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Extraneous neuroscience information improves ratings of scientific explanations, and affects mock juror decisions in many studies, but others have yielded little to no effect. To establish the magnitude of this effect, we conducted a random-effects meta-analysis using 60 experiments from 28 publications. We found a mild but highly significant effect, with substantial heterogeneity. Planned subgroup analyses revealed that within-subjects studies, where people can compare the same material with and without neuroscience, and those using text, have stronger effects than between-subjects designs, and studies using brain image stimuli. We serendipitously found that effect sizes were stronger on outcomes of evaluating satisfaction or metacomprehension, compared with jury verdicts or assessments of convincingness. In conclusion, there is more than one type of neuroscience explanations effect. Irrelevant neuroscience does have a seductive allure, especially on self-appraised satisfaction and understanding, and when presented as text., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The overarching goal of this work is to investigate the size-dependent characteristics of the ionization potential of PbS and CdS quantum dots. The ionization potentials of quantum dots provide critical information about the energies of occupied states, which can then be used to quantify the electron-removal characteristics of quantum dots. The energy of the highest-occupied molecular orbital is used to understand electron-transfer processes when invesigating the energy-level alignment between quantum dots and electron-accepting ligands. Ionization potential is also important for investigating and interpreting electron-detachment processes induced by light (photoelectron spectra), external voltage (chemiresistance), and collision with other electrons (impact ionization). Accurate first-principles calculations of ionization potential continue to be challenging because of the computational cost associated with the construction of the frequency-dependent self-energy operator and the numerical solution of the associated Dyson equation. The computational cost becomes prohibitive as the system size increases because of the large number of 2particle-1hole (2p1h) and 1particle-2hole (1p2h) terms needed for the calculation. In this work, we present the Stratified Stochastic Enumeration of Molecular Orbitals (SSE-MO) method for efficient construction of the self-energy operator. The SSE-MO method is a real-space method and the central strategy of this method is to use stochastically enumerated sampling of molecular orbitals and molecular-orbital indices for the construction of the 2p1h and 1p2h terms. This is achieved by first constructing a composite MO-index Cartesian coordinate space followed by transformation of the frequency-dependent self-energy operator to this composite space. The evaluation of both the real and imaginary components of the self-energy operator is performed using a stratified Monte Carlo technique. The SSE-MO method was used to calculate the ionization potentials and the frequency-dependent spectral functions for a series of PbS and CdS quantum dots by solving the Dyson equation using both single-shot and iterative procedures. The ionization potentials for both PbS and CdS quantum dots were found to decrease with increasing dot size. Analysis of the frequency-dependent spectral functions revealed that for PbS quantum dots the intermediate dot size exhibited a longer relative lifetime whereas in CdS the smallest dot size had the longest relative lifetime. The results from these calculations demonstrate the efficacy of the SSE-MO method for calculating accurate ionization potentials and spectral functions of chemical systems.

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange-correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an "open teamware" model and an increasingly modular design.

Divided attention may be more important than ever to comprehend, given ubiquitous distractors in modern living. In humans, concern has been expressed about the negative impact of distraction in education, the home, and the workplace. While acetylcholine supports divided attention, in part via muscarinic receptors, little is known about the specific muscarinic subtypes that may contribute. We designed a novel, high-response rate test of auditory sustained attention, in which rats complete variable-ratio runs on one of two levers, rather than emitting a single response. By doing this, we can present a secondary visual distractor task during some trials, for which a correct nosepoke response is reinforced with a more palatable food pellet. The nonspecific muscarinic antagonist scopolamine impaired performance, and slowed and reduced lever press activity. We then explored antagonists that preferentially block the M1 and M4 subtypes, because these receptors are potential therapeutic targets for cognitive enhancers. Telenzepine, an M1-preferring antagonist, impaired divided attention performance, but not performance of the attention task without distraction. Telenzepine also had fewer nonspecific effects than scopolamine. In contrast, the M4-preferring antagonist tropicamide had no effects. Analysis of overall behavior also indicated that accuracy in the main attention task decreased as a function of engagement with the distractor task. These results implicate the M1 receptor in divided attention., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fat-filled milk powders (FMP) are inexpensive milk alternatives predominantly exported to developing countries to satisfy growing demands for dairy proteins. Harsh climatic and sanitary conditions, poor border controls and relatively long periods for distribution and storage enhance the inherent vulnerability of FMP to fraud and stability. Rapid, low-cost methods are needed for extensive routine authentication of FMP products. This study investigated, for the first time, the sample integrity and the quality dynamics of 7 Nigerian FMP brands stored for 7 weeks at 40 °C. The prominent melamine and urea absorption peaks were absent, but protein contents were below the permitted limit. The peak absorbance of the OH functional group increased while the tryptophan contents decreased with storage time. Multiclass analyses differentiated the fresh FMP brands from one another, and from those that were aged. Robust interval-PLS predictions obtained for storage time may be excellent indicators of FMP freshness and stability., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) can induce molecular remissions in indolent lymphoma. The addition of 90 yttrium ibritumomab tiuxetan ( 90 YIT) radioimmunotherapy following first-line induction treatment in patients with advanced follicular lymphoma (FL) may improve remission rates. We now report 10-year follow-up results from our sequential treatment approach with an abbreviated regimen of R-FND followed by 90 YIT consolidation and rituximab maintenance. Forty-nine patients were enrolled; 47 received treatment. Patients had high-risk (FLIPI score ≥3) FL of grade 1-3A and stage III/IV with adequate hematologic function. Following R-FND, the complete and partial response rates were 91% and 8.5%, respectively. After 90 YIT consolidation, the CR rate increased to 97%. The 10-year PFS rate was 49%. The most common non-hematologic, grade 3 or 4 adverse events were fatigue, dyspnea, and myalgia. Five developed myelodysplastic syndrome (MDS). This treatment approach is most appropriate in FLIPI-based high-risk patients whose outlook with standard therapy is inadequate.

