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Background: GATA3 is pivotal for the development of T lymphocytes. While its effects in later stages of T cell differentiation are well recognized, the role of GATA3 in the generation of early T cell precursors (ETP) has only recently been explored. As aberrant GATA3 mRNA expression has been linked to cancerogenesis, we investigated the role of GATA3 in early T cell precursor acute lymphoblastic leukemia (ETP-ALL). Methods: We analyzed GATA3 mRNA expression by RT-PCR (n = 182) in adult patients with T-ALL. Of these, we identified 70 of 182 patients with ETP-ALL by immunophenotyping. DNA methylation was assessed genome wide (Illumina Infinium® HumanMethylation450 BeadChip platform) in 12 patients and GATA3-specifically by pyrosequencing in 70 patients with ETP-ALL. The mutational landscape of ETP-ALL with respect to GATA3 expression was investigated in 18 patients and validated by Sanger sequencing in 65 patients with ETP-ALL. Gene expression profiles (Affymetrix Human genome U133 Plus 2.0) of an independent cohort of adult T-ALL (n = 83) were used to identify ETP-ALL and investigate GATA3low and GATA3high expressing T-ALL patients. In addition, the ETP-ALL cell line PER-117 was investigated for cytotoxicity, apoptosis, GATA3 mRNA expression, DNA methylation, and global gene expression before and after treatment with decitabine. Results: In our cohort of 70 ETP-ALL patients, 33% (23/70) lacked GATA3 expression and were thus defined as GATA3low. DNA methylation analysis revealed a high degree of GATA3 CpG island methylation in GATA3low compared with GATA3high ETP-ALL patients (mean 46 vs. 21%, p < 0.0001). Genome-wide expression profiling of GATA3low ETP-ALL exhibited enrichment of myeloid/lymphoid progenitor (MLP) and granulocyte/monocyte progenitor (GMP) genes, while T cell-specific signatures were downregulated compared to GATA3high ETP-ALL. Among others, FLT3 expression was upregulated and mutational analyses demonstrated a high rate (79%) of FLT3 mutations. Hypomethylating agents induced reversal of GATA3 silencing, and gene expression profiling revealed downregulation of hematopoietic stem cell genes and upregulation of T cell differentiation. Conclusions: We propose GATA3low ETP-ALL as a novel stem cell-like leukemia with implications for the use of myeloid-derived therapies. [ABSTRACT FROM AUTHOR]

Prognosis is poor for patients with biologically aggressive Non-Hodgkin lymphoma (NHL), refractory to chemotherapy or relapsed after autologous transplantation, especially when no disease control before allogeneic transplantation is achieved. In 16 patients (median age 53, median prior regimes 5) with relapsed or refractory non-remission NHL, we analysed retrospectively the efficacy of a sequential therapy comprising clofarabine re-induction followed by a reduced-intensity conditioning with fludarabine, CY and melphalan, and T-cell-replete HLA-haploidentical transplantation. High-dose CY was utilized post-transplantation. All patients engrafted. Early response (day +30) was achieved in 94%. Treatment-related grade III-IV toxicity occurred in 56%, most commonly transient elevation of transaminases (36%), while there was a low incidence of infections (19% CMV reactivation, 19% invasive fungal infection) and GVHD (GVHD: acute III-IV: 6%; mild chronic: 25%). One-year non-relapse mortality was 19%. After a median follow-up of 21 months, estimated 1- and 2-year PFS was 56 and 50%, respectively, with 11 patients (69%) still alive after 2 years. In summary, sequential therapy is feasible and effective and provides an acceptable toxicity profile in high-risk non-remission NHL. Presumably, cytotoxic reinduction with clofarabine provides enough remission time for the graft-versus lymphoma effect of HLA-haploidentical transplantation to kick in, even in lymphomas that are otherwise chemo-refractory. [ABSTRACT FROM AUTHOR]

In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK-2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9+/FLT3-ITD+ xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9+ and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9+ samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K-targeted therapies in AML. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study correlation of 5-hydroxymethylcytosine (5mC) to ten-eleven translocation 2 (TET2) gene mutations in secondary acute myeloid leukemia (AML) patients.

