Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells.

Synthetic selective modulators of the estrogen receptors (SERMs) have shown to protect neurons and glial cells against toxic insults. Among the most relevant beneficial effects attributed to these compounds are the regulation of inflammation, attenuation of astrogliosis and microglial activation, prevention of excitotoxicity and as a consequence the reduction of neuronal cell death. Under pathological conditions, the mechanism of action of the SERMs involves the activation of estrogen receptors (ERs) and G protein-coupled receptor for estrogens (GRP30). These receptors trigger neuroprotective responses such as increasing the expression of antioxidants and the activation of kinase-mediated survival signaling pathways. Despite the advances in the knowledge of the pathways activated by the SERMs, their mechanism of action is still not entirely clear, and there are several controversies. In this review, we focused on the molecular pathways activated by SERMs in brain cells, mainly astrocytes, as a response to treatment with raloxifene and tamoxifen.

First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

BACKGROUND: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. METHODS: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. MAIN OBJECTIVE: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). RESULTS: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). CONCLUSIONS: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. TRIAL REGISTRATION: This trial was prospectively registered at EudraCT ( 2013-000236-94 ). Date of trial registration: April 9th, 2013.

Evaluation of the safety, tolerance and efficacy of 1-year consumption of infant formula supplemented with Lactobacillus fermentum CECT5716 Lc40 or Bifidobacterium breve CECT7263: a randomized controlled trial.

BACKGROUND: The microorganism present in breast milk, added to other factors, determine the colonization of infants. The objective of the present study is to evaluate the safety, tolerance and effects of the consumption of a milk formula during the first year of life that is supplemented with L. fermentum CECT5716 or Bifidobacterium breve CECT7263, two strains originally isolated from breast milk. METHODS: A randomized, double blind, controlled, parallel group study including healthy, formula-fed infants was conducted. Two hundred and thirty-six 1-month-old infants were selected and randomly divided into three study groups according to a randomization list. Infants in the control group received a standard powdered infant formula until 12 months of age. Infants in the probiotic groups received the same infant formula but supplemented with L. fermentum CECT5716 Lc40 or B. breve CECT7263. Main outcome was weigh-gain of infants as safety marker. RESULTS: One hundred and eighty-nine infants completed the eleven months of intervention (61 in control group, 65 in Lf group and 63 in Bb group). The growth of infants in the three groups was consistent with standards. No significant differences were observed in the main outcome, weight-gain (Control group: 5.77 Kg ± 0.95, Lf group: 5.77 Kg ± 1.31, Bb group: 5.58 Kg ± 1.10; p = 0.527). The three milk formulae were well tolerated, and no adverse effects were related to the consumption of any of the formula. Infants receiving B. breve CECT7263 had a 1.7 times lower risk of crying than the control group (OR = 0.569, CI 95% 0.568-0.571; p = 0.001). On the other hand, the incidence of diarrhoea in infants receiving the formula supplemented with L. fermentum CECT5716 was a 44% lower than in infants receiving the control formula (p = 0.014). The consumption of this Lactobacillus strain also reduced the duration of diarrhoea by 2.5 days versus control group (p = 0.044). CONCLUSIONS: The addition of L. fermentum CECT5716 Lc40 or B. breve CECT7263, two probiotic strains naturally found in breast milk, to infant formulae is safe and induces beneficial effects on the health of infants. TRIAL REGISTRATION: The trial was retrospectively registered in the US Library of Medicine ( www.clinicaltrial.gov ) with the number NCT03204630 . Registered 11 August 2016.

In vivo selection for Haemonchus contortus resistance to monepantel.

Gastrointestinal nematodes significantly affect the ovine industry, and Haemonchus contortus is considered the most pathogenic parasite in tropical regions. This situation is aggravated when the main strategy to control worms fails because of the genetic resistance that parasites acquire against anthelmintics. Aiming to anticipate the events involved in anthelmintic resistance, we induced monepantel resistance in H. contortus by in vivo subdosing of sheep hosts. Four successive passages of a monepantel-susceptible H. contortus isolate in Santa Ines or Ile de France sheep hosts resulted in three monepantel-resistant (efficacy varying from 0 to 58.5%) H. contortus isolates. Sheep hosts were treated from 0.075 mg/kg to the therapeutic dose of 2.5 mg/kg of monepantel in 19-26 rounds of selection for 112-133 weeks. Success in inducing H. contortus resistance to monepantel may have been affected by worm burden and by host-parasite interactions, including a possible effect of the breed of sheep hosts. We conclude that subdosing of sheep, although time-consuming, is an efficient in vivo strategy for the induction of monepantel resistance in H. contortus. The resistant parasites can be used in further studies to elucidate the genetic and biochemical events involved in the acquisition of anthelmintic resistance.

