Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss. METHODS: We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238. FINDINGS: Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo-abiraterone group and 547 (50%) to the ipatasertib-abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0-33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo-abiraterone group and 260 in the ipatasertib-abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9-17·0) in the placebo-abiraterone group and 18·5 months (16·3-22·1) in the ipatasertib-abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61-0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6-19·1) in the placebo-abiraterone group and 19·2 months (16·5-22·3) in the ipatasertib-abiraterone group (HR 0·84 [95% CI 0·71-0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo-abiraterone group and in 386 (70%) of 551 patients in the ipatasertib-abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo-abiraterone group and 116 (21%) in the ipatasertib-abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo-abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb-abiraterone group. INTERPRETATION: Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis. FUNDING: F Hoffmann-La Roche and Genentech.

A facile process for adipic acid production in high yield by oxidation of 1,6-hexanediol using the resting cells of Gluconobacter oxydans.

BACKGROUND: Adipic acid (AA) is one of the most important industrial chemicals used mainly for the production of Nylon 6,6 but also for making polyurethanes, plasticizers, and unsaturated polyester resins, and more recently as a component in the biodegradable polyester poly(butylene adipate terephthalate) (PBAT). The main route for AA production utilizes benzene as feedstock and generates copious amounts of the greenhouse gas NO2. Hence, alternative clean production routes for AA from renewable bio-based feedstock are drawing increasing attention. We have earlier reported the potential of Gluconobacter oxydans cells to oxidize 1,6-hexanediol, a potentially biobased diol to AA. RESULTS: The present report involves a study on the effect of different parameters on the microbial transformation of 1,6-hexanediol to adipic acid, and subsequently testing the process on a larger lab scale for achieving maximal conversion and yield. Comparison of three wild-type strains of G. oxydans DSM50049, DSM2003, and DSM2343 for the whole-cell biotransformation of 10 g/L 1,6-hexanediol to adipic acid in batch mode at pH 7 and 30 °C led to the selection of G. oxydans DSM50049, which showed 100% conversion of the substrate with over 99% yield of adipic acid in 30 h. An increase in the concentrations of the substrate decreased the degree of conversion, while the product up to 25 g/L in batch and 40 g/L in fed-batch showed no inhibition on the conversion. Moreover, controlling the pH of the reaction at 5-5.5 was required for the cascade oxidation reactions to work. Cell recycling for the biotransformation resulted in a significant decrease in activity during the third cycle. Meanwhile, the fed-batch mode of transformation by intermittent addition of 1,6-hexanediol (30 g in total) in 1 L scale resulted in complete conversion with over 99% yield of adipic acid (approximately 37 g/L). The product was recovered in a pure form using downstream steps without the use of any solvent. CONCLUSION: A facile, efficient microbial process for oxidation of 1,6-hexanediol to adipic acid, having potential for scale up was demonstrated. The entire process is performed in aqueous medium at ambient temperatures with minimal greenhouse gas emissions. The enzymes involved in catalyzing the oxidation steps are currently being identified.

Helminth-fauna of Patagonian armadillos: comparative analysis of parasites geographical variation.

The similarity between parasites communities' decay with distance and its analysis may explain important ecological process such host dispersion. Patagonia is inhabited by two armadillo species, Chaetophractus villosus and Zaedyus pichiy. In this study we describe and analyze the variation on helminth fauna of these armadillos in Patagonia compared with northern localities described in previous studies. A total of 49 armadillos were collected in Patagonia. Quantitative descriptors of parasite ecology were calculated and community structure of helminths was analyzed following the central-satellite species hypothesis. The parasite richness in Patagonia decreases almost 50% in both armadillos. Zaedyus pichiy present the same central species in Patagonia as in northern localities. For C. villosus central-satellite species analysis could not be applied. The loss of some helminths in Z. pichiy could be the result of lower temperatures or the absence of intermediate arthropods hosts. But in C. villosus the absence of some helminths with Patagonian distribution could be explained by its recent dispersion in Patagonia. Trichohelix tuberculata still being the only helminth in C. villosus introduced population of Tierra del Fuego.

Prostate cancer mortality rates in Peru and its geographical regions.

