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BACKGROUND: In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. PATIENTS AND METHODS: Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. RESULTS: A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). CONCLUSIONS: Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:299-309 ispartof: location:England status: published

Management guidelines for allergic rhinitis and urticaria recommend oral second-generation antihistamines as first-line treatment. The efficacy and safety of bilastine, the newest nonsedating second-generation antihistamine, are well established in adolescents/adults with these allergic conditions. The bilastine development program for pediatric use (2–

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6–8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.

Introduction Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition. Methods We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging. Results Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8–40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months. Conclusions The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer., Highlights • CDK4/6 inhibitors with endocrine therapy is a preferred first line therapy for HR+, HER2-metastatic breast cancer. • Limited data exists on safety of combined radiotherapy and CDK4/6 inhibition in patients with metastatic breast cancer. • This retrospective cohort study included 30 patients who underwent palliative RT with combined CDK4/6 inhibitor use. • RT within 2 weeks of CDK4/6 inhibitor had low toxicity and high efficacy, supporting its safety in metastatic breast cancer.

Hepatitis C virus (HCV) exacerbation is relatively rare as compared with hepatitis B virus reactivation in patients treated with immunosuppressive or anticancer drugs. We herein present the first reported case of acute exacerbation of chronic hepatitis in a patient with HCV persistent infection caused by combination treatment with daratumumab (DARA), bortezomib, and dexamethasone (DVd therapy). A 79-year-old woman diagnosed as having chronic HCV infection 11 years prior without successful viral elimination was referred to our hospital for the treatment of acute liver injury. Multiple myeloma (MM; IgG-κ type) was diagnosed two years before referral and subjected to several treatments. She had commenced DVd therapy four months prior to admission. Since her liver enzymes did not normalize with drug discontinuation and hepatoprotective therapy, we suspected HCV exacerbation and began direct-acting antiviral (DAA) treatment with glecaprevir/pibrentasvir (GLE/PIB). Soon afterwards, her liver enzymes normalized, and she achieved a sustained virological response after 8 weeks of treatment. Clinicians should bear in mind HCV exacerbation when encountering chronic HCV with acute liver injury under MM treatment including a DARA-based regimen. In such cases, DAA therapy is an option when other urgent treatments are needed.

Objectives Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. Materials and Methods Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. Results Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80–240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80–240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. Conclusion Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug–drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.

Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint. However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan-"to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat." This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.

The US Food and Drug Administration (FDA) has approved two drugs for ‘hypoactive sexual desire disorder’ in women, flibanserin (Addyi) in 2015 and bremelanotide (Vyleesi) in 2019. In this paper we examine the outcome measures and clinical trial data upon which regulatory approval was based. In clinical trials, flibanserin led to an average of only one additional enjoyable sexual experience every two months, bremelanotide to none. Trials for both drugs feature shifts in primary outcomes and a contested indication. A politicised industry-sponsored advocacy campaign and conflicted patient and expert testimony likely influenced flibanserin’s approval at its third attempt. Bremelanotide, with even weaker efficacy, capitalised on the regulatory precedent set by the approval of flibanserin. Reconsideration of regulatory decisions to approve these drugs is in order, as well as a broader examination of how future regulatory decisions can better address conflicts of interest and clinically meaningful benefit.

Background & Aims Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Methods Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Results Of 177 patients, 169 (95.5%) were PI-naive. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Conclusion Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Lay summary Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. Clinical trial number NCT03092375 .

BACKGROUND Hepatitis C virus (HCV)-related decompensated cirrhosis is a severe life-threatening illness. The safety of direct-acting antivirals (DAAs) has opened a gate of hope for that subgroup of patients who were previously contraindicated for interferon therapy. OBJECTIVE We aimed at the investigation of the safety and efficacy of different DAAs regimens in the treatment of HCV-related decompensated cirrhosis patients, to determine sustained virological response (SVR)12 rates and to analyze the factors associated with response. METHODS A retrospective, single-center study including HCV-related decompensated cirrhosis patients who received DAAs. Demographic, laboratory and clinical data were analyzed. The SVR12 rate was the primary outcome measure. Secondary outcomes included the predictors of response, changes in the baseline model for end-stage liver disease and child-turcotte-pugh (CTP) scores, and fibroindices (APRI and fibrosis-4 index) at 12 weeks after treatment. RESULTS In total, 145 eligible patients (141 with CTP class B and 4 with class C) were enrolled in this study. SVR12 was achieved by 88.06% (118/134) of efficacy population on different DAAs regimens, Treatment was discontinued in 11 patients because of severe side effects without any deaths. Younger age showed a significant positive association with SVR12. CONCLUSIONS DAAs can be used for the treatment of HCV-related decompensated liver disease, with acceptable SVR12 rates and safety profiles.

