International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.

BACKGROUND: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Vitamin E differentially affects short term exercise induced changes in oxidative stress, lipids, and inflammatory markers.

BACKGROUND AND AIM: Physical activity or exercise is a proven deterrent of cardiovascular diseases. The purpose of this study was to examine whether vitamin E supplementation interfere with the potential benefits of exercise. METHODS AND RESULTS: A total of 455 apparently healthy men and women were recruited, for a 2-month aerobic/cardiovascular exercise program. Subjects were randomly assigned for soft gel vitamin E or placebo (800 IU), and required to give blood at 0, 2, 4 and 8 weeks of exercise. Levels of lipid and markers of oxidative stress and inflammation were measured along with the VO2 and duration time spent on treadmill. Statistical analysis did not show significant changes in the levels of lipids and markers of oxidative stress and inflammation. Favorable trends among both of the randomization groups were observed in lipids, and some of the oxidative stress and inflammatory markers. This study also established several interesting correlations between VO2, and lipids on one hand and markers of oxidation and inflammation on the other hand. Reduction in LDL levels positively associated with increased levels of MCP-1 (P < 0.008) among placebo group, and also decreased hCRP levels strongly correlated with the increases in VO2 (P < 0.0004) among the placebo, and vitamin E subjects (P < 0.01). CONCLUSIONS: Exercise training induces oxidative stress might be instrumental in favorable lipid reduction and markers of oxidative stress and inflammation. However interestingly, vitamin E didn't demonstrate favorable effects on the level of oxidative stress and inflammation associated with exercise.

Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis.

BACKGROUND: Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin's lymphoma (NHL) that may be cured with intensive chemotherapy. The addition of the CD20-directed monoclonal antibody rituximab to CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine) has not been studied despite efficacy in other aggressive CD20-positive NHLs. PATIENTS AND METHODS: Eighty adult BL patients treated with or without rituximab were identified at our institutions. Response rate, overall survival (OS), and progression-free survival (PFS) are calculated. RESULTS: There were fewer relapses in rituximab-treated patients (3 of 40 versus 13 of 40, P = 0.01). There was a trend for improvement in outcome favoring rituximab-containing therapy, with 3-year PFS (74% versus 61%) and 3-year OS (77% versus 66%), although these did not reach statistical significance. Advanced age and central nervous system involvement were associated with poorer OS on multivariable Cox regression analysis, adjusting for treatment, human immunodeficiency virus (HIV) involvement, and risk group. CONCLUSIONS: CODOX-M/IVAC, with or without rituximab, is a highly effective regimen for the treatment of adult BL. Rituximab decreased the recurrence rate and showed a trend in favor of improvement in PFS and OS. HIV-infected patients achieved outcomes comparable with those of their non-HIV-infected counterparts.

End-of-treatment but not interim PET scan predicts outcome in nonbulky limited-stage Hodgkin's lymphoma.

BACKGROUND: Early interim positron emission tomography (PET) scans appear powerfully predictive of outcome in Hodgkin's lymphoma (HL), particularly in advanced-stage disease where it has been predominantly studied. The prognostic value of interim PET in limited-stage patients with nonbulky disease has not been well established. PATIENTS AND METHODS: Ninety-six patients with nonbulky limited-stage HL were identified who had interim and end-of-treatment PET scans. Response rate, overall survival (OS), and progression-free survival (PFS) were calculated. RESULTS: Four-year PFS and OS for the entire cohort were 88% and 97%, respectively. Interim PET did not predict outcome, with PFS in positive and negative patients 87% versus 91% (P=0.57), respectively. End-of-treatment PET result was predictive of outcome, with PFS of 94% in end PET-negative patients versus 54% in end PET-positive patients (P<0.0001). Four-year OS was 100% in end PET-negative patients and 84% in end PET-positive patients (P<0.0001). CONCLUSIONS: Interim PET scans were not predictive of outcome, compared with scans carried out at completion of therapy. End-of-treatment PET was highly predictive of PFS and OS, regardless of interim PET result. In this low-risk patient population, even patients with interim positive PET scans show a favorable prognosis.

Fabrication of Nanoscale Bioarrays for the Study of Cytoskeletal Protein Binding Interactions Using Nanoimprint Lithography.

We describe a high throughput patterning process used to create arrays of molecular-scale features for the study of cytoskeletal protein binding interactions. The process uses a shadow-evaporated metal mask to facilitate lift-off of features defined by nanoimprint lithography. This simple and robust approach alleviates difficulties in pattern transfer of ultra-small features and results in arrays of highly ordered sub-10 nm features which are then functionalized with extracellular matrix proteins. Application of these arrays is demonstrated in cell spreading assays.

Nighttime administration of high-dose, sustained-release melatonin does not decrease nocturnal blood pressure in African-American patients: Results from a preliminary randomized, crossover trial.

OBJECTIVES: This preliminary study tested whether a high-dose, sustained-release form of melatonin reduced 24-hour blood pressure in African-Americans. DESIGN: Randomized, placebo-controlled, crossover pilot study of 40 self-defined African-American patients with essential hypertension. SETTINGS/LOCATION: Urban, academic medical center and associated outpatient clinics. INTERVENTIONS: Patients ingested either melatonin (high dose [24 mg], sustained-release formulation] or placebo in randomized order over a 4-week period. OUTCOME MEASURES: Mean nighttime and daytime systolic and diastolic blood pressures, as measured with 24-hour ambulatory blood pressure monitors. The primary outcome was mean nighttime systolic blood pressure. RESULTS: There were no statistically differences between melatonin and placebo conditions in mean nighttime or daytime systolic or diastolic blood pressures. CONCLUSIONS: In contrast with studies in other populations, this preliminary study showed that nighttime dosing of continuous-release melatonin had no significant effect on nocturnal blood pressure in African Americans with essential hypertension when compared to placebo.

Fabrication of a versatile substrate for finding samples on the nanometer scale.

With increasing interest in nanometer scale studies, a common research issue is the need to use different analytical systems with a universal substrate to relocate objects on the nanometer scale. Our paper addresses this need. Using the delicate milling capability of a focused ion beam (FIB) system, a region of interest (ROI) on a sample is labelled via a milled reference grid. FIB technology allows for milling and deposition of material at the sub 20-nm level, in a similar user environment as a standard scanning electron microscope (SEM). Presently commercially available transmission electron microscope (TEM) grids have spacings on the order 100 mum on average; this technique can extend this dimension down to the submicrometre level. With a grid on the order of a few micrometres optical, FIBs, TEMs, scanning electron microscopes (SEMs), and atomic force microscopes (AFM) are able to image the ROI, without special chemical processes or conductive coatings required. To demonstrate, Au nanoparticles of approximately 25 nm in size were placed on a commercial Formvar- and carbon-coated TEM grid and later milled with a grid pattern. Demonstration of this technique is also extended to bulk glass substrates for the purpose of sample location. This process is explained and demonstrated using all of the aforementioned analytical techniques.

Inhibition of neutrophil lysosome-phagosome fusion associated with influenza virus infection in vitro. Role in depressed bactericidal activity.

The present study examined the effect of various unopsonized strains of influenza A virus on release of myeloperoxidase (MPO) and acid phosphatase in polymorphonuclear leukocytes (PMNL). These results were correlated with the effect that these same viruses had on bactericidal activity in PMNL. Several strains of virus inhibited the fusion of azurophil granules with phagosomes containing Staphylococcus aureus. These same strains inhibited the extracellular release of MPO from PMNL (39-59%) and caused depressed killing (42-77%). In contrast, one of the influenza viruses (X-47a) did not inhibit PMNL MPO release or killing. The data indicate a close relationship between the ability of influenza virus to ablate normal intracellular lysosome-phagosome fusion with subsequent depression of bactericidal functions of PMNL.

A case-control study of Hodgkin's disease in Israel.

Jewish residents of Israel in 1960-72 with Hodgkin's disease (HD) were compared with controls drawn from the general population. The controls were individually matched by sex, age, origin, and date of immigration. The comparison showed a significant association between HD and parental consanguinity and pointed to the possible etiologic role of recessive inheritance. Females with HD tended to have a lower parity than did their controls. Associations between HD and a high educational level and the presence of a flush toilet in the childhood home were significant and gave limited support to the hypothesis that a high standard of living in childhood increases the risk of subsequent HD. Tonsillectomy and a history of work with wood or trees were significantly associated with mixed cellularity but not with other histologic subtypes. Differences between patients with HD and controls with respect to cigarette smoking, exposure to animals, marital status, previous blood transfusions or jaundice, contact with asbestos, residual or occupational mobility, or other characteristics were not significant.

Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium.

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a unique subtype of DLBCL. The impact of rituximab on survival and patterns of treatment failure in PT-DLBCL patient remain controversial. We analyzed the clinical and biological feature of 280 PT-DLBCL cases, 64% of which were treated with rituximab-containing regimens. Although most (95%) patients achieved complete remission, a continuous risk of relapse was observed. Rituximab significantly reduced the cumulative risk of relapse (P=0.022) and improved both progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027) of PT-DLBCL patients (5-year PFS, 56% vs 36%; 5-year OS, 68% vs 48%). Central nervous system and contralateral testis were the most common sites of relapse, but other extranodal and nodal sites of relapse were also observed. Most cases of PT-DLBCL had a non-germinal center B-cell like (84%) immunophenotype and an activated B-cell like (86%) gene expression profile (GEP) subtype. The distinctive GEP signature of primary testicular lymphoma was relevant to tumor cell proliferation, dysregulated expression of adhesion molecules and immune response, likely accounting for the poor outcome. Accordingly, forkhead box P1 transcription factor (FOXP1) and T-cell leukemia/lymphoma 1 (TCL1) oncogenic activation were confirmed and predicted a significant trend of poor survival. This study provides valuable observations for better understanding of both clinical and biological features in PT-DLBCL patients.

Fusion protein approach to improve the crystal quality of cytochrome bo(3) ubiquinol oxidase from Escherichia coli.

Crystals of cytochrome bo(3) ubiquinol oxidase from E. coli diffract X-rays to 3.5 A and the structure determination is in progress. The limiting factor to the elucidation of the structural detail is the quality of the crystals; the diffraction spots from the crystals are diffused which leads to difficulties in processing the data beyond 4.0 A. Weak protein-protein contacts within the crystal lattice is assumed to be the cause of this problem. To improve these contacts, we have introduced protein Z to the C-terminal end of the subunit IV of cytochrome bo(3) and expressed both proteins as a single fusion. We have successfully obtained crystals of this fusion protein. The spot shape problem has clearly been solved in the crystals of the fusion protein although further optimization is necessary to obtain higher resolution. We also discuss the potential applications of this approach to the crystallization of membrane proteins in general.

Rapid Ag+-induced release of Ca2+ from sarcoplasmic reticulum vesicles of skeletal muscle: a rapid filtration study.

Using a rapid filtration method, we show that Ag+ is able to trigger Ca2+ release from sarcoplasmic reticulum vesicles at a rate as fast as that induced by Ca2+ itself. The Ag+ concentration dependence of the rate constant of Ca2+ release presents a bell shape, similar to that of Ca2+-induced Ca2+ release, with a maximum at 30 microM free Ag+. The rapid phase of Ca2+-release induced by Ag+ is activated by millimolar ATP and inhibited by 5 microM ruthenium red. Moreover, micromolar Ca2+ produces a shift of the Ag+ concentration dependence of the Ca2+ release rate. All these results suggest that Ag+ acts on the same sites as Ca2+ to regulate the release of Ca2+.

Structure of cytochrome c oxidase: a comparison of the bacterial and mitochondrial enzymes.

It has been almost 5 years since the first structures of cytochrome c oxidase, from Paracoccus denitrificans and bovine heart mitochondria, were revealed. Since then many different proton pumping mechanisms have been proposed for the enzyme; however, no definitive conclusion has been achieved. In this article, we revisit the original structures of bacterial and mitochondrial oxidases and try to clarify similarities as well as differences between the two structures.

Depressive symptoms and risk of functional decline and death in patients with heart failure.

OBJECTIVES: We sought to examine whether depressive symptoms are associated with poorer prognosis in patients with heart failure. BACKGROUND: Depression is an established risk factor for poor outcome in patients with coronary heart disease (CHD). Little is known of its role in patients with heart failure. METHODS: We prospectively followed 391 patients > or =50 years of age who met criteria for decompensated heart failure on hospital admission. The outcome of the study was death or decline in activities of daily living (ADL) at six months, relative to baseline. Depressive symptoms were measured at baseline by means of the Geriatric Depression Scale, Short-Form, with 6 to 7 symptoms, 8 to 10 symptoms and > or =11 symptoms indicating mild, moderate and severe levels of depressive symptoms, respectively. RESULTS: There was a strong and graded association between the severity of depressive symptoms at baseline and the rate of the combined end point of either functional decline or death at six months. After adjustment for demographic factors, medical history, baseline functional status and clinical severity, patients with > or =11 depressive symptoms, compared with those with <6 depressive symptoms, had an 82% higher risk of either functional decline or death, whereas the intermediate levels of depressive symptoms showed intermediate risk (p = 0.003 for trend). A similar graded association was found for functional decline and death separately; however, after multivariate analysis, the association with mortality was less strong and no longer statistically significant. CONCLUSIONS: An increasing number of depressive symptoms is a negative prognostic factor for patients with heart failure, just as it is for patients with CHD.

Regulation of mast cell secretory response to the type I Fcepsilon receptor: inhibitory elements and desensitization.

While the current understanding of the stimulus-response coupling networks triggered by the multi-chain immune-recognition receptors (MIRRs) has markedly advanced, knowledge of its control mechanisms is only emerging. Regulation of the secretory response of mast cells to the stimulus provided by the type I Fcepsilon receptor (FcepsilonRI) is our topic of interest. Several mast cell membrane receptors capable of inhibiting both immediate and late responses have so far been identified. However, their ligands and mechanism(s) of operation are only partly known. Moreover, desensitization of mast cells' response to the FcepsilonRI, a well-known and widespread control process of many neural or hormone receptors, is hardly understood in this case. In this brief report we describe results of recent experiments in which we studied both of these aspects of mast cells' response to the FcepsilonRI stimulus by an inhibitory receptor MAFA, as well as those where we have established that these cells are susceptible to physiological modes of FcepsilonRI desensitization caused by prolonged exposure to sub-threshold concentrations of FcepsilonRI clustering agents.

The ability of polymorphonuclear leukocyte priming agents to overcome influenza A virus-induced cell dysfunction.

The major mortality and morbidity resulting from influenza virus infections are due to secondary bacterial infections which occur in association with virus-induced inhibition of polymorphonuclear leukocyte (PMNL) function. The present study was undertaken to determine if compounds which prime PMNL function to subsequent stimulation with N-formylmethionyl-leucylphenylalanine (FMLP) or phorbol 12-myristate 13-acetate (PMA) can overcome influenza A virus (IAV)-induced inhibition of the PMNL chemiluminescence response to these stimuli. Granulocyte-macrophage colony stimulating factor (GM-CSF), guanosine triphosphate (GTP), and 1-oleoyl-2-acetylglycerol (OAG) were able to prime the PMNL response to FMLP and/or PMA and totally or partially overcome IAV-induced PMNL dysfunction in cells stimulated with FMLP or PMA. A direct correlation was found between the extent of PMNL priming due to GM-CSF, GTP, and OAG and the capacity of these compounds to overcome virus-induced PMNL dysfunction. The implications of these findings in regard to the mechanism by which priming agents overcome IAV-induced cell dysfunction and the potential of these compounds as therapeutic agents to treat secondary bacterial infections are discussed.

