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The objective of this study was to study the performance of two available home spirometers used by people with Cystic Fibrosis (PwCF) over a short-term period and to assess user experience.This was a prospective observational study. Participants age 6 years and older were recruited to participate if they could complete acceptable spirometry in the clinic setting.Participants used either the NuvoAir Air Next or the ZEPHYRx MIR Spirobank Smart spirometer. They underwent a one-time virtual training session, then completed 2 weeks of daily spirometry followed by 2 months of weekly spirometry. Participants responded to surveys and completed a debrief interview to understand user experience. Statistical analyses examined feasibility, reliability, and accuracy of each spirometer in an unsupervised, real-world setting.We report high adherence (80% [95% CI 61%-92%]) to our study protocol in all session attempts, but lower rates of adherence after discarding sessions performed with inadequate technique (47% [95% CI 28%-66%] to 63% [95% CI 44%-80%]). We found high reliability of each device by analyzing day-to-day variability and good concordance to recent in-clinic testing (NuvoAir r = 0.91 [0.82-0.93]; ZEPHYRx r = 0.70 [0.45-0.84]). Patient experience in this cohort was favorable with most reporting ease of use and reassurance knowing lung function was being tracked over time.This real-world study showed good performance of two different available home spirometers used by children and adults with CF. While overall adherence was high, suboptimal technique reduced the total interpretable data, possibly limiting feasibility. Future work should focus on developing sustainable training and coaching programs to support the success of home spirometry in a CF chronic care model.

The pharmacokinetics (PK) and safety of ofatumumab and bendamustine alone and in combination were evaluated in patients with treatment-naive or relapsed indolent B-cell non-Hodgkin lymphoma (iNHL). Patients were randomly assigned to ofatumumab and bendamustine or ofatumumab alone. Ofatumumab PK concentration profiles and parameters were similar, alone or in combination with bendamustine. A decrease of 14% in the maximum observed plasma concentration (C

This case demonstrates the importance of considering septic pulmonary embolism (SPE) on the differential for chest pain in the pediatric population, especially in patients with a history of skin and soft tissue infection. The adolescent patient in this report, with a history of axillary hidradenitis suppurativa complicated by methicillin-resistant Staphylococcus aureus (MRSA) superinfection and recent completion of a 3-month course of doxycycline, presented with isolated focal chest pain in the absence of other infectious or respiratory signs or symptoms. Initial pulmonary imaging revealed multiple bilateral wedge-shaped nodules. Three specialty teams were consulted in the patient's evaluation, resulting in biopsy of a suspicious lesion that confirmed the diagnosis of MRSA SPE. Following a course of targeted antibiotic therapy, the patient's chest pain resolved and imaging findings improved. Insights gleaned from the workup of this patient are useful in formulating a framework for recognition of SPE in children presenting with chest pain, and also highlight the importance of considering insidious SPE presentation in the setting of antibiotic pretreatment.

Because of high relapse rates with rituximab combinations, there is an unmet need for new therapeutic agents for treatment of indolent B-cell non-Hodgkin lymphoma (iNHL) or follicular lymphoma (FL). In previous trials, ofatumumab in combination with chemotherapy showed good results in relapsed/refractory FL pretreated with rituximab. This phase 3 trial evaluated the efficacy and safety of single-agent ofatumumab vs single-agent rituximab in rituximab-sensitive relapsed FL that relapsed at least 6 months after completing the last prior treatment with single-agent rituximab or a rituximab-containing regimen. Patients were randomized 1:1 to receive either ofatumumab (1000 mg) or rituximab (375 mg/m2) every week for 4 weeks for the induction phase, followed by once every 2 months for 4 additional doses. The primary endpoint, progression-free survival (PFS) and secondary endpoints, overall response rate (ORR) and overall survival (OS), were evaluated. Overall, 438 patients were assigned to receive ofatumumab (n = 219) and rituximab (n = 219). Baseline characteristics were similar in both arms. The independent review committee assessed whether median PFS was shorter in the ofatumumab arm than in the rituximab arm (16.33 vs 21.29 months), with no significant difference (hazard ratio, 1.15; 95% confidence interval, 0.89-1.49; P = .29) and also showed a lower ORR (50%) compared with the rituximab arm (66%). At the time of analysis, data were not matured for OS results. The number of grade >3 adverse events was higher in the ofatumumab arm (37%) than the rituximab arm (28%). Ofatumumab showed no superiority over rituximab in patients with FL who had relapsed after a rituximab-containing therapy. This study was registered at www.clinicaltrials.gov as #NCT01200589.

