Race/ethnic associations with comprehensive cancer center access and clinical trial enrollment for acute leukemia.

BACKGROUND: Clinical trial participation at Comprehensive Cancer Centers (CCC) is inequitable for minoritized race/ethnic groups with acute leukemia. CCCs care for a high proportion of adults with acute leukemia. It is unclear if participation inequities are due to CCC access, post-access enrollment, or both. METHODS: We conducted a retrospective cohort study of adults with acute leukemia (2010-2019) residing within Massachusetts, the designated catchment area of the Dana-Farber/Harvard Cancer Center (DF/HCC). Individuals were categorized as non-Hispanic Asian (NHA), Black (NHB), White (NHW), Hispanic White (HW), or Other. Decomposition analyses assessed covariate contributions to disparities in (1) access to DF/HCC care and (2) post-access enrollment. RESULTS: Of 3698 individuals with acute leukemia, 85.9% were NHW, 4.5% HW, 4.3% NHB, 3.7% NHA, and 1.3% Other. Access was lower for HW (age- and sex-adjusted OR 0.64 95%CI 0.45,0.90) and reduced post-access enrollment for HW (aOR 0.54 95%CI 0.34,0.86) and NHB (aOR 0.60 95%CI 0.39,0.92) compared to NHW. Payor and socioeconomic status (SES) accounted for 25.2% and 21.2% of the +1.1% absolute difference in HW access. Marital status and SES accounted for 8.0% and 7.0% of the -8.8% absolute disparity in HW enrollment; 76.4% of the disparity was unexplained. SES and marital status accounted for 8.2% and 7.1% of the -9.1% absolute disparity in NHB enrollment; 73.0% of the disparity was unexplained. CONCLUSIONS: A substantial proportion of race/ethnic inequities in acute leukemia trial enrollment at CCCs are from post-access enrollment, the majority of which was not explained by sociodemographic factors.

Herramientas para el tamizaje de aneurisma de aorta abdominal / Tools for abdominal aortic aneurysm screening

Introducción. El aneurisma de la aorta abdominal (AAA) es la dilatación de la aorta abdominal mayor de 1,5 veces el diámetro esperado. Su prevalencia es variable, con tasas reportadas de hasta el 12,5 %. Se considera como causa de muerte de más de 10.000 personas al año en los Estados Unidos. El objetivo de esta revisión de la literatura fue describir los factores de riesgo y las herramientas de tamizaje de AAA. Métodos. Se realizó una búsqueda de la literatura utilizando dos ecuaciones en bases de datos electrónicas, empleando términos seleccionados de "Medical Subject Heading" (MeSH) y "Descriptores en Ciencias de la Salud" (DeCS). Se evaluó la calidad de los estudios con la herramienta STROBE (Strengthening the Reporting of Observational Studies in Epidemiology). Resultados. Se recolectaron 40 artículos y a partir de ellos se construyó el texto de revisión, identificando en estos, los factores de riesgo asociados al desarrollo de AAA, tales como sexo masculino, tabaquismo, hipertensión arterial, antecedente familiar y obesidad, entre otros. La diabetes mellitus parece actuar como factor protector. Dentro de los instrumentos de tamizaje, el ultrasonido abdominal es uno de los más usados. Conclusión. El AAA es una patología multifactorial. En la actualidad la ultrasonografía de aorta es el método de elección para el tamizaje, permitiendo la detección precoz. El tamizaje de AAA con métodos no invasivos, como el ultrasonido, es útil sobre todo en zonas con prevalencia alta de la patología y en pacientes con determinados factores de riesgo.

Introduction. Abdominal aortic aneurysm (AAA) is a dilation of the abdominal aorta greater than 1.5 times the expected diameter. Its prevalence is variable, with reported rates of up to 12.5%. It is considered the cause of death of more than 10,000 people a year in the United States. The objective of this literature review was to describe risk factors and screening tools for AAA. Methods. A literature search was conducted using two equations in electronic databases, using terms selected from "Medical Subject Heading" (MeSH) and "Descriptors in Health Sciences" (DeCS). The quality of the studies was evaluated with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) tool. Results. Forty articles were collected and from them the review text was constructed, identifying the risk factors associated with the development of AAA, such as male sex, smoking, high blood pressure, family history and obesity, among others. Diabetes mellitus seems to act as a protective factor. Among the screening instruments, abdominal ultrasound is one of the most used. Conclusion. AAA is a multifactorial pathology. Currently, aortic ultrasonography is the method of choice for screening, allowing early detection. Screening for AAA with non-invasive methods, such as ultrasound, is useful especially in areas with a high prevalence of this pathology and in patients with certain risk factors.

Immune checkpoint blockade in hematological malignancies: current state and future potential.

Malignant cells are known to evade immune surveillance by engaging immune checkpoints which are negative regulators of the immune system. By restoring the T-lymphocyte mediated anti-tumor effect, immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors but have met rather modest success in hematological malignancies. Currently, the only FDA approved indications for ICI therapy are in classic hodgkin lymphoma and primary mediastinal B cell lymphoma. Multiple clinical trials have assessed ICI therapy alone and in combination with standard of care treatments in other lymphomas, plasma cell neoplasms and myeloid neoplasms but were noted to have limited efficacy. These trials mostly focused on PD-1/PDL-1 and CTLA-4 inhibitors. Recently, there has been an effort to target other T-lymphocyte checkpoints like LAG-3, TIM-3, TIGIT along with improving strategies of PD-1/PDL-1 and CTLA-4 inhibition. Drugs targeting the macrophage checkpoint, CD47, are also being tested. Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies.

Analysis of Gut Characteristics and Microbiota Changes with Maternal Supplementation in a Neural Tube Defect Mouse Model.

Adequate nutrient supply is crucial for the proper development of the embryo. Although nutrient supply is determined by maternal diet, the gut microbiota also influences nutrient availability. While currently there is no cure for neural tube defects (NTDs), their prevention is largely amenable to maternal folic acid and inositol supplementation. The gut microbiota also contributes to the production of these nutrients, which are absorbed by the host, but its role in this context remains largely unexplored. In this study, we performed a functional and morphological analysis of the intestinal tract of loop-tail mice (Vangl2 mutants), a mouse model of folate/inositol-resistant NTDs. In addition, we investigated the changes in gut microbiota using 16S rRNA gene sequencing regarding (1) the host genotype; (2) the sample source for metagenomics analysis; (3) the pregnancy status in the gestational window of neural tube closure; (4) folic acid and (5) D-chiro-inositol supplementation. We observed that Vangl2+/Lp mice showed no apparent changes in gastrointestinal transit time or fecal output, yet exhibited increased intestinal length and cecal weight and gut dysbiosis. Moreover, our results showed that the mice supplemented with folic acid and D-chiro-inositol had significant changes in their microbiota composition, which are changes that could have implications for nutrient absorption.

Overcoming Barriers to Referral for Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma. Although outcomes to frontline therapy are encouraging, patients who are refractory to or in relapse after first-line therapy experience inferior outcomes. A significant proportion of patients treated with additional lines of cytotoxic chemotherapy ultimately succumb to their disease, as established in the SCHOLAR-1 study. Chimeric antigen receptor (CAR) T cell therapy is a novel approach to cancer management that reprograms a patient's own T cells to better target and eliminate cancer cells. It was initially approved by the US Food and Drug Administration for patients with relapsed/refractory (r/r) DLBCL as a third line of treatment. Based on recently published randomized data, CAR-T therapy (axicabtagene ciloleucel and lisocabtagene maraleucel) also has been approved as a second line of treatment for patients who are primary refractory or relapse within 12 months of first-line therapy. Despite the proven efficacy in treating r/r DLBCL with CD19-directed CAR-T therapy, several barriers may prevent eligible patients from receiving treatment. Barriers to CAR-T therapy include cost of therapy, patient hesitancy, required travel to academic treatment centers, nonreferrals, poor understanding of CAR-T therapy, lack of caregiver support, knowledge of available resources, and timely patient selection by referring oncologists. In this review, we provide an overview of the FDA-approved CD19-directed CAR-T cell therapies (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel) from pivotal clinical trials and supporting real-world evidence from retrospective studies. In both clinical trials and real-world settings, CAR-T therapy has been shown to be safe and efficacious for treating patients with r/r DLBCL: however, several barriers prevent eligible patients from accessing these therapies. Barriers to referrals for CAR-T therapy are described, along with recommendations to improve collaboration between community oncologists and physicians from CAR-T therapy treatment centers and subsequent long-term care of patients in community treatment centers.

