PURPOSE: The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. PATIENTS AND METHODS: EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). RESULTS: Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. CONCLUSION: Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

• MeSH
• antigeny CD22 * MeSH
• cyklofosfamid aplikace a dávkování   terapeutické užití   MeSH
• dexamethason aplikace a dávkování   terapeutické užití   MeSH
• filadelfský chromozom MeSH
• inotuzumab ozogamicin * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pre-B-buněčná leukemie * farmakoterapie   mortalita   genetika   MeSH
• prospektivní studie MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vinkristin aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH

The study aimed to investigate prevalent chromosomal breakpoints identified in balanced structural chromosomal anomalies and to pinpoint potential candidate genes linked with male infertility. This was acchieved through a comprehensive approach combining RNA-seq and microarray data analysis, enabling precise identification of candidate genes. The Cytogenetics data from 2,500 infertile males referred to Royan Research Institute between 2009 and 2022 were analyzed, with 391 cases meeting the inclusion criteria of balanced chromosomal rearrangement. Of these, 193 cases exhibited normal variations and were excluded from the analysis. By examining the breakpoints, potential candidate genes were suggested. Among the remaining 198 cases, reciprocal translocations were the most frequent anomaly (129 cases), followed by Robertsonian translocations (43 cases), inversions (34 cases), and insertions (3 cases).Some patients had more than one chromosomal abnormality. Chromosomal anomalies were most frequently observed in chromosomes 13 (21.1%), 14 (20.1%), and 1 (16.3%) with 13q12, 14q12, and 1p36.3 being the most prevalent breakpoints, respectively. Chromosome 1 contributed the most to reciprocal translocations (20.2%) and inversions (17.6%), while chromosome 14 was the most involved in the Robertsonian translocations (82.2%). The findings suggested that breakpoints at 1p36.3 and 14q12 might be associated with pregestational infertility, whereas breakpoints at 13q12 could be linked to both gestational and pregestational infertility. Several candidate genes located on common breakpoints were proposed as potentially involved in male infertility. Bioinformatics analyses utilizing three databases were conducted to examine the expression patterns of 78 candidate genes implicated in various causes of infertility.‏ In azoospermic individuals, significant differential expression was observed in 19 genes: 15 were downregulated (TSSK2, SPINK2, TSSK4, CDY1, CFAP70, BPY2, BTG4, FKBP6, PPP2R1B, SPECC1L, CENPJ, ‏SKA3, FGF9, NODAL, CLOCK), while four genes were upregulated ‏(‏HSPB1, MIF, PRF1, ENTPD6). In the case of Asthenozoospermia, seven genes showed significant upregulation (PRF1, DDX21, KIT, SRD5A3, MTCH1, DDX50, NODAL). Though RNA-seq data for Teratozoospermia were unavailable, microarray data revealed differential expression insix genes: three downregulated (BUB1, KLK4, PIWIL2) and three upregulated (AURKC, NPM2, RANBP2). These findings enhance our understanding of the molecular basis of male infertility and could provide valuable insights for future diagnostic and therapeutic strategies.

• MeSH
• body zlomu chromozomu MeSH
• chromozomální aberace MeSH
• cytogenetické vyšetření MeSH
• lidé MeSH
• mužská infertilita * genetika   MeSH
• translokace genetická * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) originates from the T-lineage and is marked by rearrangements of the ALK gene. More than 10 fusion partners with the ALK gene are known, with the most common being the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion. In 10% to 20% of the ALK+ ALCL cases, the ALK gene fuses with various other partners. Modern molecular techniques, especially next-generation sequencing (NGS), have eased the identification of ALK gene fusion partners and have allowed in-depth characterization of the T-cell receptor (TCR) repertoire. We devised a real-time quantitative reverse-transcription polymerase chain reaction to measure the expression of the translocated portion of the ALK gene. Fusion partners for the ALK gene were analyzed using rapid amplification of 5'cDNA ends (RACE) method or NGS. TCR immunoprofiling was performed by amplicon NGS. We studied 96 ALK+ ALCL patients. NPM1::ALK fusion gene was observed in 71 patients, ATIC::ALK in 9, and TPM3::ALK in 3. CLTC::ALK, MYH9::ALK, and RNF213::ALK fusions were identified in 2 patients each. We also discovered the TPM4::ALK and SATB1::ALK fusion genes, plus the following 2 previously unidentified ALK+ ALCL fusions: SQSTM1::ALK and CAPRIN1::ALK. High expression of the translocated ALK gene segment was observed in all 93 analyzed samples. TCR testing was conducted on 23 patients with available DNA. In 18 (78%) patients, we discerned at least one (ranging from 1 to 4) clonal TCR rearrangement. In 59% of the patients, clonal TCR beta junctions corresponded with sequences previously observed in both healthy donors and under various pathological conditions. Reverse-transcriptase quantitative detection of ALK expression is a fast and reliable method for both diagnosing and monitoring treatment response in ALK+ ALCL patients, irrespective of the ALK gene translocation. NGS reveals new ALK translocation partners. Both malignant and reactive TCR repertoires in ALK+ ALCL patients are unique and do not consistently occur among different patients.