The standard of care for indolent non-Hodgkin lymphoma (iNHL) is rituximab, an anti-CD20 antibody, with/without chemotherapy. However, multiple relapses are common in these patients. This phase 3, randomized study compared outcomes of a combination of ofatumumab (a second-generation anti-CD20 antibody) and bendamustine, with bendamustine alone in patients unresponsive to prior rituximab-based treatment. Overall, 346 patients were randomized to receive either the combination or bendamustine alone. Bendamustine was given for ≤8 cycles and ofatumumab for ≤12 cycles. The primary end-point was progression-free survival (PFS) after 215 protocol-defined events assessed by independent review committee (IRC). Median IRC-assessed PFS was 16·7 and 13·8 months in the combination and monotherapy arms respectively [hazard ratio (HR) = 0·82; P = 0·1390]. Median overall survival (OS) was 58·2 and 51·8 months in the combination and monotherapy arms respectively (HR = 0·89, P = 0·4968). The safety profile was consistent with previous reports. Overall, 73% and 80% of patients in the combination and monotherapy arms, respectively, experienced a ≥grade 3 adverse event. The study did not meet its primary end-point. No significant improvement in PFS and OS was seen with the combination of ofatumumab and bendamustine as compared with bendamustine alone in rituximab-refractory iNHL (NCT01077518). ispartof: BRITISH JOURNAL OF HAEMATOLOGY vol:193 issue:6 pages:1123-1133 ispartof: location:England status: published

Significance Research on incarceration has focused on prisons, but the scale of admissions to local jails is significantly higher. The average length of stay in jail is brief compared to imprisonment, but jail incarceration has been found to adversely affect court outcomes, earnings, and family life. Although New York has one of the lowest jail incarceration rates among large cities, over a quarter of Black men and a sixth of Latino men in the city have been jailed by age 38 y. Risks of jail incarceration are 40 to 50% higher in poor neighborhoods., Research on incarceration has focused on prisons, but jail detention is far more common than imprisonment. Jails are local institutions that detain people before trial or incarcerate them for short sentences for low-level offenses. Research from the 1970s and 1980s viewed jails as “managing the rabble,” a small and deeply disadvantaged segment of urban populations that struggled with problems of addiction, mental illness, and homelessness. The 1990s and 2000s marked a period of mass criminalization in which new styles of policing and court processing produced large numbers of criminal cases for minor crimes, concentrated in low-income communities of color. In a period of widespread criminal justice contact for minor offenses, how common is jail incarceration for minority men, particularly in poor neighborhoods? We estimate cumulative risks of jail incarceration with an administrative data file that records all jail admissions and discharges in New York City from 2008 to 2017. Although New York has a low jail incarceration rate, we find that 26.8% of Black men and 16.2% of Latino men, in contrast to only 3% of White men, in New York have been jailed by age 38 y. We also find evidence of high rates of repeated incarceration among Black men and high incarceration risks in high-poverty neighborhoods. Despite the jail’s great reach in New York, we also find that the incarcerated population declined in the study period, producing a large reduction in the prevalence of jail incarceration for Black and Latino men.

OBJECTIVES The coronavirus pandemic created significant, abrupt challenges to the delivery of ambulatory health care. Because tertiary medical centers limited elective in-person services, telehealth was rapidly enacted in settings with minimal previous experience to allow continued access to care. With this quality improvement (QI) initiative, we aimed to achieve a virtual visit volume of at least 75% of our prepandemic volume. We also describe patient and provider experience with telehealth services. METHODS Our QI team identified the primary drivers contributing to low telehealth volume and developed a telehealth scheduling protocol and data tracking system using QI-based strategies. Patients and providers were surveyed on their telehealth experience. RESULTS At the onset of the pandemic, weekly visit volume dropped by 65% (99 weekly visits; historical average of 281). Over the subsequent 3 weeks, using rapid Plan-Do-Study-Act cycles, we achieved our goal volume. In surveys, it was indicated that most participants had never before used telehealth (71% of patients; 82% of providers) yet reported high satisfaction (90% of patients; 81% of providers). Both groups expressed concern over the lack of in-person assessments. Most respondents were interested in future use of telehealth. CONCLUSIONS With a QI-based approach, we successfully maintained access to care via telehealth services for pediatric pulmonary patients during the coronavirus pandemic and found high rates of satisfaction among patients and providers. Telehealth will likely continue to be a part of our health care delivery platform, expanding the reach of our services. Further work is needed to understand the effects on clinical outcomes.

