Environmental risk management: A participatory diagnosis from a rural school in Colombia.

The rural population is potentially exposed to several environmental risks. Environmental risk management is a recurring challenge in rural educational communities that are far from large urban areas. Assessing and identifying the knowledge on prevention and response to environmental risks and natural disasters is fundamental for planning and designing educational programs for communities to face disasters. This article presented the practical application of a participatory methodology to obtain information about the knowledge and experience in the prevention and attention of environmental threats and natural disasters in the rural school Las Huacas, village of Quintana, municipality of Popayán, in the region of Cauca, Colombia. The diagnosis methodology consisted of three phases: preparatory, fieldwork and analytical. The participatory diagnosis allowed the construction of instruments and tools for social interaction, the conduction of dynamic workshops and the systematisation of the collected information. The results evidenced the lack of knowledge on environmental disasters and how parents and children must face them. The absence of communication facilities implied a high degree of vulnerability, which was compensated with the awareness, commitment and participation in the processes led by the educational community. The next challenge is the participatory construction of a scholar environmental risk-management plan supported on appropriated information and communication technologies. Contribution: This article presents the practical application of a participatory methodology to obtain information about the rural context and the knowledge and experience in the prevention and attention of environmental threats and natural disasters in a rural school in Cauca, Colombia.

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial).

PURPOSE: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. RESULTS: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C. CONCLUSIONS: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. GOV IDENTIFIER: NCT02835924.

Super-resolution microscopy for the study of store-operated calcium entry.

The use of a variety of techniques based on super-resolution (SR) microscopy unveiled a close and complex relationship between cytoskeleton reorganization and SOCE. By using SR microscopy many new proteins involved in SOCE regulation have been identified over the last few years. Many enigmas remain unsolved in this highly dynamic field, however, recent developments in SR microscopy promise new answers soon. In the present review, we describe the most relevant findings in SOCE components and SOCE modulation using different methods derived from SR microscopy.

Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study. METHODS: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients. FINDINGS: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. INTERPRETATION: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. FUNDING: MSD.

Acceleration of the DNA methylation clock among lynch syndrome-associated mutation carriers.

BACKGROUND: DNA methylation (DNAm) age metrics have been widely accepted as an epigenetic biomarker for biological aging and disease. The purpose of this study is to assess whether or not individuals carrying Lynch Syndrome-associated mutations are affected in their rate of biological aging, as measured by the epigenetic clock. METHODS: Genome-wide bisulfite DNA sequencing data were generated using DNA from CD4 + T-cells obtained from peripheral blood using 27 patient samples from Lynch syndrome families. Horvath's DNAm age model based on penalized linear regression was applied to estimate DNAm age from patient samples with distinct clinical and genetic characteristics to investigate cancer mutation-related aging effects. RESULTS: Both Lynch mutation carriers and controls exhibited high variability in their estimated DNAm age, but regression analysis showed steeper slope for the Lynch mutation carriers. Remarkably, six Lynch Syndrome-associated mutation carriers showed a strong correlation to the control group, and two sisters carrying Lynch Syndrome-associated mutations, with no significant difference in lifestyle and similar chronological age, were assigned very different DNAm age. CONCLUSIONS: Future studies will be required to explore, in larger patient populations, whether specific epigenetic age acceleration is predictive of time-to-cancer development, treatment response, and survival. Epigenetic clock DNAm metrics may be affected by the presence of cancer mutations in the germline, and thus show promise of potential clinical utility for stratified surveillance strategies based on the relative risk for imminent emergence of tumor lesions in otherwise healthy Lynch Syndrome-associated mutation carriers.

Upfront primary tumour resection and survival in synchronous metastatic colorectal cancer according to primary tumour location and RAS status: Pooled analysis of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

INTRODUCTION: Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. PATIENTS AND METHODS: Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. RESULTS: Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. CONCLUSION: Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study.

First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.

Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

BACKGROUND: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. METHODS: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. RESULTS: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. CONCLUSIONS: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).

Phase II Trial of Palbociclib in Recurrent Retinoblastoma-Positive Anaplastic Oligodendroglioma: A Study from the Spanish Group for Research in Neuro-Oncology (GEINO).

BACKGROUND: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs). OBJECTIVE: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off. RESULTS: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6-3.1] and the median overall survival was 32.1 months (95% CI 5.1-59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact. CONCLUSION: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, identifier NCT0253032 (retrospectively registered on 21 August 2015).

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results.

BACKGROUND: Although occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Treatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan. RESULTS: Eleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%. CONCLUSIONS: The regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion.

Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.

Tumour location and efficacy of first-line EGFR inhibitors in KRAS/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials.

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis. Methods: Patients with KRAS/RAS-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Patients with KRAS-wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with KRAS-wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the RAS-wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours. Conclusion: We observed significantly improved efficacy outcomes in patients with KRAS/RAS-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours. Trial registration numbers: NCT01161316 and NCT00885885.

Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel.

PURPOSE: To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing. EXPERIMENTAL DESIGN: Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated. RESULTS: cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit. CONCLUSIONS: cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887.

Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples.

