VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a ...VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma.
For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117.
Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio HR 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months 5·5–6·5 vs 5·4 months 4·5–5·7). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months 9·9–11·9 in the ramucirumab group vs 10·7 months 9·5–11·9 in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 26% of 323 patients in the ramucirumab group vs 85 27% of 315 in the placebo group), anaemia (39 12% vs 44 14%), and hypertension (32 10% vs 5 2%). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 4% in the ramucirumab group vs 21 7% in the placebo group) and diarrhoea (11 3% vs 19 6%). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1).
Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population.
Eli Lilly and Company.
Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with ...non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index IPI score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m
intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.
Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term ...tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL.
In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety.
The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients.
Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.
ABSTRACT
Introduction
Spinal cord injuries (SCI) in military personnel, veterans, and others require an evidence-based, multidisciplinary approach to their care. This appraisal used the Appraisal of ...Guidelines for Research and Evaluation (AGREE) II instrument to evaluate the methodological quality of clinical guidelines for the management of SCI published by the Paralyzed Veterans of America (PVA) organization.
Materials and Methods
We searched clinical guidelines on SCI published by PVA until December 2019. Four appraisers across three international centers independently evaluated the quality of eligible clinical guidelines using AGREE II. Mean AGREE II scores for each domain were calculated. In higher quality domains, scores for individual items were analyzed.
Results
A total of 12 guidelines published by PVA on SCI were assessed. Mean scores for all six domains were as follows: Scope and Purpose (78.8%), Stakeholder Involvement (63.7%), Rigor of Development (68.4%), Clarity of Presentation (80.1%), Applicability (53.0%), and Editorial Independence (28.5%). The mean score for the overall quality of all PVA guidelines was 71.9% (95% CI: 69.7–74.1). No guideline was assessed as “not recommended” by any appraiser. Overall quality was significantly associated with year of publication (rs = 0.754, P = 0.0046). Overall agreement among appraisers was excellent (intraclass correlation coefficients for each guideline ranged from 0.96 to 0.99).
Conclusions
PVA guidelines for the management of SCI demonstrated acceptable or good quality across most domains. We recommend the use of PVA guidelines for the assessment and treatment of SCI and related disorders. The quality of PVA guidelines for the management of SCI have improved over time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
TiO(2) nanoparticles (< 100 nm diameter) have been reported to cause oxidative stress related effects, including inflammation, cytotoxicity and genomic instability, either alone or in the presence of ...UVA irradiation in mammalian studies. Despite the fact that the aquatic environment is often the ultimate recipient of all contaminants there is a paucity of data pertaining to the potential detrimental effects of nanoparticles on aquatic organisms. Therefore, these investigations aimed to evaluate the potential cytotoxic and genotoxic effects of TiO(2) nanoparticles on goldfish skin cells (GFSk-S1), either alone or in combination with UVA. Whilst neutral red retention (NRR) assay (a measure of lysosomal membrane integrity) was used to evaluate cell viability, a modified Comet assay using bacterial lesion-specific repair endonucleases (Endo-III, Fpg) was employed to specifically target oxidative DNA damage. Additionally, electron spin resonance (ESR) studies with different spin traps were carried out for qualitative analysis of free radical generation. For cell viability, TiO(2) alone (0.1-1000 microg ml(-1)) had little effect whereas co-exposure with UVA (0.5-2.0 kJm(-2)) caused a significant dose-dependent decrease which was dependent on both the concentration of TiO(2) and the dose of UVA administered. For the Comet assay, doses of 1, 10 and 100 microg ml(-1) in the absence of UVA caused elevated levels of Fpg-sensitive sites, indicating the oxidation of purine DNA bases (i.e. guanine) by TiO(2). UVA irradiation of TiO(2)-treated cells caused further increases in DNA damage. ESR studies revealed that the observed toxic effects of nanoparticulate TiO(2) were most likely due to hydroxyl radical (OH) formation.
