combined overexpression of miR-221 and miR-483-3p (log-rank p = 0.0410). To identify target genes affected by miRNA overexpression, we transfected the corresponding mimic RNA (miRVANA) for either miR-221 or miR-483-3p in a well-characterized esophageal adenocarcinoma cell line (OE19) and performed RNA-seq analysis. In the miRNA-overexpressing cells, we discovered a convergent dysregulation of genes linked to apoptosis, ATP synthesis, angiogenesis, and cancer progression, including a long non-coding RNA associated with oncogenesis, i.e., MALAT1. In conclusion, dysregulated miRNA expression, especially overexpression of miR-221 and 483-3p, was found in EAC samples. These alterations were connected with a lower cancer-specific patient survival, suggesting that these miRNAs could be useful for patient stratification and prognosis.

Introduction: The progressive technologies in albumin in situ hybridization (ISH) changed the routine application and the differential diagnosis of hepatic malignancies in the last years. The aim of the present work was to assess the diagnostic utility of albumin ISH on different cholangiocarcinoma (CCA) subtypes, as well as to assess how albumin production changes along the biliary tree., Methods: Forty-five CCAs were retrospectively selected: 29 intrahepatic (15 small-duct and 14 large-duct subtypes), 7 perihilar, and 9 extrahepatic. Histology was revised in all cases, and albumin ISH was automatically performed by the RNAscope®., Results: ISH was always negative in extrahepatic CCAs, only 1 perihilar case was positive, and any positivity was observed in 25/29 (86.2%) intrahepatic CCAs (p &lt; 0.001). Concerning CCA subtypes, mean cell positivity was 38.8 ± 29.8% in small-duct CCAs and 11.4 ± 21.9 in large-duct CCAs, respectively (p = 0.003); 12/15 (80.0%) small-duct and 3/14 (21.4%) large-duct CCAs showed &gt;5% positive cells (p = 0.002; odds ratio 14.7)., Conclusions: The introduction of more sensitive techniques changed the indications for ISH since most small-duct intrahepatic CCAs show diffuse positivity. Albumin positivity decreases from liver periphery to the large ducts, suggesting that ISH can be helpful in the differential diagnosis between small-duct and large-duct CCAs, as well as between intrahepatic large-duct CCAs and metastases., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive high-grade neuroendocrine tumor, commonly arising in the lung or in the gastrointestinal tract, with a frequent proportion of unknown primary origin (20%). In the metastatic setting, platinum-based or fluoropyrimidine-based chemotherapeutic regimens are as considered the first-line treatment, despite the limited duration of response. To date, the prognosis of advanced high-grade neuroendocrine carcinoma remains poor, suggesting the need to explore new treatment strategies in this orphan tumor. The evolving molecular landscape of LCNEC, not yet been completely defined, could explain the heterogeneous response to different chemotherapeutic regimens and suggest that treatment strategy could be driven by molecular features. v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, well described in melanoma, thyroid cancer, colon cancer and lung adenocarcinoma, account for approximately 2% of cases in lung LCNEC. Here, we describe the case of a patient with a BRAF V600E-mutated LCNEC of unknown primary origin who partially responded to BRAF/mitogen-activated protein kinase kinase inhibitors after standard treatment. Additionally, BRAF V600E circulating tumor DNA was used to monitor disease response. Thereafter, we reviewed the available literature about the role of targeted therapy in high-grade neuroendocrine neoplasms to provide insight for future research to identify patients with driver oncogenic mutations, who can potentially benefit from target therapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale & Objective: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex., Study Design: Single-center, case series., Setting & Participants: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System., Observations: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age., Limitations: Retrospective design and inclusion of outpatients partially based on family pedigree., Conclusions: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Diabetic donors are recognized as a reliable source of organs, although the discard rate of kidneys is still high. Few data are available on the histological evolution of these organs especially on kidneys transplanted into non-diabetic patients who remain euglycemic., Methods: We describe the histological evolution of ten kidney biopsies performed on non-diabetic recipients of diabetic donors., Results: Mean donor age was 69 ± 7 years, 60% were males. Two donors were treated with insulin, eight with oral antidiabetic drugs. Mean recipient age was 59.9 ± 7 years, 70% were males. The pre-existing diabetic lesions identified in the pre-implantation biopsies, encompassed all histological classes, and were associated with mild IF/TA and vascular damages. The median follow-up was 59.5 [IQR 32.5-99.0] months; at follow-up, 40% of cases did not change histologic classification, two patients with class IIb downgraded to IIa or I and one with class III downgraded to IIb. Conversely, three cases showed a worsening, from class 0 to I, I to IIb or from IIa to IIb. We also observed a moderate evolution of IF/TA and vascular damages. At follow-up visit, estimated GFR was stable (50.7 mL/min vs. 54.8 at baseline) and proteinuria was mild (51.1 ± 78.6 mg/day)., Conclusions: Kidneys from diabetic donors show variable evolution of the histologic features of diabetic nephropathy after transplant. This variability may be associated to recipients characteristics such as euglycemic milieu, in case of improvement, or obesity and hypertension, in case of worsening of histologic lesions., (© 2023. The Author(s).)