Background: Despite unprecedented efficacy of existing CAR-T cell therapy, many pts fail to respond to the therapy, or relapse after initial response. YTB323 is an autologous CD19-directed CAR-T cell therapy utilizing the FMC63 domain for CD19 recognition and 4-1BB costimulatory domain. YTB323 is manufactured with an innovative simplified process, called T-Charge TM, which reduces the ex vivo culture time to about 24 hours and takes Methods: This Phase I, multicenter, dose-escalation study (NCT03960840) is evaluating safety and preliminary efficacy of YTB323 in pts with B-cell malignancies. Results presented here focus on the DLBCL cohort. Eligible pts are adults with measurable disease at enrollment, ECOG 0-1, and r/r DLBCL after ≥2 lines of prior therapies, including autologous hematopoietic stem cell transplantation (aHSCT). Pts received single-dose YTB323 at dose level 1 (DL1; 1-2.5×10 6 CAR+ cells), DL2 (5-12.5×10 6 CAR+ cells), or DL3 (25-40×10 6 CAR+ cells). Bridging therapy prior to YTB323 was optional. Primary endpoints are rate of dose-limiting toxicities (DLTs) in the first 28 d and safety to determine a recommended Phase II dose (RP2D). Secondary endpoints are cellular kinetics, overall response rate (ORR) by local investigator assessment, duration of response, and overall survival. Results: As of April 16, 2021, 15 pts with r/r DLBCL were infused with YTB323: 4 at DL1, 10 at DL2, and 1 at DL3 (Fig, n=14 for DL1 and DL2). Median age was 65 years; most (60%) received 2 prior lines of therapy and 4 (27%) had prior aHSCT. All adverse events were reported regardless of study drug relationship. Of the 15 pts evaluable for safety, 4 pts (27%) reported at least one Grade (Gr) 3 AE, 6 (40%) at least one Gr 4 AE, and 2 (13%) at least one Gr 5 AE. Most commonly reported Gr 3/4 AEs were thrombocytopenia (n=2, 13%), neutropenia (n=3, 20%), and decreased neutrophil count (n=3, 20%). Seven pts (47%) had neurological AEs, of which 2 events (13%) were considered serious-1 event each of Gr 3 peripheral neuropathy (unrelated) and Gr 2 seizure (immune effector cell-associated neurotoxicity syndrome Grade 3, related to treatment). Four pts (27%) experienced cytokine release syndrome (CRS), including 3 (20%) Gr 1/2 and 1 (7%) Gr 4 (Lee et al, 2014), which met DLT criteria. Tocilizumab and corticosteroids were administered for CRS management in 2 (13%) and 1 (7%) pts, respectively. There have been 4 deaths on trial, all unrelated to YTB323: 2 due to disease progression and 2 to sepsis (1 at DL1 and 1 at DL3). Median time to onset of CRS was 9 d (range, 9-9 d) for DL1 and 11 d (range, 8-17 d) for DL2. Preliminary dose-dependent response was observed. At DL1, 4 pts were evaluable for efficacy at Mo 3 and the ORR and CR rates were both 25% (95% CI, 0.6%-80.6%). At DL2, 8 pts were evaluable for efficacy at Mo 3, including 2 pts in CR prior to YTB323 infusion; ORR and CR rates were both 75% (95% CI, 34.9%-96.8%). Dose-dependent expansion (C max and AUC 0-28d) was observed following infusion with mean peak expansion (C max) at DL2 of 13.6% CAR+ in CD3+ cells or 32,100 copies/µg DNA. Although long-term persistence cannot be evaluated yet, of the 8 pts at DL2 with 3-mo follow-up, 3 had detectable CAR expression by flow cytometry (≥1%). Time of peak expansion (T max) coincided with peak cytokine levels (~16 d post infusion). The novel manufacturing methodology of YTB323 allowed preservation of CD4 and CD8 naive/T scm cells in the final product as ascertained by flow cytometry. Bulk and single-cell RNAseq analysis demonstrated that YTB323 retained a naive stem-like phenotype. Conclusions: YTB323 recruitment is ongoing at DL3; RP2D remains to be identified. At DL2, YTB323 showed promising efficacy and a favorable safety profile. Current data support continued development of YTB323 in r/r DLBCL pts. Clinical trial information: CYTB323A12101 Figure 1 Figure 1. Disclosures Flinn: ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Jaeger: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah: Epizyme: Consultancy; Legend: Consultancy; Incyte: Consultancy; Umoja: Consultancy; Lily: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Boissel: Novartis: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Bondanza: Novartis: Ended employment in the past 24 months, Patents & Royalties: Author of patent related to abstract; AstraZeneca: Current Employment. Lu: Novartis: Current Employment. Zhu: Novartis: Current equity holder in publicly-traded company; NIBR: Current Employment. Engels: Novartis: Current Employment, Current equity holder in publicly-traded company. Brogdon: Novartis Institutes for Biomedical Research: Current Employment. Mataraza: Novartis: Current Employment, Current holder of stock options in a privately-held company. Davis: Novartis: Current Employment, Current holder of stock options in a privately-held company. Marchal: Novartis: Current Employment. Mariconti: Novartis: Current Employment. Moschetta: Novartis: Current Employment. Parseval: Novartis: Current Employment. Barba: Gilead: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Dickinson: Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria.

