Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Lessening the Impact of Financial Toxicity (LIFT): a protocol for a multi-site, single-arm trial examining the effect of financial navigation on financial toxicity in adult patients with cancer in rural and non-rural settings.

BACKGROUND: Almost half of the patients with cancer report cancer-related financial hardship, termed "financial toxicity" (FT), which affects health-related quality of life, care retention, and, in extreme cases, mortality. This increasingly prevalent hardship warrants urgent intervention. Financial navigation (FN) targets FT by systematically identifying patients at high risk, assessing eligibility for existing resources, clarifying treatment cost expectations, and working with patients and caregivers to develop a plan to cope with cancer costs. This trial seeks to (1) identify FN implementation determinants and implementation outcomes, and (2) evaluate the effectiveness of FN in improving patient outcomes. METHODS: The Lessening the Impact of Financial Toxicity (LIFT) study is a multi-site Phase 2 clinical trial. We use a pre-/post- single-arm intervention to examine the effect of FN on FT in adults with cancer. The LIFT trial is being conducted at nine oncology care settings across North Carolina in the United States. Sites vary in geography (five rural, four non-rural), size (21-974 inpatient beds), and ownership structure (governmental, non-profit). The study will enroll 780 patients total over approximately 2 years. Eligible patients must be 18 years or older, have a confirmed cancer diagnosis (any type) within the past 5 years or be living with advanced disease, and screen positive for cancer-related financial distress. LIFT will be delivered by full- or part-time financial navigators and consists of 3 components: (1) systematic FT screening identification and comprehensive intake assessment; (2) connecting patients experiencing FT to financial support resources via trained oncology financial navigators; and (3) ongoing check-ins and electronic tracking of patients' progress and outcomes by financial navigators. We will measure intervention effectiveness by evaluating change in FT (via the validated Comprehensive Score of Financial Toxicity, or COST instrument) (primary outcome), as well as health-related quality of life (PROMIS Global Health Questionnaire), and patient-reported delayed or forgone care due to cost. We also assess patient- and stakeholder-reported implementation and service outcomes post-intervention, including uptake, fidelity, acceptability, cost, patient-centeredness, and timeliness. DISCUSSION: This study adds to the growing evidence on FN by evaluating its implementation and effectiveness across diverse oncology care settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04931251. Registered on June 18, 2021.

Pustular lesions in patients with Crohn disease and treatment with tumour necrosis factor-α inhibitors.

We present seven new cases of patients with Crohn disease who developed lesions clinically compatible with amicrobial pustulosis of the flexures during their treatment with anti-tumour necrosis factor therapy.

Obesity status and obesity-associated gut dysbiosis effects on hypothalamic structural covariance.

BACKGROUND: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms. METHODS: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms. RESULTS: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms. CONCLUSIONS: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation.

Cervical Squamous Intraepithelial Lesions Are Associated with Differences in the Vaginal Microbiota of Mexican Women.

Cervical cancer is an important health concern worldwide and is one of the leading causes of death in Mexican women. Previous studies have shown changes in the female genital tract microbe community related to human papillomavirus (HPV) infection and cervical cancer; yet, this link remains unexplored in many human populations. This study evaluated the vaginal bacterial community among Mexican women with precancerous squamous intraepithelial lesions (SIL). We sequenced the V3 region of the 16S rRNA gene in cervical samples from 228 Mexican women, including 121 participants with SIL, most of which were HPV positive, and 107 healthy women without HPV infection or SIL. The presence of SIL was associated with changes in composition (beta diversity) and with a higher species richness (Chao1). A comparison of HPV-positive women with and without SIL showed that microbiota changes occurred even in the absence of SIL. Multivariate association with linear models (MaAsLin) analysis yielded independent associations between HPV infection and an increase in the relative abundance of Brachybacterium conglomeratum and Brevibacterium aureum as well as a decrease in two Lactobacillus iners operational taxonomic units (OTUs). We also identified a positive independent association between HPV-16, the most common HPV subtype linked to SIL, and Brachybacterium conglomeratum. Our work indicates that HPV infection leading to SIL is primarily associated with shifts in vaginal microbiota composition, some of which may be specific to this human population. IMPORTANCE Human papillomavirus (HPV) plays a critical role in cervical carcinogenesis but is not sufficient for cervical cancer development, indicating the involvement of other factors. The vaginal microbiota is an important factor in controlling infections caused by HPV, and, depending on its composition, it can modulate the microenvironment in vaginal mucosa against viral infections. Ethnic and sociodemographic factors influence differences in vaginal microbiome composition, which underlies the dysbiotic patterns linked to HPV infection and cervical cancer across different populations of women. Here, we provide evidence for associations between vaginal microbiota patterns and HPV infection linked to ethnic and sociodemographic factors. To our knowledge, this is the first report of the species Brevibacterium aureum and Brachybacterium conglomeratum linked to HPV infection or squamous intraepithelial lesions (SIL).