Long-term outcomes of transmesenteric portal vein recanalization for the treatment of chronic portal vein thrombosis after pediatric liver transplantation.

Portal vein thrombosis (PVT) may occur at any time following liver transplantation. We describe our experience with portal vein recanalization in cases of thrombosis after liver transplantation. Twenty-eight children (5%) out of 566 liver transplant recipients underwent portal vein recanalization using a transmesenteric approach. All children received left hepatic segments, developed PVT, and had symptoms or signs of portal hypertension. Portal vein recanalization was performed via the transmesenteric route in all cases. Twenty-two (78.6%) patients underwent successful recanalization and stent placement. They received oral anticoagulants after the procedure, and clinical symptoms subsided. Symptoms recurred due to portal vein restenosis/thrombosis in seven patients. On an intention-to-treat basis, the success rate of the proposed treatment was 60.7%. Only 17 out of 28 children with posttransplant chronic PVT retained stent patency (primary + assisted) at the end of the study period. In cases of portal vein obstruction, the transmesenteric approach via minilaparotomy is technically feasible with good clinical and hemodynamic results. It is an alternative procedure to reestablish the portal flow to the liver graft that can be performed in selected cases and a therapeutic addition to other treatment strategies currently used to treat chronic PVT.

Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial.

Background: There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods: This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point. Results: Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions: This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov: NCT01071655.

Efficacy of a high free iodine barrier teat disinfectant for the prevention of naturally occurring new intramammary infections and clinical mastitis in dairy cows.

Using a natural exposure trial design, the goal of our study was to evaluate the clinical efficacy of an iodine teat disinfectant with barrier properties and a high level of free iodine relative to a conventional iodine teat disinfectant with no barrier properties and low levels of free iodine. During the 18 wk of the trial, quarter milk samples were collected every 2 wk from 385 dairy cows from 2 herds. Cows on both farms were assigned in a balanced way according to milk yield, number of lactation, days in milk, somatic cell count (SCC) and microbiology culture pretrial into one of following groups: nonbarrier post milking teat disinfectant (NBAR; n = 195 cows; 747 quarters) or barrier postmilking teat disinfectant (BAR; n = 190 cows; 728 quarters). Afterward, at each scoring date every 2 wk, milk SCC was quantified in samples from all mammary quarters and microbiologic culture was only performed on milk samples with SCC >200,000 cells/mL for multiparous cows and SCC >100,000 cells/mL for primiparous cows. A new intramammary infection (NIMI) was defined when a quarter had milk SCC <200,000 cells/mL for multiparous cows and <100,000 cells/mL for primiparous without microorganism isolation, and in a subsequent sampling visit had milk SCC >200,000 cells/mL for multiparous cows and >100,000 cells/mL for primiparous cows, and positive microorganism isolation. A quarter could have several NIMI, but only 1 case per specific pathogen was considered. The most frequently isolated microorganism group on both farms was Streptococcus spp. (6.25% of total mammary quarters), followed by coagulase-negative staphylococci (3.6%) and Corynebacterium spp. (1.5%). In the present study, an interaction occurred between treatment and week of trial on the incidence risk of NIMI. Quarters disinfected with BAR had 54 and 37% lower odds of NIMI than quarters disinfected with NBAR at 8 and 16 wk of the trial, respectively; whereas at other weeks of the study both products had similar incidence risks of NIMI. Overall, teats disinfected with BAR had 46% lower odds of acquiring a clinical mastitis than those disinfected with NBAR. We concluded that the postmilking teat disinfectant with barrier properties and higher free iodine content reduced the risk of clinical mastitis, although differences in new infections were detected at only weekly time points.

Short communication: Efficacy of glycolic acid-based and iodine-based postmilking barrier teat disinfectants for prevention of new intramammary infections in dairy cattle.

