Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.

INTRODUCTION: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors. MATERIALS AND METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B. RESULTS: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional. CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited. GOV IDENTIFIER: NCT03724890.

[Translated article] Lower mortality and readmission in patients with few comorbidities who underwent hip fracture surgery and were discharged early.

INTRODUCTION: Pre-operative delay in patients with hip fracture surgery (HF) has been associated with poorer outcomes; however, the optimal timing of discharge from hospital after surgery has been little studied. The aim of this study was to determine mortality and readmission outcomes in HF patients with and without early hospital discharge. MATERIAL AND METHODS: A retrospective observational study was conducted selecting 607 patients over 65years of age with HF intervened between January 2015 and December 2019, from which 164 patients with fewer comorbidities and ASA≤II were included for analysis and divided according to their post-operative hospital stay into early discharge or stay ≤4 days (n=115), and non-early or post-operative stay >4days (n=49). Demographic characteristics; fracture and surgical-related characteristics; 30-day and one-year post-operative mortality rates; 30-day post-operative hospital readmission rate; and medical or surgical cause were recorded. RESULTS: In the early discharge group all outcomes were better compared to the non-early discharge group: lower 30-day (0.9% versus 4.1%, p=.16) and 1-year post-operative (4.3% versus 16.3%, p=.009) mortality rates, as well as a lower rate of hospital readmission for medical reasons (7.8% versus 16.3%, p=.037). CONCLUSIONS: In the present study, the early discharge group obtained better results 30-day and 1-year post-operative mortality indicators, as well as readmission for medical reasons.

Lower mortality and readmission in patients with few comorbidities who underwent hip fracture surgery and were discharged early. / Menor mortalidad y reingreso en pacientes con pocas comorbilidades intervenidos de fractura de cadera y con alta precoz.

INTRODUCTION: Preoperative delay in patients with hip fracture surgery (HF) has been associated with poorer outcomes; however, the optimal timing of discharge from hospital after surgery has been little studied. The aim of this study was to determine mortality and readmission outcomes in HF patients with and without early hospital discharge. MATERIAL AND METHODS: A retrospective observational study was conducted selecting 607 patients over 65years of age with HF intervened between January 2015 and December 2019, from which 164 patients with fewer comorbidities and ASA ≤II were included for analysis and divided according to their postoperative hospital stay into early discharge or stay ≤4 days (n=115), and non-early or post-operative stay >4days (n=49). Demographic characteristics; fracture and surgical-related characteristics; 30-day and one-year postoperative mortality rates; 30-day postoperative hospital readmission rate; and medical or surgical cause were recorded. RESULTS: In the early discharge group all outcomes were better compared to the non-early discharge group: lower 30-day (0.9% vs 4.1%, P=.16) and 1-year postoperative (4.3% vs 16.3%, P=.009) mortality rates, as well as a lower rate of hospital readmission for medical reasons (7.8% vs 16.3%, P=.037). CONCLUSIONS: In the present study, the early discharge group obtained better results 30-day and 1-year postoperative mortality indicators, as well as readmission for medical reasons.

[Total Aortic Arch Replacement. Does a management protocol impact the results?] / Reemplazo Total de Arco Aórtico. ¿Un protocolo de manejo impacta en los resultados?

Aortic arch surgery is a surgical challenge due to its technical complexity and brain and body protection requirements. AIM: To describe the surgical protocol and the short and long-term results of aortic arch replacement surgery in a center in the metropolitan region of Santiago, Chile. METHODS: Retrospective descriptive study from April 2015 to August 2022. Elective, urgent, and emergency patients were included, with diagnoses of arch aneurysm and acute or chronic type I and II DeBakey aortic dissection. TECHNIQUE: Arterial cannulation at the brachiocephalic trunk, right axillary artery, or directly into the true lumen of the aortic dissection with Seldinger technique, guided by epiaortic and transesophagic ultrasound. Deep hypothermia at 24°C. Uni or bilateral antegrade cerebral perfusion according to runoff. Four devices were used: a straight tube, a tube with 3 or 4 branches, and a frozen elephant trunk. RESULTS: 37 patients were operated on; 24 of them were men. The average age was 57 years old. In seven patients, a straight tube with anastomosis was used with anastomosis on the island; in six patients, a tube with 3 branches; in ten patients, a tube with four branches; and in fourteen patients, a frozen elephant trunk. There were twenty-one patients (57%) with associated morbidity: prolonged mechanical ventilation 14 the most frequent, paralysis chordae in 7 patients; there were six neurological morbidities, one of them permanent, renal dysfunction in 5 patients, pneumonia associated with mechanical ventilation in 4 patients, reoperation due to bleeding in 4. There was no associated cardiac morbidity. Operative and global mortality at 30 days was 13.5%. Follow-up was closed in October 2022 and is complete in the 30 survivors; the average was 20 months. Two patients died in the follow-up at five years; the survival in the follow-up was 90%. CONCLUSION: The management protocol has good results regarding morbidity and mortality, similar to the international series.