Influenza A virus alters structural and biochemical functions of the neutrophil cytoskeleton.

Influenza A virus (IAV) has previously been shown to alter chemotactic, oxidative, and secretory functions of polymorphonuclear leukocytes (PMNL). Because of the role of cytoskeletal proteins in these processes, studies were carried out to determine if IAV altered the PMNL cytoskeleton. PMNL were incubated with buffer of IAV, stimulated with f-met-leu-phe (FMLP), fixed and stained with NBD-phallacidin (NBD-Ph) and studied by flow cytometry. Mean F-actin fluorescence was increased 18% in virus treated cells pre-FMLP stimulation and 13% 5 and 10 min post-FMLP (P less than .03); no significant difference in F-actin fluorescence was noted in virus treated PMNL 15-30 s post-FMLP compared to control cells. PMNL exposed to the same conditions were solubilized and actin content was determined following SDS-PAGE of triton insoluble precipitates. Increased actin was recovered from virus treated compared to buffer treated cells before and after FMLP stimulation in the 8,000g precipitates (P less than .001). Immunofluorescent microscopy studies of F-actin distribution were done in PMNL stained with NBD-Ph following FMLP stimulation for 10 min. These studies showed an increased lamellipod F-actin/uropod F-actin ratio in PMNL pre-incubated with IAV compared to controls (4.6 vs. 1.0; P less than .025). Phosphorylation of specific cytoskeletal proteins was examined after immunoprecipitation. IAV alone altered phosphorylation of both vimentin and vinculin, and in stimulated PMNL virus led to decreased phosphorylation of vimentin and vinculin. These data show distributional and biochemical effects of IAV on PMNL cytoskeletal proteins, indicating additional targets for IAV interference in the PMNL signal-transduction-function process.

Depression and risk of heart failure among older persons with isolated systolic hypertension.

BACKGROUND: Investigators have shown that depression is associated with an increased risk of coronary heart disease in general and myocardial infarction in particular. However, it is unknown whether depression, independent of its association with myocardial infarction, is a risk factor for heart failure. METHODS: This study examined whether depression was a predictor of incident heart failure among 4538 persons aged 60 years and older with isolated systolic hypertension who were enrolled in the Systolic Hypertension in the Elderly Program (SHEP). Depression was defined as a score of 16 or more at baseline on the Center for Epidemiological Studies Depression Scale (CES-D). The relationship between depression and heart failure was assessed using Cox proportional hazards regression. RESULTS: The average follow-up was 4.5 years. Heart failure developed in 138 (3.2%) of 4317 nondepressed persons and in 18 (8.1%) of 221 depressed persons. After controlling for age; sex; race; history of myocardial infarction, diabetes, or angina; blood pressure; cholesterol levels; electrocardiographic abnormalities; smoking; disability; and SHEP treatment group, depressed persons had more than a 2-fold higher risk of developing heart failure compared with nondepressed persons (hazard ratio, 2.59; 95% confidence interval, 1.57-4.27; P<.001). After additional adjustment for the occurrence of myocardial infarction during follow-up, depressed persons remained at elevated risk of heart failure (hazard ratio, 2.82; 95% confidence interval, 1.71-4.67; P<.001). CONCLUSIONS: Depression is independently associated with a substantial increase in the risk of heart failure among older persons with isolated systolic hypertension. This association does not appear to be mediated by myocardial infarction.