Mechanical and electrical uncoupling: the role of cardiac magnetic resonance imaging in arrhythmogenic cardiomyopathy. Proof of concept.

OBJECTIVES: Arrhythmogenic cardiomyopathy (ACM) is a complex cardiac disorder associated with ventricular arrhythmias. Understanding the relationship between mechanical uncoupling and cardiac structural changes in ACM patients is crucial for improved risk stratification and management. METHODS: In this study, we enrolled 25 ACM patients (median age 34 years, 72% men) based on the 2019 Modified Task Force and Padua criteria. Patients were categorized by the presence or absence of clinically relevant ventricular tachycardia (crVT), necessitating emergency interventions. Right ventricular-arterial coupling (VAC) was assessed using echocardiography. Low-rank regression splines were employed to model left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) in relation to VAC. RESULTS: Positive associations were observed between VAC and LVEF (ρ = 0.472, p = 0.023), RVEF (ρ = 0.522, p = 0.038), and right ventricular (RV) indexed stroke volume (ρ = 0.79, p < 0.001). Patients with crVT exhibited correlations with RV shortening, reduced RVEF (39.6 vs. 32.2%, p = 0.025), increased left ventricular (LV) mass (38.99 vs. 45.55, p = 0.045), and LV end-diastolic volume (LVEDV) (56.99 vs. 68.15 mL/m2, p = 0.045). Positive associations for VAC were noted with LVEDV (p = 0.039) and LV mass (p = 0.039), while negative correlations were observed with RVEF by CMR (p = 0.023) and RV shortening by echocardiography (p = 0.026). CONCLUSIONS: Our findings underscore the significance of right VAC in ACM, demonstrating correlations with RV and LVEF, RV stroke volume, and clinically relevant arrhythmias. Insights into RVEF, LV mass, and end-diastolic volume provide valuable contributions to the understanding of ACM pathophysiology and may inform risk assessment strategies.

OBJETIVOS: La miocardiopatía arritmogénica (MCA) es un trastorno cardíaco complejo asociado con arritmias ventriculares (AV). Comprender la relación entre el desacoplamiento mecánico y los cambios estructurales cardíacos en pacientes con MCA es crucial para una estratificación de riesgos y una gestión mejorada. MÉTODOS: En este estudio, reclutamos a 25 pacientes con MCA (edad media 34 años, 72% hombres) basándonos en los criterios del Task Force 2019 y los criterios de Padua. Los pacientes se clasificaron según la presencia o ausencia de taquicardia ventricular clínicamente relevante (crVT), que requería intervenciones de emergencia. Se evaluó el acoplamiento ventricular derecho-arterial (VAC) mediante ecocardiografía. Se utilizaron low-rank regression splines para modelar la fracción de eyección del ventrículo izquierdo (FEVI) y la fracción de eyección del ventrículo derecho (FEVD) en relación con el VAC. RESULTADOS: Se observaron asociaciones positivas entre el VAC y la FEVI (ρ = 0.472, p = 0.023), la FEVD (ρ = 0.522, p = 0.038) y el volumen de eyección indexado del ventrículo derecho (ρ = 0.79, p < 0.001). Los pacientes con crVT mostraron correlaciones con acortamiento del ventrículo derecho, disminución de la FEVD (39.6 vs. 32.2%, p = 0.025), aumento de la masa ventricular izquierda (38.99 vs. 45.55, p = 0.045) y volumen diastólico final del ventrículo izquierdo (VDVI) (56.99 vs. 68.15 mL/m2, p = 0.045). Se observaron asociaciones positivas para el VAC con el VDVI (p = 0.039) y la masa ventricular izquierda (p = 0.039), mientras que se observaron correlaciones negativas con la FEVD por RMC (p = 0.023) y el acortamiento del ventrículo derecho por ecocardiografía (p = 0.026). CONCLUSIONES: Nuestros hallazgos subrayan la importancia del VAC derecho en la MCA, demostrando correlaciones con la FEVD y FEVI, el volumen de eyección del ventrículo derecho y arritmias clínicamente relevantes. Las percepciones sobre la FEVD, la masa ventricular izquierda y el volumen diastólico final proporcionan contribuciones valiosas para comprender la fisiopatología de la MCA y pueden informar estrategias de evaluación de riesgos.