A positive-control, natural exposure noninferiority field study was conducted to test the efficacy of a novel glycolic acid-based postmilking barrier teat disinfectant compared with a commercial iodine-based postmilking barrier teat disinfectant (positive control). Cows from 2 pens from a California Central Valley dairy farm were dipped after milking either with the positive-control product (PC) or the experimental product (EX) over 12 wk. New intramammary infections (NIMI) were determined by biweekly sampling of all quarters of study cows and classified as a NIMI based on somatic cell count and milk bacteriological culture results. The mean quarter-level incidence risks during a 2 wk study period were 3.50% (EX) and 4.28% (PC). The majority of NIMI were caused by coagulase-negative staphylococci, followed by non-agalactiae streptococci. The study results indicated that EX was noninferior to PC, with a 17% relative efficacy (improvement) in reducing NIMI compared with the PC group. Also, quarter somatic cell count was not affected by the postmilking teat disinfectant used. Finally, the EX product was safe in terms of teat conditioning: teat condition scores were not different between study groups. The study concluded that the glycolic acid-based experimental post-dip barrier was noninferior to the control, and could be considered a safe and effective postmilking teat disinfectant.

Randomized noninferiority study evaluating the efficacy of a postmilking teat disinfectant for the prevention of naturally occurring intramammary infections.

The objective of this study was to complete a positive-control, natural exposure, noninferiority design field study to test the efficacy of a novel glycolic acid-based postmilking teat disinfectant as compared with a previously proven iodine-based postmilking teat disinfectant (positive control). The primary outcome of interest was the effect of treatment on incidence of new intramammary infections. Secondary outcomes included the effect of treatment on prevalence of infection, somatic cell count, and teat condition. After blocking by parity, approximately 300 early- to mid-lactation cows on a large Wisconsin dairy farm were randomly assigned to 1 of 2 groups. For a 12-wk period between May and August 2014, the 2 groups were dipped after each milking with either the experimental (EX) or positive control (PC) product. Individual quarters were sampled to establish bacteriological infection status at the beginning of the study, and every 2 wk thereafter, by use of a 2-stage process evaluating somatic cell count (SCC), and then culturing milk samples only when SCC exceeded a parity-specific threshold. Teat condition scoring was completed at the beginning of the study and on wk 4, 8, and 12. Mixed logistic regression was used to evaluate the effect of treatment on dichotomous outcome measures including the odds of acquiring a new infection during a given 2-wk sampling interval (incidence), the odds for presence of infection at sampling (prevalence), and odds for a normal teat skin condition score. Mixed linear regression was used to evaluate the effect of treatment on somatic cell count. For the noninferiority analysis, the upper bound of the 95% confidence interval for the difference in new infection rate between the 2 treatments (EX - PC), had to be to the left of the critical value d (0.035) to conclude that EX was noninferior relative to PC with respect to risk for new infections. Results showed that the incidence of new infections was not different for quarters dipped with EX (3.2%) as compared with PC (4.2%). Similarly, the prevalence of infection tended to be lower for quarters dipped with EX (3.92%) as compared with PC (5.03%). No overall difference was found between treatments when evaluating somatic cell count measures and teat condition scores. Because the upper bound of the 95% confidence interval of the new IMI rate difference was smaller than the predefined noninferiority limit, it was concluded that the experimental product was not inferior compared with the positive control. As such, the glycolic acid-based teat disinfectant evaluated in this study can be considered an effective postmilking teat disinfectant, as well as safe, in so far as the product was not irritating to teat skin and did not negatively affect skin condition measures, as compared with the positive control group.

Factors related to advanced colorectal neoplasm at the Policlínico Peruano Japonés.

