Molecular classification improves preoperative risk assessment of endometrial cancer.

OBJECTIVE: We aimed to evaluate the performance of endometrial cancer (EC) molecular classification in predicting extrauterine disease after primary surgery alone and in combination with other clinical data available in preoperative setting. METHODS: Retrospective single-center observational study including patients with endometrial adenocarcinoma treated with primary surgery between December 1994 and May 2022. Molecular profiling was performed using immunohistochemistry of p53, MLH1, PMS2, MSH2 and MSH6; and KASP genotyping of the 6 most common mutations of POLE gene. Clinical, pathological and imaging information was reviewed. Logistic regression, regression trees and random forest classification techniques (CART) were performed. RESULTS: We enrolled 658 patients, 47 with POLEmut (7.1%), 234 with MMRd (35.6%), 95 with p53abn (14.4%) and 282 with NSMP (42.8%) tumors. Advanced stage after primary surgery (III-IV FIGO 2009) was diagnosed in 11.7% of patients, p53abn tumors showed increased extrauterine spread (34.1%) and nodal involvement (30.1%) (p < .001). In multivariate analysis, only p53abn subgroup (aOR = 16.0, CI95% = 1.5-165.1) and radiological suspicion of extrauterine disease (aOR = 24.2, CI95% = 12.2-48.2) independently predicted the finding of extrauterine disease after primary surgery. In patients with preoperative uterine-confined disease, deep myometrial and cervical involvement in radiological assessment and p53abn molecular subtype were the best variables to identify patients at-risk of occult extrauterine disease after the staging surgery. CONCLUSION: EC molecular classification is more accurate than histotype or grade in preoperative biopsy to predict advanced disease, and together with imaging tests are the most reliable preoperative information. This work provides an initial framework for using molecular information preoperatively to tailor surgical treatment.

Molecular profile is a strong predictor of the pattern of recurrence in patients with endometrial cancer.

OBJECTIVES: To investigate the pattern of first recurrence of disease in patients with endometrial cancer according to molecular classification, and to assess the independent role of molecular profiling in each type of failure. METHODS: Retrospective single-center study including patients diagnosed with endometrial cancer stage I-IVB (International Federation of Gynecology and Obstetrics 2009) between December 1994 and May 2022, who underwent primary surgical treatment and had a complete molecular profile. First recurrence was classified as isolated or multiple, and as vaginal, pelvic, peritoneal, nodal, and distant according to its location. The log-rank test and univariate and multivariate adjusted Cox regression models were used for comparison between groups. RESULTS: A total of 658 patients were included. Recurrence was observed in 122 patients (18.5%) with a recurrence rate of 12.4% among mismatch-repair deficient tumors, 14.5% among non-specific molecular profile, 2.1% among POLE-mutated, and 53.7% among p53-abnormal tumors. Recurrences were found to be isolated in 80 (65.6%) and multiple in 42 (34.4%) patients, with no differences in molecular subtype (p=0.92). Patients with p53-abnormal tumors had a recurrence mainly as distant (28.4%) and peritoneal (21.1%) disease, while patients with non-specific molecular profile tumors presented predominantly with distant failures (10.3%), and mismatch-repair deficient tumors with locoregional recurrences (9.4%).On multivariate analysis, p53-abnormal molecular profile was the only independent risk factor for peritoneal failure (OR=8.54, 95% CI 2.0 to 36.3). Vaginal recurrence was independently associated with p53-abnormal molecular profile (OR=6.51, 95% CI 1.1 to 37.4) and lymphovascular space invasion. p53-abnormal and non-specific molecular profiles were independent predictors for distant recurrence (OR=3.13, 95% CI 1.1 to 8.7 and OR=2.35, 95% CI 1.1 to 5.0, respectively), along with lymphovascular space invasion and high-grade tumors. Molecular profile was not independently associated with pelvic and nodal recurrences. CONCLUSIONS: Endometrial cancer featured different patterns of recurrence depending on the molecular profile. p53-abnormal molecular profiling was the only independent risk factor for peritoneal relapse, while non-specific molecular profile showed a strong association with distant failures.

Hybrid neurofibroma/schwannoma of the orbit.

Hybrid neurofibroma/schwannoma is a rare variant of hybrid peripheral nerve sheath tumours (HPNST). A Medline search up to December 2021 identified only six cases of this tumour in the orbit. We report the case of a 78-year-old man who presented with left exophthalmos. Computed tomography showed a left intraconal orbital mass. The clinico-radiological diagnosis was consistent with an intraconal cavernous angioma. Orbitotomy was performed, obtaining an 18×16×11mm mass. Two different morphologies were seen microscopically, diagnostic of hybrid neurofibroma/schwannoma. HPNSTs of the orbit are uncommon and most reported cases showed a hybrid neurofibroma/schwannoma morphology. Hybrid neurofibroma/schwannomas have been associated with neurofibromatosis and schwannomatosis. Local recurrences have been reported. The correct identification of these tumours is important due to their potential use as a syndromic marker.

