SEOM-GG clinical guidelines for the management of germ-cell testicular cancer (2023).

Testicular germ cell tumors are the most common tumors in adolescent and young men. They are curable malignancies that should be treated with curative intent, minimizing acute and long-term side effects. Inguinal orchiectomy is the main diagnostic procedure, and is also curative for most localized tumors, while patients with unfavorable risk factors for recurrence, or those who are unable or unwilling to undergo close follow-up, may require adjuvant treatment. Patients with persistent markers after orchiectomy or advanced disease at diagnosis should be staged and classified according to the IGCCCG prognostic classification. BEP is the most recommended chemotherapy, but other schedules such as EP or VIP may be used to avoid bleomycin in some patients. Efforts should be made to avoid unnecessary delays and dose reductions wherever possible. Insufficient marker decline after each cycle is associated with poor prognosis. Management of residual masses after chemotherapy differs between patients with seminoma and non-seminoma tumors. Patients at high risk of relapse, those with refractory tumors, or those who relapse after chemotherapy should be managed by multidisciplinary teams in experienced centers. Salvage treatment for these patients includes conventional-dose chemotherapy (TIP) and/or high-dose chemotherapy, although the best regimen and strategy for each subgroup of patients is not yet well established. In late recurrences, early complete surgical resection should be performed when feasible. Given the high cure rate of TGCT, oncologists should work with patients to prevent and identify potential long-term side effects of the treatment. The above recommendations also apply to extragonadal retroperitoneal and mediastinal tumors.

Comparative biological activity of palbociclib and ribociclib in hormone receptor-positive breast cancer.

This study examines the biological effects of palbociclib and ribociclib in hormone receptor-positive breast cancer, pivotal to the HARMONIA prospective phase III clinical trial. We explore the downstream impacts of these CDK4/6 inhibitors, focusing on cell lines and patient-derived tumor samples. We treated HR+ breast cancer cell lines (T47D, MCF7, and BT474) with palbociclib or ribociclib (100 nM or 500 nM), alone or combined with fulvestrant (1 nM), over periods of 24, 72, or 144 h. Our assessments included PAM50 gene expression, RB1 phosphorylation, Lamin-B1 protein levels, and senescence-associated ß-galactosidase activity. We further analyzed PAM50 gene signatures from the CORALLEEN and NeoPalAna phase II trials. Both CDK4/6 inhibitors similarly inhibited proliferation across the cell lines. At 100 nM, both drugs partially reduced p-RB1, with further decreases at 500 nM over 144 h. Treatment led to reduced Lamin-B1 expression and increased senescence-associated ß-galactosidase activity. Both drugs enhanced Luminal A and reduced Luminal B and proliferation signatures at both doses. However, the HER2-enriched signature significantly diminished only at the higher dose of 500 nM. Corresponding changes were observed in tumor samples from the CORALLEEN and NeoPalAna studies. At 2 weeks of treatment, both drugs significantly reduced the HER2-enriched signature, but at surgery, this reduction was consistent only with ribociclib. Our findings suggest that while both CDK4/6 inhibitors effectively modulate key biological pathways in HR+/HER2- breast cancer, nuances in their impact, particularly on the HER2-enriched signature, are dose-dependent, influenced by the addition of fulvestrant and warrant further investigation.

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response.

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

Sex-specific impact of inflammation on traditional cardiovascular risk factors and atherosclerosis in axial spondyloarthritis. A multicentre study of 913 patients.

INTRODUCTION: The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and sex differences in this regard are yet to be assessed. METHODS: Study including 611 men and 302 women from the Spanish multicentre AtheSpAin cohort to assess CV disease in axSpA. Data on CV disease risk factors were collected both at disease diagnosis and at enrolment, and data on disease activity, functional indices and carotid ultrasonography only at enrolment. RESULTS: After a median disease duration of 9 years, patients of both sexes who at disease diagnosis had elevated acute phase reactants (APRs), more frequently had hypertension and obesity. The same occurred with dyslipidaemia in men and with diabetes mellitus in women. At enrolment, CV risk factors were independently associated with APR and with activity and functional indices, with various sex differences. C reactive protein (CRP) values were inversely associated with HDL-cholesterol in men (ß coefficient: -1.2 (95% CI: -0.3 to -0.07) mg/dL, p=0.001), while erythrocyte sedimentation rate values were positively associated with triglycerides in women (ß coefficient: 0.6 (95% CI: 0.04 to 1) mg/dL, p=0.035). Furthermore, only women showed an independent relationship between insulin resistance parameters and APR or disease activity. Both men and women with high-very high CV risk according to the Systematic Assessment of Coronary Risk Evaluation 2 and CRP levels higher than 3 mg/L at diagnosis of the disease presented carotid plaques significantly more frequently than those with normal CRP levels at disease diagnosis. CONCLUSION: Inflammation is associated with atherosclerosis and CV disease in axSpA. A gender-driven effect is observed in this relationship.