We report the final analysis of the PROLONG study on ofatumumab maintenance in relapsed chronic lymphocytic leukemia (CLL). In all, 480 patients with CLL in complete or partial remission after second- or third-line treatment were randomized 1:1 to ofatumumab (300 mg first week, followed by 1000 mg every 8 weeks for up to 2 years) or observation. Median follow-up duration was 40.9 months. Median progression-free survival was 34.2 and 16.9 months for ofatumumab and observation arms, respectively, (hazard ratio, 0.55 [95% confidence interval, 0.43–0.70]; P P = 0.0044). Overall survival was similar in both arms; median was not reached (0.99 [0.72–1.37]). Grade ≥ 3 adverse events occurred in 62% and 51% of patients in ofatumumab and observation arms, respectively, the most common being neutropenia (23% and 10%), pneumonia (13% and 12%) and febrile neutropenia (6% and 4%). Up to 60 days after the last treatment, four deaths were reported in the ofatumumab arm versus six in the observation arm, none considered related to ofatumumab. Ofatumumab maintenance significantly prolonged progression-free survival in patients with relapsed CLL and was well tolerated.

e22504 Background: Pediatric/YA pts with r/r B-NHL are rare and have heterogenous, aggressive histology and poor prognosis. We report early results for tisagenlecleucel (anti-CD19 CAR-T cell therapy) in pediatric/YA pts with r/r B-NHL. Methods: BIANCA (NCT03610724) is a phase 2, single-arm, global, open-label trial of tisagenlecleucel in pediatric/YA pts with CD19+ r/r B-NHL. Pts must have confirmed mature B-NHL r/r to ≥1 prior lines of therapy and no active CNS involvement. Primary endpoint is ORR. Secondary outcomes include DOR, EFS, safety and pharmacokinetics. Results: As of Nov 4, 2019, 8 pts were enrolled, of whom 4 had large B-cell lymphoma (LBCL), 3 Burkitt lymphoma (BL), and 1 gray zone lymphoma (GZL) (Table). Five pts had ≥2 lines of prior therapy. Suitable apheresis product was harvested in all 8 pts. Five pts were infused and 3 were pending infusion at data cut off. Product was successfully manufactured within specifications for all infused pts. Median time from enrollment to infusion was 33 days (range 30-67). All 5 pts have ≥28 days follow up; 2 pts have ≥3 months follow up (median [range] 85 days [69-97]). All 8 pts received bridging chemotherapy (including 1 pt who also had surgery and 1 who also had radiotherapy). Tisagenlecleucel dose range was 0.3-1.1 × 108 CAR+ viable T cells (weight-based: 0.9-1.7 × 106 CAR+ viable T cells/kg). Cmax (range: Cmax= 8520-14,200 copies/µg; time to Cmax= 2-21 days; n = 4) was within range of expansion observed in pediatric/YA acute lymphoblastic leukemia and adult diffuse LBCL. All 5 pts had CRS; no grade ≥3 CRS was recorded. Three pts had neurologic events, including 2 grade 3/4 events. One pt died due to disease progression. Conclusions: Pediatric/YA pts with r/r B-NHL (including BL) were successfully infused with tisagenlecleucel in the BIANCA trial with a manageable safety profile. Apheresis/manufacturing were feasible in this cohort of rapidly progressing disorders. Tisagenlecleucel was shown to expand in vivo. BIANCA provides the first systematic data on CAR-T cell therapy in highly aggressive, pediatric/YA B-NHL. Planned enrollment is 35 pts (26 infused and evaluable). Clinical trial information: NCT03610724. [Table: see text]

We aimed to study the relationship between measures of adiposity, insulin sensitivity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the Diabetes Prevention Program (DPP).The DPP is a completed clinical trial. Using stored samples from this resource, we measured BMI, waist circumference (WC), an insulin sensitivity index (ISI; [1/HOMA-IR]) and NT-proBNP at baseline and at 2 years of follow-up in participants randomised to placebo (n = 692), intensive lifestyle intervention (n = 832) or metformin (n = 887).At baseline, log NT-proBNP did not differ between treatment arms and was correlated with baseline log ISI (p 0.0001) and WC (p = 0.0003) but not with BMI (p = 0.39). After 2 years of treatment, BMI decreased in the lifestyle and metformin groups (both p 0.0001); WC decreased in all three groups (p 0.05 for all); and log ISI increased in the lifestyle and metformin groups (both p 0.001). The change in log NT-proBNP did not differ in the lifestyle or metformin group vs the placebo group (p 0.05 for both). In regression models, the change in log NT-proBNP was positively associated with the change in log ISI (p 0.005) in all three study groups after adjusting for changes in BMI and WC, but was not associated with the change in BMI or WC after adjusting for changes in log ISI.Circulating NT-proBNP was associated with a measure of insulin sensitivity before and during preventive interventions for type 2 diabetes in the DPP. This relationship persisted after adjustment for measures of adiposity and was consistent regardless of whether a participant was treated with placebo, intensive lifestyle intervention or metformin.