A Case of Low-Grade Appendiceal Mucinous Neoplasm: The Role of Preoperative Imaging and Surgical Technique in Achieving Favorable Outcomes.

Appendiceal mucinous neoplasms may present without symptoms or with chronic pain in the right lower quadrant. This report describes a case of a 35-year-old woman who presented with chronic right lower quadrant pain and was found to have a low-grade appendiceal mucinous neoplasm (LAMN). Physical examination revealed localized tenderness in the right lower quadrant with no additional symptoms. Preoperative laboratory results were normal, and a CT scan revealed a cystic appendiceal lesion with an internal calcification, initially mistaken for a fecalith, which led to the decision for exploratory laparotomy. Intraoperative findings confirmed the presence of a cystic-like appendiceal lesion, and an open appendectomy was performed. Histopathological examination revealed a low-grade appendiceal mucinous neoplasm (LAMN) confined to the mucosa, without evidence of metastatic disease. The patient had an uneventful recovery and required no additional treatment. This case highlights that surgical intervention with proper technique for confined appendiceal neoplasms, combined with effective preoperative imaging and thorough histopathological examination, is crucial for diagnosis and effective management, ensuring favorable outcomes.

Targeting GPC2 on intraocular and CNS metastatic retinoblastomas with local and systemic delivery of CAR T-cells.

PURPOSE: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T-cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy. EXPERIMENTAL DESIGN: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T-cells with different co-stimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T-cells were evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models. RESULTS: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2 and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB co-stimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence that led to significant tumor regression compared to either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T-cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T-cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival. CONCLUSIONS: GPC2-directed CAR T-cells are effective against intraocular and CNS metastatic retinoblastomas.

Acute effect of ultramarathon on systolic and diastolic cardiac function: Systematic review and meta-analysis.

BACKGROUND: Ultramarathon running poses physiological challenges, impacting cardiac function. This systematic review and meta-analysis explore the acute effects of single-stage ultramarathon running on cardiac function. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations were followed. Searches covered Medline, Embase, CINAHL, SPORTDiscus, Web of Science, Central Cochrane, and Scopus. Random effects meta-analyses assessed left ventricular (LV) and right ventricular (RV) variables, expressed as mean differences (MD) with 95% confidence intervals (CI). RESULTS: Among 6972 studies, 17 were included. Post-ultramarathon reductions were found in LV end-diastolic diameter (LVEDD) (-1.24; 95% CI = -1.77, -0.71 mm), LV end-diastolic volume (LVEDV) (-9.92; 95% CI = -15.25, -4.60 ml), LV stroke volume (LVSV) (-8.96 ml, 95% CI -13.20, -4.72 ml), LV ejection fraction (LVEF) (-3.71; 95% CI = -5.21, -2.22%), LV global longitudinal strain (LVGLS) (-1.48; 95% CI = -2.21, -0.76%), E/A (-0.30; 95% CI = -0.38, -0.22 cm/s), .E' (-1.35 cm/s, 95% CI -1.91, -0.79 cm/s), RV fractional area change (RVFAC) (-3.34, 95% CI = -5.84, -0.84%), tricuspid annular plane systolic excursion (TAPSE) (-0.12, 95% CI = -0.22, -0.02 cm), RV global longitudinal strain (RVGLS) (-1.73, 95% CI = -2.87, -0.59%), with increases in RV end-diastolic area (RVEDA) (1.89, 95% CI = 0.63, 3.14 cm2), RV Peak A' (1.32 cm/s, 95% CI 0.20, 2.44), and heart rate (18.24, 95% CI = 15.16, 21.32). No significant differences were observed in LV end-systolic diameter (LVESD), LV end-systolic volume (LVESV), RV end-diastolic diameter (RVEDD), RV Peak E', and RV Peak S'. CONCLUSIONS: Evidence suggests immediate impairment of systolic and diastolic cardiac function post-ultramarathon running.

Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers.

Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members as well as genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.

Physical Activity and Obesity Risk in Adults in Colombia: The Prospective Urban Rural Epidemiology (PURE) Study.