OBJECTIVE: To evaluate the mortality rates for prostate cancer according to geographical areas in Peru between 2005 and 2014. MATERIALS AND METHODS: Information was extracted from the Deceased Registry of the Peruvian Ministry of Health. We analysed age-standardised mortality rates (world population) per 100 000 men. Spatial autocorrelation was determined according to the Moran Index. In addition, we used Cluster Map to explore relations between regions. RESULTS: Mortality rates increased from 20.9 (2005-2009) to 24.1 (2010-2014) per 100 000 men, an increase of 15.2%. According to regions, during the period 2010-2014, the coast had the highest mortality rate (28.9 per 100 000), whilst the rainforest had the lowest (7.43 per 100 000). In addition, there was an increase in mortality in the coast and a decline in the rainforest over the period 2005-2014. The provinces with the highest mortality were Piura, Lambayeque, La Libertad, Callao, Lima, Ica, and Arequipa. Moreover, these provinces (except Arequipa) showed increasing trends during the years under study. The provinces with the lowest observed prostate cancer mortality rates were Loreto, Ucayali, and Madre de Dios. This study showed positive spatial autocorrelation (Moran's I: 0.30, P = 0.01). CONCLUSION: Mortality rates from prostate cancer in Peru continue to increase. These rates are higher in the coastal region compared to those in the highlands or rainforest.

Relationship between Pulmonary Adverse Events and Everolimus Exposure in Japanese and Non-Japanese Patients: A Meta-Analysis of Oncology Trials.

AIMS: This meta-analysis explores the relationship between the everolimus minimum (Cmin) and maximum (Cmax) exposure and the risk for pulmonary adverse events (AEs) in Japanese versus non-Japanese patients. METHODS: Patient-level data from patients treated with daily everolimus in advanced solid tumor trials were evaluated using a Cox regression model, stratified by cancer type or treatment arm, with log-transformed time-averaged Cmin or Cmax as a time-varying covariate. Kaplan-Meier analysis was used to evaluate the relationship between pulmonary AEs and pharmacokinetic parameters. RESULTS: Thirty studies were identified. In the Cmin population (n = 1,962), all-grade pulmonary AE incidence was significantly higher in Japanese versus non-Japanese patients (19.9 vs. 9.4%). Pharmacokinetic parameters were similar between Japanese and non-Japanese patients. A 2-fold increase in everolimus Cmin significantly increased the risk for the first any-grade pulmonary AE in Japanese (risk ratio: 1.824; 95% CI: 1.141-2.918) and non-Japanese patients (risk ratio: 1.406; 95% CI: 1.156-1.710). CONCLUSIONS: The risk for pulmonary AEs is related to everolimus exposure. Local monitoring and reporting differences might account for the significantly higher reported incidence of low-grade everolimus-associated pulmonary AEs in Japanese versus non-Japanese patients. Patients should be carefully monitored for early signs of pulmonary AEs, and appropriate medical management should be implemented.

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer.

PURPOSE: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors. PATIENTS AND METHODS: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status. RESULTS: Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0-8.1], and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). CONCLUSIONS: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.

Quantitative and nutritional characterization of fruit and vegetable waste from marketplace: a potential use as bovine feedstuff?

There are different sources for the generation of solid waste, and marketplaces are considered one of them. Fruit and vegetable waste (FV) from a marketplace in Colombia was quantitatively and nutritionally characterized to contribute to its use in bovine feeding and to contribute minimizing its environmental impact. The evaluation was carried out 7 days per week during 4 periods of the year. FV was grouped by cluster analysis using SAS(®) 2006. FV was composed of 43% fruit, 30% vegetables and 27% stems, leaves, leaf wrappers, corncobs, roots, refuse and others. FV was defined in four main groups. On average, FV contained 10% crude protein (CP), 36.6% neutral detergent fiber (NDF), 29.6% acid detergent fiber (ADF), 87.8% ruminal degradability at 24 h, 3657 kcal/kg, 0.59% calcium (Ca(+2)), and 0.21% phosphorous (P). There were no statistical differences between days or between periods of evaluation (p > 0.05) for CP or for Ca(+2). As for NDF and ADF, there were statistically significant differences between periods but not between days. The microbiological parameters only increased when the humidity was up to 12%. FV represents a potential feedstuff for bovine feeding, and its recycling could avoid the discharge of a large amount of waste to landfills, which would minimize its environmental impact.

Nutritional evaluation of fruit and vegetable waste as feedstuff for diets of lactating Holstein cows.

Organic waste from markets represents about 10-20% of the total waste of a city. A large proportion comes from the overproduction of fruit and vegetables, turning them into potential pollutant. The nutritional value found for fruit and vegetable waste (FV) from a marketplace, in a previous work, showed that this product might be considered as a potential alternative for animal feeding. This study evaluated the use of FV as feedstuff for diets of lactating Holstein cows with an emphasis on milk yield and quality. FV was included in 0, 6, 8, 12, and 18% of the concentrate. A 4 x 4 Latin squares model was used to analyze data (4 animal groups, 4 periods of evaluation, and 4 treatments). No statistical differences in milk yield per kilogram of eaten concentrate or concentrate intake were recorded between groups fed FV and the control group. There was a significant effect of the treatment on cis-9,trans-11 CLA and α-linolenic acid content in milk. These results showed that FV can be used as a dietary ingredient for high-yield lactating cows without detriment in the milk yield and with improvement in the milk quality. FV could be included at proportions of between 6% and 18% in the concentrate, as long as the animal's dietary requirements are covered. The main impact of these results is the alternative generated for the improvement of the environment.