KRAS mutations are common in colorectal cancer (CRC). In this setting, mutation status determination in circulating-free DNA from blood samples (liquid biopsy) has been shown to be a viable alternative to tissue testing. The objective of this study was to compare the sensitivity of two liquid biopsy methods for detecting KRAS mutations in plasma samples from metastatic CRC patients. Samples with a positive (KRAS-MUT+) result and a mutant allelic fraction (MAF) < 5% according to the OncoBEAM RAS CRC assay were pairly analyzed by the Idylla ctKRAS Mutation Test (n = 116). In a cohort of 71 patients with at least 1 year of follow-up, the progression-free survival (PFS) was determined according to MAF values. Idylla detected KRAS mutations in 81/116 OncoBEAM KRAS-MUT+ samples with MAF < 5% and in 48/79 samples with MAF < 1%. Concordance between OncoBEAM and Idylla significantly improved at higher MAF values. PFS rates at 6 and 12 months tended to be lower in patients with MAF levels between 1% and 5% than in those with levels <1%. OncoBEAM demonstrated greater sensitivity for plasma detection of KRAS mutations than Idylla. Importantly, our data identified a "gray zone" below 1% MAF where Idylla showed reduced KRAS mutation detection, highlighting the importance of an accurate method to provide the mutational status of CRC patients.

Morphological MRI-based features provide pretreatment survival prediction in glioblastoma.

OBJECTIVES: We wished to determine whether tumor morphology descriptors obtained from pretreatment magnetic resonance images and clinical variables could predict survival for glioblastoma patients. METHODS: A cohort of 404 glioblastoma patients (311 discoveries and 93 validations) was used in the study. Pretreatment volumetric postcontrast T1-weighted magnetic resonance images were segmented to obtain the relevant morphological measures. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell's concordance indexes (c-indexes) were used for the statistical analysis. RESULTS: A linear prognostic model based on the outstanding variables (age, contrast-enhanced (CE) rim width, and surface regularity) identified a group of patients with significantly better survival (p < 0.001, HR = 2.57) with high accuracy (discovery c-index = 0.74; validation c-index = 0.77). A similar model applied to totally resected patients was also able to predict survival (p < 0.001, HR = 3.43) with high predictive value (discovery c-index = 0.81; validation c-index = 0.92). Biopsied patients with better survival were well identified (p < 0.001, HR = 7.25) by a model including age and CE volume (c-index = 0.87). CONCLUSIONS: Simple linear models based on small sets of meaningful MRI-based pretreatment morphological features and age predicted survival of glioblastoma patients to a high degree of accuracy. The partition of the population using the extent of resection improved the prognostic value of those measures. KEY POINTS: • A combination of two MRI-based morphological features (CE rim width and surface regularity) and patients' age outperformed previous prognosis scores for glioblastoma. • Prognosis models for homogeneous surgical procedure groups led to even more accurate survival prediction based on Kaplan-Meier analysis and concordance indexes.

Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: Results of the PANOVA phase 2 study.

BACKGROUND: Tumor Treating Fields (TTFields), low intensity alternating electric fields with antimitotic activity, have demonstrated survival benefit in patients with glioblastoma. This phase 2 PANOVA study was conducted to examine the combination of TTFields plus chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Forty patients with newly-diagnosed, locally advanced or metastatic PDAC received continuous TTFields (150 KHz for ≥18 h/day) plus gemcitabine (1000 mg/m2), or gemcitabine plus nab-paclitaxel (125 mg/m2). The primary endpoint was safety and secondary endpoints included compliance to TTFields, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventeen patients (85%) in each cohort reported Grade ≥3 adverse events (AEs). No increase in serious AEs (SAEs) was observed compared to that anticipated with systemic chemotherapy alone. Twenty-one patients reported TTFields-related skin toxicity, of which 7 were Grade 3; all resolved following temporary reduction of daily TTFields usage. No TTFields-related SAEs were reported. Compliance to TTFields was 68-78% of the recommended average daily use in both cohorts. Median PFS was 8.3 months (95% CI 4.3, 10.3) and median OS was 14.9 months (95% CI 6.2, NA) in the TTFields + gemcitabine cohort. In the TTFields + gemcitabine + nab-paclitaxel cohort, the median PFS was 12.7 months (95% CI 5.4, NA); median OS has not been reached. CONCLUSION: The PANOVA trial demonstrated that the combination of TTFields and systemic chemotherapy is safe and tolerable in patients with advanced PDAC. Based on the safety and preliminary efficacy results of this phase 2 study, a randomized phase 3 study (PANOVA-3) is underway.

Correction to: Morphological MRI-based features provide pretreatment survival prediction in glioblastoma.

The original version of this article, published on 15 October 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The name of Mariano Amo-Salas and the affiliation of Ismael Herruzo were presented incorrectly.

Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer.