PURPOSE: This study aimed to investigate longitudinal associations between physical activity levels and obesity in adults in Colombia, where participation in large amounts of light-intensity physical activity is a necessity for many people. METHODS: Participation in moderate- and vigorous-intensity physical activity was assessed from 2005 to 2009, and obesity was assessed from 2011 to 2019 in men and women from the Prospective Urban Rural Epidemiology (PURE) study. Total physical activity level was categorized as low (<600 MET·min·wk -1 ), medium (600-3000 MET·min·wk -1 ), or high (>3000 MET·min·wk -1 ; 600 MET·min·wk -1 is equivalent to 150 min of moderate activity or 75 min of vigorous activity per week). Obesity was defined as body mass index ≥30 kg·m -2 . Analyses were adjusted for age, sex, smoking, socioeconomic status, diet, alcohol, sedentary time, and sleep. RESULTS: The main analysis included 3086 men and women aged 51 ± 9 yr at baseline (mean ± SD). Compared with the low physical activity group, the odds ratio (95% confidence interval) for obesity was 0.67 (0.53-0.85) in the medium physical activity group and 0.78 (0.62-0.98) in the high physical activity group after adjustment for potential confounders. Smoking is probably a major confounder, and it is noteworthy that similar associations were observed in participants who reported never smoking. CONCLUSIONS: The PURE study is the only prospective cohort study in Colombia. The present analysis is important because it suggests that even the busy people of Colombia could substantially reduce their risk of obesity by participating in moderate- and vigorous-intensity physical activity.

SBRT-SG-01: final results of a prospective multicenter study on stereotactic body radiotherapy for liver metastases.

OBJECTIVE: This study aimed to assess the efficacy and tolerability of stereotactic body radiation therapy (SBRT) for the treatment of liver metastases. METHODS: Patients with up to 5 liver metastases were enrolled in this prospective multicenter study and underwent SBRT. Efficacy outcomes included in-field local control (LC), progression-free survival (PFS), and overall survival (OS). Acute and late toxicities were evaluated using CTCAE v.4.0. RESULTS: A total of 52 patients with 105 liver metastases were treated between 2015 and 2018. The most common primary tumor was colorectal cancer (72% of cases). Liver metastases were synchronous with the primary tumor diagnosis in 24 patients (46.2%), and 21 patients (40.4%) presented with other extrahepatic oligometastases. All patients underwent intensity-modulated radiation therapy (IMRT)/volumetric-modulated arc therapy (VMAT) with image-guided radiation therapy (IGRT) and respiratory gating, and a minimum biologically effective dose (BED10Gy) of 100 Gy was delivered to all lesions. With a median follow-up of 23.1 months (range: 13.4-30.9 months) since liver SBRT, the median actuarial local progression-free survival (local-PFS) was not reached. The actuarial in-field LC rates were 84.9% and 78.4% at 24 and 48 months, respectively. The median actuarial liver-PFS and distant-PFS were 11 and 10.8 months, respectively. The actuarial median overall survival (OS) was 27.7 months from SBRT and 52.5 months from metastases diagnosis. Patients with lesion diameter ≤ 5 cm had significantly better median liver-PFS (p = 0.006) and OS (p = 0.018). No acute or late toxicities of grade ≥ 3 were observed. CONCLUSIONS: This prospective multicenter study confirms that liver SBRT is an effective alternative for the treatment of liver metastases, demonstrating high rates of local control and survival while maintaining a low toxicity profile.

Safety of helicopter transport in patients with acute coronary syndrome / Seguridad del transporte en helicóptero en pacientes con síndrome coronario agudo

Abstract Background: ST-elevation myocardial infarction (STEMI) systems of care have reduced inter-hospital transfer times and facilitated timely reperfusion goals. Helicopters may be an option when land transportation is not feasible; however, the safety of air transport in patients with acute coronary syndrome (ACS) is a factor to consider. Objetives: The aim of this study was to evaluate the safety of helicopter transport for patients with ACS. Methods: Prospective, observational, and descriptive study including patients diagnosed with ACS within the STEMI network of a metropolitan city transferred by helicopter to a large cardiovascular center to undergo percutaneous coronary intervention. The primary outcome of the study was the incidence of air-travel-related complications defined as IV dislodgement, hypoxia, arrhythmia, angina, anxiety, bleeding, and hypothermia. Secondary outcomes included the individual components of the primary outcome. Results: A total of 106 patients were included in the study; the mean age was 54 years and 84.9% were male. The most frequent diagnosis was STEMI after successful fibrinolysis (51.8%), followed by STEMI with failed fibrinolysis (23.7%) and non-reperfused STEMI (9.4%). Five patients (4.7%) developed at least one complication: IV dislodgement (1.8%) and hypoxemia (1.8%) in two patients and an episode of angina during flight (0.9%). A flight altitude of > 10,000 ft was not associated with complications. Conclusions: The results of this study suggest that helicopter transportation is safe in patients undergoing acute coronary syndrome, despite the altitude of a metropolitan area.

Resumen Antecedentes: Los sistemas de atención de IAMCEST han reducido los tiempos de transferencia interhospitalaria y han facilitado las metas de reperfusión oportuna. Los helicópteros pueden ser una opción cuando el transporte terrestre no es factible; sin embargo, la seguridad del transporte aéreo en pacientes con síndrome coronario agudo (SICA) es un factor a considerar. Objetivos: Evaluar la seguridad del transporte en helicóptero para pacientes con SICA. Métodos: Estudio prospectivo, observacional, descriptivo. Se incluyeron pacientes con diagnóstico de SICA dentro de la red IAMCEST en metrópolis extensa, trasladados en helicóptero a un centro cardiovascular. El resultado primario del estudio fue la incidencia de complicaciones relacionadas con los viajes aéreos definidas cómo desalojo de catéter intravenoso, hipoxia, arritmia, angina, ansiedad, sangrado e hipotermia. Resultados: Total de 106 pacientes; la edad media fue de 54 años y 84,9% eran hombres. La altitud media de vuelo fue de 10,100 pies y la distancia media de vuelo fue de 50,0 km. El diagnóstico más frecuente fue IAMCEST tras fibrinolisis exitosa (51,8%), seguido de IAMCEST con fibrinolisis fallida (23,7%). Cinco pacientes (4,7%) desarrollaron una complicación: desalojo IV (1,8%) e hipoxemia (1,8%) en dos pacientes y un episodio de angina durante el vuelo (0,9%). Una altitud de vuelo mayor de 10,000 pies no se asoció a complicaciones. Conclusiones: Los resultados de este estudio sugieren que el transporte en helicóptero es seguro en pacientes con SICA, incluso en altitudes > 10,000 pies.

Influencia del antecedente de intervención coronaria percutánea sobre los desenlaces angiográficos y clínicos en pacientes con infarto agudo de miocardio con elevación del segmento ST / Impact of previous percutaneous coronary intervention on angiographic and clinical outcomes in patients with ST-segment elevation myocardial infarction

Resumen Antecedentes: El pronóstico de los pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMCEST) y antecedente de intervención coronaria percutánea (ICP) es incierto. Objetivos: Evaluar si la ICP previa en pacientes con IAMCEST incrementa el riesgo de eventos cardiovasculares mayores y si el flujo final epicárdico varía según la estrategia de reperfusión. Material y métodos: Subestudio de PHASE-MX, observacional, longitudinal y comparativo, de pacientes con IAMCEST reperfundidos en menos de 12 horas de iniciados los síntomas, divididos conforme el antecedente de ICP. El acaecimiento del criterio de valoración principal (muerte cardiovascular, reinfarto, insuficiencia cardíaca y choque cardiogénico) dentro de los 30 días se comparó con estimaciones de Kaplan-Meier, prueba de rangos logarítmicos y modelo de riesgos proporcionales de Cox. El flujo epicárdico final se evaluó con el sistema de clasificación del flujo TIMI después de la reperfusión. Resultados: Se incluyeron 935 pacientes, 85.6 % del sexo masculino, 6.9 % de los cuales tenía antecedente de ICP; 53 % recibió terapia farmacoinvasiva y 47 %, ICP primaria. La incidencia del criterio de valoración principal en pacientes con ICP previa fue de 9.8 % versus 13.3 % en aquellos sin ese antecedente (p = 0.06); 87.1 % de los pacientes con ICP previa obtuvo flujo final de grado TIMI 3 versus 75 % del grupo con estrategia farmacoinvasiva (p = 0.235). Conclusiones: El antecedente de ICP no incrementa el riesgo de eventos cardiovasculares mayores a los 30 días en pacientes con IAMCEST; sin embargo, impacta negativamente en el flujo sanguíneo angiográfico final de los pacientes que recibieron terapia farmacoinvasiva (en comparación con ICP primaria).