We present the frequency-dependent geminal-screened electron-hole interaction kernel (FD-GSIK) method for describing electron-hole correlation in electronically excited many-electron systems. The FD-GSIK is a parameter-free, first-principles method derived from excited-state wave function that was both frequency-dependent and r12-explicitly correlated. The FD-GSIK avoids using unoccupied orbitals for kernel construction by performing an infinite-order summation of particle-hole excitation and representing it as a compact real-space operator. It bypasses the computationally demanding steps of evaluation, storage, and transformation of atomic-orbital integrals by directly evaluating molecular orbital integrals in real space using the stratified Monte Carlo method. We demonstrate and discuss the advantages of this method by presenting excitation and electron-hole binding energies of large nanoparticles including Pb 140 S 140 , Pb 140 Se 140 , Cd 144 Se 144 , and Cd 72 S 72 .

Doping through the incorporation of transition metal ions allows for the emergence of new optical, electrical, and magnetic properties in quantum dots (QDs). While dopants can be introduced into QDs through many synthetic methods, the control of dopant location and host-dopant (H-D) coupling through directional dopant movement is still largely unexplored. In this work, we have studied dopant behaviors in Mn:CdS/ZnS core/shell QDs and found that dopant transport behavior is very sensitive to the temperature and microenvironments within the QDs. The migration of Mn toward the alloyed interface of the core/shell QDs, below a temperature boundary ( T b ) at ∼200 °C, weakens the H-D interactions. At temperatures higher than the T b , however, dopant ejection and global alloying of CdS/ZnS QDs can occur, leading to stronger H-D coupling. The behavior of incorporated dopants inside QDs is fundamentally important for understanding doping mechanisms and the host-dopant interaction-dependent properties of doped nanomaterials.

The serotonergic 5-HT 1A receptor is known to be involved in both impulsivity and anxiety-related behavior. Although anxiety and impulsivity are different constructs, it has been shown that anxiogenesis can result in impulsiveness. It is therefore important to determine if the 5-HT 1A receptor is involved in the commission of impulsive actions independent of its effects on anxiety. The 5-HT 1A agonist 8-OH-DPAT (0.0125-0.1 mg/kg subcutaneous) increased impulsive action at low doses, but decreased it at higher doses, on the novel paced variable consecutive number with discriminative stimulus task (VCN). Neither the 5-HT 1A antagonist WAY 100,635 (0.2-1.2 mg/kg subcutaneous), nor the noradrenergic antagonist and pharmacological stressor yohimbine (1-2 mg/kg intraperitoneal) altered measures of impulsivity. Stress induced by yohimbine was sufficient to produce anxiety-like behavior in the elevated zero maze, confirming that the VCN task is a selective assay of impulsive action that is not affected by anxiety. We hypothesize that the biphasic effect of 8-OH-DPAT is due to actions on presynaptic raphe 5-HT 1A autoreceptors, and also postsynaptic 5-HT 1A receptors. These results suggest that this receptor mediates impulsive action and that this is not secondary to its role in anxiety.

