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Objectives: Imatinib is the first therapeutic option for the treatment of unresectable or metastatic gastrointestinal stromal tumours. Previous studies have shown an improvement in patient survival rates following the use of imatinib. Nevertheless, adequate plasma concentrations of imatinib are necessary to achieve such improvement in survival and limit the toxicity of the drug. This study aims to analyse the influence of imatinib plasma concentrations on efficacy and safety in the treatment of gastrointestinal stromal tumour., Materials and Methods: This descriptive, multicentre study analysed plasma levels of imatinib in patients diagnosed with gastrointestinal stromal tumour in the period 2019-2020. An optimal therapeutic range of 750-1500 ng/mL was established for the patient stratification based on their minimum plasma concentrations measured at the steady state., Results: This study included 11 patients with metastatic disease in total, among whom only 54.5% (n  =  6) had a minimum plasma concentrations measured at the steady state value within the therapeutic range. A median progression-free survival of 7.0 months was recorded for those patients with minimum plasma concentrations measured at the steady state < 750 ng/mL, while that median progression-free survival value remained unachieved for the group with minimum plasma concentrations measured at the steady state > 750 ng/mL ( p    =    0.005 ). The toxicity rate was 25% and 14.3% for patients with minimum plasma concentrations measured at the steady state > 1500 ng/mL and minimum plasma concentrations measured at the steady state ≤1500 ng/mL, respectively ( p   =  0.66)., Conclusions: The present study aims to describe the correlation between the toxicity and effectiveness of imatinib as a function of minimum plasma concentrations measured at the steady state under routine clinical practice conditions. The results described here show the usefulness of imatinib plasma concentrations monitoring as part of the standard daily routine in our hospitals., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care., Patients and Methods: AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management., Results: Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo., Conclusions: Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management. CLINICALTRIALS., Gov Id: NCT02437318., Competing Interests: Disclosures HSR reports personal fees from Genomic Health, Novartis, Roche/Genentech, OBI Pharma, Bayer, Pfizer, during the conduct of the study; grants from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Eli Lilly, GlaxoSmithKline, Genentech, Celsion, Merck, outside the submitted work; FA reports grants from Novartis during the conduct of the study; grants from Astra Zeneca, Pfizer, Lilly, Roche, outside the submitted work; TY reports grants and other from Chugai, Kyowa Kirin; other from Eisai, Novartis, Taiho, Sanofi, AstraZeneca, Pfizer Japan, outside the submitted work; SMS reports non-financial support from Pfizer, Lilly, outside the submitted work. JCJ reports personal fees from GlaxoSmithKline, Roche, Novartis, PharmaMar, Eisai, Lilly, Celgene, Astellas, Amgen, Pfizer, during the conduct of the study; other from GlaxoSmithKline, AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Celgene, Astellas, Amgen, Pfizer, outside the submitted work; DJ reports personal fees from Novartis, Genentech, Eisai, Ipsen, EMD Serono, during the conduct of the study; IM reports personal fees from Novartis, Genentech, during the conduct of the study; grants from Novartis, Pfizer, outside the submitted work; EMC reports personal fees from Pfizer, Novartis, Lilly, Roche, Celgene, during the conduct of the study; PC reports personal fees from Roche, Novartis, AstraZeneca, Celgene, Tesaro, during the conduct of the study; grants from Roche, Novartis, Merck, Bristol-Myers Squibb, outside the submitted work; MC reports personal fees from Novartis, Lilly, during the conduct of the study; grants from Pfizer, AstraZeneca, Sanofi, Pierre Fabre, Takeda, outside the submitted work; CW reports other from Novartis, during the conduct of the study; DM reports other from Novartis, during the conduct of the study; AL reports other from Novartis, during the conduct of the study; MM reports other from Novartis, during the conduct of the study; FG reports other from Novartis, during the conduct of the study; SL reports grants from Pfizer, Celgene, Amgen, Roche, AstraZeneca, AbbVie, outside the submitted work; other from Pfizer, Celgene, Amgen, Roche, AstraZeneca, AbbVie, Lilly, Daiichi Sankyo, EirGenix, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and size >5 cm are at high-risk of death. This risk varies depending also on other patient and tumour features, including histologic subtype. This study investigated whether a prognostic nomogram can improve risk assessment of these patients., Methods: Data from high-risk STS patients enrolled in a randomised controlled trial investigating different perioperative chemotherapy regimens were analysed. Ten-year probability of overall survival (OS) and incidence of distant metastasis (DM) were computed using the prognostic nomogram Sarculator (pr-OS and inc-DM, respectively). Tumour response according to RECIST and Choi criteria was also investigated., Findings: Variation in pr-OS and inc-DM were observed and patients stratified in three prognostic groups. The 10-year OS in the low, intermediate, and high pr-OS categories were 0·42 (95%CI 0·32-0·52), 0·63 (95%CI 0·53-0·72), and 0·78 (95%CI 0·68-0·85), respectively. Patients in the intermediate (HR 0·51, P = 0·002) and high (HR 0·28, P < 0·001) pr-OS categories were at statistically significant lower risk of death compared with those in the low pr-OS category. Higher rate of Choi partial tumour responses were detected in intermediate pr-OS category. Tumour response according to Choi but not to RECIST criteria stratified patient survival of pr-OS categories, particularly for patients with intermediate to low pr-OS. Analyses conducted for 10-year inc-DM were consistent with results for pr-OS for prognostic value of Sarculator predictions and Choi tumour response., Interpretation: Sarculator identifies variations in outcomes of high-risk STS treated with perioperative chemotherapy and improve prognostic classification, which is also associated with different patterns of tumour response, an outcome that further stratifies survival particularly for patients predicted at higher risk. Future trials investigating neoadjuvant chemotherapy should consider prognostic tool for selecting patients to be enrolled., Trial Registration Number: European Union Drug Regulating Authorities Clinical Trials No. 2004-003979-36., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS)., Methods: Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m 2 and ifosfamide 9 g/m 2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model., Results: Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively., Conclusions: At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Keratoconus is a corneal dystrophy that degrades the optical function of the cornea. The onset of the process manifests optical signs: evolving astigmatism, failure of optical correction by spectacles, and distorted images. We report data from 74 keratoconus patients in need of keratoplasty. The variables studied included sex, age of onset, and refractive error. We find that the average age of the appearance of keratoconus is the second decade of life (mean age of onset = 15.39 years, SD = 3.95), with earlier onset occurring in females that in males, although the differences are not statistically significant. The mean corneal astigmatism before keratoplasty was 4.07 D (SD = 1.57). Optometrists should refer patients for surgery when all optical treatment has failed.