Molecular characterization of acute lymphoblastic leukemia (ALL) has greatly improved the ability to categorize and prognostify patients with this disease. In this study, we show that the proto-oncogene CDX2 is aberrantly expressed in the majority of cases with B-lineage ALL and T-ALL. High expression of CDX2 correlated significantly with the ALL subtype pro-B ALL, cALL, Ph(+) ALL and early T-ALL. Furthermore, high expression of CDX2 was associated with inferior overall survival and showed up as a novel and strong risk factor for ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in adult patients with ALL. [ABSTRACT FROM AUTHOR]

Abstract: Cold spray (CS) technology is a recent development for producing dense, oxide-free metallic and cermet coatings with attributes not achievable by established atmospheric thermal spray (TS) techniques. Little or no thermal component (i.e. high temperature) is introduced in the CS process; deposit formation relies mainly on dynamic compaction as particles impact the substrate. In this paper, we discuss and evaluate the relationships between the microstructure, properties and residual stresses in CS Al coatings, combining indentation, dilatometry, resistivity measurements and neutron diffraction techniques. In addition, we provide mechanistic arguments for the evolution of such characteristics with post-deposit annealing. [Copyright &y& Elsevier]

Abstract: Residual stresses in gas pipelines come from forming operations in producing the coil and pipe, seam welding the pipe, and girth welding pipes together to form a gas pipeline. Welding is used extensively in gas pipelines, the welds are made without post weld heat treatment. The three normal stresses were measured by neutron diffraction for three types of sample: coil, unwelded rings cut from the pipe made from this coil, and girth welded rings cut from linepipe. All three specimens came from three thicknesses of manufacture (5.4, 6.4, and 7.1mm). The welds are manual metal arc cellulosic electrode welds made in X70 linepipe, these were measured at 5 through-thickness positions at 19 locations (from the center of the weld up to 35mm away from the weld) with a spatial resolution of 1mm3. The coil and unwelded rings were measured at the same five through-thickness positions. [Copyright &y& Elsevier]

Abstract: Cold-drawing is employed to fabricate wires and rods, which are mainly used as structural reinforcements in construction as well as in the tyre industry. As a consequence of processing, a residual stress profile is developed. The wires are subjected to post-drawing thermo-mechanical treatments with the aim of improving their durability and stress relaxation behaviour. It is claimed that they do so by reducing the residual stresses produced by cold-drawing, although no conclusive data have been given. In this paper, residual stress profiles are measured by neutron diffraction in two cold-drawn pearlitic steel rods subjected to a true strain 1.7: “as-drawn” and “stabilized” (thermo-mechanical treatment). The results show that the post-drawing treatment is very successful in reducing the residual stresses produced by drawing, especially in the surface region of the rods. This explains the improvement of the stress relaxation and stress corrosion behaviour observed in the “stabilized” samples. [Copyright &y& Elsevier]

Abstract: This paper presents a multiscale simulation methodology for the study of texture and residual strain development applied to deformation of friction stir welded material and includes a coordinated experimental program for model initialization and verification. Based on elastoviscoplastic polycrystal plasticity implemented in a finite element framework, the simulation methodology involves detailed tracking of selected elements in a relatively coarse macroscopic model followed by highly resolved simulations of the selected elements at the microscopic level. The results are compared with neutron diffraction data obtained by subjecting friction stir welded specimens to a program of in situ loadings and unloadings. The model performs well for three different specimen geometries—both at the macroscopic level in predicting deformed shape, hardness and extension, and at the microscopic level in predicting lattice strain and intensity changes. [Copyright &y& Elsevier]

Abstract: In a simplified composite design, an unalloyed Al matrix was reinforced by spherical Al–Cu–Fe alloy particles (30vol.%), using either commercial purity (99.7%) or high purity (99.99%) fine powders (diameter < 10μm). This composite material was consolidated by either vacuum hot pressing (VHP) or quasi-isostatic forging. The spatial distribution of reinforcement particles in both VHP and forged samples was shown to be almost the same by quantitative characterization with a multi-scale area fraction analysis technique. The tensile properties of all composite samples were tested and the forged materials showed significantly higher strength, while the elastic modulus values of all composite materials were close to the upper bound of theoretical predictions. Neutron diffraction measurements showed that there were high compressive residual stresses in the Al matrix of the forged samples and relatively low Al matrix residual stresses (predominantly compressive) in the VHP samples. By tensile tests and neutron diffraction measurements of the forged samples after annealing, it was shown that the high compressive residual stresses in the Al matrix were relieved and that tensile strength was also reduced to almost the same level as that of the VHP samples. Therefore, it was deduced that increased compressive residual stresses and enhanced dislocation densities in the forged composites raised the tensile strength to higher values than those of the VHP composites. [Copyright &y& Elsevier]