Relación de IMC con marcadores de inflamación y hemoglobina glicosilada en niños y jóvenes con diabetes mellitus 1 / Relationship of BMI with markers of inflammation and glycosylated hemoglobin in children and young adults with diabetes mellitus 1

La diabetes mellitus tipo 1 (DM1) es una enfermedad autoinmune que genera dependencia exógena de insulina de forma permanente, presenta inflamación subclínica crónica lo que conlleva a una elevación de marcadores de inflamación como factor de necrosis tumoral alfa (TNF-α), proteína C reactiva (PCR) e interleuquina 6 (IL-6). OBJETIVO: determinar la relación entre el IMC sobre los marcadores de inflamación y el control metabólico en niños y jóvenes con DM1 entre 5 a 15 años de edad. METODOLOGÍA: Se realizó un estudio clínico, observacional, exploratorio. A partir de La recolección de datos de fichas clínicas y muestras de sangre en el Instituto de Investigaciones Materno Infantil (IDIMI) del Hospital San Borja Arriarán de la Universidad de Chile. Clasificación del estado nutricional utilizando datos registrados en ficha clínica. Marcadores de inflamación por medio de ELISA, hemoglobina glicosilada mediante métodos estándares. El análisis estadístico incluyó correlaciones mediante test de Spearman y diferencia de medias mediante test de Kruskal-Wallis seguido de post hoc Dunns. RESULTADOS: Un 30% de los pacientes con DM1 presentaron malnutrición por exceso. Al analizar la relación entre los niveles de marcadores inflamatorios y Hb glicosilada se observó la existencia de asociacion positiva entre usPCR y HbA1c (r= 0,30; p=0,0352) y entre IL-6 y HbA1c (r= - 0,038; p=0,0352). CONCLUSIONES: este estudio describe una posible asociación entre parámetros clásicos de inflamación con la hemoglobina glicosilada en las categorias de sobrepeso y obesidad en pacientes con DM1.

Type 1 diabetes mellitus (T1D) is an autoimmune disease that generates permanent exogenous insulin dependence, accompanied by chronic subclinical inflammation that leads to an elevation of inflammation markers such as tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6). OBJECTIVE: To determine the relationship between BMI on markers of inflammation and metabolic control in children and young people with T1D between 5 and 15 years of age. METHODOLOGY: A clinical, observational and exploratory study was carried out, based on the collection of data from clinical records and blood samples of children and adolescents with DM1 at the Instituto de Investigaciones Materno Infantil (IDIMI) of the Hospital San Borja Arriarán of the Universidad de Chile. Nutritional status, levels of inflammation markers and glycosylated hemoglobin were determined by standardized methods. Statistical analysis included correlations by Spearman test and mean difference by Kruskal-Wallis test followed by post hoc Dunns test. RESULTS: A total of 56 patients with T1D were analyzed, 30% of whom presented excess malnutrition. Those children or adolescents with obesity presented significantly higher usPCR levels compared to underweight patients or patients at risk of malnutrition (p=0.039). In addition, HbA1c levels were determined which were negatively associated with usPCR (r= 0.30; p=0.0352) and IL-6 (r= - 0.038; p=0.0352) levels. CONCLUSIONS: This study points out that nutritional status is associated with usPCR levels, in agreement with what is described in the literature and shows a possible association between classical parameters of inflammation with glycosylated hemoglobin in children and adolescents with nutritional diagnosis of overweight or obesity.

Autoimmune retinopathy with onconeuronal antibodies: Case report.

