Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy.

BACKGROUND: Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. MATERIALS AND METHODS: Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. RESULTS: As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6). CONCLUSION: Avapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations. IMPLICATIONS FOR PRACTICE: In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.

Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.

BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial.

BACKGROUND: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). METHODS: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. FINDINGS: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2-25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2-24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3-4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76-95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30-400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). INTERPRETATION: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. FUNDING: Blueprint Medicines.

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism.

Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.

A phase II trial of Sunitinib malate in recurrent and refractory ovarian, fallopian tube and peritoneal carcinoma.

OBJECTIVE: Ovarian cancer is a highly angiogenic tumor and a model for antiangiogenic research. The tyrosine kinase receptor inhibitors target several receptors allowing for the pharmacological disruption of several independent pathways. Sunitinib malate is a multitargeted tyrosine kinase inhibitor. A phase II study utilizing a modified dosing schedule was conducted to assess the efficacy and safety of Sunitinib in recurrent ovarian, fallopian tube and peritoneal carcinoma. METHODS: A nonrandomized phase II study was modeled as a two-stage Simon design initially enrolling 17 evaluable participants in stage one and 18 patients in stage two. Patients received the study drug at 37.5mg every day over a 28 day treatment cycle until clinical or radiological evidence of progressive disease. Disease was evaluated radiographically and best overall response was defined using the RECIST 1.0 criteria. The primary objective of this study was to define the response rate (defined as complete response and partial response) while the secondary objectives included both the progression free rate as well as the safety of this agent in this patient population. RESULTS: The response rate (PR+CR) was 8.3% (95% confidence interval: 1.8%, 22.5%). The 16-week and 24 week progression-free survival estimate was 36% (95% confidence interval and 19.2%), respectively. The median progression-free survival estimate was 9.9 weeks. Hypertension and gastrointestional events were the most common toxicities noted. CONCLUSIONS: A modest response rate of 8.3% was achieved with Sunitinib malate. This phase II study adds to the body of literature of VEGFR inhibitors and further underscores the need of defining a genetic angiogenic signature.

Salmonella Control in Fattening Pigs through the Use of Esterified Formic Acid in Drinking Water Shortly before Slaughter.

The presence of Salmonella in pig feces is a major source of abattoir and carcass contamination, and one of the main sources of human salmonellosis. This study assessed whether using a form of esterified formic acid (30% formic acid) in drinking water (10 kg/1000 L) 5 days before slaughter could be a helpful strategy to mitigate this public health issue. Thus, 240 pigs from three Salmonella-positive commercial fattening farms were selected. From each farm, 40 pigs were allocated to a control group (CG) and 40 to a treatment group (TG). At the abattoir, fecal samples from both groups were collected for Salmonella detection (ISO 6579-1:2017) and quantification (ISO/TS 6579-2:2012). Salmonella was present in 35% (95% IC = 29.24-41.23) of the samples collected. The prevalence was significantly higher in the CG than in the TG (50% vs. 20%; p < 0.001). In all farms, the TG showed a lower percentage of shedders than the CG. A random-effects logistic model showed that the odds of shedding Salmonella were 5.63 times higher (95% CI = 2.92-10.8) for the CG than for the TG. Thus, the proportion of pigs shedding Salmonella that was prevented in the TG due to the use of this form of organic acid was 82.2%. In addition, a Chi-squared analysis for trends showed that the higher the Salmonella count, the higher the odds of the sample belonging to the CG. These results suggest that adding this type of acid to drinking water 5 days before slaughter could reduce the proportion of Salmonella-shedding pigs and the Salmonella loads in the guts of shedder pigs.

Building a predictive model for assessing the risk of Salmonella shedding at slaughter in fattening pigs.

