Omission of axillary lymph node dissection in breast cancer patients with micrometastasis or isolated tumor cells in sentinel lymph nodes: a 12-year experience in a tertiary breast unit.

INTRODUCTION: After the IBCSG 23-01 trial, our breast center no longer performed axillary lymph node dissection (ALND) after detection of isolated tumor cells (ITC) or micrometastasis in the sentinel lymph nodes (SLN). A recent study suggested that up to half of the patients with micrometastasis in the SLN could benefit from ALND in terms of disease-free survival (DFS) and overall survival (OS). METHODS: This retrospective, unicentric, study analyzed 261 consecutive cT1-3 cN0 breast cancer patients with ITC or micrometastasis in their SLN. Primary objective was comparison of ALND vs. SLN biopsy (SLNB) with regard to DFS and OS. Secondary objectives included analysis of factors associated with an increased rate of locoregional recurrence (LRR), distant metastasis (DM) and metachronous contralateral breast cancer (MCBC). RESULTS: DFS events occurred in 19 patients (7.3%) and 14 patients died (5.4%). Median follow-up time was 78 months. 251 patients (96.2%) had micrometastasis in their SLN. There was no difference in the OS or DFS of ALND vs. SLNB patients. History of previous contralateral breast cancer and WBI were associated with an increased and decreased rate of LRR, respectively. Larger tumor size was associated with an increased rate of DM. Non-ductal histological types were associated with an increased rate of MCBC. DISCUSSION: Avoiding ALND may be safe in pN1mi/pN0(i+) patients. Besides, we strongly encourage clinicians to develop their own follow-up protocols based on the best available evidence, to rapidly identify and treat breast cancer recurrence.

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas.

BACKGROUND: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas. METHODS: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021. RESULTS: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41-74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment-emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs. CONCLUSIONS: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow-up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas. PLAIN LANGUAGE SUMMARY: Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types. Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. Over half of patients had a durable response to larotrectinib, with no unexpected side effects. These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas.

Pattern recognition of hematological profiles of tumors of the digestive tract: an exploratory study.

Aims: In this study, we aimed to apply laboratory blood analysis to identify the hematological (based on hemoglobin concentration, erythrocytes, hematocrit, and RDW count) profiles associated with the most prevalent forms of digestive tract malignancies. Furthermore, we aimed to evaluate how these profiles contributed to distinguishing these tumors at diagnosis. Methods: We collected data from the date of ICD-10 diagnostic coding for C15 esophagus, C16 stomach, C18 colon, and C19 rectum tumors of 184 individuals. The statistical analysis and data visualization approaches, notably the heat map and principal component analysis (PCA), allowed for creating a summary hematological profile and identifying the most associated parameters for each pathologic state. Univariate and multivariate data modeling and ROC analysis were performed in both SPSS and Python. Results: Our data reveal unique patterns based on tumor development anatomical location, clustering the C18 colon and C19 rectum from the C15 esophagus and C16 stomach. We found a significant difference between C16 stomach carcinoma and the other tumors, which substantially correlated with raised RDW in conjunction with low hemoglobin concentration, erythrocytes, and hematocrit counts. In contrast, C18 colon carcinoma had the higher red blood cell count, allowing for the best classification metrics in the test set of the binary logistic regression (LR) model, accounting for an AUC of 0.77 with 94% sensitivity and 52% specificity. Conclusion: This study emphasizes the significance of adding hematological patterns in diagnosing these malignancies, which could path further investigations regarding profiling and monitoring at the point of care.

Total Tumor Load to assist in the decision for additional axillary surgery in the positive sentinel node breast cancer patients.