We present a case of autoimmune retinopathy in a patient with unknown small cell lung cáncer (SCLC), which was diagnosed after ophthalmological examination. Serology was positive for CV2/CRMP5 onconeuronal antibodies. Autoimmune retinopathy is a rare entity that can be missed and underdiagnosed. It is produced by an immune-mediated reaction against retinal antigens. The importance of its early diagnosis lies in the fact that in many of the patients, ocular symptoms appear before the diagnosis of the primary cancer, so its early identification and referral for an extension study may lead to the diagnosis of a hidden primary neoplasm.

Hepatocyte-like cells differentiated from methylmalonic aciduria cblB type induced pluripotent stem cells: A platform for the evaluation of pharmacochaperoning.

Methylmalonic aciduria cblB type (MMA cblB type, MMAB OMIM #251110), caused by a deficiency in the enzyme ATP:cob(I)alamin adenosyltransferase (ATR, E.C_2. 5.1.17), is a severe metabolic disorder with a poor prognosis despite treatment. We recently described the potential therapeutic use of pharmacological chaperones (PCs) after increasing the residual activity of ATR in patient-derived fibroblasts. The present work reports the successful generation of hepatocyte-like cells (HLCs) differentiated from two healthy and two MMAB induced pluripotent stem cell (iPSC) lines, and the use of this platform for testing the effects of PCs. The MMAB cells produced little ATR, showed reduced residual ATR activity, and had higher concentrations of methylmalonic acid compared to healthy HLCs. Differential proteome analysis revealed the two MMAB HCLs to show reproducible differentiation, but this was not so for the healthy HLCs. Interestingly, PC treatment in combination with vitamin B12 increased the amount of ATR available, and subsequently ATR activity, in both MMAB HLCs. More importantly, the treatment significantly reduced the methylmalonic acid content of both. In summary, the HLC model would appear to be an excellent candidate for the pharmacological testing of the described PCs, for analyzing the effects of new drugs, and investigating the repurposing of older drugs, before testing in animal models.

Tipos de conocimientos que, relacionados a la sexualidad, las prácticas sexuales y la salud reproductiva manifiesta los estudiantes de nuevo ingreso, Ciclo 02, de la Universidad Salvadoreña Alberto Masferrer, año 2020 / Types of knowledge that, related to sexuality, sexual practices and reproductive health, manifest new students, Cycle 02, of the Universidad Salvadoreña Alberto Masferrer, year 2020

La investigación constituye una aproximación cualitativa al fenómeno de la sexualidad adolescente, centrada en describir la mentalidad de los jóvenes respecto a su propia sexualidad. Es decir; los conocimientos relacionados a las prácticas sexuales y la salud reproductiva asociada a dichos conocimientos, manifestados por los estudiantes participantes en el estudio. La finalidad fue descubrir la calidad y procedencia del tipo de conocimiento que poseen los jóvenes y su coherencia con las ideas sobre las prácticas sexuales y la salud reproductiva, a fin de identificar qué porcentaje de la población posee un conocimiento confiable, atendiendo a la calidad. Condición que los exponen a adquirir infecciones de transmisión sexual que pueden poner en riesgo su salud reproductiva. El objetivo perseguido fue: describir el tipo de conocimiento y las prácticas sobre salud sexual y reproductiva en los 306 estudiantes del primer año de la Universidad Salvadoreña Alberto Masferrer que participaron en el estudio. Los resultados señalan que un 30 % de la población estudiada, no poseen un conocimiento confiable, sino basado en creencias y mitos, que no existe una fuente científica confiable que les permita desarrollarse plenamente en esta área fundamental en sus vidas. El otro descubrimiento fue la presencia de un carácter constante es sus conocimientos: y que los conocimientos que poseen no son coherentes entre sí. Por lo que carecen consistencia y revelan la falta de correspondencia a un sistema teórico confiable para orientar correctamente su sexualidad y su salud sexual y reproductiva.

