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Background: Relapse in pediatric acute myeloid leukemia (pedAML) patients is known to be associated with residual leukemic stem cells (LSC). We have previously shown that epithelial membrane protein 1 (EMP1) is significantly overexpressed in LSC compared to hematological stem cell fractions. EMP1 was also documented as part of the 17-gene stemness score and a 6-membrane protein gene score, both correlating high EMP1 expression with worse overall survival. However, its potential as a therapeutic target in pedAML is still unexplored., Methods: Association analyses of EMP1 expression with clinical and molecular AML characteristics were performed. Expression of EMP1 was evaluated in pedAML and cord blood samples. Expression in normal blood cells and tissues was evaluated by flow cytometry and immunohistochemistry, respectively., Results: In silico analyses showed variable mRNA expression of EMP1 in multiple pedAML datasets, and a significant correlation between high EMP1 transcript levels and the presence of inv(16). Flow cytometry showed overexpression of EMP1 in pedAML samples, as well as expression in normal blood subsets. Importantly, immunohistochemistry revealed EMP1 expression in multiple normal tissues., Conclusion: Although EMP1 presents as an interesting membrane-associated target in pedAML, its abundant expression in normal blood cells and tissues will impede it from further exploration as a therapeutic target., Impact: EMP1 is highly expressed in multiple cancer types, but expression in acute myeloid leukemia (AML) and normal tissues is unexplored. As EMP1 is investigated in other cancer types, expression in normal tissues and blood cells is relevant in predicting the success of EMP1-targeted therapies. In this study, we showed expression of EMP1 in multiple tissues, predicting high on-target off-tumor toxicity, which will warn other researchers of possible toxicities when generating EMP1-targeted therapy. Finally, we showed that high EMP1 expression is associated with better overall survival of pediatric AML patients, reducing the need for EMP1-targeted therapy., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: Portal hypertension (PHT) and its sequelae are the most clinically important manifestations in cystic fibrosis-related liver disease (CFLD). This paper aimed to evaluate the safety and efficacy of a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) to prevent PHT-related complications in pediatric patients with CFLD., Methods: This was a prospective single-arm study on pediatric patients with CFLD, signs of PHT, and preserved liver function who underwent a pre-emptive TIPS in a single tertiary CF center between 2007 and 2012. The long-term safety and clinical efficacy were assessed., Results: A pre-emptive TIPS was performed on seven patients with a mean age of 9.2 years (± standard deviation: 2.2). The procedure was technically successful in all patients, with an estimated median primary patency of 10.7 years [interquartile range (IQR) 0.5-10.7)]. No variceal bleeding was observed during the median follow-up of 9 years (IQR 8.1-12.9). In two patients with advanced PHT and rapidly progressive liver disease, severe thrombocytopenia could not be stopped. Subsequent liver transplantation revealed biliary cirrhosis in both patients. In the remaining patients with early PHT and milder porto-sinusoidal vascular disease, symptomatic hypersplenism did not occur, and liver function remained stable until the end of the follow-up. Inclusion for pre-emptive TIPS was discontinued in 2013 following an episode of severe hepatic encephalopathy., Conclusion: TIPS is a feasible treatment with encouraging long-term primary patency to avoid variceal bleeding in selected patients with CF and PHT. However, as the progression of liver fibrosis, thrombocytopenia, and splenomegaly is inevitable, the clinical benefits due to pre-emptive placement appear to be minor.

The incidence of neuroendocrine neoplasms (NEN) in the rectum is rising since the introduction of colonoscopy screening programs. Guidelines, such as the European NeuroEndocrine Tumor Society (ENETS) algorithm, are mainly based on expert opinion. The goal of this nationwide study is to gain a better insight into the evolution in pathology reporting and adherence to the ENETS guidelines in Belgium. In Belgium, all NENs have to be reported to the Belgian Cancer Registry. We thoroughly reviewed all available pathology reports, coded as rectal NEN between 2004 and 2015, and reclassified according to World Health Organisation (WHO) classification 2019. To evaluate the adherence to the ENETS guidelines, population-based cancer registry data were linked with the medical procedures of the Belgian Health Insurance database. A total of 670 rectal NEN were retained and 16% of the cases needed reclassification. Annual incidence between 2004 and 2015 tripled from 0,20 to 0,61 per 100.000 inhabitants. Reporting of Ki67 proliferation index ameliorated most, while reporting of tumor size, lymphovascular and perineural invasion remained disappointing. Endoscopic ultrasound was performed in only 36.6% of the cases, while the mostly recommended mode of treatment (endoscopic/surgical/no resection) was followed in the majority of the cases. Incidence of rectal NEN in Belgium increased throughout the years and quality of pathology reporting improved especially after the WHO classification update in 2010. The growing awareness and knowledge among clinicians and pathologists in the community counters the need for centralization.

