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Individual comorbidities have distinct contributions to nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the 4 comorbidities predictive of NRM, as well as age >60 years, stratified patients into 5 groups with a stepwise increase in NRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjusted hazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patients who underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The area under the receiver operating characteristic curve (AUC) of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small set of comorbidities, aggregated into the SCI, is highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than does the HCT-CI.

Pulmonary complications (PC) of hematologic malignancies and their treatments are common causes of morbidity and mortality. Early diagnosis is challenging due to host risk factors, clinical instability, and provider preference. Delayed diagnosis impairs targeted treatment and may contribute to poor outcomes. An integrated understanding of clinical risk and radiographic patterns informs a timely approach to diagnosis and treatment. There is little prospective evidence guiding optimal modality and timing of minimally invasive lung sampling; however, a low threshold for diagnostic bronchoscopy during the first 24 to 72 hours after presentation should be a guiding principle in high-risk patients.

In order to realize an economical injection molding process, high process speeds and a consistently high quality of the products is necessary. A very effective possibility, which gets more and more famous, is the use of so-called smart machines and processes. If corresponding interactions between machine parameters, process variables and quality characteristics are known, the machine can design the process independently itself – a so-called self-optimizing process. This study presents a concept for optimizing the residual cooling time of the injection molding process. For this purpose, a special mold is used, which allows to detect forces initiated by thermal shrinkages on the mold core. A new evaluation method allows an automated determination of the time of the completed thermal shrinkage, which should also represent the ideal time for ejection. The principle is demonstrated using polypropylene. It is also shown that the measuring principle can be used to characterize material additives and how processing parameters influence the residual cooling time.

Background Limited data is available on long-term effects of autologous hematopoietic cell transplantation (AHCT) in older patients (pts). Methods This single-center, retrospective study examines late cardiopulmonary effects, and overall outcomes of AHCT in 41 pts age ≥ 70, with non-Hodgkin lymphoma (NHL), between 2000-2016. Pre- and post-HCT pulmonary function tests (PFT) and echocardiograms (echo) were compared. Overall survival (OS) and progression-free survival (PFS) were analyzed according to age, gender, histology, stage, number of lines of treatment, diffusing capacity of lungs for carbon monoxide (DLCO), left ventricular ejection fraction (LVEF), and comorbidity index (HCT-CI). Results 41 pts [median age 72 (range 70-75)] received AHCT for follicular or diffuse large B-cell lymphoma (n=18 44%), mantle cell lymphoma (n=15 37%) and T-cell or other NHL subtypes (n=8 20%). Eight (20%), 6 (15%) and 27 (66%) pts had a low (0), intermediate (1-2) and high (≥3) HCT-CI, respectively. All pts except 1, had received anthracycline as part of initial therapy. BEAM was the most common conditioning regimen (n=38 93%). Pre-HCT LVEF was normal in all pts except 1 (45%). Median (range) pre- and post-HCT LVEF was 63% (45-74%) and 64% (39-71%), respectively. Of the 23 pts who had post-HCT echo (median time between pre- and post-HCT echo was 423 days), a mild decrease in LVEF was noted in 3. Only 1 pt had a significant decline of 19%. Pre- and post-HCT pulmonary artery pressure was normal in all. The median (range) of pre-transplant DLCO, FEV1 and FVC were 70% (48-125%), 97% (83-141%), and 98% (57-123%), respectively. Of the 10 pts who had post-HCT PFT (median time between pre- and post-HCT PFT was 405 days), DLCO decline of >10% was the most common abnormality and developed in 4. In 5 pts DLCO improvement of >10% was observed. A >15% improvement in FEV1 and FVC was observed in 5 and 4 pts respectively. The median improvements in FVC, FEV1 and DLCO were 4%, 6% and 10%, respectively. With a median follow-up of 58 months (range 5-123) for survivors, PFS and OS at 3 years were 84% (95% CI, 67-92%) and 94% (95% CI, 80-99%), respectively. In a univariate analysis, age, gender, histology, stage, number of lines of treatment, DLCO, LVEF, and HCT-CI did not affect OS or PFS. Relapse occurred in 11 pts (27%), 8 of whom died. Median time to relapse was 38 months (range 27-100). Secondary malignancies developed in 4 pts (10%) and led to death in 3. Conclusion In our cohort of elderly pts who underwent AHCT, late declines in cardiopulmonary function were minimal, and none resulted in mortality. The most common cause of death was lymphoma recurrence. Secondary malignancy was the only cause of non-relapse mortality. While prospective studies with larger number of pts are needed to evaluate long-term effects of AHCT on different organ functions in elderly, strategies to mitigate risk of relapse remain the most important area to improve outcomes.

Rationale Sarcoidosis is an idiopathic granulomatous disorder with heterogeneous clinical manifestations and variable prognosis. Monitoring disease activity is important to identify patients requiring treatment. Several cytokines have previously been shown to be elevated in the serum of patients with sarcoidosis and may be useful biomarkers of disease activity. Objectives To identify novel biomarkers of sarcoidosis disease activity. To identify the relationship between plasma cytokines, disease severity and prognosis. Methods The study was approved by the institutional review board. Plasma concentration of 19 cytokines was measured in 112 subjects with chronic sarcoidosis and 52 matched controls, using the bead-based Milliplex xMAP multiplex technology. Plasma levels of individual cytokines were compared between the two groups, and between the groups with clinically active vs. inactive disease. Sensitivity, specificity and receiver operating characteristics curves were used to evaluate biomarker performance. Linear regression analyses were performed to identify associations between cytokine levels, pulmonary function tests and changes in pulmonary function. Measurements and main results Subjects with sarcoidosis had higher plasma levels of interferon gamma induced protein 10 (IP-10) and tumor necrosis factor α (TNFα). IP-10 had the highest sensitivity and specificity in identifying active disease. Higher levels of IP-10 and TNFα were associated with greater disease severity and better prognosis. Conclusions IP-10 is a potentially useful biomarker of sarcoidosis and its severity.

BACKGROUND:Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis. METHODS:Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β(1) on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS:Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β(1). In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin. CONCLUSION:Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β(1) may represent a mechanism for the promotion of fibrogenesis in IPF.

e15243 Background: Gemcitabine (G) is a key component of therapy for pancreatic adenocarcinoma (PC). Pulmonary injury is an infrequent but not rare adverse effect of varying manifestation and is ob...