BACKGROUND: Identifying persons at high risk for advanced colorectal neoplasia can aid in the prevention of colon cancer. Previous studies have shown that some patients can present with proximal advanced neoplasia with no distal findings. AIMS: To determine the factors related to advanced neoplasia and advanced proximal colorectal neoplasia in a Latin American population. MATERIAL AND METHODS: A prospective, cross-sectional, observational, analytic study was conducted. It included patients that underwent colonoscopy at the Policlínico Peruano Japonés within the time frame of January and July 2012. Advanced neoplasia was defined as the presence of lesions ≥ 10mm with a villous component, high-grade dysplasia, or carcinoma. The splenic flexure was the limit between the proximal and distal colon. RESULTS: A total of 846 patients were included in the study. Advanced neoplasia was detected in 108 patients (12.8%) and advanced proximal neoplasia in 55 patients (6.7%), 42 (76.4%) of whom had no neoplasia in the distal colon. Factors related to advanced neoplasia found in the multivariate analysis were age, at the intervals of 50-59 (p=0.019), 60-69 (p=0.016), and ≥ 70 years (0.002) and male sex (p=0.003). In the evaluation of advanced proximal neoplasia, the multivariate analysis identified the 60-69 year age interval (p=0.039) and advanced distal neoplasia (p=0.028) as factors related to advanced proximal disease. The ROC curve established the age cut-off point at 60 years for initially performing colonoscopy, rather than sigmoidoscopy. CONCLUSIONS: Age and sex are related to advanced neoplasia, whereas age and advanced distal neoplasia are related to advanced proximal neoplasia.

Efficacy of erlotinib in patients with relapsed gliobastoma multiforme who expressed EGFRVIII and PTEN determined by immunohistochemistry.

Epidermal growth factor receptor gene (EGFR) alteration is a common feature in most of glioblastoma multiforme (GBM). Robust response of anti-EGFR treatments has been mostly associated with the EGFR deletion mutant variant III (EGFRvIII) and expression of PTEN. We have performed a prospective trial in order to confirm the efficacy of erlotinib treatment in patients with relapsed GBM who expressed EGFRvIII and PTEN. All patients included in the trial were required to be PTEN (+++), EGFR (+++) and EGFRvIII (+++) positives by immunohistochemistry. This new phase II trial enrolled 40 patients and was design to be stopped in case of fewer than two responses in the first 13 patients. Patient eligibility included histopathology criteria, radiological progression, more than 18 years old, Karnofsky performed status, KPS > 50, and adequate bone marrow and organ function. There was no limit to the number of prior treatments for relapses. No enzyme-inducing antiepileptic drugs were allowed. The primary endpoints were response and progression-free survival at 6 months (PFS6). Thirteen patients (6 men, 7 women) with recurrent GBM received erlotinib 150 mg/day. Median age was 53 years, median KPS was 80, and median prior treatments for relapses were 2. There was one partial response and three stable diseases (one at 18 months). PFS at 6 months was 20 %. Dose reduction for toxicity was not needed in any patient. Dermatitis was the main treatment-related toxicity, grade 1 in 8 patients and grade 2 in 5 patients. No grade 3 toxicity was observed. Median survival was 7 months (95 % IC 1.41-4.7). As conclusion, monotherapy with erlotinib in GBM relapses patients with high protein expression for PTEN (+++), EGFR (+++), and EGFRvlII (+++) showed low toxicity but minimal efficacy and the trial stopped.

Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes.

Litter size (LS) in sheep is determined mainly by ovulation rate (OR). Several polymorphisms have been identified in the growth differentiation factor 9 (GDF9) gene that result in an increase in OR and prolificacy of sheep. Screening the databank of the Brazilian Sheep Breeders Association for triplet delivery, we identified flocks of prolific Ile de France ewes. After resequencing of GDF9, a point mutation (c.943C>T) was identified, resulting in a non-conservative amino acid change (p.Arg315Cys) in the cleavage site of the propeptide. This new allele was called Vacaria (FecG(v) ). A flock of half-sib ewes was evaluated for OR in the first three breeding seasons, and Vacaria heterozygotes had higher OR (P < 0.001), averaging 2.1 ± 0.1 when compared to 1.2 ± 0.1 in wild-type ewes. The OR was also influenced by age, increasing in the second and third breeding seasons (P < 0.001). In flocks segregating this allele, the LS was higher in mutant sheep (P < 0.001), averaging 1.61 ± 0.07 in heterozygotes and 1.29 ± 0.03 in wild-type ewes. Analysis of homozygote reproductive tract morphology revealed uterine and ovarian hypoplasia. Ovarian follicles continue to develop up to small antral stages, although with abnormal oocyte morphology and altered arrangement of granulosa cells. After the collapse of the oocyte in most follicles, the remaining cells formed clusters that persisted in the ovary. This SNP is useful to improve selection for dam prolificacy and also as a model to investigate GDF9 post-translation processing and the fate of the follicular cells that remain after the oocyte demise.