Background: In the transplant setting, the definition of the risk of neoplastic transmission from donor to recipient often requires intraoperative pathological evaluation on frozen sections. Although most lesions can be easily classified into acceptable or unacceptable risk according to the Italian National Guidelines, there are cases in which unusual histologic features cannot be further investigated because of the lack of ancillary techniques on frozen sections., Case Presentation: Here we present a case of a liver lesion in a 51-year-old male donor, subjected to histopathological on-call examination. The frozen sections showed a well-demarcated lesion consisting of epithelioid cells disposed in laminar structures and intermingled with a dense lymphocytic population: this led to organ discard with interruption of the donation process. The definitive histological analysis required an extensive immunohistochemical (IHC) investigation: the final diagnosis was "bile duct adenoma with oncocytic features", eventually confirmed by a strongly positive anti-mitochondrial IHC. Finally, an NGS panel analysis was performed, which revealed NRAS mutation., Discussion: To the best of our knowledge, this is the first case of oncocytic bile duct adenoma confirmed by anti-mitochondrial IHC and with NRAS mutation. The most challenging aspect of this case was represented by the transplant setting. In fact, the oncocytic features and the dense lymphocytic infiltrate represented concomitant unusual histological features that led to the halt of the organ donation procedures., Competing Interests: Declaration of Competing Interest I, DEBORAH MALVI, on behalf of all Authors, declare that there are no conflicts of interest to be disclosed concerning the manuscript “NRAS-Mutated oncocytic benign liver lesion in an organ donor: pitfalls and troubles in frozen section diagnosis and risk assessment”., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments., Methods: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort., Results: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX / ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%)., Conclusions: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs.

Second opinion consultation is a well-established practice in different clinical settings of diagnostic medicine. However, little is known about second opinion consultation activity in transplantation, and even less is known about it concerning donor assessment. The consultations provided by the second opinion service led to the safer and homogeneous management of donors with a history of malignancy or ongoing neoplasm by transplant centers. Indeed, two of the most important aspects are the reduction of semantic differences in cancer reporting and the standardization of procedures, which are mainly due to the different settings and logistics of different pathology services. This article aims to discuss the role and the future of the second opinion in Italy during organ procurement, highlighting the critical issues and areas for improvement.

MXene, a new member of 2D material, unites the eminence of hydrophilicity, large surface groups, superb flexibility and excellent conductivity. Because of its prodigious characteristics, MXene has gained much approbation among researchers worldwide. MXene's noteworthy features, such as its electrical conductivity, structural property, magnetic behaviour, etc., manifest a broad spectrum of applications, including environment, catalytic, wireless communications, electromagnetic interference (EMI) shielding, drug delivery, wound dressing, bio-imaging, antimicrobial and biosensor. In this review article, an overview of the latest advancements in the applications of MXene has been reported. First, various synthesis strategies of MXene will be summarized, followed by the different structural, physical and chemical properties. The current advances in versatile applications have been discussed. The article aims to incorporate all the possible applications of MXene, making it a versatile material that juxtaposes it with other 2D materials. A separate section is dedicated to the bottlenecks for future developments and recommendations., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.

