Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin.

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Lymphovascular Invasion and High Mitotic Count Are Associated With Increased Risk of Recurrence in Pleomorphic Dermal Sarcoma. / La presencia de infiltración linfovascular y de un alto número de mitosis se asocia a un mayor riesgo de recidiva en sarcoma pleomórfico dérmico.

BACKGROUND AND OBJECTIVE: Atypical fibroxanthoma and pleomorphic dermal sarcoma (PDS) are rare mesenchymal tumors. Due to the low incidence of PDS and a historically confusing nomenclature, little is known about the true aggressiveness of this tumor. The aim of this study was to investigate clinical and histologic risk factors for recurrence in PDS. MATERIAL AND METHODS: Retrospective, observational, bicentric study of 31 PDSs diagnosed and treated at Hospital Clínico Universitario de Valencia and Instituto Valenciano de Oncología in Valencia, Spain, between 2005 and 2020. We described the clinical and histologic features of these tumors and performed univariate analysis and multivariate Cox regression analysis. RESULTS: In the univariate analysis, tumor recurrence (P<.001), necrosis (P=.020), lymphovascular invasion (P=.037), perineural invasion (P=.041), and mitotic count (<18 vs ≥18 mitoses per 10 high-power fields) (P=.093) were associated with worse disease-free survival. In the multivariate Cox regression analysis, mitotic count and lymphovascular invasion retained their significance as predictors of worse disease-free survival (P<.05). CONCLUSIONS: PDS is an aggressive tumor in which a high mitotic count (≥18) and lymphovascular invasion are associated with a higher risk of recurrence and worse disease-free survival. Necrosis and perineural invasion are also probably linked to increased tumor aggressiveness.

A metabolic readout of the urine metabolome of COVID-19 patients.

Analysis of urine samples from COVID-19 patients by 1H NMR reveals important metabolic alterations due to SAR-CoV-2 infection. Previous studies have identified biomarkers in urine that reflect metabolic alterations in COVID-19 patients. We have used 1H NMR to better define these metabolic alterations since this technique allows us to obtain a broad profile of the metabolites present in urine. This technique offers the advantage that sample preparation is very simple and gives us very complete information on the metabolites present. To detect these alterations, we have compared urine samples from COVID-19 patients (n = 35) with healthy people (n = 18). We used unsupervised (Robust PCA) and supervised (PLS-LDA) multivariate analysis methods to evaluate the differences between the two groups: COVID-19 and healthy controls. The differences focus on a group of metabolites related to energy metabolism (glucose, ketone bodies, glycine, creatinine, and citrate) and other processes related to bacterial flora (TMAO and formic acid) and detoxification (hippuric acid). The alterations in the urinary metabolome shown in this work indicate that SARS-CoV-2 causes a metabolic change from a normal situation of glucose consumption towards a gluconeogenic situation and possible insulin resistance.

Systemic Corticosteroids in Patients with Bronchial Asthma: A Real-Life Study.

OBJECTIVES: The objective of the present study was to determine the use of systemic corti-costeroids (SCs) in patients with bronchial asthma using big data analysis. METHODS: We performed an observational, retrospective, noninterventional study based on secondary data captured from free text in the electronic health records. This study was per-formed based on data from the regional health service of Castille-La Mancha (SESCAM), Spain. We performed the analysis using big data and artificial intelligence via Savana® Manager version 3.0. RESULTS: During the study period, 103 667 patients were diagnosed with and treated for asthma at different care levels. The search was restricted to patients aged 10 to 90 years (mean age, 43.5 [95%CI, 43.4-43.7] years). Of these, 59.8% were women. SCs were taken for treatment of asthma by 58 745 patients at some point during the study period. These patients were older, with a higher prevalence of hypertension, dyslipidemia, diabetes, ob-esity, depression, and hiatus hernia. SCs are used frequently in the general population with asthma (31.4% in 2015 and 39.6% in 2019). SCs were prescribed mainly in primary care (59%), allergy (13%) and pulmonology (20%). The frequency of prescription of SCs had a direct impact on the main associated adverse effects. CONCLUSION: In clinical practice, SCs are frequently prescribed to patients with asthma, especially in primary care. Use of SCs is associated with a greater number of adverse events. It is necessary to implement measures to reduce prescription of SCs to patients with asthma, especially in primary care.

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018).

NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.

Antiproliferative and cytotoxic effects of green coffee and yerba mate extracts, their main hydroxycinnamic acids, methylxanthine and metabolites in different human cell lines.

