Baseline [18F]FDG PET features are associated with survival and toxicity in patients treated with CAR T cells for large B cell lymphoma.

PURPOSE: Chimeric antigen receptor (CAR) T cells have established themselves as an effective treatment for refractory or relapsed large B cell lymphoma (LBCL). Recently, the sDmax, which corresponds to the distance separating the two farthest lesions standardized by the patient's body surface area, has appeared as a prognostic factor in LBCL. This study aimed to identify [18F]FDG-PET biomarkers associated with prognosis and predictive of adverse events in patients treated with CAR T cells. METHODS: Patients were retrospectively included from two different university hospitals. They were being treated with CAR T cells for LBCL and underwent [18F]FDG-PET just before CAR T cell infusion. Lesions were segmented semi-automatically with a threshold of 41% of the maximal uptake. In addition to clinico-biological features, sDmax, total metabolic tumor volume (TMTV), SUVmax, and uptake intensity of healthy lymphoid organs and liver were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The occurrence of adverse events, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), was reported. RESULTS: Fifty-six patients were included. The median follow-up was 9.7 months. Multivariate analysis showed that TMTV (cut-off of 36 mL) was an independent prognostic factor for PFS (p < 0.001) and that sDmax (cut-off of 0.15 m-1) was an independent prognostic factor for OS (p = 0.008). Concerning the occurrence of adverse events, a C-reactive protein level > 35 mg/L (p = 0.006) and a liver SUVmean > 2.5 (p = 0.027) before CAR T cells were associated with grade 2 to 4 CRS and a spleen SUVmean > 1.9 with grade 2 to 4 ICANS. CONCLUSION: TMTV and sDmax had independent prognostic values, respectively, on PFS and OS. Regarding adverse events, the mean liver and spleen uptakes were associated with the occurrence of grade 2 to 4 CRS and ICANS, respectively. Integrating these biomarkers into the clinical workflow could be useful for early adaptation of patients management.

Risk of relapse after anti-PD1 discontinuation in patients with Hodgkin lymphoma.

INTRODUCTION: Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation are unknown. METHODS: We retrospectively analyzed patients with R/R HL who responded to anti-PD1 monotherapy and discontinued the treatment either because of unacceptable toxicity or prolonged remission. A machine learning algorithm based on 17 candidate variables was trained and validated to predict progression-free survival (PFS) landmarked at the time of discontinuation of anti-PD1 therapy. RESULTS: Forty patients from 14 centers were randomly assigned to training (n = 25) and validation (n = 15) sets. At the time of anti-PD1 discontinuation, patients had received treatment for a median duration of 11.2 (range, 0-time to best response was not statistically significant in discriminating patients with PFS lesser or greater than 12 months). Considering PFS status as a binary variable (alive or dead) at a specific time point (12 months) is convenient, intuitive and allows for comparing the value of potential predicting variables in these two groups of patients. Nonetheless, this approach has two drawbacks: first, it binarizes outcome; second, it excludes patients alive with a time to last follow up lesser 12 months. Therefore, it is less powerful to demonstrate statistically significant association with PFS even if it exists 5 months. Patients discontinued anti-PD1 treatment either because of prolonged remission (N = 27, 67.5%) or unacceptable toxicity (N = 13, 32.5%). Most patients were in CR (N = 35, 87.5%) at the time of anti-PD1 discontinuation. In the training set, the machine learning algorithm identified that the most important variables to predict PFS were patients' age, time to best response, and presence or absence of CR. The performance observed in the training set was validated in the validation set. CONCLUSION: In this pilot, proof of concept study using a machine learning algorithm, we identified biomarkers capable of predicting the risk of relapse after anti-PD1 discontinuation (age, time to best response, quality of response). Once confirmed, these simple biomarkers will represent useful tools to guide the management of these patients.

Next-generation immunotherapies for lymphoma: one foot in the future.

Improved understanding of the interactions between cancer cells and the immune system combined with technological advances has led to the development of novel types of immunotherapies. These include checkpoint inhibitors, T-cell engager antibodies and chimeric antigen receptor T cells which have demonstrated remarkable efficacy in B-cell malignancies, including anti-PD1 antibodies in Hodgkin lymphoma, and T-cell engager antibodies and chimeric antigen receptor T cells in B-cell acute lymphoblastic leukemia, leading to their approval in these indications. Recent clinical data suggest that these immunotherapies may also benefit patients with other types of hematologic malignancies, particularly patients with Hodgkin and non-Hodgkin lymphomas. Here, we review the most recent clinical data regarding these different immunotherapies in patients with lymphoma. Ongoing and future studies should further define which immunotherapy may best apply to a given patient in order to provide a 'personalized immunotherapy'.

Biomarkers associated with checkpoint inhibitors.

Checkpoint inhibitors (CPI), namely anti-CTLA4 and anti-PD1/PD-L1 antibodies, demonstrated efficacy across multiple types of cancer. However, only subgroups of patients respond to these therapies. Additionally, CPI can induce severe immune-related adverse events (irAE). Biomarkers that predict efficacy and toxicity may help define the patients who may benefit the most from these costly and potentially toxic therapies. In this study, we review the main biomarkers that have been associated with the efficacy (pharmacodynamics and clinical benefit) and the toxicity (irAE) of CPIs in patients.

Secondary MGUS after autologous hematopoietic progenitor cell transplantation in plasma cell myeloma: a matter of undetermined significance.

