A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

BACKGROUND: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin. METHODS: Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations. RESULTS: Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted. CONCLUSION: The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

Low muscle mass in COVID-19 critically-ill patients: Prognostic significance and surrogate markers for assessment.

INTRODUCTION: Low muscle mass is a common condition in the critically ill population and is associated with adverse clinical outcomes. The primary aim of this study was to analyze the prognostic significance of low muscle mass using computed tomography (CT) scans in COVID-19 critically ill patients. A second objective was to determine the accuracy and agreement in low muscle mass identification using diverse markers compared to CT as the gold standard. METHODS: This was a prospective cohort study of COVID-19 critically ill patients. Skeletal muscle area at the third lumbar vertebra was measured. Clinical outcomes (intensive care unit [ICU] and hospital length of stay [LOS], tracheostomy, days on mechanical ventilation [MV], and in-hospital mortality) were assessed. Phase angle, estimated fat-free mass index, calf circumference, and mid-upper arm circumference were measured as surrogate markers of muscle mass. RESULTS: Eighty-six patients were included (mean age ± SD: 48.6 ± 12.9; 74% males). Patients with low muscle mass (48%) had a higher rate of tracheostomy (50 vs 20%, p = 0.01), prolonged ICU (adjusted HR 0.53, 95%CI 0.30-0.92, p = 0.024) and hospital LOS (adjusted HR 0.50, 95% CI 0.29-0.86, p = 0.014). Bedside markers of muscle mass showed poor to fair agreement and accuracy compared to CT-assessed low muscle mass. CONCLUSION: Low muscle mass at admission was associated with prolonged length of ICU and hospital stays. Further studies are needed to establish targeted nutritional interventions to halt and correct the catabolic impact of COVID-19 in critically ill patients, based on standardized and reliable measurements of body composition.

Aminoglycoside antibiotics: structure, functions and effects on in vitro plant culture and genetic transformation protocols.

Plant transformation protocols generally involve the use of selectable marker genes for the screening of transgenic material. The bacterial gene nptII, coding for a neomycin phosphotransferase, and the hpt gene, coding for a hygromycin phosphotransferase, are frequently used. These enzymes detoxify aminoglycoside antibiotics by phosphorylation, thereby permitting cell growth in the presence of antibiotics. Nevertheless, the screening for transgenic regenerated shoots is often partial and difficult due to regeneration of escapes and chimeras. These difficulties can be caused, in part, by an incorrect assumption about the mode of action of antibiotics in bacterial and eukaryotic cells and in in vitro tissue culture. The information contained in this review could be useful to establish better selection strategies by taking into account factors such as explant complexity, transformation and selection protocols that allow better accessibility to cells of Agrobacterium and antibiotics, and faster regeneration methods that avoid collateral effects of antibiotics on recovered, putative transgenic shoots.

Dietary Acid Load: mechanisms and evidence of its health repercussions. / Carga ácida de la dieta; mecanismos y evidencia de sus repercusiones en la salud.

Diet composition has long been known to influence acid-base balance by providing acid or base precursors. In general, foods rich in protein, such as meat, cheese, eggs, and others, increase the production of acid in the body, whereas fruit and vegetables increase alkalis. The capacity of acid or base production of any food is called potential renal acid load (PRAL). Diets high in PRAL induce a low-grade metabolic acidosis state, which is associated with the development of metabolic alterations such as insulin resistance, diabetes, hypertension, chronic kidney disease, bone disorders, low muscle mass and other complications. The aim of this paper is to review the available evidence which evaluates the association of the PRAL of the diet with the incidence of chronic diseases and metabolic disorders, as well as related mechanisms involved in their development.

Goodpasture's syndrome in a patient using cocaine--a case report and review of the literature.

Glomerulonephritis is a very rare form of cocaine-induced renal pathology. We report a 26-year-old woman having inhaled cocaine, who presented with antiglomerular basement membrane glomerulonephritis and pulmonary hemorrhage. She was treated with immunosuppressive therapy and plasmapheresis. Maintenance hemodialysis was required on discharge. We stress the importance of early detection and treatment of this renal association for the potential fatal consequences implicated.

[Is it necessary to prescribe antibiotics in impacted third molar surgical removal?: comparative study between prescribing patterns]. / ¿Está indicada la prescripción de antibióticos en la extracción del tercer molar retenido?: Estudio comparativo entre patrones de prescripción.

