Citations

Leadership of a multispecialty group practice within a health system recognized in 2015 that population health management requires quality performance improvement and organizational culture change. While blueprints for building successful Accountable Care Organizations (ACOs) exist in the literature, few describe the journey to achieving both shared savings and high quality outcomes achieved by a medical group within an academic health system. Clinician education and engagement, prioritizing prevention and achieving benchmarks, developing supportive roles, more precise documentation of accurate diagnostic coding, and risk stratification constituted the approach. When first participating as an ACO, the medical group built programs and teams to improve quality, while CMS simultaneously changed quality measurements from pay-for-reporting to pay-for-performance. Quality scores initially dipped, though scores have since risen to 98.44% in 2020. Between 2015 and 2017, financial results were more than $10 million below the threshold, while in performance years 2018 to 2020, Northeast Medical Group achieved $24 million in aggregate in shared savings.

Causes and treatments for heart failure (HF) have been investigated for over a century culminating in data that have led to numerous pharmacological and surgical therapies. Unfortunately, to date, even with the most current treatments, HF remains a progressive disease with no therapies targeting the cardiomyocytes directly. Technological advances within the past two to three years have brought about new paradigms for treating many diseases that previously had been extremely difficult to resolve. One of these new paradigms has been a shift from pharmacological agents to antisense technology (e.g., microRNAs) to target the molecular underpinnings of pathological processes leading to disease onset. Although this paradigm shift may have been postulated over a decade ago, only within the past few years has it become feasible. Here, we show that miRNA106a targets genes that, when misregulated, have been shown to cause hypertrophy and eventual HF. The addition of miRNA106a suppresses misexpressed HF genes and reverses hypertrophy. Most importantly, using a cardiac targeting peptide reversibly linked to miRNA106a, we show delivery is specific to cardiomyocytes.

Consistent differences between males and females have been shown in land-based measurements of anaerobic power and capacity. However, these differences have not been investigated for a tethered 30-s maximal swimming test (TST). The purpose of this study is to explore gender differences in land and pool-based assessments of anaerobic power (Fpeak) and capacity (Fmean), as well as the influence of body composition. Thirteen males and fifteen females completed land (Wingate (WAnT)) and pool-based (TST) measures of anaerobic power and capacity previously described in the literature. Additionally, the subjects completed assessments of body composition via air displacement plethysmography. The males produced higher force than the females for Fpeak (p < 0.001) and Fmean (p = 0.008) during the TST. However, linear regression analysis determined that lean mass significantly predicted Fpeak (p = 0.002) and Fmean (p < 0.001) during the TST, while gender was no longer significant (p = 0.694 and p = 0.136, respectively). In conclusion, increases in anaerobic power and capacity (Fpeak and Fmean) may be a function of increased lean mass in males and females, warranting future research on the impact of resistance training programs on force production and swimming performance.

AbstractBackgroundWhole blood (WB) is carried by special operations forces as part of a remote damage control resuscitation strategy. The effects of an underwater mission on the quality and coagulation profile of WB were simulated by exposure to hyperbaric pressures in a chamber.MethodsWB units collected in CPDA‐1 were exposed to three different combinations of hyperbaric pressure and duration of exposure: Group A 153.52 kPa (15.24 msw; 1.52 atm) for 4 h; n = 9, Group B 506.63 kPa (50.29 msw; 5.00 atm) for 1 h; n = 9, Group C 153.52 kPa (15.24 msw; 1.52 atm) for 1 h; n = 7. The following parameters were measured on each unit: prothrombin time/international normalized ratio, activated partial thromboplastin time, thromboelastography and concentration determinations of platelets, lactate, fibrinogen, and lactate dehydrogenase. Each sample underwent baseline, prepressurization, immediate postpressurization, and 6 h postpressurization laboratory testing.ResultsSix hours following hyperbaric exposure, the lactate concentration in group C was higher than prepressurization measurement and the platelet concentration in Group A was lower than prepressurization measurement. There were no changes in any of the other analyzed biochemical, coagulation and thromboelastogram parameters following exposure to hyperbaric stress.DiscussionThese data suggest that pressurization of WB up to 5 atm did not impact parameters tested. Changes observed in lactate and platelet count need further study, as well as complementary testing of red blood cell integrity. Further investigation of the hyperbaric extremes is necessary to determine if there is a damage inducing pressure to which WB should not be exposed.