Sustained virologic response at posttreatment Week 12 (SVR12) is the widely accepted efficacy endpoint for direct-acting antiviral agents. Those with hepatitis C virus (HCV) are presenting younger with milder liver disease, potentially reducing need for long-term liver posttreatment monitoring. This analysis aimed to determine the positive predictive value (PPV) of SVR at posttreatment Week 4 (SVR4) for achieving SVR12 in patients with HCV, without cirrhosis or with compensated cirrhosis, receiving glecaprevir/pibrentasvir (G/P) in clinical trials. An integrated dataset from 20 Phase 2 and 3 clinical trials of G/P was evaluated in patients with 8-, 12- or 16-week treatment duration consistent with the current label (label-consistent group), and in all patients regardless of treatment duration consistency with the current label (overall group). Sensitivity analyses handled missing data either by backward imputation or were excluded. SVR4 PPV, negative predictive value (NPV), sensitivity and specificity were calculated for achieving SVR12 in both groups, and by treatment duration in the label-consistent group. SVR was defined as HCV ribonucleic acidlower limit of quantification. The label-consistent group and overall group included 2890 and 4390 patients, respectively. PPV of SVR4 for SVR12 was99% in both groups regardless of treatment duration. Not achieving SVR4 had 100% NPV and sensitivity for all groups. SVR4 measure had 79.5% specificity for identifying patients who did not achieve SVR12. Across 20 Phase 2/3 clinical trials of G/P, SVR4 was highly predictive of SVR12. Long-term follow-up to confirm SVR may not be necessary for certain populations of patients with HCV.

BACKGROUND: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease. METHODS: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5. Carboplatin (AUC 6) was administered on day 1, and paclitaxel (80 mg/m2) on days 1, 8 and 15 (21-day cycles). Patients discontinuing carboplatin-paclitaxel for reasons besides progression could continue veliparib/placebo monotherapy (300 mg BID, increasing to 400 mg BID if tolerated) until progression. The primary end-point was PFS assessed by investigator. RESULTS: Of 509 patients in the intention-to-treat population (98.6% female; mean age 47, standard deviation 11), 413 (81%) had no previous cytotoxic therapy for metastatic disease (274, veliparib; 139, placebo). In the first-line subgroup, median PFS was 16.6 months (95% confidence interval [CI] 13.4-18.7) versus 13.1 months (95% CI 11.4-14.5) for the veliparib versus control groups (hazard ratio 0.70, 95% CI 0.54-0.89, P = .004). More patients were alive and progression-free at 2 years (36% versus 23.2%) and 3 years (27.9% versus 13.3%) in the veliparib versus control group. Adverse events unrelated to progression leading to study drug discontinuation occurred in 25 (9.1%) and 8 (5.8%) patients. CONCLUSIONS: Veliparib with carboplatin-paclitaxel led to durable disease control among first-line patients, suggesting a benefit of this treatment approach in early lines. CLINICAL TRIAL REGISTRATION: NCT02163694. ispartof: European Journal Of Cancer vol:154 pages:35-45 ispartof: location:England status: accepted

Background This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Methods Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. Results In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380–1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390–1.463). Conclusions Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. Clinical trial registration NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703.

Summary Introduction. The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea. Case report. We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions.

Background Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early‐ and intermediate‐stage HCC. Materials and Methods Twenty‐four patients with modified Child‐Pugh class A early‐ and intermediate‐stage HCC received neoadjuvant oral dovitinib 500 mg daily (5 days on/2 days off) for 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR‐blockade, time to progression (TTP), and overall survival (OS). Results Modified RECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3–4 adverse events, most frequently (on‐target) hypertension (54%), fatigue (25%), and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF‐A, VEGF‐D, and placental growth factor increased significantly, whereas sTie‐2 decreased, consistent with VEGFR‐blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (three early, four intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer‐specific survival was not reached. Conclusion Already after a short 4‐week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC. Implications for Practice Orthotopic liver transplantation may cure early and intermediate‐stage hepatocellular carcinoma. Considering the expected waiting time >6 months because of donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy, and may provide a novel treatment approach to improve patient outcomes if tolerability in patients with hepatocellular carcinoma can be improved by therapeutic drug monitoring and personalized dosing., Considering the scarcity of liver donors and expected waiting time to liver transplantation, there is an unmet need for effective neoadjuvant downsizing strategies. This article reports on the safety and efficacy of neoadjuvant dovitinib in patients with hepatocellular carcinoma eligible for locoregional treatment.

Background In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR] 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial. Methods The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n = 72; placebo plus fulvestrant, n = 42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS). Results At the primary objective cutoff (February 14, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR 0.415; 95% CI 0.246–0.698). At the pre-specified OS interim cutoff (20-June-2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR 0.477; 95% CI 0.302–0.755). A numerical OS benefit was observed with abemaciclib plus fulvestrant compared to fulvestrant alone (HR 0.689; 95% CI 0.379–1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR 0.599), TTC (HR 0.674), and CFS (HR 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously. Conclusions Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant. Clinical trial registration: NCT02107703. Registered April 08, 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703.

OBJECTIVE: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR).METHODS: Patients received veliparib or placebo with carboplatin-paclitaxel (6 cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRD + BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed.RESULTS: Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5 months in the veliparib-throughout arm versus 17.3 months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562-0.831; P CONCLUSIONS: Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials.

A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient's history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.