The Total Tumor Load (TTL) concept has been demonstrated to accurately predict the status of the non-sentinel lymph nodes (NSLN) in breast cancer patients. In 2019, our center implemented the TTL cut-off of 30,000 CK19 mRNA copies/µL as sole criterion for deciding on performing ALND. This retrospective, unicentric, study analyzed 87 cT1-3N0 breast cancer patients treated consecutively in a period of two years and aimed to evaluate the performance of this criterion. Secondary objectives included the comparison of the criterion versus our previous Clinical Decision Rule (CDR) versus ACOSOG Z0011 criteria for avoiding an ALND in proportion of patients spared an ALND and in proportion of patients left with a surgically untreated metastasized axilla. An interim analysis revealed new TTL cut-offs for deciding on performing an ALND. The 30,000 CK19 mRNA copies/µL criterion yielded an area under the ROC Curve (AUC) of 0.849, a false positive (FP) rate of 30.1% and a positive predictive value (PPV) of 38.9%. The 30,000 CK19 mRNA copies/µL criterion spared 58.6% of the patients an ALND versus 41.4% with CDR versus 73.6% with Z0011 and left 0.0% patients with a surgically untreated metastasized axilla versus 21.4% with CDR versus 42.9% with Z0011. The new TTL cut-off of 260,000 CK19 mRNA copies/µL for deciding on an ALND yielded an AUC of 0.753, a FP rate of 13.7% and a PPV of 47.4%. This new criterion spared 78.2% of the study sample an ALND and left 35.7% of metastasized axillae surgically untreated. This study emphasizes the need to find a new balance between locoregional control and the morbidity associated with Berg levels I + II axillary lymph node dissection.

Lipocalin-2 does not influence EAE clinical score but it increases inflammation in central nervous system.

The contribution of lipocalin-2 (LCN2) to multiple sclerosis (MS) is controversial. Herein, we induced experimental autoimmune encephalomyelitis (EAE) in LCN2-null and wild-type (Wt) mice. While we did not find differences between genotypes regarding clinical score, LCN2-null EAE mice presented decreased expression of interferon gamma and diminished demyelination in the cerebellum. Both genotypes presented similar alterations in the thymocyte and splenocyte populations. In MS patients, higher LCN2 CSF levels at diagnosis could be associated with faster disease progression, however further studies are needed to confirm these results, since this association was lost after controlling for the patients age, presence of oligoclonal bands and gender. Overall, our results support a harmful role for LCN2 in the disease context.

Chronic Stress Does Not Influence the Survival of Mouse Models of Glioblastoma.

The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain tumors is not known. Glioblastoma (GBM) is a highly malignant primary brain cancer, for which effective treatments do not exist. Understanding how chronic stress, or its effector hormones glucocorticoids (GCs), may modulate GBM aggressiveness is of great importance. To address this, we used both syngeneic and xenograft in vivo orthotopic mouse models of GBM, in immunocompetent C57BL/6J or immunodeficient NSG mice, respectively, to evaluate how different paradigms of stress exposure could influence GBM aggressiveness and animals' overall survival (OS). Our results demonstrated that a previous exposure to exogenous corticosterone administration, chronic restraint stress, or chronic unpredictable stress do not impact the OS of these mice models of GBM. Concordantly, ex vivo analyses of various GBM-relevant genes showed similar intra-tumor expression levels across all experimental groups. These findings suggest that corticosterone and chronic stress do not significantly affect GBM aggressiveness in murine models.

Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial.

IMPORTANCE: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer. OBJECTIVE: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017. Data analyses were performed from December 2019 to July 2020. INTERVENTIONS: Eligible patients were randomized (2:1) to receive DCVAC/PCa (add-on and maintenance) or placebo, both in combination with chemotherapy (docetaxel plus prednisone). The stratification was applied according to geographical region (US or non-US), prior therapy (abiraterone, enzalutamide, or neither), and Eastern Cooperative Oncology Group performance status (0-1 or 2). DCVAC/PCa or placebo was administered subcutaneously every 3 to 4 weeks (up to 15 doses). MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS), defined as the time from randomization until death due to any cause, in all randomized patients. Survival was compared using 2-sided log-rank test stratified by geographical region, prior therapy with abiraterone and/or enzalutamide, and Eastern Cooperative Oncology Group performance status. RESULTS: A total of 1182 men with mCRPC (median [range] age, 68 [46-89] years) were randomized to receive DCVAC/PCa (n = 787) or placebo (n = 395). Of these, 610 (81.8%) started DCVAC/PCa, and 376 (98.4%) started placebo. There was no difference in OS between the DCVAC/PCa and placebo groups in all randomized patients (median OS, 23.9 months [95% CI, 21.6-25.3] vs 24.3 months [95% CI, 22.6-26.0]; hazard ratio, 1.04; 95% CI, 0.90-1.21; P = .60). No differences in the secondary efficacy end points (radiological progression-free survival, time to prostate-specific antigen progression, or skeletal-related events) were observed. Treatment-emergent adverse events related to DCVAC/PCa or placebo occurred in 69 of 749 (9.2%) and 48 of 379 (12.7%) patients, respectively. The most common treatment-emergent adverse events (DCVAC/PCa [n = 749] vs placebo [n = 379]) were fatigue (271 [36.2%] vs 152 [40.1%]), alopecia (222 [29.6%] vs 130 [34.3%]), and diarrhea (206 [27.5%] vs 117 [30.9%]). CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, DCVAC/PCa combined with docetaxel plus prednisone and continued as maintenance treatment did not extend OS in patients with mCRPC and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02111577.

Time-course effects of functional fitness sessions performed at different intensities on the metabolic, hormonal, and BDNF responses in trained men.

BACKGROUND: To investigate the time-course effects of a self-regulated training session (performed at an rating perceived exertion of 6/10), all-out session, and a control session on the metabolic, hormonal, and brain derived neurotrophic factor (BDNF) responses in Functional-Fitness (FFT) participants. METHODS: In a randomized, crossover fashion, eight healthy males (age 28.1 ± 5.4 years old; body mass 77.2 ± 4.4 kg; VO2max: 52.6 ± 4.6 mL.(kg.min)-1; 2000 m rowing test 7.35 ± 0.18 min; 1RM back squat 135.6 ± 21.9 kg) performed a FFT session under two different conditions: all-out, or with the intensity controlled to elicit an rating perceived exertion (RPE) of 6 in the Borg 10-point scale (RPE6). A control session (no exercise) was also completed. Metabolic (lactate and creatine kinase), hormonal (testosterone and cortisol), and BDNF responses were assessed pre, post-0 h, 1 h, 2 h and 24 h after the sessions. RESULTS: Creatine kinase concentrations were significantly higher (p ≤ 0.05) after 24 h for both training sessions. Total and free testosterone concentrations were lower post-2 h for all-out when compared to the RPE6 session (p ≤ 0.05). Serum cortisol concentration increased post-0 h (p = 0.011) for RPE6 and post-0 h (p = 0.003) and post-1 h (p = 0.030) for all-out session when comparing to baseline concentrations. BDNF was significantly higher (p = 0.002) post-0 h only for the all-out session when compared to baseline. A positive correlation between blood lactate concentrations and BDNF (r = 0.51; p = 0.01) was found for both effort interventions. CONCLUSIONS: A single FFT session when performed in all-out format acutely increases the concentrations of serum BDNF. However, physiological stress markers show that the all-out session requires a longer recovery period when compared to the RPE6 protocol. These findings can be helpful to coaches and practitioners design FFT session.

Acute organ failure and risk of admission to intensive medical care in cancer patients: a single center prospective cohort study. / Falência aguda de órgão e risco de admissão em unidade de terapia intensiva nos pacientes oncológicos: estudo de coorte prospectivo unicêntrico.

OBJECTIVE: To ascertain the cumulative incidence of acute organ failure and intensive care unit admission in cancer patients. METHODS: This was a single-center prospective cohort study of adult cancer patients admitted for unscheduled inpatient care while on systemic cancer treatment. RESULTS: Between August 2018 and February 2019, 10,392 patients were on systemic treatment, 358 had unscheduled inpatient care and were eligible for inclusion, and 285 were included. The mean age was 60.9 years, 50.9% were male, and 17.9% of patients had hematologic cancers. The cumulative risk of acute organ failure was 39.6% (95%CI: 35 - 44), and that of intensive care unit admission among patients with acute organ failure was 15.0% (95%CI: 12 - 18). On admission, 62.1% of patients were considered not eligible for artificial organ replacement therapy. The median follow-up time was 9.5 months. Inpatient mortality was 17.5%, with an intensive care unit mortality rate of 58.8% and a median cohort survival of 134 days (95%CI: 106 - 162). In multivariate analysis, acute organ failure was associated with 6-month postdischarge mortality (HR 1.6; 95%CI: 1.2 - 2.2). CONCLUSION: The risk of acute organ failure in cancer patients admitted for unscheduled inpatient care while on systemic treatment was 39.6%, and the risk of intensive care unit admission was 15.0%. Acute organ failure in cancer patients was an independent poor prognostic factor for inpatient hospital mortality and 6-month survival.

OBJETIVO: Determinar a incidência cumulativa de falência aguda de órgão e internamento em unidade de terapia intensiva em pacientes oncológicos. MÉTODOS: Estudo de coorte prospectivo de pacientes oncológicos adultos em tratamento sistêmico antineoplásico, internados de forma não programada. RESULTADOS: Entre agosto de 2018 e fevereiro de 2019, 10.392 pacientes foram submetidos a tratamento sistêmico antineoplásico, sendo que 358 necessitaram de internamento hospitalar não programado e foram elegíveis para inclusão; por fim, 258 desses pacientes foram incluídos. A média de idade foi de 60,9 anos, e 50,9% eram do sexo masculino; 17,9% dos pacientes tinham câncer hematológico. O risco acumulado de falência de órgãos foi de 39,6% (IC95% 35 - 44) e o risco de internamento na unidade de terapia intensiva em pacientes com falência aguda de órgão foi de 15,0% (IC95% 12 - 18). À admissão em internamento, 62,1% dos pacientes foram considerados não elegíveis para terapia de substituição artificial de órgãos. O tempo mediano de seguimento foi de 9,5 meses. A mortalidade hospitalar foi de 17,5%, na unidade de terapia intensiva de 58,8%. A mediana de sobrevivência da coorte foi de 134 dias (IC95% 106 - 162). Na análise multivariada, a falência aguda de órgão se associou com a mortalidade aos 6 meses após a alta (hazard ratio: 1,6; IC95% 1,2 - 2,2). CONCLUSÃO: O risco de falência aguda de órgão em pacientes oncológicos admitidos para tratamento hospitalar não programado durante o tratamento sistémico foi de 39,6% e o risco de internamento em unidade de terapia intensiva foi de 15,0%. A falência aguda de órgão em pacientes oncológicos foi um fator de prognóstico independente para maior mortalidade intra-hospitalar e menor sobrevivência aos 6 meses após a alta.

Cadherin-3 is a novel oncogenic biomarker with prognostic value in glioblastoma.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin-3 (also known as P-cadherin), a cell-cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P-cadherin in this highly malignant brain tumor. CDH3/P-cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P-cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3-associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P-cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high-grade gliomas. P-cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P-cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P-cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor.

Falência aguda de órgão e risco de admissão em unidade de terapia intensiva nos pacientes oncológicos: estudo de coorte prospectivo unicêntrico / Acute organ failure and risk of admission to intensive medical care in cancer patients: a single center prospective cohort study

RESUMO Objetivo: Determinar a incidência cumulativa de falência aguda de órgão e internamento em unidade de terapia intensiva em pacientes oncológicos. Métodos: Estudo de coorte prospectivo de pacientes oncológicos adultos em tratamento sistêmico antineoplásico, internados de forma não programada. Resultados: Entre agosto de 2018 e fevereiro de 2019, 10.392 pacientes foram submetidos a tratamento sistêmico antineoplásico, sendo que 358 necessitaram de internamento hospitalar não programado e foram elegíveis para inclusão; por fim, 258 desses pacientes foram incluídos. A média de idade foi de 60,9 anos, e 50,9% eram do sexo masculino; 17,9% dos pacientes tinham câncer hematológico. O risco acumulado de falência de órgãos foi de 39,6% (IC95% 35 - 44) e o risco de internamento na unidade de terapia intensiva em pacientes com falência aguda de órgão foi de 15,0% (IC95% 12 - 18). À admissão em internamento, 62,1% dos pacientes foram considerados não elegíveis para terapia de substituição artificial de órgãos. O tempo mediano de seguimento foi de 9,5 meses. A mortalidade hospitalar foi de 17,5%, na unidade de terapia intensiva de 58,8%. A mediana de sobrevivência da coorte foi de 134 dias (IC95% 106 - 162). Na análise multivariada, a falência aguda de órgão se associou com a mortalidade aos 6 meses após a alta (hazard ratio: 1,6; IC95% 1,2 - 2,2). Conclusão: O risco de falência aguda de órgão em pacientes oncológicos admitidos para tratamento hospitalar não programado durante o tratamento sistémico foi de 39,6% e o risco de internamento em unidade de terapia intensiva foi de 15,0%. A falência aguda de órgão em pacientes oncológicos foi um fator de prognóstico independente para maior mortalidade intra-hospitalar e menor sobrevivência aos 6 meses após a alta.

ABSTRACT Objective: To ascertain the cumulative incidence of acute organ failure and intensive care unit admission in cancer patients. Methods: This was a single-center prospective cohort study of adult cancer patients admitted for unscheduled inpatient care while on systemic cancer treatment. Results: Between August 2018 and February 2019, 10,392 patients were on systemic treatment, 358 had unscheduled inpatient care and were eligible for inclusion, and 285 were included. The mean age was 60.9 years, 50.9% were male, and 17.9% of patients had hematologic cancers. The cumulative risk of acute organ failure was 39.6% (95%CI: 35 - 44), and that of intensive care unit admission among patients with acute organ failure was 15.0% (95%CI: 12 - 18). On admission, 62.1% of patients were considered not eligible for artificial organ replacement therapy. The median follow-up time was 9.5 months. Inpatient mortality was 17.5%, with an intensive care unit mortality rate of 58.8% and a median cohort survival of 134 days (95%CI: 106 - 162). In multivariate analysis, acute organ failure was associated with 6-month postdischarge mortality (HR 1.6; 95%CI: 1.2 - 2.2). Conclusion: The risk of acute organ failure in cancer patients admitted for unscheduled inpatient care while on systemic treatment was 39.6%, and the risk of intensive care unit admission was 15.0%. Acute organ failure in cancer patients was an independent poor prognostic factor for inpatient hospital mortality and 6-month survival.

Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine.

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.

Fabry Disease and the Heart: A Comprehensive Review.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat.

Intracellular Autofluorescence as a New Biomarker for Cancer Stem Cells in Glioblastoma.

The identification of cancer stem cells (CSCs), which are implicated in tumor initiation, progression, therapy resistance, and relapse, is of great biological and clinical relevance. In glioblastoma (GBM), this is still a challenge, as no single marker is able to universally identify populations of GBM cancer stem cells (GSCs). Indeed, there is still controversy on whether biomarker-expressing cells fulfill the functional criteria of bona fide GSCs, despite being widely used. Here, we describe a novel subpopulation of autofluorescent (Fluo+) cells in GBM that bear all the functional characteristics of GSCs, including higher capacity to grow as neurospheres, long-term self-renewal ability, increased expression of stem cell markers, and enhanced in vivo tumorigenicity. Mechanistically, the autofluorescent phenotype is largely due to the intracellular accumulation of riboflavin, mediated by the ABC transporter ABCG2. In summary, our work identifies an intrinsic cellular autofluorescent phenotype enriched in GBM cells with functional stem cells features that can be used as a novel, simple and reliable biomarker to target these highly malignant tumors, with implications for GBM biological and clinical research.

Reappraising the need for a control CT in mild head injury patients on anticoagulation.

BACKGROUND: Head injury is a frequent reason for admission to the emergency department. In parallel, there is a growing use of anticoagulants in an increasingly aging population, which renders this particular group of trauma patients more frequent. In several countries, including Portugal, a 24-h surveillance period followed by repetition of head computed tomography (CT) is the standard procedure for these patients. However, these recommendations have not been based on studies of prevalence of intracranial hemorrhages in control head CTs, namely in this group of anticoagulated patients. This study intends to evaluate the prevalence of de novo intracranial hemorrhages in control head CTs in anticoagulated patients. METHOD: An observational study was carried out, which included patients admitted to Hospital de Braga between June 2017 and January 2018, victims of head injury and on anticoagulation therapy, whose admission head CT excluded intracranial hemorrhage. RESULTS: We collected a total of 201 patients, with a mean age of 81.6 years, and 57.5% of them were prescribed warfarin; 181 of these patients repeated the head CT 24 h later. Of these 181 patients, 3 (1.66%) exhibited intracranial hemorrhage in control CT, without surgical indication. All patients were followed up 1 month after the trauma, and there was no readmission requiring hospitalization, surgery or death. CONCLUSIONS: In conclusion, de novo intracranial hemorrhage in control head CT of anticoagulated patients is rare. We propose that these patients may be discharged if the admission CT does not reveal intracranial hemorrhage, providing that they are accompanied by a caregiver and informed about red flags.

Fabry Disease Therapy: State-of-the-Art and Current Challenges.

Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that "in vitro" amenability may not always reflect "in vivo" amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.

Iron Status is Associated with Mood, Cognition, and Functional Ability in Older Adults: A Cross-Sectional Study.

Several conditions are risk factors for iron deficiency (ID), some of which are highly prevalent in older individuals. Despite the amount of evidence pointing for a role of ID in cognition, mood and physical functional ability, the research addressing these associations in older individuals is still scarce. In the present study, 162 older community-dwelling individuals (29.53% classified as ID) were enrolled in a cross-sectional analysis and characterized regarding cognition, mood, functional ability, general nutritional intake and iron status. Assessment of iron status was performed using several blood biomarkers. Storage and erythropoiesis dimensions were positively associated with memory, along with an interaction (moderator effect) between iron storage and nutritional status. A more depressed mood was negatively associated with (iron) transport, transport saturation and erythropoiesis dimensions, and functional tiredness was positively associated with the erythropoiesis dimension. These observations indicate that lower iron status is associated with depressive mood, functional tiredness and poorer memory ability, with the latter moderated by nutritional status. These findings suggest that using iron as a continuous variable may be useful in finding associations with iron homeostasis, eventually missed when iron levels are considered within the usual classification groups.

Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study.

Background: Cognition in the elderly is heterogeneous. Senescence of the immune system is increasingly considered as a potential player in cognitive performance. We explored here the interplay between cognitive performance and peripheral immune molecules in healthy older individuals. Methods: A cross-sectional study of clinically well characterized senior healthy individuals (120; 51-87 years old) previously clustered as "Good" and "Poor" performers based on established tests that evaluate memory and executive function. A plasma concentration of 30 immune molecules was assessed by multiplex analysis and correlated with parameters of cognitive performance. Results: Participants with worse cognitive performance ("Poor") exhibited increased concentrations of IL-1ß, IL-8, IL-13, and tumor necrosis factor (TNF) when compared to individuals with a better cognitive performance ("Good"). The cognitive dimensions memory and executive function, when considered separately, displayed a negative association with several immune molecules (IL-1ß, IL-1RA, IL-6, IL-13, IP-10, and TNF with memory and only IL-1ß with executive function), even controlling for age, sex, years of formal education, mood, and use of anti-inflammatory drugs. Regression analysis showed that several of these molecules (IL-1ß, IL-6, IL-8, and IL-13) contribute to predicting whether an individual belongs to the "Good" or "Poor" cognitive performance group. Conclusion: These results strengthen the hypothesis that increased concentrations of peripheral immune molecules, like IL-1ß, are associated with worse cognitive performance in senior healthy individuals. It further highlights that some poorly studied immune molecules should be considered in the context of cognitive aging, such as IL-13, here revealed as a new player in such interaction.

Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy?

BACKGROUND: Fabry disease (FD) is a treatable cause of hypertrophic cardiomyopathy (HCM). We aimed to determine the independent predictors of FD and to define a clinically useful strategy to discriminate FD among HCM. METHODS: Multicenter study including 780 patients with the ESC definition of HCM. FD screening was performed by enzymatic assay in males and genetic testing in females. Multivariate regression analysis identified independent predictors of FD in HCM. A discriminant function analysis defined a score based on the weighted combination of these predictors. RESULTS: FD was found in 37 of 780 patients with HCM (4.7%): 31 with p.F113L mutation due to a founder effect; and 6 with other variants (p.C94S; p.M96V; p.G183V; p.E203X; p.M290I; p.R356Q/p.G360R). FD prevalence in HCM adjusted for the founder effect was 0.9%. Symmetric HCM (OR 3.464, CI95% 1.151-10.430), basal inferolateral late gadolinium enhancement (LGE) (OR 10.677, CI95% 3.633-31.380), bifascicular block (OR 10.909, CI95% 2.377-50.059) and ST-segment depression (OR 4.401, CI95% 1.431-13.533) were independent predictors of FD in HCM. The score ID FABRY-HCM [-0.729 + (2.781xBifascicular block) + (0.590xST depression) + (0.831xSymmetric HCM) + (2.130xbasal inferolateral LGE)] had a negative predictive value of 95.8% for FD, with a cut-off of 1.0, meaning that, in the absence of both bifascicular block and basal inferolateral LGE, FD is a less probable cause of HCM, being more appropriate to perform HCM gene panel than targeted FD screening. CONCLUSION: FD prevalence in HCM was 0.9%. Bifascicular block and basal inferolateral LGE were the most powerful predictors of FD in HCM. In their absence, HCM gene panel is the most appropriate step in etiological study of HCM.