12094 Background: The Functional Assessment of Cancer Therapy patient-reported outcomes (PRO) item GP5 (“I am bothered by side effects of treatment”) estimates treatment tolerability. We aimed to extend our previous finding that GP5 predicts early aromatase inhibitor (AI) discontinuation (E1Z03, 96% White) in the racially diverse E1Z11 trial cohort. Methods: E1Z11 was coordinated by the ECOG-ACRIN NCI Community Oncology Research Program (NCORP) Research Base. Postmenopausal women initiating anastrozole per clinical care for ER+ stage I-III breast cancer with a pain score 0-3/10 and no rheumatologic comorbidities were eligible. Accrual of a racially diverse cohort of 1,000 women, including Black and Asian women, was planned. GP5 was administered prior to initiating anastrozole (trial baseline) and at 3, 6, 9 and 12 months. GP5 was scored on a 5-point Likert scale from 0 (not at all) to 4 (very much) and dichotomized as no/little treatment bother (0/1) or moderate/high treatment bother (2-4), consistent with previous analyses. A univariate Cox proportional hazards model estimated baseline GP5’s association with treatment duration via hazard ratio (HR). Early treatment discontinuation status was defined as treatment duration < 12 months with discontinuation not attributed to disease progression or death (n = 4), consistent with previous analyses. Results: 1,046 women enrolled from 6/2013-10/2018 (640 White, 201 Black, 205 Asian), including 590 (56%) from NCORP Community or Minority/Underserved Sites. Approximately 10% (100/987 with GP5 data) reported moderate/high treatment bother prior to initiating anastrozole. Anastrozole discontinuation rate at 1-year was 26.2% overall; it was lower among women with no/little treatment bother (25.7%, GP5 = 0-1) compared to moderate/high treatment bother prior to initiating anastrozole (34.7%, GP5 = 2-4; HR = 1.50, 95% confidence interval [CI]:1.04-2.15, p = 0.027). Subgroup analyses by racial cohort showed a similar predictive effect of GP5 in the White (n = 606, HR = 1.76, 95% CI: 1.12-2.77, p = 0.014) and Black (n = 184, HR = 1.85, 95% CI: 0.92-3.71, p = 0.079) cohorts, but not in the Asian cohort (n = 197, HR = 0.40, 95% CI: 0.10-1.62, p = 0.20). Conclusions: Moderate/high treatment bother prior to starting anastrozole was observed in 10% of patients and associated with a higher risk of early discontinuation, except in Asian patients. Our findings support the presence of a treatment tolerability threshold which can be compromised by pre-treatment burden. Treatment tolerability may also be influenced by cultural and genetic factors, which will be explored in further analysis of genetic and PRO data. Clinical trial information: NCT01824836.