Purpose: The aim is to clarify the use of perioperative chemotherapy in resectable goblet cell carcinoma (GCC)., Methods: A retrospective study was carried out based on the Surveillance, Epidemiology, and End Results study. The population was divided: into patients who received only radical surgery (group A) and those who received radical surgery plus chemotherapy (group B). An entropy balancing was carried out to correct the imbalance between the two groups. Two models were generated. Model 1 contained only high-risk patients: group B and a "virtual" group A with similar characteristics. Model 2 included only low-risk patients: group A and "virtual" group B with identical attributes. The efficacy of entropy balancing was evaluated with the d value. The overall survival was compared and reported with Hazard Ratio (HR) within a confidence interval of 95% (95 CI)., Results: The groups A and B were imbalanced for tumor size (d = 0.392), T (d = 1.128), N (d = 1.340), M (d = 1.456), mean number of positive lymph nodes (d = 0.907), and LNR (d = 0.889). Before the balancing, the risk of death was higher in group B than in A (4.3; 2.5 to 7.4). After reweighting, all large differences were eliminated (d < 0.200). In high-risk patients, the risk of death was higher in patients who underwent surgery alone than those who received perioperative chemotherapy (HR 0.5; 0.2 to 1.3) without statistical significance (p = 0.187). In low-risk patients, the risk of death was similar (HR 1.1; 0.3 to 3.3)., Conclusion: Perioperative chemotherapy could provide some marginal advantages to high-risk patients., (© 2023. The Author(s).)

TP53, CTNNB1, and TERT-promoter mutations are the most common driver mutations in hepatocellular carcinoma (HCC). The morphological and genetical HCC heterogeneities are difficult to discriminate by the eye of the pathologist. Here, we describe two rare cases of HCC with simultaneous co-mutation of all three of genes, which represent a poorly described occurrence in the literature. In these two cases, areas with different tumor grade and different β-catenin and Glutamine Synthetase expression (performed by automated immunohistochemistry) were observed. NGS analysis was performed in these different areas, to check for potential diversity of mutation burden on the different regions, but no differences were found: all micro-areas analyzed showed the co-presence of mutations in TP53, CTNNB1, and TERT. The evidence that all mutations were found in all the different areas analyzed by NGS leads to hypothesize that the tumor is not composed of different clones harboring different mutations. All the variants are harbored by the same neoplastic clone, albeit leading to different phenotypes. Mutation prediction Artificial Intelligence models could help the morpho-genetic classification of HCC in the future, since they can find variabilities not obvious to the human eye, with increased sensitivity, specificity and reproducibility.

The number of patients awaiting a kidney transplant is constantly rising but lack of organs leads kidneys from extended criteria donors (ECD) to be used to increase the donor pool. Pre-transplant biopsies are routinely evaluated through the Karpinski-Remuzzi score but consensus on its correlation with graft survival is controversial. This study aims to test a new diagnostic model relying on digital pathology to evaluate pre-transplant biopsies and to correlate it with graft outcomes. Pre-transplant biopsies from 78 ECD utilized as single kidney transplantation were scanned, converted to whole-slide images (WSIs), and reassessed by two expert nephropathologists using the Remuzzi-Karpinski score. The correlation between graft survival at 36 months median follow-up and parameters assigned by either WSI or glass slide score (GSL) by on-call pathologists was evaluated, as well as the agreement between the GSL and the WSIs score. No relation was found between the GSL assessed by on-call pathologists and graft survival (P = 0.413). Conversely, the WSI score assigned by the two nephropathologists strongly correlated with graft loss probability, as confirmed by the ROC curves analysis (DeLong test P = 0.046). Digital pathology allows to share expertise in the transplant urgent setting, ensuring higher accuracy and favoring standardization of the process. Its employment may significantly increase the predictive capability of the pre-transplant biopsy evaluation for ECD, improving the quality of allocation and patient safety.