Abstract Background: The prognosis of patients with ST-segment elevation myocardial infarction (STEMI) and previous percutaneous coronary intervention (PCI) is uncertain. Objectives: To evaluate if previous PCI in patients with STEMI increases the risk of major cardiovascular events, and if final epicardial blood flow differs according to the reperfusion strategy. Material and methods: Observational, longitudinal, comparative sub-study of the PHASE-MX trial that included patients with STEMI and reperfusion within 12 hours of symptom onset, who were divided according to their history of PCI. The occurrence of the composite primary endpoint (cardiovascular death, re-infarction, congestive heart failure and cardiogenic shock) within 30 days was evaluated using Kaplan-Meier estimates, log-rank test and Cox proportional hazards model. Final epicardial blood flow was assessed using the TIMI grading system after reperfusion. Results: A total of 935 patients were included; 85.6% were males, and 6.9% had a history of PCI; 53% underwent pharmacoinvasive therapy, and 47%, primary PCI. The incidence of the composite primary endpoint at 30 days in patients with a history of PCI was 9.8% vs. 13.3% in those with no previous PCI (p = 0.06). Among the patients with previous PCI, 87.1% reached a final TIMI grade 3 flow after primary PCI vs. 75% in the group with pharmacoinvasive strategy (p = 0.235). Conclusions: A history of PCI does not increase the risk of major cardiovascular events at 30 days; however, it impacted negatively on the final angiographic blood flow of patients that received pharmacoinvasive therapy (compared to primary PCI).

BPTF cooperates with MYCN and MYC to link neuroblastoma cell cycle control to epigenetic cellular states.

The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of one Bptf allele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). High BPTF levels are associated with high-risk features and decreased survival. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation of BPTF and CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.

Outcomes of initially nonoperative management of diverticulitis with abscess formation in immunosuppressed patients. DIPLICAB study COLLABORATIVE group.

AIM: Management of diverticulitis with abscess formation in immunosuppressed patients (IMS) remains unclear. The main objective of the study was to assess short- and long-term outcomes between IMS and immunocompetent patients (IC). The secondary aim was to identify risk factors for emergency surgery. METHODS: A nationwide retrospective cohort study was performed at 29 Spanish referral centres between 2015-2019 including consecutive patients with first episode of diverticulitis classified as modified Hinchey Ib or II. IMS included immunosuppressive therapy, biologic therapy, malignant neoplasm with active chemotherapy and chronic steroid therapy. A multivariate analysis was performed to identify independent risk factors to emergency surgery in IMS. RESULTS: A total of 1395 patients were included; 118 IMS and 1277 IC. There were no significant differences in emergency surgery between IMS and IC (19.5% and 13.5%, p = 0.075) but IMS was associated with higher mortality (15.1% vs. 0.6%, p < 0.001). Similar recurrent episodes were found between IMS and IC (28% vs. 28.2%, p = 0.963). Following multivariate analysis, immunosuppressive treatment, p = 0.002; OR: 3.35 (1.57-7.15), free gas bubbles, p < 0.001; OR: 2.91 (2.01-4.21), Hinchey II, p = 0.002; OR: 1.88 (1.26-2.83), use of morphine, p < 0.001; OR: 3.08 (1.98-4.80), abscess size ≥5 cm, p = 0.001; OR: 1.97 (1.33-2.93) and leucocytosis at third day, p < 0.001; OR: 1.001 (1.001-1.002) were independently associated with emergency surgery in IMS. CONCLUSION: Nonoperative management in IMS has been shown to be safe with similar treatment failure than IC. IMS presented higher mortality in emergency surgery and similar rate of recurrent diverticulitis than IC. Identifying risk factors to emergency surgery may anticipate emergency surgery.

Identification of biomarkers for the early detection of non-small cell lung cancer: a systematic review and meta-analysis.

