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Undifferentiated embryonal sarcoma of the liver is an aggressive mesenchymal tumor that occurs predominantly in children. Although this entity has been described for decades, its pathogenesis is still obscure. Its association with mesenchymal hamartoma has been well described on the basis of identical chromosomal abnormalities. The clinical and radiological diagnoses are often difficult, and the diagnosis of undifferentiated embryonal sarcoma of the liver is based on its histology and immunophenotype. It is essential to recognize the characteristic histologic findings and the pattern of the immunohistochemistry staining to rule out other hepatic lesions. Multimodal therapy with surgery, chemotherapy, and radiation therapy has drastically improved the prognosis of patients with undifferentiated embryonal sarcoma of the liver. This successful management requires timely diagnosis for superior outcome.

Significance Multiple immune-checkpoint proteins, such as programmed death 1 (PD-1), LAG3, and TIM3, are coexpressed on immune cells and functionally synergize with each other. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a recently identified immune-checkpoint molecule that suppresses T-cell activation. This study establishes that VISTA and PD-1 exert nonredundant immune regulatory functions and synergistically regulate T-cell responses. Combinatorial treatment using VISTA- and PD-ligand 1-specific monoclonal antibodies achieved synergistic therapeutic efficacy in murine tumor models. This study critically advances our knowledge of the immune regulatory function of VISTA and provides a rationale for targeting both VISTA and PD-1 to more effectively treat T-cell-regulated diseases such as cancer. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.

ObjectiveTo assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC).MethodsThis retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months.ResultsQualitative (r = − 0.41–0.40, p < 0.042) and quantitative (r = − 0.52–0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41–0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = − 0.48–0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76–0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098–0929).ConclusionsMRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation.Key Points• MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma.• Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.

V domain-containing Ig suppressor of T-cell activation (VISTA) is a negative checkpoint regulator that suppresses T cell-mediated immune responses. Previous studies using a VISTA-neutralizing monoclonal antibody show that VISTA blockade enhances T-cell activation. The current study describes a comprehensive characterization of mice in which the gene for VISTA has been deleted. Despite the apparent normal hematopoietic development in young mice, VISTA genetic deficiency leads to a gradual accumulation of spontaneously activated T cells, accompanied by the production of a spectrum of inflammatory cytokines and chemokines. Enhanced T-cell responsiveness was also observed upon immunization with neoantigen. Despite the presence of multi organ chronic inflammation, aged VISTA-deficient mice did not develop systemic or organspecific autoimmune disease. Interbreeding of the VISTA-deficient mice with 2D2 T-cell receptor transgenic mice, which are predisposed to the development of experimental autoimmune encephalomyelitis, drastically enhanced disease incidence and intensity. Disease development is correlated with the increase in the activation of encephalitogenic T cells in the periphery and enhanced infiltration into the CNS. Taken together, our data suggest that VISTA is a negative checkpoint regulator whose loss of function lowers the threshold for T-cell activation, allowing for an enhanced proinflammatory phenotype and an increase in the frequency and intensity of autoimmunity under susceptible conditions.

Inflammatory bowel disease (IBD) in the pediatric population presents distinct characteristics compared to adult cases. Pathology plays a critical role in its diagnosis, and this review underscores key considerations in the pathologic evaluation of pediatric IBD. Recognizing inflammatory patterns in the upper gastrointestinal tract can improve disease classification and aid in diagnosing IBD in certain scenarios, such as isolated upper gastrointestinal or small bowel involvement. Additionally, familiarity with distinctive subtypes, including IBD associated with primary sclerosing cholangitis and monogenic forms of IBD, supports early comorbidity detection, enhances patient management, and improves prognostication.

This review highlights two rare entities that are predominantly seen in children: hepatic mesenchymal hamartoma (HMH) and undifferentiated embryonal sarcoma of the liver (UESL). HMH is a benign lesion predominantly seen in the first 2 years of life, while UESL is malignant and usually identified in patients between 6 and 10 years of age. UESL may arise in the background of HMH, and the association has been supported by similar chromosomal aberrations (19q13.4). The diagnosis of both lesions is primarily based on histologic evaluation, as the clinical and radiological features are not always typical. The clinicopathologic characteristics, pathogenesis, differential diagnoses and treatment for both lesions are discussed.

Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also experience chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small-molecule inhibitor of the erythroid cell-surface glycine transporter GLYT1. We established the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirmed a marked reduction of PPIX in erythroblasts derived from patients with EPP. We demonstrate that bitopertin also reduced erythrocyte and plasma PPIX accumulation in vivo in both EPP and XLPP mouse models. Finally, the reduction in erythroid PPIX ameliorated liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.

