The IL-7R antagonist Lusvertikimab reduces leukemic burden in xenograft-ALL via antibody-dependent cellular phagocytosis.

Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of precursor B or T cells (BCP- or T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (r/r) disease, high-risk leukemias and T-ALL, where immunotherapy approaches remain scarce. While the Interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R-targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)-targeting IgG4 antibody Lusvertikimab (formerly OSE-127) is a full antagonist of the IL-7R pathway showing a good safety profile in healthy volunteers. Here, we show that ~85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of Lusvertikimab immunotherapy in a heterogeneous cohort of BCP- and T-ALL patient-derived xenografts (PDX) in minimal residual disease (MRD) and overt leukemia models, including r/r and high-risk leukemias. Importantly, Lusvertikimab was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127high samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, Lusvertikimab targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Lusvertikimab-mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, Lusvertikimab may represent a novel immunotherapy option for any CD127-positive ALL, particularly in combination with standard-of-care polychemotherapy.

The landscape of cytogenetic and molecular genetic methods in diagnostics for hematologic neoplasia.

Improvements made during the last decades in the management of patients with hematologic neoplasia have resulted in increase of overall survival. These advancements have become possible through progress in our understanding of genetic basis of different hematologic malignancies and their role in the current risk-adapted treatment protocols. In this review, we provide an overview of current cytogenetic and molecular genetic methods, commonly used in the genetic characterization of hematologic malignancies, describe the current developments in the cytogenetic and molecular diagnostics, and give an outlook into their future development. Furthermore, we give a brief overview of the most important public databases and guidelines for sequence variant interpretation.

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer.

BACKGROUND: Approximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high-grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss-of-function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression-free survival and overall survival. METHODS: The study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2. RESULTS: A total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression-free survival. CONCLUSION: Frequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non-functional or non-functional somatic variants, while eight 14.2% presented likely non-functional or non-functional somatic variants in BRCA1 or BRCA2.

SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

Efficacy of supervised exercise on sleep of women who survived breast cancer: a systematic review with meta-analysis.

PURPOSE: To analyze the efficacy of supervised exercise (SE) compared with control protocols on sleep parameters of women who survived breast cancer. METHODS: This systematic review with meta-analysis searched studies using the following electronic databases: PubMed, Scopus, Physiotherapy Evidence Database (PEDro), Cochrane Library, and EMBASE. The PEDro scale assessed the bias risk, and the study protocol was registered in the PROSPERO (no. CRD42023420894). RESULTS: Of 3,566 identified studies, 13 randomized clinical trials involving 847 women diagnosed with breast cancer were included. Interventions consisted of SE in an outpatient setting (62%) or combined protocols with supervised and home exercises. Most interventions (85%) used multicomponent protocols with aerobic and resistance exercises. Usual care and health education were the most reported controls. SE decreased the sleep disturbance score (- 31.61 [95% confidence interval = - 39.40 to - 23.83]) of the European Organisation for Research and Treatment of Cancer quality of life questionnaire and daytime dysfunction score (- 0.41 [95% confidence interval = - 0.73 to - 0.09]) of the Pittsburgh Sleep Quality Index (PSQI). Also, SE presented a tendency to improve the self-reported sleep quality score of the PSQI (p = 0.06). CONCLUSION: SE increased the subjective sleep quality and immobility time and decreased sleep disturbance and daytime dysfunction symptoms in women who survived breast cancer. Most SE protocols were multicomponent, with aerobic and resistance exercises ranging from moderate to high intensity. IMPLICATIONS FOR CANCER SURVIVORS: Supervised exercise may improve sleep quality and reduce symptoms of sleep disorders, contributing to survival outcomes.

Multilamellated Basement Membranes in the Capillary Network of Alveolar Capillary Dysplasia.