Drug-Drug Interaction Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Ipatasertib in Combination with Darolutamide in Patients with Advanced Prostate Cancer.

Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC0-24 h,ss and Cmax,ss exposures was observed (~8% and ~21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs.

Mitigating ipatasertib-induced glucose increase through dose and meal timing modifications.

Ipatasertib, an AKT inhibitor, in combination with prednisone and abiraterone, is under evaluation for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Hyperglycemia is an on-target effect of ipatasertib. An open-label, single-arm, single-sequence, signal-seeking study (n = 25 mCRPC patients) was conducted to evaluate the glucose changes across four different treatment periods: ipatasertib alone, ipatasertib-prednisone combination, ipatasertib-prednisone-abiraterone combination (morning dose), and ipatasertib-prednisone-abiraterone combination (evening dose). Continuous glucose monitoring (CGM) was used in this study to compare the dynamic glucose changes across the different treatment periods. Four key parameters: average glucose, peak glucose and % time in range (70-180 and >180 mg/dl) were evaluated for this comparison. Ipatasertib-prednisone-abiraterone combination when administered in the morning after an overnight fast significantly increased average glucose, peak glucose and % time in range >180 mg/dl compared to ipatasertib monotherapy. Ipatasertib, when co-administered with abiraterone, increased ipatasertib and M1 (G-037720) metabolite exposures by approximately 1.5- and 2.2-fold, respectively. Exposure-response analysis results show that increased exposures of ipatasertib in combination with abiraterone are associated with increased glucose levels. When ipatasertib-prednisone-abiraterone combination was administered as an evening dose compared to a morning dose, lowered peak glucose and improved % time in range was observed. The results from this study suggest that dosing ipatasertib after an evening meal followed by overnight fasting can be an effective strategy for managing increased glucose levels.

Fleas and ticks in armadillos from Argentinean Patagonia: Diversity, abundance and distribution.

In Argentina, quantitative information on the composition and structure of assemblages of arthropod parasites in Xenarthra is scarce. The aim of this study was to describe and compare the community of arthropod parasites of Chaetophractus villosus and Zaedyus pichiy in the Argentinean Patagonia. A total of 1300 ectoparasites (1224 fleas and 76 ticks) were collected from both host species. Seven different species were found, namely Phthiropsylla agenoris, Malacopsylla grossiventris, Hectopsylla broscus, Tunga penetrans, Tunga perforans (Siphonaptera), Amblyomma pseudoconcolor and Amblyomma auricularium s.l. (Ixodida). Four species were present in both host armadillos (P. agenoris, M. grossiventris, H. broscus and A. pseudoconcolor). Phthiropsylla agenoris was the most prevalent and abundant ectoparasite showing significant differences in prevalences, mean intensities and mean abundance. Malacopsylla grossiventris only showed significant differences in mean intensity. The structure and composition of the ectoparasite assemblage and the high values of ectoparasites aggregation recorded in the Patagonian armadillos strongly suggest that these associations are stable throughout their geographical distribution.

[Low-intensity extracorporeal shock wave treatment improves erectile function in non-responder PDEi5 patients: A systematic review]. / Ondas de choque de baja intensidad para la mejora en el tratamiento de la disfunción eréctil en pacientes no respondedores a PDE5-i: revisión sistemática.

OBJECTIVE: To determine the effectiveness and safety in the short, medium, and long term of LISWT in patients with Erectile Dysfunction who do not respond to PDE5 inhibitors. METHODOLOGY: Clinical study, quasi-experimental cohort and systematic review following the guidelines of the Cochrane collaboration and the PRISMA writing guides. The measurement of the variables was determined as a primary outcome to the evaluation of erectile function, by means of a validated questionnaire. The baseline scale was evaluated, as well as the difference at 1, 3 and 6 months, evidenced by the possibility of maintaining an erection or responding to therapy with PDEi5. An information search was carried out from its beginning to the current date, in the databases: Medline, Embase, Central, Science Direct and Lilacs. RESULTS: The studies found used different outcome variables to show efficacy in the follow-up: All the studies used the IIEF-EF as outcome variable in its different variations. CONCLUSION: LISWT could be an effective and safe treatment in patients not responding to PDEi5. It is important to point out that the evidence is currently limited, randomized studies with greater methodological rigidity and follow-up longer than 12 months are needed in order to verify the medium and long-term effect of the application of shock waves in this group of patients.