Pancreatic ductal adenocarcinoma (PDAC) is an increasing disease having a poor prognosis. The aim of the present study was to evaluate the effect of different models of care for pancreatic cancer in a tertiary referral centre in the period 2006-2020. Retrospective study of patients with PDAC observed from January 2006 to December 2020. The demographic and clinical data, and data regarding the imaging techniques used, preoperative staging, management, survival and multidisciplinary tumour board (MDTB) evaluation were collected and compared in three different periods characterised by different organisation of pancreatic cancer services: period A (2006-2010); period B (2011-2015) and period C (2016-2020). One thousand four hundred seven patients were analysed: 441(31.3%) in period A; 413 (29.4%) in B and 553 (39.3%) in C. The proportion of patients increased significantly, from 31.3% to 39.3% (P = 0.032). Body mass index (P = 0.033), comorbidity rate (P = 0.002) and Karnofsky performance status (P < 0.001) showed significant differences. Computed tomography scans (P < 0.001), endoscopic ultrasound (P < 0.001), fine needle aspiration, fine needle biopsy (P < 0.001), and fluorodeoxyglucose-positron emission tomography/computed tomography (P < 0.001) increased; contrast-enhanced ultrasound (P = 0.028) decreased. The cTNM was significantly different (P < 0.001). The MDTB evaluation increased significantly (P < 0.001). Up-front surgery and exploratory laparotomy decreased (P < 0.001), neoadjuvant treatment increased (P < 0.001). The present study showed the evolving knowledge in surgical oncology of pancreatic cancer at a tertiary referral centre over the time. The different models of care of pancreatic cancer, in particular the introduction of the MDTB and the institution of a pancreas unit to the decision-making process seemed to be influential., (© 2022. The Author(s).)

Despite increased use of digital pathology, its application in the transplantation setting remains limited. One of the restraints is related to concerns that this technology is inadequate for supporting diagnostic work. In this study, we sought to establish non inferiority of whole slide imaging (WSI) to light microscopy (LM) for intraoperative transplantation diagnosis using inexpensive portable devices. A validation study was conducted according to updated guidelines from the College of American Pathologists (CAP) utilizing 80 intraoperative transplantation cases. Two pathologists reviewed glass slides with LM and digital slides on two different tablets after a washout period of 4 weeks. Diagnostic concordance and intra-observer agreement were recorded. A total of 45 (56%) cases were suitable for rendering transplant diagnoses and 35 (44%) for assessing cancer risk. Intra-observer agreement was 95.1% for organ suitability and 100% for cancer risk. There were no major discordances that could affect patient transplant management. Digital evaluation of intraoperative transplant specimens using tablets to view whole slide images was non-inferior to LM for primary diagnosis. This suggests that after validating WSI these digital tools can be safely used for remote intraoperative transplantation diagnostic work., Competing Interests: Liron Pantanowitz serves as a consultant for NTP. The other authors have no relevant financial or non-financial interests to disclose., (© 2022 The Author(s).)

