Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Lynch syndrome. Accurate diagnosis of this predisposition, along with meaningful predictive testing for family members, necessitates the identification of pathogenic variants. However, classifying small coding genetic variants identified in cancer patients is very challenging, specifically in the case of PMS2 variants, since PMS2 pathogenic variants display a lower penetrance and less severe phenotype and therefore a lower tumor burden in affected families. We have assembled clinical data on four PMS2 missense variants of uncertain significance (VUS) identified in 23 patients (p.(Asp286Gly), p.(Asn335Ser), p.(Ile679Thr) and p.(Arg799Trp)). For these variants, functional testing was performed (RNA splicing, protein stability and catalytic activity). Since many protein ortholog sequences and accurate predictive models from AlphaFold2 are available, we also included a systematic analysis of residue conservation and structural role (ConStruct assessment). Overall, our findings indicate that p.(Asp286Gly) and p.(Arg799Trp) behave similarly to wild-type PMS2 and are thus probably neutral. In contrast, p.(Asn335Ser) and p.(Ile679Thr) conferred defects in protein expression or MMR activity. These could be explained by the relevant roles of these amino acids in MLH1-PMS2-N-terminal dimerization (p.Asn335) and C-terminal dimerization (p.Ile679). Our data thus suggest that p.(Asp286Gly) and p.(Arg799Trp) are benign, while the tumor risk in the other two variants remains to be established. Taken together, we suggest roadmaps for the individualized evaluation of difficult uncertain variants by comprising information from all available sources.
Background Glioblastoma (GB) is the most aggressive primary brain tumor in adults and is traditionally associated with a poor prognosis. In 2009, Uruguay's National Resource Fund (Fondo Nacional de Recursos [FNR]) began guaranteeing universal public funding for standard temozolomide (TMZ), establishing an accessible standard of care. This study evaluates the long-term real-world survival impact of that policy and discusses its implications for the future integration of high-cost immunotherapies. Methods We conducted a retrospective observational cohort study of adult patients with histologically confirmed supratentorial hemispheric GB who completed initial diagnosis and treatment between January 2009 and December 2017 at the Neuro-Oncology Unit of the Hospital de Clínicas "Dr. Manuel Quintela", Montevideo, Uruguay. Follow-up extended through December 2018. Overall survival (OS) was estimated using the Kaplan-Meier method, and the study was reported in accordance with the STROBE guidelines. Results A total of 32 patients met the inclusion criteria. Mean age was 50.7 ± 15.3 years (range: 19-75 years), and 62.5% (n = 20) were male. Gross total resection was achieved in 56.3% of cases. Median OS for the entire cohort was 17 months (95% CI: 7.0-26.9). Patients who completed the full adjuvant Stupp regimen achieved a significantly longer median OS than those with incomplete treatment (24 vs. 11 months; log-rank p = 0.023). Conclusions Universal public funding for TMZ in Uruguay has achieved real-world outcomes consistent with international benchmarks. However, the biological ceiling of the Stupp regimen underscores the urgent need for molecular profiling. As the therapeutic landscape shifts toward ultra-high-cost immunotherapies, establishing this historical baseline is essential for the development of sustainable, equity-driven health policies in middle-income countries.
Introducción: El cáncer gástrico es el quinto cáncer en frecuencia a nivel mundial, con morbimortalidad considerable. Nuestro país no es ajeno a esa realidad, donde es la octava causa de muerte por cáncer. En la última década hemos visto cambios en su manejo, especialmente en cuanto a la discusión multidisciplinaria, el rol de las terapias oncológicas y el abordaje mínimamente invasivo, lo que ha impactado globalmente en mejores resultados. A partir del año 2014 en nuestra Unidad de Cirugía Esófago Gástrica se realizaron cambios en el abordaje del paciente con cáncer gástrico, en busca de optimizar el tratamiento y mejorar los resultados. Objetivo: analizar los resultados de gastrectomías oncológicas realizadas por un mismo servicio en dos períodos consecutivos 2003-2013 y 2014-2024. Materiales y métodos: estudio retrospectivo y observacional de los pacientes sometidos a gastrectomía por adenocarcinoma con intención curativa por el mismo equipo entre enero de 2003 y diciembre de 2024, separando en dos períodos (primer período o inicial entre 2003 y 2013, y segundo período de 2014 a 2024). Se realizó una búsqueda de historia clínica de las siguientes variables: forma de presentación, tratamiento oncológico, tipo de cirugía, vía de abordaje, calidad de resección quirúrgica, complicaciones a 30 días, sobrevida libre de enfermedad y sobrevida global. Resultados: en el primer período 2003 y 2013 se realizaron 57 gastrectomías por vía laparotómica, con una incidencia de falla de sutura de 12,3% y una mortalidad de 8,8%. Ningún paciente fue a neoadyuvancia, y el porcentaje de adyuvancia fue del 29,8%. La sobrevida global fue de 70,6%, 46,7% y 21,1% a 1, 2 y 5 años respectivamente. En el segundo período se realizaron 70 gastrectomías con intención curativa, 29 gastrectomías totales (GT) y 41 gastrectomías subtotales (GST). De ellas, 25 fueron realizadas por vía laparoscópica (36%). La tasa de resección R0 fue del 88%. El recuento ganglionar promedio fue de 20,7. La morbilidad fue del 30%, con una tasa de falla de sutura de 18,5% (4/29 en GT, 2/41 en GST y 7 de muñón duodenal). La mortalidad de la serie atribuida a falla de sutura fue del 5,7%. Se realizó neoadyuvancia en 15,7%, y adyuvancia en 50% de los pacientes. La sobrevida global a 1, 2 y 5 años fue del 70,3%, 54,7% y 29,7%. Conclusiones: en esta segunda década se lograron avances importantes, aumentando el número de cirugías con criterio curativo, el abordaje laparoscópico, la tasa de resección oncológica R0, el número de pacientes con tratamiento oncológico y una mejoría en la sobrevida global a 5 años. También surge del análisis un mayor número de cirugías abiertas y paliativas con relación a los años de pandemia por Covid.
