Citations

SummaryNon‐endemic Burkitt lymphoma (BL) is a rare germinal centre B‐cell‐derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic‐based and population‐based lymphoma registries from six countries were used to identify 264 real‐world patients. The median age was 47 years and the majority had advanced‐stage disease and elevated LDH. Treatment protocols were R‐CODOX‐M/IVAC (47%), R‐hyper‐CVAD (16%), DA‐EPOCH‐R (11%), R‐BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two‐year overall survival and event‐free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two‐year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post‐remission event‐free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real‐world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow‐up strategies with increased focus on survivorship and less focus on routine disease surveillance.

RXRA is an endothelial- and early stage–predominant therapeutic target for treating anthracycline-induced cardiotoxicity.

The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1 mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.

Background: The authors compared long-term health care use and cost in women undergoing immediate autologous breast reconstruction and implant-based breast reconstruction. Methods: This study was conducted using the OptumLabs Data Warehouse, which contains deidentified retrospective administrative claims data, including medical claims and eligibility information from a large U.S. health insurance plan. Women who underwent autologous or implant-based breast reconstruction between January of 2004 and December of 2014 were included. The authors compared 2-year use rates and predicted costs of care. Comparisons were tested using the t test. Results: Overall, 12,296 women with immediate breast reconstruction were identified; 4257 with autologous (35 percent) and 8039 with implant-based (65 percent) breast reconstruction. The proportion of autologous breast reconstruction decreased from 47.2 percent in 2004 to 32.7 percent in 2014. The mean predicted reconstruction cost of autologous reconstruction was higher than that of implant-based reconstruction in both unilateral and bilateral surgery. Similar results for mean predicted 2-year cost of care were seen in bilateral procedures. However, in unilateral procedures, the 2-year total costs were higher for implant-based than for autologous reconstruction. Two-year health care use rates were higher for implant-based reconstruction than for autologous reconstruction for both unilateral and bilateral procedures. Women undergoing unilateral implant-based reconstruction had higher rates of hospital admissions (30.3 versus 23.1 per 100; p < 0.01) and office visits (2445.1 versus 2283.6 per 100; p < 0.01) than those who underwent autologous reconstruction. Emergency room visit rates were similar between the two methods. Bilateral procedures yielded similar results. Conclusion: Although implant-based breast reconstruction is a less expensive index operation than autologous breast reconstruction, it was associated with higher health care use, resulting in similar total cost of care over 2 years.

AbstractDeletion of TGFβ inducible early gene‐1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl‐Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl‐Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl‐Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl‐Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl‐Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX‐1 serum levels were unaffected by Scl‐Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl‐Ab therapy elicits potent bone‐forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.

While genetic research (GR) is fueling discoveries in fields like precision medicine, there is a growing concern that underrepresentation of racial and ethnic populations in GR will limit access to its benefits and subsequently worsen health disparities. This study aimed to understand GR perceptions among members from underrepresented communities by studying discourse and language use in focus group discussions. Nine focus groups were conducted with adults from three populations: African American, Hispanic/Latino, and Native American; 53 women and 15 men participated. Data were analyzed using methods of discourse and content analysis. Discourse analysis highlighted how conceptualization of science and family—rooted in historical experiences—can influence views on GR risks and benefits to self and others. The use of focus group discourse in particular provided an opportunity for group sense making around the science and ethics of GR. Content analysis highlighted differences between the language use of focus group moderators, who spoke about scientific discovery and research oversight, and that of participants, whose talk highlighted ancestral bloodline, personal risk, and ethical concerns. The findings can inform efforts to bolster GR participation, including recruitment and educational campaigns. However, they also challenge researchers to consider areas of discordance between their own and community members’ conceptualization of the risks and benefits of GR participation, including the notion of future and family benefit.

OBJECTIVES Administrative records such as Medicare fee‐for‐service (FFS) claims provide accurate information on services paid for by Medicare. However, the increasing availability of electronic health records means many researchers may be inclined to rely on data coded in hospital information systems rather than claims. The current quality and accuracy of hospital reports on the use of post‐acute care (PAC) services are not known. DESIGN This study examined differences in the PAC use between hospital discharge status recorded on Medicare Provider and Analysis Review inpatient hospital records and claims for PAC services. SETTING In addition to assessments of the three types of Medicare‐reimbursed PAC (home health agency [HHA], skilled nursing facility [SNF], and inpatient rehabilitation facility [IRF]), the analysis also considered home without PAC services as a default discharge location. PARTICIPANTS The analysis was conducted using data for FFS beneficiaries who participated in the Medicare Current Beneficiary Survey and had one or more inpatient hospitalizations from 2006 to 2011. MEASUREMENTS This study measured discrepancies between hospital‐reported discharges to PAC and PAC use based on Medicare claims. RESULTS The study found that, on average, 27.9% of hospital reports of discharging to Medicare‐covered PAC services were not substantiated by Medicare PAC claims. Among all the discharge pathways, discharging to HHAs had the highest discrepancy rate (29.6%), followed by IRFs (14.7%) and SNFs (13.8%). CONCLUSION The study results call for cautions about the extent to which the reported discharge locations on hospital claims may differ from actual PAC services used. Assuming that Medicare FFS claims were complete and accurate, researchers using the discharge status reported on Medicare hospital claims should be aware of possible measurement errors when using hospital‐reported discharge locations. J Am Geriatr Soc 68:847–851, 2020