Heterophase interfaces play a crucial role in deformation microstructures and thus govern mechanical properties of multilayered composites. Here, we fabricated Ti/Nb multilayers by accumulative roll bonding (ARB) where shear bands became predominant with increasing rolling cycles. To explore correlation between micromechanical behavior and mechanical properties of the composites with various lamellar morphologies, in-situ high-energy X-ray diffraction tensile tests were performed. The results quantitatively reveal that the rapid strengthening of the composites with increasing ARB cycles mainly originates from the Nb layers strengthened by dislocations, grain boundaries and heterophase interfaces, and the {211} grains mostly contribute to the global strain hardening. The softer Ti grains also extend global strain hardening to a wide range and postpone necking. Furthermore, complete stress state analysis show that in the presence of extensive shear bands, significant load partitioning between the neighboring metals leads to triaxial stresses in each constituent and dislocations tend to slip along the shear direction. This promotes dislocation multiplication and motion, which is conducive to overall strength enhancement while maintaining a satisfactory ductility. These findings elucidate the effect of strong constraints of the interfaces on mechanical properties, which provides a fundamental understanding of load partitioning and strengthening mechanisms of the multilayers processed by multiple ARB cycles. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Objectives: To determine real-life quantitative changes in OCT biomarkers in a large set of treatment naive patients in a real-life setting undergoing anti-VEGF therapy. For this purpose, we devised a novel deep learning based semantic segmentation algorithm providing the first benchmark results for automatic segmentation of 11 OCT features including biomarkers for neovascular age-related macular degeneration (nAMD)., Methods: Training of a Deep U-net based semantic segmentation ensemble algorithm for state-of-the-art semantic segmentation performance which was used to analyze OCT features prior to, after 3 and 12 months of anti-VEGF therapy., Results: High F1 scores of almost 1.0 for neurosensory retina and subretinal fluid on a separate hold-out test set with unseen patients. The algorithm performed worse for subretinal hyperreflective material and fibrovascular PED, on par with drusenoid PED, and better in segmenting fibrosis. In the evaluation of treatment naive OCT scans, significant changes occurred for intraretinal fluid (mean: 0.03 µm 3 to 0.01 µm 3 , p < 0.001), subretinal fluid (0.08 µm 3 to 0.01 µm 3 , p < 0.001), subretinal hyperreflective material (0.02 µm 3 to 0.01 µm 3 , p < 0.001), fibrovascular PED (0.12 µm 3 to 0.09 µm 3 , p = 0.02) and central retinal thickness C0 (225.78 µm 3 to 169.40 µm 3 ). The amounts of intraretinal fluid, fibrovascular PED, and ERM were predictive of poor outcome., Conclusions: The segmentation algorithm allows efficient volumetric analysis of OCT scans. Anti-VEGF provokes most potent changes in the first 3 months while a gradual loss of RPE hints at a progressing decline of visual acuity. Additional research is required to understand how these accurate OCT predictions can be leveraged for a personalized therapy regimen., (© 2024. The Author(s).)

Assignment of patients diagnosed with acute myeloid leukemia (AML) to the 2022 European LeukemiaNet (ELN) favorable genetic risk group has important clinical implications, as allogeneic stem cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients receiving chemotherapy alone and transplant-associated mortality. However, not all favorable genetic risk patients experience long-term relapse-free survival (RFS), making recognition of patients who would most likely be cured of high importance. We analyzed 297 patients aged <60 years with de novo AML classified as 2022 ELN favorable genetic risk who achieved a CR and had RNA sequencing (RNA-seq) and gene mutation data from diagnostic samples available (Alliance trial A152010). To identify prognostically relevant transcripts that can distinguish patients cured from patients susceptible to lower or higher risk of relapse or death, we fit a regularized mixture cure model (MCM) where RNA-seq expression values were our candidate covariates. To validate the identified transcripts, we analyzed 75 patients with de novo AML aged <60 years included in the 2022 ELN favorable genetic risk group who achieved a CR in an independent test set from Gene Expression Omnibus (GSE37642). Our MCM identified 145 transcripts associated with cure or long-term RFS and 149 transcripts associated with latency or shorter-term time to relapse. The area under the curve and C-statistic were, respectively, 0.946 and 0.856 for our training set and 0.877 and 0.857 for our test set. Our results suggest that the favorable risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this genetic risk category., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Predictive modeling based on multi-omics data, which incorporates several types of omics data for the same patients, has shown potential to outperform single-omics predictive modeling. Most research in this domain focuses on incorporating numerous data types, despite the complexity and cost of acquiring them. The prevailing assumption is that increasing the number of data types necessarily improves predictive performance. However, the integration of less informative or redundant data types could potentially hinder this performance. Therefore, identifying the most effective combinations of omics data types that enhance predictive performance is critical for cost-effective and accurate predictions., Methods: In this study, we systematically evaluated the predictive performance of all 31 possible combinations including at least one of five genomic data types (mRNA, miRNA, methylation, DNAseq, and copy number variation) using 14 cancer datasets with right-censored survival outcomes, publicly available from the TCGA database. We employed various prediction methods and up-weighted clinical data in every model to leverage their predictive importance. Harrell's C-index and the integrated Brier Score were used as performance measures. To assess the robustness of our findings, we performed a bootstrap analysis at the level of the included datasets. Statistical testing was conducted for key results, limiting the number of tests to ensure a low risk of false positives., Results: Contrary to expectations, we found that using only mRNA data or a combination of mRNA and miRNA data was sufficient for most cancer types. For some cancer types, the additional inclusion of methylation data led to improved prediction results. Far from enhancing performance, the introduction of more data types most often resulted in a decline in performance, which varied between the two performance measures., Conclusions: Our findings challenge the prevailing notion that combining multiple omics data types in multi-omics survival prediction improves predictive performance. Thus, the widespread approach in multi-omics prediction of incorporating as many data types as possible should be reconsidered to avoid suboptimal prediction results and unnecessary expenditure., (© 2024. The Author(s).)

