Nonlinear association between body mass index and overall survival in advanced NSCLC patients treated with immune checkpoint blockade.

BACKGROUND: We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). METHODS: We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis. RESULTS: Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67 years, median BMI was 25.9 kg/m2, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (p < 0.01). Mortality risk decreased as the BMI increased from 20 to 30 kg/m2 (HR 0.49, 95% CI 0.28-0.84); however, it was reversed as the BMI surpassed ~ 30 kg/m2. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0-1 had a longer OS (HR 0.42, 95% CI 0.28-0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker. CONCLUSION: We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30 kg/m2.

Real-World Outcomes and Clinical Predictors of Immune Checkpoint Inhibitor Monotherapy in Advanced Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of advanced-stage non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The aim of this study was to evaluate the effectiveness and tolerance of ICIs in a real-world patient population and to investigate the predictive factors associated with survival outcomes. METHODS: Medical records of patients with advanced lung cancer who started ICI monotherapy were reviewed for data collection. Treatment outcomes included objective response rate, progression-free survival (PFS), and overall survival (OS). Immune-related adverse events (irAEs) were assessed. Multiple Cox regression models were fit to investigate the predictive factors for survival outcomes. RESULTS: We included 220 patients (median 66.5 years). Seventy-nine (35.9%) patients had Eastern Cooperative Oncology Group (ECOG) performance-status (PS) score ⩾2. Median follow-up was 11.4 months. In NSCLC, median PFS was 3.8 months (4.7 months for first line and 3.7 months for subsequent line). Median OS was 12.4 months (15.6 months for first line therapy and 11.5 months for subsequent line). In SCLC, median PFS was 1.8 months, and median OS was 4.6 months. A quarter of patients developed irAEs. There was 1 disease flare among 17 patients with pre-existing autoimmune diseases. ECOG PS of 0 to 1 and body mass index (BMI) ⩾ 25 kg/m2 (but not occurrence of irAE) were independently associated with improved OS in NSCLC, with a hazard ratio of 0.41 (95% confidence interval [CI], 0.29-0.59) and 0.62 (95% CI, 0.44-0.87), respectively. CONCLUSIONS: The clinical benefit of ICIs appears to persist in a real-world population of relatively older age, including those with poor PS and pre-existing autoimmune diseases. ECOG PS of 0 to 1 and BMI ⩾ 25 kg/m2 were independently associated with improved OS.

Mixed vs full donor engraftment early after hematopoietic cell transplant: Impact on incidence and control of cytomegalovirus infection.

Recovery of cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is essential in controlling CMV infection. We hypothesize that mixed donor engraftment as measured by chimerism at day 30 in CMV D(+) HCTs and full chimerism in CMV D(-) HCTs will be predictive of CMV reactivation. Prospectively collected data for 407 CMV R+ HCT recipients transplanted from 2006 to 2014 at the University of Minnesota were retrospectively analyzed. Full and mixed donor engraftment were defined as ≥95% or <95% donor cells at day 30, respectively. Source of engraftment determination included preferentially peripheral blood CD3 fraction, then myeloid cell fraction (CD15+), then bone marrow. In 407 CMV R+ subjects, 77% (n = 313) were CMV D(-) cells from umbilical cord blood (n = 209), peripheral blood (n = 58) or marrow (n = 46). Fifty three per cent received reduced intensity conditioning (RIC). At day +30, full donor engraftment was seen in 82% of myeloablative and 55% of RIC transplants. The cumulative incidence of CMV infection 1-year after transplant was not different in patients with full (54%, n = 276) or mixed (53%, n = 131) donor engraftment. Control of CMV did not significantly differ among the two groups. In multiple regression analysis, there was no significant association between donor engraftment (mixed or full) and incidence or control of CMV.

The Frequency of Carpal Tunnel Syndrome in Hurler Syndrome After Peritransplant Enzyme Replacement Therapy: A Retrospective Comparison.

