Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n = 44, cerebrospinal fluid n = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.

• Keywords
• CSF sampling site, Droplet digital PCR, Glioma, Liquid biopsy, Longitudinal monitoring, Targeted therapy,
• MeSH
• Circulating Tumor DNA cerebrospinal fluid   genetics   MeSH
• Child MeSH
• Adult MeSH
• Glioma * genetics   pathology   diagnosis   MeSH
• Histones * genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   cerebrospinal fluid   MeSH
• Brain Neoplasms * genetics   diagnosis   pathology   MeSH
• Child, Preschool MeSH
• Proto-Oncogene Proteins B-raf * genetics   MeSH
• Liquid Biopsy methods   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• Circulating Tumor DNA MeSH
• H3-3A protein, human MeSH Browser
• Histones * MeSH
• Biomarkers, Tumor * MeSH
• Proto-Oncogene Proteins B-raf * MeSH

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

• MeSH
• Antineoplastic Agents, Alkylating therapeutic use   pharmacokinetics   MeSH
• Chemoradiotherapy * methods   MeSH
• Disulfiram * therapeutic use   pharmacokinetics   administration & dosage   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Glioblastoma * radiotherapy   genetics   mortality   therapy   drug therapy   MeSH
• Isocitrate Dehydrogenase genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Copper * blood   therapeutic use   MeSH
• Brain Neoplasms * radiotherapy   mortality   genetics   therapy   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Aged MeSH
• Temozolomide * therapeutic use   pharmacokinetics   administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Names of Substances
• Antineoplastic Agents, Alkylating MeSH
• Disulfiram * MeSH
• Isocitrate Dehydrogenase MeSH
• Copper * MeSH
• Proto-Oncogene Proteins B-raf MeSH
• Temozolomide * MeSH

The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.

• Keywords
• DUSP6, ERK, MAP kinase, eIF4F, melanoma,
• MeSH
• Eukaryotic Initiation Factor-4F * metabolism   genetics   MeSH
• Extracellular Signal-Regulated MAP Kinases metabolism   MeSH
• Dual Specificity Phosphatase 6 metabolism   genetics   MeSH
• GTP Phosphohydrolases * metabolism   genetics   MeSH
• Humans MeSH
• MAP Kinase Signaling System * genetics   MeSH
• Melanoma * genetics   metabolism   pathology   MeSH
• Membrane Proteins * metabolism   genetics   MeSH
• Mutation * MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Proto-Oncogene Proteins B-raf * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• DUSP6 protein, human MeSH Browser
• EIF4E protein, human MeSH Browser
• Eukaryotic Initiation Factor-4F * MeSH
• Extracellular Signal-Regulated MAP Kinases MeSH
• Dual Specificity Phosphatase 6 MeSH
• GTP Phosphohydrolases * MeSH
• Membrane Proteins * MeSH
• NRAS protein, human MeSH Browser
• Proto-Oncogene Proteins B-raf * MeSH

BACKGROUND: Melanoma is the most aggressive skin cancer with ability to recur also after early-stage tumor surgery. The aim was to identify early-stage melanoma patients at high risk of recurrence using liquid biopsy, estimating of mutated BRAF ctDNA and the level of tumor marker S100B in plasma. METHODS: Eighty patients were enrolled in the study. BRAF V600E mutation was determined in FFPE tissue and plasma samples using ultrasensitive ddPCR with pre-amplification. The level of S100B was determined in plasma by immunoassay chemiluminescent method. RESULTS: The best prediction of melanoma recurrence after surgery was observed in patients with combined high level of S100B (S100Bhigh) and ctDNA BRAFV600E (BRAFmut) in preoperative (57.1% vs. 12.5%, p = 0.025) as well as postoperative blood samples (83.3% vs. 14.3%, resp., p = 0.001) in comparison with low S100B and BRAF wild-type. Similarly, patients with preoperative and postoperative S100Bhigh and BRAFmut experienced worse prognosis (DFI p = 0.05, OS p = 0.131 and DFI p = 0.001, OS = 0.001, resp.). CONCLUSION: We observed the benefit of the estimation of combination of S100B and ctDNA BRAFmut in peripheral blood for identification of patients at high risk of recurrence and unfavorable prognosis. SIGNIFICANCE: There is still no general consensus on molecular markers for deciding the appropriateness of adjuvant treatment of early-stage melanoma. We have shown for the first time that the combined determination of the ctDNA BRAFmut oncogene (liquid biopsy) and the high level of tumor marker S100B in pre- and postoperative plasma samples can identify patients with the worst prognosis and the highest risk of tumor recurrence. Therefore, modern adjuvant therapy would be appropriate for these patients with resectable melanoma, regardless of disease stage.

