Citations

BACKGROUNDEarly treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high‐risk group of patients with an expected 5‐year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated.METHODSThis study compared autologous hematopoietic stem cell transplantation (auto‐HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo‐HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto‐HCT or allo‐HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression‐free survival, relapse, and nonrelapse mortality (NRM).RESULTSFour hundred forty FL patients had ETF (auto‐HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow‐up of 69 to 73 months, the adjusted probability of 5‐year OS was significantly higher after auto‐HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5‐year adjusted probability of NRM was significantly lower for auto‐HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5‐year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto‐HCT (58%; P < .0001).CONCLUSIONSPatients with high‐risk FL, as defined by ETF, undergoing auto‐HCT for FL have low NRM and a promising 5‐year OS rate (70%). MSD HCT has lower relapse rates than auto‐HCT but similar OS. Cancer 2018;124:2541‐51. © 2018 American Cancer Society.

Abstract Yoga is increasing in popularity in the United States and across the globe. However, most yoga programs are provided outside the worksite; although many companies offer worksite wellness programs, at present there is limited documentation regarding the potential benefits of participating in a worksite yoga program. Therefore, the purpose of this project was to examine the potential effect of a worksite yoga program on self-acceptance, quality of life, and perceived stress. A prospective cohort pilot study that examined a structured worksite yoga program was designed and tailored to individuals new to yoga. The 8-week Yoga Foundations program was conducted at an academic medical center's worksite wellness center with 86 subjects. Outcome measures were the 36-item Self-Acceptance Scale; a six-item quality-of-life measure that assesses overall, social, mental, physical, emotional, and spiritual well-being; and the ten-item Perceived Stress Scale. Participants demonstrated significant improvement in their overall self-acceptance (p &lt; 0.001), quality of life (p &lt; 0.001), and perceived stress (p &lt; 0.001) levels. They also highly rated the yoga instructors and the weekly format of the program. Participation in a Yoga Foundations program was associated with improvements in self-acceptance, quality of life and stress levels in worksite wellness center members. Future studies should use randomized designs and examine other wellness domains to learn more about the potential benefits of worksite yoga programs.

243 Background: AA and D have been shown in separate trials to increase overall survival in patients with mCSPC compared to Androgen Derivation Therapy (ADT). In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison of AA and D using network meta-analysis. Methods: We performed a search of MEDLINE, EMBASE, Cochrane Library, and Cochrane Central Register of Controlled Trials to identify relevant clinical trials. Collected data included hazard ratio and confidence interval (CI) for Overall Survival (OS) and number of adverse events in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparison of D and AA. Results: Five clinical trials were included in this analysis. Two trials (LATITUDE, STAMPEDE) compared AA to ADT and three trials (CHAARTED,STAMPEDE, GETUG-AFU 15 study) compared D to ADT. Results from both fixed effect and random effect network meta-analyses for the primary outcome (OS) revealed no statistical significance between AA and D (HR 0.81,95%CI 0.65-1.01; HR 0.81, 95%CI 0.40-1.82) respectively. Comparatively, abiraterone had statistically significant fewer events of anemia (OR 0.14,95%CI 0.08-0.23), neutropenia (OR 0.06,95%CI 0.03-0.12), peripheral edema (OR 0.21,95%CI 0.09-0.44), dyspnea (OR 0.22,95%CI 0.08-0.51), nausea (OR 0.09,95%CI 0.02-0.24), diarrhea (OR 0.06,95%CI 0.02-0.15), constipation (OR 0.25,95%CI 0.11-0.53), and fatigue (OR 0.12,95%CI 0.07-0.20). AA had statistically significant more events of hot flashes (OR 3.85, 95% CI2.33-6.25). For other adverse events, both drugs were statistically similar. Conclusions: There is no difference in OS using AA for longer periods in CSPC than a regimen of a limited number of cycles of D. There are significant differences in side effect profile of these drugs. Further analyses are needed to determine cost effectiveness of AA vs D under consideration of comparative efficacy and safety.

