STUDY OBJECTIVE To compare the efficacy and safety of once-weekly and twice-weekly bortezomib therapy in patients with hematologic malignancies. DESIGN Meta-analysis of 13 clinical or randomized controlled trials, with trial sequential analysis (TSA). PATIENTS A total of 1567 patients with hematologic malignancies who received either once-weekly or twice-weekly bortezomib therapy. MEASUREMENTS AND MAIN RESULTS We conducted a comprehensive literature search of the PubMed, EMBASE, and Cochrane Library databases. A meta-analysis was conducted to calculate the pooled effect size; TSA was performed to assess the reliability of the pooled results. The pooled risk ratio (RR) for the overall response rate (ORR) was 1.00 (95% confidence interval [CI] 0.77-1.29, p=0.99), indicating no significant differences between patients who received once-weekly bortezomib and those who received twice-weekly bortezomib. TSA showed that the cumulative Z-curve of the ORR entered the futility area, implying that reliable evidence was obtained for this pooled result. The pooled RR for any grade of peripheral neuropathy was 0.48 (95% CI 0.26-0.88, p=0.02); however, the TSA plot revealed that there was insufficient evidence for this result. The pooled RR for peripheral neuropathy grade 3 or higher was 0.21 (95% CI 0.13-0.34, p<0.00001), and reliable evidence was obtained according to TSA. Regarding the other toxicities, including anemia, thrombocytopenia, neutropenia, infection, diarrhea, constipation, nausea, vomiting, and fatigue, we did not find any significant differences between patients who received once-weekly bortezomib and those who received twice-weekly bortezomib. CONCLUSION Compared with twice-weekly bortezomib, once-weekly bortezomib had a comparable ORR and a probable lower incidence of peripheral neuropathy. More clinical trials are needed to draw a conclusion regarding the difference in peripheral neuropathy between the two groups because of the insufficient evidence detected by TSA and the inconsistent results among subgroups.
Aim: To explore the action of doxorubicin on vascular smooth muscle cells. Methods: Isometric tension of denuded or intact thoracic aortic vessels was recorded and [Ca 2+ ] i in isolated aortic smooth muscle cells was measured by using Fluo-3. Results: Doxorubicin induced phasic and tonic contractions in denuded vessels and increased levels of [Ca 2+ ] i in single muscle cells. Treatment with 10 µmol/L ryanodine had no effect on basal tension, but it did abolish doxorubicin-induced phasic contraction. Treatment with 10 mmol/L caffeine induced a transient phasic contraction only, and the effect was not significantly altered by ryanodine, the omission of extracellular Ca 2+ or both. Phenylephrine induced rhythmic contraction (RC) in intact vessels. Treatment with 100 µmol/L doxorubicin enhanced RC amplitude, but 1 mmol/L doxorubicin abolished RC, with an increase in maximal tension. Caffeine at 100 µmol/L increased the frequency of the RC only. In the presence of 100 µmol/L caffeine, however, 100 µmol/L doxorubicin abolished the RC and decreased its maximal tension. Treatment with 10 µmol/L ryanodine abolished the RC, with an increase in the maximal tension. In Ca 2+ -free solution, doxorubicin induced a transient [Ca 2+ ] i increase that could be abolished by ryanodine pretreatment in single muscle cells. The doxorubicin-induced increase in [Ca 2+ ] i was suppressed by nifedipine and potentiated by ryanodine and charybdotoxin. Conclusion: Doxorubicin not only releases Ca 2+ from the sarcoplasmic reticulum but also promotes the entry of extracellular Ca 2+ into vascular smooth muscle cells.
Subcutaneous bortezomib did not significantly reduce therapeutic efficacy but resulted in a lower incidence of peripheral neuropathy than intravenous bortezomib. Compared with intravenous bortezomib, subcutaneous bortezomib might reduce the incidence of thrombocytopenia and renal and urinary disorders, but this needs more clinical trials to confirm. .
Background: TAS-102 is approved for patients with refractory mCRC. It remains to be defined which patients may benefit from this drug in real-life clinical practice.Methods: Multicenter retrospective observational analysis of mCRC patients receiving TAS-102 in Spanish centers from November 2015 to the present.Results: 222 patients were included. Median age of 62 yr(31-83); 62.6% male. TAS-102 was mostly used in 3o (54.5%), 4o line(29.3%). TAS-102 was very well tolerated. Dose reduction was required in 34.7% but only 4.1% discontinued therapy. Toxicity included neutropenia 74.1%(>G3 20.2%), fatigue 57.8%(G3 5.1%), diarrhea 21.5%(G3 0.5%) and nausea 24.7%(G3 0.9%). Among patients who had SD/PR, 70.7% had neutropenia>G2 with respect to those who did not (p ¼ 0.02). Median of 3 cycles(2-23), median duration of treatment 4.4 months(1.2-26.2), disease control rate(DCR) 33.8% (PR achieved in 1.8%). Median PFS 3.9m (95% CI 3.5-4.2) and median OS 9.3m (95% CI 7.9-10.67). There was no statistically significant difference of PFS/OS according to primary tumor location or RAS/BRAF mutation status, although MMRp tumors was associated with longer PFS (6.1 vs 3.4m, p¼0.002) and OS (14.2 vs 6.3, p¼0.001). Patients with low-volume metastatic disease(LVMD), defined as no massive hepatic metastasis or simultaneous liver and lung involvement had better DCR than patients with high volume(44,9% vs 24,2%, respectively, p¼0.03). PFS (4.1 vs 3.5m, respectively, p¼0.024, HR 1.73 95%CI 1.04-1.81) and OS (11.7 vs 7.8m, p¼0.012 HR 1.49 95%CI 1.08-2.3) were also significantly better for patients with LVMD. In the subgroup of who received prolonged treatment (>6 cycles;N¼51), 43.1% were <65 years, 60.8% had LVMD and 54.9% of patients had received TAS102 as second/third line. Almost all patients in this subgroup (92.2%) presented SD and PFS was significantly higher than in subgroup of patients >5 cycles (9.
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