OBJECTIVE: To assess whether there is a significant difference in infection rate after surgery tooth extraction in two different hospitals from Norway and Spain where different surgical antimicrobial prophylaxis protocols are applied. METHODS: An analytical observational study was conducted, retrospective cohorts type, analyzing healthy patients with no risk factors, who were third molar tooth operated in maxillofacial services of two different hospitals: St. Olav in Trondheim (Norway) and Clínico San Carlos in Madrid (Spain). The collected variables were: age, number of tooth removed, anesthesia type, and observations about the course of the operation registered in the clinical history. To assess the development of postoperative infection, patient's data of those who chose the hospital as the place to remove the suture thread were collected in Norway, whereas in Spain a telephone survey was conducted to determine the course of the operation months later. RESULTS: In St. Olav Hospital 11.1% of patients operated received antibiotic regimen after surgery, while in Hospital San Carlos were 100%. The infection rate was 15% in St.Olav Hospital and 7.5% in Hospital San Carlos. These differences were no statistically significant. CONCLUSIONS: The routine administration of antibiotics to healthy patients with no risk factors undergoing impacted third molar surgical removal is a common clinical practice which it does not seem to be justified.

Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience.

PURPOSE: Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival. METHODS/PATIENTS: All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed. RESULTS: Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7). CONCLUSIONS: Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

Clinical evolution of diabetic rats after transplant of electrofused pancreatic islet cells and dermic cells.

This work was designed to study an alternative treatment of diabetes mellitus by using a transplant of hybrid cells obtained by the electrofusion of pancreatic islet cells from a healthy donor with dermic cells obtained from a recipient. The hybrid cells kept the capacity of insulin production, its regulation, and the natural control of glycemia, as well as the factors of histocompatibility to avoid the rejection. Four groups of four rats each were established: Group 1. Healthy animals (healthy control), Group 2. Diabetized non-treated animals (diabetic control), Group 3. Transplant recipient rats with extraction of dermic cells which were mixed with pancreatic insular cells from a healthy donor (transplant without fusion), and Group 4. Transplant recipient rats, with extraction of dermic cells which were electrofused with pancreatic insular cells from a healthy donor (transplant with fusion). For the Group 4, the cells were combined and they were submitted to dielectrophoresis conditions with an alternating current pulse of 15 s of 10 V RMS of 0.5 MHz. The fusion was made with a direct current pulse of 1 ms of 300 V. Clinical signs were registered (weight, diuresis, food and water intake), and several biochemical parameters in blood which included basal glycemia, uric acid, cholesterol, triglycerides, glutamate oxalacetate transaminase, glutamate pyruvate transaminase, urea, creatinine, insulin, glycated hemoglobin were registered. Additionally, ketone bodies and glucose were also measured in urine. All determinations were made at 30, 60, and 90 days. Animals of Group 1 maintained its parameters within the normal ranges. Rats of Group 2 presented alterations corresponding to a diabetic state in almost all the parameters measured, none of the animals showed a tendency to improve spontaneously, two of the rats died at 66 and 72 days. The Group 3 showed a clinical profile similar to the diabetic control group without improvement, only one rat died at day 33, while in the rats transplanted with fusion (Group 4) an improvement was observed on some parameters including body weight, water intake and glycemia. Although insulin concentration was under the normal range, it was higher than in the Group 3. None rat died. These results indicate that it is possible to improve the diabetic profile by the transplant of dermic cells from a diabetic animal fused with insular cells from a healthy donor in the recipient animal.

Comparison of laser ablation and dried solution aerosol as sampling systems in inductively coupled plasma mass spectrometry.

This paper describes a study designed to determine the possibility of using a dried aerosol solution for calibration in laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The relative sensitivities of tested materials mobilized by laser ablation and by aqueous nebulization were established, and the experimentally determined relative sensitivity factors (RSFs) were used in conjunction with aqueous calibration for the analysis of solid steel samples. To such a purpose a set of CRM carbon steel samples (SS-451/1 to SS-460/1) were sampled into an ICP-MS instrument by solution nebulization using a microconcentric nebulizer with membrane desolvating (D-MCN) and by laser ablation (LA). Both systems were applied with the same ICP-MS operating parameters and the analyte signals were compared. The RSF (desolvated aerosol response/ablated solid response) values were close to 1 for the analytes Cr, Ni, Co, V, and W, about 1.3 for Mo, and 1.7 for As, P, and Mn. Complementary tests were carried out using CRM SS-455/1 as a solid standard for one-point calibration, applying LAMTRACE software for data reduction and quantification. The analytical results are in good agreement with the certified values in all cases, showing that the applicability of dried aerosol solutions is a good alternative calibration system for laser ablation sampling.

Preconcentration and analysis of gold from cyanide solutions with the use of a microcolumn packed with the phosphine oxide Cyanex 921.

The phosphine oxide Cyanex 921 (tri-n-octylphosphine oxide) was found to be a very efficient extradant for gold from aurocyanide aqueous solutions. A system comprising a microcolumn packed with this new reagent was developed for the separation and enrichment of gold. Because of the high selectivity of the developed system it is possible to analyze gold in the presence of an excess of other metals and/or in high ionic strengh solutions.