Salmonellosis continues to be a major cause of foodborne outbreaks worldwide, and pigs are one of the main sources of human infection. Salmonella pork contamination is a major concern for abattoirs and is related to the presence of Salmonella in pigs' feces at slaughter. Being able to predict the risk of Salmonella shedding in pigs arriving at the slaughterhouse could help mitigate abattoir and carcass contamination. For this purpose, 30 batches of 50 pigs each were selected from 30 different fattening units. The pigs were tagged and bled for the detection of antibodies against Salmonella approximately one month before slaughter. Pooled floor fecal samples were also collected from 10 pens per unit for Salmonella detection, and a questionnaire on biosecurity was administered to each farm. At the abattoir, colon content was collected from each tagged pig for the Salmonella shedding assessment. A predictive model for Salmonella shedding at slaughter was built with two-third of the pigs by employing random-effects logistic regression analysis, with Salmonella shedding as the dependent variable and pig serology and other farm/environmental characteristics as the independent variables. The model included farm as the grouping factor. Data from the remaining one-third of the pigs were used for model validation. Out of 1,500 pigs initially selected, 1,341 were identified at the abattoir and analyzed. Salmonella was detected in 13 (43.3%; 95%CI = 27.4-60.8) of the fattening units. The mean batch seroprevalence (cut-off OD% ≥40) among the fattening units was 31.7% (95%CI = 21.8-41.0), and a total of 316 pigs (23.6%; 95%CI = 21.4-25.9) shed Salmonella at slaughter. The model predicted reasonably well (Area under the curve = 0.76; P < 0.05) whether a pig would shed Salmonella at slaughter, with estimates of sensitivity and specificity at 71.6% and 73.6%, respectively. Serology, the percentage of Salmonella-positive pens on the farm, and the internal biosecurity score were significantly associated (P < 0.05) with Salmonella shedding at the abattoir, and several scenarios were observed by the model. The study highlighted that although serology may be helpful for identifying batches of pigs at risk of shedding Salmonella upon their arrival at the abattoir, it may not be necessary in some scenarios.

Different Brain Phenotypes in Magnetic Resonance Imaging of Healthy Children after Prenatal Insults.

In this study, we used magnetic resonance imaging (MRI) to identify the different brain phenotypes within apparently healthy children and to evaluate whether these phenotypes had different prenatal characteristics. We included 65 healthy children (mean age, 10 years old) with normal neurological examinations and without structural abnormalities. We performed cluster analyses to identify the different brain phenotypes in the brain MRI images. We performed descriptive analyses, including demographic and perinatal characteristics, to assess the differences between the clusters. We identified two clusters: Cluster 1, or the "small brain phenotype" (n = 44), which was characterized by a global reduction in the brain volumes, with smaller total intracranial volumes (1044.53 ± 68.37 vs. 1200.87 ± 65.92 cm3 (p < 0.001)), total grey-matter volumes (644.65 ± 38.85 vs. 746.79 ± 39.37 cm3 (p < 0.001)), and total white-matter volumes (383.68 ± 40.17 vs. 443.55 ± 36.27 cm3 (p < 0.001)), compared with Cluster 2, or the "normal brain phenotype" (n = 21). Moreover, almost all the brain areas had decreased volumes, except for the ventricles, caudate nuclei, and pallidum areas. The risk of belonging to "the small phenotype" was 82% if the child was preterm, 76% if he/she was born small for his/her gestational age and up to 80% if the mother smoked during the pregnancy. However, preterm birth appears to be the only substantially significant risk factor associated with decreased brain volumes.

Salmonella Shedding in Slaughter Pigs and the Use of Esterified Formic Acid in the Drinking Water as a Potential Abattoir-Based Mitigation Measure.

Pigs shedding Salmonella at slaughter are considered a source of carcass contamination and human infection. To assess this potential risk, the proportion of Salmonella shedders that arrive for slaughter was evaluated in a population of 1068 pigs from 24 farms. Shedding was present in 27.3% of the pigs, and the monophasic variant of Salmonella Typhimurium, an emerging zoonotic serotype, was the most prevalent (46.9%). Antimicrobial resistance (AMR) in Salmonella isolates was common, but few isolates showed AMR to antimicrobials of critical importance for humans such as third-generation cephalosporins (5%), colistin (0%), or carbapenems (0%). However, AMR to tigecycline was moderately high (15%). The efficacy of an esterified formic acid in the lairage drinking water (3 kg formic acid/1000 L) was also assessed as a potential abattoir-based strategy to reduce Salmonella shedding. It was able to reduce the proportion of shedders (60.7% in the control group (CG) vs. 44.3% in the treatment group (TG); p < 0.01). After considering clustering and confounding factors, the odds of shedding Salmonella in the CG were 2.75 (95% CI = 1.80−4.21) times higher than those of the TG, suggesting a potential efficacy of reduction in shedding as high as 63.6%. This strategy may contribute to mitigating the burden of abattoir environmental contamination.

Visual Acuity and Contrast Sensitivity in Preterm and Full-Term Children Using a Novel Digital Test.

