Sirolimus Is an Acceptable Alternative to Tacrolimus for Graft-versus-Host Disease Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide.

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT.

Proteomic analysis of chromophobe renal cell carcinoma and benign renal oncocytoma biopsies reveals shared metabolic dysregulation.

BACKGROUND: This study investigates the proteomic landscapes of chromophobe renal cell carcinoma (chRCC) and renal oncocytomas (RO), two subtypes of renal cell carcinoma that together account for approximately 10% of all renal tumors. Despite their histological similarities and shared origins, chRCC is a malignant tumor necessitating aggressive intervention, while RO, a benign growth, is often subject to overtreatment due to difficulties in accurate differentiation. METHODS: We conducted a label-free quantitative proteomic analysis on solid biopsies of chRCC (n = 5), RO (n = 5), and normal adjacent tissue (NAT, n = 5). The quantitative analysis was carried out by comparing protein abundances between tumor and NAT specimens. Our analysis identified a total of 1610 proteins across all samples, with 1379 (85.7%) of these proteins quantified in at least seven out of ten LC‒MS/MS runs for one renal tissue type (chRCC, RO, or NAT). RESULTS: Our findings revealed significant similarities in the dysregulation of key metabolic pathways, including carbohydrate, lipid, and amino acid metabolism, in both chRCC and RO. Compared to NAT, both chRCC and RO showed a marked downregulation in gluconeogenesis proteins, but a significant upregulation of proteins integral to the citrate cycle. Interestingly, we observed a distinct divergence in the oxidative phosphorylation pathway, with RO showing a significant increase in the number and degree of alterations in proteins, surpassing that observed in chRCC. CONCLUSIONS: This study underscores the value of integrating high-resolution mass spectrometry protein quantification to effectively characterize and differentiate the proteomic landscapes of solid tumor biopsies diagnosed as chRCC and RO. The insights gained from this research offer valuable information for enhancing our understanding of these conditions and may aid in the development of improved diagnostic and therapeutic strategies.

Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis.

BACKGROUND: Obesity (body mass index [BMI] ≥30 kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. METHODS: The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). RESULTS: Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90 mg/m2 ) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p = .14). CONCLUSIONS: Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.

PanDrugs2: prioritizing cancer therapies using integrated individual multi-omics data.

Genomics studies routinely confront researchers with long lists of tumor alterations detected in patients. Such lists are difficult to interpret since only a minority of the alterations are relevant biomarkers for diagnosis and for designing therapeutic strategies. PanDrugs is a methodology that facilitates the interpretation of tumor molecular alterations and guides the selection of personalized treatments. To do so, PanDrugs scores gene actionability and drug feasibility to provide a prioritized evidence-based list of drugs. Here, we introduce PanDrugs2, a major upgrade of PanDrugs that, in addition to somatic variant analysis, supports a new integrated multi-omics analysis which simultaneously combines somatic and germline variants, copy number variation and gene expression data. Moreover, PanDrugs2 now considers cancer genetic dependencies to extend tumor vulnerabilities providing therapeutic options for untargetable genes. Importantly, a novel intuitive report to support clinical decision-making is generated. PanDrugs database has been updated, integrating 23 primary sources that support >74K drug-gene associations obtained from 4642 genes and 14 659 unique compounds. The database has also been reimplemented to allow semi-automatic updates to facilitate maintenance and release of future versions. PanDrugs2 does not require login and is freely available at https://www.pandrugs.org/.

Negative Samples for Improving Object Detection-A Case Study in AI-Assisted Colonoscopy for Polyp Detection.

Deep learning object-detection models are being successfully applied to develop computer-aided diagnosis systems for aiding polyp detection during colonoscopies. Here, we evidence the need to include negative samples for both (i) reducing false positives during the polyp-finding phase, by including images with artifacts that may confuse the detection models (e.g., medical instruments, water jets, feces, blood, excessive proximity of the camera to the colon wall, blurred images, etc.) that are usually not included in model development datasets, and (ii) correctly estimating a more realistic performance of the models. By retraining our previously developed YOLOv3-based detection model with a dataset that includes 15% of additional not-polyp images with a variety of artifacts, we were able to generally improve its F1 performance in our internal test datasets (from an average F1 of 0.869 to 0.893), which now include such type of images, as well as in four public datasets that include not-polyp images (from an average F1 of 0.695 to 0.722).

