Arun Kumar Arunachalam

Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

Hematological malignancies, namely, leukemias and lymphomas comprise the major part of clinical practice for most centers that manage children with cancer.[1] Survival of children with common pediatric malignancies such as acute lymphoblastic leukemia (ALL), Hodgkin's lymphoma, and Burkitt's lymphoma has improved by leaps and bounds over the last few decades. This can be largely attributed to superior diagnostic techniques and risk-stratified approaches that tailor the therapy for different patient subgroups. The pathology laboratory, by performing indispensable tests ranging from cytology and histomorphology to immunohistochemistry (IHC), flow cytometry, and molecular methods, has veritably paved the way for this success story. The evolution of hematology as a specialty can be attributed to doctors who played the dual role of managing patients at the bedside and examining their peripheral smears and bone marrow aspirates in the laboratory.[2] It is only in the last 20 years that clinical and laboratory hematologists are emerging as distinct specialists. The dichotomy is necessitated by the growing number of children being diagnosed with hematological disorders and the multitude of investigations that are now mandatory for their standard of care. Yet, it is noteworthy that contemporary courses that train clinical and laboratory hematologists ensure the rotation of the trainees in the laboratory and clinical areas, respectively. In this perspective, the authors illustrate the importance of a healthy relationship between the two groups of professionals with the help of some real-life scenarios. The manuscript has been read and approved by all the authors that the requirements for authorship have been met and that each author believes that the manuscript represents honest work. Article published online: 04 November 2023 © 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

The assessment of measurable residual disease (MRD) has emerged as a powerful prognostic tool for both pediatric and adult acute lymphoblastic leukemia (ALL). This retrospective study aimed to evaluate the prognostic relevance of the end of induction MRD in B‐cell acute lymphoblastic leukemia (B ALL) patients. The study included 481 patients who underwent treatment for B ALL between August 2012 and March 2019 and had their MRD at the end of induction assessed by flow cytometry. Baseline demographic characteristics were collected from the patient's clinical records. Event free survival (EFS) and relapse free survival (RFS) were calculated using Kaplan–Meier analysis and survival estimates were compared using the log‐rank test. End of induction MRD and baseline karyotype were the strongest predictors of EFS and RFS on multivariate analysis. The EFS was inversely related to the MRD value and the outcomes were similar in patients without morphological remission at the end of induction and patients in remission with MRD ≥1.0%. Even within the subgroups of ALL based on age, karyotype, BCR::ABL1 translocation and the treatment protocol, end of induction MRD positive patients had poor outcomes compared to patients who were MRD negative. The study outcome would help draft end of induction MRD‐based treatment guidelines for the management of B ALL patients.

The diagnostic evaluation of myeloproliferative neoplasms (MPNs) depends on the close correlation between clinical features, morphologic assessment of a trephine bone marrow biopsy, and molecular markers. Typically, MPNs have driver mutations in JAK2, CALR, or MPL, as well as mutations in genes related to epigenetic regulation, RNA splicing, and signaling. Mutations in these genes are a hallmark of diagnostic, prognostic, and therapeutic assessment in patients with MPNs. In line with the World Health Organization classification, all myeloproliferative disorders require molecular characterization to support diagnoses or confirm entities defined by underlying molecular abnormalities. A structured molecular analysis workflow is essential for a rapid and cost-effective diagnosis of MPN. The purpose of this review is to explore the role of molecular diagnostics in the assessment of BCR::ABL1-negative MPNs.

Purpose: Severe myelosuppression in patients with acute lymphoblastic leukemia (ALL) undergoing 6-MP-based maintenance therapy is attributed to TPMT gene polymorphisms, which is rare in Asian populations. This study aims to evaluate the role of selected polymorphisms in NUDT15, ITPA, and MRP4 genes in addition to TPMT in predicting 6-MP intolerance during ALL maintenance therapy. Patients and Methods: We screened for the presence of NUDT15*3 (c.415 C>T, rs116855232); MRP4 c.2269 C>T (rs3765534), ITPA c.94 C>A (rs1127354) polymorphisms in addition to TPMT *2 (rs1800462), *3A (*3B and *3C; rs1800460 and rs1142345) in ALL patients with documented severe neutropenia (cohort-1; n=42). These polymorphisms were then screened in a prospective cohort of ALL patients (cohort-2; n=133) and compared with 6-MP dose reduction, early/late myelotoxicity. Results: Nineteen (45%) patients in cohort-1 and 18 (14%) in cohort-2 had NUDT15 c.415 C>T variant while 4 (3%) patients in cohort-2 had TPMT*3C variant. Five (12%) in cohort-1 and 30 (24%) in cohort-2 had ITPA c.94 C>A variant while 9 (22%) and 15 (12%) had MRP4 c.2269 C>T variant in cohorts-1 and 2, respectively. All in cohort-1 and 36 (27%) in cohort-2 had severe myelotoxicity. Twenty-eight patients (66.6%) in cohort-1 and 40 (30%) patients in cohort-2 had significant 6-MP dose reduction. NUDT15 c.415 C>T variant explained severe myelotoxicity in 63% and 33% in cohort 1 and 2. TPMT*3C and ITPA c.94 C>A variants also explained myelotoxicity in cohort-2 (Median ANC: 376 vs 1014 mm³; p=0.04 and 776 vs 1023 mm³; p=0.04 respectively). NUDT15 c.415 C>T polymorphism explained significant myelotoxicity (507 vs 1298 mm³; p< 0.0001) in the multivariate analysis as well (β=− 0.314, p< 0.0001). Conclusion: NUDT15 c.415 C>T (15*3), TPMT*3C, as well as ITPA c.94 C>A and MRP4 c.2269 C>T polymorphisms explain hematotoxicities. Preemptive genotype-based (NUDT15*3, TPMT, ITPA c.94 C>A) 6-MP dosing could improve the outcome after maintenance therapy.