Genomic landscape of lung cancer in the young.

Background: Lung cancer in the young is a rare entity of great interest due to the high frequency of targetable mutations. In this study, we explored the genomic landscape of non-small cell lung cancer (NSCLC) in young patients and compared it with genetic alterations in older patients. Methods: Comparative study of the genomic profile of NSCLC young (≤40 years old) vs older patients (>40 years old) from Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru. Archival paraffin-embedded tumor samples were profiled with FoundationOne CDx assay to identify short variants alterations (insertions and deletions), copy number variations (CNV), tumor mutational burden and microsatellite instability in 324 driver genes and rearrangements in 28 commonly rearranged genes. A targetable alteration was defined as any alteration in a driver oncogene for which an FDA approved therapy existed at the time of study enrollment. Results: Overall, 62 tumors were profiled, 32 from young and 30 from older patients. All clinicopathological features (smoking status, clinical stage, and histology) were similar between groups, except for gender (65.6% of females in the younger group vs 40% in the older group, P=0.043). At least one actionable mutation was present in 84.4% and 83.3% in younger and older patients, respectively. Alteration rates in the main genes were: BRAF, 3.1%(n=1) vs 0%; EGFR, 46.9% (n=15) vs 43.3% (n=13); ERBB2, 12.5% (n=4) vs 16.7% (n=5); KRAS, 15.6% (n=5) vs 16.7% (n=5); ALK, 6.3% (n=2) vs 3.3% (n=1); RET, 0.0% vs 3.3% (n=1); ROS1, 3.1% (n=1) vs 3.3% (n=1); NTRK1, 0.0% vs 3.3% (n=1) and MET, 3.1% (n=1) vs 13.3% (n=4). Mean TMB was 4.04 Mut/Mb (SD ± 3.98) for young vs 8.06 Mut/Mb (SD ± 9.84) for older patients (P=0.016). There were not significant differences in CNV, frequency of gene rearrangements, or microsatellites instability. Conclusion: NSCLC in the young in our cohort was characterized by a high frequency of actionable genetic aberrations and a low TMB, which was also true for our older patients. The enrichment of actionable mutations in young patients described in other reports might be attributed to differences in the etiology and clinicopathological characteristics between younger and older patients and therefore not be applicable to all populations.

A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology.

Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes.

Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease.

Fabry disease, a rare X-linked α-galactosidase A deficiency, causes progressive lysosomal accumulation of globotriaosylceramide (GL-3) in a variety of cell types. As the disease progresses, renal failure, left ventricular hypertrophy, and strokes may occur. Enzyme replacement therapy (ERT), with recombinant α-galactosidase A, is currently available for use to reduce GL-3 deposits. However, although it improves cardiac function and decreases left ventricular mass, GL-3 clearance upon ERT has been demonstrated in cardiac capillary endothelium but not in cardiomyocytes of patients. Relevant models are needed to understand the pathogenesis of cardiac disease and explore new therapeutic approaches. We generated induced pluripotent stem cells (iPSC) from Fabry patients and differentiated them into cardiomyocytes. In these cells, GL-3 accumulates in the lysosomes over time, resulting in phenotypic changes similar to those found in cardiac tissue from Fabry patients. Using this human in vitro model, we demonstrated that substrate reduction therapy via glucosylceramide synthase inhibition was able to prevent accumulation and to clear lysosomal GL-3 in cardiomyocytes. This new in vitro model recapitulates essential features of cardiomyocytes from patients with Fabry disease and therefore provides a useful and relevant tool for further investigations of new therapy.

[Gastric cancer in a general hospital. Santa Rosa Hospital. Experience]. / Cáncer gástrico en un hospital general: Hospital Santa Rosa.

PURPOSE: Determine the frequency of gastric cancer and its clinical and pathological characteristics, clinical stages, surgical treatment, morbimortality and survival in a general hospital. MATERIALS AND METHODS: Retrospective, descriptive study on 71 consecutive patients diagnosed with gastric cancer at the Santa Rosa Hospital from January 1, 2005 to January 31, 2008. RESULTS: During the study period, 71 cases of gastric adenocarcinoma were confirmed by histopathology. This disease is more frequent in men, with a 1.54 to 1 ratio, as compared to women. The most frequent age of appearance is between the fifth and seventh decades of life. Distal tumors (81.7%) are four times more common than proximal tumors (18,3%). The most common histological type was carcinoma in signet-ring cells (40.8%). The most frequent degree of differentiation was Undifferentiated (42.3%). A 62% (n=44) of patients entered the operating room. The resectability rate was 68% (n=30). The advanced stage was the most common form of presentation in patients (97.2%), while the early stage was rare (2.8%). The most frequent surgeries were the distal subtotal gastrectomy (73.3%) and the total gastrectomy (26.7%). The D2 (73.3%) dissection was performed. The mortality rate was 6.7% and the morbidity rate was 26.7%. Survival was better in patients who underwent resection than in patients who only underwent biopsy or were unresectable, evidencing statistical significance. CONCLUSION: Gastric cancer is diagnosed in a late stage and surgical treatment plays a pivotal role and, even in advanced cases, morbidity/mortality is acceptable for the initial experience at a third-level general hospital. It is necessary to carry out screening program to detect the disease in earlier stages.