In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents., Methods: This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL., Results: The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls., Conclusions: BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Data on the incidence of adverse liver outcomes are limited for cancer patients with chronic (hepatitis B surface antigen [HBsAg]-positive/hepatitis B core antibody [anti-HBc]-positive) or past (HBsAg-negative/anti-HBc-positive) hepatitis B virus (HBV) after chemotherapy. This study was aimed at determining the impact of test timing and anti-HBV therapy on adverse liver outcomes in these patients., Methods: Patients with solid or hematologic malignancies who received chemotherapy between 2004 and 2011 were retrospectively studied. HBV testing and anti-HBV therapy were defined as early at the initiation of cancer therapy and as late after initiation. Outcomes included hepatitis flares, hepatic impairment, liver failure, and death. Time-to-event analysis was used to determine incidence, and multivariate hazard models were used to determine predictors of outcomes., Results: There were 18,688 study patients (80.4% with solid tumors). The prevalence of chronic HBV was 1.1% (52 of 4905), and the prevalence of past HBV was 7.1% (350 of 4905). Among patients with solid tumors, late identification of chronic HBV was associated with a higher risk of hepatitis flare (hazard ratio [HR], 4.02; 95% confidence interval [CI], 1.26-12.86), hepatic impairment (HR, 8.48; 95% CI, 1.86-38.66), liver failure (HR, 9.38; 95% CI, 1.50-58.86), and death (HR, 3.90; 95% CI, 1.19-12.83) in comparison with early identification. Among patients with hematologic malignancies and chronic HBV, the risk of death was 7.8 (95% CI, 1.73-35.27) times higher for persons with late initiation of anti-HBV therapy versus early initiation. Patients with late identification of chronic HBV had late or no anti-HBV therapy. Chronic HBV predicted liver failure in patients with solid or hematologic malignancies, whereas male sex and late identification were predictors for patients with solid tumors., Conclusions: Early identification correlates with early anti-HBV therapy and reduces the risk of liver failure and death in chronic HBV patients receiving chemotherapy. Cancer 2017;123:3367-76. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Nodular lymphocyte Hodgkin lymphoma (NLPHL) is a rare disease for which the optimal therapy is unknown. We hypothesized that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) could decrease rates of relapse and transformation. We retrospectively reviewed patients with NLPHL diagnosed between 1995 and 2015 confirmed by central pathologic review. Fifty-nine had sufficient treatment and follow-up data for analysis. We described progression-free survival (PFS), overall survival (OS), and histologic transformation according to treatment strategy and explored prognostic factors for PFS and OS. The median age at diagnosis was 41 years; 75% were male, and 61% had a typical growth pattern. Twenty-seven patients were treated with R-CHOP with an overall response rate of 100% (complete responses 89%). The median follow-up was 6.7 years, and the estimated 5- and 10-year PFS rates for patients treated with R-CHOP were 88.5% (95% confidence interval [CI], 68.4% to 96.1%) and 59.3 (95% CI, 25.3% to 89.1%), respectively. Excluding patients with histologic transformation at diagnosis, the 5-year cumulative incidence of histologic transformation was 2% (95% CI, 87% to 100%). No patient treated with R-CHOP experienced transformation. A high-risk score from the German Hodgkin Study Group was adversely prognostic for OS ( P = .036), whereas male sex and splenic involvement were adversely prognostic for PFS ( P = .006 and .002, respectively) but not OS. Our data support a potential role for R-CHOP in patients with NLPHL. Larger prospective trials are needed to define the optimal chemotherapy regimen., (© 2017 by The American Society of Hematology.)

We report a single-centre, randomized study evaluating the efficacy and safety of concurrent fludarabine, mitoxantrone, dexamethasone (FND) and rituximab versus sequential FND followed by rituximab in 158 patients with advanced stage, previously untreated indolent lymphoma, enrolled between 1997 and 2002. Patients were randomized to 6-8 cycles of FND followed by 6 monthly doses of rituximab or 6 doses of rituximab given concurrently with FND. All patients who achieved at least a partial response received 12 months of interferon (IFN) maintenance. Median ages were 54 and 55 years. The two groups were comparable with the exception of a higher percentage of females (65% vs. 43%) and baseline anaemia (23% vs. 11%) in the FND followed by rituximab group. Complete response/unconfirmed complete response rates were 89% and 93%. The most frequent grade ≥ 3 toxicity was neutropenia (86% vs. 96%). Neutropenic fever occurred in 21% and 16%. Late toxicity included myelodysplastic syndrome (n = 3) and acute myeloid leukaemia (n = 5). With 12·5 years of follow-up, no significant differences based on treatment schedule were observed. 10-year overall survival estimates were 76% and 73%. 10-year progression-free survival estimates were 52% and 51%. FND with concurrent or sequential rituximab, and IFN maintenance in indolent lymphoma demonstrated high response rates and robust survival., (© 2017 John Wiley & Sons Ltd.)

Rationale: Cannabinoid CB1 inverse agonists hold therapeutic promise as appetite suppressants but have produced suicidal behaviors among a small subpopulation in clinical trials. Anatomical and pharmacological evidence implicate the 5HT 1A serotonin receptor in suicide in humans and impulsivity in humans and animals., Objective: The objective of the study is to assess whether 5HT 1A blockade is necessary for CB1 ligands to produce impulsivity., Methods: Sprague Dawley rats were administered the CB1 inverse agonist AM 251, the CB1 antagonist AM 6527, or the peripherally restricted antagonist AM 6545, with or without pretreatment with the 5HT 1A antagonist WAY 100,635 (WAY) on the paced fixed consecutive number (FCN) task, which measures choice to terminate a chain of responses prematurely. As FCN is sensitive to changes in time perception, which have been demonstrated with CB1 blockade, a novel variable consecutive number task with discriminative stimulus (VCN-S D ) was also performed and proposed to be less sensitive to changes in timing., Results: Pretreatment with WAY enabled mild but significant reductions in FCN accuracy for AM 251 and AM 6527. No effects were found for AM 6545. On the VCN-S D task, substantial impairments were found for the combination of WAY and AM 251., Conclusions: AM 251, but not the antagonists AM 6527 or AM 6545, produced impulsivity only following systemic 5HT 1A blockade. Although preliminary, the results may indicate that disrupted serotonin signaling produces a vulnerability to undesirable effects of CB1 inverse agonists, which is not evident in the general population. Furthermore, neutral CB1 antagonists do not produce this effect and therefore may have greater safety.

There are limited reports that baseline peripheral absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute lymphocyte count (ALC) and serum β2-microglobulin level independently predict survival in patients with diffuse large B-cell lymphoma (DLBCL). To confirm these findings, we analysed these parameters together with components of the International Prognostic Index (IPI) in patients with newly-diagnosed DLBCL. We evaluated baseline clinical features for their ability to predict survival in 817 newly diagnosed, previously untreated patients with DLBCL who received frontline treatments between October 2001 and December 2011. The median age at diagnosis was 58 years. Multivariate analysis identified elevated baseline ANC (P = 0·036), AMC (P = 0·028) and serum β2-microglobulin level (P < 0·001), poor performance status (P < 0·001) and high number of extranodal disease sites (P = 0·0497) as independent unfavourable predictors of OS; serum β2-microglobulin level was the strongest predictor of survival outcomes among all the parameters. High baseline serum β2-microglobulin, ANC and AMC levels are independent prognostic factors for short overall survival in patients with newly diagnosed DLBCL. Our new model, based on the above five parameters, better stratifies patients into various risk categories than the IPI for newly diagnosed DLBCL., (© 2016 John Wiley & Sons Ltd.)

Cannabinoid CB1 antagonists are widely known to reduce motivation for food, but it is not known whether they induce satiety or reduce reward value of food. It may therefore be necessary to compare effects of altered satiety and reward food value in the same appetitive task, and determine whether CB1 antagonism produces a behavior pattern similar to either, both, or neither. A fine-grained analysis of fixed-ratio 10 (FR10) responding for palatable food initially included number and duration of, and between, all lever presses and food tray entries in order to differentiate the pattern of suppression of prefeeding from that caused by reducing the reward value of the pellets with quinine. Discriminant function analysis then determined that these manipulations were best differentiated by effects on tray entries, pellet retrieval latencies, and time of the first response. At 0.5 mg/kg, AM 6527 produced similar effects to reducing reward value, but at 1.0 and 4.0 mg/kg, effects were more similar to those when animals were satiated. We conclude that AM 6527 both reduced reward value and enhanced satiety, but as dose increased, effects on satiety became much more prominent. These findings contribute to knowledge about the behavioral processes affected by CB1 antagonism., (© The Author(s) 2016.)

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long-term follow-up results for patients treated with these regimens. We present long-term survival outcomes from a pivotal phase II trial of rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R-HCVAD/MA). At 15 years of follow-up (median: 13·4 years), the median failure-free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15-year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10-year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5-12·2%). In patients with newly diagnosed MCL, R-HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one-third of the younger patients (≤65 years)., (© 2015 John Wiley & Sons Ltd.)

A phase II study was performed to evaluate the efficacy of hyper-fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine (HCVIDD/MA) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL), excluding ALK-positive anaplastic large cell lymphoma. Fifty-three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression (n = 13) or prolonged thrombocytopenia (n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression-free survival (PFS) was 7·5 months. With a median follow-up of 7·6 years, 5-year PFS and overall survival (OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer-cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patients, respectively. Of note, 23% of patients discontinued therapy due to prolonged thrombocytopenia. In conclusion, HCVIDD/MA for the first-line treatment of PTCL patients is associated with significant myelosuppression leading to poor treatment adherence, and the response and survival outcomes with this regimen are similar to standard CHOP. This study was registered at www.clinicaltrials.gov as #NCT00290433., (© 2015 John Wiley & Sons Ltd.)

We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas (iNHLs). Of 83 evaluable patients, 91·6% attained an overall response and 86·8% a complete or unconfirmed complete response. The 3-year progression-free survival (PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses (P = 0·01): 83% [95% confidence interval (CI): 0·72, 0·96] for follicular lymphomas, 73% (95% CI: 0·54, 1·0) for marginal zone lymphomas and 61% (95% CI: 0·46, 0·81) for small lymphocytic lymphomas. The most common adverse events were haematological. Of 509 cycles of chemotherapy administered, grade 3 or 4 neutropenia was reported in 68 cycles (13% of cycles administered) and most frequently occurred during cycles 4-6. This is the first report demonstrating the effectiveness of pentostatin, cyclophosphamide and rituximab in patients with previously untreated iNHLs, including those over 60 years of age., Competing Interests: Author's disclosures of potential conflict of interest Employment or leadership positions: None. Non-consultant or advisory role: None. Stock ownership: None. Honoraria: None. Research funding: Pharmatech for supporting the clinical trial. Expert testimony: None. Other remuneration: None., (© 2015 John Wiley & Sons Ltd.)

Nontypeable Haemophilus influenzae (NTHi) is a prevalent bacterium found in a variety of chronic respiratory diseases. The role of this bacterium in the pathogenesis of lung inflammation is not well defined. In this study we examined the effect of NTHi on two important lung inflammatory processes 1), oxidative stress and 2), protease expression. Bronchoalveolar macrophages were obtained from 121 human subjects, blood neutrophils from 15 subjects, and human-lung fibroblast and epithelial cell lines from 16 subjects. Cells were stimulated with NTHi to measure the effect on reactive oxygen species (ROS) production and extracellular trap formation. We also measured the production of the oxidant, 3-nitrotyrosine (3-NT) in the lungs of mice infected with this bacterium. NTHi induced widespread production of 3-NT in mouse lungs. This bacterium induced significantly increased ROS production in human fibroblasts, epithelial cells, macrophages and neutrophils; with the highest levels in the phagocytic cells. In human macrophages NTHi caused a sustained, extracellular production of ROS that increased over time. The production of ROS was associated with the formation of macrophage extracellular trap-like structures which co-expressed the protease metalloproteinase-12. The formation of the macrophage extracellular trap-like structures was markedly inhibited by the addition of DNase. In this study we have demonstrated that NTHi induces lung oxidative stress with macrophage extracellular trap formation and associated protease expression. DNase inhibited the formation of extracellular traps.