Multirresistencia, resistencia extendida y panresistencia a antibacterianos en el norte de México.

OBJETIVO: Describir el perfil de multirresistencia (MDR), resistencia extendida (XDR) y panresistencia (PDR) a antibacterianos en aislados de muestras de pacientes de un hospital privado de tercer nivel en el norte de México. MÉTODO: Se realizó un estudio retrospectivo durante el periodo comprendido de febrero de 2016 a abril de 2019. A partir de 156 muestras clínicas de orina, heridas, sangre, expectoración y otros fluidos se aislaron 166 bacterias; 10 de las muestras incluyeron dos microorganismos. Los microrganismos aislados se clasificaron en MDR, XDR o PDR. RESULTADOS: El 78% de los aislados gramnegativos y el 69% de los aislados grampositivos mostraron MDR, XDR o PDR. Staphylococcus epidermidis fue la bacteria grampositiva con multirresistencia más frecuentemente aislada. Escherichia coli y Klebsiella sp. se encontraron entre los gramnegativos MDR más frecuentes. En dos casos, los aislados clínicos de Pseudomonas aeruginosa procedentes de la unidad de cuidados intensivos neonatales mostraron PDR. CONCLUSIÓN: Los servicios de terapia intensiva, cirugía y unidad de cuidados intensivos neonatales merecen especial atención por la alta proporción de aislados MDR y la presencia de PDR a causa de P. aeruginosa. OBJECTIVE: To describe the profile of multidrug-resistance (MDR), extensively resistance (XDR) and pandrug-resistance (PDR) to antibacterial drugs in isolates from patient samples from a third level private hospital in the North of Mexico. METHOD: A retrospective study was carried out during the period from February 2016 to April 2019. From 156 clinical samples of urine, wounds, blood, expectoration and other fluids, 166 bacteria were isolated; 10 samples included two microorganisms. Isolated microorganisms were classified into MDR, XDR or PDR. RESULTS: 78% of the Gram negative and 69% of the Gram positive isolates showed MDR, XDR or PDR. Staphylococcus epidermidis was the most frequently isolated MDR Gram positive bacteria. Escherichia coli and Klebsiella sp. were among the most frequent MDR Gram negative. In two cases, the clinical isolates of Pseudomonas aeruginosa from the neonatal intensive care unit showed PDR. CONCLUSIONS: The intensive care, surgery and neonatal intensive care unit services deserve special attention due to the high proportion of MDR isolates and the presence of PDR due to P. aeruginosa.

Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib.

The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1+ melanoma, with hazard ratios (HRs; PD-L1+ vs. PD-L1- ) of 0.70 (95% CI, 0.46-1.07) and 0.69 (95% CI, 0.42-1.13) for PFS and OS, respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HRs (PD-L1+ versus PD-L1- ) of 1.04 (95% CI, 0.66-1.68) and 0.94 (95% CI, 0.57-1.57) for PFS and OS, respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD-L1 expression.

Eosinophilic cystitis treated with hydrodistention and complementary methods: Case report. / Cistitis eosinofílica tratada con hidrodistensión y métodos complementarios: comunicación de un caso.

OBJECTIVE: Even though there is no established standard therapy for Eosinophilic cystitis (EC), the series of cases guide us in the treatment of patients. We report our therapeutic experience with hydrodistention and complementary methods. In order to establish a standard treatment in patients with EC. METHODS: Retrospective review of the clinical history of a patient diagnosed with eosinophilic cystitis. RESULTS: A 66-year-old woman presented female urethral syndrome 1 year before and was initially treated as a chronic cystitis. After further investigations including cystoscopy and bladder biopsy, she was diagnosed with EC.Urothelial mucosa bleeding was evidenced and cauterization and hydrodistention were performed. After the surgical treatment, corticosteroids and antibiotics were initiated.The maintenance treatment was continued with Vitamin C, Maurita flexuosa and Peumus boldus. The patient's condition has been improving and she is still asymptomatic one year later. CONCLUSION: The efficacy of treatment with hydrodistention, corticosteroids and antibiotics showed positive results in short and long term in this patient. Vitamin C, Maurita flexuosa and Peumus boldus showed favorable results in EC maintenance treatment.

