Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2.

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Wnt inhibition alleviates resistance to immune checkpoint blockade in glioblastoma.

Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. Acquired resistance to αPD1 was found to be associated with the upregulation of Wnt7b and ß-catenin protein levels in GBM in patients and in a clinically relevant, stem-rich GBM model. Combining the porcupine inhibitor WNT974 with αPD1 prolonged the survival of GBM-bearing mice. However, this combination had a dichotomous response, with a subset of tumors showing refractoriness. WNT974 and αPD1 expanded a subset of DC3-like dendritic cells (DCs) and decreased the granulocytic myeloid-derived suppressor cells (gMDSCs) in the tumor microenvironment (TME). By contrast, monocytic MDSCs (mMDSCs) increased, while T-cell infiltration remained unchanged, suggesting potential TME-mediated resistance. Our preclinical findings warrant the testing of Wnt7b/ß-catenin combined with αPD1 in GBM patients with elevated Wnt7b/ß-catenin signaling.

Focal segmental glomerulosclerosis in a patient with congenital lecithin-cholesterol acyltransferase deficiency

Lecithin-cholesterol acyltransferase deficiency is a rare genetic disease caused by a mutation of the gene coding for the lecithin-cholesterol acyltransferase protein, and mainly affects low density lipoprotein metabolism. It typically manifests with diffuse corneal opacities, normocytic anemia and kidney disease. We present the case of a 30-year-old man with chronic kidney disease and nephrotic syndrome. His initial kidney biopsy showed focal segmental glomerulosclerosis, thought to be primary, a disease which was refractory to multiple immunosuppressive schemes. Manifestations such as anemia, splenomegaly, corneal opacities and an association with low high-density lipoproteins alerted to the possibility of glomerular damage secondary to lecithin-cholesterol acyltransferase enzyme deficiency, which was confirmed through genetic sequenc ing. Due to the low incidence of the disease, diagnosis is a clinical challenge. The signs and symptoms tend to be interpreted as isolated events, which significantly delays its confirmation. Understanding this entity and the clinical exercise needed to arrive at its diagnosis will serve as a reference, resulting in the suspicion and reporting of cases in the future. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2558).

La deficiencia de lecitin-colesterol aciltransferasa es una enfermedad genética rara, causada por una mutación en el gen que codifica la proteína lecitin-colesterol aciltransferasa y afecta principalmente el metabolismo de las lipoproteínas de baja densidad. Se manifiesta típicamente con opacidades corneales difusas, anemia normocítica y enfermedad renal. Se presenta el caso de un hombre de 30 años con enfermedad renal crónica y síndrome nefrótico, con biopsia renal inicial que demostró un patrón de glomeruloesclerosis focal y segmentaria, interpretada como primaria, enfermedad que fue refractaria a múltiples esquemas de inmunosupresión. Las manifestaciones como anemia, esplenomegalia, opacidades corneales y la asociación con lipoproteínas de alta densidad bajas, alertaron sobre la posibilidad de compromiso glomerular secundario a un déficit de la enzima lecitin-colesterol aciltransferasa, confirmado mediante estudio de secuenciación genética. Dada la baja incidencia de la enfermedad, el diagnóstico representa un desafío clínico. Las manifestaciones suelen interpretarse como eventos aislados, lo que lleva a retraso significativo en su confirmación. El conocimiento de esta entidad y el ejercicio clínico necesario para llegar al diagnóstico, servirán como referencia que derive en la sospecha y reporte de futuros casos. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2558).

Qué pensar antes de decir que el paciente tiene un diagnóstico psiquiátrico. Parte I / What do you think before that you said: the patient has a psychiatric diagnosis. Part I

Resumen Los pacientes refieren sus síntomas en una gran variedad de términos como: "estoy cansado", "me duelen las articulaciones", "me pica todo el cuerpo", "tengo la boca seca", entre otros. Ante estos síntomas el médico piensa de manera automática en un número limitado de patologías que le son familiares, pero existen muchas otras causas a estos síntomas que no se tienen en cuenta. El desconocimiento del médico hace que en el paciente se genere inconformidad al no tenerse un diagnóstico correcto y un tratamiento adecuado, esto lleva a múltiples consultas y que el médico llegue a preguntarse a sí mismo "¿será que este paciente tiene un diagnóstico psiquiátrico?". En este artículo se enumeran las causas frecuentes de estos síntomas mencionados, se describen causas que son pocas veces sospechadas y las claves clínicas para que el médico pueda hacer el diagnóstico de éstas. La primera parte desarrollará los síntomas: fatiga, parestesias, prurito, artralgias, ansiedad y cambios en el comportamiento. La segunda parte desarrollará los síntomas: intolerancia a los alimentos, xerostomía, síncope, disfagia y manifestaciones en pacientes con cirugía bariátrica.

Abstract Patients refer their symptoms in a variety of terms such as: "I am tired", "my joints hurt", "my body itches", "my mouth is dry", among others. Given these symptoms, the doctor automatically thinks in a limited number of pathologies that are familiar to him, but there are many other causes to these symptoms that are not taken into account. The lack of knowledge of the doctor causes the patient to be dissatisfied by not having a correct diagnosis and adequate treatment, this leads to multiple visits and the doctor comes to ask himself "will this patient have a psychiatric diagnosis?". This article lists the frequent causes of these symptoms, describes causes that are rarely suspected and the clinical keys for the doctor to diagnose them. The first part will address the symptoms: fatigue, paresthesia, pruritus, arthralgia, anxiety and changes in behavior. The second part will develop the symptoms: intolerance to food, xerostomia, syncope, dysphagia and manifestations in patients with bariatric surgery.