Background: The present multicenter phase II trial evaluated the safety and efficacy of pegylated liposomal doxorubicin (PLD) instead of conventional doxorubicin in standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) therapy for elderly patients with diffuse large B-cell lymphoma., Materials and Methods: Patients aged > 60 years who had stage II to IV disease were included. Treatment consisted of rituximab 375 mg/m(2) intravenously (I.V.); cyclophosphamide 750 mg/m(2) IV; PLD 40 mg/m(2) (maximum, 90 mg) I.V. over 1 hour; and vincristine 2.0 mg I.V., all on day 1. Additionally prednisone, 40 mg/m(2), was given orally on days 1 to 1 to 5 (DRCOP [rituximab, cyclophosphamide, PLD, vincristine, and prednisone]). The cycles were repeated every 3 weeks for 6 to 8 cycles., Results: Eighty patients were enrolled and were evaluable for toxicity. The median age was 69 years. All except 1 had additional cardiac risk factors for anthracycline-induced cardiac toxicity beyond advanced age. From the intent-to-treat analysis of 79 eligible patients, the overall response rate was 86%, and the complete response rate was 78%. Cardiac events greater than grade 3 were identified in 3 patients (4%); grade 1 to 2 events, mostly asymptomatic declines in ejection fraction, were noted in another 16 patients. One death was attributed to cardiac failure. The estimated 5-year event-free and overall survival rate was 52% and 70%, respectively., Conclusion: DRCOP represents an effective strategy for potentially mitigating cardiotoxicity in elderly patients with aggressive B-cell lymphoma. Future studies incorporating baseline cardiac risk assessments, long-term follow-up data, and biospecimen collection for correlative science should be undertaken., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma., Methods: In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786., Findings: 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%])., Interpretation: Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress., Funding: Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

(90) Y-ibritumomab-tiuxetan ((90) YIT) was used as a first-line therapy for patients with early-stage follicular lymphoma (FL) or marginal zone B-cell lymphoma (MZL). Thirty-one patients were treated, with an overall 3-month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow-up of 56 months, ten patients (32%) had disease relapse or progression. The progression-free rates at 3 and 5 years were lower in males, patients with FL, stage II disease and non-bulky disease, although they did not reach statistical significance. Grade 3-4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. (90) YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early-stage low-grade B-cell lymphomas. Bulky disease did not adversely affect tumour response., (© 2014 John Wiley & Sons Ltd.)

Relapsed aggressive lymphomas are often treated with platinum-based chemotherapy (PBC) followed by an autologous stem cell transplant (ASCT). Response rates to PBC in patients with relapsed aggressive lymphomas are c. 60%, and non-responders have a dismal prognosis. Novel therapies for aggressive lymphomas, including those failing PBC, are needed. We performed a phase II study of paclitaxel, topotecan and rituximab (TTR) in patients with relapsed or refractory diffuse large B-cell, follicular grade IIIB, or transformed lymphomas, including those who previously failed PBC. The median age of the 72 patients enrolled was 54 years. Responding patients were offered ASCT after two courses. The overall response rate was 69% for all patients (n = 49/71) and 45% for those who previously failed PBC (n = 9/20). With a median follow up of 125 months for the censored observations, the overall survival (OS) and progression-free survival at 5 years was 39% and 27%, respectively. Responding patients who received ASCT had an OS of 63% at 5 years. Our results demonstrate that TTR is an effective salvage regimen for patients with relapsed aggressive B-cell lymphomas, including those who previously failed PBC. Given the declining therapeutic outcomes of salvage PBC in the rituximab era, further evaluation of TTR is warranted., Competing Interests: We have no conflicts of interested related to the current manuscript to disclose., (© 2014 John Wiley & Sons Ltd.)

Abstract The objective of this study was to assess the value of magnetic resonance imaging (MRI) of the orbit for conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. The yield of other staging tests at baseline were also evaluated. Twenty-one consecutive patients treated for conjunctival MALT lymphoma were retrospectively studied. Lymphoma was staged according to both the Ann Arbor system and the seventh edition of the AJCC [American Joint Committee on Cancer] cancer staging manual. Findings on MRI of the orbit, whole-body positron emission tomography/computed tomography (PET/CT), CT of the chest/abdomen/pelvis, bone marrow (BM) biopsy and gastrointestinal (GI) endoscopy were recorded. Seventeen patients had orbital MRI. Fourteen of 17 patients (82%) with obvious conjunctival MALT lymphoma on clinical examination had a negative MRI scan. Only three patients had subtle conjunctival enhancement on orbital MRI. Ann Arbor stage at presentation was as follows: stage IE (15 patients), stage IIE (two patients) and stage IV (four patients). Eighteen of 21 patients had total-body PET/CT; four patients (22%) had hypermetabolic activity evident on PET scan. All 21 patients had bilateral BM biopsies. Fifteen of 21 patients (71%) had GI endoscopy. None of the patients had a positive BM biopsy or findings on GI endoscopy. Our data suggest that orbital MRI has a very low yield for identification of conjunctival MALT lymphoma. Clinical examination is critical in diagnosing and assessing treatment response in conjunctival MALT lymphoma. The yield for GI endoscopy and BM biopsy may also be low in staging of conjunctival MALT lymphoma.