Pathway-guided monitoring of the disease course in bladder cancer with longitudinal urine proteomics.

BACKGROUND: Monitoring bladder cancer over time requires invasive and costly procedures. Less invasive approaches are required using readily available biological samples such as urine. In this study, we demonstrate a method for longitudinal analysis of the urine proteome to monitor the disease course in patients with bladder cancer. METHODS: We compared the urine proteomes of patients who experienced recurrence and/or progression (n = 13) with those who did not (n = 17). We identified differentially expressed proteins within various pathways related to the hallmarks of cancer. The variation of such pathways during the disease course was determined using our differential personal pathway index (dPPi) calculation, which could indicate disease progression and the need for medical intervention. RESULTS: Seven hallmark pathways are used to develop the dPPi. We demonstrate that we can successfully longitudinally monitor the disease course in bladder cancer patients through a combination of urine proteomic analysis and the dPPi calculation, over a period of 62 months. CONCLUSIONS: Using the information contained in the patient's urinary proteome, the dPPi reflects the individual's course of bladder cancer, and helps to optimise the use of more invasive procedures such as cystoscopy.

Bladder cancer must be closely monitored for progression, but this requires expensive and invasive procedures such as cystoscopy. Less invasive procedures using readily available samples such as urine are needed. Here, we present an approach that measures the levels of various proteins in the urine. We compare protein levels at different points during the disease course in patients with bladder cancer, and show this helps to flag disease recurrence and the need for medical intervention. Our approach could help clinicians to determine which patients require more invasive testing and treatment.

DNA polymerase θ protects leukemia cells from metabolically induced DNA damage.

Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK-dependent nonhomologous end-joining, was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.

Efecto de la deforestación ribereña sobre la materia orgánica particulada gruesa en quebradas con influencia ganadera de la región Andina de Colombia / Effect of riparian deforestation on coarse particulate organic matter in streams with livestock influence in the Andean region of Colombia

Introducción: La materia orgánica particulada gruesa originada en la vegetación ribereña es la fuente principal de energía en muchas cuencas de cabecera. Sin embargo, la transferencia de dicha materia es alterada por la destrucción de los bosques. Objetivo: Evaluar diferencias en la materia orgánica en quebradas con bosques y con pastizales. Métodos: Comparar las entradas, el almacenamiento y la exportación de esta materia orgánica en el cauce de quebradas con bosques y con pastizales, en la región central de los Andes de Colombia. En cada quebrada, se midieron los aportes verticales y laterales de hojarasca con canastas; hojarasca del lecho de las quebradas con cuadrantes, y la exportación de material con redes de deriva, con un alcance de 100 m. Resultados: Las quebradas con bosques ribereños recibieron un promedio anual de 915 g m-2 de materia orgánica particulada gruesa, exportando un total de 334 g m-3 y almacenando 732 g m-2, valores que fueron significativamente más altos que en quebradas con pastizales, donde los valores correspondientes fueron: 125.4 g m-2; 128 g m-3 y 205.5 g m-2. Conclusiones: La remoción de cobertura boscosa de la zona ribereña reduce la materia orgánica en estas cuencas de cabecera en Colombia.

Introduction: Coarse particulate organic matter originated in riparian vegetation is the main source of energy in many headwater streams. However, the transfer of such material is altered by the destruction of forests. Objective: To assess flow differences of this organic matter in streams with forests and grasslands. Methods: We compared input, storage and export of this organic matter in the riparian belts of streams with forests, and streams with grasslands, in the central Andean region of Colombia. For each stream, we measured vertical and lateral litter with baskets; stream bed litter with a quadrant, and matter export with drift nets, in a 100 m reach. Results: The streams with riparian forest received an average of 915 g m-2 of coarse particulate organic matter annually, exported a total of 334 g m-3 and stored 732 g m-2, values that were significantly higher than in grassland streams, where the corresponding values were: 125.4 g m-2; 128 g m-3 and 205.5 g m-2. Conclusions: The removal of tree cover from the riparian zone reduced the organic matter in these headwater streams of Colombia.

Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling.

Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0-120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.

Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes.

PURPOSE: Outcomes are poor in TP53-mutant (mTP53) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), even after allogeneic hematopoietic stem-cell transplant (HCT). Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. PATIENTS AND METHODS: We conducted a phase II, multicenter, open-label trial to assess efficacy and safety of eprenetapopt combined with azacitidine as maintenance therapy after HCT (ClinicalTrials.gov identifier: NCT03931291). Patients with mTP53 MDS or AML received up to 12 cycles of eprenetapopt 3.7 g once daily intravenously on days 1-4 and azacitidine 36 mg/m2 once daily intravenously/subcutaneously on days 1-5 in 28-day cycles. The primary outcomes were relapse-free survival (RFS) and safety. RESULTS: Of the 84 patients screened for eligibility before HCT, 55 received a transplant. Thirty-three patients ultimately received maintenance treatment (14 AML and 19 MDS); the median age was 65 (range, 40-74) years. The median number of eprenetapopt cycles was 7 (range, 1-12). With a median follow-up of 14.5 months, the median RFS was 12.5 months (95% CI, 9.6 to not estimable) and the 1-year RFS probability was 59.9% (95% CI, 41 to 74). With a median follow-up of 17.0 months, the median overall survival (OS) was 20.6 months (95% CI, 14.2 to not estimable) and the 1-year OS probability was 78.8% (95% CI, 60.6 to 89.3). Thirty-day and 60-day mortalities from the first dose were 0% and 6% (n = 2), respectively. Acute and chronic (all grade) graft-versus-host disease adverse events were reported in 12% (n = 4) and 33% (n = 11) of patients, respectively. CONCLUSION: In patients with mTP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population.

Variational autoencoders learn transferrable representations of metabolomics data.

Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn nonlinear latent representations which generalize to unseen data. Here, we trained a VAE on a large-scale metabolomics population cohort of human blood samples consisting of over 4500 individuals. We analyzed the pathway composition of the latent space using a global feature importance score, which demonstrated that latent dimensions represent distinct cellular processes. To demonstrate model generalizability, we generated latent representations of unseen metabolomics datasets on type 2 diabetes, acute myeloid leukemia, and schizophrenia and found significant correlations with clinical patient groups. Notably, the VAE representations showed stronger effects than latent dimensions derived by linear and non-linear principal component analysis. Taken together, we demonstrate that the VAE is a powerful method that learns biologically meaningful, nonlinear, and transferrable latent representations of metabolomics data.

Performance of Convolutional Neural Networks for Polyp Localization on Public Colonoscopy Image Datasets.

Colorectal cancer is one of the most frequent malignancies. Colonoscopy is the de facto standard for precancerous lesion detection in the colon, i.e., polyps, during screening studies or after facultative recommendation. In recent years, artificial intelligence, and especially deep learning techniques such as convolutional neural networks, have been applied to polyp detection and localization in order to develop real-time CADe systems. However, the performance of machine learning models is very sensitive to changes in the nature of the testing instances, especially when trying to reproduce results for totally different datasets to those used for model development, i.e., inter-dataset testing. Here, we report the results of testing of our previously published polyp detection model using ten public colonoscopy image datasets and analyze them in the context of the results of other 20 state-of-the-art publications using the same datasets. The F1-score of our recently published model was 0.88 when evaluated on a private test partition, i.e., intra-dataset testing, but it decayed, on average, by 13.65% when tested on ten public datasets. In the published research, the average intra-dataset F1-score is 0.91, and we observed that it also decays in the inter-dataset setting to an average F1-score of 0.83.

Surgical multicenter collaborative studies: ¿What happen in Latin America?

BACKGROUND: GlobalSurg is an international group of researchers whose purpose is to conduct and disseminate robust collaborative, international and multicenter studies. OBJECTIVE: To expose the necessary strategies and the barriers crossed in conducting massive multicenter studies in surgery. METHOD: During the second semester of 2020, the study Surg-Week Prospective International Cohort Study was carried out. Surg-Week has been the largest international study in the field of surgery to date, with 141,582 patients included. A total of 4975 mini-teams, of between 1 and 5 members, collected data from 116 countries on all continents. RESULTS: The creation of an official website for the study, reports with relevant information via email or groups via WhatsApp, formation of a Dissemination Committee of the protocol, delivery of webinars on recent team publications, appointment of leaders at the national and international level, and outreach through partnerships, were the strategies used for the development of the research. However, the barriers turned out to involve different aspects. CONCLUSIONS: Collaborative work allows establishing networks between different professionals with the goal of improving the quality of management, health policies and care of our patients in a timely manner of constant change.

ANTECEDENTES: GlobalSurg es un grupo internacional de investigadores que tiene como propósito la conducción y la diseminación de robustos estudios colaborativos, internacionales y multicéntricos. OBJETIVO: Exponer las estrategias necesarias y las barreras encontradas en la conducción de estudios multicéntricos masivos en cirugía. MÉTODO: Durante el segundo semestre del año 2020 se llevó a cabo el estudio Surg-Week Prospective International Cohort Study, hasta la fecha el estudio internacional más grande en el campo de la cirugía, con 141,582 pacientes incluidos. Un total de 4975 miniequipos, de uno a cinco integrantes, recopilaron datos de 116 países de todos los continentes. RESULTADOS: La creación de un sitio web oficial del estudio, reportes con información relevante vía e-mail o grupos vía WhatsApp, conformación de un comité de diseminación del protocolo, dictado de webinars sobre publicaciones recientes del equipo, designación de líderes nacionales e internacionales, y la divulgación por medio de sociedades, fueron las estrategias utilizadas para el desarrollo de la investigación. Sin embargo, las barreras detectadas para llevar a cabo el estudio multicéntrico fueron variadas. CONCLUSIONES: Los trabajos colaborativos permiten establecer redes entre diferentes profesionales con el fin de mejorar la calidad de la gestión, las políticas sanitarias y la atención a los pacientes en tiempos de constante cambio.

CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials.

Central nervous system (CNS) involvement in patients with newly diagnosed acute myeloid leukemia (AML) is rare, and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials for patients with newly diagnosed AML. In all, 3240 patients with AML were analyzed, and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies in which LP was performed at the discretion of the investigator (0.86% vs 1.41%; P = .18). There was no significant difference in the rate of complete remission (CR) among patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs 59.3%-60%). The median overall survival (OS) for patients who were CNS positive, who had other EMD, or who had no EMD was 11.4, 11.3, and 12.7 months, respectively. There was no difference in OS among patients with CNS involvement, those with other EMD (hazard ratio [HR], 0.96; adjusted P = .84), and those with no EMD (HR, 1.19; adjusted P = .44). In conclusion, the reported incidence of CNS involvement in patients with newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis in and of itself does not seem to portend a poor prognosis for achieving an initial CR or for OS.

Objective and subjective physical function in allogeneic hematopoietic stem cell transplant recipients.

We conducted a prospective study of adult allogeneic hematopoietic cell transplantation (HCT) recipients to assess pre- and post-HCT physical function. Baseline measurements included a wrist actigraphy, a 6 min walk test (6MWT), an international physical activity questionnaire (IPAQ), and a Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) as well as serial post-HCT assessments of 6MWT, IPAQ, and FACT-BMT. Forty-seven patients were evaluable for functionality assessments, with a median follow-up of 54.5 months for surviving recipients. No patients demonstrated vigorous or very vigorous activity at any time during monitoring by wrist actigraphy; patients spent a median of 6 h daily sedentary. Self-reported activity via the IPAQ showed 36%, 43%, and 21% of subjects reporting light, moderate, and vigorous activity prior to HCT, respectively. Post-HCT 6MWTs on day +30 demonstrated the greatest association with subsequent survival and non-relapse mortality. A decline in 6MWT distance over time also demonstrated worsened overall survival. This study shows the feasibility of fitness assessments and the ability to risk stratify for subsequent mortality, particularly using the 6MWT on the day +30 single time point assessment and change scores from baseline to day +30 post HCT. These pilot findings suggest important targets for future study.

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.

TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F , and MPLW515L , or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52 . Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2-Wilms' tumor 1 (WT1)-binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. SIGNIFICANCE: TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase-positive malignant hematopoietic cells to PARP inhibitors.

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.