Introduction Neutropenia and diarrhoea are common and potentially serious adverse events associated with abemaciclib in advanced breast cancer (ABC), and the risk factors have been minimally explored. The study aimed to develop clinical prediction tools that allow personalized predictions of neutropenia and diarrhoea following abemaciclib initiation. Materials and methods Data was pooled from MONARCH 1, 2 and 3 trials investigating abemaciclib. Cox proportional hazard analysis was used to assess the association between pre-treatment clinicopathological data and grade ≥3 diarrhoea and neutropenia occurring within the first 365 days of abemaciclib use. Results Older age was associated with increased risk of grade ≥3 diarrhoea [HR [95%CI] for age > 70: 1.72 [1.14–2.58]; P = 0.009]. A clinical prediction tool for abemaciclib induced grade ≥3 neutropenia was optimally defined by race, ECOGPS and white blood cell count. Large discrimination between subgroups was observed; the highest risk subgroup had a 64% probability of grade ≥3 neutropenia within the first 365 days of abemaciclib (150 mg twice daily) + fulvestrant/NSAI, compared to 5% for the lowest risk subgroup. Conclusion The study identified advanced age as significantly associated with an increased risk of abemaciclib induced grade ≥ 3 diarrhoea. A clinical prediction tool, defined by race, ECOGPS and pre-treatment white blood cell count, was able to discriminate subgroups with significantly different risks of grade ≥3 neutropenia following abemaciclib initiation. The tool may enable improved interpretation of personalized risks and the risk-benefit ratio of abemaciclib., Highlights • Neutropenia and diarrhoea are common adverse effects of abemaciclib. • Higher age was associated with abemaciclib induced diarrhoea. • White blood cell count, Race, and performance status were linked with neutropenia. • A prediction tool was developed to provide personalized risks of neutropenia.

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. Results: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

Graphical abstract, Background This study aimed to investigate whether the addition of candesartan to the standard care regimen improved the outcome in patients with coronavirus 2019 (COVID-19). Methods A prospective non-randomized open-label study was undertaken from May to August 2020 on 75 subjects (aged 18–70 years) hospitalized in Siloam Kelapa Dua Hospital. Uni- and multi-variable Cox regression analyses were performed to obtain hazard ratios (HRs). The primary outcomes were: (1) length of hospital stay; (2) time to negative swab; and (3) radiological outcome (time to improvement on chest X ray). Results None of the 75 patients with COVID-19 required intensive care. All patients were angiotensin-receptor-blocker naïve. In comparison with the control group, the candesartan group had a significantly shorter hospital stay [adjusted HR 2.47, 95% confidence interval (CI) 1.16–5.29] after adjusting for a wide range of confounders, and no increased risk of intensive care. In the non-obese subgroup, the candesartan group had a shorter time to negative swab (unadjusted HR 2.11, 95% CI 1.02–4.36; adjusted HR 2.40, 95% CI 1.08–5.09) and shorter time to improvement in chest x ray (adjusted HR 2.82, 95% CI 1.13–7.03) compared with the control group. Conclusion Candesartan significantly reduces the length of hospital stay after adjustment for covariates. All primary outcomes improved significantly in the non-obese subgroup receiving candesartan.

A 74-year-old man with a history of transfusion at 35 years old in Egypt was referred to our hospital. He was infected with hepatitis C virus (HCV) genotype 4 (GT4), which is a rare HCV GT in Japan, and was also diagnosed with hepatic compensated cirrhosis. We safely treated the patient for 12 weeks with the combination of glecaprevir and pibrentasvir, and a sustained virologic response (SVR) was achieved. This is the first report of HCV GT4 infection in a treatment-naïve Japanese patient with cirrhosis in whom SVR was achieved with the combination treatment of glecaprevir and pibrentasvir.

Background and Aims Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV‐infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. Approach and Results Children with chronic HCV infection, genotype 1‐6, with or without compensated cirrhosis, were divided into three cohorts by age—cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)—and given weight‐based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady‐state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug‐related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. Conclusions A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV‐infected children 3 to < 12 years old.

Vascular calcification (VC) is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process, in which vascular smooth muscle cells (VSMCs) transform into osteoblast/chondrocyte-like cells as in bone formation. VC is associated with significant morbidity and mortality in chronic kidney disease (CKD) and cardiovascular disease, but the underlying mechanisms remain unclear. In this study we investigated the role of large-conductance calcium-activated potassium (BK) channels in 3 experimental VC models. VC was induced in vascular smooth muscle cells (VSMCs) by β-glycerophosphate (β-GP), or in rats by subtotal nephrectomy, or in mice by high-dosage vitamin D3. We showed that the expression of BK channels in the artery of CKD rats with VC and in β-GP-treated VSMCs was significantly decreased, which was functionally confirmed by patch-clamp recording. In β-GP-treated VSMCs, BK channel opener NS1619 (20 μM) significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity. Furthermore, NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN, as well as Runx2 (a key transcription factor involved in preosteoblast to osteoblast differentiation), and increased the expression of α-SMA protein, whereas BK channel inhibitor paxilline (10 μM) caused the opposite effects. In primary cultured VSMCs from BK(−/−) mice, BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs. Moreover, calcification was more severe in thoracic aorta rings of BK(−/−) mice than in those of wild-type littermates. Administration of BK channel activator BMS191011 (10 mg· kg(−1) ·d(−1)) in high-dosage vitamin D3-treated mice significantly ameliorated calcification. Finally, co-treatment with Akt inhibitor MK2206 (1 μM) or FoxO1 inhibitor AS1842856 (3 μM) in calcified VSMCs abrogated the effects of BK channel opener NS1619. Taken together, activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways. Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.

INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1–6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0–4: 100%; weeks 5–8: 98.3%; and weeks 9–12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (

Iron is a crucial element necessary for blood formation in the body and its normal growth. However, irregular metabolism of iron due to absence of an elimination mechanism may deposit excess iron in the organs (iron overload) leading to metabolic disorders. Interactions between the iron regulatory peptide hormone, hepcidin and the iron exporter ferroportin plays major role in regulating the iron metabolism. Mutations in the ferroportin encoding genes, and dysregulation of hepsidin production often results in iron overload resulting in conditions like hemochromatosis, β-thalassemia, and sickle cell anemia. Until today, there is no efficacious treatment available for managing iron overload targeting ferroportin inhibition via oral administration.Novel salts of substituted benzoimidazole compounds useful for the prophylaxis and/or treatment of iron overload are claimed. These compounds act as hepcidin mimetic and inhibit the ferroportin thereby preventing iron overload. The claimed actives are useful in the treatment of disease conditions such as neurodegenerative and cardiac diseases triggered by iron overload. Preclinical studies of these salts on mouse model are also discussed.Prevention and/or treatment of iron overload is critical. The claimed compounds are the first oral drug candidate to treat iron overload and reach the pre-clinical development stage.

Objectives The aim of this study was to evaluate the efficacy and safety of sofosbuvir/ledipasvir ± ribavirin in Malagasy patients with hepatitis C virus genotypes 1 and 2, in real conditions. Patients and methods This was a retrospective monocentric clinical study, carried out over a period of 3 years from March 1, 2017 to February 28, 2020, in a hospital hepato-gastroenterology department. Results In total, 26 patients (M/F: 11/15) with hepatitis C virus genotype 1 (n = 13) or genotype 2 (n = 13), were treated with sofosbuvir/ledipasvir without (n = 21) or with (n = 5) ribavirin for 12 weeks. The mean age was 61.38 ± 7.09 years. Seventeen patients (65.4%) had cirrhosis. The overall sustained virological response was 96.2% (95% CI = 80.4–99.9%). There was no significant difference between the sustained virological responses of genotypes 1 and 2 (92.3% vs 100%; p = 0.31) or those of cirrhotic or non-cirrhotic patients (94.1% vs 100%; p = 0.46). A relapse was observed in one patient (5.9%) — cirrhotic and genotype 1b — under sofosbuvir/ledipasvir with ribavirin. Seven patients (26.9%) experienced mild adverse reactions, including asthenia (57.1%) and insomnia (42.9%). Conclusion Treatment with sofosbuvir/ledipasvir ± ribavirin for infection with hepatitis C virus genotype 1 has been shown to be safe and effective, even in the presence of cirrhosis. The sofosbuvir/ledipasvir combination is a good option for genotype 2 non-cirrhotic patients.

Summary Viral resistance is a major reason for virological failure in patients being treated with direct-acting antivirals (DAAs) for chronic HCV infection. However, the importance of viral resistance mainly depends on the DAA regimen and HCV genotype. For first-line therapy with glecaprevir/pibrentasvir (G/P) or velpatasvir/sofosbuvir (VEL/SOF) no general baseline resistance analysis is required because of the high antiviral activity and high barrier to resistance. If available, resistance testing may help to optimise therapy in certain subgroups of patients with HCV genotype 3 and other rare HCV geno/subtypes. Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is the first choice for the second-line treatment of patients following a previous DAA failure, with rates of viral eradication above 90% irrespective of the presence of resistance-associated substitutions (RASs). However, in resource-limited settings, only first-generation DAAs may be available for second-line therapy. Here, RASs selected during initial antiviral therapy should be considered if testing is available and rescue treatment should include a switch to a regimen with a new DAA class to optimise treatment response. Patients with HCV genotype 3 are overrepresented in the group who experience DAA treatment failure. Limited data are available for third-line therapies, but promising results have been achieved with G/P plus SOF or VOX/VEL/SOF with or without ribavirin for 12 to 24 weeks; these regimens should be administered irrespective of a patient’s RAS profile.

