Cierre de herida en cirugía protésica de rodilla y cadera (PTR y PTC): Resultados de una encuesta sobre la práctica clínica en España / Wound closure after knee and hip replacement (TKA and THA): Survey results on the clinical practice in Spain

Introducción y objetivos: En cirugía protésica de rodilla y cadera está claro que aún no se ha desarrollado una técnica de cierre estandarizada óptima. A nivel local no existen datos que describan la práctica quirúrgica habitual en cierre de herida. El objetivo de este trabajo es analizar el cierre de herida en cirugía protésica a través de una encuesta sobre una muestra representativa a nivel nacional y así obtener información sobre el contexto del cierre en España. Material y método: Se conforma un grupo ad hoc de especialistas en cirugía protésica. El grupo de expertos, posterior al análisis de la literatura, elabora un cuestionario de 32 preguntas cerradas de opción múltiple, divididas en los siguientes bloques: hemostasia, cierre quirúrgico de la herida y apósitos. Resultados: Un total de 471 cirujanos respondieron la encuesta de forma completa y con información suficiente para efectuar el análisis descriptivo; 79% cree que el ácido tranexámico (ATX) puede influir en la disminución de tasa de infección de sitio quirúrgico; 96% cree que el tipo de cierre profundo a nivel de la artrotomía podría influir en los resultados y complicaciones tras prótesis de cadera y/o rodilla; 85% cree que el tipo de cierre superficial a nivel subcutáneo puede influir en los resultados y complicaciones tras prótesis de cadera y/o rodilla; 64% de los cirujanos utiliza la terapia de presión negativa incisional de simple uso para el tratamiento de las complicaciones de la herida quirúrgica (seromas, drenaje prolongado, dehiscencias). Conclusiones: Existe en nuestro entorno una alta variabilidad en el cierre de la herida y una baja inversión en formación sobre este tema. Los autores recomiendan a las diferentes sociedades científicas la inversión de recursos para mejorar la formación en dicho campo y reducir el porcentaje de cirujanos que se consideran inadecuadamente formados, así como adaptar las técnicas de cierre a aquellas consideradas patrón oro según la evidencia.(AU)

Background and objective: In orthopedic surgery, it is clear that an optimal standardized closure technique has not yet been developed. Locally, there are no objective data describing the standard surgical practice in wound closure. The aim of this study is to analyze the clinical practice of surgical wound closure in orthopedic surgery by means of a survey of a representative local sample and thus obtain information on the context of closure in Spain. Method: an ad hoc group of specialists in orthopedic surgery and traumatology was formed. The group of experts, after analyzing the literature, developed a questionnaire of 32 closed multiple-choice questions divided into the following blocks: hemostasis, surgical wound closure (deep, superficial, and cutaneous), and dressings. Results: A total of 471 surgeons responded to the survey completely and with sufficient information to perform the descriptive analysis. 79% believe that ATX can influence the decrease in surgical site infection rate. 96% believe that the type of deep closure at the level of the arthrotomy could influence outcomes and complications after hip and/or knee replacements. 85% believe that the type of shallow closure at the subcutaneous level may influence outcomes and complications after hip and/or knee replacement. 64% of surgeons use single-use incisional negative pressure therapy for the treatment of surgical wound complications (seroma, prolonged drainage, dehiscence). Conclusions: There is a high level of variability in wound closure in our setting and a low level of training on the subject. The authors recommend that the different scientific societies invest resources to improve training in this field and reduce the percentage of surgeons who are considered inadequately trained, as well as adapting closure techniques to those considered gold standard according to the evidence.(AU)

[Translated article] Wound closure after knee and hip replacement (TKA and THA): Survey results on the clinical practice in Spain / Cierre de herida en cirugía protésica de rodilla y cadera (PTR y PTC): resultados de una encuesta sobre la práctica clínica en España

Introducción y objetivos: En cirugía protésica de rodilla y cadera está claro que aún no se ha desarrollado una técnica de cierre estandarizada óptima. A nivel local no existen datos que describan la práctica quirúrgica habitual en cierre de herida. El objetivo de este trabajo es analizar el cierre de herida en cirugía protésica a través de una encuesta sobre una muestra representativa a nivel nacional y así obtener información sobre el contexto del cierre en España. Material y método: Se conforma un grupo ad hoc de especialistas en cirugía protésica. El grupo de expertos, posterior al análisis de la literatura, elabora un cuestionario de 32 preguntas cerradas de opción múltiple, divididas en los siguientes bloques: hemostasia, cierre quirúrgico de la herida y apósitos. Resultados: Un total de 471 cirujanos respondieron la encuesta de forma completa y con información suficiente para efectuar el análisis descriptivo; 79% cree que el ácido tranexámico (ATX) puede influir en la disminución de tasa de infección de sitio quirúrgico; 96% cree que el tipo de cierre profundo a nivel de la artrotomía podría influir en los resultados y complicaciones tras prótesis de cadera y/o rodilla; 85% cree que el tipo de cierre superficial a nivel subcutáneo puede influir en los resultados y complicaciones tras prótesis de cadera y/o rodilla; 64% de los cirujanos utiliza la terapia de presión negativa incisional de simple uso para el tratamiento de las complicaciones de la herida quirúrgica (seromas, drenaje prolongado, dehiscencias). Conclusiones: Existe en nuestro entorno una alta variabilidad en el cierre de la herida y una baja inversión en formación sobre este tema. Los autores recomiendan a las diferentes sociedades científicas la inversión de recursos para mejorar la formación en dicho campo y reducir el porcentaje de cirujanos que se consideran inadecuadamente formados, así como adaptar las técnicas de cierre a aquellas consideradas patrón oro según la evidencia.(AU)

Background and objective: In orthopedic surgery, it is clear that an optimal standardized closure technique has not yet been developed. Locally, there are no objective data describing the standard surgical practice in wound closure. The aim of this study is to analyze the clinical practice of surgical wound closure in orthopedic surgery by means of a survey of a representative local sample and thus obtain information on the context of closure in Spain. Method: an ad hoc group of specialists in orthopedic surgery and traumatology was formed. The group of experts, after analyzing the literature, developed a questionnaire of 32 closed multiple-choice questions divided into the following blocks: hemostasis, surgical wound closure (deep, superficial, and cutaneous), and dressings. Results: A total of 471 surgeons responded to the survey completely and with sufficient information to perform the descriptive analysis. 79% believe that ATX can influence the decrease in surgical site infection rate. 96% believe that the type of deep closure at the level of the arthrotomy could influence outcomes and complications after hip and/or knee replacements. 85% believe that the type of shallow closure at the subcutaneous level may influence outcomes and complications after hip and/or knee replacement. 64% of surgeons use single-use incisional negative pressure therapy for the treatment of surgical wound complications (seroma, prolonged drainage, dehiscence). Conclusions: There is a high level of variability in wound closure in our setting and a low level of training on the subject. The authors recommend that the different scientific societies invest resources to improve training in this field and reduce the percentage of surgeons who are considered inadequately trained, as well as adapting closure techniques to those considered gold standard according to the evidence.(AU)

Wound closure after knee and hip replacement (TKA and THA): Survey results on the clinical practice in Spain. / Cierre de herida en cirugía protésica de rodilla y cadera (PTR y PTC): Resultados de una encuesta sobre la práctica clínica en España.

BACKGROUND AND OBJECTIVE: In orthopedic surgery, it is clear that an optimal standardized closure technique has not yet been developed. Locally, there are no objective data describing the standard surgical practice in wound closure. The aim of this study is to analyze the clinical practice of surgical wound closure in orthopedic surgery by means of a survey of a representative local sample and thus obtain information on the context of closure in Spain. METHOD: an ad hoc group of specialists in orthopedic surgery and traumatology was formed. The group of experts, after analyzing the literature, developed a questionnaire of 32 closed multiple-choice questions divided into the following blocks: hemostasis, surgical wound closure (deep, superficial, and cutaneous), and dressings. RESULTS: A total of 471 surgeons responded to the survey completely and with sufficient information to perform the descriptive analysis. 79% believe that ATX can influence the decrease in surgical site infection rate. 96% believe that the type of deep closure at the level of the arthrotomy could influence outcomes and complications after hip and/or knee replacements. 85% believe that the type of shallow closure at the subcutaneous level may influence outcomes and complications after hip and/or knee replacement. 64% of surgeons use single-use incisional negative pressure therapy for the treatment of surgical wound complications (seroma, prolonged drainage, dehiscence). CONCLUSIONS: There is a high level of variability in wound closure in our setting and a low level of training on the subject. The authors recommend that the different scientific societies invest resources to improve training in this field and reduce the percentage of surgeons who are considered inadequately trained, as well as adapting closure techniques to those considered gold standard according to the evidence.

Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement.

Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.

[Translated article] Wound closure after knee and hip replacement (TKA and THA): Survey results on the clinical practice in Spain.

BACKGROUND AND OBJECTIVE: In orthopaedic surgery, it is clear that an optimal standardised closure technique has not yet been developed. Locally, there are no objective data describing the standard surgical practice in wound closure. The aim of this study is to analyse the clinical practice of surgical wound closure in orthopaedic surgery by means of a survey of a representative local sample and thus obtain information on the context of closure in Spain. MATERIAL AND METHOD: An ad hoc group of specialists in orthopaedic surgery and traumatology was formed. The group of experts, after analyzing the literature, developed a questionnaire of 32 closed multiple-choice questions divided into the following blocks: hemostasis, surgical wound closure (deep, superficial, and cutaneous), and dressings. RESULTS: A total of 471 surgeons responded to the survey completely and with sufficient information to perform the descriptive analysis. 79% believe that ATX can influence the decrease in surgical site infection rate. 96% believe that the type of deep closure at the level of the arthrotomy could influence outcomes and complications after hip and/or knee replacements. 85% believe that the type of shallow closure at the subcutaneous level may influence outcomes and complications after hip and/or knee replacement. 64% of surgeons use single-use incisional negative pressure therapy for the treatment of surgical wound complications (seroma, prolonged drainage, dehiscence). CONCLUSIONS: There is a high level of variability in wound closure in our setting and a low level of training on the subject. The authors recommend that the different scientific societies invest resources to improve training in this field and reduce the percentage of surgeons who are considered inadequately trained, as well as adapting closure techniques to those considered gold standard according to the evidence.

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.

OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.

Protocolo de manejo de pacientes con enfermedad pulmonar obstructiva crónica tras agudización en urgencias / Protocol for the management of patients with chronic obstructive pulmonary disease after exacerbation in the emergency department

En la enfermedad pulmonar obstructiva crónica el síndrome de agudización (SAE) es un episodio de inestabilidad clínica por agravamiento de la limitación espiratoria al flujo aéreo o del proceso inflamatorio subyacente. La gravedad del SAE depende de la estratificación del riesgo basal y la intensidad del episodio agudo. La Atención Primaria es el epicentro del circuito asistencial del SAE, pero puede extenderse al Servicio de Urgencias Extrahospitalarias y al propio hospital dependiendo de la situación clínica, del nivel de gravedad, de la disponibilidad de pruebas complementarias y de los recursos terapéuticos necesarios para cada paciente. El registro de los datos clínicos, antecedentes, factores desencadenantes, tratamiento y evolución de los episodios previos de SAE en la historia clínica electrónica son un aspecto esencial para ajustar el tratamiento actual y prevenir la aparición de futuros episodios (AU)

In chronic obstructive pulmonary disease, an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an episode of clinical instability due to the worsening of expiratory airflow limitation or of the underlying inflammatory process. The severity of AECOPD depends on baseline risk stratification and the intensity of the acute episode. Primary Care is the epicenter of the AECOPD care circuit, but it can be extended to the out-of-hospital emergency department and the hospital itself depending on the clinical situation, the level of severity, the availability of complementary tests, and the therapeutic resources required for each patient. Recording clinical data, history, triggering factors, treatment, and evolution of previous episodes of AECOPD in the electronic medical record is an essential aspect to adjust current treatment and prevent the occurrence of future episodes (AU)

[Protocol for the management of patients with chronic obstructive pulmonary disease after exacerbation in the emergency department]. / Protocolo de manejo de pacientes con enfermedad pulmonar obstructiva crónica tras agudización en urgencias.

In chronic obstructive pulmonary disease, an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an episode of clinical instability due to the worsening of expiratory airflow limitation or of the underlying inflammatory process. The severity of AECOPD depends on baseline risk stratification and the intensity of the acute episode. Primary Care is the epicenter of the AECOPD care circuit, but it can be extended to the out-of-hospital emergency department and the hospital itself depending on the clinical situation, the level of severity, the availability of complementary tests, and the therapeutic resources required for each patient. Recording clinical data, history, triggering factors, treatment, and evolution of previous episodes of AECOPD in the electronic medical record is an essential aspect to adjust current treatment and prevent the occurrence of future episodes.

Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry.

BACKGROUND: Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. PATIENTS AND METHODS: A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. RESULTS: Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n = 1, BM 40.9% versus 25.4%; n = 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. CONCLUSIONS: In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.

Non-dispersive sensing scheme based on mid-infrared LED and differential mode excitation photoacoustic spectroscopy.

A robust and simple sensing scheme utilizing a Mid-Infrared Light Emitting Diode (MIR-LED) and based on Differential Mode Excitation Photoacoustic (DME-PA) spectroscopy is presented. A MIR-LED light source in combination with optical correlation is used for simplicity and compactness. The sensing setup takes advantage of the non-linearity in the excitation of various acoustic modes in a cylindrical resonant photoacoustic cell to provide a high selectivity. The sensing device is tested using methane and hydrocarbon mixtures (propane, butane). The obtained limit of detection for methane is 25 ppm m-1. Using the presented DME-PA scheme, the derived gas concentration is hardly affected neither by intensity fluctuations of the light source nor by any microphone or electronics drifts. Furthermore, a considerably improved selectivity is obtained compared to conventional Non-Dispersive Infrared (NDIR) techniques.

Consenso Delphi sobre Estrategias Terapéuticas y de Prevención Sanitaria de la hipovitaminosis D / Delphi Consensus on Therapeutic and Preventive Health Strategies for Hypovitaminosis D

Antecedentes: La elevada prevalencia de hipovitaminosis D en España es considerada una verdadera epidemia con importantes implicaciones para la salud por las múltiples funciones que ejerce la vitamina D tanto a nivel esquelético como extraesquelético. Para que las personas con insuficiencia o deficiencia en vitamina D alcancen los niveles séricos más adecuados, deben recibir suplementos de vitamina D. Este estudio se realizó con la finalidad de evaluar si en la práctica clínica habitual, el manejo de la hipovitaminosis D era llevada a cabo según las recomendaciones internacionales establecidas por las sociedades científicas.Métodos: Se realizaron dos rondas de circulación de un cuestionario Delphi entre un panel formado por médicos prescriptores habituales de vitamina D.Resultados: En general, los médicos del panel reconocieron la alta prevalencia de la hipovitaminosis D en España, la necesidad del cribado en los distintos grupos de riesgo y los beneficios de la suplementación en los pacientes con insuficiencia o déficit de vitamina D. Sin embargo, no se alcanzó el consenso en algunas de las aseveraciones relacionadas con los métodos de cuantificación de la vitamina D o con las recomendaciones para el manejo de la hipovitaminosis D.Conclusiones: La ausencia de acuerdo para algunos de los ítems reveló la necesidad de realizar acciones formativas destinadas a proporcionar un conocimiento adecuado y actualizado sobre las evidencias científicas y las recomendaciones para la práctica clínica de la suplementación de vitamina D. (AU)

Neoplasia papilar de polaridad inversa: un nuevo subtipo de tumor renal de buen pronóstico / Papillary renal cell neoplasm with reverse polarity: A new subtype of renal tumour with favorable prognosis

Introducción: La neoplasia papilar renal de polaridad inversa (NPRPI) ha sido recientemente reconocida como una entidad separada de la clasificación tradicional de los carcinomas papilares de células renales por sus peculiares características histopatológicas, inmunofenotípicas y moleculares, y un comportamiento indolente. Material y métodos: En este trabajo aportamos 6 nuevos casos y realizamos una revisión de la literatura publicada al respecto hasta el momento actual, recopilándose un total de 104 casos. Resultados: Nuestros casos de NPRPI corresponden a 5 hombres y una mujer, con edades comprendidas entre los 47 y los 91 años. En 5 casos la NPRPI resultó un hallazgo incidental en piezas de nefrectomía indicada por la presencia de otro tumor renal y en uno la NPRPI fue el motivo de la intervención quirúrgica. Nuestros casos presentan tamaños entre los 2 y los 13mm, y una histología papilar con revestimiento en monocapa de células eosinófilas con núcleos de bajo grado en localización apical. Inmunohistoquímicamente muestran una constante positividad para GATA3 y negatividad para vimentina. Se identificaron mutaciones en KRAS en el 50% de ellos. Tras un seguimiento comprendido entre uno y 60 meses, 5 de los pacientes seguían vivos sin recurrencia o metástasis y uno falleció a causa de un carcinoma urotelial. Conclusiones: Nuestros casos concuerdan con las características clínicas y patológicas descritas en los publicados hasta el momento. Aportamos la primera serie nacional y corroboramos la existencia de unos criterios diagnósticos definidos y constantes que permiten considerar la NPRPI como una entidad propia distintiva. (AU)

Introduction: Papillary renal cell neoplasm with reverse polarity (PRNRP) has recently been recognized as an entity separate from the traditional classification of papillary renal cell carcinomas, due to its specific histopathological, immunophenotypic and molecular characteristics, as well as its indolent behavior . Material and methods: We provide 6 new cases and a review of the literature published until the present time, which comprises a total number of 104 cases. Results: Our PRNRP cases correspond to 5 men and one woman aged between 47 and 91 years. In 5 of the 6 cases, the PRNRP was an incidental finding in nephrectomy specimens. Nephrectomy had been indicated due to the presence of another renal tumor, except for one case, in which surgical intervention was indicated due to PRNRP. Our cases present mass sizes between 2 and 13mm, as well as papillary histology with a monolayered lining of eosinophilic cells with low-grade nuclei in apical location. Immunohistochemically, they show a constant positivity for GATA3 and negativity for vimentin. KRAS mutations were identified in 50% of our cases. After a follow-up ranging between one and 60 months, 5 of the cases were still alive without recurrences or metastases, and one died from urothelial carcinoma. Conclusions: Our cases agree with the clinical and pathological characteristics described in the PRNRP cases published to date. With the present study, we provide the first series of national cases corroborating the existence of well-defined and constant diagnostic criteria that allow PRNRP to be considered as a distinctive entity. (AU)

Using a robotic exoskeleton at home: An activity tolerance case study of a child with spinal muscular atrophy.

PURPOSE: Spinal Muscular Atrophy (SMA) Type II is a neurodegenerative disease that leads to progressive muscle weakness. It prevents children from walking and affects their respiratory function and their activity tolerance, among other health problems. We aimed to assess the activity tolerance showed by a child with SMA using a pediatric gait exoskeleton at home when walking and performing activities. DESIGN AND METHODS: This study presents the case of a 6-year-old boy with SMA Type II and respiratory failure who used a pediatric gait exoskeleton at home for a period of two months. A nursing assessment was done before and during the use of the device to evaluate the child's activity tolerance during the sessions. Nursing interviews, performance, vital signs, fatigue, field notes, and functional scales were analyzed. RESULTS: The nursing assessment showed a good activity tolerance of the child. Performance using the device improved over time; vital signs did not vary significantly during the sessions; fatigue perception decreased over time; and the child reached a higher score on some functional outcomes. CONCLUSIONS: A first step has been taken to evaluate the impact of exoskeleton technology in children with SMA Type II from the nursing point of view, exposing the potential of this technology for the care of children with neuromuscular diseases, and the need for more research on the topic. PRACTICE IMPLICATIONS: The information in this study will be useful to nurses to know the effects of gait exoskeletons in pediatric care of children with neuromuscular diseases like SMA.

