The prognosis of peripheral T-cell lymphoma (PTCL) is heterogenous. Baseline or interim imaging characteristics may inform risk-adapted treatment paradigms. We identified 112 patients with PTCL who were consecutively treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)/CHOP-like regimens with the intent to consolidate with an autologous transplant. Baseline (n = 93) and interim (after 4 cycles, n = 99) positron emission tomography (PET) images were reevaluated, and we calculated baseline total metabolic tumor volume (TMTV). Interim PET (iPET) responses were graded visually by 5-point score (i5PS) and by percentage change of standardized uptake value. By univariate analysis, predictors of event-free survival (EFS) included Prognostic Index for Peripheral TCL (PIT) higher than 1 (hazard ratio [HR], 1.83; P = .021), International Prognostic Index (IPI) higher than 3 (HR, 2.01; P = .021), high TMTV (>125 cm3; HR, 3.92; P = .003), and positive iPET (HR, 3.57; P < .001). By multivariate analysis, high baseline TMTV predicted worse overall survival (OS; HR, 6.025; P = .022) and EFS (HR, 3.861; P = .005). Patients with i5PS of 1 to 3 had a longer median OS and EFS (104 months, 64 months) than those with i5PS of 4 to 5 (19 months, 11 months; P < .001). Four-year OS and EFS for patients with i5PS of 1 to 3 and PIT of 1 or less were 85% and 62%, respectively. However, 4-year OS and EFS for those with i5PS of 4 to 5 and PIT higher than 1 were both 0% (P < .001). In multivariate analysis, after controlling for IPI and PIT, i5PS was independently prognostic for EFS (HR, 3.400 95% confidence interval, 1.750-6.750; P < .001) and OS (HR, 10.243; 95% confidence interval, 4.052-25.891; P < .001). In conjunction with clinical parameters, iPET helps risk stratify patients with PTCL and could inform risk-adapted treatment strategies. Prospective studies are needed to confirm these findings.

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PurposeChronic Lymphocytic Leukemia (CLL) is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation.Experimental DesignWe developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR). Results from multidimensional modeling were validated using an independent test cohort of 38 patients.ResultsWe identified a dynamic and variable imbalance between proximal (pSYK, pBTK) and distal (pPLCγ2, pBLNK, ppERK) phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness.ConclusionSingle-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets.

The vertebral column is the primary stiffening element of the body of fish. This serially jointed axial support system offers mechanical control of body bending through kinematic constraint and viscoelastic behavior. Because of the functional importance of the vertebral column in the body undulations that power swimming, we targeted the vertebral column of cartilaginous fishes—sharks, skates, and rays—for biomimetic replication. We examined the anatomy and mechanical properties of shark vertebral columns. Based on the vertebral anatomy, we built two classes of biomimetic vertebral column (BVC): (1) one in which the shape of the vertebrae varied and all else was held constant and (2) one in which the axial length of the invertebral joint varied and all else was held constant. Viscoelastic properties of the BVCs were compared to those of sharks at physiological bending frequencies. The BVCs with variable joint lengths were then used to build a propulsive tail, consisting of the BVC, a vertical septum, and a rigid caudal fin. The tail, in turn, was used as the propeller in a surface-swimming robot that was itself modeled after a biological system. As the BVC becomes stiffer, swimming speed of the robot increases, all else being equal. In addition, stiffer BVCs give the robot a longer stride length, the distance traveled in one cycle of the flapping tail.

Introduction: Limited information exists on the best treatment strategy for Primary Refractory (ref) Hodgkin Lymphoma (HL). For the past 20 years, we have treated patients (pts) on sequential ifosfamide, carboplatin, etoposide (ICE)-based clinical trials with the intent to undergo high dose therapy (HDT) and autologous stem cell transplantation (ASCT). As previously reported (Moskowitz, Blood 2010) and confirmed by other centers, a negative PET scan prior to ASCT predicts for marked improvement in outcome in pts with relapsed HL. We aimed to identify risk factors that predict PET response to salvage chemotherapy in ref HL and evaluate outcomes following HDT and ASCT in this patient population. Methods: From 10/1/94 to 7/10/15, 192 ref HL pts were treated on sequential trials at MSKCC. Demographic and clinical factors were collected. Event free survival (EFS) and overall survival (OS) were calculated from the date of histologic confirmation of ref disease, estimated by Kaplan-Meier method, and compared by the log rank test. Events included relapse or death. Cox regression was used for the multivariate regression model. Patients were selected to receive a radiation-based conditioning regimen if all sites of nodal disease could be encompassed into a radiation field. Results: Patient characteristics included a median age of 31 (range 14-79) with 54% female. B symptoms, extranodal disease, stage IV disease, and disease bulk > 5cm were present in 31%, 48%, 44%, 40%, respectively. In the intent-to-treat (ITT) population, 41% had a positive post-salvage PET scan. As analyzed by ITT, median EFS was 8.9 years with a median OS of 10.4 years. On multivariate analysis, the presence of B symptoms and bulk >5cm at documentation of ref disease predicted for a reduced chance of achieving a negative PET after salvage therapy, with an odds ratio (OR) of 2.03 for B symptoms and 2.13 for bulk >5cm. For the 169 (88%) transplanted patients, 68% had a negative pre-ASCT PET. Radiation based conditioning was used for 70% of the pts. Median EFS was 12.8 yrs and median OS was not reached with a median follow-up of 3.6 yrs (range, 0.55 to 18.04 yrs) for the surviving patients (Figure 1). On multivariate analysis, both stage (IV vs I-III) and persistent PET abnormality pre- ASCT correlated with a shorter EFS. A risk stratification model was created and pts could be divided into 4 groups. 1) stage I-III disease and a negative PET pre-ASCT, the median EFS was not reached; 2) stage I-III disease and a positive PET pre-ASCT scan-the OR of an event was 4.04 (95% CI 1.93 to 8.45) with the median EFS not reached, 3) Stage IV disease and a negative PET pre-ASCT, the OR was 3.78 (95% CI 1.64 - 8.74) with a median EFS of 8.9 yrs, 4) Stage IV disease and a positive PET pre-ASCT, the OR was 8.22 (95% CI 3.99 to 16.94) with a median EFS of 0.9 yrs (Figure 2). Conclusions: B symptoms and bulk >5cm predicted for residual PET avidity after salvage therapy in ref HL. Persistent PET abnormality pre-ASCT and stage were risk factors for earlier relapse and death and can be used to prognosticate survival. Further studies are needed to determine optimal therapy for patients with multiple risk factors. Figure 1. EFS for the Transplanted Patients Figure 1. EFS for the Transplanted Patients Figure 2. EFS for the transplanted pts based on the presence of risk factors (PET avidity pre-HSCT and Stage) Figure 2. EFS for the transplanted pts based on the presence of risk factors (PET avidity pre-HSCT and Stage) Disclosures Moskowitz: GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.