Relapse and regimen-related toxicities remain major challenges in achieving long-term survival, particularly among older patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated the feasibility of treosulfan-based conditioning, noting stable engraftment and low non-relapse mortality (NRM) in patients undergoing HLA-matched allo-HSCT. However, data on treosulfan-based conditioning in the HLA-haploidentical transplantation (HaploT) setting are limited. We retrospectively compared conditioning with fludarabine-cyclophosphamide (FC)-melphalan (110 mg/m 2 ) and FC-treosulfan (30 g/m 2 ) prior to HaploT using post-transplantation cyclophosphamide (PTCy) in patients with high-risk MDS/AML patients ≥ 50 years, transplanted from 2009-2021 at our institution ( n = 80). After balancing patient characteristics by a matched-pair analysis, we identified twenty-one matched pairs. Two-year OS and LFS were similar among the groups (OS 66% and LFS 66%, p = 0.8 and p = 0.57). However, FC-melphalan was associated with a significantly lower probability of relapse compared to FC-treosulfan (0% vs. 24%, p = 0.006), counterbalanced by a higher NRM (33% vs. 10%, p = 0.05). Time to engraftment and incidences of acute and chronic graft-versus-host disease (GvHD) did not differ significantly. In conclusion, HaploT using FC-treosulfan in combination with PTCy in patients aged ≥50 years with MDS/AML appears safe and effective, particularly in advanced disease stages. We confirm the favorable extramedullary toxicity profile, allowing for potential dose intensification to enhance antileukemic activity.

Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has established the precision oncology paradigm in lung cancer. Most patients with EGFR -mutated lung cancer respond but eventually acquire resistance. Methods: Patients exhibiting the EGFR p.T790M resistance biomarker benefit from sequenced targeted therapy with osimertinib. We hypothesized that metabolic response as detected by 18 F-FDG PET after short-course osimertinib identifies additional patients susceptible to sequenced therapy. Results: Fourteen patients with EGFR -mutated lung cancer and resistance to first- or second-generation EGFR TKI testing negatively for EGFR p.T790M were enrolled in a phase II study. Five patients (36%) achieved a metabolic 18 F-FDG PET response and continued osimertinib. In those, the median duration of treatment was not reached (95% CI, 24 mo to not estimable), median progression-free survival was 18.7 mo (95% CI, 14.6 mo to not estimable), and median overall survival was 41.5 mo. Conclusion: Connecting theranostic osimertinib treatment with early metabolic response assessment by PET enables early identification of patients with unknown mechanisms of TKI resistance who derive dramatic clinical benefit from sequenced osimertinib. This defines a novel paradigm for personalization of targeted therapies in patients with lung cancer dependent on a tractable driver oncogene., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP InDel ), frameshift InDel or nonsense mutations inducing translational stop (bZIP STOP ) or single base-pair missense alterations (bZIP ms ), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP InDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIP InDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP InDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP ms )., (© 2024. The Author(s).)

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients' sex in analyses of AML biology and prognostication., (© 2023. The Author(s).)