7562 Background: Lymphoma is the 6th most common cancer and a top 10 cause of cancer deaths. To date, there are no blood test approaches to population screening, and accurate surveillance markers are limited. Methylated DNA markers (MDMs) are broadly informative for early detection of cancer but have not been extensively studied for lymphomas. We sought to discover and validate MDMs in DNA extracted from lymphoma tissue, then test these MDMs in archival blood plasma specimens. Methods: Reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from a discovery set of frozen tissues of classic Hodgkin lymphoma (CHL, n=24), non-Hodgkin lymphoma (NHL, n=78: T-cell-TCL (8); diffuse large B-cell-DLBCL (18); follicular-FL (12); mantle cell-MCL (20); marginal zone-MZL (15)), and lymphoma cell line samples (27); controls included benign lymph node (n=11) and healthy donor buffy coat (n=30). 30 MDMs were ranked by fold-change and AUC and used to design methylation-specific PCR assays for biological validation on independent DNA samples extracted from FFPE tissue from 13 normal lymph node and 63 lymphoma samples and 36 buffy coats from healthy patients. Target enrichment long-probe quantitative-amplified signal assays were developed for 16 MDMs and then assayed in plasma-extracted, bisulfite-converted DNA samples from 390 independent treatment-naïve lymphoma patients (100 CHL and 290 NHL:100 DLBCL, 73 FL, 41 MCL, 41 MZL, 35 TCL), and 210 controls without cancer. Lymphoma plasma samples and 159 controls were provided by the Lymphoma SPORE (CA97274); 51 controls came from a 7-county population archive. Classification of lymphoma cases vs controls was modeled with random forest method and cross-validated across 500 bootstrap samples of each dataset. Results: For MDMs tested in DNA from independent biological validation samples, cross-validated random forest models identified 60/63 cases (95% sensitivity) and 12/13 normal controls (92% specificity). In plasmas, a panel of 16 MDMs ( ZNF503, VWA5B1, HOXA9_5195, GABRG3, ITGA5, MAX_chr17_793, BNC1_2407, CDK20, MAX_chr4_184, TPBG, DNAH14, SYT2, CACNG8, FAM110B, and NRN1) detected 78% (95% CI, 74-82%) of lymphoma cases at 90% specificity. Excluding MZL and TCL, sensitivity increased to 84% (80-88%) including 26/49 (53% (38-67%)) of stage I and 59/71 (83% (71-90%)) of stage II cases. Conclusions: MDMs show promise to detect lymphoma. These markers could be evaluated as part of multicancer early detection testing and could also be evaluated as response markers to treatment and subsequent surveillance.[Table: see text]

e17610 Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin, by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA-OC) and 48 BOT ( BRCA-BOT); among non- BRCA, we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA-BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA-BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies.[Table: see text]

Introduction and hypothesis: Recent data have indicated an increase in the rate of early, confirmed pump thrombosis of the HeartMate II (HMII) left ventricular assist device. Factors related to this increase were not known, but one of the hypotheses was change in clinical management over time. The PREVENT ( PREVEN tion of Heartmate II Pump T hrombosis through Clinical Management) study was designed to evaluate the impact of clinical practices developed to reduce the risk of HMII pump thrombosis. Methods: PREVENT is a prospective, multi-center, single-arm, non-randomized study of up to 300 patients at up to 25 sites. Patient and pump management, including implant technique, anticoagulation, and pump settings are guided by protocol (Table 1). Primary endpoint is incidence of confirmed pump thrombosis at 3 months, with a total follow-up of 6 months. Presented here are the preliminary results from the first 100 subjects enrolled. Results: Median age was 61 years [25-79], 87% were male, and 79% were destination therapy. At implant, 9% were in INTERMACS Profile1, 68% Profiles 2-3, and 22% Profiles 4-7. Preliminary analysis of 90-day outcomes demonstrated an incidence of 1% for confirmed and 2% for suspected thrombosis with a 38% incidence of INTERMACS-defined bleeding. Adherence to the protocol recommendations was as follows: 91% of the pumps were anchored, 97% of the patients were bridged with heparin, median pump speed at 1 month was 9190 [range: 8400-10000], with 93% of the patients having a pump speed > 8600, and 78% of the patients having pump speeds > 9000. Median INR per patient was 2.2 [IQR: 2.0-2.4]. Overall Kaplan-Meier survival was 93%. Conclusions: Preliminary results are encouraging and suggest good adherence to the PREVENT protocol and low rates of pump thrombosis without a resultant increase in bleeding complications. Overall survival after HM II implantation remains excellent.

PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.