Visual assessment in preverbal children mostly relies on the preferential looking paradigm. It requires an experienced observer to interpret the child's responses to a stimulus. DIVE (Device for an Integral Visual Examination) is a digital tool with an integrated eye tracker (ET) that lifts this requirement and automatizes this process. The aim of our study was to assess the development of two visual functions, visual acuity (VA) and contrast sensitivity (CS), with DIVE, in a large sample of children from 6 months to 14 years (y) of age, and to compare the results of preterm and full-term children. Participants were recruited in clinical settings from five countries. There were 2208 children tested, 609 of them were born preterm. Both VA and CS improved throughout childhood, with the maximum increase during the first 5 years of age. Gestational age, refractive error and age had an impact on VA results, while CS values were only influenced by age. With this study we report normative reference outcomes for VA and CS throughout childhood and validate the DIVE tests as a useful tool to measure basic visual functions in children.

Effects of Dietary Supplementation with Protected Sodium Butyrate on Gut Microbiota in Growing-Finishing Pigs.

The study assessed changes in the gut microbiota of pigs after dietary supplementation with protected sodium butyrate (PSB) during the growing-fattening period (≈90 days). One gram of colon content from 18 pigs (9 from the treatment group -TG- and 9 from the control group -CG-) was collected. Bacterial DNA was extracted and 16S rRNA high-throughput amplicon sequencing used to assess microbiota changes between groups. The groups shared 75.4% of the 4697 operational taxonomic units identified. No differences in alpha diversity were found, but significant differences for some specific taxa were detected between groups. The low-represented phylum Deinococcus-Thermus, which is associated with the production of carotenoids with antioxidant, anti-apoptotic, and anti-inflammatory properties, was increased in the TG (p = 0.032). Prevotellaceae, Lachnospiraceae, Peptostreptococcaceae, Peptococcaceae, and Terrisporobacter were increased in the TG. Members of these families have the ability to ferment complex dietary polysaccharides and produce larger amounts of short chain fatty acids. Regarding species, only Clostridium butyricum was increased in the TG (p = 0.048). Clostridium butyricum is well-known as probiotic in humans, but it has also been associated with overall positive gut effects (increased villus height, improved body weight, reduction of diarrhea, etc.) in weanling pigs. Although the use of PSB did not modify the overall richness of microbiota composition of these slaughter pigs, it may have increased specific taxa associated with better gut health parameters.

Salmonella Infection in Nursery Piglets and Its Role in the Spread of Salmonellosis to Further Production Periods.

Few studies have focused on assessing Salmonella infection in the nursery and its role in further pig production periods. Mesenteric lymph nodes, intestinal content, and meat juice from 389 6-week-old male piglets intended for human consumption from five breeding farms and 191 pooled floor fecal samples from gilt development units (GDU) from the same farms were analyzed to estimate and characterize (by pulsed-field gel electrophoresis and antimicrobial resistance analyses) Salmonella infection. The prevalence of infection and shedding among piglets was 36.5% and 37.3%, respectively, shedding being significantly associated with infection (Odds Ratio = 12.7; CI 7.3-22.0). Salmonella Rissen; S. 4,[5],12:i:-; and S. Derby were the most common serotypes. A low level of Salmonella-specific maternal antibodies at the beginning of the nursery period suggested it was a period of high risk of infection. Resistance to 3rd- and 4th-generation cephalosporins was detected in piglet isolates although the piglets never received antibiotics, indicating they could be vectors of antimicrobial resistance. The same Salmonella clones were detected in piglet and GDU isolates, suggesting that infected piglets play a significant role in the infection of gilts and consequently of finishing pigs in the case of production farms. The control of Salmonella infection in nursery piglets may decrease the risk of abattoir and carcass contamination.

Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial.

BACKGROUND: PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. METHODS: NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. RESULTS: Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached. CONCLUSION: Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.

Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study.

PURPOSE: Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS: VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.

Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors.

OBJECTIVE: GM-CSF is a recombinant human cytokine, which promotes the proliferation and differentiation of granulocytes and monocytes, and is associated with anti-tumor activity. The primary objective was to define the median time to treatment termination (TTT) with women with relapsed ovarian cancer treated with single agent GM-CSF delivered subcutaneously (SC). PATIENTS AND METHODS: Open label phase II study in asymptomatic patients with recurrent müllerian malignancy without an indication for immediate systemic chemotherapy. In the first cohort of 35 women, GM-CSF 250 microg/m(2) was administered SC on days 1-14 of a 28-day cycle, the second cohort received continuous GM-CSF 150 microg/m(2) given with dose escalation. RESULTS: Seventy-two women were enrolled. Best overall response included one complete response, and 20 patients with stable disease (23%), 4 of whom had stable disease for >6 months. Median TTT was 78 days. Toxicity in both cohorts was generally mild; however, four patients experienced excessive toxicity and withdrew consent. In the first cohort, CA-125 dropped in 70% of women from their baseline on study value (median change -23%, range -48 to +116%) after 14 days of GM-CSF. The magnitude of CA-125 drop during the first 2 weeks of therapy also showed a positive inverse correlation with day 15 white cell count for the whole group (p=0.038). CONCLUSION: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT is modest, a subset of women had prolonged stable disease.

In-band optical signal-to-noise ratio monitoring method based on high-resolution polarization analysis and induced differential group delay.

We report on an in-band optical signal-to-noise ratio monitoring technique for wavelength division multiplexed channels. Our proposal relies on the different degree of polarization between the signal (highly polarized) and the noise (not polarized). Using this principle, we divide the signal under test into two orthogonal polarization components and induce a differential group delay via a controlled birefringence apparatus that produces a wavelength-dependent shift of the polarization state of the signal. After a linear polarizing filter, high-resolution spectral analysis allows measurement of the amplified spontaneous emission noise level. The method is tested by experimental measurements of a 40 Gbit/s differential phase-shift keying channel showing very good performance.

[Rate of episiotomy in the University Clinical Hospital of Arrixaca and factors that influence in its practice.] / Tasa de episiotomía en el Hospital Clínico Universitario de La Arrixaca y factores que influyen en su práctica.

OBJECTIVE: The conduction of episiotomy is a questioned practice given the strong scientific evidence on its adverse effects. The study objectives were to know the episiotomy rate and its adaptation to the recommendations of the Ministry of Health, Consumption and Social Welfare and assess the associated factors. METHODS: It has been made a Observational, descriptive and transversal quantitative study, it was carried out in the university clinical hospital arrixaca. Data were collected from deliveries attended between January 1, 2016 and October 30, 2017, obtaining a sample of 10,630 women, registered in the SELENE computer program which is the clinical database of said hospital. To perform the data analysis, were used the SPSS statistical program and an Excel database. At the first level, it was carried out a descriptive analysis of the obstetric variables and, at a second level, the data were compared with the Ministry of Health indicators by means of a comparison of two proportions and the chi-square test. In order to estimate the Effect Size, the Cramer V was used for qualitative variables and the relative risk was calculated for each pair of qualitative variablesas a relative measure of the effect, to determine the strength of association between the variables. RESULTS: The episiotomy rate was 36.5%. When the birth started spontaneously, the percentage was 35.5%, when it was induced 47.2% and stimulated rate was 42.3%. The rate in eutocic deliveries was 20.6% and in instrumented was 95.25%. In primiparas, the episiotomy was 49.64% and in multiparas the conduction was 15.55%. Was observed a tendency of second-degree tears (43.40%), followed by first-degree (35.61%) and third-degree (19.81%) with episiotomy. CONCLUSIONS: The episiotomy rate in our study exceeds current recommendations. The variables associated with the performance of the episiotomy are induced or stimulated delivery, instrumentation and primiparity. There is a significant relationship between the practice of episiotomy and the greater degree of tear.

OBJETIVO: La realización de episiotomías es una práctica cuestionada dada la fuerte evidencia científica existente sobre sus efectos adversos. Los objetivos de este estudio fueron conocer la tasa de episiotomías y su adecuación a las recomendaciones del Ministerio de Sanidad, Consumo y Bienestar Social y valorar los factores asociados. METODOS: Se realizó un estudio cuantitativo observacional, descriptivo y transversal, que fue llevado a cabo en el Hospital Clinico Universitario Arrixaca. Se recogieron datos De los partos atendidos entre el 1 de enero de 2016 y el 30 de octubre de 2017, obteniendo una muestra de 10.630 mujeres, a través del programa informático SELENE, que es la base de datos clínicos de dicho hospital. Para realizar el análisis de datos se utilizó el programa estadístico SPSS y una base de datos Excel. En un primer nivel, se efectuó un análisis descriptivo de las variables obstétricas y, en un segundo nivel, se contrastaron los datos con los indicadores del Ministerio de Sanidad, Consumo y Bienestar Social mediante una comparación de dos proporciones y el test de la ji al cuadrado. Para poder estimar el Tamaño del Efecto se utilizó la V de Cramer para variables cualitativas, y se calculó el riesgo relativo para cada par de variables cualitativas como medida relativa del efecto, para determinar así la fuerza de asociación entre las variables. RESULTADOS: La tasa de episiotomías fue del 36,5%. Cuando el parto comenzó espontáneamente el porcentaje fue del 35,5%; cuando fue inducido, la tasa fue del 47,2% y cuando fue estimulado, el porcentaje fue del 42,3%. La tasa en partos eutócicos fue del 20,6% y en instrumentados fue del 95,25%. En primíparas, la realización de episiotomía fue del 49,64% y en multíparas la realización fue del 15,55%. Se observó una tendencia a desgarros de segundo grado (43,40%), seguidos de primer grado (35,61%) y de tercer grado (19,81%) con episiotomía. CONCLUSIONES: La tasa de episiotomía de nuestro estudio supera las actuales recomendaciones. Las variables asociadas a la realización de la episiotomía son el parto inducido o estimulado, la instrumentación y la primiparidad. Se evidencia una relación significativa entre la práctica de episiotomia y el mayor grado de desgarro.