Long-Term Survival of Subcutaneous Biosimilar Tumor Necrosis Factor Inhibitors Compared to Originators: Results From a Multicenter Prospective Registry.

OBJECTIVE: To analyze the long-term survival of subcutaneous biosimilar tumor necrosis factor inhibitors compared to the originator molecules in patients with rheumatic diseases, as well as the factors associated with drug discontinuation. METHODS: Retrospective analysis of BIOBADASER, the Spanish multicenter prospective registry of patients with rheumatic disease receiving biologic and targeted disease-modifying antirheumatic drugs. Patients who started etanercept (ETN) or adalimumab (ADA) from January 2016 to October 2023 were included. The survival probabilities of biosimilars and originators were compared using Kaplan-Meier estimating curves. To identify factors associated with differences in the retention rates, hazard ratios (HR) were estimated using Cox regression models for all and specific causes (inefficacy or adverse events [AEs]) of discontinuation. RESULTS: A total of 4162 patients received 4723 treatment courses (2991 courses of ADA and 1732 courses of ETN), of which 722 (15.29%) were with originator molecules and 4001 (84.71%) were with biosimilars. The originators were more frequently discontinued than biosimilars (53.32% vs 33.37%, respectively). The main reason for discontinuation was inefficacy (60.35% of the treatments). The risk of overall discontinuation was lower for biosimilars (adjusted HR 0.84, 95% CI 0.75-0.95). Female sex, obesity, and second or later treatment lines increased the risk of discontinuation, whereas disease duration and the use of concomitant methotrexate were associated with a greater survival. When assessing cause-specific reasons of discontinuation, excluding nonmedical switching, the results from the crude and adjusted analyses showed no significant differences in the retention rate between biosimilars and originators. CONCLUSION: No significant differences were found between treatments in long-term survival due to inefficacy or AEs.

Unveiling the Binding between the Armadillo-Repeat Domain of Plakophilin 1 and the Intrinsically Disordered Transcriptional Repressor RYBP.

Plakophilin 1 (PKP1), a member of the p120ctn subfamily of the armadillo (ARM)-repeat-containing proteins, is an important structural component of cell-cell adhesion scaffolds although it can also be ubiquitously found in the cytoplasm and the nucleus. RYBP (RING 1A and YY1 binding protein) is a multifunctional intrinsically disordered protein (IDP) best described as a transcriptional regulator. Both proteins are involved in the development and metastasis of several types of tumors. We studied the binding of the armadillo domain of PKP1 (ARM-PKP1) with RYBP by using in cellulo methods, namely immunofluorescence (IF) and proximity ligation assay (PLA), and in vitro biophysical techniques, namely fluorescence, far-ultraviolet (far-UV) circular dichroism (CD), and isothermal titration calorimetry (ITC). We also characterized the binding of the two proteins by using in silico experiments. Our results showed that there was binding in tumor and non-tumoral cell lines. Binding in vitro between the two proteins was also monitored and found to occur with a dissociation constant in the low micromolar range (~10 µM). Finally, in silico experiments provided additional information on the possible structure of the binding complex, especially on the binding ARM-PKP1 hot-spot. Our findings suggest that RYBP might be a rescuer of the high expression of PKP1 in tumors, where it could decrease the epithelial-mesenchymal transition in some cancer cells.

Effect of Intravitreal Anti-Endothelial Growth Factor Agents on Renal Function in Patients With Diabetes Mellitus.

