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.).
•Soil water evaporation pattern under high temperature is different from ambient levels.•The behavior of evaporation from the surface of the soil body significantly enhances the dewatering effect of ...high temperature heat sources on the soil abody.•The temperature gradient in the shallow soil (0–20 cm) and the moisture content gradient in the superficial soil (0–10 cm) at high temperature significantly affect the evaporation coefficient of the soil.
The high-temperature dewatering method has a broad application prospect in loess reinforcement, and the evaporation boundary is a crucial factor in determining the dewatering effect. This study conducts evaporation tests on unsaturated loess columns at high temperatures using a self-made high-temperature evaporation test apparatus to reveal the laws of water and heat transfer and surface evaporation in unsaturated loess under high temperatures. Based on the study's results, high temperatures have a significant driving effect on water. Under high temperatures, the portion of soil near the hot end is rapidly dewatered, forming a drying zone. The presence of an evaporation boundary intensifies the high-temperature dewatering effect. Under hot-end dewatering and surface evaporation, soil water content presents the distribution laws of high at both ends and low in the middle. High temperatures greatly increase surface evaporation. The water content and temperature of surface soil significantly affect evaporation intensity, as do the water gradient and temperature gradient of shallow soil. The evaporation coefficient, defined as the ratio of evaporation intensity to saturated evaporation intensity (potential evaporation intensity), is employed to characterize soil evaporation efficiency. The evaporation coefficient measured under high temperatures is found to be higher than that calculated by the existing models for the evaporation coefficient. A new evaporation coefficient model is built using modifying existing models. The new model comprehensively considers surface and shallow soil temperatures and water contents. Validation results showed that the model can more precisely calculate the evaporation rate of surface soil under the influence of a high-temperature heat source. The research results of this paper reveal the evaporation characteristics of the surface and water migration characteristics inside loess under high temperature, which is helpful for promoting the application of thermal dewatering method in the reinforcement engineering of loess pit slopes.
Patients of diabetes mellitus urgently need noninvasive and continuous glucose monitoring in daily point-of-care. As the tear glucose concentration has a positive correlation with that in blood, the ...hydrogel colloidal crystal integrated into contact lens possesses promising potential for noninvasive monitoring of glucose in tears. This paper presents a new glucose-responsive sensor, which consists a crystalline colloidal array (CCA) embedded in hydrogel matrix, attached onto a rigid gas permeable (RGP) contact lens. This novel sensing lens is able to selectively diffract visible light, whose wavelength shifts between 567 and 468 nm according to the alternation of the glucose concentration between 0 and 50 mM and its visible color change between reddish yellow, green, and blue. The detection limit of responsive glucose concentration can be reduced to 0.05 mM. Its combination with a contact lens endows it with excellent biocompatibility and portability, which shows great possibility for it to push the development of glucose-detecting devices into new era.
Muscle-invasive bladder cancer has a 40% to 60% 5-year survival rate with radical treatment by surgical removal of the bladder or radiation therapy–based bladder preservation techniques, including ...concurrent chemoradiation. Elderly patients cannot tolerate current chemoradiation therapy regimens and often receive only radiation therapy, which is less effective. We urgently need effective chemotherapy agents for use with radiation therapy combinations that are nontoxic to normal tissues and tolerated by elderly patients.
We have identified histone deacetylase (HDAC) inhibitors as promising agents to study. Pan-HDAC inhibition, using panobinostat, is a good strategy for radiosensitization, but more selective agents may be more useful radiosensitizers in a clinical setting, resulting in fewer systemic side effects. Herein, we study the HDAC class I-selective agent romidepsin, which we predict to have fewer off-target effects than panobinostat while maintaining an effective level of tumor radiosensitization.
In vitro effects of romidepsin were assessed by clonogenic assay and showed that romidepsin was effective in the nanomolar range in different bladder cancer cells and radiosensitized these cells. The radiosensitizing effect of romidepsin was confirmed in vivo using superficial xenografts. The drug/irradiation combination treatment resulted in significant tumor growth delay but did not increase the severity of acute (3.75 days) intestinal normal tissue toxicity or late toxicity at 29 weeks. Moreover, we showed that romidepsin treatment impaired both homologous recombination and nonhomologous end joining DNA repair pathways, suggesting that the disruption of DNA repair pathways caused by romidepsin is a key mechanism for its radiosensitizing effect in bladder cancer cells.