PURPOSE: Children with Hurler syndrome (HS) develop carpal tunnel syndrome (CTS) owing to glycosaminoglycan deposition secondary to enzyme deficiency. Advancement in the treatment of the underlying enzyme deficiency now commonly includes peritransplant intravenous enzyme replacement therapy (ERT). The primary objective of this study was to determine if the use of limited ERT in addition to hematopoietic stem cell transplantation (HCT) for the treatment of children with HS reduces the incidence of surgical intervention for CTS compared with a cohort of historical controls treated with HCT alone. The secondary objectives were to evaluate the impact of demographic and transplant-related characteristics on the incidence of CTS. Lastly, the results of surgical treatment of CTS in HS are reported. METHODS: Medical records for a historical group of 43 HS patients who underwent HCT alone (group 1) were compared with 31 HS patients who underwent HCT + ERT (group 2). Both groups were compared for genotype, age at transplant, sex, transplant graft source, median/ulnar nerve conduction study parameters as well as the incidence and treatment of CTS. Pre- and postoperative nerve conduction studies were compared for children treated surgically for CTS. RESULTS: The cumulative incidence of CTS at 5 years for HS children treated with HCT + ERT was 51% compared with 47% for HS children treated with HCT alone. The incidence of CTS did not depend upon graft source, age at transplant, or sex. Median nerve conduction velocity for both sensory and motor potentials demonstrated significant improvement after carpal tunnel release. CONCLUSIONS: Although the administration of ERT prior to and for several months after HCT has become routine in our institution, our findings do not suggest this combined therapy is sufficient to decrease the development of CTS. Surgical intervention for median nerve compression remains the treatment of choice for CTS in HS children. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Pharmacogenetics of steroid-responsive acute graft-versus-host disease.

Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance.

High-throughput multiple-mouse imaging with micro-PET/CT for whole-skeleton assessment.

Recent studies have proven that skeleton-wide functional assessment is essential to comprehensively understand physiological aspects of the skeletal system. Therefore, in contrast to regional imaging studies utilizing a multiple-animal holder (mouse hotel), we attempted to develop and characterize a multiple-mouse imaging system with micro-PET/CT for high-throughput whole-skeleton assessment. Using items found in a laboratory, a simple mouse hotel that houses four mice linked with gas anesthesia was constructed. A mouse-simulating phantom was used to measure uniformity in a cross sectional area and flatness (Amax/Amin*100) along the axial, radial and tangential directions, where Amax and Amin are maximum and minimum activity concentration in the profile, respectively. Fourteen mice were used for single- or multiple-micro-PET/CT scans. NaF uptake was measured at eight skeletal sites (skull to tibia). Skeletal (18)F activities measured with mice in the mouse hotel were within 1.6 ± 4% (mean ± standard deviation) of those measured with mice in the single-mouse holder. Single-holder scanning yields slightly better uniformity and flatness over the hotel. Compared to use of the single-mouse holder, scanning with the mouse hotel reduced study time (by 65%), decreased the number of scans (four-fold), reduced cost, required less computer storage space (40%), and maximized (18)F usage. The mouse hotel allows high-throughput, quantitatively equivalent scanning compared to the single-mouse holder for micro-PET/CT imaging for whole-skeleton assessment of mice.

A dual-radioisotope hybrid whole-body micro-positron emission tomography/computed tomography system reveals functional heterogeneity and early local and systemic changes following targeted radiation to the murine caudal skeleton.

The purpose of this study was to develop a longitudinal non-invasive functional imaging method using a dual-radioisotope hybrid micro-positron emission tomography/computed tomography (PET/CT) scanner in order to assess both the skeletal metabolic heterogeneity and the effect of localized radiation that models therapeutic cancer treatment on marrow and bone metabolism. Skeletally mature BALB/c female mice were given clinically relevant local radiation (16 Gy) to the hind limbs on day 0. Micro-PET/CT acquisition was performed serially for the same mice on days -5 and +2 with FDG and days -4 and +3 with NaF. Serum levels of pro-inflammatory cytokines were measured. Significant differences (p < 0.0001) in marrow metabolism (measured by FDG) and bone metabolism (measured by NaF) were observed among bones before radiation, which demonstrates functional heterogeneity in the marrow and mineralized bone throughout the skeleton. Radiation significantly (p < 0.0001) decreased FDG uptake but increased NaF uptake (p = 0.0314) in both irradiated and non-irradiated bones at early time points. An increase in IL-6 was observed with a significant abscopal (distant) effect on marrow and bone metabolic function. Radiation significantly decreased circulating IGF-1 (p < 0.01). Non-invasive longitudinal imaging with dual-radioisotope micro-PET/CT is feasible to investigate simultaneous changes in marrow and bone metabolic function at local and distant skeletal sites in response to focused radiation injury. Distinct local and remote changes may be affected by several cytokines activated early after local radiation exposure. This approach has the potential for longer-term studies to clarify the effects of radiation on marrow and bone.

Lung reirradiation with stereotactic body radiotherapy (SBRT).