Objective Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD. Research design and methods In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin. Results Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r s =−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r s =0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased. Conclusions Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

Abstract Introduction: Classical Hodgkin lymphoma (cHL) is characterized by Reed Sternberg (RS) cells surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. Recent studies suggest that Hodgkin RS cells have developed mechanisms that exploit the programmed cell death-1 (PD-1) pathway to evade immune detection. In cHL, chromosome 9p24.1 gain is a frequent structural alteration that increases the gene dosage of the PD-1 ligands, PD-L1 and PD-L2, and their induction via JAK/STAT signaling. Epstein-Barr Virus (EBV) infection also increases the expression of the PD-1 ligands in EBV-positive cHL. Ligand binding to PD-1 receptor-positive activated T cells induces “T cell exhaustion,” a reversible inhibition of T cell activation and proliferation. Nivolumab (BMS-936558, Bristol-Myers Squibb) is a fully human IgG4 monoclonal PD-1 blocking antibody that potentiates anti-tumor T cell activity, and exhibits clinical efficacy in several solid tumors. We hypothesized that nivolumab may augment anti-tumor activity in patients with relapsed or refractory (R/R) cHL, including those who had failed brentuximab vedotin (BV), and evaluated the PD-1 blocking antibody. These are the first analyses being reported with PD-1 antibody for the treatment of cHL. Methods: Patients with R/R cHL were included as an independent cohort in a dose escalation and cohort expansion phase I study of nivolumab in lymphoma and multiple myeloma (MM). Results for patients with non-Hodgkin lymphoma and MM are reported separately. Patients with cHL received nivolumab 3 mg/kg every 2 weeks until confirmed tumor progression or excessive toxicity. Responses were evaluated using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. Results: Twenty-three patients were enrolled with R/R cHL. Patients were heavily pre-treated, 87% had received ≥ 3 prior treatment regimens, 78% had prior autologous stem cell transplant (ASCT), and 78% had prior BV treatment. Drug-related adverse events (AEs) of any grade occurred in 78% of patients, the most common of which were rash (22%), decreased platelet count (17%), diarrhea, nausea, pruritus, fatigue, and pyrexia (each at 13%). Drug-related grade 3/4 AEs occurred in 22% of patients. Three patients experienced 1 serious AE each (grade 3 myelodysplastic syndrome [MDS], grade 3 pancreatitis, and grade 2 lymph node pain). The objective response rate (ORR) was 87% (20/23), with 4 patients (17%) achieving a complete response (CR) and 16 (70%) obtaining a partial response (PR). The remaining 3 patients (13%) had stable disease (SD). All 23 patients had a reduction in tumor burden at 1 or more efficacy assessments during treatment with nivolumab (Figure). Among the 18 patients who had previously failed BV, the ORR was 89% (16/18), with 6% (1/18) achieving CR and 83% (15/18) PR. Progression-free survival (PFS) rate at 24 weeks was 86% (95% CI, 62-95%). The median overall survival (OS) has not been reached (range, 21+ to 75+ weeks). Six of 23 patients elected to discontinue study treatment to undergo stem cell transplantation, 2 patients discontinued due to toxicities (MDS and thrombocytopenia in 1 patient; pancreatitis in 1 patient), 4 patients discontinued due to disease progression, and 11 patients continue on study as of June 16, 2014. In a subset of study patients (10/23), PD-L1 and PD-L2 copy numbers in RS cells were assessed using fixed tumor biopsy specimens and a 3-probe fluorescence in situ assay (PD-L1,PD-L2, and control centromeric probe). In all tumors, RS cells had copy gains of PD-L1 and PD-L2, as a result of either polysomy or amplification; these tumors also exhibited increased protein expression of PD-L1. RS cells were also largely positive for pSTAT3, indicative of active JAK/STAT signaling. Conclusions In patients with R/R cHL, nivolumab-mediated PD-1 blockade is safe and tolerable with a safety profile similar to that in solid tumors. The frequent and long-lasting responses in heavily pretreated, R/R patients, including those who have failed BV, highlight the importance of the PD-1 pathway in cHL, and the genetically defined sensitivity to PD-1 blockade in this disease. Based on these results, the FDA granted nivolumab breakthrough status in relapsed cHL and a large, multinational, phase II trial of this therapy is underway. Figure 1 Figure 1. Disclosures Armand: Merck: Consultancy. Off Label Use: Nivolumab was tested for the treatment of hematologic malignancies.. Ansell:Bristol-Myers Squibb: Research Funding. Lesokhin:Bristol-Myers Squibb: Consultancy, Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding. Borrello:Bristol-Myers Squibb: Research Funding. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity's Board of Directors or advisory committees.