Papillary renal cell neoplasm with reverse polarity: A new subtype of renal tumour with favorable prognosis.

INTRODUCTION: Papillary renal cell neoplasm with reverse polarity (PRNRP) has recently been recognized as an entity separate from the traditional classification of papillary renal cell carcinomas, due to its specific histopathological, immunophenotypic and molecular characteristics, as well as its indolent behavior. MATERIAL AND METHODS: We provide 6 new cases and a review of the literature published until the present time, which comprises a total number of 104 cases. RESULTS: Our PRNRP cases correspond to 5 men and one woman aged between 47 and 91 years. In 5 of the 6 cases, the PRNRP was an incidental finding in nephrectomy specimens. Nephrectomy had been indicated due to the presence of another renal tumor, except for one case, in which surgical intervention was indicated due to PRNRP. Our cases present mass sizes between 2 and 13 mm, as well as papillary histology with a monolayered lining of eosinophilic cells with low-grade nuclei in apical location. Immunohistochemically, they show a constant positivity for GATA3 and negativity for vimentin. KRAS mutations were identified in 50% of our cases. After a follow-up ranging between one and 60 months, 5 of the cases were still alive without recurrences or metastases, and one died from urothelial carcinoma. CONCLUSIONS: Our cases agree with the clinical and pathological characteristics described in the PRNRP cases published to date. With the present study, we provide the first series of national cases corroborating the existence of well-defined and constant diagnostic criteria that allow PRNRP to be considered as a distinctive entity.

Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.

BACKGROUND: Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287). PATIENTS AND METHODS: Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). RESULTS: A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred. CONCLUSIONS: Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.

A new paradigm for regulation of protein phosphatase 2A function via Src and Fyn kinase-mediated tyrosine phosphorylation.

Protein phosphatase 2A (PP2A) is a major phospho-Ser/Thr phosphatase and a key regulator of cellular signal transduction pathways. While PP2A dysfunction has been linked to human cancer and neurodegenerative disorders such as Alzheimer's disease (AD), PP2A regulation remains relatively poorly understood. It has been reported that the PP2A catalytic subunit (PP2Ac) is inactivated by a single phosphorylation at the Tyr307 residue by tyrosine kinases such as v-Src. However, multiple mass spectrometry studies have revealed the existence of other putative PP2Ac phosphorylation sites in response to activation of Src and Fyn, two major Src family kinases (SFKs). Here, using PP2Ac phosphomutants and novel phosphosite-specific PP2Ac antibodies, we show that cellular pools of PP2Ac are instead phosphorylated on both Tyr127 and Tyr284 upon Src activation, and on Tyr284 following Fyn activation. We found these phosphorylation events enhanced the interaction of PP2Ac with SFKs. In addition, we reveal SFK-mediated phosphorylation of PP2Ac at Y284 promotes dissociation of the regulatory Bα subunit, altering PP2A substrate specificity; the phosphodeficient Y127/284F and Y284F PP2Ac mutants prevented SFK-mediated phosphorylation of Tau at the CP13 (pSer202) epitope, a pathological hallmark of AD, and SFK-dependent activation of ERK, a major growth regulatory kinase upregulated in many cancers. Our findings demonstrate a novel PP2A regulatory mechanism that challenges the existing dogma on the inhibition of PP2A catalytic activity by Tyr307 phosphorylation. We propose dysregulation of SFK signaling in cancer and AD can lead to alterations in PP2A phosphorylation and subsequent deregulation of key PP2A substrates, including ERK and Tau.

Characteristics of patients with brain metastases from human epidermal growth factor receptor 2-positive breast cancer: subanalysis of Brain Metastases in Breast Cancer Registry.

BACKGROUND: Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital. PATIENTS AND METHODS: A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype. RESULTS: Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups. CONCLUSIONS: We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.