Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies.

BACKGROUND: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138). PATIENTS AND METHODS: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs. RESULTS: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines. CONCLUSIONS: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065023 and NCT03739138.

An adaptation of meaning-centered psychotherapy integrating "essential care": A pilot study.

INTRODUCTION: There is a growing interest in the emotional state of cancer patients. The main objective of this pilot study is to assess the feasibility, acceptability, and preliminary efficacy of Meaning-Centered Psychotherapy and Essential Care (MCP-EC) in patients with advanced cancer compared with usual psychological support. We define "Essential Care" as the promotion of patient care and self-care through the recall of good care experiences and discussion of the concepts: responsibility, self-compassion, kindness, and attitude. METHOD: Pilot, single-center, and prospective study of 30 patients with advanced cancer and emotional distress. Our adaptation consisted in three session Meaning-Centered Psychotherapy-Palliative Care, plus a fourth session named "Essential Care". The study was carried out in two phases. First, 20 patients were randomized to one of the two arms: individual MCP-EC (experimental, n = 10) or usual psychological supportive (control, n = 10). In a second phase, 10 patients were assigned consecutively to Group MCP-EC (n = 10). All patients were evaluated at baseline (pre-) and post-intervention with questionnaires for sociodemographic data and clinical scales. RESULTS: Nineteen patients completed the 4 sessions of MCP-EC, 9 individual format and 10 group format. Usual supportive intervention was delivered to 10 control patients. Total 28 patients completed pre- and post-treatment evaluations. There were no pre- vs. post-differences in the evaluations of the control group. In the experimental group, significant pre- vs. post-differences were found in EQ-5D-3L, HADS, FACIT, DM, HAI, SCS-SF, and TD questionnaires. These results indicated that MCP-EC reduced anxiety and depression symptoms, hopelessness, demoralization, as well as increased spiritual well-being and sense of meaning. Participants were satisfied and found the MCP-EC intervention positively. CONCLUSIONS: This pilot study suggests that the MCP-EC has feasibility, acceptability, and preliminary efficacy reducing the emotional distress in advanced cancer patients. Larger studies are warranted to clarify the strengths and limitations of this psychotherapy.

Vanadium and Cadmium in Water from the Perdido Area, Northwest of the Gulf of Mexico: 2 years' Monitoring and Current Status.

Surface water samples from the Perdido study area presented Cd and V concentrations similar to those reported internationally for waters with: (1) fossil fuel extraction, processing and burning, and (2) sites polluted by anthropogenic wastewater. Results showed an order of magnitude increase in time for Cd, therefore, no general average value was established. For V, however, results of this study suggest a general average value of 1.4 µg L-1 for the area. The observed spatial variation of concentrations could be the result of: (1) temporal variation of external inputs to the area, and coincide with previously reported hydrodynamic patterns of dispersion related to significant river contributions and accumulation areas indicative of eddy circulation or fronts. The Perdido area showed Cd and V concentrations in surface water reflective of anthropogenic impacts, while its spatial and temporal variation could depend significantly on the hydrodynamics of the area.

Spatial and Temporal Distribution of Trace Metals in Shallow Marine Sediments of the Yucatan Shelf, Gulf of Mexico.

We investigated the spatial and temporal distribution of V and Cd in surface sediments of the Yucatan Shelf to establish current average values for the area. V and Cd concentrations are similar to those reported internationally for limestone rocks and surface marine sediments. The observed variability of V concentrations between cruises may be the result of changes in ocean current direction in summer (SW-S) and strong prevailing winds in autumn (N-NE). In addition to the hydrodynamics described above, Cd variations may also be associated with inputs of particulate material by upwelling events and subsequent transport and distribution to the shelf by the Yucatan Channel current (autumn). Considering that both metals showed significant spatial and temporal differences, a range of values for V (0.4-1.5 µg g-1) and Cd (0.05-0.2 µg g-1) are proposed as baseline reference for sediments of the Yucatan Shelf.

Vanadium and Cadmium in Shallow Marine Sediments: Spatial and Temporal Behavior in the Tamaulipas Continental Platform, Gulf of Mexico, Mexico.

This study analyzed 27 surface sediment samples from the Tamaulipas Continental shelf to determine the spatial-temporal distribution of V and Cd (spring-summer 2016; summer 2017). Average V concentrations (99 ± 18 mg g-1) were similar to that previously reported values for the area, while average Cd concentrations reflect uncontaminated sediments at surface level of the shelf. Inputs of V and Cd may be related to hydrocarbon and anthropogenic contributions from South and North of the Gulf of Mexico. The variability shown by both elements results from the hydrodynamics and hydrology of the area produced by local currents, eddies of the Loop Current, resuspension of fine sediments and contribution of terrigenous material. Considering that both metals showed significant differences (Shapiro-Wilk, p = 0), baseline concentrations could not be established, instead a reference interval of 79-122 µg g-1 for V and 0.121-0.258 µg g-1 for Cd in sediments from the Tamaulipas platform is suggested.

Spatial and Temporal Variations of Vanadium and Cadmium in Surface Water from the Yucatan Shelf.

Surface water samples from the Yucatan shelf presented Cd concentrations similar to those reported internationally for non-polluted coastal and marine waters. V concentrations, on the other hand, fall within the range of anthropogenically polluted waters (25% of the sampling sites). In the study area, the probable sources of V could be: (1) carbonate sediments leaching V into the water column and co-transported with fine sediments resuspending as a result of the complex hydrodynamics in the area or, (2) accidental spills from cargo ships transporting oil between the Atlantic and the Gulf of Mexico. Significant spatial and temporal differences were found for both metals; therefore, a regional interval concentration is suggested for V from 1.28 to 1.84 µg L-1 and Cd from 0.003 to 0.09 µg L-1. These differences could primarily be the result of the observed hydrology and hydrodynamics created by the Yucatan current, submarine groundwater discharges and upwelling.

Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor. PATIENTS AND METHODS: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21-80) and the median number of prior regimens was four (range, 1-9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months. CONCLUSIONS: CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors.

Pupil inversion Mach-Zehnder interferometry for diffraction-limited optical astronomical imaging.

We present theoretical and laboratory experimental results on a robust interferometric device based on pupil inversion, or 180° rotational shearing interferometry. The image of an astronomical object degraded by the atmosphere turbulence can be restored (ideally up to the diffraction limit) by a numerical post-processing of the interferogram. Unlike previous Michelson configurations that return half of the light to the sky, the Mach-Zehnder interferometer has no fundamental losses when both outputs are used. The interferogram is formed by two overlapped images of the telescope pupil, but one of them is spatially inverted, and out of phase by π/2 only in its half. This optical operation is achieved in a robust way by inserting a refractive optical image inverter and a binary phase plate in one of the arms of the interferometer. In this way, the system has no polarization dependence or moving parts since the plate allows the object to be retrieved numerically from just one interferogram (single exposition) or a few independent interferograms. For that, several algorithms are proposed. Likewise, we include a laboratory proof-of-concept in which a diffraction-limited image is obtained in spite of presence of aberrations and photon noise.

Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.

BACKGROUND: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). PATIENTS AND METHODS: We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). RESULTS: In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). CONCLUSIONS: Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

The association between type 2 diabetes mellitus, hip fracture, and post-hip fracture mortality: a multi-state cohort analysis.

Type 2 diabetes mellitus (T2DM) is associated with an excess risk of fractures and overall mortality. This study compared hip fracture and post-hip fracture mortality in T2DM and non-diabetic subjects. The salient findings are that subjects in T2DM are at higher risk of dying after suffering a hip fracture. INTRODUCTION: Previous research suggests that individuals with T2DM are at an excess risk of both fractures and overall mortality, but their combined effect is unknown. Using multi-state cohort analyses, we estimate the association between T2DM and the transition to hip fracture, post-hip fracture mortality, and hip fracture-free all-cause death. METHODS: Population-based cohort from Catalonia, Spain, including all individuals aged 65 to 80 years with a recorded diagnosis of T2DM on 1 January 2006; and non-T2DM matched (up to 2:1) by year of birth, gender, and primary care practice. RESULTS: A total of 44,802 T2DM and 81,233 matched controls (53% women, mean age 72 years old) were followed for a median of 8 years: 23,818 died without fracturing and 3317 broke a hip, of whom 838 subsequently died. Adjusted HRs for hip fracture-free mortality were 1.32 (95% CI 1.28 to 1.37) for men and 1.72 (95% CI 1.65 to 1.79) for women. HRs for hip fracture were 1.24 (95% CI 1.08 to 1.43) and 1.48 (95% CI 1.36 to 1.60), whilst HRs for post-hip fracture mortality were 1.28 (95% CI 1.02 to 1.60) and 1.57 (95% CI 1.31 to 1.88) in men and women, respectively. CONCLUSION: T2DM individuals are at increased risk of hip fracture, post-hip fracture mortality, and hip fracture-free death. After adjustment, T2DM men were at a 28% higher risk of dying after suffering a hip fracture and women had 57% excess risk of post-hip fracture mortality.

Testing behavioral interventions to optimize participation in a population-based colorectal cancer screening program in Catalonia, Spain.

The aim of the study was to measure the effect of three cost-neutral behavioral interventions on participation compared to the standard invitation letter in a population-based colorectal cancer screening program in 2014. For that purpose, a four-arm randomized field trial was conducted among 5077 individuals aged 50 to 69 years. Over an 8-week period, each week was randomly allocated to the intervention or the control conditions. Individuals assigned to the intervention conditions additionally received a prompt to write down the date to pick up the screening test in a pharmacy. Two of the three intervention groups also included an additional paragraph in the invitation letter on either: 1) the high proportion of individuals participating regularly (social norms condition) or 2) the importance of regular participation (benefit condition). We measured screening participation before and after receiving a reminder letter six weeks after the screening invitation. An overall 8.0 percentage point increase in CRC screening was achieved as a direct result of receiving a reminder letter; however none of the intervention strategies influenced participation. The only significant difference was found for newly invited individuals. There, participation rates decreased from 34.9% to 24.2% when the invitation mailing mentioned the importance of regular participation (OR: 0.60; 95% CI: 0.38-0.95). While none of the intervention strategies improved participation rates we found that praising the benefit of regular screening may discourage individuals who have never been invited before as the continuous behavior may be perceived as a large request. Nevertheless, the reminder letter boosted participation rates independently of the intervention assigned.

Software Suite Training Tool for MSK Exploration and Botulinum Toxin Infiltration Based on Ultrasound Imaging for the Spasticity Treatment.

Nowadays, one of the choice techniques for the spasticity treatment is the ultrasound-guided infiltration of Botulinum Toxin, because it is safe and effective. In order to medical professionals can carry out this technique, they need training and education. One of the safest and most time-free ways to facilitate the acquisition of practical medical skills is through simulators. In this paper we present an innovative technological environment, which includes an ultrasound simulator for training in muscle exploration and infiltration. The simulation platform will guide health professionals, with great realism and high degree of interactivity, in the autonomous training of all the tasks involved in the spasticity treatment procedure by infiltration of Botulinum Toxin, without the need for a real patient or costly phantoms.

Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study.

BACKGROUND: Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval ≥90 days) and 15 with resistant disease (platinum-free interval <90 days). RESULTS: Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n = 2, 8%) and partial response (n = 13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease [median progression-free survival (PFS)=5.8 months] and 33.3% in resistant disease (median PFS = 3.5 months). At third line, response rate was 20.0% (median PFS = 1.2 months), all in resistant disease. CONCLUSION: Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial.

Perceived efficacy and satisfaction of patients with subcutaneous hypoallergenic high-dose house dust mite extract.

SUMMARY: The efficacy and safety of subcutaneous immunotherapy with modified, high-dose, major allergen house dust mite extract is widely supported by double-blind, placebo-controlled studies. However, little is known regarding patient-perceived efficacy and satisfaction. An observational, retrospective, multicentre study in patients treated with Acaroid® was conducted to assess the efficacy and degree of satisfaction of the patients after the first six months of treatment with it. All the clinical study procedures were performed according to the routine clinical practice. This study demonstrates that Acaroid® is effective and well tolerated. The patients' condition demonstrated a clear and marked improvement in the first 6 months after treatment initiation. Patients treated with Acaroid® were very satisfied, with a correlation to improvement in patient-perceived symptoms and the administration of treatment by a healthcare professional.

Satisfaction and perceived effectiveness in patients on subcutaneous immunotherapy with a high-dose hypoallergenic pollen extract.

This study was designed to determine the level of satisfaction, tolerance and perceived effectiveness by patients in the first pollen season after starting treatment with Alergovit(®). For this purpose, a nationwide, retrospective, multicentre and cross-sectional observational study was carried on 256 patients. Perceived effectiveness by the patients was measured using a visual analogue scale and was clinically significant in 92.4% of the patients. The satisfaction level was evaluated with a specific questionnaire. 32.5% of the patients were totally satisfied with Allergovit(®) and 48.8% reported a high degree of satisfaction. The treatment was well tolerated by 99.2% of the patients. Our results demonstrate that subcutaneous immunotherapy with Allergovit(®) is effective and well-tolerated in routine clinical practice.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.