Diffraction elastic constants (DEC) describe the elastic response of a sub-set of orientation correlated grains which share a common lattice vector. DEC reflect the elastic behaviour of the single crystal constituents through their dependence on grain orientation. DEC furthermore depend on the behaviour of the polycrystal aggregate both through the dependence on preferred orientation and through the average elastic interaction of the grains in the sub-set with their surroundings. The latter is also known as grain-matrix interaction which is grain shape dependent. Both dependencies can make the DEC uniquely sensitive to the elastic effects of the grain shape, texture, and phase composition. Several micro-mechanical models are explored with respect for use both in calculating diffraction elastic constants and overall elastic constants. Furthermore, it is shown how discrete data from electron backscatter diffraction on grain shape, grain orientations, and neighbouring grains can be used for DEC calculations. Lastly, the inverse problem of calculating single crystal elastic constants from DEC is discussed in detail. All calculations discussed in this work can be verified using the freely available computer program IsoDEC.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The onset of radioiodine-refractory thyroid carcinoma (RR-TC) is a negative predictor of survival and has been linked to the presence of BRAF V600E mutations in papillary thyroid cancer. We aimed to identify further genetic alterations associated with RR-TC. Methods: We included 38 patients with papillary thyroid cancer who underwent radioiodine imaging and 18 F-FDG PET/CT after total thyroidectomy. The molecular profile was assessed by next-generation sequencing. The time to the onset of RR-TC for different genetic alterations was compared using the log-rank test. Results: The median onset to RR-TC was 0.7 and 19.8 mo in patients with and without, respectively, telomerase reverse transcriptase promoter mutations ( P = 0.02) and 1.7 and 19.8 mo in patients with and without, respectively, a tumor protein 53 mutation ( P < 0.01). This association was not observed for BRAF V600E mutations ( P = 0.49). Conclusion: Our data show a significant association between the onset of RR-TC and mutations in telomerase reverse transcriptase promoter and tumor protein 53, indicating the need for a more extensive diagnostic workup in these patients. Certain genetic changes put patients with thyroid cancer at risk of developing cancer spread that does not respond to radioiodine therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Patients with BRAF V600E -mutant metastatic colorectal cancer (mCRC) have a dismal prognosis. The best strategies in these patients remain elusive. Against this background, we report the clinical course of patients with BRAF V600E -mutant mCRC to retrieve the best treatment strategy., Patients and Methods: Clinico-pathological data were extracted from the electronic health records. Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Objective response rate (ORR) was assessed according to RECIST 1.1., Results: In total, 51 patients were enrolled. FOLFOXIRI was administered to 12 patients; 29 patients received FOLFOX or FOLFIRI as first-line treatment. Median OS was 17.6 months. Median PFS with FOLFOXIRI (13.0 months) was significantly prolonged (HR 0.325) as compared to FOLFOX/FOLFIRI (4.3 months). However, this failed to translate into an OS benefit (p = 0.433). Interestingly, addition of a monoclonal antibody to chemotherapy associated with superior OS (HR 0.523). A total of 64.7% patients received further-line therapy, which included a BRAF inhibitor in 17 patients. Targeted therapy associated with very favourable OS (25.1 months)., Conclusion: Patients with BRAF V600E -mutated mCRC benefit from the addition of an antibody to first-line chemotherapy. Further-line treatment including a BRAF inhibitor has a dramatic impact on survival., (© 2023. The Author(s).)

Activating colony-stimulating factor-3 receptor gene ( CSF3R ) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21-80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21-45). Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated lung cancer is limited by acquired resistance. In half of the patients treated with first/second-generation (1st/2nd gen) TKI, resistance is associated with EGFR p.T790M mutation. Sequential treatment with osimertinib is highly active in such patients. Currently, there is no approved targeted second-line option for patients receiving first-line osimertinib, which thus may not be the best choice for all patients. The present study aimed to evaluate the feasibility and efficacy of a sequential TKI treatment with 1st/2nd gen TKI, followed by osimertinib in a real-world setting., Methods: Patients with EGFR-mutated lung cancer treated at two major comprehensive cancer centers were retrospectively analyzed by the Kaplan-Meier method and log rank test., Results: A cohort of 150 patients, of which 133 received first-line treatment with a first/second gen EGFR TKI, and 17 received first-line osimertinib, was included. Median age was 63.9 years, 55% had ECOG performance score of ≥ 1. First-line osimertinib was associated with prolonged progression-free survival (P = 0.038). Since the approval of osimertinib (February 2016), 91 patients were under treatment with a 1st/2nd gen TKI. Median overall survival (OS) of this cohort was 39.3 months. At data cutoff, 87% had progressed. Of those, 92% underwent new biomarker analyses, revealing EGFR p.T790M in 51%. Overall, 91% of progressing patients received second-line therapy, which was osimertinib in 46%. Median OS with sequenced osimertinib was 50 months. Median OS of patients with p.T790M-negative progression was 23.4 months., Conclusion: Real-world survival outcomes of patients with EGFR-mutated lung cancer may be superior with a sequenced TKI strategy. Predictors of p.T790M-associated resistance are needed to personalize first-line treatment decisions., (© 2023. The Author(s).)