Risk stratification and outreach to hematology/oncology patients during the COVID-19 pandemic.

PURPOSE: Cancer patients have many medical and psychosocial needs, which may increase during the COVID-19 pandemic. We sought to (1) risk-stratify hematology/oncology patients using general medicine and cancer-specific methods to identify those at high risk for acute care utilization, (2) measure the correlation between two risk stratification methods, and (3) perform a telephone-based needs assessment with intervention for high-risk patients. METHODS: Patients were risk-stratified using a general medical health composite score (HCS) and a cancer-specific risk (CSR) stratification based on disease and treatment characteristics. The correlation between HCS and CSR was measured using Spearman's correlation. A multi-disciplinary team developed a focused needs assessment script with recommended interventions for patients categorized as high-risk by either method. The number of patient needs identified and referrals for services made in the first month of outreach are reported. RESULTS: A total of 1697 patients were risk-stratified, with 17% high-risk using HCS and 22% high-risk using CSR. Correlation between HCS and CSR was modest (ρ = 0.41). During the first month of the pilot, 286 patients were called for outreach with 245 contacted (86%). Commonly identified needs were financial difficulties (17%), uncontrolled symptoms (15%), and interest in advance care planning (13%), resulting in referral for supportive services for 33% of patients. CONCLUSION: There is a high burden of unmet medical and psychosocial needs in hematology/oncology patients during the COVID-19 pandemic. A telephone-based outreach program results in the identification of and intervention for these needs; however, additional cancer-specific risk models are needed to improve targeting to high-risk patients.

Imaging and diagnostic approach of the adnexal mass: what the oncologist should know.

Early detection and characterization of ovarian lesions is of utmost importance for adequate management. Ovarian cancer accounts for 3.3% of all cancers in women worldwide but has only a 5% of female cancer deaths because of low survival rates. The majority of ovarian lesions are benign and have spontaneous resolution. The adequate discrimination between benign and malignant lesions is the most important starting point for a correct and optimal management. Ultrasound is the method of choice up until now for adequate assessment of adnexal abnormalities, no other method has proven superior. Along time, there has been many classification systems that aim standardization of adnexal masses The Gynecology Imaging Reporting and Data System (GI-RADS), published in 2019. The International Ovarian Tumor Analysis (IOTA) group standardized in 2013 the approach of adnexal pathology descriptions by ultrasound with the limitation of needing pathologic reports for complete assessment. The Ovarian Adnexal Reporting and Data System (O-RADS) is a lexicon designed in 2018 to standardize definitions of characteristics by ultrasound. This system offers an interpretation method to decrease ambiguity and recommends management guides according to its classification.

Changing Trends in Drug Prescription and Causes of Treatment Discontinuation of First Biologic Over Ten Years in Psoriasis in the Spanish Biobadaderm Registry. / Cambios en las tendencias de la prescripción y causas de la interrupción en los tratamientos biológicos indicados en la psoriasis durante los primeros 10 años. Datos obtenidos del registro español Biobadaderm.

BACKGROUND AND OBJECTIVES: Current psoriasis guidelines do not usually include recommendations about first line classical or biologic treatment. The objectives of this study were: to describe shifts in the prescription of the first biological treatment, and to compare treatment withdrawal and rates of adverse events over ten years. MATERIAL AND METHODS: Biobadaderm registry was analyzed to describe: first biological prescription in bio-naïve patients, adverse events rate and reasons for drug withdrawal comparing three periods of time (2008-2010, 2011-2014, 2015-2018). RESULTS: Anti-TNF drugs were the most prescribed biological drug from 2008 to 2010. Ustekinumab has become the most prescribed first biologic since 2014. The main reasons for drug discontinuation were adverse events, lack of efficacy and remission. In each period any treatment was less likely to be discontinued due to any of these three reasons comparing to the previous period. CONCLUSIONS: The present study identifies trends in prescription of the first biological antipsoriatic drug in clinical practice from 2008 to 2018. It suggests that we have become more comfortable with the safety profile and more exigent with the efficacy of the drugs.