[Diagnostic usefulness of the determination of serum neuron-specific enolase in small cell bronchial carcinoma]. / Utilidad diagnóstica de la determinación sérica de la enolasa neuroespecífica en el carcinoma bronquial de células pequeñas.

The plasma level of neuron-specific enolase (NSE) was measured in 55 patients with small cell bronchial carcinoma (SCC) with cytohistological confirmation to evaluate its diagnostic usefulness. As a control group, 132 patients with non-small cell bronchial carcinoma, 81 with non-neoplastic disease and 37 healthy individuals were used. The sensitivity of the test was 84% with a specificity of 79% when values below 13 ng/mg were considered as normal. To achieve a specificity of 95% and 99% cutoff values had to be increased to 25 and 50 ng/ml, respectively, and then the sensitivity was reduced to 51% and 38%. There were false positive findings in the three control groups, although they were more common (28%) and had higher values in patients with widespread disease the sensitivity was significantly higher (p less than 0.005) than in those with limited disease. Carcinoembryonic antigen, which was measured with comparative purposes, had a lower sensitivity. In our area, a NSE level over 50 ng/ml is closely correlated with the diagnosis of SCC, whereas values over 13 ng/ml select a wider group of individuals where most patients with this type of carcinoma are included.

[Diagnostic usefulness of neurospecific enolase determination in pleural fluid]. / Utilidad diagnóstica de la determinación de la enolasa neuroespecífica en líquido pleural.

To investigate the diagnostic usefulness of the measurement of neurospecific enolase (NSE) in pleural fluid 116 consecutive patients with pleural effusion were prospectively evaluated. In 95 of them, carcinoembryonic antigen (CEA) was also measured for comparative purposes. The habit of smoking did not apparently influence the NSE levels. In the 43 malignant effusions the mean value of NSE (25.0 +/- 27.4) was significantly higher (p less than 0.001) than in benign effusions (8.7 +/- 7.1). The values above 12 ng/ml had a sensitivity of 51% for malignancy, with a specificity of only 74%. The specific sensitivity of NSE was lower than that of CEA; neither individually nor as a whole these markers modified the diagnostic yield of cytology (67%). The mean value of NSE in tuberculous pleural effusions (14.4 +/- 8.3), different from that found in malignancies (p less than 0.05), was significantly higher (p less than 0.001) than that found in other benign diseases (6.2 +/- 4.7). The results of this study demonstrate the nonspecific character of an increased level of NSE, and the low diagnostic yield of this enzyme as a pleural tumour marker.

Phase 1 study of nab-paclitaxel, cisplatin and 5-fluorouracil as induction chemotherapy followed by concurrent chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the oropharynx.

BACKGROUND: Induction chemotherapy followed by concurrent chemoradiation (CRT) (sequential therapy) has been evaluated in the treatment of locoregionally-advanced squamous cell cancer of the head and neck (LA-SCCHN), with docetaxel, cisplatin (P) and 5-flurouracil (F) shown to be superior to PF doublet. Nab-paclitaxel (A) is a novel albumin-bound paclitaxel with a superior therapeutic index to docetaxel. METHODS: A phase I trial [Clinical trials.gov identifier NCT00731380] to assess the safety and efficacy of nab-paclitaxel+cisplatin+5-fluorouracil (APF) as induction chemotherapy for three cycles, followed by concurrent carboplatin (area-under-curve (AUC) 1.5 weekly) with radiation therapy (RT) (70 Gy/35 fractions), was conducted using a 3+3 design in patients with previously untreated LA-SCCHN. Dose-limiting toxicities (DLTs) included: standard haematologic and non-haematologic toxicities, treatment delays, inability to complete ⩾95% of RT and skin/mucosal toxicity related to RT assessed from day 1 of treatment to 8 weeks after completion of CRT. RESULTS: 17 patients with oropharyngeal cancer were enrolled in three dose levels, with 15 patients evaluable for DLT. The median age was 54 years (range, 44-65 years), 14 patients were male, and 11 patients' tumours were p16 positive and four negative. Grade 3/4 adverse events during APF (%total number of cycles) were hyponatraemia (14%) neutropenia (10%), lymphopaenia (4%) and thrombocytopenia (2%) during 49 evaluable APF cycles. Febrile neutropenia occurred during one cycle of treatment. CONCLUSION: The recommended phase 2 dose of APF is nab-paclitaxel 100mg/m(2) days 1 and 8, cisplatin 75 mg/mg(2) day 1 and 5-fluorouracil 1000 mg/m(2)/day×96 h days 1-4, every 3 weeks, for three cycles prior to CRT.