This study demonstrates that romidepsin is an effective radiosensitizer in vitro and in vivo and does not increase the acute and late toxicity after ionizing radiation. Romidepsin is already in clinical use for the cutaneous T-cell lymphoma, but a phase 1 clinical trial of romidepsin as a radiosensitizer could be considered in muscle-invasive bladder cancer.
Previous meta-analyses have reported the superiority of tanezumab versus placebo in the treatment of osteoarthritis (OA). However, they did not compare different injection methods (intravenous or ...subcutaneous), doses of injection.
The goal of this network meta-analysis (NMA) was to evaluate the therapeutic effects of different dosages and methods of injection of tanezumab on relieving pain in patients with OA.
An online systematic search was performed by using the PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov databases from inception to November 9, 2019. The goal was to identify randomized controlled trials (RCTs) that concentrated on the therapeutic effects of different dosages and methods of injection of tanezumab in patients with OA. The pairwise meta-analyses with the fixed effects model were undertaken with the “meta” package using R 3.6.0 programming language. In addition, an NMA with fixed effects was assessed using a gemtc software. The surface under the cumulative ranking curve value of each intervention was calculated to obtain a hierarchy of treatments.
Of the 328 RCTs identified through the literature search, 12 RCTs were included in the current NMA. In terms of the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales, the most effective treatment was intravenous injection of tanezumab (10 mg; surface under the cumulative ranking curve values of 90% and 88%, respectively), and the least effective therapy was subcutaneous injection of tanezumab (2.5 mg; 20% and 19%).
To achieve high therapeutic efficacy and avoid treatment failure, an intravenous injection of tanezumab (10 mg) is recommended as an efficacious therapy, facilitating pain relief in patients with OA. However, this conclusion may also be affected by the limitations of this study owing to the small sample size and data heterogeneity, and further research should therefore be conducted to eliminate these limitations and to confirm the findings.
Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely ...unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE.
C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus.
CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities.
Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.
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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Nanosecond pulsed laser etching for fabricating anti-reflective gratings and inducing synchronous laser annealing was performed on Ag/AZO films. The optimum grating pitch was determined by ...performance analyses of laser-etched unidirectional gratings, based on which laser-etched bidirectional gratings were fabricated to further determine the optimum grating tilt angle. The results revealed that with the increase of grating pitch, the grating ridge total-side-area was gradually decreased to cause a gradually weakened anti-reflective effect, but the superimposed heat-affected zones between adjacent grooves became smaller or even disappeared, which brought about different synchronous laser annealing effects. The unidirectional grating-textured film with a medium grating pitch of 200 μm showed the best overall performance under the combined influence from anti-reflective gratings and synchronous laser annealing. For the bidirectional gratings, although increasing the grating tilt angle did not change the grating ridge total-side-area, it would enable the laser energy to be more uniformly distributed on the whole film surface, producing a better synchronous laser annealing effect. The bidirectional grating-textured film with a grating tilt angle of 90° had the best overall performance with the highest FOM value of 2.18 × 10−2 Ω−1 that was ∼3.2 times that of the as-prepared film. The results are instructive for preparing high-performance TCO-based films.
To compare recurrence and survival in patients with stage III endometrial cancer after radical surgery, followed by either adjuvant chemoradiotherapy (ACR) or adjuvant chemotherapy (AC).
We searched ...for relevant studies in PubMed Central, Embase and the Cochrane Central Register of Controlled Trials. Data were pooled on rates of recurrence as well as rates of progression-free, disease-free and overall survival. Heterogeneity was evaluated using the I
test. Subgroup and sensitivity analyses were performed to identify potential sources of heterogeneity.
Data from 18,375 patients in 15 retrospective studies and one randomized controlled trial were meta-analyzed. Compared to the AC group, the ACR showed significantly lower risk of local recurrence (OR 0.43, 95%CI 0.32-0.59) and total recurrence (OR 0.72, 95%CI 0.58-0.89). ACR was also associated with significantly better overall survival (HR 0.66, 95%CI 0.57-0.76), progression-free survival (HR 0.56, 95%CI 0.39-0.81) and disease-free survival (HR 0.66, 95%CI 0.53-0.83).
Adding adjuvant radiotherapy to adjuvant chemotherapy after radical surgery may significantly reduce risk of local and overall recurrence, while significantly improving survival of patients with stage III endometrial cancer.
Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously ...demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.
•Ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle could be safely administered to patients with previously treated MCL.•Complete responses and duration of response (median, >2 years) were high relative to studies of single-agent ibrutinib.
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