Dominios culturales relacionados con la depresión en adultos / Cultural domains related to depression in adults / Domínios culturais relacionados com a depressão em adultos

RESUMEN Introducción: La depresión representa un problema de salud que repercute de manera importante en la estabilidad mental y calidad de vida de las personas. Estudiar los dominios culturales relacionados con esta patología es relevante para diferenciarla, pues suele confundirse con otros estados emocionales. Objetivo: Analizar los dominios culturales relacionados con la depresión en mujeres y hombres adultos. Material y métodos: Estudio mixto de consenso cultural realizado en San Luis Potosí, México, que incluyó a 163 participantes. La recolección de datos se efectuó por muestreo a conveniencia mediante listados libres, entrevistas estructuradas y sorteos por montones. Se identificaron 20 elementos categorizados en áreas temáticas, se organizaron en conjuntos jerárquicos para observar la distribución y dimensiones de los dominios culturales. Resultados: Las personas tienen nociones en común respecto a lo que implica la depresión. Los elementos relacionados con mayor frecuencia fueron: tristeza, desánimo y soledad, a su vez, la agrupación de estos mostró dos dimensiones principales: consecuencias y atención. Discusión: La literatura reporta que hay diferencias subjetivas entre la depresión y otros padecimientos, también indica que existen contrastes por sexo y que las condiciones sociales desfavorables se relacionan con malestares emocionales; sin embargo, en las dimensiones culturales no están presentes la promoción ni la prevención de esta enfermedad. Conclusiones: Considerar los dominios culturales de la población adulta con respecto a la depresión posibilita la creación de programas dirigidos a promocionar la salud y prevenir la enfermedad, así como facilitar la práctica clínica fundamentada en el contexto social y cultural de las personas.

ABSTRACT Introduction: Depression represents a health problem which has important impacts on the mental stability and quality of life. Therefore, studying the related cultural domains becomes relevant in order to differentiate this pathology from other emotional states. Objective: To analyze the cultural domains related to depression in adults. Materials and methods: This is a mixed study with cultural consensus carried out in the state of San Luis Potosi, Mexico, which included 163 participants. Data collection was based on sampling by convenience using free listings, structured interviews, and lots. Twenty elements related to the thematic areas were identified, and organized in hierarchical sets in order to observe the distributions and dimensions of the cultural domains. Results: Participants showed common notions regarding what depression implies. The most cited related elements were sadness, discouragement, and loneliness, which were grouped in two main dimensions: consequences and attention. Discussion: The literature reports the existance of subjective differences between depression and other emotional pathologies, and that these differences are influenced by sex and social conditions. Nevertheless, the related cultural dimensions are not always considered, in particular regarding the prevention of the illness. Conclusions: The precise consideration of the cultural domains which are associated with adults suffering from depression can allow the design and implementation of programs aimed at promoting health and preventing illness, as well as at fostering a clinical practice based on the social and cultural context of these persons.

RESUMO Introdução: A depressão representa um problema de saúde que reverbera de maneira importante na estabilidade mental e qualidade de vida das pessoas; estudar os domínios culturais relacionados com esta patologia é relevante para diferenciá-la, já que geralmente confunde-se com outros estados emocionais. Objetivo: Analisar os domínios culturais relacionados com a depressão em mulheres e homens adultos. Material e métodos: Estudo misto de consenso cultural realizado em San Luis Potosí, México; que incluía 163 participantes, a coleta de dados efetuou-se por amostragem a conveniência mediante listados livres, entrevistas estruturadas e classificação da pilha, identificaram-se 20 elementos categorizados por áreas temáticas, organizaram-se em conjuntos hierárquicos para observar a distribuição e dimensões dos domínios culturais. Resultados: As pessoas têm noções em comum ao respeito do que envolve a depressão. Os elementos relacionados com maior frequência foram: tristeza, desânimo e solidão; enquanto a agrupação deles mostrou duas dimensões principais: consequências e atenção. Discussão: A literatura relata que existem diferenças subjetivas entre a depressão e outras doenças, indica também que existem contrastes por sexo e que as condições sociais desfavoráveis se relacionam ao desconforto emocional, porém, nas dimensões culturais não estão presentes a promoção nem a prevenção desta doença. Conclusões: Considerar os domínios culturais da população adulta ao respeito da depressão, possibilita a criação de programas dirigidos a promover a saúde e prevenir a doença, assim como facilitar a prática clínica fundamentada no contexto social e cultural das pessoas.