Elderly seasonal migrators share time between homes in different states, presenting challenges for care coordination and patient attribution methods. Medicare has prioritized alternative payment models, putting health care providers at risk for quality and value of services delivered to their attributed patients, regardless of the location of care. Little research is available to guide providers and payers on the service use of seasonal migrators. The authors use claims data on fee-for-service (FFS) Medicare beneficiaries' locations throughout the year to (1) identify seasonal migrators and (2) describe the care they receive in each seasonal home, focusing on primary care and emergency department (ED) visits and the relationships between the two. In all, 5.5% of the Medicare aged FFS population were identified as seasonal migrators, with 4.1% following the traditional snowbird pattern of migration, spending warm months in the north and cold months in the south. Migrators had higher rates of ED visits and primary care treatable (PCT) ED visits than the nonmigratory groups, controlling for location, age, race, sex, Medicaid status, season, and comorbidities. They also had more visits with specialist physicians, more days with outpatient services, and more days seeing a physician in any setting. Having local primary care strongly reduced rates of both PCT ED visits and total ED visits for all migration categories, with the greatest reduction seen in PCT ED visits by migrators (local primary care was associated with a 58% reduction in PCT ED visits by snowbirds and a 65% reduction in PCT ED visits by other migrators).

ABSTRACT Mutations in genes encoding ion channels have increasingly been identified to cause disease conditions collectively termed channelopathies. Recognizing the molecular basis of an ion channel disease has provided new opportunities for screening, early diagnosis, and therapy of such conditions. This synopsis provides an overview of progress in the identification of molecular defects in inwardly rectifying potassium (Kir) channels. Structurally and functionally distinct from other channel families, Kir channels are ubiquitously expressed and serve functions as diverse as regulation of resting membrane potential, maintenance of K + homeostasis, control of heart rate, and hormone secretion. In humans, persistent hyperinsulinemic hypoglycemia of infancy, a disorder affecting the function of pancreatic β cells, and Bartter's syndrome, characterized by hypokalemic alkalosis, hypercalciuria, increased serum aldosterone, and plasma renin activity, are the two major diseases linked so far to mutations in a Kir channel or associated protein. In addition, the weaver phenotype, a neurological disorder in mice, has also been associated with mutations in a Kir channel subtype. Further genetic linkage analysis and full understanding of the consequence that a defect in a Kir channel would have on disease pathogenesis are among the priorities in this emerging field of molecular medicine.—Abraham, M. R., Jahangir, A., Alekseev, A. E., Terzic, A. Channelopathies of inwardly rectifying potassium channels. FASEB J . 13, 1901–1910 (1999)

Abstract Interleukin-2 (IL-2) potently stimulates natural killer (NK) cell proliferation and cytotoxic function. However, the molecular mechanisms by which IL-2 delivers activation signals from the IL-2 receptor to the NK cell interior are incompletely understood. Previous studies demonstrated that IL-2 stimulation induced the tyrosine phosphorylation of multiple proteins in NK cells, together with a prominent reduction in the elec- trophoretic mobility of p56lac. The present studies indicate that IL-2 induces a rapid (≤1 min) increase in the catalytic activity of p56lck, as measured by increases in protein tyrosine kinase activity in vitro. Furthermore, in response to IL-2, p56lck itself undergoes complex alterations in serine and tyrosine phosphorylation. Cyanogen bromide cleavage maps indicate that IL-2 stimulates a pronounced increase in the phosphorvlation of the NH2-terminal region of p56lck containing multiple known sites of serine phosphorylation. In addition, IL-2 induced a marked increase in the phosphorylation of a COOH-terminal peptide containing the regulatory Tyr-505 residue of p56lck. These results suggest that p56lck serves as a substrate for both protein serine and tyrosine kinases activated during stimulation of this cell type with IL-2. Furthermore, these results indicate that the pleiotropic effects of IL-2 on NK cell physiology are initiated and regulated by a complex and multitiered interaction of different protein kinases including p56lck.

Abstract The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253

Significance The intestinal parasite Strongyloides stercoralis infects an estimated 100 million people. This nematode’s unique ability to autoinfect its host enables it to persist for decades undetected and to progress to a potentially fatal hyperinfection that often is induced by glucocorticoid treatment. We report a mouse model, involving the NSG strain, that recapitulates all forms of human strongyloidiasis. Even in severely immunocompromised NSG mice, glucocorticoid treatment was required for autoinfection, raising intriguing questions about the mechanism of glucocorticoid action. Notably, administering a nematode-derived steroid, Δ7-dafachronic acid, which acts through a receptor within S. stercoralis to regulate parasite development, significantly diminished autoinfection in glucocorticoid-treated NSG mice. This opens the possibility of new chemotherapy for hyperinfective strongyloidiasis, targeting the parasite’s own steroid hormone mechanisms.