This work aimed at studying the effects of green coffee bean (GCBE) and yerba mate (YME) extracts, their main phenolic components (5-caffeoylquinic acid, 5-CQA; 3,5-dicaffeoylquinic acid, 3,5-DCQA) and metabolites (ferulic acid, FA; caffeic acid, CA; dihydrocaffeic acid, DHCA; and dihydroferulic acid, DHFA) along with caffeine (CAF) on the viability and proliferation of different human cell lines. Extracts (10-1000 µg/mL) and standards (10-1000 µM) were assayed in colon (Caco-2), lung (A549), oesophageal (OE-33), urinary bladder (T24) human carcinoma cells, and a non-cancer cell line (CCD-18Co). YME significantly reduced viability of cancer cells at all assayed concentrations, the higher doses also reducing cell proliferation. GCBE effects on cell viability were more effective at 100 and 1000 µg/mL, showing modest effects on cell proliferation. The highest doses of 5-CQA and 3,5-DCQA reduced cell viability and proliferation in all cell lines, whereas FA, DHCA and DHFA had lower and variable effects. Caffeine had no effect. Dietary-attainable concentrations (0.1, 1 and 10 µg/mL) of YME were tested for cytotoxicity and reactive oxygen species generation, showing no cytotoxic effect. Low concentrations of all tested compounds were non-cytotoxic to CCD-18Co cells. CONCLUSION: YME and to a lower degree GCBE, their phenolic components and metabolites may decrease cancer cell viability and proliferation.

A phenolic extract from grape by-products and its main hydroxybenzoic acids protect Caco-2 cells against pro-oxidant induced toxicity.

Grape/wine industry produces large amounts of by-products, however knowledge on their health-promoting qualities is limited. This study investigated the effects of a grape phenolic extract (GPE) and its phenolic compounds, gallic acid (GA) and syringic acid (SA) on human intestinal Caco-2 cells, directly or after cytotoxicity induced by tert-butylhydroperoxide (t-BOOH). Direct treatment with 0.1-10 µg/mL GPE, or 0.1-10 µM GA and SA produced no major cytotoxic effect, either changes in antioxidant defences (glutathione content, glutathione peroxidase and reductase activities) or protein damage (carbonyl groups). However, 10 µg/mL GPE, 1 and 10 µM GA and 10 µM SA decreased reactive oxygen species (ROS) production. Pre-treatment with GPE, SA and GA at the same concentrations for 20 h showed that 10 µg/mL GPE and 10 µM GA or SA significantly counteracted ROS increase induced by t-BOOH. 10 µg/mL GPE and 1-10 µM GA or 10 µM of SA significantly reduced pro-oxidant-induced cytotoxicity. 1-10 µg/mL GPE, 1-10 µM GA and 10 µM SA significantly recovered both depleted glutathione and enhanced glutathione reductase and peroxidase activities, and reduced protein oxidative damage. Therefore, treatment with realistic concentrations of GPE and its main hydroxybenzoic acids protected Caco-2 cells against induced oxidative stress.

Diagnostic value of combined assessment of olfaction and sustantia nigra hyperechogenicity for Parkinson's disease.

INTRODUCTION: Hyposmia and substantia nigra hyperechogenicity (SN+) are characteristic markers of Parkinson's disease (PD), although their diagnostic value in isolation may be limited. We evaluated the combined prevalence of both disorders in patients diagnosed with PD and assessed their diagnostic yield compared to a sample with essential tremor (ET) and another group of healthy subjects. METHODS: Patients diagnosed with PD and ET and treated in our outpatient clinic were enrolled. Olfaction was assessed using the "Sniffin' Sticks" odour identification test (SS-12) and hyperechogenicity of the substantia nigra (SN+) was assessed by transcranial duplex ultrasound. RESULTS: A total of 98 subjects were analysed, comprising 30 with PD, 21 with ET, and 47 controls. The respective prevalence rates of hyposmia (SS-12 < 8) and SN+ (area > .24cm(2)) were 70% and 83.3% in PD, 33.3% and 9.5% in ET, and 17% and 10.6% in controls. Both markers were present in 63% of patients with PD, none of the patients with ET, and only 2 of the controls. CONCLUSIONS: Combined use of substantia nigra sonography and olfactory testing with SS-12, two rapid, safe, and accessible tests, was more specific than each isolated marker for distinguishing patients with PD from patients with ET and control subjects. Since both markers have been described in very early phases of PD, combined use may be helpful in providing early diagnosis of PD.

[Cardiovascular and respiratory changes during laparoscopy in neonates and infants]. / Cambios cardiovasculares y ventilatorios durante la laparoscopia en neonatos y lactantes pequeños.