El músculo pectoral mayor como opción para la valoración electromiográfica del plexo braquial / The major pectoral muscle as an option for the electromyographic value of the brachial plexus

El registro electromiográfico es una forma de evaluación de los impulsos eléctricos aferentes y eferentes del sistema muscular al sistema nervioso, su valoración permite explorar lesiones nerviosas o patologías neuromusculares en unidades motoras o nerviosas específicas, en este caso, valoramos el plexo braquial y se desea comparar la actividad de este plexo entre los músculos del brazo con el pectoral mayor, ya que, este último puede servir como una opción de valoración del plexo braquial y además de fácil acceso. Este estudio se realizó comparando 4 pacientes de la unidad de neurofisiología de la Caja Nacional de Salud de la ciudad de La Paz, donde se comparó la actividad eléctrica de los músculos del brazo y el pectoral mayor. Los resultados obtenidos mostraron que el músculo pectoral mayor sería suficiente para valorar la actividad eléctrica en las lesiones del plexo braquial, hemos observado que, sirve para valorar lesiones, tanto del tronco superior e inferior del plexo braquial como una lesión total de este plexo, además, permite mejor acceso que los músculos del brazo en caso de accidentes con lesión de los miembros superiores.

[Headache triggered exclusively by laughing, as a presenting symptom of a posterior fossa meningioma]. / Cefalea desencadenada exclusivamente por la risa, como forma de presentacion de un meningioma de fosa posterior.

TITLE: Cefalea desencadenada exclusivamente por la risa, como forma de presentacion de un meningioma de fosa posterior.

Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: A split-mouth randomised clinical trial.

BACKGROUND: Since the discovery of adult mesenchymal stem cells extensive research has been conducted to determine their mechanisms of differentiation and effectiveness in cell therapy and regenerative medicine. MATERIAL AND METHODS: To assess the efficacy of autologous dental pulp mesenchymal stem cells delivered in a collagen matrix for post-extraction socket healing, a single-centre, double-blind, randomised, split-mouth, controlled clinical trial was performed. Both impacted mandibular third molars were extracted from 32 patients. Dental pulp was collected and dissociated; the resulting cell suspension, obtained by centrifugation, was incorporated into a resorbable collagen matrix and implanted in 32 experimental post-extraction sockets. Collagen matrices alone were implanted in 32 contralateral, control post-extraction sockets. Two neuroradiologists independently assessed the extent of bone repair at 6 months after the extractions. Computed tomography (CT, Philips Brilliance) and an advanced display platform (IntelliSpace Portal) was used to record extraction socket density, expressed as Hounsfield units (HU) and height (mm) of the distal interdental bone septum of the second molar. Measurements at 6 months post-extraction were compared with measurements obtained immediately after extraction. Data were analysed with the statistical program STATA 14. RESULTS: Two patients dropped out of the study. The final sample consisted of 22 women and 8 men (mean age, 23 years; range: 18-30 years). Clinical, radiological, and surgical characteristics of impacted third molars of the control and experimental groups were homogeneous. Measurements obtained by the two neuroradiologists showed agreement. No significant differences were found in the extent of bone repair during analyses of density (p=0.4203 neuroradiologist 1; p=0.2525 neuroradiologist 2) or interdental septum height (p=0.2280 neuroradiologist 1; p=0.4784 neuroradiologist 2). CONCLUSIONS: In our clinical trial, we were unable to demonstrate that autologous dental pulp mesenchymal stem cells reduce socket bone resorption after inferior third molar extraction.