ObjectiveTo evaluate the ability of volumetric quantitative apparent diffusion coefficient (ADC) histogram parameters and LI-RADS categorization to distinguish hepatocellular carcinoma (HCC) from other primary liver cancers [intrahepatic cholangiocarcinoma (ICC) and combined HCC-ICC].MethodsSixty-three consecutive patients (44 M/19F; mean age 62 years) with primary liver cancers and pre-treatment MRI including diffusion-weighted imaging (DWI) were included in this IRB-approved single-center retrospective study. Tumor type was categorized pathologically. Qualitative tumor features and LI-RADS categorization were assessed by 2 independent observers. Lesion volume of interest measurements (VOIs) were placed on ADC maps to extract first-order radiomics (histogram) features. ADC histogram metrics and qualitative findings were compared. Binary logistic regression and AUROC were used to assess performance for distinction of HCC from ICC and combined tumors.ResultsSixty-five lesions (HCC, n = 36; ICC, n = 17; and combined tumor, n = 12) were assessed. Only enhancement pattern (p < 0.015) and capsule were useful for tumor diagnosis (p < 0.014). ADC 5th/10th/95th percentiles were significant for discrimination between each tumor types (all p values < 0.05). Accuracy of LI-RADS for HCC diagnosis was 76.9% (p < 0.0001) and 69.2% (p = 0.001) for both observers. The combination of male gender, LI-RADS, and ADC 5th percentile yielded an AUROC/sensitivity/specificity/accuracy of 0.90/79.3%/88.9%/81.5% and 0.89/86.2%/77.8%/80.0% (all p values < 0.027) for the diagnosis of HCC compared to ICC and combined tumors for both observers, respectively.ConclusionThe combination of quantitative ADC histogram parameters and LI-RADS categorization yielded the best prediction accuracy for distinction of HCC compared to ICC and combined HCC-ICC.

INTRODUCTION:We aimed to evaluate the reliability and validity of the Ulcerative Colitis (UC) Endoscopic Index of Severity (UCEIS) and Mayo Endoscopy Score (MES) and to validate the Robarts Histopathology Index (RHI) and Nancy Index (NI) in pediatric UC. We examined rectosigmoid and pancolonic versions of each instrument.METHODS:Single-center cross-sectional study of 60 prospectively enrolled participants. Through central endoscopy review, 4 pediatric gastroenterologists assigned rectosigmoid and pancolonic (mean of 5 colonic segments) UCEIS and MES scores. Two blinded pathologists assigned rectosigmoid and pancolonic RHI and NI scores. We assessed reliability with intraclass correlation coefficients and weighted kappa statistics and explored construct validity with correlations, boxplots, and receiver operator characteristic curves.RESULTS:The UCEIS and MES displayed almost perfect intra-rater and inter-rater reliability (intraclass correlation coefficient and weighted kappa ≥0.85), moderate-to-strong correlation with histologic/clinical activity and fecal calprotectin (FC), and very strong correlation with global endoscopic severity (r > 0.9). Rectosigmoid UCEIS and MES scores of 0 were highly specific (≥95%) for endoscopic and histologic remission throughout the colon. Pancolonic endoscopy scores correlated more strongly with histologic activity, clinical activity, and systemic inflammatory markers and better discriminated between degrees of active disease. RHI and NI showed moderate-to-strong correlation (r = 0.5–0.83) with endoscopic/clinical activity and FC.DISCUSSION:Our findings support the reliability and construct validity of the UCEIS and MES and the construct validity of the RHI and NI in pediatric UC. Normal rectosigmoid findings predicted pancolonic healing, but, given active disease, pancolonic endoscopic assessment more accurately captured global disease burden.

Background Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an immunologic syndrome characterized by widespread neutrophilic infiltration. Histiocytoid Sweet syndrome (H-SS) is a histopathologic variant of SS. While SS most commonly occurs in adults, this case report discusses an infant patient who presented with H-SS. Case presentation Through a multidisciplinary approach, this patient was also found to have very early onset inflammatory bowel disease (VEO-IBD) and Mevalonate kinase-associated disease (MKAD). While prior case studies have characterized an association between VEO-IBD and MKAD, there is no literature describing the association of all three diagnoses this case: H-SS, VEO-IBD and MKAD. Initiation of canakinumab in this patient resulted in successful control of the disease. Conclusions This case highlights the importance of a multidisciplinary approach to rare diagnoses, and collaboration during cases with significant diagnostic uncertainty.