Cáncer Gástrico en un Hospital General: Hospital Santa Rosa / Gastric cancer in a general hospital. Santa Rosa Hospital. experience

OBJETIVO: Determinar la frecuencia de cáncer gástrico y sus características clínico patológicas, estadios clínicos, tratamiento quirúrgico, morbimortalidad y sobrevida en un hospital general. MATERIALES Y MÉTODOS: Estudio retrospectivo, descriptivo, de 71 pacientes consecutivos diagnosticados con cáncer gástrico en el Hospital Santa Rosa desde el 1 de enero 2005 hasta el 31 de enero 2008. RESULTADOS: En el periodo de estudio se confirmaron por histopatologia 71 casos de adenocarcinoma gástrico. El sexo masculino es el más frecuente, con una relación de 1,54 a 1 con respecto al sexo femenino. La edad de presentación más frecuente se encuentra entre la 5ta y 7ma década de vida. Los tumores distales (81,7 por ciento) son cuatro veces más frecuentes que los proximales (18,3 por ciento). El tipo histológico más frecuente fue el carcinoma en células de anillo de sello (40,8 por ciento). El grado de diferenciación más frecuente fue el Indiferenciado (42,3 por ciento). El 62 por ciento (n=44) ingresó a sala de operaciones. La tasa de resecabilidad fue de 68 por ciento (n=30). El estadío clínico avanzado ha sido la forma depresentación más frecuente de los pacientes (97,2 por ciento), mientras que el estadío precoz ha sido raro (2,8 por ciento). La cirugía más frecuente fue la gastrectomía subtotal distal (73,3 por ciento) y gastrectomía total (26,7 por ciento). La disección realizada fue la D2 (73,3 por ciento). La tasa de mortalidadfue 6,7 por ciento y morbilidad de 26,7 por ciento. La sobrevida fue mejor en los pacientes que tuvieron resección frente a los que sólo se les realizó biopsia o fueron irresecables, evidenciandosignificancia estadística. CONCLUSIÓN: El cáncer gástrico se diagnóstica en etapa tardía y el tratamiento quirúrgicojuega un rol fundamental e incluso en casos avanzados, la morbimortalidad es aceptable para la experiencia inicial en un Hospital general de tercer nivel. Es necesario realizar programas de tamizaje para detectar la enfermedad en...

PURPOSE: Determine the frequency of gastric cancer and its clinical and pathological characteristics, clinical stages, surgical treatment, morbimortality and survival in ageneral hospital. MATERIALS AND METHODS: Retrospective, descriptive study on 71 consecutive patients diagnosed with gastric cancer at the Santa Rosa Hospital from January 1, 2005 to January 31, 2008. RESULTS: During the study period, 71 cases of gastric adenocarcinoma were confirmed by histopathology. This disease is more frequent in men, with a 1.54 to 1 ratio, as compared to women. The most frequent age of appearance is between the fifth and seventh decadesof life. Distal tumors (81.7 per cent) are four times more common than proximal tumors (18,3 per cent).The most common histological type was carcinoma in signet-ring cells (40.8 per cent). The mostfrequent degree of differentiation was Undifferentiated (42.3 per cent). A 62 per cent (n=44) of patients entered the operating room. The resectability rate was 68 per cent (n=30). The advanced stagewas the most common form of presentation in patients (97.2 per cent), while the early stage was rare (2.8 per cent). The most frequent surgeries were the distal subtotal gastrectomy (73.3 per cent) and the total gastrectomy (26.7 per cent). The D2 (73.3 per cent) dissection was performed. The mortality rate was 6.7 per cent and the morbidity rate was 26.7 per cent. Survival was better in patients who underwent resection than in patients who only underwent biopsy or were unresectable, evidencing statistical significance. CONCLUSIÓN: Gastric cancer is diagnosed in a late stage and surgical treatment playsa pivotal role and, even in advanced cases, morbidity/mortality is acceptable for the initial experience at a third-level general hospital. It is necessary to carry out screening program to detect the disease in earlier stages.