The pneumoperitoneum induced during laparoscopy has cardiovascular and respiratory effects that have to be taken into account to perform laparoscopic procedures in neonates and small infants. The aim of this paper is to describe the hemodynamic and ventilatory changes that occur in a group of these patients undergoing standard laparoscopic procedure. We performed a retrospective review of patients undergoing laparoscopic pyloromyotomy in our institution. We collected demographic data, data from the intervention, outcome and complications and hemodynamic parameters (heart rate--HR--and blood pressure--BP--) and respiratory (O2 saturation--SO2--and exhaled CO2--ECO2--) at different times during surgery. We performed statistical analysis of these data. We reviewed a total of 55 charts. Mean age was 34 days and average weight 3,785 g. All patients were ventilated with pressure control mode and received maintenance fluid therapy. BP, HR and SO2 were stable throughout the surgery not showing significant differences. The ECO2 increased significantly after inflation, however it was controlled by increasig respiratory rate. In conclusion, the hemodynamic and ventilatory response in these patients is controllable with anesthetic and surgical measures but it is important to consider the possible consequences of pneumoperitoneum in this group of patients.

[Laparoscopy as diagnostic-therapeutic method in abdominal traumatism in the pediatric age]. / Laparoscopia como método diagnóstico-terapéutico en el traumatismo abdominal en la edad pediátrica.

The management of blunt abdominal traumatism with a moderate amount of free peritoneal fluid and without solid organ injury as well as the one of minimal penetrating trauma is controversial. We present three cases of blunt abdominal trauma and two of penetrating trauma that underwent diagnostic laparoscopy in our department. We found a small bowel perforation in one of the cases of blunt trauma that was repaired by externalization of the jejuna loop by one of the ports. In the other two cases we found intestinal and mesenteric contusions and free fluid that were treated by peritoneal drainage. One of the cases of penetrating trauma presented omentum evisceration with no other injuries and the second presented a gastric perforation that needed reconversion to laparotomy. In our experience and according to literature, laparoscopy should be taken into account as a diagnostic procedure and sometimes also therapeutic in selected cases of both blunt and penetrating abdominal trauma in pediatric population.

[Minimally invasive surgery in pediatric patients with ventriculo-peritoneal shunts]. / Cirugía laparoscópica en pacientes con válvula de derivación ventrículo-peritoneal.

The use of laparoscopy in patients with ventriculo-peritoneal shunts has been controversial. There is concern about the risk malfunction or infection of the shunt as well as about the possibility of adhesions that could make the surgical procedures too difficult to be undertaken by minimally invasive surgery. We present our results in pediatric patients with ventriculoperitoneal shunts that have undergone laparoscopic procedures in our department. We have performed 16 surgical procedures. The most frequent indication was fundoplication. During surgery there were no complications or intracranial hypertension episodes. Two of the procedures were considered by the surgeons more difficult and longer than usual. None of them required conversion to open technique. One shunt had to be replaced after surgery because of infection. According to our experience minimally invasive surgery is feasible and safe in pediatric patients with ventriculo-peritoneal shunts.

[The influence of docosahexaenoic acid and moderate perinatal hypoxia on the performance of one-month-old Wistar rats in a T-maze test]. / Influencia del acido docosahexaenoico y la hipoxia perinatal moderada en la resolucion de un laberinto en T en ratas Wistar de un mes de edad.

INTRODUCTION: Docosahexaenoic acid (DHA) has been shown to improve neurodevelopment in both human observations and animal models. Perinatal hypoxic insults have been recognized as a major cause of neurodevelopmental disturbances. AIM: To find out if the CNS-improving effect of DHA could be induced in animals subjected to mild perinatal hypoxic conditions. MATERIALS AND METHODS: A total of 140 Wistar rat pups were separated into two main groups of 70 each, and one group was reared on a DHA-supplemented diet while the other was not. One half of each group was subjected to immediate post-natal hypoxia (FiO2 = 0.05, 1 h). All the rats were individually subjected to a T-maze to test their passive-avoidance performance, among other skills, on days P25 (three trials) and P30 (one trial). All the trials were videotaped and reviewed to record the maze-solving time (MST), the number of electrical hazards (NEH) and the correct maze-solution percentage (CMS). RESULTS: The animals in the control group significantly improved their MST (p < 0.01). The group on the DHA-supplemented diet improved only the CMS (p < 0.001). The hypoxic group improved the MST (p < 0.014) and the NEH (p < 0.004). The hypoxic group on the DHA-supplemented diet improved the NEH (p < 0.0000) and the CMS (p < 0.0001). CONCLUSIONS: The subgroups subjected to one experimental condition or the other (DHA-supplemented diet or perinatal hypoxia) independently improved their T-maze-test performance more than the absolute control group. The rats subjected to both conditions appeared to improve their T-maze-test solution performance more effectively than the control groups and the groups subjected to only one of the two conditions.