A minimal diffusion barrier is key to the pulmonary gas exchange. In alveolar capillary dysplasia (ACD), a rare genetically driven disease of early infancy, this crucial fibrovascular interface is compromised while the underlying pathophysiology is insufficiently understood. Recent in-depth analyses of vascular alterations in adult lung disease encouraged researchers to extend these studies to ACD and compare the changes of the microvasculature. Lung tissue samples of children with ACD (n = 12), adults with non-specific interstitial pneumonia (n = 12), and controls (n = 20) were studied using transmission electron microscopy, single-gene sequencing, immunostaining, exome sequencing, and broad transcriptome profiling. In ACD, pulmonary capillary basement membranes were hypertrophied, thickened, and multilamellated. Transcriptome profiling revealed increased CDH5, COL4A1, COL15A1, PTK2B, and FN1 and decreased VIT expression, confirmed by immunohistochemistry. In contrast, non-specific interstitial pneumonia samples showed a regular basement membrane architecture with preserved VIT expression but also increased COL15A1+ vessels. This study provides insight into the ultrastructure and pathophysiology of ACD. The lack of normally developed lung capillaries appeared to cause a replacement by COL15A1+ vessels, a mechanism recently described in interstitial lung disease. The VIT loss and FN1 overexpression might contribute to the unique appearance of basement membranes in ACD. Future studies are needed to explore the therapeutic potential of down-regulating the expression of FN1 and balancing VIT deficiency.

Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.

Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome.

Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).

Treatment outcomes of childhood PICALM::MLLT10 acute leukaemias.

The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted.

Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in pediatric cancer patients.

Genetic predisposition is one of the major risk factors for pediatric cancer, with ~10% of children being carriers of a predisposing germline alteration. It is likely that this is the tip of the iceberg and many children are underdiagnosed, as most of the analysis focuses on single or short nucleotide variants, not considering the full spectrum of DNA alterations. Hence, we applied optical genome mapping (OGM) to our cohort of 34 pediatric cancer patients to perform an unbiased germline screening and analyze the frequency of structural variants (SVs) and their impact on cancer predisposition. All children were clinically highly suspicious for germline alterations (concomitant conditions or congenital anomalies, positive family cancer history, particular cancer type, synchronous or metachronous tumors), but whole exome sequencing (WES) had failed to detect pathogenic variants in cancer predisposing genes. OGM detected a median of 49 rare SVs (range 27-149) per patient. By analysis of 18 patient-parent trios, we identified three de novo SVs. Moreover, we discovered a likely pathogenic deletion of exon 3 in the known cancer predisposition gene BRCA2, and identified a duplication in RPA1, which might represent a new cancer predisposition gene. We conclude that optical genome mapping is a suitable tool for detecting potentially predisposing SVs in addition to WES in pediatric cancer patients.

Evolução Clínica e Fatores Prognósticos de Pacientes Oncológicos com Covid-19 em Ventilação Mecânica / Clinical Evolution and Prognostic Factors of Cancer Patients with COVID-19 in Mechanical Ventilation

Introdução: Pacientes com câncer apresentaram risco de desenvolver quadros respiratórios graves quando acometidos por covid-19, com necessidade de suporte intensivo e de ventilação mecânica invasiva (VMI). Objetivo: Avaliar os fatores associados ao óbito em pacientes oncológicos que tiveram covid-19 e evoluíram com insuficiência respiratória e necessidade de VMI. Método: Estudo de coorte retrospectivo de pacientes com câncer em uma unidade de terapia intensiva (UTI) oncológica, com covid-19 e em VMI de abril de 2020 a dezembro de 2021. Foram incluídos de forma sequencial todos os pacientes com câncer admitidos na UTI em VMI ou que evoluíram com VMI por agravamento da covid-19, sendo excluídos aqueles em controle da doença oncológica há mais de cinco anos. Para a análise estatística, foram utilizadas medidas de tendência central e dispersão, assim como frequências absolutas e relativas. A regressão logística múltipla foi aplicada para a avaliação dos fatores associados à mortalidade, considerando estatisticamente significantes valores de p < 0,05. Resultados: Foram incluídos no estudo 85 pacientes. O óbito foi maior entre os pacientes com tumores sólidos (OR = 3,64; IC 95%: 1,06-12,52; p = 0,04), entre os que necessitaram de suporte renal durante a internação na UTI (OR = 6,88; IC 95%: 1,82-25,98; p = 0,004), os que não puderam ser extubados (OR = 8,00; IC 95%: 2,16-29,67; p = 0,002) e os que apresentaram o valor de pressão de distensão alveolar maior do que 15cmH2O por pelo menos um dia (OR = 5,9; IC 95%: 1,76-19,80; p = 0,004). Conclusão: Características clínicas e de VMI estavam associadas à morte de pacientes oncológicos com covid-19 e em VMI.