Objective To define reference ranges for oxygen saturation (SpO2) values in healthy full-term infants in the first days of life and in preterm infants off supplemental oxygen as they approach neonatal intensive care unit (NICU) discharge. Methods From April 2009 to March 2010, we enrolled convenience samples of full-term infants from the newborn nursery and former preterm infants who did not require supplemental oxygen at the time of discharge from the NICU. Overnight SpO2 and signal quality recordings were obtained and analyzed for duration of artifact-free recording time (AFRT), time (s) with SpO2 less than several different target saturations (90–95%), and number of falls in SpO2 by ≥4% and ≥10%. Results We studied 102 full-term infants and 52 preterm infants. Preterm and full-term infants spent similar amounts of time less than 90%, 91%, 92%, 93%, 94%, and 95% although preterm infants had more falls in SpO2 by ≥4% per hour of AFRT. Over 67% of term and preterm infants spent less than 6% of their time below 93%. Conclusion These data represent reference SpO2 ranges for both preterm infants not requiring supplemental oxygen at NICU discharge and full-term infants in the first days of life. As we currently lack guidelines dictating the optimal target oxygen saturations for infants and the acceptable maximal time that they can safely spend below set target saturations, our data may serve as a guide to interpreting SpO2 recordings of premature outpatient infants who are weaning from supplemental oxygen. Pediatr Pulmonol. 2012; 47:453–459. © 2011 Wiley Periodicals, Inc.

Background: Despite a variety of treatment options, indolent non-Hodgkin's lymphoma (iNHL) remains a largely incurable disease with patients experiencing multiple relapses. Both rituximab (RTX) and bendamustine (Benda) are used as single agents for the treatment of relapsed/refractory iNHL. When given in combination to patients with relapsed iNHL, high response rates were observed (Rummel, 2016). Ofatumumab (OFA) is a human, anti-CD20 type-I antibody that binds a distinct epitope from RTX. A phase I/II study showed that OFA has activity in patients with follicular lymphoma (FL) who relapsed after RTX-containing therapy (Hagenbeek, 2008). Based on these experiences, COMPLEMENT A+B evaluated if OFA+Benda would improve progression-free survival (PFS) compared to Benda alone in unresponsive or progressive iNHL after RTX or RTX-containing regimen. Methods: This phase III, open-label, randomized, global, multi-center study enrolled adult patients (≥18 years) with CD20+ small lymphocytic, marginal zone, lymphophasmacytic and Grades 1-3A FL who had either stable disease after or disease progression during or within 6 months of RTX or RTX-containing regimen. Patients were randomized (1:1) to receive either OFA+Benda or Benda. Benda (90 mg/m2 in OFA+Benda arm and 120 mg/m2 in Bendaarm) was given on Days 1 and 2 every 21 days for up to 8 cycles. OFA (1000 mg) was given on Day 1 of Benda cycles and then every 28 days for a total of 12 doses. The primary endpoint was PFS as assessed by an independent review committee (IRC). Key secondary endpoints included PFS in patients with FL, overall response rates (ORR) and overall survival (OS) in all patients and in patients with FL which were tested hierarchically if the prior endpoint was statistically significant. Results: Overall, 346 patients were enrolled (173 in each arm) in 85 centers across 15 countries. Baseline characteristics were similar between the 2 arms. Median (range) age was 62 (21-87) years, majority were males (59%) and 69% had FL. Ann Arbor Stage IVA was common (OFA+Benda: 43%; Benda: 42%). Median duration of follow up was 61.1 months. Median treatment duration was longer in the OFA+Benda arm (OFA+Benda: 260 days; Benda: 135 days). Median (range) number of prior RTX therapy was 1 (1-8). In the OFA+Benda arm, 58% and 65% completed treatment with OFA and Benda, respectively, whereas in the Benda arm, 43% completed treatment. The main reason for premature discontinuation of OFA treatment in OFA+Benda arm was adverse events (AEs), 14%. The main reason for premature treatment discontinuation of Benda was AEs (OFA+Benda: 17%; Benda: 27%). Primary analysis was performed after 217 IRC-assessed PFS events occurred. In the OFA+Benda and Benda arms, 61% and 65% of patients, respectively, had PFS events (Figure 1). Median IRC-assessed PFS was 16.7 months in the OFA+Benda arm and 13.8 months in the Benda arm (hazard ratio [HR]=0.82, 95% confidence interval [CI] [0.62, 1.07]; p=0.1390). Similar results were seen in patients with FL where the median IRC-assessed PFS was similar in FL patients - 16.6 months in the OFA+Benda arm and 12.1 months in the Benda arm (HR=0.76, 95% CI [0.55,1.06]; p=0.1076) (Figure 2). IRC-assessed ORR was similar in both arms (OFA+Benda: 73%; Benda: 75%; difference in ORR [95% C]: -1.2% [-10.4%, 8.1]; p=0.8003). Median OS was 58.2 months and 51.8 months in the OFA+Benda and Benda arms, respectively (HR=0.89, 95% CI [0.63, 1.25]; p=0.4968). Frequencies of deaths (OFA+Benda: 38%; Benda: 41%) and on-treatment deaths (OFA+Benda: 7%; Benda: 9%) were similar in both arms. The main cause of death during the study was disease under study (OFA+Benda: 20%; Benda: 15%). Overall, 73% of patients in the OFA+Benda arm and 80% in the Benda arm experienced a ≥ Grade 3 AE. The most common ≥ Grade 3 AEs were neutropenia, thrombocytopenia, anemia, and leukopenia (Table 1). Conclusions: No significant improvement in PFS was seen with OFA+Benda as compared with Benda alone for patients with RTX-refractory iNHL. The safety profile for OFA was consistent with prior experience. The difference in outcomes compared to those in the GADOLIN trial (Sehn, 2016) could be due to the differences in drug exposure as patients in the GADOLIN study received maintenance anti-CD 20 therapy for up to 2 years; in the patient population as approximately 80% had FL in GADOLIN versus 69% in COMPLEMENT A+B; and in the mechanism of action of type-1 versus type-2 monoclonal antibody. Disclosures Rummel: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Eisai: Honoraria. Janssens:Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. MacDonald:Roche Canada: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Merck: Honoraria. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davis:Novartis: Employment. Lasher:Novartis: Employment. Lobe:Novartis: Employment. Izquierdo:Novartis: Employment, Equity Ownership. Friedberg:Bayer: Honoraria.