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R-HCVAD) alternating with rituximab, high-dose methotrexate, and cytarabine (R-MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in diffuse large B-cell lymphoma (DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age-adjusted international prognostic index ≥2 to R-HCVAD/R-MA or R-CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate (CRR) was higher with R-HCVAD/R-MA than R-CHOP (P = 0·03); thus, R-CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R-HCVAD/R-MA and R-CHOP arms respectively; CRR were 82% and 60% respectively (P = 0·13); 3-year progression-free survival (PFS) rates were 75·7% and 77·8% respectively (P = 0·53). In the R-HCVAD/R-MA arm, 3-year PFS rates in patients aged 46-60 years and ≤45 years were 70·3% and 87·1% respectively (P = 0·13), and the treatment-associated early mortality rate in patients >45 years was 12%. In conclusion, R-HCVAD/R-MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R-HCVAD/R-MA is associated with unacceptable mortality rates., Competing Interests: L. F. received research funding for this study from Genentech. Other authors disclosed no conflict of interest., (© 2013 John Wiley & Sons Ltd.)

The effects of cannabinoid CB1 agonists (including Δ9-tetrahydrocannabinol, the main psychoactive component of marijuana) on attention are uncertain, with reports of impairments, no effects, and occasionally performance enhancements. To better understand these effects, we sought to uncover a role of changing online (within-session) strategy as a possible mediator of the effects of the novel, potent CB1 agonist AM 4054, on a model of sustained attention in male Sprague-Dawley rats. In this operant, two-choice reaction time (RT) task, AM 4054 decreased accuracy in an asymmetric manner; that is, performance was spared on one lever but impaired on the other. Furthermore, this pattern was enhanced by the outcome of the previous trial such that AM 4054 strengthened a win-stay strategy on the "preferred" lever and a lose-shift strategy on the "nonpreferred" lever. This pattern is often found in tests of expectancy; therefore, in a second experiment AM 4054 enhanced expectancy that we engendered by altering the probability of the two stimulus cues. Accuracy was impaired in reporting the less frequent cue, but only after two or more presentations of the more frequent cue. Taking the results of the experiments together, AM 4054 engendered expectancy by increasing the role of previous trial location and outcome on performance of future trials, diminishing stimulus control (and therefore, accuracy). This novel effect of CB1 receptor agonism may contribute to the deleterious effects of cannabinoids on attention., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing., (© 2013 John Wiley & Sons Ltd.)

BACH2, a B-cell specific transcription factor, plays a critical role in oxidative stress-mediated apoptosis. Bortezomib (Velcade(TM)) is widely used to treat relapsed mantle cell lymphoma (MCL) patients despite varying clinical outcomes. As one of the potential mechanisms of action, bortezomib was reported to elicit endoplasmic reticulum (ER) stress which triggers reactive oxygen species (ROS). In the present study, we investigated the redox-sensitive intracellular mechanism that might play a critical role in bortezomib response in MCL cells. We demonstrated that in MCL cells that are sensitive to bortezomib treatments, BACH2 was translocated to the nucleus in response to bortezomib and induced apoptotic responses through the modulation of anti-oxidative and anti-apoptotic genes. On the other hand, in bortezomib resistant cells, BACH2 expression was confined in the cytoplasm and no suppression of antiapoptotic or antioxidative genes, Nrf2, Gss, CAT, HO-1 and MCL1, was detected. Importantly, levels of BACH2 were significantly higher in bortezomib sensitive MCL patient cells, indicating that BACH2 levels could be an indicator for clinical bortezomib responses. BACH2 translocation to the cytoplasm after phosphorylation was inhibited by PI3K inhibitors and combinatory regimens of bortezomib and PI3K inhibitors sensitized MCL cells to bortezomib. These data suggest that cellular distribution of BACH2 in response to ROS determines the threshold for the induction of apoptosis. Therapies that inhibit BACH2 phosphorylation could be the key for increasing bortezomib cytotoxic response in patients.

Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625-1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625-0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125-0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: In patients with newly diagnosed lymphoma, low bone mineral density (BMD) is common at diagnosis and worsens with therapy. Our randomized phase III trial demonstrates that 2 doses of zoledronic acid (ZA) and supplementation with calcium and vitamin D effectively prevent further bone loss., Background: Patients with lymphoma are at risk of development of bone mineral density (BMD) loss from therapy with high-dose corticosteroids and alkylating agents. Zoledronic acid (ZA), a bisphosphonate, may prevent this complication of therapy. We evaluated the effect of ZA on the change in BMD and surrogate biomarkers in patients with lymphoma receiving initial chemotherapy., Patients and Methods: Our phase III trial randomized 74 patients with newly diagnosed lymphoma and a baseline BMD of ≥ -2.0 to receive oral calcium and vitamin D daily with or without ZA at enrollment and at 6 months after enrollment. BMD was evaluated at baseline and 1 year after enrollment. Secondary biomarker endpoints were collected at baseline and at 3, 6, 9, and 12 months after enrollment., Results: Forty-three percent of patients had baseline osteopenia. Fifty-three patients were evaluable for response: 24 received ZA and had stable BMD during the observation period, whereas 29 patients in the control group had decreased BMD (P < .05 at lumbar spine and bilateral femoral neck). Twenty-one randomized patients were not evaluable for response because of lymphoma progression or death, withdrawn consent/incomplete testing, or ineligibility. Bone biomarkers were higher in the control group at all intervals after treatment (P < .001). No fractures or intervention-related toxicities were observed during this trial., Conclusions: Newly diagnosed patients with lymphoma are at risk of low BMD, which may worsen with therapy. Treatment with ZA effectively stabilizes BMD and prevents bone loss. Our data suggest that BMD testing and prophylaxis should be considered as an early intervention for a preventable problem., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The baseline absolute monocyte count and absolute lymphocyte count were used to generate a prognostic index (the AMLPI) for survival in diffuse large B-cell lymphoma (DLBCL)., Methods: Data from 245 patients with DLBCL who were treated with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) were reviewed. By using the values previously reported for the AMLPI, its prognostic value was examined in our population., Results: After a median follow-up of 22 months for censored observations, the 3-year progression-free survival (PFS) rates for the international prognostic index (IPI) 0-2 and 3-5 risk groups were 73% and 58%, respectively (P = .0004); comparable overall survival (OS) rates were 88% and 68%, respectively (P < .0001). For patients with IPI scores of 0-2, 1-year PFS rates for AMLPI low-, intermediate-, and high-risk groups were 92%, 89%, and 80%, respectively (P = .022); comparable 1-year OS rates were 96%, 95%, and 80%, respectively (P = .049). By multivariate analysis, with the adjustment of IPI in the model, AMLPI effects (low- vs. high-risk groups) on PFS and OS rates were significant, with P = .046 (hazard ratio [HR] 0.402 [95% CI, 0.164-0.986] and P = .052 (HR 0.325 [95% CI, 0.104-1.011]), respectively., Conclusions: The absolute monocyte and lymphocyte counts prognostic index (the AMLPI) may add prognostic value beyond that of the IPI for patients with DLBCL who receive R-CHOP., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma., Patients and Methods: Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks., Results: Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%., Conclusion: SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

Purpose: Patients with follicular lymphoma (FL) registered in the F2-study and initially managed without treatment were analyzed to describe the presentation and outcome of a watch and wait (W&W) strategy in the rituximab era, to identify parameters for initiating treatment, and to evaluate whether initial W&W could have deleterious effects on treatment efficacy after progression or relapse., Patients and Methods: Between 2003 and 2005, 120 patients selected from the 1,093 treatment-naive patients with FL in the F2-study cohort were initially managed expectantly (W&W), and 107 patients were assessed. Most of these patients (80%) had disseminated disease with a low tumor burden according to Groupe d'Etudes des Lymphomes Folliculaires criteria., Results: After a median follow-up of 64 months, treatment was initiated in 54 patients (50%), with a median delay of 55 months for the entire cohort. In a univariate analysis, involvement of more than four nodal areas (hazard ratio [HR], 2.26) and serum albumin less than 3.5 g/dL (HR, 3.51) were predictive of a shorter time to lymphoma treatment initiation. In a multivariate analysis, only involvement of more than four nodal areas remained significant (HR, 2.32). The 4-year freedom from treatment failure (FFTF) rate of W&W patients (79%; 95% CI, 69% to 85%) was not inferior to that of a subgroup of 242 patients from the F2-study cohort with good prognosis characteristics who were initially treated with a rituximab-based regimen (69%; 95% CI, 61% to 76%; P = .103)., Conclusion: In the rituximab era, patients with FL in a selected prognostically favorable group can still be managed with W&W. W&W does not seem to have detrimental effects on FFTF and overall survival rates after treatment.

CB1 antagonists, including rimonabant (SR 141716A), hold considerable therapeutic potential in the reduction of appetite and lipogenesis and in improving the metabolic profile of obese individuals and those with diabetes. However, rimonabant has not been approved in the USA because of its numerous side-effects, including depression and anxiety. Because of this, it is expected that fewer attempts will be made to introduce CB1 antagonists into the market. However, a 'second generation' of compounds has produced promising results in animal models in terms of these side-effects, and may pave the way toward new development and clinical testing of compounds that lack the side-effects of rimonabant. This new generation includes neutral CB1 antagonists, which likely have less intrinsic activity than clinically tested drugs, and peripherally restricted compounds. The current paper reviews the behavioral profile of rimonabant and related compounds, including a similarity in hypophagic effects with putative neutral antagonists and peripherally restricted antagonists. Emerging evidence of a lack of effects in models of nausea, anxiety, and depression is discussed. It is concluded that, with increasing emphasis on modeling the more troublesome side-effects of CB1 antagonists, safe, efficacious therapeutic targets may emerge. Further rigorous preclinical testing should be carried out.

Background: The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL., Methods: Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632., Findings: 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response., Interpretation: Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL., Funding: Celgene., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In the present study, we evaluated the efficacy and safety of rituximab in combination with standard doxorubicin, bleomycin, vinblastine, and dacarbazine (RABVD) in patients with classical Hodgkin lymphoma (cHL). In this phase 2 study, patients with chemotherapy-naive, advanced-stage cHL were treated with rituximab 375 mg/m(2) weekly for 6 weeks and standard ABVD for 6 cycles. The primary outcome was event-free survival (EFS) at 5 years. Eighty-five patients were enrolled, of whom 78 were eligible. With a median follow-up duration of 68 months (range, 26-110), and based on an intent-to-treat analysis, the 5-year EFS and overall survival rates were 83% and 96%, respectively. The 5-year EFS for patients with stage III/IV cHL was 82%. Furthermore, the 5-year EFS for patients with an International Prognostic Score of 0-2 was 88% and for those with a score of > 2, it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutropenia (23%), fatigue (9%), and nausea (8%). Our results demonstrate that the addition of rituximab to ABVD is safe and has a promising clinical activity in patients with advanced-stage cHL. These data are currently being confirmed in a multicenter randomized trial.