Noninferiority trial on the efficacy of premilking teat disinfectant against naturally occurring new intramammary infections using a novel 2-step diagnostic process.

The objective of the study was to evaluate premilking teat disinfectant efficacy with the use of a novel diagnostic protocol against a positive control. The evaluation of efficacy was based on establishing noninferiority of a new premilking teat disinfectant compared with an existing premilking teat disinfectant. Approximately 200 cows were randomly allocated to 1 of 2 groups. Study personnel were blinded as to cow allocation and identification of the premilking disinfectants. Quarters were disinfected using a dip cup before milking with either the control or experimental product. The disinfectant was left on the teat for approximately 30s before being wiped off in preparation for milking. Quarter-level bacteriological infection status was established at the beginning of the study and quarter milk samples were collected biweekly thereafter. Bacteriological analyses were performed only when somatic cell counts in milk samples crossed a parity-specific threshold. Poisson regression models were used to analyze data. The difference in the rate of new intramammary infections was small and the upper bound of the 95% confidence interval of the rate difference was smaller than a predefined noninferiority limit. Based on the observed difference in new intramammary infections rate between the experimental and control product, it was concluded that the experimental disinfectant was not inferior compared with the positive control. The protocol used in this study proposes a valid and economically attractive methodology to evaluate the efficacy of teat disinfectants relative to a positive control.

Short communication: minimum bactericidal concentration of disinfectants evaluated for bovine digital dermatitis-associated Treponema phagedenis-like spirochetes.

The bacterial spirochetes, Treponema spp., are thought to be a major contributor to the etiology of bovine digital dermatitis (DD), a skin disease with worldwide economic impact. Hoofbath strategies are commonly used in an attempt to control and prevent the development of DD and continuing research has been done to develop an optimal hoofbath strategy for this purpose. The aim of this study was to develop a protocol that can be used as part of the screening process for candidate hoofbath disinfectants. This protocol allows an accurate determination of the in vitro minimum inhibitory concentration and minimum bactericidal concentration of a series of disinfectants for Treponema microorganisms. Assays were performed in triplicate for each of the disinfectants at 30-s and 10-min exposure times and exposed to 10 and 20% manure (vol/vol). The results of this study can be used to categorize disinfectants based on the effect of exposure and manure concentration regarding their ability to inhibit Treponema growth. This information can then aid in optimizing strategies for hoofbath-based control of DD development and spread.

Correlation and validity of imputed PaO2/FiO2 and SpO2/FiO2 in patients with invasive mechanical ventilation at 2600m above sea level.

OBJECTIVE: To establish the correlation and validity between PaO2/FiO2 obtained on arterial gases versus noninvasive methods (linear, nonlinear, logarithmic imputation of PaO2/FiO2 and SpO2/FiO2) in patients under mechanical ventilation living at high altitude. DESIGN: Ambispective descriptive multicenter cohort study. SETTING: Two intensive care units (ICU) from Colombia at 2600m a.s.l. PATIENTS OR PARTICIPANTS: Consecutive critically ill patients older than 18 years with at least 24h of mechanical ventilation were included from June 2016 to June 2019. INTERVENTIONS: None. VARIABLES: Variables analyzed were demographic, physiological messures, laboratory findings, oxygenation index and clinical condition. Nonlinear, linear and logarithmic imputation formulas were used to calculate PaO2 from SpO2, and at the same time the SpO2/FiO2 by severe hypoxemia diagnosis. The intraclass correlation coefficient, area under the ROC curve, sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratio were calculated. RESULTS: The correlation between PaO2/FiO2 obtained from arterial gases, PaO2/FiO2 derived from one of the proposed methods (linear, non-linear, and logarithmic formula), and SpO2/FiO2 measured by the intraclass correlation coefficient was high (greater than 0.77, p<0.001). The different imputation methods and SpO2/FiO2 have a similar diagnostic performance in patients with severe hypoxemia (PaO2/FiO2 <150). PaO2/FiO2 linear imputation AUC ROC 0,84 (IC 0.81-0.87, p<0.001), PaO2/FiO2 logarithmic imputation AUC ROC 0.84 (IC 0.80-0.87, p<0.001), PaO2/FiO2 non-linear imputation AUC ROC 0.82 (IC 0.79-0.85, p<0.001), SpO2/FiO2 oximetry AUC ROC 0.84 (IC 0.81-0.87, p<0.001). CONCLUSIONS: At high altitude, the SaO2/FiO2 ratio and the imputed PaO2/FiO2 ratio have similar diagnostic performance in patients with severe hypoxemia ventilated by various pathological conditions.

Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

Study of colorectal mortality in the Andalusian population.

OBJECTIVES: to provide up-to-date information and to analyze recent changes in colorectal cancer mortality trends in Andalusia during the period of 1980-2008 using joinpoint regression models. PATIENTS AND METHODS: age- and sex-specific colorectal cancer deaths were taken from the official vital statistics published by the Instituto de Estadística de Andalucía for the years 1980 to 2008. We computed age-specific rates for each 5-year age group and calendar year and age-standardized mortality rates per 100,000 men and women. A joinpoint regression analysis was used for trend analysis of standardized rates. Joinpoint regression analysis was used to identify the years when a significant change in the linear slope of the temporal trend occurred. The best fitting points (the "join-points") are chosen where the rate significantly changes. RESULTS: mortality from colorectal cancer in Andalusia during the period studied has increased, from 277 deaths in 1980 to 1,227 in 2008 in men, and from 333 to 805 deaths in women. Adjusted overall colorectal cancer mortality rates increased from 7.7 to 17.0 deaths per 100,000 person-years in men and from 6.6 to 9.0 per 100,000 person-years in women Changes in mortality did not evolve similarly for men and women. Age-specific CRC mortality rates are lower in women than in men, which imply that women reach comparable levels of colorectal cancer mortality at higher ages than men. CONCLUSIONS: sex differences for colorectal cancer mortality have been widening in the last decade in Andalusia. In spite of the decreasing trends in age-adjusted mortality rates in women, incidence rates and the absolute numbers of deaths are still increasing, largely because of the aging of the population. Consequently, colorectal cancer still has a large impact on health care services, and this impact will continue to increase for many more years.

Correlation and validity of imputed PaO2/FiO2 and SpO2/FiO2 in patients with invasive mechanical ventilation at 2600m above sea level.

OBJECTIVE: To establish the correlation and validity between PaO2/FiO2 obtained on arterial gases versus noninvasive methods (linear, nonlinear, logarithmic imputation of PaO2/FiO2 and SpO2/FiO2) in patients under mechanical ventilation living at high altitude. DESIGN: Ambispective descriptive multicenter cohort study. SETTING: Two intensive care units (ICU) from Colombia at 2600m a.s.l. PATIENTS OR PARTICIPANTS: Consecutive critically ill patients older than 18 years with at least 24h of mechanical ventilation were included from June 2016 to June 2019. INTERVENTIONS: None. VARIABLES: Variables analyzed were demographic, physiological messures, laboratory findings, oxygenation index and clinical condition. Nonlinear, linear and logarithmic imputation formulas were used to calculate PaO2 from SpO2, and at the same time the SpO2/FiO2 by severe hypoxemia diagnosis. The intraclass correlation coefficient, area under the ROC curve, sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratio were calculated. RESULTS: The correlation between PaO2/FiO2 obtained from arterial gases, PaO2/FiO2 derived from one of the proposed methods (linear, non-linear, and logarithmic formula), and SpO2/FiO2 measured by the intraclass correlation coefficient was high (greater than 0.77, p<0.001). The different imputation methods and SpO2/FiO2 have a similar diagnostic performance in patients with severe hypoxemia (PaO2/FiO2 <150). PaO2/FiO2 linear imputation AUC ROC 0,84 (IC 0.81-0.87, p<0.001), PaO2/FiO2 logarithmic imputation AUC ROC 0.84 (IC 0.80-0.87, p<0.001), PaO2/FiO2 non-linear imputation AUC ROC 0.82 (IC 0.79-0.85, p<0.001), SpO2/FiO2 oximetry AUC ROC 0.84 (IC 0.81-0.87, p<0.001). CONCLUSIONS: At high altitude, the SaO2/FiO2 ratio and the imputed PaO2/FiO2 ratio have similar diagnostic performance in patients with severe hypoxemia ventilated by various pathological conditions.