This research constitutes a qualitative approximation to the phenomenon of adolescent sexuality focused on describing the mentality of young people regarding their own sexuality. That is, the knowledge as it relates to the sexual practices and reproductive health associated with said knowledge, manifested (expressed) by the students participating in the study. The purpose was to describe the quality and provenance of the type of knowledge that young people possess; its coherence with ideas about sexual practices and reproductive health, lastly to identify the type of knowledge the population have and how reliable is such knowledge. Conditions that exposes them to acquire sexually transmitted diseases potentially putting their reproductive health at risk. The objective was to describe the type of knowledge and practices on sexual and reproductive health in 306 first year Salvadorian University Alberto Masferrer students, who participated in the study. The results indicates that 30% of the studied population do not possess reliable knowledge, but based on beliefs, and myths, there is no reliable scientific source that allows them to fully develop in this fundamental area in their life. The other discovery was the presence of constant character in their knowledge: and that the knowledge possessed is not coherent within each other. They lack consistency and reveal a lack of correspondence and reliable theoretical system to correctly guide their sexuality and sexual and reproductive health.

The impact of fluorescence angiography on anastomotic leak rate following transanal total mesorectal excision for rectal cancer: a comparative study.

BACKGROUND: Anastomotic leak (AL) is the most feared complication in colorectal surgery. Indocyanine green (ICG) fluorescence angiography allows for real-time intraoperative evaluation of bowel perfusion. This study aimed to assess the impact of ICG on perioperative outcomes in patients treated with transanal total mesorectal excision (TaTME) for rectal cancer. METHODS: Comparative study based on a retrospective analysis of prospectively collected data, to validate the use of ICG assessment (ICGA) during TaTME (November/2011-June/2018). The primary outcome was the clinical AL rate. The secondary outcomes included modification of proximal colonic transection, anastomotic redo, additional surgical maneuvers and surgical morbidity. RESULTS: Two hundred and eighty-four patients were included, 204 (71.8%) in non-ICG group and 80 (28.2%) in ICG group. No significant differences were found in patient and tumor features. Mean anastomotic height was 4.85 cm vs. 5.04 cm (p = 0.500), diverting stoma was constructed in 205 patients (72.1% vs. 72.5%; p = 0.941). Fluorescence angiography modified the surgical plan in 23 patients (28.7%). AL was diagnosed in 23 patients (11.3%) in the non-ICG group and in two patients (2.5%) in the ICG group (p = 0.020). Postoperative intraabdominal collection was diagnosed in 19 patients (7.4% vs. 5.1%; p = 0.490), and reintervention was needed in 24 patients (10.8% vs. 7.6%; p = 0.420). Median length of hospital stay was 6.0 (IQR 5.0-9) vs. 4.0 (IQR 3.0-8.5) (p = 0.005). ICGA was found as independent protective factor for AL in the multivariate analysis of the whole cohort (n = 284) (OR 0.142; 95% CI 0.032-0.633; p = 0.010). CONCLUSION: ICG fluorescence angiography modified the proximal colonic transection in more than one-quarter of patients, leading to a significant decrease of AL rate.

Capillary malformation-arteriovenous malformation syndrome: a multicentre study.

BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a rare syndrome with characteristic skin lesions that are associated with fast-flow vascular malformations (FFVMs) in one-third of patients. Few case series have been described, and none in Spain. AIM: To identify the prevalence of dermatological parameters, FFVMs and associated features in a large series of patients with CM-AVM. METHODS: We conducted an observational study of patients with CM-AVM syndrome diagnosed in 15 Spanish hospitals over 3 years. The main clinical, radiological, genetic findings and associated diseases were analysed. RESULTS: In total, 64 patients were assessed. In 26.5% of cases, the diagnosis was incidental. In 75% of patients, there was one significantly larger macule, which we termed the 'herald patch'. FFVMs were detected in 34% of the patients, with 30% located on the skin, 7.8% in the brain and in 1.5% in the spine. There was a positive family history in 65% of the 64 patients. Genetic analysis was performed for RASA1 mutations in 57 patients, of whom 42 (73%) had a positive result. All 4 patients tested for EPHB4 mutations had a positive result. No tumour lesions were detected in the series, except for five infantile haemangiomas. CONCLUSIONS: Our data on clinical lesions, associated FFVM, family history and genetics are similar to those previously published in the literature. An extensive data analysis failed to demonstrate any statistically significant association between the presence of an FFVM and any clinical, familial or genetic parameter that could predict its onset, although a link between the presence of a herald patch on the midline face and the presence of a brain FFVM was observed. We did not detect any genotype-phenotype correlation.

