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Systemic mastocytosis (SM) comprises a group of rare disorders resulting from tissue infiltration by pathological mast cells. In a percentage ranging from 5 to 40% in various patient series, SM appears to be associated with an accompanying hematologic neoplasm (SM-AHN). The coexistence of SM with chronic myelogenous leukemia (CML) is extremely rare with only 3 cases in the literature. The natural course of CML has changed dramatically over the past 2 decades with the use of tyrosine kinase inhibitors (TKIs). We report a case of diagnosing SM in a patient in complete molecular remission of CML after stopping TKI treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Christos Fokoloros et al.)

Despite the significant contributions of immunocompetent mouse models to the development and assessment of cancer immunotherapies, they inadequately represent the genetic and biological complexity of corresponding human cancers. Immunocompromised mice reconstituted with a human immune system (HIS) and engrafted with patient-derived tumor xenografts are a promising novel preclinical model for the study of human tumor-immune interactions. Whilst overcoming limitations of immunocompetent models, HIS-tumor models often rely on reconstitution with allogeneic immune cells, making it difficult to distinguish between anti-tumor and alloantigen responses. Models that comprise of autologous human tumor and human immune cells provide a platform that is more representative of the patient immune-tumor interaction. However, limited access to autologous tissues, short experimental windows, and poor retention of tumor microenvironment and tumor infiltrating lymphocyte components are major challenges affecting the establishment and application of autologous models. This review outlines existing preclinical murine models for the study of immuno-oncology, and highlights innovations that can be applied to improve the feasibility and efficacy of autologous models., (© 2021. The Author(s).)

Background: This study aimed to compare the diagnostic accuracy of stress single-photon emission computed tomography (SPECT) and stress cardiac magnetic resonance (CMR) for the assessment of coronary artery disease (CAD) in the same patients, using coronary angiography as the reference standard., Methods: Thirty patients with known or suspected CAD who were referred for exercise SPECT myocardial perfusion imaging (MPI) for the evaluation of myocardial ischemia underwent stress CMR MPI and computed tomography coronary angiography (CTCA) or selective coronary angiography (SCA). The data from the two stress modalities were compared against the data from angiography., Results: In our study population, 30% of the recruited subjects had significant CAD. The CMR sensitivity for the detection of significant CAD and/or myocardial ischemia was 89% and specificity was 76%. For SPECT, the corresponding sensitivity was 78% and specificity was 52%. The negative predictive value was 92% for CMR and 83% for SPECT. The receiver-operating characteristic (ROC) analysis evaluating the presence of significant CAD, CMR (area under the curve (AUC) 0.78) outperformed SPECT (AUC 0.59) (p < 0.01). The ROC analysis evaluating the presence of myocardial ischemia was also in favor of CMR (AUC 0.82) versus SPECT (AUC 0.67) (p < 0.01)., Conclusions: CMR has high diagnostic accuracy for the detection of CAD and stress-induced ischemia and appears to outperform SPECT. CMR may thus be the preferred noninvasive imaging modality to assess patients with known or suspected CAD., Competing Interests: The authors declare conflicts of interest.

Background: Pancreatic organoid systems have recently been described for the in vitro culture of pancreatic ductal cells from mouse and human. Mouse pancreatic organoids exhibit unlimited expansion potential, while previously reported human pancreas organoid (hPO) cultures do not expand efficiently long-term in a chemically defined, serum-free medium. We sought to generate a 3D culture system for long-term expansion of human pancreas ductal cells as hPOs to serve as the basis for studies of human pancreas ductal epithelium, exocrine pancreatic diseases and the development of a genomically stable replacement cell therapy for diabetes mellitus., Results: Our chemically defined, serum-free, human pancreas organoid culture medium supports the generation and expansion of hPOs with high efficiency from both fresh and cryopreserved primary tissue. hPOs can be expanded from a single cell, enabling their genetic manipulation and generation of clonal cultures. hPOs expanded for months in vitro maintain their ductal morphology, biomarker expression and chromosomal integrity. Xenografts of hPOs survive long-term in vivo when transplanted into the pancreas of immunodeficient mice. Notably, mouse orthotopic transplants show no signs of tumorigenicity. Crucially, our medium also supports the establishment and expansion of hPOs in a chemically defined, modifiable and scalable, biomimetic hydrogel., Conclusions: hPOs can be expanded long-term, from both fresh and cryopreserved human pancreas tissue in a chemically defined, serum-free medium with no detectable tumorigenicity. hPOs can be clonally expanded, genetically manipulated and are amenable to culture in a chemically defined hydrogel. hPOs therefore represent an abundant source of pancreas ductal cells that retain the characteristics of the tissue-of-origin, which opens up avenues for modelling diseases of the ductal epithelium and increasing understanding of human pancreas exocrine biology as well as for potentially producing insulin-secreting cells for the treatment of diabetes.

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer 1 . However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.

This is a case report of a 46-year-old man diagnosed with early pre-B acute lymphoblastic leukemia (ALL), bearing the translocation t(12;17)(p13;q21) as the sole chromosomal abnormality. This is a rare chromosomal abnormality that has been reported in approximately 25 cases worldwide. FISH analysis revealed a rearrangement of ZNF384 (12p13) and TAF15 (17q12) genes, which is usually associated with a pre-B ALL phenotype with co-expression of the myeloid markers CD13 and/or CD33. ZNF384 encodes a zinc finger protein, which acts as a transcription factor, regulating the expression of several matrix metalloproteinases and TAF15 belongs to the FET (FUS, EWS, and TAF15) family, consisting of RNA and DNA-binding proteins. Unlike most of the cases where CD10 expression was absent or weak, in our case CD10 was highly expressed. The prognostic significance of ZNF384/TAF15 fusion is not very clear since several reports support a generally good prognosis, while others support a poor clinical outcome. Our patient was treated with the German multicenter ALL (GMALL) protocol for B-ALL, but experienced a fulminant gram-negative sepsis and eventually died during induction therapy., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

Measures of left ventricular function during exercise provide information that is more accurate than the exercise ECG in the diagnosis of coronary artery disease, supportive of the data provided by myocardial perfusion studies, and of great prognostic significance. We review basic methods for evaluating left ventricular function during exercise and responses to various types of exercise, including incremental exercise and exercise training conditions. Additionally, we review changes in both incremental exercise test responses and responses to training in various pathological conditions. Case reports are included to illustrate the utility of measuring left ventricular function during exercise.