7517Background: An interim analysis of the PROLONG phase 3 study in patients (pts) with CLL showed a significant increase in progression free survival (PFS) with OFA maintenance without unexpected ...

The historic increase in U.S. incarceration rates made the transition from prison to community common for poor, prime-age men and women. Leaving prison presents the challenge of social integration--of connecting with family and finding housing and a means of subsistence. The authors study variation in social integration in the first months after prison release with data from the Boston Reentry Study, a unique panel survey of 122 newly released prisoners. The data indicate severe material hardship immediately after incarceration. Over half of sample respondents were unemployed, two-thirds received public assistance, and many relied on female relatives for financial support and housing. Older respondents and those with histories of addiction and mental illness were the least socially integrated, with weak family ties, unstable housing, and low levels of employment. Qualitative interviews show that anxiety and feelings of isolation accompanied extreme material insecurity. Material insecurity combined with the adjustment to social life outside prison creates a stress of transition that burdens social relationships in high-incarceration communities.

ClinicalTrials.gov NCT01762046; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; OBJECTIVE Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future. METHODS All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured. RESULTS Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels. CONCLUSIONS SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01762046. Yes

The essential oil of Chamaebatiaria millefolium from California is dominated by 24.90 ± 4.46% camphor, 17.36 ± 4.23% borneol, 11.17 ± 4.26% camphene, and 10.95 ± 4.59% α-pinene. The essential oil of Chamaebatia australis from California is dominated by no constituent greater than 10% but contains 7.07 ± 0.97% δ-cadinene, 6.84 ± 1.47% terpinen-4-ol, and 5.46 ± 1.50% linalool. The essential oil of Chamaebatia foliolosa from California is dominated by 12.90 ± 3.67% unidentified sesquiterpene alcohol and 15.96 ± 6.61% viridiflorol. No scientific literature exists to substantiate the medicinal claims for “Chamae Rose.” Neither Chamaebatiaria multiflorium nor Chamabatiaria nelleae exist in the scientific literature.