Therapeutic management of epithelial ovarian cancer during pregnancy.

Epithelial ovarian cancer (EOC) during pregnancy is a rare condition. The diagnosis and treatment strategies are therefore not well defined. The evidence is scarce and limited to small case reports or case series. In this review we describe the safety, utility and limitations of each diagnostic tool and surgical procedure in pregnant women with ovarian cancer. We also discuss the role of chemotherapy for ovarian cancer during pregnancy. Finally, we delineate different strategies of treatment according to the stage of the disease at diagnosis and gestational age. Due to the complexity of the management of EOC during pregnancy, patients should be referred to specialized centers. Gestational age at diagnosis, the initial surgical procedure, disease stage and patient's preferences are the key factors in the decision-making process to establish the best treatment strategy for each individual case.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective.

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.

Formation of metacinnabar by milling of liquid mercury and elemental sulfur for long term mercury storage.

In this paper we present the results of the formation of black HgS (metacinnabar) from liquid mercury and elemental sulfur using the mechanical energy provided by a ball mill in different conditions. Metacinnabar formation was observed even after short milling times (15 min) and unreacted liquid mercury was no longer detected after 60 min of milling. The reaction mechanism was monitored with a scanning electron microscope. The impact and friction forces of milling on the Hg and S mixture resulted in the formation of metacinnabar by reducing the size of mercury drops, giving rise to microspheres, and lowering the surface tension to allow sulfur grains to become adhered at the reaction interface. After 60 min of milling, the metacinnabar formation reaction was observed to be more than 99.99% complete, yielding a Toxicity Characteristic Leaching Procedure value of 3.1 microg/L Hg. The reaction product thus complies with the limits of the most stringent Universal Treatment Standard requirements, which allow a maximum TCLP concentration of 25 microg/L.

Endometriosis peritoneal masiva asociada a gran elevación de CA-125: discrepancia entre hallazgos y clínica / Massive peritoneal endometriosis associated with high elevation of CA-125: discrepancy between findings and symptoms

ANTECEDENTES: Frecuentemente, las pacientes con endometriosis presentan una elevación de marcadores tumorales Ca 125 y Ca 19.9. No obstante, no existe correlación clara con la expresión clínica ni con el grado de afectación. En algunos casos, es necesario un diagnóstico diferencial con patologías malignas. CASO CLÍNICO: Mujer de 29 años con clínica aislada de dismenorrea moderada y hallazgo de masas ováricas bilaterales con elevación intensa de marcadores tumorales: Ca-125: 7.716 U/mL y Ca-19.9: 995 U/mL. Se decide intervención quirúrgica laparoscópica evidenciándose endometriosis ovárica y extensión peritoneal masiva con afectación de peritoneo parietal abdominal, superficie uterina, fondo de Douglas, parametrios, vejiga, hemidiafragma derecho, hígado y serosa intestinal. Se realiza adhesiolisis cuidadosa, quistectomía y extirpación de múltiples implantes endometriósicos en cavidad abdominal. Se observó un descenso de los marcadores a las 48 horas: Ca-125 de 253 U/mL y Ca 19.9 de 4,9 U/mL, ambos negativos al mes de la cirugía. CONCLUSIÓN: Una elevación intensa de los marcadores tumorales precisa de diagnóstico diferencial en el contexto de la endometriosis. Existe una gran discrepancia entre los valores de los marcadores tumorales con la clínica y severidad de la endometriosis. Los hallazgos quirúrgicos son fundamentales, evidenciando una afectación masiva subdiagnosticada hasta la cirugía.

BACKGROUND: Frequently, patients with endometriosis present elevated tumor marker Ca 125 and Ca 19.9. However, there is no clear correlation with the clinical expression or the degree of involvement. In some cases, differential diagnosis is necessary with malignancies. CASE REPORT: A 29 year old woman with moderate dysmenorrhea and finding of bilateral ovarian masses with intense elevation of tumor markers, CA125: 7,716 U/mL and Ca-19.9: 995 U/mL. Laparoscopic surgery is decided evidenced massive ovarian endometriosis and peritoneal extension with involvement of abdominal peritoneum, uterine surface, Douglas, parametrium, bladder, right hemidiaphragm, liver and intestinal serosa. Careful liberation of adherences, ovarian cystectomy and removal of multiple endometriosic implants. A decrease of tumor markers was observed at 48 hours (Ca-125: 253 U/mL and Ca-19.9: 4.9 U/mL), and negative one month after surgery. CONCLUSION: An intense elevated tumor markers accurate differential diagnosis in the context of endometriosis. There is a large discrepancy between the values of tumor markers with clinical and severity of endometriosis.