In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV.STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA12 IU/mL in Thailand and HCV RNA15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183.Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment.In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality.National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

To assess the degree of liver stiffness using transient elastography in Egyptian children infected with hepatitis C virus (HCV) at baseline and 1 year after achievement of sustained virologic response (SVR) with direct acting antivirals.This prospective study included children infected with HCV who received treatment with sofosbuvir/ledipasvir and achieved SVR. At baseline and 1 year after achievement of SVR, the extent of hepatic fibrosis was assessed by transient elastography using FibroScan to measure liver stiffness, in addition to noninvasive markers including aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 (FIB-4) index.The study included 23 cases that had variable degrees of fibrosis at baseline; their ages ranged between 10 and 18 years. At baseline, 13 patients had F1; 3 patients had F1-F2; 1 patient had F2; 3 patients had F3; 2 had F3-F4; and 2 patients with F4. One year after achievement of SVR, there was a statistically significant improvement in liver stiffness, APRI, and FIB-4 index (P = .03,.001, .02, respectively). In 13 patients (56.5%), the liver stiffness improved; in 7 patients, it was stationary; and the remaining 3 patients showed mild increase in liver stiffness that was, however, associated with improvement in APRI and FIB-4 index. Comorbid conditions and previous treatment with interferon were not associated with increased liver stiffness 1 year after SVR.Egyptian children infected with HCV genotype 4 achieved significant regression in liver stiffness after treatment with direct acting antivirals.

Background Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood. Methods This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross‐sectional FDA’s Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques. Results In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49–69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14–2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12–2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12–2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46–60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%–36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%–20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01–2.42); p = 0.045). Conclusions and Relevance In two independent real‐world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension., In two independent real‐world cohorts, combination BRAF/MEK inhibitors were associated with increased cardiovascular adverse events compared to monotherapy, especially HF, and hypertension.

Glecaprevir/pibrentasvir, a pangenotypic, direct-acting antiviral combination approved for chronic hepatitis C virus treatment, has limited real-world evidence supporting 8-week therapy in compensated cirrhosis. We investigated effectiveness and safety of 187 hepatitis C virus-infected, treatment-naive, patients with compensated cirrhosis receiving 8-week glecaprevir/pibrentasvir therapy in the German Hepatitis C-Registry between 2 August 2017 and 1 January 2020. Sustained virologic response was 98.4% (127/129) in the per-protocol analysis (excluding patients lost to follow-up or who discontinued treatment due to compliance) and was 85.8% (127/148) in patients with data available in an intention-to-treat analysis. Nineteen patients were lost to follow-up; nine genotype 3 patients, nine nongenotype 3 patients and one mixed genotype patient. One patient relapsed, and one died, unrelated to treatment. Adverse events (>5%) were fatigue and headache. Two serious adverse events occurred; no adverse events resulted in drug discontinuation. An 8-week glecaprevir/pibrentasvir therapy was effective and well-tolerated in this real-world analysis.

This retrospective observational study described baseline characteristics, real-world treatment patterns, and outcomes among patients with metastatic breast cancer treated with abemaciclib in the United States.De-identified electronic health record-derived data were used to describe patients who began abemaciclib treatment on or after 30 June 2016 and ≥4 months before data cutoff (31 December 2018). Real-world response (rwR) and real-world progression assessments were abstracted from clinical documentation. Descriptive statistics were used to calculate the real-world best response. The Kaplan-Meier method estimated real-world time to first response (rwTTFR) and real-world progression-free survival (rwPFS).The median age of 118 female patients at abemaciclib initiation was 66.5 years (interquartile range, 57.0, 73.0). The breakdown of patients who received abemaciclib in first, second, third, or later lines was 28.8%, 21.2%, 20.3%, and 29.7%, respectively. Patients received abemaciclib as monotherapy (12.7%) or in combination with endocrine therapy: fulvestrant (59.3%); aromatase inhibitor (22.9%); aromatase inhibitor and fulvestrant (5.1%). There were 68 patients (57.6%) with ≥1 rwR assessment: 41.2% with a real-world complete response or real-world partial response. Median rwTTFR was 3.6 months (95% confidence interval, 3.5, 5.2). Twelve-month rwPFS probability was 61.7%.This study represents utilization and outcomes associated with abemaciclib approximately 1 year following FDA approval. Treatment patterns demonstrated heterogeneity and, as in clinical trials, patients appeared to benefit from abemaciclib treatment in the real world. More research investigating outcomes associated with abemaciclib treatment is needed, with larger samples and longer follow-up to enable closer evaluation by subgroup, regimen, and line of therapy.

Background There is no proven primary preventive strategy for doxorubicin‐induced subclinical cardiotoxicity (DISC), especially among patients without a cardiovascular (CV) risk. We investigated the primary preventive effect on DISC of the concomitant use of angiotensin receptor blockers (ARBs) or beta‐blockers (BBs), especially among breast cancer patients without a CV risk. Methods A total of 385 patients who were scheduled for doxorubicin chemotherapy were screened. Among them, 195 patients of the study populations were included and were randomly divided into two groups [candesartan 4 mg q.d. vs. carvedilol 3.125 mg q.d.] and patients who were unwilling to take one of the medications were evaluated as controls. The primary outcomes were the incidence of early DISC (DISC developing within 6 months after chemotherapy), and late DISC (DISC developing only at least 12 months after chemotherapy). Result Compared with the control group (8 out of 43 patients (18.6%)), only the candesartan group (4 out of 82 patients (4.9%)) showed a significantly lower incidence of early DISC (p = 0.022). Compared with the control group, the candesartan group demonstrated a significantly reduced decrease in left ventricular ejection fraction (LVEF) throughout the study period [−1.0% vs. −3.00 (p, This study showed that low cumulative doses of doxorubicin were associated with the early development of subclinical cardiotoxicity in breast cancer patients without cardiovascular risk. Concomitant treatment with low‐dose candesartan may attenuate and even reverse early left ventricular systolic dysfunction in these patients.