Impact of support networks for breastfeeding: A multicentre study.

BACKGROUND: The rates of breastfeeding worldwide are slowly improving since 1996. Europe is still trailing behind the global breastfeeding incidence and prevalence rates. Thus, breastfeeding promotion, protection, prolongation and support have become an important challenge as breastfeeding sharply decreases in the first six months of life. OBJECTIVES: The aim of this project is to determine, assess and identify the real impact of breastfeeding support networks in Murcia (Spain). METHODS: After searching unsuccessfully for a validated questionnaire, a specific one was developed and validated for measuring the impact of formal and informal support networks through five dimensions: satisfaction, consultation, experience, problems and support. The questionnaire was provided to 500 mothers with experience in breastfeeding, who brought their children to baby paediatricians between 2 June and 27 November 2014. Upon completion of the survey and fieldwork, a detailed statistical analysis was conducted. RESULTS: The degree of satisfaction perceived by the users of the services of support breastfeeding networks is remarkable. In addition, mothers who clarified their doubts and discussed their problems with health professionals and/or breastfeeding support networks were more likely to breastfeed for a longer duration compared to those who did not (p=0.005). Furthermore, mothers who sought support in breastfeeding are more likely to breastfeed for more than 6 months (p<0.0005). CONCLUSION: Based on this information, we conclude that breastfeeding support networks have a positive influence in the duration of a women's decision to breastfeed.

Diagnóstico y tratamiento quirúrgico de una paciente con una neoplasia trofoblástica gestacional / Diagnosis and surgical treatment of a patient with gestational trophoblastic neoplasia

Resumen ANTECEDENTE: La neoplasia trofoblástica gestacional forma parte del grupo de afecciones derivadas de la proliferación anómala del trofoblasto con capacidad para invasión y metástasis. CASO CLÍNICO: Paciente de 42 años, asintomática, con sospecha ecográfica de mola hidatiforme. El legrado uterino y el estudio anatomopatológico confirmaron el diagnóstico de mola hidatiforme completa. Con la cuantificación consecutiva de tres elevaciones de la β-HCG se diagnosticó: neoplasia trofoblástica gestacional. Se estadificó en estadio I, bajo riesgo y ante el deseo genésico satisfecho la paciente aceptó la histerectomía más salpingectomía bilateral. En el seguimiento posterior la paciente se encontró asintomática, con determinaciones seriadas de b-HCG negativa y ecografías vaginales sin hallazgos. CONCLUSIÓN: La histerectomía con salpingectomía bilateral puede ser el tratamiento definitivo en casos seleccionados de neoplasia trofoblástica. La evidencia disponible es escasa, por lo que es necesario seguir investigando en este campo.

Abstract BACKGROUND: Gestational trophoblastic neoplasia is one of a group of conditions resulting from abnormal trophoblast proliferation with capacity for invasion and metastasis. CLINICAL CASE: 42-year-old asymptomatic patient with ultrasound suspicion of hydatidiform mole. Uterine curettage and anatomopathological study confirmed the diagnosis of complete hydatidiform mole. With the consecutive quantification of three elevations of β-HCG a diagnosis of gestational trophoblastic neoplasia was made. It was staged as stage I, low-risk, and the patient agreed to hysterectomy plus bilateral salpingectomy. At subsequent follow-up the patient was found to be asymptomatic, with negative serial determinations of β-HCG and vaginal ultrasound scans without findings. CONCLUSION: Hysterectomy with bilateral salpingectomy may be the definitive treatment in selected cases of trophoblastic neoplasia. The available evidence is scarce and further research is needed in this field.