Los pacientes con cáncer corrían riesgo de desarrollar afecciones respiratorias graves al ser afectados por la COVID-19, requiriendo soporte intensivo y ventilación mecánica invasiva (VMI). Objetivo: Evaluar los factores asociados a la muerte en pacientes con cáncer que tuvieron COVID-19 y que desarrollaron insuficiencia respiratoria y necesidad de VMI. Método: Estudio de cohorte retrospectivo en pacientes oncológicos internados en una unidad de cuidados intensivos (UCI) de oncología, con COVID-19 y en VMI de abril de 2020 a diciembre de 2021. Se incluyeron secuencialmente todos los pacientes con cáncer ingresados en UCI con VMI o que necesitaron VMI por empeoramiento de la COVID-19, excluyendo a aquellos que llevaban más de cinco años bajo control de la enfermedad oncológica. Para el análisis estadístico se utilizaron medidas de tendencia central y dispersión, así como frecuencias absolutas y relativas. Se aplicó regresión logística múltiple para evaluar los factores asociados a la mortalidad, considerando valores de p<0,05 estadísticamente significativos. Resultados: Se incluyeron en el estudio 85 pacientes. La muerte fue mayor entre los pacientes con tumores sólidos (OR= 3,64; IC 95%, 1,06-12,52; p=0,04), entre los que requirieron soporte renal durante la estancia en UCI (OR = 6,88; IC 95%, 1,82-25,98; p= 0,004), entre los que no pudieron ser extubados (OR= 8,00; IC 95%, 2,16-29,67; p= 0,002) y entre los que presentaron un valor de presión de distensión alveolar mayor a 15cmH2O durante al menos un día (OR = 5,9; IC 95%, 1,76-19,80; p=0,004). Conclusión: Las características clínicas y de VMI se asociaron con la muerte en pacientes oncológicos con COVID-19 y en VMI.

Cancer patients were at risk of developing severe respiratory conditions when affected by COVID-19, requiring intensive support and invasive mechanical ventilation (IMV). Objective: Evaluate the factors associated with death of cancer patients by COVID-19 who developed respiratory failure and need of IMV. Method: Retrospective cohort study of cancer patients in an oncology intensive care unit (ICU), with COVID-19 and on IMV was carried out from April 2020 to December 2021. All patients with cancer admitted to the ICU on IMV or who developed IMV due to worsening of COVID-19 were sequentially included, excluding those who had been in follow-up of the oncological disease for more than five years. For statistical analysis, measures of central tendency and dispersion were used, as well as absolute and relative frequencies. Multiple logistic regression was applied to evaluate factors associated with mortality, considering statistically significant values of p < 0.05. Results: 85 patients were included in the study. Death was higher for patients with solid tumors (OR= 3.64; 95% CI, 1.06-12.52; p = 0.04), in addition to those who required renal support while in ICU (OR = 6.88; 95% CI, 1.82-25.98; p = 0.004), those who could not be extubated (OR= 8.00; 95% CI, 2.16-29.67; p = 0.002) and who presented an alveolar distension pressure value greater than 15cmH2O for at least one day (OR= 5.9; 95% CI, 1.76-19.80; p = 0.004). Conclusion:Clinical and IMV characteristics were associated with death in cancer patients with COVID-19 and IMV

Construction of a Guide for Assessment and Physiotherapeutic Management of Pain in Cancer Patients / Construction of a Guide for Assessment and Physiotherapeutic Management of Pain in Cancer Patients / Construção de um Guia para Avaliação e Manejo Fisioterapêutico da Dor em Pacientes com Câncer

Physiotherapy can contribute to control pain in cancer patients and educational strategies should be developed to increase physiotherapeutic actions in this context. Objective: To develop a guide for the assessment and physiotherapeutic management of cancer pain. Method: Study developed in three stages: 1. Descriptive analysis of sociodemographic, clinical, functional data, pain characteristics and physiotherapeutic treatments performed on cancer patients receiving palliative care; 2. Development of the preliminary version of the guide based on the results of the first stage and theoretical content; 3. Focus group formed by physiotherapists that resulted in the final version of the guide. Results: 62 patients were included, mainly females (69.3%). The most common tumor site was gynecological (25.8%) and half presented bone metastasis. Neuropathic pain (51.6%), located in the spine (29.0%) was the most prevalent type of pain. The physiotherapeutic treatments most used were: positioning (98.0%), kinesiotherapy (68.0%), walking (39.0%), orthoses (32.0%) and transcutaneous electrical nerve stimulation (21.0%). The focus group suggested changes and positively evaluated the preliminary version of the guide, highlighting that, in addition to an easy-to-understand language, it provided a comprehensive view of the methods for evaluating and physiotherapy treatment of pain.

A fisioterapia pode contribuir para o controle da dor em pacientes com câncer e estratégias educativas devem ser desenvolvidas para aumentar as ações fisioterapêuticas nesse contexto. Objetivo: Elaborar um guia para avaliação e manejo fisioterapêutico da dor no câncer. Método:Estudo desenvolvido em três etapas: 1. Análise descritiva de dados sociodemográficos, clínicos, funcionais, características da dor e tratamentos fisioterapêuticos realizados em pacientes com câncer em cuidados paliativos; 2. Desenvolvimento da versão preliminar do guia a partir dos resultados da primeira etapa e de conteúdo teórico na temática; 3. Realização de grupo focal composto por fisioterapeutas que originou a versão final do guia. Resultados: Foram incluídos 62 pacientes, principalmente do sexo feminino (69,3%). O sítio tumoral mais frequente foi o ginecológico (25,8%) e metade apresentou metástase óssea. O tipo de dor mais prevalente foi a neuropática (51,6%), localizada na coluna (29,0%). Os tratamentos fisioterapêuticos mais utilizados foram: posicionamento (98,0%), cinesioterapia (68,0%), deambulação (39,0%), uso de órteses (32,0%) e transcutaneous electrical nerve stimulation (21,0%). O grupo focal sugeriu alterações e avaliou positivamente a versão preliminar do guia, ressaltando que, além de ser elaborado com linguagem de fácil compreensão, possibilitou a visão integral sobre os métodos para avaliação e tratamento fisioterapêutico da dor.

La fisioterapia puede contribuir al control del dolor en pacientes con cáncer y se deben desarrollar estrategias educativas para incrementar las acciones fisioterapéuticas en este contexto. Objetivo:Desarrollar una guía para la evaluación y manejo fisioterapéutico del dolor oncológico. Método: Estudio desarrollado en tres etapas: 1. Análisis descriptivo de datos sociodemográficos, clínicos, funcionales, características del dolor y tratamientos fisioterapéuticos realizados a pacientes con cáncer que reciben cuidados paliativos; 2. Elaboración de la versión preliminar de la guía con base en los resultados de la primera etapa y contenidos teóricos sobre el tema; 3. Realización de un grupo focal compuesto por fisioterapeutas que dio como resultado la versión final de la guía. Resultados: Se incluyeron 62 pacientes, principalmente mujeres (69,3%). La localización tumoral más frecuente fue ginecológica (25,8%) y la mitad presentó metástasis óseas. El tipo de dolor más prevalente fue el neuropático (51,6%), localizado en la columna (29,0%). Los tratamientos fisioterapéuticos más utilizados fueron: posicionamiento (98,0%), kinesioterapia (68,0%), marcha (39,0%), uso de órtesis (32,0%) y estimulación nerviosa eléctrica transcutánea (21,0%). El grupo focal sugirió cambios y evaluó positivamente la versión preliminar de la guía, destacando que, además de estar elaborada en un lenguaje fácil de entender, proporcionó una visión integral de los métodos de evaluación y tratamiento fisioterapéutico del dolor.

Cytogenetics and genomics in pediatric acute lymphoblastic leukaemia.

The last five decades have witnessed significant improvement in diagnostics, treatment and management of children with acute lymphoblastic leukaemia (ALL). These advancements have become possible through progress in our understanding of the genetic and biological background of ALL, resulting in the introduction of risk-adapted treatment and novel therapeutic targets, e.g., tyrosine kinase inhibitors for BCR::ABL1-positive ALL. Further advances in the taxonomy of ALL and the discovery of new genetic biomarkers and therapeutic targets, as well as the introduction of targeted and immunotherapies into the frontline treatment protocols, may improve management and outcome of children with ALL. In this review we describe the current developments in the (cyto)genetic diagnostics and management of children with ALL, and provide an overview of the most important advances in the genetic classification of ALL. Furthermore, we discuss perspectives resulting from the development of new techniques, including artificial intelligence (AI).

Deciphering the molecular complexity of the IKZF1plus genomic profile using Optical Genome Mapping.

Not available.

Prevalence and factors associated with the occurrence of pathological fractures and their impact on the overall survival of patients with bone metastases under palliative care.

OBJECTIVES: To assess the prevalence and factors associated with the occurrence of pathological fractures and their impact on the overall survival of patients with bone metastases under palliative care. METHODS: An observational retrospective cohort assessment concerning both male and female patients with cancer presenting with bone metastases referred to a palliative care unit. Sociodemographic and clinical data were obtained before and after care unit referral. Patients were followed up until death or the last follow-up (4 years after referral). Logistic regression models and survival curves employing a log-rank test were applied. RESULTS: A total of 348 patients were included in the study. Most were <65 years (65%) and female (62%), and the most frequent primary tumour site was the breast (40%). The prevalence of pathological fractures was 28%, more frequent in the axial skeleton (49%), with no association with overall patient survival (p=0.348). Patients with breast cancer exhibited a 2.96-fold higher chance (95% CI: 1.80 to 4.86) of developing a fracture compared with other tumours, and not receiving previous radiotherapy increased the chances of fracture occurrence by 5.60-fold (95% CI: 2.46 to 12.77). CONCLUSION: A high prevalence of pathological fractures was observed. Presenting with breast cancer and not having undergone previous radiotherapy increase the chances of fracture occurrence, although this is not associated with overall survival in patients under palliative care.

Complex physical therapy employing self-adjusting garment (ReadyWrap®) in breast cancer-related lymphedema cases in Brazilian women: a protocol for a randomized controlled trial.

BACKGROUND: Lymphedema is a common complication following breast cancer treatment. The aim of this study is to evaluate the effectiveness of a self-adjusting compression garment (ReadyWrap®) in reducing (phase 1) and maintaining (phase 2) upper limb volume in women presenting breast cancer-related lymphedema. METHODS: This study will comprise a randomized, controlled, single-blind clinical trial concerning women with breast cancer-related lymphedema undergoing treatment at a public cancer treatment reference hospital in the city of Rio de Janeiro, Brazil. The intervention will be carried out by adapting self-dressing versus the standard treatment of compressive bandaging (phase 1) and compressive mesh (phase 2). Both groups will be assessed at the beginning and end of intensive treatment and followed up for up to 12 months to evaluate immediate and late outcomes. Assessments will be carried out by physical upper limb examination (inspection, palpation, volume, dynamometry, and thermography) and questionnaires application to assess patient's quality of life pertaining to the health, functionality, and symptoms of the affected upper limb, as well adverse effects and adherence to treatment. Data will be analyzed descriptively and analytically through univariate and multiple linear regressions. P values < 0.05 will be considered statistically significant. DISCUSSION: This study will evaluate the effectiveness of a self-adjustable garment (ReadyWrap®) in the treatment of lymphedema secondary to breast cancer in Brazilian women compared to the gold standard treatment for limb volume reduction (phase 1) and maintenance (phase 2) phases comprising, respectively, a compressive bandaging and a compressive mesh. The outcome results will provide data based on both quantitative responses and self-reported participant outcomes. The study will also assess the cost-effectiveness of the ReadyWrap® treatment versus standard care. Finally, we expect to reaffirm one more product/therapy as a treatment for this extremely complex and impactful condition following the data analysis. TRIAL REGISTRATION: NCT04934098 [Clinical trials phase 1]. Registered on June 22, 2021. NCT04881604 [Clinical trials phase 2]. Registered on May 11, 2021.

The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age.

Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning-based classifier using RNA-Seq gene expression data to allocate BCP-ALL samples to all 21 gene expression-defined molecular subtypes. Trained on n = 1869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n = 1018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High-confidence predictions were achieved in 83.7% of samples with 98.9% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel driver candidates in previously unassigned samples. Additional modules provided predictions of samples blast counts, patient's sex, and immunophenotype, allowing the imputation in cases where these information are missing. We established a novel RNA-Seq reference of human B-lymphopoiesis using 7 FACS-sorted progenitor stages from healthy bone marrow donors. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory. This identified shared proximity patterns of BCP-ALL subtypes to normal lymphopoiesis stages, extending immunophenotypic classifications with a novel framework for developmental comparisons of BCP-ALL. ALLCatchR enables RNA-Seq routine application for BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocation and novel insights into underlying developmental trajectories.

Differential survival of Brazilian patients with diffuse large B-cell lymphoma with and without HIV infection.

OBJECTIVE: Combinatorial antiretroviral therapy provided improvement of HIV patients' immune function and a decrease in the incidence of non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is one of the most common NHL forms affecting HIV+ patients. The present study aimed to evaluate the impact of HIV infection on the prognosis of patients treated for DLBCL in a reference cancer treatment center in Brazil. METHODS: A retrospective case-control study was developed with patients followed-up at the Brazilian National Cancer Institute, in which 243 DLBCL patients (91 HIV+ and 152 HIV-) were enrolled. HIV- controls were matched to HIV+ according to date of cancer diagnosis, clinical staging, primary cancer treatment and date of birth. Sociodemographic and cancer treatment data were extracted from medical charts. Kaplan-Meier analyses were carried out to estimate survival, while univariate and multiple Cox regression analyses were used to determine factors associated with mortality. RESULTS: A total of 98 deaths were observed in a 5-year period after cancer diagnosis. A negative association of HIV infection with both overall and disease-specific survival 1 year after cancer diagnosis was observed [hazard ratio (HR) = 1.98 and 1.96, respectively]. The negative association with HIV infection with disease-specific survival remained significant for a 5-year period after cancer diagnosis (HR = 1.53). HIV viral load above 1000 copies/ml at study entry was also associated with shorter overall and cancer-specific survival. CONCLUSIONS: HIV infection negatively impacted prognosis and mortality of DLBCL patients irrespective of cancer-related clinical factors.