Hepatocellular carcinoma (HCC) represents the primary carcinoma of the liver and the fourth leading cause of cancer-related deaths. The World Health Organization estimates an increase in cases in the coming years. The risk factors of HCC are multiple, and the incidence in different countries is closely related to the different risk factors to which the population is exposed. The molecular mechanisms that drive HCC tumorigenesis are extremely complex, but understanding this multistep process is essential for the identification of diagnostic, prognostic, and therapeutic markers. The development of multigenic next-generation sequencing panels through the parallel analysis of multiple markers can provide a landscape of the genomic status of the tumor. Considering the literature and our preliminary data based on 36 HCCs, the most frequently altered genes in HCCs are TERT , CTNNB1 , and TP53 . Over the years, many groups have attempted to classify HCCs on a molecular basis, but a univocal classification has never been achieved. Nevertheless, statistically significant correlations have been found in HCCs between the molecular signature and morphologic features, and this leads us to think that it would be desirable to integrate the approach between anatomic pathology and molecular laboratories., Competing Interests: Conflict-of-interest statement: Dario de Biase has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim and Eli Lilly, unrelated to the current work., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Despite the efforts made in the management of PDAC, the 5-year relative survival rate of pancreatic ductal adenocarcinoma (PDAC) still remains very low (10%). To date, precision oncology is far from being ready to be applied in cases of PDAC, although studies exploring the molecular and genetic alterations have been conducted, and the genomic landscape of PDAC has been characterized. This study aimed to apply a next-generation sequencing (NGS) laboratory-developed multigene panel to PDAC samples to find molecular alterations that could be associated with histopathological features and clinical outcomes. A total of 68 PDACs were characterized by using a laboratory-developed multigene NGS panel. KRAS and TP53 mutations were the more frequent alterations in 75.0% and 44.6% of cases, respectively. In the majority (58.7%) of specimens, more than one mutation was detected, mainly in KRAS and TP53 genes. KRAS mutation was significantly associated with a shorter time in tumor recurrence compared with KRAS wild-type tumors. Intriguingly, KRAS wild-type cases had a better short-term prognosis despite the lymph node status. In conclusion, our work highlights that the combination of KRAS mutation with the age of the patient and the lymph node status may help in predicting the outcome in PDAC patients.

Background: Acute kidney injury (AKI) is common in advanced liver cirrhosis, a consequence of reduced kidney perfusion due to splanchnic arterial vasodilation and intrarenal vasoconstriction. It clinically manifests as hepatorenal syndrome type 1, type 2, or as acute tubular necrosis. Beyond hemodynamic factors, an additional mechanism may be hypothesized to explain the renal dysfunction during liver cirrhosis. Recent evidence suggest that such mechanisms may be closely related to obstructive jaundice., Methods: Given the not completely elucidated role of bile acids in kidney tissue damage, this study developed a rat model of AKI with liver cirrhosis induction by carbon tetrachloride (CCl 4 ) inhalation for 12 weeks. Histological analyses of renal and liver biopsies were performed at sacrifice. Organic anion tubular transporter distribution and apoptosis in kidney cells were analyzed by immunohistochemistry. Circulating and urinary markers of inflammation and tubular injury were assayed in 21 treated rats over time (1, 2, 4, 8, and 12 weeks of CCl 4 administration) and 5 controls., Results: No renal histopathological alterations were found at sacrifice. Comparing treated rats with controls, organic anion transporters were differentially expressed and localized. High serum bile acid values were detected in cirrhotic animals, while caspase-3 staining was negative in both groups. Increased levels of serum inflammatory and urinary tubular injury biomarkers were observed during cirrhosis progression, with a peak after 4 and 8 weeks of treatment., Conclusions: These findings suggest possible adaptive tubular mechanisms for bile acid transporters in response to cirrhosis-induced AKI.

Introduction: Kidney biopsy is performed to assess if an extended criteria graft can be used for transplantation. It may be performed before or after cross-clamping during organ procurement. This study aims to evaluate whether the timing of biopsy may modify cold ischemia times (CIT) and/or graft outcomes., Methods: Kidney transplants performed in our center from January 2007 to December 2017 were analyzed. Grafts with preimplantation kidney biopsy were included. Biopsies were performed during surgical back table (ex situ kidney biopsy [ESKB]) until 2012 and since then before the aortic cross-clamping (in situ kidney biopsy [ISKB]). To overcome biases owing to different distributions, a propensity score model was developed. The study population consists in 322 patients, 115 ESKB, and 207 ISKB., Results: CIT was significantly lower for ISKB (730 min ISKB vs. 840 min ESKB, p value = 0.001). In both crude (OR 0.27; 95% confidence interval, 95% CI 0.12-0.60; p value = 0.002) and adjusted analyses (OR 0.37; 95% CI 0.14-0.94; p value = 0.039), ISKB was associated with a reduced odd of graft loss when compared to ESKB., Discussion/conclusion: Performing preimplantation kidney biopsy during the recovery, prior to the aortic cross-clamping, may be a strategy to reduce CIT and improve transplant outcomes., (© 2021 S. Karger AG, Basel.)

