Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials.

Observational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline ß2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.

Delirium and delirium severity screening in the intensive care-correspondence of screenings tools.

BACKGROUND: Delirium severity scores are gaining acceptance for measuring delirium in the intensive care unit (ICU). OBJECTIVE: The aim of this study was to evaluate the concordance between the Confusion Assessment Method for the intensive care unit (CAM-ICU)-7 and the Intensive Care Delirium Screening Checklist (ICDSC) as delirium severity measurement tools. METHODS: This was a prospective, comparative, observational multicentre study. This study was conducted in 18 Danish ICUs. Delirium was assessed in adult critically ill patients admitted to an ICU with a Richmond Agitation and Sedation Score (RASS) of -2 or above. ICU nurses assessed delirium with randomised paired delirium screening instruments, using the CAM-ICU, the ICDSC, and the CAM-ICU-7. The correlation between the CAM-ICU-7 and the ICDSC severity scores was evaluated for all predefined patient subgroups. RESULTS: A total of 1126 paired screenings were conducted by 127 ICU nurses in 850 patients. The patients' median age was 70 years (interquartile range: 61-77), 40% (339/850) were female, and 54% (457/850) had at least one positive delirium score. Delirium severity ranges (CAM-ICU-7: 0-7; and ICDSC: 0-8) were positively correlated (Pearson's correlation coefficient, r = 0.83; p < 0.0001). The overall agreement between the CAM-ICU-7 and the ICDSC for delirium measurement (CAM-ICU-7: >2, and ICDSC: >3) was substantial (kappa = 0.74), but the agreement decreased to fair (kappa = 0.38) if a patient had a RASS less than 0. CONCLUSIONS: The agreement between the CAM-ICU-7 and the ICDSC for delirium severity measurement was substantial but might be affected by the patient's sedation and agitation level at the time of assessment. IMPLICATIONS FOR PRACTICE: Both CAM-ICU-7 and ICDSC can be implemented for delirium severity measurement. Attention is warranted in both scores if a patient has a RASS of -2.

Composition of mucus- and digesta-associated bacteria in growing pigs with and without diarrhea differed according to the presence of colonic inflammation.

BACKGROUND: In the pig production, diarrhea can occur during different growth stages including the period 4-16 weeks post weaning, during which a diarrheal outbreak also termed as colitis-complex diarrhea (CCD) can occur and it is distinct from post-weaning diarrhea (1-2 weeks post weaning). We hypothesized that CCD in growing pigs is associated with changes in colonic microbiota composition and fermentation patterns, and the aim of the present observational study was to identify changes in digesta-associated bacteria (DAB) and mucus-associated bacteria (MAB) in the colon of growing pigs with and without diarrhea. A total number of 30 pigs (8, 11, and 12 weeks of age) were selected; 20 showed clinical signs of diarrhea and 10 appeared healthy. Based on histopathological examination of colonic tissues, 21 pigs were selected for further studies and classified as follows: without diarrhea, no colon inflammation (NoDiar; n = 5), with diarrhea, without colonic inflammation (DiarNoInfl; n = 4), and with diarrhea, with colonic inflammation (DiarInfl; n = 12). Composition (based on 16S rRNA gene amplicon sequencing) and fermentation pattern (short-chain fatty acids; SCFA profile) of the DAB and MAB communities were characterized. RESULTS: The DAB showed higher alpha diversity compared to MAB in all pigs, and both DAB and MAB showed lowest alpha diversity in the DiarNoInfl group. Beta diversity was significantly different between DAB and MAB as well as between diarrheal groups in both DAB and MAB. Compared to NoDiar, DiarInfl showed increased abundance of various taxa, incl. certain pathogens, in both digesta and mucus, as well as decreased digesta butyrate concentration. However, DiarNoInfl showed reduced abundance of different genera (mainly Firmicutes) compared to NoDiar, but still lower butyrate concentration. CONCLUSION: Diversity and composition of MAB and DAB changed in diarrheal groups depending on presence/absence of colonic inflammation. We also suggest that DiarNoInfl group was at the earlier stage of diarrhea compared with DiarInfl, with a link to dysbiosis of colonic bacterial composition as well as reduced butyrate concentration, which plays a pivotal role in gut health. This could have led to diarrhea with inflammation due to a dysbiosis, associated with an increase in e.g., Escherichia-Shigella (Proteobacteria), Helicobacter (Campylobacterota), and Bifidobacterium (Actinobacteriota), which may tolerate or utilize oxygen and cause epithelial hypoxia and inflammation. The increased consumption of oxygen in epithelial mucosal layer by infiltrated neutrophils may also have added up to this hypoxia. Overall, the results confirmed that changes in DAB and MAB were associated with CCD and reduced butyrate concentration in digesta. Moreover, DAB might suffice for future community-based studies of CCD.

Intensive care unit nurses' perception of three different methods for delirium screening: A survey (DELIS-3).

BACKGROUND: Delirium is common in critically ill patients with detrimental effects in terms of increased morbidity, mortality, costs, and human suffering. Delirium detection and management depends on systematic screening for delirium, which can be challenging to implement in clinical practice. OBJECTIVES: The aim of this study was to explore how nurses in the intensive care unit perceived the use of Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), the Confusion Assessment Method for the Intensive Care Unit-7 (CAM-ICU-7), and Intensive Care Delirium Screening Checklist (ICDSC) for delirium screening of patients in the intensive care unit. METHODS: This was a cross-sectional, electronic-based survey of nurses' perceptions of delirium screening with the three different instruments for delirium screening. Nurses were asked to grade their perception of the usability of the three instruments and how well they were perceived to detect delirium and delirium symptom changes on a 1- to 6-point Likert scale. Open questions about perceived advantages and disadvantages of each instrument were analysed using the framework method. RESULTS: One hundred twenty-seven of 167 invited nurses completed the survey and rated the CAM-ICU-7 as faster and easier than the ICDSC, which was more nuanced and reflected changes in the patient's delirium better. Despite being rated as the fastest, easiest, and most used, the CAM-ICU provided less information and was considered inferior to the CAM-ICU-7 and ICDSC. Using familiar instruments made delirium screening easier, but being able to grade and nuance the delirium assessment was experienced as important for clinical practice. CONCLUSIONS: Both the ICDSC and the CAM-ICU-7 were perceived well suited for detection of delirium and reflected changes in delirium intensity. The CAM-ICU was rated as fast and easy but inferior in its ability to grade and nuance the assessment of delirium. Emphasis on clinical meaningfulness and continued education in delirium screening are necessary for adherence to delirium management guidelines.

End of induction positron emission tomography complete response (PET-CR) as a surrogate for progression-free survival in previously untreated follicular lymphoma.

Progression-free survival (PFS) has been the regulatory primary end-point for recent phase III trials in first-line follicular lymphoma (FL), but requires prolonged follow-up. Complete response (CR) at 30 months after initiation of induction treatment was validated as surrogate end-point for PFS. Our objective was to further evaluate surrogacy of CR measured by [18 F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial-level surrogacy examining the association between treatment effects on EoI-PET-CR and PFS was evaluated using linear regression ( RWLS2 ) and bivariate Copula ( RCopula2 ) models. Although EoI-PET-CR strongly predicted PFS at a prognostic level, the trial-level assessment did not show strong correlation ( RWLS2=0.56 , confidence interval [CI]: 0.20-0.88; RCopula2=0.35 , CI: 0.0-0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI-PET-CR end-point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET-CR based surrogate end-points is still warranted.

Baseline SUVmax did not predict histological transformation in follicular lymphoma in the phase 3 GALLIUM study.

A minority of patients with follicular lymphoma (FL) undergo histological transformation (HT). This retrospective analysis of 549 patients from the phase 3 GALLIUM study (NCT01332968) assessed the relationship between maximum standardized uptake value (SUVmax) at baseline on positron emission tomography (PET) and HT risk. Previously untreated patients with high tumor burden grade 1-3a FL received obinutuzumab- or rituximab-based chemotherapy induction. The relationship between baseline SUVmax (bSUVmax) and HT risk was assessed using cutoff values for SUVmax >10 and >20. Overall, 15 of 549 (2.7%) patients with baseline PET scans experienced biopsy-confirmed HT (median follow-up, 59 months). More than 65% of patients had bSUVmax > 10, with 3.3% of these experiencing HT. Only 1 of 74 (1.4%) patients with bSUVmax > 20 underwent HT. Median bSUVmax in patients with HT vs without HT was 12.4 (range, 8.1-28.0) vs 11.8 (range, 3.1-64.4), respectively; median bSUVrange (the difference between bSUVmax of the most and least 18F-fluorodeoxyglucose-avid lymphoma sites) was 8.0 (range, 1.1-23.9) vs 7.1 (range, 0.0-59.8), respectively. There was no temporal relationship between bSUVmax and HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting that there may be little benefit in rebiopsy of lesions to exclude HT based on SUVmax alone before initiating therapy in patients with high tumor burden FL.

Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study.

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.35- 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.

Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome sequence data has previously been used to identify six distinct molecular clusters in DLBCL with potential clinical relevance. In this study, we applied NMF-clustering to targeted sequencing data utilizing the FoundationOne Heme® panel from the Phase III GOYA (NCT01287741) and Phase Ib/II CAVALLI studies (NCT02055820) in de novo DLBCL. Biopsy samples, survival outcomes, RNA-Seq and targeted exome-sequencing data were available for 423 patients in GOYA (obinutuzumab [G]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] vs rituximab [R]-CHOP) and 86 patients in CAVALLI (venetoclax+[G/R]-CHOP). RESULTS: When the NMF algorithm was applied to samples from the GOYA study analyzed using a comprehensive genomic profiling platform, four of the six groups previously reported were observed: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations. Mutation profiles, cell-of-origin subset distributions and clinical associations of MYD88/CD79B and BCL2/EZH2 groups were similar to those described in previous NMF studies. In contrast, application of NMF to the CAVALLI study yielded only three; MYD88/CD79B-, BCL2/EZH2-like clusters, and a no mutations group, and there was a trend towards improved outcomes for BCL2/EZH2 over MYD88/CD79B. CONCLUSIONS: This analysis supports the utility of NMF used in conjunction with targeted sequencing platforms for identifying patients with different prognostic subsets. The observed trend for improved overall survival in the BCL2/EZH2 group is consistent with the mechanism of action of venetoclax, suggesting that targeting sequencing and NMF has potential for identifying patients who are more likely to gain benefit from venetoclax therapy.

Heart and bladder detection and segmentation on FDG PET/CT by deep learning.

PURPOSE: Positron emission tomography (PET)/ computed tomography (CT) has been extensively used to quantify metabolically active tumors in various oncology indications. However, FDG-PET/CT often encounters false positives in tumor detection due to 18fluorodeoxyglucose (FDG) accumulation from the heart and bladder that often exhibit similar FDG uptake as tumors. Thus, it is necessary to eliminate this source of physiological noise. Major challenges for this task include: (1) large inter-patient variability in the appearance for the heart and bladder. (2) The size and shape of bladder or heart may appear different on PET and CT. (3) Tumors can be very close or connected to the heart or bladder. APPROACH: A deep learning based approach is proposed to segment the heart and bladder on whole body PET/CT automatically. Two 3D U-Nets were developed separately to segment the heart and bladder, where each network receives the PET and CT as a multi-modal input. Data sets were obtained from retrospective clinical trials and include 575 PET/CT for heart segmentation and 538 for bladder segmentation. RESULTS: The models were evaluated on a test set from an independent trial and achieved a Dice Similarity Coefficient (DSC) of 0.96 for heart segmentation and 0.95 for bladder segmentation, Average Surface Distance (ASD) of 0.44 mm on heart and 0.90 mm on bladder. CONCLUSIONS: This methodology could be a valuable component to the FDG-PET/CT data processing chain by removing FDG physiological noise associated with heart and/or bladder accumulation prior to image analysis by manual, semi- or automated tumor analysis methods.

Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy.

Risk of hepatitis B virus (HBV) reactivation was assessed in B-cell non-Hodgkin lymphoma (NHL) patients with resolved HBV infection (hepatitis B surface antigen negative, hepatitis B core antibody positive) who received obinutuzumab- or rituximab-containing immunochemotherapy in the phase 3 GOYA and GALLIUM studies. HBV DNA monitoring was undertaken monthly to 1 year after the last dose of study drug. In case of HBV reactivation (confirmed, HBV DNA ≥29 IU/mL), immunochemotherapy was withheld and nucleos(t)ide analog treatment (preemptive NAT) started. Immunochemotherapy was restarted if HBV DNA became undetectable or reactivation was not confirmed, and discontinued if HBV DNA exceeded 100 IU/mL on NAT. Prophylactic NAT was allowed by investigator discretion. Among 326 patients with resolved HBV infection, 27 (8.2%) had HBV reactivation, occurring a median of 125 days (interquartile range, 85-331 days) after the first dose. In 232 patients without prophylactic NAT, 25 (10.8%) had HBV reactivation; all received preemptive NAT. Ninety-four patients received prophylactic NAT; 2 (2.1%) had HBV reactivation. No patients developed HBV-related hepatitis. On multivariate Cox analysis, detectable HBV DNA at baseline was strongly associated with an increased risk of reactivation (adjusted hazard ratio [HR], 18.22; 95% confidence interval [CI], 6.04-54.93; P < .0001). Prophylactic NAT was strongly associated with a reduced risk (adjusted HR, 0.09; 95% CI, 0.02-0.41; P = .0018). HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during anti-CD20-containing immunochemotherapy in B-cell NHL patients with resolved HBV infection. Antiviral prophylaxis was also effective and may be appropriate for high-risk patients. These trials were registered at www.clinicaltrials.gov as NCT01287741 (GOYA) and NCT01332968 (GALLIUM).

Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL.

Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS-International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: data from the phase III GOYA study.

Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.

Follicular Lymphoma Evaluation Index (FLEX): A new clinical prognostic model that is superior to existing risk scores for predicting progression-free survival and early treatment failure after frontline immunochemotherapy.

Patients with advanced-stage follicular lymphoma (FL) who progress early after receiving first-line therapy have poor overall survival (OS). Currently applied clinical prognostic models such as FL International Prognostic Index [FLIPI], FLIPI-2 and PRIMA-Prognostic Index [PRIMA-PI] have suboptimal sensitivity and specificity to predict this poor prognosis subgroup. The primary objective was to develop a novel prognostic model, the FL Evaluation Index (FLEX) score, to identify high-risk patients and compare its performance with FLIPI, FLIPI-2 and PRIMA-PI. Progression-free survival (PFS) after first-line immunochemotherapy was the key endpoint, while OS and progression of disease within 24 months (POD24) were also assessed. The model, which includes nine clinical variables, was developed using a cohort of patients with previously untreated advanced-stage FL from the phase 3 GALLIUM trial (NCT01332968). The performance of the model was validated using data from the SABRINA trial (NCT01200758). In GALLIUM (n = 1004; 127 with and 877 without POD24), FLEX increased the intergroup (low-risk/high-risk) difference in 2-year and 3-year PFS rates and demonstrated superior intergroup differences in 2-year and 3-year OS rates compared with FLIPI, FLIPI-2 and PRIMA-PI. Sensitivity for a high-risk score to predict POD24 was 60% using FLEX compared with 53% for FLIPI and FLIPI-2, and 69% for PRIMA-PI, while specificity was 68% for FLEX compared with 58% for FLIPI, 59% for FLIPI-2 and 48% for PRIMA-PI. The prognostic value of FLEX in SABRINA was similar to FLIPI. Therefore, FLEX appears to perform better than existing prognostic models in previously untreated FL, in particular for the newer treatment regimens.

Tumor Segmentation and Feature Extraction from Whole-Body FDG-PET/CT Using Cascaded 2D and 3D Convolutional Neural Networks.

18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) is commonly used in clinical practice and clinical drug development to identify and quantify metabolically active tumors. Manual or computer-assisted tumor segmentation in FDG-PET images is a common way to assess tumor burden, such approaches are both labor intensive and may suffer from high inter-reader variability. We propose an end-to-end method leveraging 2D and 3D convolutional neural networks to rapidly identify and segment tumors and to extract metabolic information in eyes to thighs (whole body) FDG-PET/CT scans. The developed architecture is computationally efficient and devised to accommodate the size of whole-body scans, the extreme imbalance between tumor burden and the volume of healthy tissue, and the heterogeneous nature of the input images. Our dataset consists of a total of 3664 eyes to thighs FDG-PET/CT scans, from multi-site clinical trials in patients with non-Hodgkin's lymphoma (NHL) and advanced non-small cell lung cancer (NSCLC). Tumors were segmented and reviewed by board-certified radiologists. We report a mean 3D Dice score of 88.6% on an NHL hold-out set of 1124 scans and a 93% sensitivity on 274 NSCLC hold-out scans. The method is a potential tool for radiologists to rapidly assess eyes to thighs FDG-avid tumor burden.

Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression.

We evaluated early disease progression and its impact on overall survival (OS) in previously untreated follicular lymphoma patients in GALLIUM (clinicaltrials.gov identifier: 01332968), and investigated the effect on early disease progression of the two randomization arms: obinutuzumab-based versus rituximab-based immunochemotherapy. Cause-specific Cox regression was used to estimate the effect of treatment on the risk of disease progression or death due to disease progression within 24 months of randomization and to analyze OS in patients with or without disease progression after 24 months. Mortality in both groups was analyzed 6, 12, and 18 months post randomization (median follow up, 41 months). Fewer early disease progression events occurred in obinutuzumab (57 out of 601) versus rituximab (98 out of 601) immunochemotherapy patients, with an average risk reduction of 46.0% (95%CI: 25.0-61.1%; cumulative incidence rate 10.1% vs 17.4%). At a median post-progression follow up of 22.6 months, risk of mortality increased markedly following a progression event [HR of time-varying progression status, 25.5 (95%CI: 16.2-40.3)]. Mortality risk was higher the earlier patients progressed within the first 24 months. Age-adjusted HR for OS after 24 months in surviving patients with disease progression versus those without was 12.2 (95%CI: 5.6-26.5). Post-progression survival was similar by treatment arm. In conclusion, obinutuzumab plus chemotherapy was associated with a marked reduction in the rate of early disease progression events relative to rituximab plus chemotherapy. Early disease progression in patients with follicular lymphoma was associated with poor prognosis, with mortality risk higher after earlier progression. Survival post progression did not seem to be influenced by treatment arm.

Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion.

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18-20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

Dietary protein source and butyrylated high-amylose maize starch included in a high-protein diet determines the urinary metabolome of rats.

Intake of red and processed meat increases the risk of colorectal cancer (CRC), whereas dairy product consumption and the intake of dietary fibre are negatively associated with this risk. We investigated the effect of (i) low-protein diets with either whey or cooked meat (beef) as the protein source and (ii) high-protein diets with cooked meat (beef) either without or with the inclusion of 10% butyrylated high-amylose maize starch (HAMSB), on the urinary metabolome of rats. Urine samples from rats were analysed using untargeted LC-MS metabolomics. The level and source of the dietary protein affected the urinary excretion of numerous metabolites indicating that several metabolic pathways were changed. The inclusion of HAMSB in a high-protein diet caused significant alterations in the excretion of several metabolites. HAMSB reduced urinary excretion of potentially harmful metabolites resulting from a high level of meat consumption.

High-Amylose Maize, Potato, and Butyrylated Starch Modulate Large Intestinal Fermentation, Microbial Composition, and Oncogenic miRNA Expression in Rats Fed A High-Protein Meat Diet.

High red meat intake is associated with the risk of colorectal cancer (CRC), whereas dietary fibers, such as resistant starch (RS) seemed to protect against CRC. The aim of this study was to determine whether high-amylose potato starch (HAPS), high-amylose maize starch (HAMS), and butyrylated high-amylose maize starch (HAMSB)-produced by an organocatalytic route-could oppose the negative effects of a high-protein meat diet (HPM), in terms of fermentation pattern, cecal microbial composition, and colonic biomarkers of CRC. Rats were fed a HPM diet or an HPM diet where 10% of the maize starch was substituted with either HAPS, HAMS, or HAMSB, for 4 weeks. Feces, cecum digesta, and colonic tissue were obtained for biochemical, microbial, gene expression (oncogenic microRNA), and immuno-histochemical (O6-methyl-2-deoxyguanosine (O6MeG) adduct) analysis. The HAMS and HAMSB diets shifted the fecal fermentation pattern from protein towards carbohydrate metabolism. The HAMSB diet also substantially increased fecal butyrate concentration and the pool, compared with the other diets. All three RS treatments altered the cecal microbial composition in a diet specific manner. HAPS and HAMSB showed CRC preventive effects, based on the reduced colonic oncogenic miR17-92 cluster miRNA expression, but there was no significant diet-induced differences in the colonic O6MeG adduct levels. Overall, HAMSB consumption showed the most potential for limiting the negative effects of a high-meat diet.

Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001). INTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. FUNDING: F Hoffmann-La Roche.