Molecular epidemiology of pneumococcal carriage in children from Seville, following implementation of the PCV13 immunization program in Andalusia, Spain.

INTRODUCTION: The 13-valent pneumococcal conjugate vaccine (PCV13) universal vaccination programme was introduced in December 2016 in Andalusia. METHODS: A cross-sectional study was conducted on the molecular epidemiology of pneumococcal nasopharyngeal colonization. A total of 397 healthy children were recruited from primary healthcare centres in Seville for the periods 1/4/2018 to 28/2/2020 and 1/11/2021 to 28/2/2022 (PCV13 period). Data from a previous carriage study conducted among healthy and sick children from 1/01/2006 to 30/06/2008 (PCV7 period), were used for comparison of serotype/genotype distributions and antibiotic resistance rates. RESULTS: Overall, 76 (19%) children were colonized with S. pneumoniae during the PCV13 period and there were information available from 154 isolates collected during the PCV7 period. Colonization with PCV13 serotypes declined significantly in the PCV13 period compared with historical controls (11% vs 38%, p = 0.0001), being serotypes 19F (8%), 3 (1%) and 6B (1%) the only circulating vaccine types. Serotypes 15B/C and 11A were the most frequently identified non-PCV13 serotypes during the PCV13 period (14% and 11%, respectively); the later one increased significantly between time periods (p = 0.04). Serotype 11A was exclusively associated in the PCV13 period with ampicillin-resistant variants of the Spain9V-ST156 clone (ST6521 and genetically related ST14698), not detected in the preceding period. CONCLUSIONS: There was a residual circulation of vaccine types following PCV13 introduction, apart from serotype 19F. Serotype 11A increased between PCV13 and PCV7 periods due to emergence and clonal expansion of ampicillin-resistant genotype ST6521.

Analysis of Serial Neuroblastoma PDX Passages in Mice Allows the Identification of New Mediators of Neuroblastoma Aggressiveness.

Neuroblastoma is a neural crest cell-derived pediatric tumor characterized by high inter- and intra-tumor heterogeneity, and by a poor outcome in advanced stages. Patient-derived xenografts (PDXs) have been shown to be useful models for preserving and expanding original patient biopsies in vivo, and for studying neuroblastoma biology in a more physiological setting. The maintenance of genetic, histologic, and phenotypic characteristics of the original biopsy along serial PDX passages in mice is a major concern regarding this model. Here we analyze consecutive PDX passages in mice, at both transcriptomic and histological levels, in order to identify potential changes or highlight similarities to the primary sample. We studied temporal changes using mRNA and miRNA expression and correlate those with neuroblastoma aggressiveness using patient-derived databases. We observed a shortening of tumor onset and an increase in proliferative potential in the PDXs along serial passages. This behavior correlates with changes in the expression of genes related to cell proliferation and neuronal differentiation, including signaling pathways described as relevant for neuroblastoma malignancy. We also identified new genes and miRNAs that can be used to stratify patients according to survival, and which could be potential new players in neuroblastoma aggressiveness. Our results highlight the usefulness of the PDX neuroblastoma model and reflect phenotypic changes that might be occurring in the mouse environment. These findings could be useful for understanding the progression of tumor aggressiveness in this pathology.

Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation.

Conditioning intensity contributes significantly to outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated two myeloablative conditioning dosing ranges of intravenous (IV) busulfan (Bu) in combination with fludarabine in 70 patients. In 2015, our practice changed to target busulfan area under the curve (AUC) of ≥ 19.7 mg*h/L. We assessed responses in patients receiving busulfan AUCs of < 19.7 mg*h/L (Low-Bu) and ≥ 19.7 mg*h/L (High-Bu). At 18-month median follow-up, no differences in overall survival (OS) and relapse-free survival (RFS) were found between Low-Bu and High-Bu groups (p = 0.35 and p = 0.29, respectively). Relapses occurred in 25.7% of patients. No differences in median time to relapse were noted. Minimal residual disease (MRD)-positive patients had a shorter median OS and RFS than MRD-negative patients. No differences were found in OS and RFS between Low-Bu and High-Bu groups in MRD-positive patients (p = 0.86 and p = 0.83, respectively), or MRD-negative patients (p = 0.56 and p = 0.38, respectively). Non-relapsed mortality (NRM) at 100 days was 3.4% vs. 4.1% in the Low-Bu vs. High-Bu groups. There were no significant differences in the incidence of acute-graft-versus-host disease (aGVHD) (71.4% vs. 63.4%) or chronic GVHD (cGVHD) (48.3% vs. 43.9%) between the groups. The cumulative incidence of grades III-IV aGVHD was 24.1% in Low-Bu group and 22.4% in High-Bu group. In conclusion, targeting a busulfan AUC of > 19.7 mg*h/L with fludarabine does not appear to add an advantage in OS and RFS.

Cryopreserved versus fresh peripheral blood allogeneic stem cell transplantation outcomes in patients receiving post-transplant cyclophosphamide for graft-versus-host prophylaxis during the COVID-19 pandemic: a single center experience.

BACKGROUND/OBJECTIVE: Cryopreservation of grafts is not common practice in allogeneic hematopoietic stem cell transplant (HSCT) recipients. However, our center had to use cryopreserved cells for allogeneic HSCT during the COVID-19 pandemic to avoid delays in transplantation due to uncertainty regarding patient and donor exposures. STUDY DESIGN: We retrospectively evaluated post-transplant engraftment and survival outcomes of adult patients who received cryopreserved versus fresh allografts during the COVID-19 pandemic. RESULTS: Fifty-five patients with hematologic malignancies received either cryopreserved (n = 34) or fresh (n = 21) allogeneic HSCT using peripheral blood stem cells between January 2020 and December 2020. At a median follow-up time of 15 months, cryopreserved allograft recipients had significantly lower overall survival (OS) (p = 0.02). They also experienced significantly delayed neutrophil (p = 0.01) and platelet engraftments (p < 0.0001), as well as higher red blood cell transfusion-dependence after day + 60 (67.6% vs. 28.6%; p = 0.01). Significantly more cryopreserved allograft recipients received donor lymphocyte infusion than fresh allograft recipients (35.3% vs. 4.8%, p = 0.01). Neither relapse-free survival nor non-relapse mortality differed significantly between the two groups. CONCLUSION: Cryopreservation of allografts in combination with post-transplant cyclophosphamide may negatively affect engraftment and OS outcomes in HSCT recipients.

Riesgo de enfermedad cardiovascular y cerebrovascular a largo plazo en mujeres con antecedente personal de abrupción placentaria

La salud materna y perinatal es una de las prioridades actuales de la salud global. La enfermedad cardiovascular y el accidente cerebrovascular son las principales causas de mortalidad materna. La abrupción placentaria sigue siendo una preocupación crítica para la morbilidad materna debido a que se ha asociado a enfermedad vascular a largo plazo. Sin embargo, no existe mucha literatura disponible en español ni evidencia reciente que haya dilucidado algunas interrogantes sobre este tópico. Entonces, el objetivo de esta revisión consiste en sintetizar evidencia reciente sobre el riesgo de enfermedad cardiovascular y cerebrovascular a largo plazo en mujeres con antecedente personal de abrupción placentaria. Se encontró que, a través de mecanismos fisiopatológicos complejos, que involucran la estructura y funcionalidad de la red vascular placentaria con posterior extensión de lesión vascular y producción de factores proinflamatorios y procoagulantes que permanecen después del parto, se precipita la aparición de eventos cardiovasculares mayores a mediano y largo plazo. Evidencia de alta calidad ha revelado que el riesgo de sufrir de complicaciones maternas en aquellas mujeres con abrupción placentaria es de 2,14, que se eleva aún más para aquellas con desprendimiento severo. A mediano y largo plazo, el riesgo de mortalidad por cardiopatía coronaria es de 2,64, y de 1,70 para desorden cerebrovascular, con igual riesgo tanto para el tipo isquémico como hemorrágico. Entonces, se puede concluir que el riesgo cardiovascular y cerebrovascular es inminente en mujeres con antecedente de abrupción placentaria, dado por numerosos mecanismos fisiopatológicos vasculares. No obstante, este riesgo se eleva considerablemente al asociarse con factores modificables tradicionales y no tradicionales.

