The combined use of sunitinib and other tyrosine kinase inhibitors (TKIs) is discouraged because of the increased risk of adverse events (AEs). Furthermore, plasma sunitinib levels are affected by drugs that affect CYP3A4 activity; therefore, caution should be exercised when using CYP3A4 inhibitors. In the present study, a 59‑year‑old Japanese man with metastatic renal cell carcinoma (RCC) was diagnosed with chronic myeloid leukemia (CML) while on sunitinib treatment and was simultaneously treated with sunitinib and dasatinib, a multi‑TKI used for CML with moderate CYP3A4 inhibitory activity. The trough levels of sunitinib and N‑desethyl sunitinib were 63.7 and 13.7 ng/ml, respectively, with sunitinib 50 mg/day alone. While grade 2 hand‑foot skin reactions and grade 2 diarrhea were observed after starting dasatinib, the trough levels of sunitinib and N‑desethyl sunitinib were stable, and dasatinib levels were lower than the reference range. Because of the risk of severe AEs, the doses of sunitinib and dasatinib were temporarily reduced or suspended. Ultimately, they were maintained at 87.5 and 83.3% of their initial doses, respectively, with no severe AEs observed. The patient achieved a complete cytogenetic response for CML on day 154 after starting dasatinib treatment; however, RCC metastasis was observed on day 186, leading to a switch from sunitinib to axitinib. This suggests that dasatinib did not significantly affect the plasma levels of sunitinib. A dose reduction at the start of combination therapy is advisable, increasing the dose while monitoring AEs may safely provide sufficient therapeutic intensity.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects of chemotherapeutic drugs. Numerous clinical trials of various targeted drugs for the prevention or treatment of CIPN have been conducted; however, previous systematic reviews with direct comparisons have failed to demonstrate the efficacy of these drugs in the prevention or treatment of CIPN. In addition, no systematic reviews have indirectly compared CIPN prevention and treatment. This article describes a protocol for evaluating the efficacy and safety of drug therapy for the prevention and treatment of CIPN. The results of the proposed systematic review with network meta-analysis (NMA) will provide new insights into the prevention and treatment of CIPN. Methods and analysis: We will conduct a literature search in MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov to find relevant articles published through January 2023. We will include studies that investigated the efficacy and safety of vitamin B₁₂, goshajinkigan, non-steroidal anti-inflammatory analgesics, opioids, calcium and magnesium, antidepressants and anticonvulsants on CIPN. Two authors will individually screen the retrieved reports and review the full text based on the selection criteria. The primary outcome is the incidence and severity of CIPN. The risk of bias will be assessed using V.2.0 of the Cochrane risk-of-bias tool. We will apply a frequentist random-effects NMA model to pool effect sizes across trials using risk ratios and mean differences with their 95% CIs. Competing interventions will be ranked using the surface under cumulative ranking probabilities. Heterogeneity will be assessed using the heterogeneity variance τ², Cochran’s Q test and I² statistic. Ethics and dissemination: This review does not require ethical approval. The research will be published in a peer-reviewed journal. PROSPERO registration number: CRD42022371829.

Background: Specific data concerning the efficacy of alternative antibiotics for carbapenems against complicated urinary tract infections (cUTIs) attributed to antimicrobial-resistant (AMR) uropathogens are lacking. Objectives: This study aimed to assess the efficacy of carbapenems and non-carbapenem antibiotics in the clinical outcomes of cUTIs caused by AMR uropathogens. Methods: In this systematic review and meta-analysis, databases, including MEDLINE/PubMed, the Cochrane Library, Embase and ClinicalTrials.gov, were searched. The study eligibility criteria were research articles conducted as randomised controlled trials that evaluated the composite outcomes of cUTIs. Participants were adult patients with cUTIs caused by gram-negative uropathogens resistant to third-generation cephalosporins. The intervention involved a non-carbapenem class of antimicrobial agents with in vitro activities against gram- negative uropathogens resistant to third-generation cephalosporins. Two independent researchers assessed the risk-of-bias using the second version of the Cochrane risk-of-bias tool for randomised trials. The treatment effects on each outcome were estimated as a risk ratio (RR) with a 95 % confidence interval (CI) using the random- effects model. Heterogeneity was assessed using the Cochrane Q-test and I2 2 statistics. Results: Through database searches, 955 articles were retrieved. After screening the titles and abstracts, 52 articles were screened in full text. Finally, 12 studies met the inclusion criteria. No significant differences in efficacy were observed between alternative antibiotics and carbapenems (composite outcome, RR, 0.96; 95 % CI, 0.63-1.49; I2 2 = 21 %; low certainty of evidence). Conclusions: Alternative antibiotics had clinical efficacy similar to that of carbapenems for treating patients with cUTI caused by gram-negative uropathogens resistant to third-generation cephalosporins.

Background: The relationship between the combination of platelet count and neutrophil‐lymphocyte ratio (COP‐NLR) and prognosis in patients with advanced non‐small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) combination therapy with chemotherapy remains unclear. Thus, we investigated prognostic factors, including the COP‐NLR, to identify patients who could benefit from the therapeutic efficacy of ICI combination therapy for advanced NSCLC. Furthermore, we evaluated the relationship between the COP‐NLR score during ICI combination therapy and treatment response.Methods: We conducted a retrospective cohort study of 88 patients with NSCLC who initially received ICI combination therapy. The primary outcome was overall survival (OS). The prognostic factors were extracted using the Cox proportional hazards model. The relationship between COP‐NLR score at 3 weeks after starting ICI combination therapy and a good response (complete response [CR] and partial response [PR]) to treatment was analyzed using the chi‐square test.Results: The median OS was 15.7 months. In the multivariable analysis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2, distant metastatic sites ≥2, and baseline COP‐NLR scores of 1, 2 were extracted as significant poor prognostic factors. The proportion of patients with CR and PR in the 3‐week COP‐NLR score of 0 group was significantly higher than that in scores of 1, 2 group.Conclusions: Baseline COP‐NLR, ECOG PS, and number of distant metastatic sites were prognostic factors in patients with NSCLC with ICI combination therapy. A lower 3‐week COP‐NLR was associated with a good response to treatment.

Purpose The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment. Methods This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson’s correlation coefficient. Results Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5–63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups. Conclusion This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.