Introduction: Electron microscopy (EM) represents an indispensable technique for the diagnosis of kidney glomerular diseases. When dedicated tissue is not available, histological and cryostat sections can be reprocessed for EM using the pop-off technique. Here the practical value of this technique is analysed with emphasis on its accuracy in measuring basement membrane thickness and detecting immune deposits., Methods: Ninety-four histological sections of kidney tissues fixed in Serra's solution, stained with H&E, PAS, and Masson's Trichrome; for EM analysis, the sections were recovered from either treated or untreated microscope slides through the pop-off technique. Some sections were recovered from cryosections allocated for immunofluorescence., Results: The ultrastructural details were sufficiently maintained on tissues fixed with Serra's solution despite being considered disadvantageous for EM. The type of microscope slides and the time of biopsy storage did not affect the quality of section recovery. The histological stains had only moderate effects on the electron-density of the glomerular basement membrane (GBM). The pop-off technique reduced the GBM thickness when compared to the conventional EM processing but preserved the electron density of immune deposits., Conclusions: The application of the pop-off method to renal biopsy is a useful recovery method that produces limited but satisfactory results when there is no suitable material for EM. The ultrastructural morphology was retained even from tissues fixed with Serra's solution, and deposits maintained the expected electron density, however, we observed an overall thickness reduction of the GBM that could have a potential impact on thin membrane disease diagnosis., (© 2021. Italian Society of Nephrology.)

Stage significantly affects survival of esophageal and esophago-gastric junction adenocarcinomas (EA/EGJAs), however, limited evidence for the prognostic role of histologic subtypes is available. The aim of the study was to describe a morphologic approach to EA/EGJAs and assess its discriminating prognostic power. Histologic slides from 299 neoadjuvant treatment-naïve EA/EGJAs, resected in five European Centers, were retrospectively reviewed. Morphologic features were re-assessed and correlated with survival. In glandular adenocarcinomas (240/299 cases-80%), WHO grade and tumors with a poorly differentiated component ≥6% were the most discriminant factors for survival (both p < 0.0001), distinguishing glandular well-differentiated from poorly differentiated adenocarcinomas. Two prognostically different histologic groups were identified: the lower risk group, comprising glandular well-differentiated (34.4%) and rare variants, such as mucinous muconodular carcinoma (2.7%) and diffuse desmoplastic carcinoma (1.7%), versus the higher risk group, comprising the glandular poorly differentiated subtype (45.8%), including invasive mucinous carcinoma (5.7%), diffuse anaplastic carcinoma (3%), mixed carcinoma (6.7%) (CSS p < 0.0001, DFS p = 0.001). Stage ( p < 0.0001), histologic groups ( p = 0.001), age >72 years ( p = 0.008), and vascular invasion ( p = 0.015) were prognostically significant in the multivariate analysis. The combined evaluation of stage/histologic group identified 5-year cancer-specific survival ranging from 87.6% (stage II, lower risk) to 14% (stage IVA, higher risk). Detailed characterization of histologic subtypes contributes to EA/EGJA prognostic prediction.

Most Crohn's disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies., (© 2021. The Author(s).)

Orbital metastases are an extremely rare finding in patients with hepatocarcinoma (HCC), especially as its first presentation. Therefore, the risk of misdiagnosis is high, as well as that of drastic delays of the therapeutic algorithm. Here we report a 71-year-old man presenting with orbital metastases as the initial sign of HCC, whose initial misdiagnosis led to the impossibility to start life-saving cancer treatment. The patient's history has begun on March 2018 with a growing tumefaction of the right orbit initially treted with antibiotics and corticosteroids without benefit. Subsequently, a facial CT scan showed a voluminous right intra-orbital mass, eroding the orbital roof. Tissue biopsy documented well differentiated malignant epithelial tumor cells. Under the suspect of primitive lachrymal gland tumor, the patient was admitted to the head and neck Unit with surgical intent. However, a subsequent 18F-FDG-PET documented the presence of liver lesions and multiple sites of metastasis. A new biopsy, this time on liver nodules, was carried out and the diagnosis of HCC was finally made. Samples from the first biopsy were then reviewed and judged consistent with HCC metastasis. Unfortunately, the initial misdiagnosis resulted in a six-month delay of the start of a therapeutic approach. During that time, patient's general conditions got extremely worse, making him unable to afford an antiblastic treatment. The patient died three months after the definitive diagnosis. This case suggests that the presence of intraorbital lesion requires a multimodal approach starting from the initial presentation. Performing a complete staging since tumor's clinical onset is mandatory, preferably before carrying out a tissue biopsy. Even though HCC represents a rare cause of intraocular metastasis, it needs to be ruled out when an orbital mass is documented, as the short median survival and the frequently poor conditions of HCC patients make a timely diagnosis crucial.