Lung cancer (LC) causes few symptoms in the earliest stages, leading to one of the highest mortality rates among cancers. Low-dose computerised tomography (LDCT) is used to screen high-risk individuals, reducing the mortality rate by 20%. However, LDCT results in a high number of false positives and is associated with unnecessary follow-up and cost. Biomarkers with high sensitivities and specificities could assist in the early detection of LC, especially in patients with high-risk features. Carcinoembryonic antigen (CEA), cytokeratin 19 fragments and cancer antigen 125 have been found to be highly expressed during the later stages of LC but have low sensitivity in the earliest stages. We determined the best biomarkers for the early diagnosis of LC, using a systematic review of eight databases. We identified 98 articles that focussed on the identification and assessment of diagnostic biomarkers and achieved a pooled area under curve of 0.85 (95% CI 0.82-0.088), indicating that the diagnostic performance of these biomarkers when combined was excellent. Of the studies, 30 focussed on single/antigen panels, 22 on autoantibodies, 31 on miRNA and RNA panels, and 15 suggested the use of circulating DNA combined with CEA or neuron-specific enolase (NSE) for early LC detection. Verification of blood biomarkers with high sensitivities (Ciz1, exoGCC2, ITGA2B), high specificities (CYFR21-1, antiHE4, OPNV) or both (HSP90α, CEA) along with miR-15b and miR-27b/miR-21 from sputum may improve early LC detection. Further assessment is needed using appropriate sample sizes, control groups that include patients with non-malignant conditions, and standardised cut-off levels for each biomarker.

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.

Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target. Highlights: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer DLK1 silencing in neuroblastoma cells results in cellular differentiation ADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Surgical fatigue syndrome and EDiS3 intervention, should every surgeon need to know how to mitigate muscle skeletal discomfort?

Background: Surgical fatigue syndrome (SFS) is a frequent, but underestimated, entity that occurs during laparoscopic surgeries. It could impair surgical outcomes, patient safety, and surgeon health. Furthermore, current surgical education lacks effective interventions to avoid it. Discomfort represents the most common manifestation and includes musculoskeletal fatigue, numbness, or frank pain. The most common affected sites are the back neck, dominant hand shoulder, and high or low back. We propose an integral intervention (surgeon posture, instruments/devices design & use and discomfort improvement) that prevents or mitigates SFS. Methods: An experimental study was conducted on 57 general surgery residents and general surgeons. Participants in the experimental and control group executed standardized laparoscopic knots in a simulator and knowledge, body discomfort, and posture/ergonomic risk was evaluated before and after intervention application. Results: A statistically significant decrease in discomfort intensity was found in the experimental group. Also, discomfort presentation by the anatomic site diminishes and surgical performance improves. Conclusions: Intervention prevents or mitigates discomfort associated with muscle-skeletal component of SFS. ACGME competency: Practice Based-Learning and Improvement.

Uncommon Presentation of a Giant Cell Tumor of the Tendon Sheath of the Hand: A Case Report.

A giant cell tumor of the tendon sheath (GCTTS) presents as a rare neoplasm demanding a heightened index of suspicion for precise diagnostic evaluation, especially when manifesting in the digital phalanges, as it is part of a group of neoplasms known as tenosynovial giant cell tumors (TCGTs). An accurate and timely diagnosis is crucial, as it significantly enhances treatment outcomes for this heterogeneous group of lesions. We describe the case of a male patient who presented with multiple nodules in the fourth finger of his left hand and was ultimately diagnosed with a localized form of a GCTTS, an unusual presentation for localized forms of this entity. Our objective is to outline the diagnostic and therapeutic approach, discussing options for differential diagnosis and treatment modalities. To achieve this, we conducted a literature review and compared our findings and the observed evolution in our patient. Early recognition of hand tumors allows for timely diagnosis, facilitating optimal resections during surgical procedures. This, in turn, reduces morbidity and enhances the functionality of the affected extremity, as detailed in the current case.

Overcoming Anatomical Challenges: Laparoscopic Cholecystectomy in Situs Inversus Totalis.

Situs inversus totalis (SIT) is a rare genetic condition characterized by the sagittal inversion of thoracoabdominal organs. Surgeons may face substantial challenges when dealing with surgical pathologies in SIT patients, particularly those involving the gallbladder and bile ducts, such as cholelithiasis and acute cholecystitis. In this report, we present the case of a 46-year-old male with a previously known diagnosis of SIT, who presented with recurrent episodes of atypical abdominal pain. Cholelithiasis was diagnosed through ultrasound and as a result, elective surgery was scheduled. In addition, we detail the adjustments implemented by our surgical team in the laparoscopic cholecystectomy procedure, which contributed to a successful surgical outcome. Nevertheless, like any patient, those with SIT are not exempt from postoperative complications, as detailed in this case. Hence, we emphasize the importance of comprehensive preoperative diagnostics to reduce the risk of perioperative complications in this group of patients.