Tumour infiltrating lymphocytes (TILs) have been described as a biomarker for the host immune response against the tumour with prognostic properties. The International Immuno-Oncology Biomarkers Working Group (IBWG) proposed a standardised method for quantifying TILs in solid tumours to improve consistent and reproducible scoring. In this study, the methodology was tested in a retrospective population of oropharyngeal squamous cell carcinoma (OPSCC). TIL quantification was performed on 92 OPSCC samples (2004-2013) by four independent observers as described by the IBWG. Interobserver variability was assessed and results were correlated with clinicopathological variables and survival. TIL evaluation turned out to be challenging in OPSCC due to heterogeneity of TILs distribution, presence of pre-existing lymphoid tissue, surface ulceration or erosion and insufficient amount of intertumoural stroma in biopsies. Nonetheless, interobserver variability proved to be good to excellent. High stromal TILs (TILstr) and intratumoural TILs (TILtum) were both correlated to favourable overall survival and multivariate analysis showed TILstr to be the sole independent prognostic factor in OPSCC. The IBWG-proposed TIL quantification method is feasible and reproducible in OPSCC and provides valuable prognostic information regarding clinicopathological characteristics and overall survival. The use of this standardised methodology may facilitate implementation of TILs scoring as a prognostic biomarker in OPSCC., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Glioblastoma (GB) is the most common primary malignant brain tumor. Standard medical treatment consists of a maximal safe surgical resection, subsequently radiation therapy (RT) and chemotherapy with temozolomide (TMZ). An accurate definition of the tumor volume is of utmost importance for guiding RT. In this project we investigated the feasibility and treatment response of subvolume boosting to a PET-defined tumor part., Method: F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (T1w) MRI. A dose of 20 Gy (5 × 5 mm 2 ) was delivered to the target volume delineated based on T1w MRI for three treatment groups. Two of those treatment groups received an additional radiation boost of 5 Gy (1 × 1 mm 2 ) delivered to the region either with maximum [ 18 F]FET or [ 18 F]FAZA PET tracer uptake, respectively. All therapy groups received intraperitoneal (IP) injections of TMZ. Finally, a control group received no RT and only control IP injections. The average, minimum and maximum dose, as well as the D 90 -, D 50 - and D 2 - values were calculated for nine rats using both RT plans. To evaluate response to therapy, follow-up tumor volumes were delineated based on T1w MRI., Results: When comparing the dose volume histograms, a significant difference was found exclusively between the D 2 -values. A significant difference in tumor growth was only found between active therapy and sham therapy respectively, while no significant differences were found when comparing the three treatment groups., Conclusion: In this study we showed the feasibility of PET guided subvolume boosting of F98 glioblastoma in rats. No evidence was found for a beneficial effect regarding tumor response. However, improvements for dose targeting in rodents and studies investigating new targeted drugs for GB treatment are mandatory.

The use of O-(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro K i determination, the most promising compound, 2-[ 18 F]-2-fluoroethyl-L-phenylalanine (2-[ 18 F]FELP), was selected for further evaluation and in vitro comparison with [ 18 F]FET. Subsequently, 2-[ 18 F]FELP was assessed in vivo and compared with [ 18 F]FET and [ 18 F]FDG in a F98 glioblastoma rat model. 2-[ 18 F]FELP showed improved in vitro characteristics over [ 18 F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[ 18 F]FELP is a promising new PET tracer for brain tumor imaging.

Background The association of hyperthyroidism with renal disease is very rare and the importance of timely clinical recognition cannot be overemphasized. Case presentation An 11-year-old girl presented with gastrointestinal symptoms while hypertension, edema and abdominal pain were noticed on clinical examination. Laboratory investigation revealed: hemoglobin 9.4 (11.5-15.5) g/dL, total white cell count 16 (4.5-12)×109/L, platelets 247 (150-450)×109/L, C-reactive protein (CRP) 31.8 (<5) mg/L, blood urea nitrogen (BUN) 126 (13-43) mg/dL, creatinine 0.98 (0.53-0.79) mg/dL, albumin 25 (35-52) g/dL, complement factor C3 0.7 (0.9-1.8) g/L, complement factor C4 0.1 (0.1-0.4) g/L, tri-iodothyronine 6.5 (2.5-5.2) pg/mL, free thyroxine 2.4 (1-1.7) ng/dL, thyroid stimulating hormone (TSH) <0.02 (0.5-4.3) mU/L. Urinalysis showed nephrotic range proteinuria. Renal function deteriorated necessitating hemodialysis (HD). A renal biopsy revealed an immune complex-mediated membranoproliferative glomerulonephritis (MPGN). Elevated thyroid hormones and suppressed TSH levels with elevated thyroperoxidase antibodies and thyroid stimulating immunoglobulins confirmed the diagnosis of Graves' disease. Corticosteroids were commenced and eventually thiamazole was added with gradual improvement of renal function, cessation of HD and discharge from the hospital. Conclusions Graves' disease complicated by MPGN is extremely rare, but can cause life-threatening complications.