Elevated circulating levels of branched chain and aromatic amino acids (BCAA/AAAs) are associated with insulin resistance and incident type 2 diabetes (T2D). BCAA/AAAs decrease acutely during an oral glucose tolerance test (OGTT), a diagnostic test for T2D. It is unknown whether changes in BCAA/AAAs also signal an early response to commonly used medical therapies for T2D.A liquid chromatography-mass spectrometry approach was used to measure BCAA/AAAs in 30 insulin sensitive (IS) and 30 insulin resistant (IR) subjects before and after: (1) one dose of a sulfonylurea medication, glipizide, 5 mg orally; (2) two days of twice daily metformin 500 mg orally; and (3) a 75-g OGTT. Percent change in BCAA/AAAs was determined after each intervention.Following glipizide, which increased insulin and decreased glucose in both subject groups, BCAA/AAAs decreased in the IS subjects only (all P0.05). Following metformin, which decreased glucose and insulin in only the IR subjects, 4 BCAA/AAAs increased in the IR subjects at or below P=0.05, and none changed in the IS subjects. Following OGTT, which increased glucose and insulin in all subjects, BCAA/AAAs decreased in all subjects (P0.05).BCAA/AAAs changed acutely during glipizide and metformin administration, and the magnitude and direction of change differed by the insulin resistance status of the individual and the intervention. These results indicate that BCAA/AAAs may be useful biomarkers for monitoring the early response to therapeutic interventions for T2D.

To define reference ranges for oxygen saturation (SpO(2) ) values in healthy full-term infants in the first days of life and in preterm infants off supplemental oxygen as they approach neonatal intensive care unit (NICU) discharge.From April 2009 to March 2010, we enrolled convenience samples of full-term infants from the newborn nursery and former preterm infants who did not require supplemental oxygen at the time of discharge from the NICU. Overnight SpO(2) and signal quality recordings were obtained and analyzed for duration of artifact-free recording time (AFRT), time (s) with SpO(2) less than several different target saturations (90-95%), and number of falls in SpO(2) by ≥4% and ≥10%.We studied 102 full-term infants and 52 preterm infants. Preterm and full-term infants spent similar amounts of time less than 90%, 91%, 92%, 93%, 94%, and 95% although preterm infants had more falls in SpO(2) by ≥4% per hour of AFRT. Over 67% of term and preterm infants spent less than 6% of their time below 93%.These data represent reference SpO(2) ranges for both preterm infants not requiring supplemental oxygen at NICU discharge and full-term infants in the first days of life. As we currently lack guidelines dictating the optimal target oxygen saturations for infants and the acceptable maximal time that they can safely spend below set target saturations, our data may serve as a guide to interpreting SpO(2) recordings of premature outpatient infants who are weaning from supplemental oxygen.

Abstract 1100 Congenital radioulnar synostostis (RUS) is a rare anomaly characterized by fusion of the radius and ulna. RUS occurs more frequently in males than females, and is bilateral in 50% of cases. Since 1793, there have been > 400 cases reported. Literature review revealed 7 rare syndromes with RUS and hematologic problems including our newly named RUS-H Syndrome: 1) Diamond-Blackfan Anemia (DBA) associated with normochromic, macrocytic anemia in early infancy and erythroblastopenia; 2) Amegakaryocytic Thrombocytopenia Radioulnar Syndrome (ATRUS, HoxA11 mutation) with thrombocytopenia since birth requiring stem-cell transplantation; 3) IVIC Syndrome with mild thrombocytopenia and leukocytosis; 4) WT Syndrome involving a wide array of hematologic abnormalities including easy bruising, hypoplastic anemia, pancytopenia, Acute Lymphoblastic Leukemia (ALL), and Acute Myeloblastic Leukemia (AML); 5) Cohen Syndrome with neutropenia and fluctuating thrombocytopenia; 6) Noonan Syndrome with abnormal bleeding and easy bruising; and 7) RUS-H Syndrome (not involving HoxA11 mutations) associated with a spectrum of hematologic abnormalities including easy bruising, recurrent epistaxis, neutropenia, thrombocytopenia, ALL and aplastic anemia. This is a subsequent report to our ASH 2010 abstract. All 7 syndromes are associated with hand abnormalities. Six of the 7 syndromes (not Cohen) are associated with hearing loss/ear abnormalities. Four syndromes (DBA, ATRUS, WT, and RUS-H) have an increased risk of hematological malignancy. DBA, IVIC, Cohen, and Noonan have abnormalities of the eye and genitourinary system. DBA, WT, Cohen, and Noonan Syndromes are associated with dysmorphic facial features. ATRUS, IVIC, Cohen, and Noonan Syndromes all exhibit lower limb abnormalities. DBA, Cohen, Noonan, and RUS-H are associated with short stature. DBA, IVIC, Noonan, and RUS-H Syndromes are associated with kidney abnormalities and structural heart defects. Three Syndromes (DBA, IVIC, and Cohen) have cranial abnormalities. DBA IVIC, and Noonan Syndrome have structural defects of the shoulder. IVIC, Cohen, and Noonan Syndromes are associated with spinal anomalies. Two Syndromes (DBA and Noonan Syndrome) are associated with liver, spleen, and neck abnormalities. Cohen and Noonan Syndrome are associated with developmental delays. Lastly, WT and Noonan Syndrome are associated with skin abnormalities (Figure 1). This abstract highlights the association of RUS, other congenital abnormalities, and hematologic problems in previously described syndromes and in the novel RUS-H Syndrome. DBA, Cohen, and Noonan Syndrome are the most common of the 7 syndromes, with DBA estimated at 5 per 1,000,000; Cohen Syndrome predicted to have a prevalence of Since RUS may often be missed on routine physical examination, we recommend specific evaluation of pronation/supination in patients with hematological problems of unknown etiology. Additionally, we recommend that a targeted genetic panel be developed to detect mutations that are known for syndromes involving RUS, blood abnormalities, and other similar orthopedic entities that have cross-over manifestations like Thrombocytopenia-Absent Radii (TAR) Syndrome. This panel might consist of mutations associated with DBA (RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 mutations), with ATRUS (HoxA11 mutation), with IVIC Syndrome (SALL4 mutations), with Cohen Syndrome (8q22.2q22.3/COH1 deletion), with Noonan Syndrome (PTPN11, SOS1, RAF1, KRAS, NRAS, and BRAF mutations) and with TAR Syndrome (RBM8A null allele and noncoding SNP). The causative mutations of WT and RUS-H Syndromes have yet to be discovered. Genetic analysis of 6 of the 12 families with RUS-H Syndrome did not reveal a HoxA11 mutation. Broader sequencing techniques are underway for all 12 families in our RUS-H cohort, with hopeful detection of a new candidate gene as the unifying causative factor for the abnormalities in limb formation and hematopoiesis. Disclosures: Bussel: Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy.

