Nonalcoholic fatty liver disease, characterized by elevated liver enzymes, central obesity, and insulin resistance, is becoming increasingly prevalent. The effects of changes in physical activity on the metabolic profile of this group have not been reported. We assessed at 3 months the impact of a behavior change-based lifestyle intervention on physical activity and the effects of this change on the metabolic profile of people with fatty liver disease. In all, 141 participants with nonalcoholic fatty liver disease were prospectively enrolled into either a low-or moderate-intensity lifestyle intervention or to a control group. Physical activity was assessed using a validated reporting tool and physical fitness was measured using the YMCA protocol on a cycle ergometer. Individualized counseling to increase physical activity was provided. Overall, 96% of participants attended the 3-month follow-up assessment. Participants in the moderate-and low-intensity intervention groups were 9 times more likely to increase physical activity by an hour or more per week compared to controls. Patients increasing or maintaining their reported physical activity to >150 minutes/week, and those who increased their objective levels of fitness, had the greatest improvements in liver enzymes and other metabolic indices compared to those who were least active. This effect was independent of weight loss and was corroborated by an objective measure of fitness. There was no dose-response effect on liver enzymes with incremental increases in physical activity above 60 minutes/week. Conclusion: Lifestyle counseling interventions are effective in improving physical activity behavior. Maintaining or increasing physical activity provides health benefits for patients with fatty liver, independent of changes in weight. (HEPATOLOGY 2009;50:68-76.)

Background and Aim: Non-alcoholic fatty liver disease associated with insulin resistance is the most common cause of abnormal liver tests in clinical practice. To date, practical and effective strategies to improve the metabolic profile of this large group of patients have not been well characterised. We sought to assess the effect at 3 months of a behavior changebased lifestyle intervention on the metabolic profile of patients characterised by elevated liver enzymes. Methods: A total of 152 patients with elevated liver enzymes, central obesity and a range of metabolic risk factors were randomised to either a moderate-(6 sessions/10 weeks) or low-intensity (3 sessions/4 weeks) lifestyle counselling intervention or control group. Results: There was improvement in all metabolic risk factors in the moderate-intensity group, versus a smaller number of changes in the low-intensity intervention group and no change in any metabolic risk factors in control subjects. Reduction in liver enzymes was greatest in the moderate-intensity intervention group and least in the control group. The likelihood of elevated alanine aminotransferase (ALT) levels in both the moderate and low-intensity groups was reduced by over 70% compared to controls. The proportion of subjects achieving weight loss (Ն 2%) was significantly higher in the moderate-intensity intervention group (66%) versus the low-intensity intervention group (39%; P < 0.05) and controls (29%; P < 0.001). Conclusions: Moderate and even low-intensity lifestyle counselling interventions targeting improvement in physical activity and nutritional behaviors and modest weight loss are a practical and effective method for improving the health of patients with elevated liver enzymes and a range of metabolic risk factors.

I n the treatment of diffuse large B-cell lymphoma, a persistently positive [ 18 F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan-BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17-20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3-4, 54% bulk, and 54% International Prognostic Index 3-5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PETpositive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progressionfree survival for PET-positive patients was 67%, a rate similar to that for

BackgroundRGM medium is an agar-based, selective culture medium designed for the isolation of nontuberculous mycobacteria (NTM) from the sputum of patients with cystic fibrosis (CF). We evaluated RGM medium for the detection of NTM in patients with CF (405 samples), bronchiectasis (323 samples) and other lung diseases necessitating lung transplantation (274 samples).MethodsIn total, 1002 respiratory samples from 676 patients were included in the study. Direct culture on RGM medium, with incubation at two temperatures (30 °C and 37 °C), was compared with conventional culture of decontaminated samples for acid-fast bacilli (AFB) using both a solid medium (Löwenstein-Jensen medium) and a liquid medium (the Mycobacterial Growth Indicator Tube; MGIT).ResultsFor all three patient groups, significantly more isolates of NTM were recovered using RGM medium incubated at 30 °C than by any other method (sensitivity: 94.6% vs. 22.4% for conventional AFB culture; P < 0.0001). Significantly more isolates of Mycobacterium abscessus complex were isolated on RGM at 30 °C than by AFB culture (sensitivity: 96.1% vs. 58.8%; P < 0.0001). The recovery of Mycobacterium avium complex was also greater using RGM medium at 30 °C compared to AFB culture (sensitivity: 83% vs. 70.2%), although this difference was not statistically significant and a combination of methods was necessary for optimal recovery (P = 0.21).ConclusionsIn the largest study of RGM medium to date, we reaffirm its utility for isolation of NTM from patients with CF. Furthermore; we show that it also provides an effective tool for culture of respiratory samples from patients with bronchiectasis and other lung diseases.

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Introduction R-mini-CHOP is an established standard of care in elderly patients with DLBCL, with a 2yr OS of 59% and PFS of 47% (Peyrade et al, Lancet Oncol 2011). The addition of ibrutinib to full dose R-CHOP in younger pts with DLBCL has efficacy, but significant toxicity limits the ability to complete therapy in pts ≥60 yrs (Younes et al, JCO 2019). We previously demonstrated the deliverability of ibrutinib with R-mini-CHOP in 80 pts ≥75yrs with DLBCL with a median average relative total dose of 97%; 77% of pts received 6 cycles of R-mini-CHOP despite SAEs in 62% (Verner et al, Haematol Oncol 2019). Here we present the primary efficacy endpoint and key secondary and exploratory endpoints. Methods This was a prospective, multicenter, single-arm, phase 2 study of patients aged ≥75yrs with newly diagnosed DLBCL. Pts received six 21-day cycles of ibrutinib 560mg/d and R-mini-CHOP (Rituximab 375mg/m 2, cyclophosphamide 400mg/m 2, doxorubicin 25mg/m 2, vincristine 1mg on day 1 & prednisone 40mg/m 2 or 100mg/d x 5) followed by an additional two 21-day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). The efficacy primary endpoint was 2yr OS. Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed reference OS (59%) and PFS (47%) rates (Peyrade et al, Lancet Oncol 2011). Results Eighty pts were recruited from Nov 2015 to Dec 2018. One died prior to receiving treatment and is not included in the analysis. Median age was 82yrs (75-95); 51% female, 81% stage III/IV and 63% IPI 3-5: 47% had a CIRS-G score of ≥6 (range 0-17). On centralized immunohistochemistry (IHC), 57% (45/79) were non-Germinal Centre B cell-like (GCB) subtype; 43% (34/79) were GCB. At a data cut-off of 6June 21, median follow-up was 29.5 months (m) (0.2 to 66.3). Two-year OS was 68% (95% CI 55-77%), not differing significantly from the null hypothesis of 59% (p=0.10), (Figure 1A). Median OS was not reached (NR) (95% CI 34m to NR), and was longer in those with lower IPI (IPI 1-3: NR, IPI 4: 35m, IPI 5: 19m). Two-year PFS was 60% (95% CI 47-70%), significantly different from the reference 47% (p&lt;0.03), (Figure 1B). Median PFS was NR (95% CI 20m to NR). Two-year DFS was 85% (95% CI 60-95%), median NR (95% CI 32m to NR). COO had no impact on either 2yr OS [median GCB NR (95% CI 29m to NR), median non-GCB NR (95% CI 24m to NR) p=0.99] or 2yr PFS [median GCB 39m (95% CI 17m to NR), median non-GCB NR (95% CI 19m to NR) p=0.97]. Cause of death in 28/79 pts (35%) was: 16 progressive lymphoma, 5 infection, 2 respiratory failure, 2 other malignancy, 1 cardiac arrest, 1 intra-abdominal hemorrhage, 1 gastric hemorrhage. At least one adverse event (AE) occurred in 99% pts (78/79): 30% (24/79) grade 1-2, 64% (49/79) grade 3-4, and 6% (5/79) grade 5. Most common grade ≥3 AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%: most commonly lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%). 12/14 pts with atrial fibrillation/flutter were new onset. Ibrutinib was temporarily ceased in 62% of patients, and permanently ceased in 25%, mostly due to adverse events. As previously reported, the overall response rate on an intention to treat basis was 57/80 (71%) (Verner et al, ASH 2019). Response rates did not differ by cell of origin (COO) (ORR: non-GCB 76%, GCB 68% p=0.44). When recorded, pt's EORTC-QLQ-C30 global health status significantly improved between screening [n=78; mean (SD) 58(25)], end of treatment [n=57; 63(23)] and 18mo post-treatment [n=29; 74(19)] p=0.007. Significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation and diarrhea were also observed in respondents. There was no impact of CIRS-G score on disease response rate or risk of death. Conclusion The addition of ibrutinib to R-mini-CHOP was deliverable and improved 2-yr PFS compared to R-mini-CHOP alone. However, while there was a trend towards improvement in 2-yr OS, a target 15% increase was not achieved in this small sample size. Despite considerable and not unexpected toxicity in this elderly cohort, the QOL and functional improvements in survivors are also promising. These data support further study of the addition of ibrutinib to R-mini-CHOP in elderly patients with DLBCL. Figure 1 Figure 1. Disclosures Verner: Janssen-Cilag Pty Ltd: Research Funding. Hawkes: Merck KgA: Research Funding; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee: Roche: Honoraria; BeiGene: Membership on an entity's Board of Directors or advisory committees. Cheah: BMS: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Enjeti: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Honoraria; Sanofi: Honoraria; Astra Zeneca: Honoraria. Curnow: Bayer: Consultancy, Research Funding; Pfizer/BMS: Consultancy, Honoraria; Mylan: Consultancy; Norgine: Consultancy, Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam. Trotman: JANSSEN: Research Funding; TAKEDA: Research Funding; BMS: Research Funding; PCYC: Research Funding; roche: Research Funding; beigene: Research Funding. OffLabel Disclosure: Ibrutinib is not approved for use in DLBCL

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Introduction The addition of Ibrutinib to R-CHOP in younger pts with DLBCL has efficacy, but significant toxicity limits the ability to complete therapy in pts ≥60 yrs (Younes et al, JCO 2019). We have previously demonstrated the deliverability of Ibrutinib with R-mini-CHOP in 80 pts ≥75yrs with DLBCL with a median Average Relative Total Dose of 97%; 77% of pts received 6 cycles of R-mini-CHOP despite SAEs in 62% (Verner et al, Haematol Oncol 2019). Here we present response rates, Cumulative Illness Rating Scale-Geriatrics (CIRS-G) score, left ventricular ejection fraction (LVEF) and quality of life (QoL) data. Methods Pts received six 21 day cycles of ibrutinib 560mg/d and R-mini-CHOP (Rituximab 375mg/m2, cyclophosphamide 400mg/m2, doxorubicin 25mg/m2, vincristine 1mg on day 1 &prednisone 100mg/d x 5) followed by an additional two 21 day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). Baseline comorbidities assessed by CIRS-G, end of treatment (EOT) response assessment per Lugano 2014 criteria and QoL (EORTC-QLQ-C30 and EQ-5D-5L visual analogue scores (VAS)) are presented for screening, throughout therapy and 1-month post treatment, with differences assessed using ANOVA. Missing values were not imputed. Results 80 pts were recruited from Nov 2015 to Dec 2018. Median age at registration was 81yrs (75-95); 51% female, 81% stage III/IV and 63% IPI 3-5. The majority of pts (88%; 70/80) had a CIRS-G score of ≥6 (range 4-21), a cut-off shown to be associated with a higher risk of early chemotherapy discontinuation in haematological malignancies (Poisson et al, EHA 2016). Median follow-up was 13.1 months (range 0.2 to 42.6). Treatment discontinuation occurred in 31% (25/80) pts. 23/80 (29%) have died; 14 due to progressive lymphoma, 5 due to infection, 1 intra-abdominal haemorrhage, 1 respiratory failure, 1 cardiac arrest, and 1 MPN/MDS. There was no association between baseline CIRS-G score, and completion of treatment, death or disease response. The overall response rate (ORR) on an intention to treat basis was 57/80 (71%). Eight cycles of treatment were completed by 55/80 (69%) pts, of whom 54 had an EOT PET. Of this population there was an ORR of 93% (50/54), with complete metabolic response (CMR) in 47/54 (87%); partial metabolic response in 4/54 (7%); and progressive metabolic disease in 3/54 (6%). A further 6 pts who discontinued treatment early achieved a CMR (between cycles 3-6) and 1 had stable metabolic disease. Progressive disease prior to cycle 8 occurred in 7/80 pts (9%). Eleven pts had no treatment response assessment, either due to death (n=5), withdrawal of consent (n=3), loss to follow up (n=2), or death prior to commencing chemotherapy. 2/80 (2%) pts had a recorded ≥10% decline in LVEF to <50%. There was no significant difference in LVEF from baseline [mean 65.0% (SD 7.1)] to 3 months post EOT [mean 62.2% (SD 9.9)] p=0.21, in the 44 pts with both assessments available for comparison. QoL outcomes are presented in Figures 1 and 2. QOL, as assessed by two globally accepted tools, improved with treatment in the population completing EOT assessment. Patients' EORTC-QLQ-C30 global health status and emotional functioning improved substantially while maintaining physical and cognitive functioning. There was a significant reduction in nausea, vomiting, pain, insomnia, constipation, and diarrhoea and an improvement in appetite with treatment. Similarly EQ-5D-5L VAS demonstrated that patients maintained mobility and independence with a significant reduction in pain/discomfort and improvement in mood. Conclusions Albeit with considerable toxicity and early mortality, Ibrutinib-R mini-CHOP is a deliverable and effective treatment for most pts ≥75yrs with DLBCL. While longer follow-up is required to assess our primary efficacy endpoint of 2yr overall survival, this promising response and reassuring QoL data highlights the merits of ongoing study to identify deliverable and effective treatments for DLBCL in the very elderly. Disclosures Verner: Janssen-Cilag Pty Ltd: Research Funding. Hawkes:Astra Zeneca: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharpe & Dohme: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Speakers Bureau; Mundi pharma: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau. Lee:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees. Cheah:F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Janssen: Honoraria; Acerta: Honoraria; Loxo: Honoraria. Purtill:MSD: Honoraria; Novartis: Honoraria, Other: Travel for speaking and advisory boards; Gilead: Honoraria, Other: Travel for speaking and advisory boards; Janssen: Honoraria. Enjeti:Astellas: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Bayer and Sanofi: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Curnow:NovoNordisk: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL: Honoraria; Mylan Pharmaceuticals: Consultancy; Freeline: Membership on an entity's Board of Directors or advisory committees; Boehringher Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pfizer/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Butcher:ALLG: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; BMS: Honoraria; Janssen-Cilag Pty Ltd: Honoraria; MSD: Honoraria; Novartis: Honoraria; Roche: Honoraria; Shire: Honoraria; Sandoz: Honoraria. Trotman:Pharmacyclics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; BeiGene: Research Funding; Roche: Research Funding. OffLabel Disclosure: Ibrutinib is not currently approved for use in DLBCL