• MeSH
• adenosintrifosfatasy genetika   MeSH
• anaplastická lymfomová kináza genetika   MeSH
• anaplastický velkobuněčný lymfom * genetika   patologie   MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• proteiny buněčného cyklu genetika   MeSH
• receptory antigenů T-buněk genetika   MeSH
• transkripční faktory genetika   MeSH
• translokace genetická MeSH
• tyrosinkinasové receptory genetika   MeSH
• tyrosinkinasy genetika   MeSH
• ubikvitinligasy * MeSH
• vazebné proteiny DNA v oblastech připojení k matrix * MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland carcinoma with a generally indolent behavior, characterized by recurrent chromosomal translocation involving EWSR1 (22q12.2) leading to two fusion genes EWSR1::ATF1 or EWSR1::CREM. We report one case of HCCC with a novel SMARCA2::CREM fusion, identified by targeted RNA next generation sequencing by LD-RT-PCR, which has until now never been described in salivary glands. The exon 4 of SMARCA2 is fused to exon 5 of CREM. This fusion has been described previously in only one tumor, a central nervous system tumor (intracranial mesenchymal tumor) but not in other FET::CREB fused tumors. This fusion was confirmed by CREM break-apart FISH and reverse transcriptase polymerase chain reaction (RT-PCR). The tumor cells showed retained expression of INI1, SMARCA2, and SMARCA4 by immunohistochemistry. We compare its clinical, histopathological, immunophenotypic, genetic features with those previously described in HCCC, FET::CREB fusion-positive. Our results added data suggesting that different histomolecular tumor subtypes seem to be included within the terminology "HCCC, FET::CREB fusion-positive," and that further series of cases are needed to better characterize them.

• MeSH
• DNA-helikasy genetika   MeSH
• exony MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• karcinom * genetika   MeSH
• lidé MeSH
• modulátor elementu responzivního pro cyklický AMP genetika   metabolismus   MeSH
• nádory slinných žláz * genetika   patologie   MeSH
• protein EWS vázající RNA genetika   MeSH
• slinné žlázy metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• translokace genetická MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

PURPOSE: We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010. PATIENTS AND METHODS: Data were retrospectively retrieved from 629 patients with 11q23/KMT2A-rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes. RESULTS: A specific 11q23/KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21_22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/KMT2A-rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/KMT2A-rearranged T-ALL (n = 16 v 10; P = .69). CONCLUSION: Compared with historical data, prognosis of patients with noninfant 11q23/KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.

• MeSH
• akutní lymfatická leukemie * terapie   MeSH
• biologické přípravky * MeSH
• lidé MeSH
• lidské chromozomy, pár 11 MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk * MeSH
• prognóza MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• reziduální nádor genetika   MeSH
• translokace genetická MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

AIMS: Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumours consistent with clear cell RCC that contain focal psammomatous calcifications. METHODS AND RESULTS: We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in-situ hybridisation (FISH and RNA ISH). Twenty-one tumours were identified: 12 men, nine women, aged 45-83 years. Tumour size was 2.3-14.0 cm (median = 6.75 cm). Nucleolar grade was 3 (n = 14), 2 (n = 4) or 4 (n = 3). In addition to clear cell pattern, morphology included eosinophilic (n = 12), syncytial giant cell (n = 4), rhabdoid (n = 2), branched glandular (n = 1), early spindle cell (n = 1) and poorly differentiated components (n = 1). Labelling for CA9 was usually 80-100% of the tumour cells (n = 17 of 21), but was sometimes decreased in areas of eosinophilic cells (n = 4). All (19 of 19) were positive for CD10. Most (19 of 20) were positive for AMACR (variable staining = 20-100%). Staining was negative for keratin 7, although four showed rare positive cells (four of 20). Results were negative for cathepsin K (none of 19), melan A (none of 17), HMB45 (none of 17), TFE3 (none of 5), TRIM63 RNA ISH (none of 13), and TFE3 (none of 19) and TFEB rearrangements (none of 12). Seven of 19 (37%) showed chromosome 3p deletion. One (one of 19) showed trisomy 7 and 17 without papillary features. CONCLUSIONS: Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.

