Some patients with diffuse large B-cell lymphoma (DLBCL) present with a concurrent indolent lymphoma at diagnosis. Their outcomes in the rituximab era are not fully defined. Using a prospectively ...followed cohort of 1324 newly diagnosed DLBCL patients treated with immunochemotherapy, we defined the prevalence, characteristics, and outcome of DLBCL with concurrent indolent lymphoma. Compared with patients with DLBCL alone (n = 1153; 87.1%), patients with concurrent DLBCL and follicular lymphoma (FL) (n = 109; 8.2%) had fewer elevations in lactate dehydrogenase, lower International Prognostic Index (IPI), and predominantly germinal center B-cell–like (GCB) subtype, whereas patients with concurrent DLBCL and other indolent lymphomas (n = 62; 4.7%) had more stage III-IV disease and a trend toward higher IPI and non-GCB subtype. After adjusting for IPI, patients with concurrent DLBCL and FL had similar event-free survival (EFS) (hazard ratio HR = 0.95) and a trend of better overall survival (OS) (HR = 0.75) compared with patients with DLBCL alone, but nearly identical EFS (HR = 1.00) and OS (HR = 0.84) compared with patients with GCB DLBCL alone. Patients with concurrent DLBCL and other indolent lymphomas had similar EFS (HR = 1.19) and OS (HR = 1.09) compared with patients with DLBCL alone. In conclusion, DLBCL patients with concurrent FL predominantly had the GCB subtype with outcomes similar to that of GCB DLBCL patients. DLBCL patients with concurrent other indolent lymphoma had similar outcomes compared with patients with DLBCL alone. These patients should not be summarily excluded from DLBCL clinical trials.
•Concurrent DLBCL and FL has a similar outcome to that of GCB DLBCL; concurrent other indolent lymphoma does not worsen the DLBCL outcome.•Inclusion of patients with concurrent DLBCL and indolent lymphoma should be considered in clinical trials of newly diagnosed DLBCL.
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Research on heterosexual mating has demonstrated that acoustic parameters (e.g., pitch) of men's voices influence their attractiveness to women and appearance of status and formidability to other ...men. However, little is known about how men's tendency to clearly articulate their speech influences these important social perceptions. In the current study, we used a repeated-measures design to investigate how men's articulatory clarity or conformity influenced women's (N = 45) evaluations of men's attractiveness for both short- and long-term relationships, and men's (N = 46) evaluations of physical formidability and prestige. Results largely supported our hypotheses: men who enunciated phonemes more distinctly were more attractive to women for long-term relationships than short-term relationships and were perceived by other men to have higher prestige than physical dominance. These findings suggest that aspects of articulatory behavior that influence perceptions of prestige and long-term mating attractiveness may indicate an early social history characterized by high socioeconomic status, likely owing to crystallization of articulatory patterns during the critical period of language development. These articulatory patterns may also be honest signals of condition or disposition owing to the nature of complex, multicomponent traits, which deserve further empirical attention.
Stratigraphic, geochronologic, and geochemical patterns of Neoproterozoic to Cambrian sedimentary and volcanic rocks in Utah, Nevada, and SE Idaho record a dynamically evolving landscape along the ...North American Cordillera margin, which included: (1) initial development of intracratonic basins with deposition of siliciclastic strata of the Uinta Mountain Group from ~770 to 740Ma; (2) early rifting and volcanism along a N–S (present day geographic coordinates) basin system with deposition of diamictite-bearing strata of the Perry Canyon and related formations from ~720 to 660Ma; (3) early, broad subsidence with deposition of mature siliciclastic strata of the lower Brigham and McCoy Creek groups from ~660 to 580Ma; (4) final rifting, volcanism, and transition to drift with deposition of variably immature siliciclastic strata of the Prospect Mountain and correlative formations from ~570 to 520Ma; and (5) regional subsidence along a passive margin with deposition of Middle Cambrian to Devonian carbonate-rich strata. The Uinta Mountain Group comprises fluvial to marine, feldspathic to quartzose sandstone, conglomerate, and mudstone, with detrital zircon (DZ) patterns recording a mix of local basement sources to the N and distal Laurentian sources to the SE. The lower Perry Canyon and related formations contain variably feldspathic sandstone, quartz-pebble diamictite deposited during an older glacial episode, and mudstone, with DZ patterns recording a mix of distal sources, local basement sources, and sediment recycling during early rifting. The upper Perry Canyon and related formations contain mafic volcanic rocks, polymict diamictite deposited during a younger glacial episode, volcaniclastic wacke, and mudstone, with DZ patterns recording local basement sources along an evolving rift margin and felsic volcanism from ~700 to 670Ma. Mafic volcanic rocks and trachyte to rhyolite clasts in diamictite have geochemical signatures typical of continental rifting. The lower Brigham and McCoy Creek groups contain mostly mature quartz arenite deposited in shallow marine environments, with DZ patterns recording distal Laurentian sources. The base of the Prospect Mountain and correlative formations is marked by an influx of feldspathic, coarse-grained sediment derived from local basement sources and ~570–540Ma basalt volcanism, which was followed by deposition of subfeldspathic strata with dominant 1.7–1.8Ga DZ grains, recording sources from the SE rift margin and a marked decrease in distal sources during uplift of the Transcontinental Arch. Overlying carbonate-rich strata were deposited in shallow marine settings, with episodic influx of siliciclastic sediment derived from basement exposed during regressions. Stratigraphic thickness-age relations of Neoproterozoic to early Paleozoic strata are consistent with two episodes of rifting concentrated at ca. 700–670Ma and 570–540Ma along western Laurentia, leading to final development of a passive margin. Early rifting was incomplete with an estimated 25–40% extension of initially thick lithosphere that was weakened by igneous activity. Final rifting of previously thinned lithosphere involved an estimated 20–35% additional extension, renewed igneous activity, and thermal thinning of mantle lithosphere, with localized extension culminating in final separation along the continental margin. Stratigraphic, geochronologic, and available paleomagnetic data are consistent with linkage of western Laurentia to Australia–East Antarctica within Rodinia, followed by protracted rifting and drift during Cambrian time.
Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic ...leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.
Summary
This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma (DLBCL) after failure of front line anthracycline‐based immunochemotherapy (IC). Patients with ...newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B‐cell lymphoma (PMBL) patients treated with front‐line anthracycline‐based IC were followed for relapse. Patients with relapse on follow‐up and subsequently retreated were included in this analysis. 1039 patients received anthracycline‐based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years (OS4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (autoHCT) with OS4 from autoHCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS4 of 47% but those with a transient or no response to initial therapy had OS4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo autoHCT. The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL.
The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively ...mediates host effector functions and is itself less immunogenic than are murine antibodies.
This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses.
From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient.
The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.
The radio technique is a promising method for detection of cosmic-ray air showers of energies around 100PeV and higher with an array of radio antennas. Since the amplitude of the radio signal can be ...measured absolutely and increases with the shower energy, radio measurements can be used to determine the air-shower energy on an absolute scale. We show that calibrated measurements of radio detectors operated in coincidence with host experiments measuring air showers based on other techniques can be used for comparing the energy scales of these host experiments. Using two approaches, first via direct amplitude measurements, and second via comparison of measurements with air shower simulations, we compare the energy scales of the air-shower experiments Tunka-133 and KASCADE-Grande, using their radio extensions, Tunka-Rex and LOPES, respectively. Due to the consistent amplitude calibration for Tunka-Rex and LOPES achieved by using the same reference source, this comparison reaches an accuracy of approximately 10% – limited by some shortcomings of LOPES, which was a prototype experiment for the digital radio technique for air showers. In particular we show that the energy scales of cosmic-ray measurements by the independently calibrated experiments KASCADE-Grande and Tunka-133 are consistent with each other on this level.
N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically ...inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR-MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity.
Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1-20). Grade 3-4 adverse events (AEs) were reported in seven (54%; 95% CI 25-81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0-36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29-539) days and 33 (95% CI 9.7- > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39-91%). PK analysis demonstrated proportional dose-concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months.
NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR-MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.
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