Background: Respiratory syncytial virus (RSV) commonly causes severe lower respiratory tract disease. Adenovirus is detected less often, but severe pneumonia may occur. The pediatric intensive care unit (PICU) course associated with adenovirus detection compared with RSV-only detection is not well defined. Methods: We studied clinician-tested, virus-positive PICU admissions of children aged 1 month to 18 years from 37 PICUs in 7 Latin American countries (2017–2025). Children with RSV and/or adenovirus detection who used respiratory support were grouped as RSV-only, adenovirus-only or RSV-adenovirus codetection. The primary outcome was PICU death or worse functional status at discharge. Adjusted associations were estimated with logistic regression; Firth penalization was used for mortality. Results: Among 3196 PICU admissions, 2859 had RSV-only, 257 adenovirus-only and 80 codetection. PICU mortality was 12/257 (4.7%) in adenovirus-only, 13/2859 (0.5%) in RSV-only and 2/80 (2.5%) in codetection. Compared with RSV-only detection, adenovirus-only detection was associated with mortality [adjusted odds ratio (OR): 10.56; 95% confidence interval (CI): 4.57–24.43] and with PICU death or worse functional status at discharge [21/222 (9.5%) vs 45/2308 (1.9%); adjusted OR: 6.57; 95% CI: 3.59–12.03]. Among nonsurvivors, the median PICU day of death was 3 (IQR: 2–6) with adenovirus-only detection and 8 (IQR: 3–9) with RSV-only detection. Conclusions: In this multicenter Latin American PICU cohort, adenovirus-only detection was associated with a higher-risk acute course than RSV-only detection, including higher mortality and worse functional status at PICU discharge.
BACKGROUND:Respiratory syncytial virus (RSV) commonly causes severe lower respiratory tract disease. Adenovirus is detected less often, but severe pneumonia may occur. The pediatric intensive care unit (PICU) course associated with adenovirus detection compared with RSV-only detection is not well defined. METHODS:We studied clinician-tested, virus-positive PICU admissions of children aged 1 month to 18 years from 37 PICUs in 7 Latin American countries (2017-2025). Children with RSV and/or adenovirus detection who used respiratory support were grouped as RSV-only, adenovirus-only or RSV-adenovirus codetection. The primary outcome was PICU death or worse functional status at discharge. Adjusted associations were estimated with logistic regression; Firth penalization was used for mortality. RESULTS:Among 3196 PICU admissions, 2859 had RSV-only, 257 adenovirus-only and 80 codetection. PICU mortality was 12/257 (4.7%) in adenovirus-only, 13/2859 (0.5%) in RSV-only and 2/80 (2.5%) in codetection. Compared with RSV-only detection, adenovirus-only detection was associated with mortality [adjusted odds ratio (OR): 10.56; 95% confidence interval (CI): 4.57-24.43] and with PICU death or worse functional status at discharge [21/222 (9.5%) vs 45/2308 (1.9%); adjusted OR: 6.57; 95% CI: 3.59-12.03]. Among nonsurvivors, the median PICU day of death was 3 (IQR: 2-6) with adenovirus-only detection and 8 (IQR: 3-9) with RSV-only detection. CONCLUSIONS:In this multicenter Latin American PICU cohort, adenovirus-only detection was associated with a higher-risk acute course than RSV-only detection, including higher mortality and worse functional status at PICU discharge.