Cell division cycle 7-related protein kinase (Cdc7) is a heterodimer of a kinase and its activator (Dbf4) and is essential for the activation of the minichromosome maintenance complex (MCM2–7), the helicase that unwinds the strands of DNA during replication. This kinase as well as its substrate have been shown to be overexpressed in many different tumors including the majority of both solid tumors and hematologic malignancies. For this reason, it represents a potential novel target for a cytotoxic chemotherapeutic agent. Previous work in our laboratory used a high throughput screen to identify compounds that inhibit Cdc7 kinase activity. MSK-747 and 3 of its naturally occurring derivatives, including MSK-777, were identified as lead compounds based on their potency, and MSK-777 was chosen as the lead compound for further preclinical and clinical development. While we are completing the FDA required studies needed to move MSK-777 to a Phase I clinical trial, we have begun work to determine an optimal Phase II regimen. Time course experiments have been performed to determine if synergy exists between known anti-leukemic chemotherapies such as etoposide, cytarabine, daunorubicin, or hydroxyurea and MSK-777. Cells were collected at time points for viable cell count, fluorescence-activated cell sorting (FACS) for DNA content, Western blotting, and caspase-3 activation assay. Multiple drug titration experiments were performed using daunorubicin, etoposide, cytarabine, and hydroxyurea in order to determine the optimal dosing of the drugs. Experiments using daunorubicin and cytarabine were performed where the standard chemotherapies were given prior to, concurrent with, and following MSK-777. Based on FACS and cell viability, it did not appear that either daunorubicin or cytarabine were synergistic with MSK-777. Etoposide caused the cells to arrest in S phase, and this arrest persisted for at least 48 hours. Based on the mechanism of action of MSK-777, etoposide was administered as a 12 hour pulse and then the cells were released into MSK-777. On FACS, at 24 hours the cells that had been treated with this combination continued to demonstrate the presence of a G1 population that was not seen with either agent alone, but by 48 hours this population no longer existed as the cells began to undergo apoptotic cell death. By 60 hours, cell death was evident by both FACS analysis and cell viability. Significant caspase-3 activation was seen at 36 hours in the cells that had received the combination therapy as compared with the controls. Given that hydroxyurea interferes with the G1/S phase progression, it was hypothesized to potentially be a more synergistic combination. Hydroxyurea was also administered as a 12 hour pulse prior to exposing the cells to MSK-777. On FACS, G1/S phase arrest is evident at 24 hours. This arrest persists with significant cell death at 60 hours being evident by cell viability, FACS analysis, and caspase-3 activation assay. This regimen demonstrated the highest degree of potential synergy. We will present data on the mechanism of this synergy and its use in primary patient samples of leukemia. Based on these results, the combination of hydroxyurea and MSK-777 is a promising regimen to be explored in further pre-clinical experiments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A75.