• MeSH
• chromozomální aberace MeSH
• kalcinóza * MeSH
• karcinom z renálních buněk * patologie   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory ledvin * patologie   MeSH
• transkripční faktory BHLH-Zip genetika   MeSH
• translokace genetická MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

In baker's yeast (Saccharomyces cerevisiae), Trk1, a member of the superfamily of K-transporters (SKT), is the main K+ uptake system under conditions when its concentration in the environment is low. Structurally, Trk1 is made up of four domains, each similar and homologous to a K-channel α subunit. Because most K-channels are proteins containing four channel-building α subunits, Trk1 could be functional as a monomer. However, related SKT proteins TrkH and KtrB were crystallised as dimers, and for Trk1, a tetrameric arrangement has been proposed based on molecular modelling. Here, based on Bimolecular Fluorescence Complementation experiments and single-molecule fluorescence microscopy combined with molecular modelling; we provide evidence that Trk1 can exist in the yeast plasma membrane as a monomer as well as a dimer. The association of monomers to dimers is regulated by the K+ concentration.

• MeSH
• biologický transport MeSH
• buněčná membrána metabolismus   MeSH
• draslík metabolismus   MeSH
• fungální proteiny metabolismus   MeSH
• proteiny přenášející kationty * genetika   metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny * genetika   metabolismus   MeSH
• Saccharomyces cerevisiae metabolismus   MeSH
• translokace genetická MeSH
• transportní proteiny metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• akutní lymfatická leukemie farmakoterapie   genetika   patologie   MeSH
• akutní nemoc MeSH
• buněčný rodokmen genetika   MeSH
• genová přestavba MeSH
• histonlysin-N-methyltransferasa genetika   MeSH
• indukční chemoterapie metody   MeSH
• kineziny genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 11 genetika   MeSH
• lidské chromozomy, pár 6 genetika   MeSH
• malování chromozomů metody   MeSH
• mladiství MeSH
• myeloidní leukemie genetika   patologie   MeSH
• myosiny genetika   MeSH
• protoonkogenní protein MLL genetika   MeSH
• translokace genetická * MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is an emerging entity in renal neoplasia with distinctive histopathological findings and a generally favorable prognosis. The presence of melanin pigment in a renal tumor typically prompts the observer to consider the microphthalmia-associated transcription family translocation renal cell carcinomas. We present a renal tumor occurring in a 19-year-old male patient which had the typical morphology of ESC-RCC but showed the additional finding of focal melanin pigment. This tumor showed strong and diffuse positive immunolabeling with paired box gene 8 and cytokeratin 20, and was negative with epithelial membrane antigen, carbonic anhydrase 9, CD117, cytokeratin 7, and transcription factor E3. Human melanoma black-45 showed focal positivity, but Melan-A was negative. Next-generation sequencing revealed a mutation in the TSC2 gene (c.4490C > G, p.[Pro1497Arg] and c.1257 + 1del) and break apart fluorescence in-situ hybridization with TFE3 and TFEB probes was negative. In this case report, we present the novel finding of melanin pigment occurring in a genetically proven and otherwise typical ESC-RCC, and briefly discuss the differential diagnostic considerations.

• MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• karcinom z renálních buněk * diagnóza   genetika   patologie   MeSH
• lidé MeSH
• melaniny MeSH
• mladý dospělý MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• nádory ledvin * diagnóza   genetika   patologie   MeSH
• translokace genetická MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• Klíčová slova
• asciminib,
• MeSH
• aplikace orální MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• filadelfský chromozom účinky léků   MeSH
• hypertenze etiologie   MeSH
• kontraindikace MeSH
• lékové interakce MeSH
• lidé MeSH
• niacinamid aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• pyrazoly farmakologie   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• srdeční arytmie etiologie   MeSH
• Check Tag
• lidé MeSH