Citations

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs ( TBX15 , BMP3 ) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86–0.99), 0.71 (0.57–0.85), and 0.72 (0.60–0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77–0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Background: Low back injuries are common in collegiate football players and can frequently lead to persistent pain, reinjuries, and time lost from participation. Purpose: To describe the epidemiology of back injuries in National Collegiate Athletic Association (NCAA) football players during the 2009/2010 through 2013/2014 academic years utilizing the NCAA Injury Surveillance Program (ISP) database. Study Design: Descriptive epidemiology study. Methods: A convenience sample of NCAA varsity football teams was utilized to determine the rates and patterns of back injuries as well as to generate national injury estimates. The rates and distribution of back injuries were identified within the context of mechanism of injury, injury chronicity, and time lost from sport. Injury rates were calculated as the number of injuries divided by the total number of athlete-exposures (AEs). Incidence rate ratios were calculated to compare the rates of injury between season, event type, mechanism of injury, injury chronicity, and time lost from sport. Results: Nationally, there were 267 low back injuries reported in the database. These were used to estimate 7076 back injuries over the 5-year period, approximately 82% of which were new injuries. The injuries occurred at a rate of 2.70 per 10,000 AEs. Overall, injuries were 3.12 times more likely to occur in competitions than in practices. Athletes were 4.67 times more likely to sustain a back injury during the preseason compared with the postseason but were 1.41 times more likely to sustain a low back injury during the preseason compared with the regular season. Both contact and noncontact were reported equally as the mechanism of injury (37.8% and 38.3%, respectively), and unspecified low back pain was the most common injury (64.2%). Only 1.6% of patients required surgery for their injury, and the majority of athletes (59.6%) returned to play within 24 hours. Conclusion: There was a relatively high rate of lumbar back injuries at the collegiate level (2.70/10,000 AEs), the majority of which were new injuries. About 18% of reported injuries were reinjuries. Although very few required surgery, a careful examination and work-up should be conducted to evaluate each injury. Regimented physical therapy and reconditioning programs are recommended to avert reinjuries.

Background:Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post‐translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors.Aims:Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T‐cell lymphoma (AITL) and CXCL12+ peripheral T‐cell lymphoma (PTCL) patients (pts).Methods:This Phase 2 study (NCT02464228) is a multi‐institutional, single‐arm, open‐label trial initially designed as a two‐stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/ = 18 years and a performance status of 0–2. Based on initial findings, the study was amended to include a cohort of AITL (n = 12) and PTCL (n = 12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1–21 of 28‐day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in pts who received tipifarnib and standard of care treatment.Results:As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL‐NOS, 1 ALK‐ ALCL, 1 gamma‐delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least one treatment‐emergent adverse event (TEAE); 39 (90%) had at least 1 study drug‐related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug‐related TEAEs of Grade ≥3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n = 3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre‐treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was also retrospectively investigated in 73 pts who received standard of care therapy (AITL N = 50, PTCL NOS = 23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR = 1.8, p = 0.09) was observed using the high CXCL12 subset using the cut‐off point that predicted clinical benefit under tipifarnib therapy. Fifty percent of AITL and 35% of non‐AITL samples overexpressed CXCL12.Summary/Conclusion:Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues.

Abstract HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

AbstractPurposeHistorical trends and factors likely to influence future pharmaceutical expenditures are discussed, and projections are made for drug spending in 2019 in nonfederal hospitals, clinics, and overall (all sectors).MethodsDrug expenditure data through calendar year 2018 were obtained from the IQVIA National Sales Perspectives database and analyzed. New drug approvals, patent expirations, and other factors that may influence drug spending in hospitals and clinics in 2019 were also reviewed. Expenditure projections for 2019 for nonfederal hospitals, clinics, and overall (all sectors) were made through a combination of quantitative analyses and expert opinion.ResultsU.S. prescription sales in calendar year 2018 totaled $476.2 billion, a 5.5% increase from 2017 spending. The top 3 drugs by expenditures were adalimumab ($19.1 billion), insulin glargine ($9.3 billion), and etanercept ($8.0 billion). Prescription expenditures in nonfederal hospitals totaled $35.8 billion, a 4.8% increase from 2017. Expenditures in clinics in 2018 increased by 13.0% to $80.5 billion. The increase in spending in nonfederal hospitals was largely driven by new products and increased utilization of existing products. The list of the top 25 drugs by expenditures in nonfederal hospitals and clinics was dominated by specialty drugs.ConclusionWe predict continued moderate growth of 4–6% in overall drug expenditures (across the entire U.S. market). We expect the clinic sector to continue to experience high (11–13%) growth in drug spending in 2019. Finally, for nonfederal hospitals we anticipate growth in the range of 3–5%. These estimates are at the national level. Health-system pharmacy leaders should carefully examine local drug utilization patterns to determine their own organization’s anticipated spending in 2019.