Maternal and perinatal health is one of today's global health priorities. Cardiovascular disease and stroke are the leading causes of maternal mortality. Placental abruption remains a critical concern for maternal morbidity because it has been associated with long-term vascular disease. However, there is neither much literature available in Spanish nor recent evidence elucidating some questions on this topic. Thus, this review aims to synthesize recent evidence on the long-term risk of cardiovascular and cerebrovascular disease in women with a personal history of placental abruption. It was found that, through complex pathophysiological mechanisms involving the structure and functionality of the placental vascular network with subsequent extension of vascular injury and production of proinflammatory and procoagulant factors which remain after delivery, major cardiovascular events are precipitated in the medium and long term. High-quality evidence has shown that the risk of maternal complications in women with placental abruption accounts for 2.14, rising even higher for those with severe placental abruption. In the medium and long term, the mortality risk caused by coronary heart diseases is 2.64 and by cerebrovascular disorders is 1.70, with equal risk for both ischemic and hemorrhagic strokes. It can therefore be concluded that cardiovascular and cerebrovascular risk is imminent in women with a history of placental abruption due to a number of vascular pathophysiological mechanisms. However, this risk is considerably increased when associated with traditional and non-traditional modifiable factors.

Molecular epidemiology of paediatric invasive pneumococcal disease in Andalusia, Spain.

This study aimed to assess the impact of the introduction of pneumococcal conjugate vaccine 13 (PCV13) on the molecular epidemiology of invasive pneumococcal disease (IPD) in children from Andalusia. A population-based prospective surveillance study was conducted on IPD in children aged <14 years from Andalusia (2018-2020). Pneumococcal invasive isolates collected between 2006 and 2009 in the two largest tertiary hospitals in Andalusia were used as pre-PCV13 controls for comparison of serotype/genotype distribution. Overall IPD incidence rate was 3.55 cases per 100 000 in 2018; increased non-significantly to 4.20 cases per 100 000 in 2019 and declined in 2020 to 1.69 cases per 100 000 (incidence rate ratio 2020 vs. 2019: 0.40, 95% confidence interval (CI) 0.20-0.89, P = 0.01). Proportion of IPD cases due to PCV13 serotypes in 2018-2020 was 28% (P = 0.0001 for comparison with 2006-2009). Serotypes 24F (15%) and 11A (8.3%) were the most frequently identified non-PCV13 serotypes (NVT) in 2018-2020. Penicillin- and/or ampicillin-resistant clones mostly belonged to clonal complex 156 (serotype 14-ST156 and ST2944 and serotype 11A-ST6521). The proportion of IPD cases caused by PCV13 serotypes declined significantly after the initiation of the PCV13 vaccination programme in 2016. Certain NVT, such as serotypes 24F and 11A, warrant future monitoring in IPD owing to invasive potential and/or antibiotic resistance rates.

Insular cortex corticotropin-releasing factor integrates stress signaling with social affective behavior.

Impairments in identifying and responding to the emotions of others manifest in a variety of psychopathologies. Therefore, elaborating the neurobiological mechanisms that underpin social responses to social emotions, or social affective behavior, is a translationally important goal. The insular cortex is consistently implicated in stress-related social and anxiety disorders, which are associated with diminished ability to make and use inferences about the emotions of others to guide behavior. We investigated how corticotropin-releasing factor (CRF), a neuromodulator evoked upon exposure to stressed conspecifics, influenced the insula. We hypothesized that social affective behavior requires CRF signaling in the insular cortex in order to detect stress in social interactions. In acute slices from male and female rats, CRF depolarized insular pyramidal neurons. In males, but not females, CRF suppressed presynaptic GABAergic inhibition leading to greater excitatory synaptic efficacy in a CRF receptor 1 (CRF1)- and cannabinoid receptor 1 (CB1)-dependent fashion. In males only, insular CRF increased social investigation, and CRF1 and CB1 antagonists interfered with social interactions with stressed conspecifics. To investigate the molecular and cellular basis for the effect of CRF we examined insular CRF1 and CB1 mRNAs and found greater total insula CRF1 mRNA in females but greater CRF1 and CB1 mRNA colocalization in male insular cortex glutamatergic neurons that suggest complex, sex-specific organization of CRF and endocannabinoid systems. Together these results reveal a new mechanism by which stress and affect contribute to social affective behavior.

Inclusion at universities: Psychometric properties of an inclusive management scale as perceived by students.

INTRODUCTION: During the last century, the inclusion of all kinds of diversity became a social imperative in all social spaces but above all in some institutions such as the educational ones. Among these, inclusion has been least studied in the tertiary education organizations. This communication proposes and evaluates the psychometric properties of a new instrument, named Inclusive Management in Tertiary Institutions Scale (IMTIS), to assess inclusive management in universities. METHOD: The researchers used a quantitative research model through survey. We based on the Index for Inclusion to design the IMTIS. We first submitted it to the assessment of experts. Then we applied the resulting version in an online survey including a sample of 1557 students from two universities and 121 different undergraduate careers. A panel of experts judged the content validity of the instrument. Participants answered the IMTIS after informed consent. We used confirmatory factor analysis to assess the construct validity of the instrument. We also evaluated the reliability of the measurements. RESULTS: From a kit of 33 originally proposed items, we obtained a version of 22 items with CVR between 0.60 and 1.00, and a IVC = 0.78. The confirmatory factor analysis showed that the six-factor solution had a better adjustment than the one and three factors solutions (RMSEA = 0.059; CFI = 0.947; TLI = 0.937). The McDonald ω coefficients were between 0.864 and 0.922. CONCLUSION: The results deliver evidence that supports the validity and reliability of the IMTIS measurements to carry out research and diagnosis of inclusive management in higher education institutions.

Mutational profiling of myeloid neoplasms associated genes may aid the diagnosis of acute myeloid leukemia with myelodysplasia-related changes.

AML with myelodysplasia-related changes (AML-MRC) is a subtype of AML known to have adverse prognosis. The karyotype abnormalities in AML-MRC have been well established; however, relatively little has been known about the role of gene mutation profiles by next generation sequencing. 177 AML patients (72 AML-MRC and 105 non-MRC AML) were analyzed by NGS panel covering 53 AML related genes. AML-MRC showed statistically significantly higher frequency of TP53 mutation, but lower frequencies of mutations in NPM1, FLT3-ITDLow, FLT3-ITDHigh, FLT3-TKD, NRAS, and PTPN11 than non-MRC AML. Supervised tree-based classification models including Decision tree, Random forest, and XGboost, and logistic regression were used to evaluate if the mutation profiles could be used to aid the diagnosis of AML-MRC. All methods showed good accuracy in differentiating AML-MRC from non-MRC AML with AUC (area under curve) of ROC ranging from 0.69 to 0.78. Additionally, logistic regression indicated 3 independent factors (age and mutations of TP53 and FLT3) could aid the diagnosis AML-MRC. Using weighted factors, a AML-MRC risk scoring equation was established for potential application in clinical setting: +1x(Age ≥ 65) + 3 x (TP53 mutation) - 2 x (FLT3 mutation). Using a cutoff score of 0, the accuracy of the risk score was 0.76 with sensitivity of 0.77 and specificity of 0.75 for predicting the diagnosis of AML-MRC. Further studies with larger sample sizes are warranted to further evaluate the potential of using gene mutation profiles to aid the diagnosis of AML-MRC.

Adverse Impact of DNA Methylation Regulatory Gene Mutations on the Prognosis of AML Patients in the 2017 ELN Favorable Risk Group, Particularly Those Defined by NPM1 Mutation.

The 2017 ELN risk stratification has been widely adopted, but some studies have suggested the outcomes are heterogenous within the ELN risk groups and may be affected by other co-existing genetic mutations. This study evaluated the impact of DNA methylation regulatory gene (TET2, IDH1/2, DNMT3A, SETBP1) mutations (DMRGM) evaluated by NGS in the outcome of AML patients in each ELN risk group. A total of 114 patients were analyzed with a median follow-up of 12 months. Overall, 30.7% (35/114) of patients had DMRGM. DMRGM status had no impact on CR rate in each ELN risk group. The OS, however, was significantly shorter in patients with DMRGM compared to those without DMRGM (median OS: 12 vs. 33 months, p = 0.0053). Multivariate analysis showed DMRGM status was an independent unfavorable factor for OS (HR: 2.704, 95% CI: 1.451-5.041, p = 0.0017). The adverse OS impact of DMRGM was only observed in the ELN favorable group (7 months vs. not reached, p = 0.0001), but not in the intermediate or adverse group. Among the favorable group with DMRGM (n = 16), DMRGM occurred predominantly in cases with mutated NPM1 (15/16, or 93.8%). Our results suggest that DMRGM adversely impact the outcomes of ELN favorable group patients, particularly those with mutated NPM1. Further studies are warranted to confirm our observations.