Summary
Hypomethylating agents (HMAs) are standard of care for higher‐risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose ...their response. Pracinostat is a pan‐histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single‐agent HMA treatment. The goal was to estimate the clinical improvement rate complete remission (CR), marrow CR, partial response (PR) and haematological improvement. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single‐agent HMAs. Forty‐five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
Novel psychoactive substances, such as designer benzodiazepines (DBZD), are a growing public health concern. There are about 30 different DZBDs reported, which can vary widely in their effect and ...potential for harmful outcomes, ranging from agitation to confusion to coma. Despite the scope of this widespread phenomena, little information on the management of DBZD dependence is available in the literature.
In this case report, we present a patient with DBZD dependence requesting assistance tapering off the DBZD, clonazolam. He began self-medicating with clonazolam seven years prior for panic attacks to the point he was using 40 drops per day and having significant withdrawal during the day. He was prescribed gabapentin for his underlying anxiety while he tapered his clonazolam dose. Once he achieved a 75% reduction in his use of clonazolam, he had trouble managing withdrawal and anxiety symptoms and could not taper further.
We discuss the challenges of treating patients with DBZD use disorder in an outpatient setting. Switching a patient from a DZBD to a prescription benzodiazepine for the purposes of a taper can be dangerous as an outpatient due to the inability to monitor at-home DBZD usage and the resulting risk of overdose. DBZDs can also be highly potent and make it difficult to achieve success using current withdrawal guidelines.
Background
First‐line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5‐fluorouracil/leucovorin/oxaliplatin (FOLFOX) or ...5‐fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI‐BEV) or sequentially (sFOLFOXIRI‐BEV, FOLFOX‐BEV alternating with FOLFIRI‐BEV), versus FOLFOX‐BEV for mCRC.
Patients and Methods
Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI‐BEV, sFOLFOXIRI‐BEV, or FOLFOX‐BEV and treated with 4–6‐month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first‐line cFOLFOXIRI‐BEV vs. FOLFOX‐BEV) and progression‐free survival (PFS; pooled first‐line cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV vs. FOLFOX‐BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety.
Results
ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI‐BEV, sFOLFOXIRI‐BEV, and FOLFOX‐BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI‐BEV and FOLFOX‐BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI‐BEV versus FOLFOX‐BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5–0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI‐BEV), 9.8% (sFOLFOXIRI‐BEV), and 8.4% (FOLFOX‐BEV). Grade ≥ 3 treatment‐emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI‐BEV), 86.7% (sFOLFOXIRI‐BEV), and 85.6% (FOLFOX‐BEV) of patients, with no increase in serious chemotherapy‐associated TEAEs.
Conclusion
cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX‐BEV, supporting triplet chemotherapy plus BEV as a first‐line treatment option for mCRC.
Implications for Practice
The combination of first‐line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI‐BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI‐BEV or FOLFOX‐BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI‐BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI‐BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI‐BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first‐line treatment options for this population.