A High-Throughput Screening Platform Identifies Novel Combination Treatments for Malignant Peripheral Nerve Sheath Tumors.

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that are the leading cause of mortality in patients with Neurofibromatosis type 1 (NF1). Single chemotherapeutic agents have shown response rates ranging from 18% to 44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that improve clinical prognosis and outcome. We screened a collection of compounds from the NCATS Mechanism Interrogation PlatE (MIPE) library in three MPNST cell lines, using cell viability and apoptosis assays. We then tested whether compounds that were active as single agents were synergistic when screened as pairwise combinations. Synergistic combinations in vitro were further evaluated in patient-derived orthotopic xenograft/orthoxenograft (PDOX) athymic models engrafted with primary MPNST matching with their paired primary-derived cell line where synergism was observed. The high-throughput screening identified 21 synergistic combinations, from which four exhibited potent synergies in a broad panel of MPNST cell lines. One of the combinations, MK-1775 with Doxorubicin, significantly reduced tumor growth in a sporadic PDOX model (MPNST-SP-01; sevenfold) and in an NF1-PDOX model (MPNST-NF1-09; fourfold) and presented greater effects in TP53 mutated MPNST cell lines. The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume in vivo at noncytotoxic doses. Our results support the utility of our screening platform of in vitro and in vivo models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacologic option for the treatment of these tumors.

Pancreatitis por citomegalovirus en inmunocomprometidos. Reporte de casos / Cytomegalovirus pancreatitis in inmunocompromised patients: a case report

Se reporta dos casos de pancreatitis secundaria a la infección por citomegalovirus confirmado por reacción en cadena de la polimerasa en tiempo real (PCR-RT) en pacientes portadores del virus de la inmunodeficiencia humana (VIH). Se descartaron otras causas mediante exámenes auxiliares. Ambos pacientes fueron tratados con ganciclovir y se obtuvo una mejoría tanto clínica como en los exámenes auxiliares. Esta patología no debe pasar desapercibida en pacientes VIH positivos a pesar de no presentar la característica clínica de pancreatitis aguda.

Concordancia entre las habilidades, conocimientos y labores de médicos peruanos recién egresados con respecto a su propia percepción de las características de un buen médico / Concordance among Peruvian physician’ s skills, knowledge and activities according to their own perception of the characteristics of a good physician

Introducción: Durante el entrenamiento profesional las personas reconocen algunas características que idealmente deberían de ser obtenidas al egreso universitario; sin embargo, no necesariamente todas ellas son alcanzadas. Objetivo: Evaluar la concordancia entre las características propias de los médicos peruanos que realizarán el Servicio Rural Urbano Marginal de Salud con las características idóneas que debería tener un buen médico según el criterio propio de cada encuestado. Materiales y Métodos: Se llevó a cabo un estudio de corte transversal en una muestra de 281 médicos. Se midió la concordancia entre las habilidades, conocimientos y labores que declaraban los participantes y las que debería poseer un buen médico según su propia percepción utilizando un cuestionario estructurado de 26 ítems. Se evaluó la concordancia con el índice Kappa de Fleiss y las diferencias de puntajes con el test de signos y rangos de Wilcoxon. Resultados: El 45,6% fueron varones, 69,6% estudiaban en una universidad privada, 78,9% admiraban a un médico y 27,3% elegiría la misma especialidad que dicha persona. Si bien la puntuación media obtenida en cada ítem fue significativamente menor en la evaluación propia de los participantes frente al puntaje idóneo en la totalidad de ítems evaluados, existió una importante proporción que reconoce haber logrado esas capacidades y en otros casos haber superado lo requerido. Conclusiones: La concordancia encontrada en las diversas características fue de pobre a aceptable. Algunos médicos consideran que aún no han desarrollado aspectos clave como liderazgo, empatía, comunicación y capacidad de escuchar. Se sugiere realizar estudios para evaluar si estas características varían durante los años de práctica tras el egreso.

Introduction: Everyone recognize certain features a good professional should have and every person hopes future professionals would have them. Objective: To evaluate the concordance between recently graduated Peruvian doctors’ characteristics and the features a good doctor should have according to each respondent’s criteria. Methods: A Cross-Sectional study among 318 physicians assessed the concordance of their declared skills, abilities, knowledge and activities (26 items) in comparison with the characteristics a good doctor should possess according to their own perception, using a Likert Scale. Concordance was evaluated applying Kappa index and the difference in scores was assessed using Wilcoxon test. Results: 45.6% of the participants were male and 69.6% studied in a private university. Total score was lower in participants’ self-assessment in comparison to the ideal score in all items studied (p<0.001), Kappa values ranged between 0.11 and 0.34. There were no gender differences (p>0.05). 78.9% admires a doctor and 27.3% would choose the same specialty as that person. Conclusion: A fair concordance was found between the characteristics participants have and those they thought a good doctor should have. Some physicians consider that they have not yet developed important aspects such as leadership, empathy, communication and listening capacity. We suggest carrying out new studies in order to evaluate if these characteristics differ after some years of medical practice.