INTRODUCTION: There is limited data on the use of SBRT in reirradiation of lung tumors. We reviewed outcomes following SBRT after previous thoracic radiotherapy at the University of Minnesota Medical Center. METHODS: From August 2006 through October 2012, fourteen lung tumors in thirteen patients with either biopsy confirmed or presumed non-small cell lung cancer in patients who were medically unable to undergo biopsy, were retreated with SBRT. Eligible patient charts were reviewed to evaluate survival, recurrence patterns and toxicity following reirradiation. RESULTS: The median age of patients at the time of SBRT was 67.9 years. The median duration of follow-up was 11.4 months. Ten patients received prior conventional thoracic irradiation (median dose 6120 cGy). Two patients received prior SBRT with curative intent. The median time to reirradiation with SBRT was 19.7 months. Following reirradiation with SBRT, four patients (33%) are alive and disease free. Eight patients (67%) experienced progressive disease. There were five distant and two regional recurrences. There was one isolated local recurrence. Local control was 92% with a median survival of 24 months (95% CI: 8-38 months). 1- and 2-year overall survival were 80% (95% CI: 41%-95%) and 36% (95% CI: 6%-68%) respectively. There was one grade 2 and one grade 3 toxicity. No grade 4 or 5 toxicities were seen. CONCLUSIONS: SBRT is a reasonable salvage therapy for lung tumor recurrence or second primary lung malignancy in patients previously treated with thoracic radiotherapy, offering good local control and resulting in acceptable toxicity. Further evaluation of this treatment option is warranted.

Enterococcal bacteremia is associated with increased risk of mortality in recipients of allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Enterococci are an important cause of healthcare-associated infections. We retrospectively analyzed risk factors and outcome of vancomycin-resistant enterococci (VRE) and vancomycin-sensitive enterococci (VSE) infections. METHODS: Seven hundred fifty-two patients who received hematopoietic stem cell transplants from 2004 through 2008 at the University of Minnesota were included. RESULTS: Ninety-three patients had enterococcal bloodstream infection (BSI) during the first year after transplant. Vancomycin resistance was observed in 66% and 31% of isolates in adults and children, respectively. Cumulative incidence of VRE and VSE bacteremia was 6.6% (95% confidence interval [CI], 4.8%-8.4%) and 5.7% (95% CI, 4.0%-7.4%), respectively. Colonization with VRE before or after transplant was a risk factor for VRE bacteremia (odds ratio [OR], 3.3 [95% CI, 1.3-8.3] and 7.0 [95% CI, 4.0-14.8], respectively). Delay in engraftment increased the incidence of VRE bacteremia from 4.5% (95% CI, 2.9-6.6) if engrafted before day 21 and to 15% (95% CI, 3.2%-38%) if engrafted between days 36 and 42. In adults, mortality 30 days after infection was 38% for both VRE (95% CI, 25%-54%) and VSE cases (95% CI, 21%-62%). The hazard ratio for all-cause mortality up to 1 year after transplant was 4.2 (95% CI, 3.1-6.9) and 2.7 (95% CI, 1.4-5.1) for patients with VRE and VSE BSIs, respectively, compared to patients without enterococcal BSI. In pediatric patients, mortality 30 days after VRE and VSE bacteremia was 20% (95% CI, 5.4%-59%) and 4.5% (95% CI, .6%-28%), respectively. CONCLUSION: High rates of vancomycin resistance and association of enterococcal infections with significant mortality warrant further efforts to optimize prevention and management of these infections.

Human parainfluenza virus infection after hematopoietic stem cell transplantation: risk factors, management, mortality, and changes over time.

Human parainfluenza viruses (HPIVs) are uncommon, yet high-risk pathogens after hematopoietic stem cell transplant (HCT). We evaluated 5178 pediatric and adult patients undergoing HCT between 1974 and 2010 to determine the incidence, risk factors, response to treatment, and outcome of HPIV infection as well as any change in frequency or character of HPIV infection over time. HPIV was identified in 173 patients (3.3%); type 3 was most common (66%). HPIV involved upper respiratory tract infection (URTI; 57%), lower respiratory tract infection (LRTI; 9%), and both areas of the respiratory tract (34%), at a median of 62 days after transplantation. In more recent years, HPIV has occurred later after HCT, whereas the proportion with nosocomial infection and mortality decreased. Over the last decade, HPIV was more common in older patients and in those receiving reduced intensity conditioning (RIC). RIC was a significant risk factor for later (beyond day +30). HPIV infections, and this association was strongest in patients with URTI. HCT using a matched unrelated donor (MURD), mismatched related donor (MMRD), age 10 to 19 years, and graft-versus-host disease (GVHD) were all risk factors for HPIV infections. LRTI, early (<30 days), age 10 to 19 years, MMRD, steroid use, and coinfection with other pathogens were risk factors for mortality. The survival of patients with LRTI, especially very early infections, was poor regardless of ribavirin treatment. HPIV incidence remains low, but may have delayed onset associated with RIC regimens and improving survival. Effective prophylaxis and treatment for HPIV are needed.