• Keywords
• BRAF V600E, S100B, ctDNA, ddPCR, melanoma,
• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * genetics   blood   MeSH
• Melanoma * genetics   blood   pathology   diagnosis   surgery   MeSH
• Mutation * MeSH
• Biomarkers, Tumor * blood   genetics   MeSH
• Skin Neoplasms * blood   genetics   pathology   diagnosis   surgery   MeSH
• Predictive Value of Tests MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins B-raf * genetics   blood   MeSH
• S100 Calcium Binding Protein beta Subunit * blood   genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Liquid Biopsy methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• Biomarkers, Tumor * MeSH
• Proto-Oncogene Proteins B-raf * MeSH
• S100 Calcium Binding Protein beta Subunit * MeSH
• S100B protein, human MeSH Browser

Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers' prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct "non-intestinal" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS. CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

• Keywords
• Claudin 18, Colorectal carcinoma, Cytokeratin 7, Mucin, NGS, SATB2,
• MeSH
• Adult MeSH
• Phenotype MeSH
• Class I Phosphatidylinositol 3-Kinases genetics   metabolism   MeSH
• Immunohistochemistry * MeSH
• Keratin-7 metabolism   genetics   MeSH
• Colorectal Neoplasms * genetics   pathology   metabolism   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-4 genetics   metabolism   MeSH
• Mucin 5AC genetics   metabolism   MeSH
• Mucin-6 genetics   metabolism   MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Transcription Factors MeSH
• Matrix Attachment Region Binding Proteins * genetics   metabolism   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• Class I Phosphatidylinositol 3-Kinases MeSH
• Keratin-7 MeSH
• KRAS protein, human MeSH Browser
• MUC4 protein, human MeSH Browser
• MUC5AC protein, human MeSH Browser
• MUC6 protein, human MeSH Browser
• Mucin-4 MeSH
• Mucin 5AC MeSH
• Mucin-6 MeSH
• Biomarkers, Tumor * MeSH
• PIK3CA protein, human MeSH Browser
• Proto-Oncogene Proteins B-raf MeSH
• Proto-Oncogene Proteins p21(ras) MeSH
• SATB2 protein, human MeSH Browser
• Transcription Factors MeSH
• Matrix Attachment Region Binding Proteins * MeSH

BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

• Keywords
• BRAF-mutant, Binimetinib, Encorafenib, Melanoma,
• MeSH
• Benzimidazoles * administration & dosage   adverse effects   therapeutic use   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Carbamates * administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * drug therapy   genetics   mortality   MeSH
• Young Adult MeSH
• Mutation * MeSH
• Skin Neoplasms drug therapy   genetics   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Proto-Oncogene Proteins B-raf * genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sulfonamides * administration & dosage   adverse effects   MeSH
• Vemurafenib * administration & dosage   adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• binimetinib MeSH Browser
• BRAF protein, human MeSH Browser
• encorafenib MeSH Browser

BACKGROUND AND OBJECTIVES: Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status. METHODS: A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex. RESULTS: Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60-75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89-3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67-3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28-2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72-3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05-2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63-3.42, p = 0.005), respectively. CONCLUSION: In this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non-colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.

• Keywords
• colorectal cancer, non‐colorectal malignancy, sporadic deficient mismatch repair,
• MeSH
• Incidence MeSH
• Colorectal Neoplasms * genetics   pathology   epidemiology   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• MutL Protein Homolog 1 genetics   MeSH
• Follow-Up Studies MeSH
• DNA Mismatch Repair * MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Europe epidemiology   MeSH
• Sweden epidemiology   MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• MLH1 protein, human MeSH Browser
• MutL Protein Homolog 1 MeSH
• Proto-Oncogene Proteins B-raf MeSH

Mutations in cancer-related genes are now known to be accompanied by epigenetic events in carcinogenesis by modification of the regulatory pathways and expression of genes involved in the pathobiology. Such cancer-related mutations, miRNAs and gene expression may be promising molecular markers of the most common papillary thyroid carcinoma (PTC). However, there are limited data on their relationships. The aim of this study was to analyse the interactions between BRAF mutations, selected microRNAs (miR-21, miR-34a, miR-146b, and miR-9) and the expression of selected genes (LGALS3, NKX2-1, TACSTD2, TPO) involved in the pathogenesis of PTC. The study cohort included 60 primary papillary thyroid carcinomas (PTC) that were classified as classical (PTC/C; n=50) and invasive follicular variant (PTC/F; n=10), and 40 paired lymph node metastases (LNM). BRAF mutation status in primary and recurrent/persistent papillary thyroid carcinomas was determined. The mutation results were compared both between primary and metastatic cancer tissue, and between BRAF mutation status and selected genes and miRNA expression in primary PTC. Furthermore, miRNAs and gene expression were compared between primary PTCs and non-neoplastic tissue, and local lymph node metastatic tumor, respectively. All studied markers showed several significant mutual interactions and contexts. In conclusion, to the best our knowledge, this is the first integrated study of BRAF mutational status, the expression levels of mRNAs of selected genes and miRNAs in primary PTC, and paired LNM.

• Keywords
• BRAF, MicroRNA, LGALS3, NKX2-1, Papillary thyroid carcinoma, TACSTD2, TPO,
• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphatic Metastasis * genetics   pathology   MeSH
• MicroRNAs * genetics   MeSH
• Mutation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Thyroid Neoplasms * genetics   pathology   MeSH
• Thyroid Cancer, Papillary * genetics   pathology   MeSH
• Proto-Oncogene Proteins B-raf * genetics   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• MicroRNAs * MeSH
• Biomarkers, Tumor MeSH
• Proto-Oncogene Proteins B-raf * MeSH

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

• Keywords
• BRAF mutation, CDKN2A, NTRK‐rearranged spindle cell neoplasms, entrectinib, infantile fibrosarcoma, kinase gene fusion, larotrectinib, methylation profiling, selpercatinib,
• MeSH
• Child MeSH
• Adult MeSH
• Fibrosarcoma * genetics   pathology   MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local genetics   MeSH
• Biomarkers, Tumor genetics   analysis   MeSH
• Soft Tissue Neoplasms * genetics   MeSH
• Neoplasms, Connective and Soft Tissue * MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Receptor, trkA genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• Biomarkers, Tumor MeSH
• Proto-Oncogene Proteins B-raf MeSH
• Receptor, trkA MeSH

Hairy cell leukemia (HCL) and HCL-like disorders have to be distinguished because of their different biology and treatment response. Thus, we conducted a retrospective study on patients with HCL and hairy cell leukemia variant (HCLv) to assess diagnostic algorithms and treatment outcomes in a real-world setting. We analyzed 225 HCL and 26 HCLv patients with median follow-up of 67.9 months (HCL) and 20.1 months (HCLv). Median age at diagnosis was 56.2 (HCL) and 69.5 years (HCLv), male predominance was observed in both groups (76.0% vs. 73.1%). Diagnostics was mostly based on morphological evidence of hairy cells in the peripheral blood and bone marrow. At diagnosis, BRAF V600E mutation was detected in 94.7% of examined HCL patients and in no HCLv patient. Front-line treatment was indicated in 205 (91.1%) HCL and 18 (69.2%) HCLv patients. The majority of HCL patients were administered a cladribine-based regimen (91.2%). Overall response rate (ORR) was higher in cladribine-treated patients compared to those given other treatments (97.7% vs. 81.3%), the same applied with achieving Complete remission (CR) (91.2% vs. 62.5%). HCLv treatment was heterogeneous, but cladribine remained the most frequent option (44.4%) with ORR 81.3% and CR rates 43.8%. Second-line treatment was indicated in 52 HCL and 8 HCLv patients, 25.4% and 44.4% of those treated in first-line. In the whole HCL group, median time to next treatment (TTNT) was not reached and 10-year TTNT was estimated at 74.1%. HCLv patients who underwent first-line treatment had a median TTNT of 56 months. The median overall survival (OS) in HCL patients was not reached compared to HCLv with a median OS of 9.5 years. These data confirm an excellent prognosis for HCL patients treated with cladribine-based therapy. On the contrary, HCLv with its aggressive behavior represents a group of patients in whom novel treatment approaches are needed.

• Keywords
• BRAF V600Emutation, cladribine, hairy cell leukemia, hairy cell leukemia variant, overall survival, time to next treatment,
• MeSH
• Adult MeSH
• Cladribine therapeutic use   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Leukemia, Hairy Cell * diagnosis   drug therapy   pathology   mortality   therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cladribine MeSH
• Proto-Oncogene Proteins B-raf MeSH