摘要
背景。转移性结直肠癌 (mCRC) 的一线治疗通常需要生物制剂，如贝伐单抗 (BEV)，以及 5‐氟尿嘧啶/亚叶酸钙/奥沙利铂 (FOLFOX) 或 5‐氟尿嘧啶/亚叶酸钙/伊立替康 (FOLFIRI)。STEAM (NCT01765582) 评估了BEV 和 FOLFOX/FOLFIRI (FOLFOXIRI) 在同步用药 (cFOLFOXIRI‐BEV) 或序贯用药(sFOLFOXIRI‐BEV，FOLFOX‐BEV 与 FOLFIRI‐BEV 交替使用)的情况下对比 FOLFOX‐BEV 治疗 mCRC 的有效性。
患者和方法。既往未经治疗的 mCRC 患者 (n = 280) 按照 1:1:1 的比例被随机分配使用 cFOLFOXIRI‐BEV、sFOLFOXIRI‐BEV 或 FOLFOX‐BEV，并在进行 4~6 个月的诱导治疗之后接受维持治疗。共同的主要终点为总缓解率(ORR；一线 cFOLFOXIRI‐BEV vs. FOLFOX‐BEV)以及无进展生存期(PFS；联合一线 cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV vs. FOLFOX‐BEV)。次要/探索性终点包括总生存期 (OS)、肝脏切除率、生物标志物分析和安全性。
结果。cFOLFOXIRI‐BEV、sFOLFOXIRI‐BEV 和 FOLFOX‐BEV 的 ORR 分别为 72.0%、72.8% 和 62.1%，中位 PFS 分别为 11.9 个月、11.4 个月和 9.5 个月。组间的 OS 很相似。cFOLFOXIRI‐BEV 和 FOLFOX‐BEV 之间的 ORR 没有显著差异 (p = 0.132)；因此，未达到主要 ORR 终点。无论 RAS 状态如何，cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV 均在数字方面改进了 ORR 和 PFS。联合同步和序贯 FOLFOXIRI‐BEV 对比 FOLFOX‐BEV 的中位 PFS 更高(11.7 个月vs. 9.5 个月；风险比，0.7；90% 置信区间，0.5–0.9；p < 0.01)。肝脏切除率为 17.2% (cFOLFOXIRI‐BEV)、9.8% (sFOLFOXIRI‐BEV) 和 8.4% (FOLFOX‐BEV)。在 91.2% (cFOLFOXIRI‐BEV)、86.7% (sFOLFOXIRI‐BEV) 和 85.6% (FOLFOX‐BEV) 的患者中观察到治疗相关的 ≥ 3 级不良反应 (TEAE)，与严重化疗相关的 TEAE 没有增加。
结论。 与 FOLFOX‐BEV 对比而言，cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV 具有良好的耐受性，在数字方面改进了 ORR、PFS 和肝脏切除率，因而支持将三联化疗加 BEV 作为 mCRC 的一线治疗方案。
实践意义:相对于 FOLFIRI‐BEV 或 FOLFOX‐BEV，一线 FOLFIRI 与 FOLFOX 和贝伐单抗(同步 FOLFOXIRI‐BEV)的组合可以为转移性结直肠癌 (mCRC) 患者改进临床结果，但是，该组合方案被认为与毒性增加有关。FOLFOX 和 FOLFIRI(序贯 FOLFOXIRI‐BEV)交替治疗可以提高耐受性。在 II 期 STEAM 试验(即美国患者中最大型的 FOLFOXIRI‐BEV 研究)中，我们发现同步和序贯 FOLFOXIRI‐BEV 对既往未经治疗的 mCRC 患者具有活性和良好的耐受性，因而支持使用此类疗法作为针对此类人群的潜在一线治疗方案。
First‐line treatment for metastatic colorectal cancer is usually a combination of a biologic, such as bevacizumab, with FOLFIRI or FOLFOX; however, these treatments are associated with increased toxicity. This article reports the results of the phase II STEAM trial, which was the largest study of FOLFOXIRI‐BEV in patients in the U.S., comparing the clinical efficacy and tolerability of FOLFOXIRI‐BEV vs FOLFOX‐BEV.
Biochar is the solid residue produced by the pyrolysis of any bio-organic material under low, or no, oxygen conditions and has generated considerable interest as a means to sequester carbon in, and ...improve the quality of, soils. However, the exact properties of biochar depend on its composition, which in turn depends on the composition of the starting material and the temperature and conditions under which the biochar is produced. Mid-infrared spectroscopy offers an excellent and rapid method for characterizing both the starting materials and the resulting biochar. Results using diffuse reflection infrared Fourier transform spectroscopy (DRIFTS) have shown that spectral changes can be easily correlated with the production temperature and that DRIFTS offers a rapid method for biochar characterization. It was demonstrated that as the temperature increases biochars become increasingly more aromatic and carbonaceous in nature. We also showed that biochars are spectrally very similar to kerogens and coals; therefore, the methods and knowledge developed from decades of studies on these materials should greatly improve our understanding of biochar composition and effects in soil. This work indicates that rapid characterization using DRIFTS can be used to predict the nature of biochar and to determine the production conditions needed to produce a so-called “Designer Biochar” which will have properties of benefit to soil quality as well as sequestering carbon.
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