OBJETIVO: A pesar de que no existe una terapia estándar establecida para la cistitis eosinofílica (CE), la serie de casos nos guía en el tratamiento de los pacientes. Presentamos nuestra experiencia terapéutica con hidrodistensión y métodos complementarios. Con el fin de establecer un tratamiento estándar en pacientes con CE.MÉTODOS: Revisión retrospectiva de la historia clínica de un paciente con diagnóstico de cistitis eosinofílica. RESULTADOS: Una mujer de 66 años presentó síndrome uretral femenino hace un año y fue tratada inicialmente como una cistitis crónica. Después de más investigaciones incluyendo una cistoscopia y una biopsia de la vejiga, se le diagnosticó CE. Se evidenció sangrado de la mucosa urotelial y se realizaron cauterización e hidrodistensión. Después del tratamiento quirúrgico, se iniciaron corticosteroides y antibióticos. El tratamiento de mantenimiento se continuó con Vitamina C, Maurita flexuosa y Peumus boldus. La condición del paciente ha mejorado y sigue estando asintomática un año después.CONCLUSIÓN: La eficacia del tratamiento con hidrodistención, corticosteroides y antibióticos mostró resultados positivos a corto y largo plazo en este paciente. La vitamina C, Maurita flexuosa y Peumus boldus mostraron resultados favorables en el tratamiento de mantenimiento de CE.

Molecular analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/everolimus.

The mTORC1 inhibitor everolimus (Afinitor/RAD001) has been approved for multiple cancer indications, including ER(+)/HER2(-) metastatic breast cancer. However, the combination of everolimus with the dual PI3K/mTOR inhibitor BEZ235 was shown to be more efficacious than either everolimus or BEZ235 alone in preclinical models. Herein, we describe a male breast cancer (MBC) patient who was diagnosed with hormone receptor-positive (HR(+))/HER2(-) stage IIIA invasive ductal carcinoma and sequentially treated with chemoradiotherapy and hormonal therapy. Upon the development of metastases, the patient began a 200 mg twice-daily BEZ235 and 2.5 mg weekly everolimus combination regimen. The patient sustained a prolonged stable disease of 18 mo while undergoing the therapy, before his tumor progressed again. Therefore, we sought to both better understand MBC and investigate the underlying molecular mechanisms of the patient's sensitivity and subsequent resistance to the BEZ235/everolimus combination therapy. Genomic and immunohistochemical analyses were performed on samples collected from the initial invasive ductal carcinoma pretreatment and a metastasis postprogression on the BEZ235/everolimus combination treatment. Both tumors were relatively quiet genomically with no overlap to recurrent MBC alterations in the literature. Markers of PI3K/mTOR pathway hyperactivation were not identified in the pretreatment sample, which complements previous reports of HR(+) female breast cancers being responsive to mTOR inhibition without this activation. The postprogression sample, however, demonstrated greater than fivefold increased estrogen receptor and pathogenesis-related protein expression, which could have constrained the PI3K/mTOR pathway inhibition by BEZ235/everolimus. Overall, these analyses have augmented the limited episteme on MBC genetics and treatment.

[Hydration status and aerobic capacity: effects on plasmatic volume during strenuous physical exercise]. / Estado de hidratación y capacidad aeróbica: sus efectos sobre el volumen plasmático durante el ejercicio físico agudo.

INTRODUCTION: During exercise, water loss frequently occurs in the intracellular spaces and there is a decrease in the plasmatic volume, with a blood concentration as a secondary characteristic. Plasmatic volume losses provoke a decrease in the blood flow, which directly affects cardiac function. Physical performance decreases and aerobic capacity deteriorates. MATERIAL AND METHODS: An observational, prospective, longitudinal, and comparative study was carried out to evaluate gender influence and the aerobic capacity level upon hydration and the plasmatic volume produced by maximal physical exercise. Twenty four individuals between 18 and 35 years old were included. All participated in aerobic physical exercise and changes in hemoglobin, hematocrit, plasmatic volume, and hydration state were evaluated. RESULTS: Gender showed a significant influence on plasmatic volume but not on the hydration state. The aerobic capacity presented a relationship with plasmatic volume, and the plasmatic volume with the hydration state. Women presented more plasmatic volume loss than men (p < 0.05). Individuals who have adequate aerobic capacity tend to lose less plasmatic volume during exercise. CONCLUSIONS: Maximal physical exercise during a short period also leads to important liquid loss; therefore, it is important that people who engage in exercise understand their liquid losses and re-hydrate themselves appropriately before, during, and after exercise.

Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers.

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets. METHODS: Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8-14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs). RESULTS: Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35-1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02-1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects. CONCLUSION: Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

PURPOSE: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. RESULTS: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. CONCLUSIONS: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies.