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Summary: The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has revolutionised the therapeutic landscape of chronic lymphocytic leukaemia (CLL). Acquired mutations emerging at position C481 in the BTK tyrosine kinase domain are the predominant genetic alterations associated with secondary ibrutinib resistance. To assess the correlation between disease progression, and the emergence and temporal dynamics of the most common resistance mutation BTKC481S, sensitive (10−4) time‐resolved screening was performed in 83 relapsed/refractory CLL patients during single‐agent ibrutinib treatment. With a median follow‐up time of 40 months, BTKC481S was detected in 48·2% (40/83) of the patients, with 80·0% (32/40) of them showing disease progression during the examined period. In these 32 cases, representing 72·7% (32/44) of all patients experiencing relapse, emergence of the BTKC481S mutation preceded the symptoms of clinical relapse with a median of nine months. Subsequent Bcl‐2 inhibition therapy applied in 28/32 patients harbouring BTKC481S and progressing on ibrutinib conferred clinical and molecular remission across the patients. Our study demonstrates the clinical value of sensitive BTKC481S monitoring with the largest longitudinally analysed real‐world patient cohort reported to date and validates the feasibility of an early prediction of relapse in the majority of ibrutinib‐treated relapsed/refractory CLL patients experiencing disease progression. [ABSTRACT FROM AUTHOR]

Despite their functional similarities, peripheral lymphoid tissues are remarkably different according to their developmental properties and structural characteristics, including their specified vasculature. Access of leukocytes to these organs critically depends on their interactions with the local endothelium, where endothelial cells are patterned to display a restricted set of adhesion molecules and other regulatory compounds necessary for extravasation. Recent advances in high throughput analyses of highly purified endothelial subsets in various lymphoid tissues as well as the expansion of various transgenic animal models have shed new light on the transcriptional complexities of lymphoid tissue vascular endothelium. This review is aimed at providing a comprehensive analysis linking the functional competence of spleen and intestinal lymphoid tissues with the developmental programming and functional divergence of their vascular specification, with particular emphasis on the transcriptional control of endothelial cells exerted by Nkx2.3 homeodomain transcription factor. [ABSTRACT FROM AUTHOR]

Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly in sensory nerves are activated by inflammatory stimuli and mediate inflammation and pain. Although they have been shown in the human endometrium, their regulation and function are unknown. Therefore, we investigated their estrogen- and progesterone-dependent alterations in the rat endometrium in comparison with the estrogen-regulated inflammatory cytokine macrophage migration inhibitory factor (MIF). Four-week-old (sexually immature) and four-month-old (sexually mature) female rats were treated with the non-selective estrogen receptor (ER) agonist diethylstilboestrol (DES), progesterone and their combination, or ovariectomized. RT-PCR and immunohistochemistry were performed to determine mRNA and protein expression levels respectively. Channel function was investigated with ratiometric [Ca2+]i measurement in cultured primary rat endometrial cells. Both TRP receptors and MIF were detected in the endometrium at mRNA and protein levels, and their localizations were similar. Immunostaining was observed in the immature epithelium, while stromal, glandular and epithelial positivity were observed in adults. Functionally active TRP receptor proteins were shown in endometrial cells by activation-induced calcium influx. In adults, Trpa1 and Trpv1 mRNA levels were significantly up-regulated after DES treatment. TRPA1 increased after every treatment, but TRPV1 remained unchanged following the combined treatment and ovariectomy. In immature rats, DES treatment resulted in increased mRNA expression of both channels and elevated TRPV1 immunopositivity. MIF expression changed in parallel with TRPA1/TRPV1 in most cases. DES up-regulated Trpa1, Trpv1 and Mif mRNA levels in endometrial cell cultures, but 17b-oestradiol having ERa-selective potency increased only the expression of Trpv1.We provide the first evidence for TRPA1/TRPV1 expression and their estrogen-induced up-regulation in the rat endometrium in correlation with the MIF. [ABSTRACT FROM AUTHOR]