Previous studies have shown that interferon-α (IFN-α) and chemotherapy is an effective treatment for patients with newly diagnosed follicular lymphoma. Therefore, we performed a phase II trial to determine the safety and effectiveness of IFN-α and standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy (IABVD) in these patients. Patients with newly diagnosed advanced stage classic Hodgkin lymphoma (HL) were enrolled between July 1997 and March 2000 on IABVD as initial therapy. This consisted of six cycles of ABVD with concurrent IFN-α followed by radiation therapy if indicated. IFN-α 6 million IU/m(2) was administered subcutaneously daily for 3 days and on day 4 patients received IFN-α with ABVD. Courses were repeated every 2 weeks for a maximum of 12 courses. IFN-α dose reduction was allowed for cytopenia. Outcome and baseline characteristics were reported. Thirty patients (median age, 30 years [range, 18-62 years]) were evaluable. Patients had Ann Arbor stage II (7%), III (30%) or IV (63%) disease, and 47% were at intermediate or high risk, as defined by the International Prognostic Score (≤ 2 vs. > 2). The 3-year event-free survival rate was 71% (95% confidence interval [CI], 56-90%), and the 3-year overall survival rate was 96% (95% CI, 89-100%). Treatment was well tolerated, with only three patients requiring IFN-α dose reduction or discontinuation because of cytopenia. IABVD is an effective regimen against advanced HL and is well tolerated. However, because of the emergence of effective new biologic agents, further development of this regimen is not warranted.

Elevated serum CD44, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been linked to poor prognosis in aggressive lymphomas, but their utility in low grade lymphomas remains undefined. We evaluated serum CD44, VCAM-1 and ICAM-1 levels in 100 patients with newly diagnosed indolent NHL. The median pre-treatment values of the markers were as follows: CD44 540 ng/mL (range 156-1201), ICAM-1 311 ng/mL (range 102-1222) and VCAM-1 1165 ng/mL (range 248-4779). On univariate analysis, elevated sCD44, sICAM-1 and sVCAM-1 were significantly associated with worse overall (OS) and progression-free survival (PFS). In a subset analysis of patients with stage IV disease, the effects of sCD44 and sICAM-1 on OS persisted (p<0.05), as did the effect of sCD44 on PFS (p<0.01). In a multivariate analysis that included conventional prognostic factors and the Follicular Lymphoma International Prognostic Index (FLIPI) model, sICAM-1 demonstrated prognostic value for OS and PFS. We conclude that serum CD44, ICAM-1 and VCAM-1 can potentially be prognostic in patients with indolent NHL. Though the FLIPI model remains the gold standard for prognosis, these quantitative serologic markers may be useful as adjunct tools in assessing disease risk.

Radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab combines a radiation-emitting radionuclide with an antibody targeting CD20 to treat B-cell non-Hodgkin lymphoma. Multiple studies demonstrate favorable RIT efficacy and safety profiles in follicular lymphoma (FL). The primary toxicity is reversible myelosuppression. Various FL treatment options include single-agent immunotherapy, radiation, chemoimmunotherapy, and RIT. Examining RIT clinical effects and position within treatment algorithms is important to optimal patient benefit. Clinical studies support using single-agent RIT in relapsed/refractory FL, in selected patients with new, untreated FL, and as consolidation after induction chemotherapy or chemoimmunotherapy. RIT as consolidation enhances response rates (with conversion of partial to complete responses following induction therapy) and prolongs disease control versus observation. The overall response rate is 60-80% in the relapsed setting. Time to progression is longer with low-bulk disease, fewer prior therapies, and retained rituximab sensitivity. RIT apparently does not preclude subsequent therapies or increase risk of secondary malignancies compared with chemotherapy's known risk. This article summarizes consensus recommendations for RIT and presents RIT treatment algorithms developed by hematologists/oncologists who regularly treat patients with FL. Maximizing RIT benefit requires healthcare providers to utilize algorithms assisting with treatment decisions.

Treatment results are improving for patients who have advanced-stage follicular lymphoma; this progress is in large part related to the inclusion of anti-CD20 monoclonal antibody therapy in front-line therapy programs. Rituximab has been combined successfully in chemo-immunotherapy regimens with several standard chemotherapy combinations, and with bendamustine. Post-remission treatment strategies, including radioimmuotherapy consolidation and rituximab maintenance, have had a favorable impact on duration of remission. Thus, although traditional palliative strategies can still have a role in many situations, such approaches must now be placed in perspective with options that have the potential to achieve durable disease control. Recent therapeutic advances have renewed the hope that potentially curative treatment options may be forthcoming for these patients., (Copyright © 2011. Published by Elsevier Inc.)

Purpose: Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas., Patients and Methods: We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas)., Results: Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis., Conclusions: Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.