Takeshi Hirota

This study aimed to evaluate the diagnostic utility of urinary exosomal microRNAs (miRNAs) in subclinical rejection following kidney transplantation by comparing miRNA expression profiles in urinary exosomes between patients with no evidence of rejection and patients with subclinical T‐cell‐mediated rejection (sc‐TCMR), as confirmed by protocol kidney biopsies performed 3 months after transplantation. To elucidate these differences, a comprehensive miRNA expression analysis was conducted using microarray profiling. Consequently, 38 urinary exosomal miRNAs were detected, among which three were upregulated and five were downregulated in patients with sc‐TCMR. To further evaluate the diagnostic value of these miRNAs, quantitative real‐time PCR analysis was performed using urinary exosomes collected at the time of protocol biopsy from 70 kidney transplant recipients. This analysis confirmed that miR‐5100 and miR‐7975 were differentially expressed in patients with sc‐TCMR at the time of the 12‐month protocol biopsy. Importantly, miR‐7975 demonstrated the ability to distinguish among three groups—no evidence of rejection, borderline changes, and sc‐TCMR—with high diagnostic accuracy, as indicated by an area under the receiver operating characteristic curve of 0.825. In vitro, exposure of proximal tubular epithelial cells to transforming growth factor‐beta 1 resulted in a reduction in miR‐7975 expression within urinary exosomes, implicating these cells as a potential source of exosomal miR‐7975. Collectively, these findings suggest that urinary exosomal miR‐7975 may serve as a promising noninvasive biomarker for diagnosing and monitoring sc‐TCMR, offering valuable insights for future research and clinical applications.

Oxaliplatin‐induced peripheral neuropathy (OIPN) causes numbness and pain in the limbs, often leading to interruption of chemotherapy and representing a significant clinical problem. Previous basic studies have suggested that the dipeptidyl peptidase‐4 (DPP‐4) inhibitor alogliptin may prevent OIPN. To evaluate whether concomitant use of DPP‐4 inhibitors could prevent the development of OIPN in clinical practice, we retrospectively analyzed data from 1180 patients who initiated oxaliplatin treatment at Kyushu University Hospital between January 1, 2009 and December 31, 2019. The primary endpoint was the occurrence of OIPN of any grade. Kaplan–Meier analysis with cumulative doses demonstrated a significantly lower incidence of OIPN in the DPP‐4 inhibitor group ( p = 0.0422). After propensity score matching to adjust for patient backgrounds, the protective association remained significant ( p = 0.0389). Furthermore, Cox proportional hazards analysis incorporating gender, age, regimen, and concomitant DPP‐4 inhibitor use as covariates confirmed that DPP‐4 inhibitor use was an independent protective factor for OIPN (HR = 0.690; 95% CI, 0.490–0.972; p = 0.034). These findings suggest that concomitant use of DPP‐4 inhibitors may moderate the development of OIPN in patients receiving oxaliplatin.

Malnutrition implies a decline in the systemic status and organ function, which is closely related to sarcopenia, frailty, osteoporosis, and prognosis. Diabetes medications work in a multifaceted manner on various tissues, such as the pancreas, muscle, liver, and adipose tissue; these medications affect metabolism, which in turn affects nutritional status. This study aimed to determine the effect of diabetes medications on the scores of the Geriatric Nutrition Risk Index (GNRI) and Controlling Nutritional Status (CONUT) nutritional indices, both cross‐sectionally and longitudinally. This cross‐sectional study included 2146 individuals who were prescribed diabetes medications. Multivariate analysis showed that both GNRI and CONUT scores tended to be improved in patients using sodium‐glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), or biguanide (BG). Additionally, propensity score matching of nutrition‐related laboratory values was performed to assess the variation in nutritional indices over time, which resulted in less deterioration of the GNRI in the SGLT2i and BG groups. In conclusion, this study suggests that SGLT2i and BG prevent the progression of malnutrition and may help in selecting drugs that consider the nutritional status of patients.

Antibody-drug conjugates (ADCs) with monomethyl auristatin E (MMAE) have recently become prevalent in cancer treatment. This study aimed to comprehensively examine the adverse events (AEs) associated with regulatory-approved MMAE-conjugated ADCs using the FDA Adverse Event Reporting System (FAERS). A disproportionality analysis of reports from July 2011 to September 2024 was conducted to detect AE signals in adult patients with cancer receiving any of the four MMAE-conjugated ADCs (brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and tisotumab vedotin) using reporting odds ratio and information component. FAERS yielded 12,655 reported cases with 4,958 drug-AE pairs. Positive signals observed across the four MMAE-ADCs included 'blood and lymphatic system disorders' and 'metabolism and nutrition disorders' at the system organ class, and anemia, febrile neutropenia, hypokalemia, peripheral neuropathy, and pneumonitis for individual AEs, with 54 other overlapping AEs shared by at least three of the ADCs. FAERS analysis revealed overlapping safety signals in MMAE-conjugated ADCs. Although further research is necessary to clarify the causal relationships, our findings provide a basis for understanding the characteristics of possible AEs in MMAE-ADCs, aiding clinical decision-making for patient safety management.

Background The immune-related adverse event (irAE), pneumonitis, is a potentially fatal complication of immune checkpoint inhibitors (ICIs). Preventing its progression is crucial, emphasizing the need for effective screening tests. We evaluated the feasibility of using Krebs von den Lungen-6 (KL-6), a marker for interstitial pneumonitis, as a screening tool for pneumonitis. Methods We examined 500 patients with cancer divided into two groups: those with cancer other than non-small cell lung cancer (NSCLC) (Group 1, n=382) and those with NSCLC (Group 2, n=118). KL-6 levels were monitored before and during ICI treatment and analyzed for their correlation with pneumonitis. Results In Group 1, 37 patients (9.7%) developed pneumonitis. KL-6 levels were significantly elevated at irAE onset (pre: 222.0 U/mL, post: 743.0 U/mL, pConclusions KL-6 is a viable screening biomarker in ICI-induced pneumonitis, particularly in patients without NSCLC. In patients with NSCLC, the significance of KL-6 monitoring is limited as it is not effective for detecting ICI-induced pneumonitis; their treatment is typically managed by pulmonary specialists. Early detection through KL-6 monitoring facilitates timely intervention for ICI-induced pneumonitis, potentially preventing treatment interruptions and reducing the need for immunosuppressants.

Nirmatrelvir/ritonavir is a treatment for COVID-19 consisting of nirmatrelvir, which has anti-SARS-CoV-2 activity, and ritonavir, a booster to maintain blood levels. Ritonavir is known to be a potent inhibitor of cytochrome P450 3A (CYP3A), and interactions with CYP3A-metabolized drugs, such as the immunosuppressant tacrolimus, can be problematic. Ritonavir's inhibition of CYP3A is irreversible due to covalent binding, and its inhibitory effects are expected to persist until replaced by new CYP3A. Here, we report a case where the combination of nirmatrelvir/ritonavir and tacrolimus resulted in toxic tacrolimus blood levels. A patient on tacrolimus for systemic lupus erythematosus (SLE) developed COVID-19 and was prescribed nirmatrelvir/ritonavir. After starting the combination of nirmatrelvir/ritonavir and tacrolimus, the patient's tacrolimus blood levels became abnormally high, leading to the discontinuation of these drugs due to symptoms of tacrolimus toxicity. Even after ritonavir blood levels had fallen below the detection limit, the decline in tacrolimus blood levels was delayed. The CYP3A inhibition of ritonavir persists even when its blood concentration decreases, emphasizing the need for careful consideration of concomitant medications before starting nirmatrelvir/ritonavir therapy. Adjustments or discontinuation may be necessary.

Background Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events. Methods We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes. Results Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2 mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4 months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34–2.86, p < 0.001). Conclusion Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal.

Fostamatinib is the first approved spleen tyrosine kinase inhibitor for chronic immune thrombocytopenia. This review summarizes the clinical development, pharmacokinetics, pharmacodynamics, drug–drug interactions, adverse events, and comprehensive analyses of fostamatinib. While integrating these findings, we discuss the fostering and improvement of fostamatinib for further clinical applications. Fostamatinib is designed as a prodrug and cleavage of its active moiety R406 in the intestine. As R406 is the major product in the blood, this review mainly discusses the pharmacokinetics and pharmacodynamics of R406. It is metabolized by cytochrome 3A4 and UGT1A9 in the liver and is dominantly excreted in feces after anaerobic modification by the gut microbiota. As fostamatinib and R406 strongly inhibit the breast cancer resistance protein, the interaction with those substrates, particularly statins, should be carefully monitored. In patients with immune thrombocytopenia, fostamatinib administration started at 100 mg twice daily, and most patients increased to 150 mg twice daily in the clinical trial. Although responders showed a higher R406 concentration than non-responders, the correlation between R406 exposure and achievement of the platelet count as a pharmacodynamic marker was uncertain in the pharmacokinetic/pharmacodynamic analysis. Additionally, R406 concentration was almost halved in patients with a heavy body weight; hence, the exposure-efficacy study for suitable dosing should be continued with post-marketing data. In contrast, the pharmacokinetic/pharmacodynamic analysis for exposure safety revealed that R406 exposure significantly correlated with the incidence of hypertension. Even though the influence of elevated exposure on other toxicities, including diarrhea and neutropenia, is still unclear, careful management is required with dose escalation to avoid toxicity-related discontinuation.