Background/aims Glecaprevir/pibrentasvir (G/P) is a combination of direct-acting antiviral agents that is an approved treatment for chronic infections by all six hepatitis C virus (HCV) genotypes. However, there are limited data on the effect of G/P in Korean patients in actual real-world settings. We evaluated the real-life effectiveness and safety of G/P at a single institution in Korea. Methods This retrospective, observational, cohort study used sustained virologic response at 12 weeks after treatment completion (SVR12) as the primary effectiveness endpoint. Safety and tolerability were also determined. Results We examined 267 individuals who received G/P for chronic HCV infections. There were 148 females (55.4%), and the overall median age was 63.0 years (range, 25 to 87 years). Eighty-three patients (31.1%) had HCV genotype-1 and 182 (68.2%) had HCV-2. A total of 212 patients (79.4%) were HCV treatment-naive, 200 (74.9%) received the 8-week treatment, 13 (4.9%) had received prior treatment for hepatocellular carcinoma, 37 (13.7%) had chronic kidney disease stage 3 or higher, and 10 (3.7%) were receiving dialysis. Intention to treat (ITT) analysis indicated that 256 (95.9%) achieved SVR12. A modified ITT analysis indicated that SVR12 was 97.7% (256/262). Six patients failed therapy because of posttreatment relapse. SVR12 was significantly lower in those who received prior sofosbuvir treatment (p=0.002) and those with detectable HCV RNA at week 4 (p=0.027). Seventy patients (26.2%) experienced one or more adverse events, and most of them were mild. Conclusions These real-life data indicated that G/P treatment was highly effective and well tolerated, regardless of viral genotype or patient comorbidities.

BackgroundTemozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.MethodsVERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.ResultsA total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.ConclusionThe veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

Introduction We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. Methods Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). Results Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. Discussion Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double‐blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent‐to‐treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression‐free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P, Abemaciclib in combination with endocrine therapy (ET) in the East Asian populations of MONARCH 2 and MONARCH 3 improved efficacy for patients with HR+, HER2− advanced breast cancer.

Introduction More than 70 million people are estimated to be infected with hepatitis C virus (HCV) globally. If left untreated, HCV infection can lead to complications such as extensive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Evolution of treatments has resulted in highly effective and well-tolerated all-oral direct-acting antivirals. The pangenotypic regimen of glecaprevir/pibrentasvir is approved for treating HCV for patients without cirrhosis or with compensated cirrhosis (CC). Guidelines have evolved to simplify treatment to enable non-specialists to manage and treat HCV-infected patients. Simultaneously, such treatment algorithms provide guidance on the pretreatment identification of small subsets of patients who may require specialist treatment and long-term follow-up for advanced liver disease, including those at risk of developing HCC. This study describes the safety profile of glecaprevir/pibrentasvir in patients identified using previously described noninvasive laboratory measures who may be eligible for treatment by non-liver specialists. Methods This post hoc analysis of glecaprevir/pibrentasvir in patients, identified by noninvasive laboratory measures, intended to exclude patients with advanced liver disease and severe renal impairment, who can be managed within non-liver specialist settings. Patients were included from clinical trials and real-world studies of glecaprevir/pibrentasvir for HCV treatment. Baseline demographics, clinical characteristics, and safety assessments, including adverse events and laboratory abnormalities, were summarized. Results Data across these large-scale studies confirm that glecaprevir/pibrentasvir is well tolerated across different patient populations, with fewer than 0.1% of patients experiencing a serious adverse event related to treatment drugs, and few patients developing HCC during or after treatment. Conclusion The safety profile of glecaprevir/pibrentasvir enhances the confidence of non-liver specialists to treat the majority of HCV-infected patients, and provides an opportunity to expand the treater pool, potentially increasing diagnosis and treatment rates for HCV, contributing to elimination of HCV. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01753-3.

Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. Conclusion: The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