Plasma cell myeloma, characterized by clonally aberrant plasma cells that produce abnormal monoclonal Igs, is the most common indication for autologous hematopoietic progenitor cell transplantation (AHPCT) in North America. We observed appearance of new monoclonal gammopathies different from the original protein in the post-AHPCT setting and termed this condition 'secondary MGUS' (monoclonal gammopathy of undetermined significance). Hence, we performed a retrospective, single institution review of serum protein electrophoresis/immunofixation electrophoresis data in 92 AHPCT recipients from the period 2000-2009. In all, 22 of 92 patients (24%) undergoing AHPCT met criteria for secondary MGUS. Contrary to previous studies, often referred to as 'abnormal protein banding,' we did not observe this condition as a favorable prognostic indicator in affected patients when compared with the control group (P=0.686). However, we did note that a subgroup of the study cohort who developed secondary MGUS after a prolonged latency (>10 months) had an improved median OS compared with the remainder of the study cohort (75 months vs 41 months, P=0.005). As there have been significant advancements in understanding the pathobiology and clinical significance of MGUS, we believe that secondary MGUS merits dedication of resources for investigation to determine its true clinical relevance, prognostic value and pathophysiology.

Bayesian sensitivity analysis of a model of the aortic valve.

Understanding the mechanics of the aortic valve has been a focus of attention for many years in the biomechanics literature, with the aim of improving the longevity of prosthetic replacements. Finite element models have been extensively used to investigate stresses and deformations in the valve in considerable detail. However, the effect of uncertainties in loading, material properties and model dimensions has remained uninvestigated. This paper presents a formal statistical consideration of a selected set of uncertainties on a fluid-driven finite element model of the aortic valve and examines the magnitudes of the resulting output uncertainties. Furthermore, the importance of each parameter is investigated by means of a global sensitivity analysis. To reduce computational cost, a Bayesian emulator-based approach is adopted whereby a Gaussian process is fitted to a small set of training data and then used to infer detailed sensitivity analysis information. From the set of uncertain parameters considered, it was found that output standard deviations were as high as 44% of the mean. It was also found that the material properties of the sinus and aorta were considerably more important in determining leaflet stress than the material properties of the leaflets themselves.

Identification of pre-sliding friction dynamics.

The hysteretic nonlinear dependence of pre-sliding friction force on displacement is modeled using different physics-based and black-box approaches including various Maxwell-slip models, NARX models, neural networks, nonparametric (local) models and dynamical networks. The efficiency and accuracy of these identification methods is compared for an experimental time series where the observed friction force is predicted from the measured displacement. All models, although varying in their degree of accuracy, show good prediction capability of pre-sliding friction. Finally, we show that even better results can be achieved by using an ensemble of the best models for prediction.

Renal medullary carcinoma: report of a case with positive urinary cytology.

Renal medullary carcinoma is an aggressive neoplasm of the renal pelvis arising in patients with a history of sickle-cell trait. The authors report a case of renal medullary carcinoma with positive urinary cytology. Due to the location of the tumor in the renal pelvis and the loosely cohesive nature of poorly differentiated neoplasms, the presence of renal medullary carcinoma in a urinary cytology specimen is not surprising. The cytologic characteristics as well as the ultrastructural features are described.

Bacterial infection complicating varicella infection: A 10-year review of hospitalized children.

An increased incidence of Streptococci pyogenes (group A streptococcus [GAS]) infections and rheumatic fever has been reported over the past decade. The present study was conducted to determine whether a similar increase in such infections was observed after varicella, an infection previously shown to be associated with a high incidence of streptococcal infections. The charts of all children admitted with chickenpox to the Hospital for Sick Children in Toronto, Ontario from January 1, 1980 to December 31, 1989 were reviewed. Immunocompromised children and those hospitalized for another reason who had an incidental diagnosis of chickenpox were excluded. Twenty-five cases with bacterial infection complicating chickenpox were compared with 103 patients without secondary infection. No statistically significant differences were observed for age, gender, duration of illness prior to hospitalization or duration of hospitalization in the two groups. GAS was the most frequent isolate in the cases, followed by Staphylococcus aureus, Escherichia coli and Haemophilus influenzae. The types of infection were significantly different for GAS compared with other organisms, with a predominance of skin infections in the former group (χ(2) analysis, P<0.05). No increase in the incidence of GAS infections was observed over time. This study confirms the importance of GAS infections in patients with varicella, but no increase was observed in hospitalized children during the 10-year study period.

A general expression for coupled enzyme assays of hysteretic enzymes.

A general description of a system consisting of a hysteretic enzyme and a series of coupling enzymes is presented. The chloroplast enzyme sedoheptulose-1,7-bisphosphatase and a sequence of three coupling enzymes is used as an example. An analysis using first-order rate equations for the coupling enzymes shows that the observed relaxation time of the system is the sum of the relaxation times of the coupling enzymes and that of the hysteretic enzyme. The behaviour of a system with relatively low concentrations of coupling enzymes, where the first-order assumption is not valid, is analysed by computer stimulation. Several methods for the accurate determination of the relaxation time of the hysteretic enzyme are discussed.

A low cost portable enuresis alarm.

The enuresis alarm described is a portable device designed for 'toilet training' of mentally sub-normal children. It weighs 70 gm with battery, has dimensions of 90 x 60 x 30 mm and conforms to DHSS recommendations. The battery life is over 1000 hours (6 weeks) in continuous use. Total component cost is is pounds 6.20 (in 1978), construction is simple and the circuit may be used as a conventional nocturnal enuresis alarm.

A solid state laboratory timer for viscosity measurement.

A low cost timer originally for use with the Harkness Viscometer is described. The timer, which may be used as a general purpose laboratory stop watch, is quiet in operation and counts to 99 seconds with 0.01 second resolution.