Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and ...transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off).
Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan–Meier method was used to estimate survival and the log-rank test to make comparisons.
Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months 95% confidence interval (CI) 3.73-11.0 months versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16).
Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.
•Regorafenib-personalized schedules are commonly adopted in daily clinical practice.•Regorafenib-personalized schedules correlate with statistically significant improvement of therapeutic outcomes.•A prompt personalization of regorafenib could help clinicians avoid early treatment discontinuation due to adverse events.•A patient-tailored approach could be applied to other metastatic solid tumors treated with regorafenib.
Cardiac troponins (cTns) are the 'gold standard' biomarker for the diagnosis and prognosis of acute coronary syndrome. Analytical performance is critical at low concentrations of cTn, and many of the ...current assays do not meet the guideline requirement of a 10% coefficient of variation (CV) at the 99th percentile concentrations. The aim of the study was to establish if the newly released Access® AccuTnI®+3 (AccuTnI+3) cardiac troponin I assay (Beckman Coulter Inc., Brea, CA, USA) reached this objective.
All AccuTnI+3 assays were performed on UniCel® DxI800 analyzer (Beckman Coulter Inc). Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ) were determined according to Clinical Laboratory Standard Institute EP17-A and EP5-A2 protocols. The 99th percentile upper reference limit (URL) was determined by analysing serum samples from 330 apparently healthy blood donors (260 men, 70 women, age range 18-70 years, median age 36 years).
LoB and LoD values were 2.6 and 12 ng/L, respectively. The 10% CV was at 18 ng/L (95% confidence interval CI 8-25). The 99th percentile URL was 22 ng/L (95% CI 11-34).
The newly released assay has improved low-end analytical performance and reaches the goal of having a total imprecision ≤ 10% at 99th percentile of a healthy reference population (guideline acceptable). With this assay, it is now possible to utilize the 99th percentile as decision level for myocardial injury detection.
This study was performed to determine the activity of adding continuous infusion (CI) of 5-fluorouracil (5-FU) to gemcitabine (GEM) vs GEM alone in advanced pancreatic cancer (APC). In all, 94 ...chemo-naïve patients with APC were randomised to receive GEM alone (arm A: 1000 mg m(-2) per week for 7 weeks followed by a 2 week rest period, then weekly for 3 consecutive weeks out of every 4 weeks) or in combination with CI 5-FU (arm B: CI 5-FU 200 mg m(-2) day(-1) for 6 weeks followed by a 2 week rest period, then for 3 weeks every 4 weeks). Overall response rate (RR) was the primary end point and criteria for decision were planned according to the Simon's optimal two-stage design. The overall RR was 8% (arm A) and 11% (arm B) (95% confidence interval: 0.5-16% and 2-22%), respectively, and stable disease was 29 and 28%. The median duration of RR was 34 weeks (range 25-101 weeks) for GEM and 26 weeks (range 16-46 weeks) for the combination. The median progression-free survival (PFS) was 14 weeks (range 2-65 weeks) and 18 weeks (range 4-51 weeks), respectively. The median overall survival (OS) was 31 weeks (range 1-101 weeks) and 30 weeks (1-101 weeks). Toxicity was mild in both arms. This study does not show promising activity in terms of RR, PFS and OS for the double combination arm in APC.
•This Clinical Practice Guideline provides key recommendations on the management of soft tissue and visceral sarcomas.•Recommendations have been agreed following a consensus meeting of ...representatives from ESMO, EURACAN and GENTURIS.•Authorship includes a multidisciplinary group of experts from several European institutions, India and Japan.
Stress can have severe psychological and physiological consequences. Thus, inappropriate regulation of the stress response is linked to the etiology of mood and anxiety disorders. The generation and ...implementation of preclinical animal models represent valuable tools to explore and characterize the mechanisms underlying the pathophysiology of stress-related psychiatric disorders and the development of novel pharmacological strategies. In this commentary, we discuss the strengths and limitations of state-of-the-art molecular and computational advances employed in stress neurobiology research, with a focus on the ever-increasing spatiotemporal resolution in cell biology and behavioral science. Finally, we share our perspective on future directions in the fields of preclinical and human stress research.
Background: 5-Fluorouracil (5-FU), doxorubicin and methotrexate (FAMTX) and cisplatin, epirubicin, leucovorin and 5-FU (PELF) have both been reported to be superior to the combination 5-FU, ...doxorubicin and mitomycin C (FAM) in advanced gastric carcinoma. On the basis of the presence and dose intensity of the included agents, we hypothesised that PELF would be superior to FAMTX. Patients and methods: Two hundred patients with untreated advanced gastric carcinoma were randomised to receive PELF or FAMTX for a maximum of six cycles or until disease progression. Results: The complete response (CR) rates to PELF and FAMTX were, respectively, 13% 95% confidence intervals (CI) 6% to 20% and 2% (95% CI 0% to 5%; P = 0.003), and the objective response rates CR plus partial response (PR) rates 39% (95% CI 29% to 49%) and 22% (95% CI 13% to 30%; P = 0.009), thus significantly favouring the PELF combination. The survival rates after 12 months (30.8% versus 22.4%) and 24 months (15.7% versus 9.5%) were also higher among patients receiving PELF, but these differences were not statistically significant. The toxicities were qualitatively different but quantitatively similar. Both regimens seem to be feasible provided that careful patient monitoring is assured. Conclusions: PELF is significantly more active than FAMTX and deserves further research in the adjuvant setting.
•This clinical practice guideline provides key recommendations on the management of gastrointestinal stromal tumours.•Recommendations have been agreed following a consensus meeting of representatives ...from ESMO, EURACAN and GENTURIS.•Authorship includes a multidisciplinary group of experts from several European institutions, India and Japan.•ESCAT scores are given for genomic alterations with actionable drug matches.
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