Objective To evaluate how women with epithelial ovarian cancer (EOC), dichotomized by BRCA status, tolerate intravenous (IV) or intraperitoneal (IP) chemotherapy given with veliparib and bevacizumab (bev) on a GOG phase I study (GOG 9923, NCT00989651). Methods This is an unplanned, post hoc analysis of an IRB approved, multi-institutional, prospective study (GOG 9923). Clinical characteristics and toxicity data based on BRCA status were evaluated and descriptive statistics were used to summarize baseline patient characteristics and toxicities. The Kaplan Meier method was used to generate survival estimates. Results Four hundred twenty-four patients were evaluable. Patients were treated with IV carboplatin, paclitaxel, and bev every 21 days (regimen 1), weekly IV paclitaxel with carboplatin and bev (regimen 2) or IV paclitaxel and bev with IP cisplatin (regimen 3). Bev was continued as maintenance in all arms. Within each of these regimens, veliparib was given either twice daily for the entirety of each cycle (continuous) or on days −2 to 5 (intermittent). Ten percent of patients treated on regimen 1, 12% on regimen 2, and 19.8% on regimen 3 had BRCA-associated tumors. Patients with BRCA-associated tumors, when compared to wild type, experienced similar rates of anemia, febrile neutropenia (, abdominal pain, colonic perforation, nausea, vomiting, and peripheral sensory neuropathy. Median progression free survival (PFS) was not significantly different between BRCA-associated and wild type cancers (HR 0.96, CI 0.65–1.42), though this study's primary aim was not to evaluate outcomes. Conclusions Germline BRCA mutations positively affect chemosensitivity in EOC, but whether differences in toxicities among BRCA-associated and BRCA wild type tumors existed was previously not reported. In this population with newly diagnosed ovarian cancer no differences in reported toxicity between the two groups was observed.

Glecaprevir/pibrentasvir (GLE/PIB) is a pan-genotype anti-hepatitis C virus (HCV) therapy with high efficacy and safety. However, evidence supporting retreatment following failure of the GLE/PIB regimen is limited. We herein report 3 non-cirrhotic cases involving two men aged 51 and 58 years old and a woman aged 68 years old infected with HCV genotype 1a, 2a, and 3b respectively who failed anti-HCV therapies including GLE/PIB therapy. With combination therapy of sofosbuvir/velpatasvir plus ribavirin (SOF/VEL+RBV) for 24 weeks, all 3 patients had achieved a sustained viral response (SVR) at 24 weeks after completing treatment. SOF/VEL+RBV therapy was effective for retreatment of HCV after failure of GLE/PIB therapy.

Introduction Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition in which mutations in key peptides involved in the low-density lipoprotein receptor (LDL-R) pathway result in markedly elevated levels of circulating LDL-cholesterol (LDL-C). Patients are at high risk of developing early-onset atherosclerotic cardiovascular disease with associated mortality risks. Treatment options are extremely limited, and aspects of society and medical care in Saudi Arabia have the potential to increase incidence and limit treatment pathways in HoFH. Methods Along with a brief review of the evidence available on HoFH we describe the treatment of two Saudi Arabian patients with HoFH diagnosed and treated in accordance with local clinical practices and with the microsomal triglyceride transferase protein inhibitor lomitapide. Results HoFH in Saudi Arabia is characterized by problems associated with consanguinity, a lack of access to lipoprotein apheresis, and pressures to proceed to liver transplant. Among the case histories, the first patient was commenced on lomitapide therapy, and underwent a dramatic decrease in LDL-C levels from 16.5 to 2.2 mmol/L (87% decrease). This patient had problems with access to lomitapide and cessation of the drug resulted in rebound in LDL-C to 22 mmol/L. The second patient experienced delayed commencement of lomitapide therapy. Despite a 45% decrease in LDL-C levels from 15.3 to 6.9 mmol/L, the patient died the following year at age 26 years from complications subsequent to cardiovascular surgery. Lomitapide was well tolerated in both patients Discussion The experience of these two cases highlights the need for prompt, effective, and sustained intervention in HoFH to prevent cardiovascular morbidity and mortality. Lomitapide is an effective therapy for HoFH, and we look forward to improved access to this drug in Saudi Arabia, where there is a chronic unmet medical need in HoFH.

Chronic hepatitis C (CHC) is a major cause of cirrhosis, hepatocellular carcinoma (HCC), and mortality. Eliminating hepatitis C virus (HCV) can greatly improve long‐term outcomes. Several direct‐acting antiviral agents (DAAs), including sofosbuvir (SOF) plus different NS5A inhibitors, as well as non‐SOF‐based DAAs, including glecaprevir/pibrentasvir (GLE/PIB), have been approved for treating CHC genotype‐2 (GT‐2) patients in Taiwan. However, there is limited real‐world effectiveness data regarding these different regimens. Thus, we aimed to evaluate the real‐world efficacy in CHC GT‐2 patients who underwent these DAA regimens. We retrospectively enrolled CHC GT‐2 patients who were treated with SOF‐based DAAs or GLE/PIB at a single medical center. A total of 704 enrolled patients were treated with either SOF + ribavirin (RBV), SOF/daclatasvir (DCV) ± RBV, SOF/ledipasvir (LDV) ± RBV, SOF/velpatasvir (VEL) ± RBV, or with GLE/PIB. The overall sustained virological response (SVR) rate was 97.9%. The SVR rate was significantly lower in the SOF + RBV group (95.6%) than in the non‐SOF + RBV (98.9%) group, especially compared to the SOF/DCV (100%) and GLE/PIB groups (99.5%). Among patients treated with SOF + RBV, cirrhotic patients had significantly lower SVR rates than noncirrhotic patients (89.4% vs 98.2%). Multivariate analysis showed that patients with a younger age, hepatitis B virus coinfection, baseline cirrhosis, or those who received SOF + RBV were less likely to achieve SVR. In conclusion, for CHC GT‐2 patients, SOF in combination with DCV, LDV, or VEL, as well as GLE/PIB, achieved similar high efficacies, regardless of cirrhosis, treatment experience, or chronic kidney disease status. Therefore, the use of DAA therapy to eradicate HCV should not be delayed in these populations.