BACKGROUND Guidelines have been designed to stratify the risk of cancer transmission in donors with a history of or ongoing malignancy, although this evaluation is not always straightforward when unexpected and rare lesions are found. CASE REPORT Here, we present a case of a 41-year-old African female donor who died from a cerebral hemorrhage. Her medical history was unavailable. At procurement, multiple diffuse grayish small nodules were noticed along the peritoneal cavity, some of which were sent to the on-call pathologist for urgent frozen section evaluation. Histology showed a multinodular proliferation of uniform bland-appearing spindle cells, with no evidence of necrosis, nor nuclear atypia or mitoses. The overall picture was consistent with the diagnosis of disseminated peritoneal leiomyomatosis, with overlapping morphology with uterine leiomyoma. Given the rarity of the lesion and the potential for recurrence or malignant degeneration, only the liver and heart were allocated to recipients with life-threatening conditions. The decision was taken in a forcedly limited time and took into account the benefit of transplantation and the risk of disease transmission. CONCLUSIONS This case highlights challenges that transplant teams often have to deal with, as lesions that are difficult to diagnose during donor assessment are usually not covered in guidelines. The acceptance and usage of organs in such cases has to be decided in a team-based fashion, with the collaboration of all the transplant professionals involved to optimally assess the transmission risk, carefully balancing the benefits of transplantation for the recipients and the need to guarantee a reasonable degree of safety.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer., Patients and Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability., Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status., Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP-NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3-4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one 177 Lu-Dotatate plus SSA, and one Bevacizumab plus SSA. 177 Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), 177 Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with 177 Lu-Dotatate.

The risk of transmission of malignancy from donor to recipient is low. However, this occurrence has dramatic consequences. Many reports of donor-derived cancers in liver transplant recipients have been published, but they have not been systematically summarized into a lucid and unified analysis. The present study is an attempt to provide clarity to this unusual but clinically important problem. We systematically reviewed all patient reports, patient series, and registries published on cancer transmission events through the end of December 2019. We identified a total of 67 publications with 92 transmission events. The most frequently transmitted cancers were lymphomas (30; 32.6%), melanomas (8; 8.7%), and neuroendocrine tumors (8; 8.7%). Most of the melanomas were metastasizing, whereas most of the lymphomas were localized to the graft. The median time to cancer diagnosis after transplantation was 7 months, with 78.1% of diagnoses established in the first year. Melanoma carried the worst prognosis, with no recipients alive at 1 year after cancer diagnosis. Lymphoma recipients had a better outcome, with more than 75% surviving at 2 years. A metastatic cancer carries a worse prognosis for recipients, and recipients with localized cancer can benefit from the chance to undergo transplantation again. The findings confirm the need to pay attention to donors with a history of melanoma but also suggest the need for a more careful evaluation of groups of donors, such as those dying from cerebral hemorrhage. Finally, recipients of organs from donors with cancer should be carefully followed to detect potential transmission., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background: We report the findings of a single Italian center in the evaluation of renal lesions in deceased donors from 2001 to 2017. In risk evaluation, we applied the current Italian guidelines, which include donors with small (< 4 cm, stage pT1a) renal carcinomas in the category of non-standard donors with a negligible risk of cancer transmission., Methods: From the revision of our registries, 2,406 donors were considered in the Emilia Romagna region of Italy; organs were accepted from 1,321 individuals for a total of 3,406 organs., Results: The evaluation of donor safety required frozen section analysis for 51 donors, in which a renal suspicious lesion was detected by ultrasound. Thirty-two primary renal tumors were finally diagnosed: 26 identified by frozen sections and 6 in discarded kidneys. The 32 tumors included 13 clear cell renal cell carcinomas (RCCs), 6 papillary RCCs, 6 angiomyolipomas, 5 oncocytomas, 1 chromophobe RCC, and 1 papillary adenoma. No cases of tumor transmission were recorded in follow-up of the recipients., Conclusion: Donors with small RCCs can be accepted to increase the donor pool. Collaboration in a multidisciplinary setting is fundamental to accurately evaluate donor candidate risk assessment and to improve standardized protocols for surgeons and pathologists.

Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA ( n = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723-7.626, p < 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, p = 0.003) and similar to that of patients with known risk factors (31.9 months, p = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156-2.718, p = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.

Telepathology has been an important application for second opinion consultation ever since the introduction of digital pathology. However, little is known regarding teleconsultation for second opinion in transplantation. There is also limited literature on telepathology during organ donor procurement, typically utilized when general pathologists on-call request back-up to help assess donor biopsies for organ suitability or to diagnose newly discovered tumors with urgent time constraints. In this review, we searched Pubmed/Embase and websites of transplant organizations to collect and analyze published evidence on teleconsultation for donor evaluation and organ procurement. Of 2725 records retrieved using the key terms 'telepathology', 'second opinion' and 'transplantation', 26 suitable studies were included. Most records were from North America and included validation studies of telepathology being used for remote frozen section interpretation of donor biopsies with whole slide imaging. The data from these published studies supports the transition towards digital teleconsultation in transplant settings where consultations among pathologists are still handled by pathologists being called on site, via telephone and/or email., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β-induced podocyte injury, potentially identifying new therapeutic targets., Competing Interests: Disclosures: J.M. Thurman reported a patent to US 7,999,082 issued "Alexion Pharmaceuticals, Inc." and a patent to US 8,703,140 B2 issued "Alexion Pharmaceuticals, Inc." J. Manrique reported personal fees from Alexion Pharmaceuticals, Inc. P.S. Heeger reported personal fees from Mallinckrodt Pharmaceuticals during the conduct of the study. No other disclosures were reported., (© 2020 Angeletti et al.)

Introduction: Our study aimed at investigating tumor heterogeneity in esophageal adenocarcinoma (EAC) cells regarding clinical outcomes., Methods: Thirty-eight surgical EAC cases who underwent gastroesophageal resection with lymph node dissection in 3 university centers were included. Archival material was analyzed via high-throughput cell sorting technology and targeted sequencing of 63 cancer-related genes. Low-pass sequencing and immunohistochemistry (IHC) were used to validate the results., Results: Thirty-five of 38 EACs carried at least one somatic mutation that was absent in the stromal cells; 73.7%, 10.5%, and 10.5% carried mutations in tumor protein 53, cyclin dependent kinase inhibitor 2A, and SMAD family member 4, respectively. In addition, 2 novel mutations were found for hepatocyte nuclear factor-1 alpha in 2 of 38 cases. Tumor protein 53 gene abnormalities were more informative than p53 IHC. Conversely, loss of SMAD4 was more frequently noted with IHC (53%) and was associated with a higher recurrence rate (P = 0.015). Only through cell sorting we were able to detect the presence of hyperdiploid and pseudodiploid subclones in 7 EACs that exhibited different mutational loads and/or additional copy number amplifications, indicating the high genetic heterogeneity of these cancers., Discussion: Selective cell sorting allowed the characterization of multiple molecular defects in EAC subclones that were missed in a significant number of cases when whole-tumor samples were analyzed. Therefore, this approach can reveal subtle differences in cancer cell subpopulations. Future studies are required to investigate whether these subclones are responsible for treatment response and disease recurrence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 + immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 + cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 + microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (LT) and kidney transplantation (KT) from Extended Criteria Donors (ECD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (SCS-L and SCS-K). HOPE and SCS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in SCS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary non-function was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in KT and in LT.