A laboratory study of root canal and isthmus disinfection in extracted teeth using various activation methods with a mixture of sodium hypochlorite and etidronic acid.

AIM: To evaluate in a laboratory setting the antibiofilm activity of several irrigating protocols including conventional irrigation, ultrasonic activation and XP-endo Finisher, with a mixture of sodium hypochlorite and etidronic acid in infected isthmuses and root canals of extracted human mandibular molar teeth. METHODOLOGY: Fifty-six mesial roots of mandibular molars, half of them with a continuous isthmus from the cervical to the apical third between the two root canals (type 1), and the other half with a continuous isthmus from the cervical to the middle third and one canal in the apical third (type 2), were included. The root canals were contaminated for 7 days with an Enterococcus faecalis suspension. There were three experimental groups plus a control group (n = 7 per type of root canal anatomy). All the root canals, except for the control group that was not treated, were chemomechanically prepared and then assigned to one of the experimental groups according to the final adjunctive procedure: conventional irrigation, ultrasonic activation or XP-endo Finisher activation. The irrigating solution used was a combination of 2.5% sodium hypochlorite and 9% etidronic acid, and the final protocols were applied for three cycles of 30 s with a 3 mL volume. The antibiofilm activity was evaluated at each location (root canal and isthmus) and third (cervical, middle and apical) using confocal laser scanning microscopy and the live/dead technique. Statistical analysis was performed using SPSS (descriptive statistics) and SUDAAN (P-value calculations). RESULTS: Root canals had significantly lower biovolume values than the isthmuses (P < 0.05). The biovolume in the root canals was significantly reduced in all the experimental groups in all the thirds except for conventional irrigation in the apical third (P > 0.05). In the cervical and middle thirds, ultrasonic activation was associated with the lowest biovolumes (P < 0.05), followed by XP-endo Finisher. In the isthmus, disinfection was similar in all the thirds for all the protocols. Conventional irrigation was associated with intermediate values with no significant differences from the control group or from the activated protocols (P > 0.05), although the latter were significantly different from the control group (P < 0.05). No differences were found between ultrasonic activation and XP-endo Finisher in the middle and apical thirds (P > 0.05) in the isthmuses. CONCLUSIONS: In this laboratory study on extracted teeth, the isthmus was more difficult to disinfect than root canals. In the root canals, ultrasonic activation and XP-endo Finisher had a greater effectiveness than conventional irrigation. In the isthmuses, no differences were observed between the two activation techniques and conventional irrigation.

Increasing experience of modified two-stage transanal ileal pouch-anal anastomosis for therapy refractory ulcerative colitis. What have we learned? A retrospective analysis on 75 consecutive cases at a tertiary referral hospital.

AIM: Ileal pouch-anal anastomosis (IPAA) should be delayed to a second stage in patients with ulcerative colitis and prolonged exposure to medical therapy. However, there is still discussion about whether a modified two-stage approach is preferable to a three-stage approach. Recently, a transanal approach has been introduced to overcome the well-known difficulties of laparoscopic pelvic surgery. This paper presents short-term outcomes of transanal IPAA (Ta-IPAA) according to a modified two-stage approach. METHODS: Data from all patients who underwent a modified two-stage Ta-IPAA for ulcerative colitis refractory to medical therapy were retrieved retrospectively from a prospective database. A comprehensive complication index was used for 90-day postoperative complications. Conversion, duration of surgery, hospital stay and reoperation were considered. A logistic regression model was used to assess risk factors for peri-pouch sepsis. RESULTS: Seventy-five (68.8%) patients were identified from 109 consecutive IPAAs. Median operation time was 159 min. Conversion rate was 4%. Mean comprehensive complication index was 7. All anastomotic leaks (10.6%) were treated with diverting ileostomy. Additionally, active rescue with transanal drainage and early resuturing of the anastomotic gap was performed in six patients. Ileostomy closure occurred after a median period of 5.4 months. At univariable analysis, factors associated with peri-pouch sepsis were male gender and age at IPAA construction. CONCLUSIONS: A modified two-stage Ta-IPAA is safe and feasible. Standardization and reproducibility of the technique are reflected in few conversions and intra-operative complications. Finally, morbidity and anastomotic leak do not differ from those reported in previous Ta-IPAA series with a variable proportion of multistage procedures.