BACKGROUND: Liquid biopsy offers a minimally invasive alternative to tissue-based evaluation of mutational status in cancer. The goal of the present study was to evaluate the aggregate performance of OncoBEAM RAS mutation analysis in plasma of colorectal cancer (CRC) patients at 10 hospital laboratories in Spain where this technology is routinely implemented. METHODS: Circulating cell-free DNA from plasma was examined for RAS mutations using the OncoBEAM platform at each hospital laboratory. Results were then compared to those obtained from DNA extracted from tumour tissue from the same patient. RESULTS: The overall percentage agreement between plasma-based and tissue-based RAS mutation testing of the 236 participants was 89% (210/236; kappa, 0.770 (95% CI: 0.689-0.852)). Re-analysis of tissue from all discordant cases by BEAMing revealed two false negative and five false positive tumour tissue RAS results, with a final concordance of 92%. Plasma false negative results were found more frequently in patients with exclusive lung metastatic disease. CONCLUSIONS: In this first prospective real-world RAS mutation performance comparison study, a high overall agreement was observed between results obtained from plasma and tissue samples. Overall, these findings indicate that the plasma-based BEAMing assay is a viable solution for rapid delivery of RAS mutation status to determine mCRC patient eligibility for anti-EGFR therapy.

Single-Agent Regorafenib in Metastatic Colorectal Cancer Patients with Any RAS or BRAF Mutation Previously Treated with FOLFOXIRI plus Bevacizumab (PREVIUM Trial).

LESSONS LEARNED: RAS- or BRAF-mutated metastatic colorectal cancers (mCRCs) progressing after first-line treatment have a poor prognosis.European and U.S. guidelines include the multikinase inhibitor regorafenib as a standard option for second-line therapy and beyond, based on the results of the randomized phase III CORRECT trial demonstrating improvement in survival.Although stopped prematurely for failing to accrue, the PREVIUM trial, the first prospective interventional study exploring regorafenib as second-line treatment for patients with mCRC bearing RAS or BRAF mutations, failed to demonstrate clinical activity in the population analyzed. BACKGROUND: Patients with RAS- or BRAF-mutated (mut) metastatic colorectal cancer (mCRC) progressing on first-line bevacizumab plus 5-FU/irinotecan/oxaliplatin (FOLFOXIRI) have a poor prognosis. We aimed to assess the efficacy and safety of regorafenib in this population. METHODS: Regorafenib was administered daily for 3 weeks of each 4-week cycle until disease progression or other reason. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: KRAS, NRAS, or BRAF was mutated in mCRC samples in 60%, 20%, and 13% of patients, respectively. Median time from initial diagnosis of metastases to the start of regorafenib and treatment duration was 13.8 months and 7 weeks, respectively. Reasons for discontinuation included disease progression (80%), investigator decision (13%), and adverse events (AEs; 7%). Seven patients (47%) required dose reduction, mostly for asthenia (43%). The most common regorafenib-related grade 3 AEs were asthenia (33%), dysphonia (13%), and hypertension (13%) (Table 1). There were no grade 4 toxicities. No patient was progression-free at 6 months. Median PFS, time to progression (TTP), and overall survival (OS) were 2.2, 2.0, and 3.3 months, respectively. CONCLUSION: Although stopped prematurely for failing to accrue, in the population analyzed, regorafenib failed to demonstrate clinical activity in KRAS- or BRAF-mutated mCRC with progression following first-line with FOLFOXIRI plus bevacizumab, although tolerability was acceptable. Our trial suggests that exploring regorafenib efficacy in an earlier line of therapy should not be undertaken without better population refinement.

Tumor Surface Regularity at MR Imaging Predicts Survival and Response to Surgery in Patients with Glioblastoma.

Purpose To evaluate the prognostic and predictive value of surface-derived imaging biomarkers obtained from contrast material-enhanced volumetric T1-weighted pretreatment magnetic resonance (MR) imaging sequences in patients with glioblastoma multiforme. Materials and Methods A discovery cohort from five local institutions (165 patients; mean age, 62 years ± 12 [standard deviation]; 43% women and 57% men) and an independent validation cohort (51 patients; mean age, 60 years ± 12; 39% women and 61% men) from The Cancer Imaging Archive with volumetric T1-weighted pretreatment contrast-enhanced MR imaging sequences were included in the study. Clinical variables such as age, treatment, and survival were collected. After tumor segmentation and image processing, tumor surface regularity, measuring how much the tumor surface deviates from a sphere of the same volume, was obtained. Kaplan-Meier, Cox proportional hazards, correlations, and concordance indexes were used to compare variables and patient subgroups. Results Surface regularity was a powerful predictor of survival in the discovery (P = .005, hazard ratio [HR] = 1.61) and validation groups (P = .05, HR = 1.84). Multivariate analysis selected age and surface regularity as significant variables in a combined prognostic model (P < .001, HR = 3.05). The model achieved concordance indexes of 0.76 and 0.74 for the discovery and validation cohorts, respectively. Tumor surface regularity was a predictor of survival for patients who underwent complete resection (P = .01, HR = 1.90). Tumors with irregular surfaces did not benefit from total over subtotal resections (P = .57, HR = 1.17), but those with regular surfaces did (P = .004, HR = 2.07). Conclusion The surface regularity obtained from high-resolution contrast-enhanced pretreatment volumetric T1-weighted MR images is a predictor of survival in patients with glioblastoma. It may help in classifying patients for surgery.