Prevalence of SARS-CoV-2 antibodies in cancer patients and healthcare workers vaccinated with two doses of BNT162b2 or AZD122. A propensity analysis.

BACKGROUND: Vaccination is the most effective intervention for reducing the burden of SARS-CoV-2-related disease; however, gaps in knowledge regarding cancer patients (CPs) immune response persist. OBJECTIVES: To evaluate the humoral response (anti-S antibodies) in CPs and healthcare workers (HCWs) vaccinated with two doses of BNT162b2 or AZD122 vaccines. MATERIAL AND METHODS: Polyspecific anti-SARS-CoV-2 spike protein (anti-S) antibodies were quantified, and a 1:1 propensity score was used to balance baseline characteristics. Multiple logistic regressions were carried out to evaluate the effect of humoral response-related variables. RESULTS: One-hundred and twenty-seven CPs (22%) and 439 HCWs (78%) were included. Both populations developed anti-S antibodies in response to vaccination. The mRNA-based vaccine (BNT162b2) was associated with higher odds of having anti-S antibody titers ≥ 1,000 U/mL, while active cancer was related to a lower probability of developing high antibody titers. CONCLUSIONS: The BNT162b2 vaccine was associated with a higher humoral response. It is necessary for more information and vaccination strategies to be available for immunosuppressed patients in order to select the best biologics for this population based on individual characteristics.

ANTECEDENTES: La vacunación es la intervención más efectiva para reducir la carga de enfermedad por SARS-CoV-2; sin embargo, persisten brechas en el conocimiento en relación con la respuesta inmunológica de los pacientes con cáncer (PC). OBJETIVOS: Evaluar la respuesta humoral (anticuerpos anti-S) en PC y trabajadores de salud (TS) vacunados con dos dosis de la vacuna BNT162b2 o AZD122. MATERIAL Y MÉTODOS: Se cuantificaron anticuerpos poliespecíficos contra la proteína de espiga de SARS-CoV-2 (anti-S) y se efectuó una puntuación de propensión 1:1 para equilibrar las características basales. Se realizaron regresiones logísticas múltiples para evaluar el efecto de las variables relacionadas con la respuesta humoral. RESULTADOS: Se incluyeron 127 PC (22 %) y 439 TS (78 %). Ambas poblaciones desarrollaron anticuerpos anti-S en respuesta a la vacunación. La vacuna de ARNm (BNT162b2) se asoció a mayor probabilidad de mostrar concentraciones de anticuerpos anti-S ≥ 1000 UI/mL, mientras que el cáncer activo se relacionó con menor probabilidad de presentar títulos altos de anticuerpos. CONCLUSIONES: La vacuna BNT162b2 se asoció a respuesta humoral mayor. Es necesario contar con más información y estrategias de vacunación en pacientes inmunosuprimidos. Es relevante la selección de los mejores biológicos para esta población y considerar las características individuales.

Eosinophilic Variant of Chromophobe Renal Cell Carcinoma During Pregnancy: A Multidisciplinary Approach and Successful Management in a Tertiary Hospital in Mexico.

Renal cell carcinoma (RCC) is rarely diagnosed during pregnancy and its management represents a challenge as it necessitates considerations for the well-being of both the mother and the developing fetus. Diagnosis can be challenging and is often an incidental finding during routine imaging, which can lead to difficult decision-making. The choice of the ideal imaging study in these cases is a matter of debate. When the tumor is detected at an early stage, radical nephrectomy is indicated. However, there is still controversy regarding whether it should be performed conventionally or laparoscopically, as both techniques have their risks and benefits. In this context, our primary objective was to provide adequate surgical treatment for the patient, while safeguarding fetal health. Here, we present a patient with a history of recurrent miscarriages, in whom a renal tumor was incidentally diagnosed during pregnancy. Adding to the uniqueness of this case, the patient was diagnosed with an eosinophilic variant of chromophobe RCC through histopathological analysis. Our aim is to highlight the controversies surrounding diagnostic and treatment methodologies and to present the surgical techniques employed in this unique situation. This case underscores the importance and need for a multidisciplinary approach, which, in our instance, resulted in favorable outcomes for both maternal and neonatal health.