Introduction: Intravitreal administration of vascular endothelial growth factor inhibitors (anti-VEGF) is the treatment of choice in retinal pathology associated with type 2 diabetes mellitus (DM2). We aimed to analyze the effect of intravitreal anti-VEGF administration on renal function in patients with DM2. Methods: This is a single-center retrospective and observational study of patients with DM2 with and without chronic kidney disease (CKD). We analyzed the evolution of renal function after anti-VEGF onset, compared with a control group. Results: We included 45 patients (55.6% male) who received anti-VEGF therapy. Mean age was 74.4±11.5 (50-91) years. These were compared with 45 patients with similar characteristics. After 12 months, 76.3% had CKD with a mean reduction in estimated glomerular filtration rate (eGFR) of 19.4%. Nine patients (20%) had a >25% reduction in eGFR, and 3 patients (6.7%) had a >50% reduction in GFR. At 24 months, 80% of patients had CKD with a mean eGFR decrease of 28%. The mean eGFR slope of patients who had received anti-VEGF treatment was 10 ml/min/year compared to 1.5 ml/min/year in the control group (P < 0.05). After the first administration, 5 patients (17.2%) in the CKD group required renal replacement therapy during follow-up (mean time 22±12 months). Main risk factors for need of dialysis were age, presence of previous CKD, and baseline proteinuria. Conclusion: Intravitreal anti-VEGF administration is a risk factor for CKD and rapid progression to end-stage kidney disease in patients with previous CKD. Knowing these drugs' implications is crucial to avoid CKD progression and opportunely limit their use in certain patients.

Use of Stable Isotopes (δ13C and δ15N) to Infer Post-Breeding Dispersal Strategies in Iberian Populations of the Kentish Plover.

Beaches are among the habitats most frequented by migratory birds for breeding and/or wintering. However, threats such as human pressure and sea level rise can reduce the availability of these habitats for different species. The presence of alternative areas, such as salt pans and brackish habitats, is essential for many migratory shorebird populations. This study addresses the post-breeding dispersal of the Kentish plover (Charadrius alexandrinus) in the Iberian Peninsula by analysing C and N isotopes in feathers. The study was conducted at six locations along the Iberian coast, which were categorized into three areas: the NW Atlantic coast, the Atlantic coast of Andalusia, and the Mediterranean coast. Although linear mixed models did not reveal any significant effects of sex or coastal area on isotopic levels, the variability in the data suggests different habitat-use strategies in the post-reproductive period. Isotopic levels in birds from the northwest of the Iberian Peninsula exhibit greater fidelity to a single habitat type, while those from the Mediterranean coast and the Atlantic coast of Andalusia show greater variability, indicating different individual dispersal strategies. The lack of alternative habitats for the northwest Iberian population, the reduction in available habitat due to rising sea levels, and human pressure together pose a serious threat to the survival of this species, already with an unfavourable conservation status.

Big jaw, small genome: first description of the mitochondrial genome of Odontomachus (Formicidae, Ponerinae): evolutionary implications for Ponerinae ants.

Mitochondrial DNA is a valuable tool for population genetics and evolutionary studies in a wide range of organisms. With advancements in sequencing techniques, it's now possible to gain deeper insights into this molecule. By understanding how many genes there are, how they're organized within the molecule, identifying the presence of spacers, and analyzing the composition of the D-Loop, we can better grasp the rearrangements that play a crucial role in the evolutionary dynamics of mitochondrial DNA. Additionally, phylogenetic analyses benefit significantly from having access to a larger pool of mtDNA genes. This wealth of genetic information allows for the establishment of evolutionary relationships with greater accuracy than ever before, providing a more robust framework than analyses based on a limited number of genes. Studies on mitogenomes belonging to the family Formicidae have proven promising, enabling the identification of gene rearrangements and enhancing our understanding of the internal relationships within the group. Despite this, the number of mitogenomes available for the subfamily Ponerinae is still limited, and here we present for the first time the complete mitogenome of Odontomachus. Our data reveal a gene duplication event in Formicidae, the first involving trnV, and new gene arrangements involving the trnM-trnI-trnQ and trnW-trnC-trnY clusters, suggesting a possible synapomorphy for the genus. Our phylogenetic analysis using the PCGs available for Formicidae supports the monophyly of the subfamily Ponerinae and sheds light on the relationship between Odontomachus and Pachycondyla.

Ideación suicida entre reclusos: análisis con perspectiva de género, durante cinco años de seguimiento (2017-2022) / Suicidal ideation among prisoners: analysis with a gender perspective in a five-year follow-up (2017-2022)

Introducción: En el entorno penitenciario, hay una elevada incidencia de conductas autolesivas, con una tasa de suicidio superior a la existente en la población general. Estudios previos describen la asociación de factores sociodemográficos, clínicos y criminológicos, con el riesgo de suicidio en la población penitenciaria masculina, pero hay pocas investigaciones centradas en el análisis de la conducta suicida entre mujeres. El objetivo del trabajo es analizar las características de las internas que ingresan en una unidad psiquiátrica por presentar ideas de suicidio o haber realizado tentativas.Material y método: Análisis descriptivo y comparativo de 97 internos (68 hombres, 29 mujeres) ingresados en la Unidad de Hospitalización Psiquiátrica de la Penitenciaria de Cataluña (UHPP-C), por ideas de suicidio, entre el 1 de enero de 2017 y el 31 de diciembre de 2022. Resultados: Se encuentran diferencias respecto al lugar de nacimiento, con mayor presencia de nacionalidades africanas en varones no nacionales, mientras que las internas extranjeras suelen ser originarias de países latinoamericanos. Los hombres tienen menor edad media, con ingresos más prolongados y una mayor tasa de reingreso. También padecen más trastornos psicóticos y adictivos. Las mujeres presentan mayor prevalencia de trastornos de personalidad y cuadros afectivos. Conclusiones: Hay diferencias sociodemográficas y clínicas entre hombres y mujeres internos en prisión que requieren ingreso por ideación suicida. Incluir la perspectiva de género en los estudios sobre el riesgo suicida en la población penitenciaria puede proporcionar una base sólida para futuros estudios, permitiendo así una comprensión más completa de la ideación suicida y las necesidades de intervención en la población penitenciaria.(AU)

Introduction: There is a high incidence of self-harming behavior in the prison setting, with a suicide rate that is higher than that of the general population. Previous studies describe the association of sociodemographic, clinical, and criminological factors with the risk of suicide in the male prison population, but there is little research that specifically analyses suicidal behavior among women. The objective of this study is to analyze the characteristics of inmates who are admitted to a psychiatric unit for suicidal thoughts or attempted suicide. Material and method: Descriptive and comparative analysis of 97 inmates (68 men, 29 women) admitted to the Unidad de Hospitalización Psiquiátrica Penitenciaria de Cataluña (UHPP-C), for suicidal ideation, between January 1, 2017, and December 31, 2022. Results: There are differences in terms of place of birth, with a more significant presence of African nationalities in non-national males, while foreign inmates tend to come from Latin American countries. Men have a lower mean age, longer admissions, and a higher readmission rate. They also suffer from more psychotic and addictive disorders. Women have a higher prevalence of personality disorders and affective symptoms. Conclusions: There are sociodemographic and clinical differences between male and female prison inmates who require admission for suicidal ideation. Including a gender perspective in studies on suicide risk in the prison population can provide a solid foundation for future studies, thus allowing a more complete understanding of suicidal ideation and intervention needs in theprison population.(AU)

Predicting risk of endometrial failure: a biomarker signature that identifies a novel disruption independent of endometrial timing in patients undergoing hormonal replacement cycles.

OBJECTIVE: To propose a new gene expression signature that identifies endometrial disruptions independent of endometrial luteal phase timing and predicts if patients are at risk of endometrial failure. DESIGN: Multicentric, prospective study. SETTING: Reproductive medicine research department in a public hospital affiliated with private fertility clinics and a reproductive genetics laboratory. PATIENTS: Caucasian women (n = 281; 39.4 ± 4.8 years old with a body mass index of 22.9 ± 3.5 kg/m2) undergoing hormone replacement therapy between July 2018 and July 2021. Endometrial samples from 217 patients met RNA quality criteria for signature discovery and analysis. INTERVENTION(S): Endometrial biopsies collected in the mid-secretory phase. MAIN OUTCOME MEASURE(S): Endometrial luteal phase timing-corrected expression of 404 genes and reproductive outcomes of the first single embryo transfer (SET) after biopsy collection to identify prognostic biomarkers of endometrial failure. RESULTS: Removal of endometrial timing variation from gene expression data allowed patients to be stratified into poor (n = 137) or good (n = 49) endometrial prognosis groups on the basis of their clinical and transcriptomic profiles. Significant differences were found between endometrial prognosis groups in terms of reproductive rates: pregnancy (44.6% vs. 79.6%), live birth (25.6% vs. 77.6%), clinical miscarriage (22.2% vs. 2.6%), and biochemical miscarriage (20.4% vs. 0%). The relative risk of endometrial failure for patients predicted as a poor endometrial prognosis was 3.3 times higher than those with a good prognosis. The differences in gene expression between both profiles were proposed as a biomarker, coined the endometrial failure risk (EFR) signature. Poor prognosis profiles were characterized by 59 upregulated and 63 downregulated genes mainly involved in regulation (17.0%), metabolism (8.4%), immune response, and inflammation (7.8%). This EFR signature had a median accuracy of 0.92 (min = 0.88, max = 0.94), median sensitivity of 0.96 (min = 0.91, max = 0.98), and median specificity of 0.84 (min = 0.77, max = 0.88), positioning itself as a promising biomarker for endometrial evaluation. CONCLUSION(S): The EFR signature revealed a novel endometrial disruption, independent of endometrial luteal phase timing, present in 73.7% of patients. This EFR signature stratified patients into 2 significantly distinct and clinically relevant prognosis profiles providing opportunities for personalized therapy. Nevertheless, further validations are needed before implementing this gene signature as an artificial intelligence (AI)-based tool to reduce the risk of patients experiencing endometrial failure.

Diabetes mellitus is associated to high-risk late gadolinium enhancement and worse outcomes in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Diabetes mellitus (DM) is associated with a worse prognosis in patients with heart failure. Our aim was to analyze the clinical and imaging features of patients with DM and their association with outcomes in comparison to nondiabetic patients in a cohort of patients with nonischemic dilated cardiomyopathy (DCM). METHODS: This is a prospective cohort study of patients with DCM evaluated in a tertiary care center from 2018 to 2021. Transthoracic echocardiography and cardiac magnetic resonance findings were assessed. A high-risk late gadolinium enhancement (LGE) pattern was defined as epicardial, transmural, or septal plus free-wall. The primary outcome was a composite of heart failure hospitalizations and all-cause mortality. Multivariable analyses were performed to evaluate the impact of DM on outcomes. RESULTS: We studied 192 patients, of which 51 (26.6%) had DM. The median left ventricular ejection fraction was 30%, and 106 (55.2%) had LGE. No significant differences were found in systolic function parameters between patients with and without DM. E/e values were higher (15 vs. 11.9, p = 0.025), and both LGE (68.6% vs. 50.4%; p = 0.025) and a high-risk LGE pattern (31.4% vs. 18.5%; p = 0.047) were more frequently found in patients with DM. The primary outcome occurred more frequently in diabetic patients (41.2% vs. 23.6%, p = 0.017). DM was an independent predictor of outcomes (OR 2.01; p = 0.049) and of LGE presence (OR 2.15; p = 0.048) in the multivariable analysis. Patients with both DM and LGE had the highest risk of events (HR 3.1; p = 0.003). CONCLUSION: DM is related to a higher presence of LGE in DCM patients and is an independent predictor of outcomes. Patients with DM and LGE had a threefold risk of events. A multimodality imaging approach allows better risk stratification of these patients and may influence therapeutic options.

Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

The role of physical activity in the association between disability and mortality among US older adults: a nationwide prospective cohort study.

To examine whether physical activity can mitigate the mortality risk associated with disability in activities of daily living and instrumental activities in daily living among older adults. This analysis comprised 177,360 US participants (104,556 women), aged ≥ 60 years, with valid data from the 1997 through 2018 waves of the US National Health Interview Survey. Participants reported the frequency and duration of leisure-time PA, and their disabilities in activities of daily living and instrumental activities in daily living. Mortality data were obtained from the National Death Index. Over a mean (SD) follow-up of 8.02 (5.43) years, 66,694 deaths occurred from all-cause, 22,673 from cardiovascular disease, and 13,845 from cancer. Among people with disability in activities in daily living, those reaching physical activity recommendations had 25%, 24% and 33% lower risk of all-cause mortality, cardiovascular diseases, and cancer death, respectively, compared with those who do not meet physical activity recommendations. Values were 23%, 22% and 24% for those with disability in instrumental activities in daily living. Risk reductions associated with reaching the recommended physical activity ranged 16% to 29% for people without disability. Combining disability type and compliance with physical activity, individuals with disability in activities of daily living or instrumental activities in daily living who meet the recommended physical activity had moderately higher mortality than those without disability who did not achieve the recommended physical activity. Compliance with physical activity recommendations can partially mitigate excess mortality resulting from disability in activities in daily living or instrumental activities in daily living in older adults.

Osteoporosis in psoriatic arthritis: Risk factors, insufficiency fractures and its association with the disease activity / Osteoporosis en la artritis psoriásica: factores de riesgo, fracturas por insuficiencia y su asociación con la actividad de la enfermedad

Objective: The prevalence of osteoporosis (OP) and insufficiency fractures in psoriatic arthritis (PsA) remains controversial. The aim of this study was to describe the prevalence of OP and insufficiency fractures in a representative cohort of patients with PsA, and to analyse its association with general risk factors and characteristics of the psoriatic disease in our geographical area. Methods: Multi-centric, descriptive study of patients with PsA. We recorded clinical characteristics, as well as protective and risk factors for OP and insufficiency fractures. Hip and lumbar densitometry and lateral X-ray of the spine were evaluated. Descriptive statistics for OP and risk factors were calculated. The patients with OP were compared to those without by univariate analyses, and results were adjusted by age and sex. The association of OP and fractures with clinical characteristics was analysed by logistic regression. Results: 166 patients (50 men; 116 women) were included. OP was present in 26.5%, and it was more frequent in women and patients above 50 years old. Insufficiency fractures occurred in 5.4% of the total sample. In the logistic regression, OP was associated with age over 50 [OR 3.7; 95% CI (1.2–11.6); p=.02]. No association with clinical parameters was found. The most frequent risk factors among patients with OP were vitamin D insufficiency, sedentary behaviour, low calcium intake, and active smoking. In the logistic regression, OP was associated with early menopause [OR 11.7; 95% CI (1.29–106.0); p=.029] and sedentary behaviour [OR 2.3; 95% CI (1.0–5.2); p=.049]. Conclusions: In patients with PsA, OP is more frequent in women and patients over 50 years old. A sedentary lifestyle and early menopause may add extra risk for OP. Type, duration disease, and treatments are not associated with OP or insufficiency fractures.(AU)

Objetivo: El objetivo de este estudio fue describir la prevalencia de osteoporosis (OP) y fracturas por insuficiencia en una cohorte representativa de pacientes con artritis psoriásica (APs) y analizar su asociación con factores de riesgo generales y características de la enfermedad psoriásica en nuestra área geográfica. Métodos: Estudio multicéntrico y descriptivo de pacientes con APs. Se registraron las características clínicas, así como los factores protectores y de riesgo de OP y fracturas por insuficiencia. Se evaluó la densitometría de cadera y lumbar y la radiografía lateral de columna. Se calcularon las estadísticas descriptivas de la OP y los factores de riesgo. Los pacientes con OP se compararon con los que no la tenían mediante análisis univariantes, y los resultados se ajustaron por edad y sexo. La asociación de la OP y las fracturas con las características clínicas se analizó mediante regresión logística. Resultados: Se incluyeron 166 pacientes (50 hombres; 116 mujeres). La OP estaba presente en el 26,5% y era más frecuente en mujeres y pacientes mayores de 50 años. Se produjeron fracturas por insuficiencia en el 5,4% de la muestra total. En la regresión logística la OP se asoció con la edad superior a 50 años (OR: 3,7; IC 95%: 1,2-11,6; p=0,02), con la menopausia precoz (OR: 11,7; IC 95%: 1,29-106,0; p=0,029) y el comportamiento sedentario (OR: 2,3; IC 95%: 1,0-5,2; p=0,049). Conclusiones: En pacientes con APs la OP es más frecuente en mujeres y en aquellos mayores de 50 años. Un estilo de vida sedentario y una menopausia precoz pueden añadir un riesgo adicional de OP. El tipo, la duración de la enfermedad y los tratamientos no se asocian a las fracturas OP ni a las fracturas por insuficiencia.(AU)

Medical oncology workload, workforce census, and needs in Spain: two nationwide studies by the Spanish Society of medical oncology

Purpose Growing complexity and demand for cancer care entail increased challenges for Medical Oncology (MO). The Spanish Society of Medical Oncology (SEOM) has promoted studies to provide updated data to estimate the need for medical oncologists in 2040 and to analyse current professional standing of young medical oncologists. Methods Two national, online surveys were conducted. The first (2021) targeted 146 Heads of MO Departments, and the second (2022), 775 young medical oncologists who had completed their MO residency between 2014 and 2021. Participants were contacted individually, and data were processed anonymously. Results Participation rates reached 78.8% and 48.8%, respectively. The updated data suggest that 87–110 new medical oncologist full-time equivalents (FTEs) should be recruited each year to achieve an optimal ratio of 110–130 new cases per medical oncologist FTE by 2040. The professional standing analysis reveals that 9.1% of medical oncologists trained in Spain do not work in clinical care in the country, with tremendous employment instability (only 15.2% have a permanent contract). A high percentage of young medical oncologists have contemplated career paths other than clinical care (64.5%) or working in other countries (51.7%). Conclusions Optimal ratios of medical oncologists must be achieved to tackle the evolution of MO workloads and challenges in comprehensive cancer care. However, the incorporation and permanence of medical oncologists in the national healthcare system in Spain could be compromised by their current sub-optimal professional standing (AU)

Neurotrophin-3 into the insular cortex strengthens conditioned taste aversion memory.

Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2 M lithium chloride i.p.) or a weak-CTA (0.1 M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region.

Osteoporosis in psoriatic arthritis: Risk factors, insufficiency fractures and its association with the disease activity.

OBJECTIVE: The prevalence of osteoporosis (OP) and insufficiency fractures in psoriatic arthritis (PsA) remains controversial. The aim of this study was to describe the prevalence of OP and insufficiency fractures in a representative cohort of patients with PsA, and to analyse its association with general risk factors and characteristics of the psoriatic disease in our geographical area. METHODS: Multi-centric, descriptive study of patients with PsA. We recorded clinical characteristics, as well as protective and risk factors for OP and insufficiency fractures. Hip and lumbar densitometry and lateral X-ray of the spine were evaluated. Descriptive statistics for OP and risk factors were calculated. The patients with OP were compared to those without by univariate analyses, and results were adjusted by age and sex. The association of OP and fractures with clinical characteristics was analysed by logistic regression. RESULTS: 166 patients (50 men; 116 women) were included. OP was present in 26.5%, and it was more frequent in women and patients above 50 years old. Insufficiency fractures occurred in 5.4% of the total sample. In the logistic regression, OP was associated with age over 50 [OR 3.7; 95% CI (1.2-11.6); p=.02]. No association with clinical parameters was found. The most frequent risk factors among patients with OP were vitamin D insufficiency, sedentary behaviour, low calcium intake, and active smoking. In the logistic regression, OP was associated with early menopause [OR 11.7; 95% CI (1.29-106.0); p=.029] and sedentary behaviour [OR 2.3; 95% CI (1.0-5.2); p=.049]. CONCLUSIONS: In patients with PsA, OP is more frequent in women and patients over 50 years old. A sedentary lifestyle and early menopause may add extra risk for OP. Type, duration disease, and treatments are not associated with OP or insufficiency fractures.

Medical oncology workload, workforce census, and needs in Spain: two nationwide studies by the Spanish Society of medical oncology.

PURPOSE: Growing complexity and demand for cancer care entail increased challenges for Medical Oncology (MO). The Spanish Society of Medical Oncology (SEOM) has promoted studies to provide updated data to estimate the need for medical oncologists in 2040 and to analyse current professional standing of young medical oncologists. METHODS: Two national, online surveys were conducted. The first (2021) targeted 146 Heads of MO Departments, and the second (2022), 775 young medical oncologists who had completed their MO residency between 2014 and 2021. Participants were contacted individually, and data were processed anonymously. RESULTS: Participation rates reached 78.8% and 48.8%, respectively. The updated data suggest that 87-110 new medical oncologist full-time equivalents (FTEs) should be recruited each year to achieve an optimal ratio of 110-130 new cases per medical oncologist FTE by 2040. The professional standing analysis reveals that 9.1% of medical oncologists trained in Spain do not work in clinical care in the country, with tremendous employment instability (only 15.2% have a permanent contract). A high percentage of young medical oncologists have contemplated career paths other than clinical care (64.5%) or working in other countries (51.7%). CONCLUSIONS: Optimal ratios of medical oncologists must be achieved to tackle the evolution of MO workloads and challenges in comprehensive cancer care. However, the incorporation and permanence of medical oncologists in the national healthcare system in Spain could be compromised by their current sub-optimal professional standing.