Comparison of Myeloablative versus Reduced-Intensity Conditioning Regimens in Allogeneic Stem Cell Transplantation Recipients with Acute Myelogenous Leukemia with Measurable Residual Disease-Negative Disease at the Time of Transplantation: A Retrospective Cohort Study.

The ideal conditioning intensity in allogeneic hematopoietic stem cell transplantation (HSCT) is evolving. Previous prospective studies comparing myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) regimens in adults with acute myelogenous leukemia (AML) have shown mixed results. In many of these studies, patients were not stratified based on measurable residual disease (MRD). We evaluated the effect of conditioning intensity on the outcomes of AML patients in complete remission (CR) with flow cytometry evidence of MRD negativity. A total of 135 patients age 20 to 75 years with AML in CR1 or CR2 and flow cytometry evidence of MRD negativity who underwent allogeneic HSCT at our center between 2011 and 2019 were evaluated. We compared overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD) in recipients of MAC (n = 89) and RIC (n = 46). Although the patients receiving RIC were older (62 versus 51 years; P < .0001), there were no statistically significant differences between the groups in terms of Eastern Cooperative Oncology Group and European Leukemia Network risk criteria and disease status (CR1 or CR2) at the time of transplantation. At a median follow-up of 24.6 months, no statistically significant differences in OS (hazard ratio [HR], 0.78; 95% confidence interval [CI] 0.42 to 1.42, P = .411) or RFS (HR, 1.004; 95% CI, 0.48 to 2.09, P = .99) were identified. The cumulative incidence of NRM (HR, 0.595; 95% CI, 0.24 to 1.48; P = .2644) and relapse (HR, 1.007; 95% CI, 0.45 to 2.23; P = .9872) was not different between the 2 groups. Grade II-IV and grade III-IV acute GVHD were more frequent in the MAC group (39.3% verses 19.9% [P = .018] and 19.3% versus 2.3% [P < .001], respectively), as was moderate/severe chronic GVHD (23.6% versus 15.8%; P = .038). Our data indicate that conditioning intensity did not appear to affect OS, RFS, NRM, and relapse risk in patients with MRD-negative AML as measured by flow cytometry. RIC resulted in less severe acute and chronic GVHD.

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

Impact of Next-Generation Sequencing Cell-free Pathogen DNA Test on Antimicrobial Management in Adults with Hematological Malignancies and Transplant Recipients with Suspected Infections.

Infections in adult patients with hematological malignancies (HM) and stem cell transplant (SCT) recipients are a significant cause of morbidity and mortality. A timely diagnosis of infections can have a major impact on outcomes. Tools that help rule out infectious causes of fever can decrease antibiotic use, toxicities, hospitalization costs, and potentially decrease antibiotic resistance in the long term. We retrospectively evaluated the ability of cell-free DNA next-generation sequencing (NGS) testing in the timely identification of pathogenic microorganisms and its impact on the antimicrobial management of immunocompromised patients with hematologic malignancies. In the period between 2018 to 2020, 95 samples were reviewed, of which 31 adult patients (32 tests) had hematologic malignancies or were recipients of SCT. The NGS tests were performed in the following patients: (a) patients with prolonged fever and negative conventional tests, (b) persistent fever despite positive conventional test and appropriate antimicrobials, and (c) fever-free patients with imaging suspicious for infection. The median time from fever to NGS sampling was 5 days (range, 1-28). The median time to NGS results was 2 days (range, 1-6). The NGS resulted in an escalation of antibiotics in 28% of cases (9/32) and de-escalation of antibiotics in 31% of cases (10/32). Overall, NGS testing changed management in nearly 59% (19/32) of patients. The sensitivity and specificity of NGS to detect clinically significant infection was 80% and 58%, respectively. The test identified uncommon and difficult to diagnose organisms such as Nocardia, Legionella, Toxoplasma and Pneumocystis jirovecii resulting in rapid antimicrobial interventions. In conclusion, in patients with HM or SCT recipients, microbial cell-free DNA sequencing allowed rapid and actionable treatment. This strategy can target appropriate antibiotic use, avoid overtreatment, and potentially decrease the hospital length-of-stay.

Early type I IFN blockade improves the efficacy of viral vaccines.

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.