Background: T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell lymphoma that is usually associated with poor prognosis and short overall survival. Methods: We present a case of a 61-year-old woman presenting with T-PLL and the leukemic cells harboring BCR::ABL1 ( BCR -breakpoint cluster region; ABL1 -ABL protooncogene 1) fusion transcripts as the result of a variant of t(9;22)(q34;q11) called Philadelphia translocation: t(9;22;18)(q34;q11;q21). Sequencing revealed a rare BCR transcript with an exon 6 breakpoint corresponding to e6a2 transcripts, which has thus far been reported in only 26 cases of leukemias. Results: After 9 months of follow-up, the disease progressed and required treatment. Following alemtuzumab and chemotherapy, a short course of imatinib therapy stabilized the disease for six months, which was followed by progression and the demise of the patient. Conclusions: To the best of our knowledge, this is the first report of a mature T-cell lymphoma with a variant Philadelphia-translocation and a very rare type of BCR::ABL1 transcript. This case highlights the importance of comprehensive genetic testing of malignancies, as abnormal molecular pathways may be uncovered that may be specifically targeted by drugs.

This review presents the latest molecular genetic diagnostic and clinical aspects related to clonal hematopoiesis of indeterminate potential (CHIP). CHIP belongs to the continuously expanding group of pre-cancerous conditions, increasingly recognized in routine patient care due to the development of molecular diagnostic tools and the increase in life expectancy. The incidence of CHIP mutations increases with age (1-2% in individuals aged 50 years, 15-45% in those aged 80 years). According to international studies, 5-8% of examinations performed on solid tumors may contain erroneous results due to the presence of leukocytes. This rate increases to 10-15% in case of liquid biopsy samples. To avoid misleading diagnostic results, it is recommended to perform comparative analysis of samples from different tissue origins, blood/tumor sample pairs. The authors illustrate CHIP-related alterations affecting targeted therapies for solid tumors (e.g. KRAS, ATM, IDH1, TP53). The impact of CHIP on the detection of germline genetic alterations is also discussed.

Aim: This study aims to evaluate the diagnostic challenges and molecular aspects of pediatric gliomas, among the most common brain tumors in children, focusing on improving early detection and personalized treatment strategies., Methods: We conducted a comprehensive review of recent literature, examining current diagnostic techniques, including imaging and histopathological analysis, alongside molecular profiling methods such as next-generation sequencing (NGS) and methylation profiling., Results: The findings highlight significant diagnostic challenges due to the heterogeneity of pediatric gliomas. Molecular profiling has proven essential in identifying key genetic alterations, such as those in the H3F3A and MAPK pathway genes, offering insights into tumor behavior and therapeutic targets., Conclusions: Early and accurate diagnosis of pediatric gliomas is hampered by their molecular diversity. Integrating molecular diagnostics with traditional methods is crucial for enhancing diagnostic accuracy and guiding personalized treatment approaches.

Background and Purpose:

Glioblastoma (GBM), a highly aggressive form of brain tumors, has been extensively studied using OMICS methods, and the most characteristic molecular determinants have been incorporated into the histopathological diagnosis. Research data, nevertheless, only partially have been adopted in clinical practice. Here we aimed to present results of our epige­no­mic GBM profiling to better understand early and late determinants of these tumors, and to share main elements of our findings with practicing professionals.

GBM specimens were surgically obtained after first diagnosis (GBM1) and at recurrence (GBM2). DNA was extracted from 24 sequential pairs of formalin-fixed, paraffin-embedded tumor tissues. The Reduced Representation Bisulfite Sequencing kit was used for library preparation. Pooled libraries were sequenced on an Illumina NextSeq 550 instrument. Methylation controls (MC) were obtained from a publicly available database. Bioinformatic analyses were performed to identify differentially methylated pathways and their elements in cohorts of MC, GBM1 and GBM2.

Several differentially methylated pathways involved in basic intracellular and brain tissue developmental processes were identified in the GBM1 vs. MC and GBM2 vs. MC comparisons. Among differentially me­thylated pathways, those involved in immune regulation, neurotransmitter (particularly dopaminergic, noradrenergic and glutaminergic) responses and regulation of stem cell differentiation and proliferation stood out in the GBM2 vs. GBM1 comparisons.

Our study revealed biological complexity of early and late gliomagenesis encompassing mechanisms from basic intracellular through distorted neurodevelopmental processes to more specific immune and highjacked neurotransmitter pathways in the tumor microenvironment. These findings may offer considerations for therapeutic approaches.