Background & Aims Grafts from HCV-seropositive donors can now be considered for liver transplantation (LT) owing to the advent of direct-acting antivirals (DAAs). We report on our multicenter experience of transplanting liver grafts from HCV-seropositive donors into HCV-seronegative recipients. Methods This is a prospective multicenter observational study evaluating outcomes in adult HCV-seronegative LT recipients who received grafts from HCV-seropositive donors in 3 US centers. Results From 01/18 to 09/19, 34 HCV-seronegative LT recipients received grafts from HCV-seropositive donors (20 HCV-viremic and 14 non-viremic). Seven grafts were from cardiac-dead donors. The median MELD-Na score at allocation was 20. Six recipients underwent simultaneous liver-kidney transplant and 4 repeat LT. No recipient of an HCV-non-viremic graft developed HCV viremia. All 20 patients who received HCV-viremic grafts had HCV viremia confirmed within 3 days after LT. DAA treatment was started at a median of 27.5 days after LT. Median pre-treatment viral load was 723,000 IU/ml. All (20/20) patients completed treatment and achieved SVR12. Treatment was well tolerated with minimal adverse events. One patient developed HCV-related acute membranous nephropathy that resulted in end-stage kidney disease, despite achieving viral clearance. This patient died due to presumed infectious complications. A recipient of an HCV-non-viremic graft died with acute myocardial infarction 610 days post LT. Conclusions Transplantation of liver grafts from HCV-seropositive donors into HCV-seronegative recipients resulted in excellent short-term outcomes. Antiviral therapy was effective and well tolerated. Careful ongoing assessment and prompt initiation of antiviral therapy are recommended. Longer term follow-up in carefully conducted clinical trials is still required to confirm these results. Lay summary This study shows that livers from donors exposed to HCV expand the donor pool and can be used safely in patients who are seronegative for hepatitis C infection. Treatment, initiated early post transplantation, is effective and resulted in cure in all patients.

Glomeruli and renal tubule injury in chronic kidney disease (CKD) is reported to involve induction of macrophage activation through the CCL2/CCR2 axis. The effects of inhibitors of the CCL2/CCR2 axis, such as anti-CCL2 antibody and CCR2 antagonist, on kidney function in animal models or humans with kidney dysfunction have been demonstrated. The N-terminal glutamine on immature CCL2 is replaced with pyroglutamate (pE) by glutaminyl cyclase (QC) and isoQC. pE-CCL2 is stable and resistant to peptidases. We hypothesized that inhibiting QC/isoQC activity would lead to the degradation of CCL2, thereby ameliorating CKD and reducing kidney inflammation. To test this hypothesis, we investigated the renoprotective properties of the QC/isoQC inhibitor PQ529 in anti-glomerular basement membrane (GBM) antibody–induced glomerulonephritis Wistar Kyoto (WKY) rats. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. Correlations between the urinary protein level and serum or urinary CCL2 levels were confirmed in tested animals. Repeated administration of PQ529 significantly reduced the expression of CD68, a macrophage marker, in the kidney cortex and mononuclear infiltration into the tubulointerstitium. In addition, decreased levels of urinary KIM-1, β2 microglobulin, and clusterin were detected, suggesting the inhibition of inflammation in both the proximal and distal tubules. These results suggest that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00210-020-02013-x.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038., Open Access funding enabled and organized by Projekt DEAL. This study was funded by Pfizer.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma–related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51–79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit–risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

Background/Purpose Genotype 2 (GT2) hepatitis C virus infection is the second common genotype in Taiwan. Real-world experience of ledipasvir/sofosbuvir (LDV/SOF) for GT2 infection is limited. The aim of this study is to evaluate the effectiveness and safety of LDV/SOF in patients with GT2 chronic hepatitis C (CHC) infection. Methods CHC patients with GT2 infection receiving 12 weeks LDV/SOF from three hospitals were enrolled. HCV RNA was checked at baseline, end-of-treatment and 12 weeks after completing treatment. Demographic data, adverse events, renal function and metabolic profiles were recorded. Results Among 392 enrolled patients, 33 patients (8.4%) were cirrhotic. Sustained virological response (SVR) rate was 96.7% (379/392) by intention-to-treat analysis and 97.2% (379/390) by per-protocol analysis. The SVR rate was lower in cirrhotic patients than in non-cirrhotic patients (90.6% vs 97.8%, p = 0.053). Two cirrhotic patients who took LDV/SOF plus ribavirin both achieved SVR. Neither drug-related severe adverse events nor discontinuation due to drug-related adverse event were reported. The estimated glomerular filtration rate (eGFR) remained stable in patients with chronic kidney disease 3a/3b. Conclusion Twelve weeks of LDV/SOF treatment provided an excellent and safe regimen for GT2 CHC infection, particularly in non-cirrhotic patients.