Abstract
Ants are key ecosystem service providers and can serve as important biological control agents in pest management. However, the effects of insecticides on common farmland ant species are ...poorly understood. We tested the effects of three commonly used insecticides on ants (Hymenoptera, Formicidae). The tested insecticides were acetamiprid (neonicotinoid; formulated as Mospilan 20 SP), deltamethrin (pyrethroid; formulated as Sanium Ultra), and sulfoxaflor (sulfilimine; formulated as Gondola). We tested two ant (Hymenoptera: Formicidae) species with different colony founding strategies,
Lasius niger
(Linnaeus, 1758) and
Myrmica rubra
(Linnaeus, 1758). We sprayed their queens with insecticides at concentrations recommended for use in foliar applications in agriculture, i.e., at 1.25 g L
−1
(acetamiprid), 0.6 g L
−1
(sulfoxaflor), and 0.875 g L
−1
(deltamethrin). Further, we diluted the compounds in distilled water and tested them at 10%, 1%, and 0.1% of the field-recommended concentrations, and used distilled water as a control. We monitored the survival of the queens and the number of eggs laid. All three tested insecticides caused severe lethal and sublethal concentration-dependent effects. Even at concentrations three orders of magnitudes lower than recommended for field applications, significantly lower numbers of eggs were found in the queens’ nests. The extent of the sublethal effects of acetamiprid and sulfoxaflor was concentration-dependent and differed between the two ant species. Besides bees and bumblebees, ants represent an important group of hymenopterans that are severely affected even by low concentrations of the tested compounds and therefore should be included in risk assessment schemes.
Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 ...antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy.
We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life.
A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome ("tumor flare") (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval CI, 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2-year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life.
Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; ClinicalTrials.gov number, NCT01472562.).
Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for ...discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58
61 years,
=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85
87 months,
=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.
Motivated by COVID-19, we develop and analyze a simple stochastic model for the spread of disease in human population. We track how the number of infected and critically ill people develops over time ...in order to estimate the demand that is imposed on the hospital system. To keep this demand under control, we consider a class of simple policies for slowing down and reopening society and we compare their efficiency in mitigating the spread of the virus from several different points of view. We find that in order to avoid overwhelming of the hospital system, a policy must impose a harsh lockdown or it must react swiftly (or both). While reacting swiftly is universally beneficial, being harsh pays off only when the country is patient about reopening and when the neighboring countries coordinate their mitigation efforts. Our work highlights the importance of acting decisively when closing down and the importance of patience and coordination between neighboring countries when reopening.
We report 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab (LR) as initial treatment of mantle cell lymphoma (MCL). The regimen includes induction and maintenance with ...the LR doublet. Treatment was continuous until progression, with optional discontinuation after 3 years. The median age of the 38 participants was 65 years, with MCL international prognostic index scores balanced among low, intermediate, and high risk (34%, 34%, and 32%, respectively). Twenty-seven (75%) of the 36 evaluable patients completed ≥3 years of study treatment. At a median follow-up of 64 months (range, 21-78), the 3-year progression-free survival (PFS) and overall survival (OS) were 80% and 90%, respectively, with 5-year estimated PFS and OS of 64% and 77%, respectively. During maintenance, hematologic adverse events (AEs) included asymptomatic grade 3 or 4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia) and mostly grade 1 or 2 infections managed in the outpatient setting (45% upper respiratory infection, 21% urinary tract infection, 13% sinusitis, 11% cellulitis, 8% pneumonia). Nonhematologic AEs, such as constitutional and inflammatory symptoms, occurred at reduced frequency and intensity compared with induction. A peripheral blood minimal residual disease (MRD) assay (clonoSEQ) showed MRD-negative complete remission in 8 of 10 subjects who had completed ≥3 years of treatment and with available samples for analysis. With longer follow-up, LR continues to demonstrate durable responses and manageable safety as initial induction and maintenance therapy for MCL (ClinicalTrials.gov NCT01472562).
•Lenalidomide plus rituximab as induction and maintenance therapy for MCL can achieve durable MRD-negative complete remissions.•Chronic therapy–associated adverse events are generally nonaccumulative and remain manageable.
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We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients ...with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Given the poor prognosis of MYC-overexpressing diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma/high grade B cell ...lymphoma (BCLU/HGBL), and preclinical data suggesting that MYC may regulate the antitumor immune response, we sought to characterize expression of immune checkpoint proteins on tumor tissue from patients diagnosed with these lymphomas. Immunohistochemical staining for immune checkpoint protein expression was applied to 56 cases of MYC-overexpressing DLBCL and BCLU/HGBL, 35 of which also harbored
MYC
rearrangement (MYC-R). Analysis revealed both frequent overexpression of immune checkpoint proteins as well as differences in overexpression patterns based upon MYC-R status, with MYC-R cases more likely to overexpress PD-L1 and PD-1 in the tumor microenvironment (50 vs. 15%,
p
= 0.02 and 32 vs. 5%,
p
= 0.02, respectively) but less likely to overexpress CTLA-4 and CD80 on tumor cells (34 vs. 71%,
p
= 0.01 and 34 vs. 81%,
p
= 0.001, respectively), as compared to cases without MYC-R. These data may suggest a biologic rationale for investigation of the effect of checkpoint inhibitor therapies in these subgroups of MYC-overexpressing DLBCL and BCLU/HGBL.
Background
Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued ...owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy.
Materials and Methods
Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post‐CBT treatment using the Lugano criteria. Secondary aims included progression‐free survival (PFS), duration of response, and overall survival (OS).
Results
Eighty‐one patients were included. Seventy‐two percent had stage III–IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post‐CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post‐CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post‐CBT regimen.
Conclusion
In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post‐CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.
Implications for Practice
Novel, life‐prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment‐related toxicity and thus improve patient quality of life.
This study investigated the outcome of checkpoint blockade therapy on subsequent treatment for patients with relapsed and refractory Hodgkin lymphoma in a large, multicenter, retrospective analysis.
The article examines the impact of the addition of Al, Ni, and Bi to a zinc bath on the microstructure and corrosion resistance of hot dip galvanizing coatings. The microstructure on the surface and ...the cross-section of the coatings obtained in the Zn-AlNiBi bath were examined. The corrosion resistance of the coatings was assessed by the standard neutral salt spray test (EN ISO 9227), the sulfur dioxide test in a humid atmosphere (EN ISO 6988), and the electrochemical test. The corrosion resistance of Zn-AlNiBi coatings was compared with the corrosion resistance of coatings attained in the bath of “pure” zinc. The corrosion tests showed higher corrosion wear of the coating obtained in the Zn-AlNiBi bath and a higher value of the corrosion current density for this coating. It was found that the cause of the reduction of the corrosion resistance of the coating, in contrast to the coating obtained in the “pure” zinc bath, may be the presence of bismuth precipitates in the coating, which may form additional corrosion cells.
Classical Hodgkin lymphoma (cHL) is one of the most common lymphomas in the Western world. Although most patients are cured with standard first-line therapy, up to 20% of patients will have relapsed ...or refractory disease. Although the conventional approach to treatment has consisted of chemotherapy, radiation, and for those who relapse, autologous or allogeneic transplantation, newer approaches have become available in recent years, including immunoconjugates and checkpoint inhibitors. These approaches have shown significant efficacy in clinical trials and might be associated with fewer long-term toxicities compared with conventional therapies. In this review we discuss the biology of cHL as it pertains to the immunosuppressive tumor microenvironment and then review the existing clinical trial results of several emerging immunotherapies in this context, including immune checkpoint inhibitors and adoptive cellular therapy. Finally, several clinical practice issues pertaining to the use of immunotherapies are discussed.
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