In Japan, amrubicin hydrochloride (AMR) is occasionally administered to patients with recurrent small cell lung cancer (SCLC). AMR therapy can induce febrile neutropenia (FN), a complication that may be fatal or compromise therapeutic efficacy due to treatment interruption or dose reduction. Identifying risk factors for FN is therefore critical to ensuring safe and effective AMR administration. Current evidence on this issue remains limited to small case series, underscoring the need for more robust studies. We conducted a multicenter retrospective analysis to examine predictors of FN during AMR treatment for recurrent SCLC. Patients who received AMR between April 1, 2013, and March 31, 2023, were included. The cohort comprised 256 patients, divided into 192 without FN and 64 with FN. Multivariate analysis demonstrated that performance status (PS) >2 (odds ratio: 5.8, 95% confidence interval: 1.70-19.80, p=0.005) and hematocrit (HCT) (odds ratio: 0.93, 95% confidence interval: 0.877-0.994, p=0.033) were significantly associated with FN development. These findings suggest that PS and HCT may serve as key indicators for predicting FN during AMR therapy in patients with recurrent SCLC.

Fluoropyrimidine anticancer agents, exemplified by 5-fluorouracil (5-FU), induce severe adverse effects-such as myelosuppression, emesis, diarrhea, and hand-foot syndrome-in approximately 10-30% of patients. As such toxicities can result in delays or discontinuation of therapy, accurate prediction of drug response prior to treatment initiation is of critical importance. The metabolic degradation of 5-FU is primarily mediated by the drug-metabolizing enzymes dihydropyrimidine dehydrogenase (DPD) and dihydropyrimidinase (DHPase). These enzymes are encoded by the DPYD and DPYS genes, respectively; polymorphisms in these genes that reduce or abolish enzymatic activity lead to elevated systemic concentrations of 5-FU, thereby increasing the risk of severe toxicity. In Caucasian populations, four DPYD polymorphisms have been identified as predictive markers of adverse drug reactions. However, these variants are rarely observed in Japanese individuals, and reliable pharmacogenomic biomarkers remain largely unreported in this population. To address this gap, we conducted a comprehensive in vitro functional analysis of DPD and DHPase activity of DPYD and DPYS variants identified through large-scale whole-genome sequencing databases. This review summarizes our findings and elucidates the underlying mechanisms affecting the function of 5-FU-metabolizing enzymes, as revealed by our prior research.

The Ser/Thr-specific kinase, polo-like kinase 1 (Plk1), is a crucial eukaryotic cell cycle regulatory protein. Overexpression of this kinase is observed in many cancer cells and where it can be related to their aggressiveness. Dysfunction of Plk1 in cancer cells causes mitotic arrest and subsequent apoptosis. Accordingly, Plk1 is considered as a target for the development of anti-cancer agents. Plk1 has two domains, a catalytic kinase domain (KD) and a polo-box domain (PBD). PBD intramolecularly interacts with its KD and regulates Plk1 activity and localization. Therefore, in addition to the KD, the PBD is considered to be a potential drug target. We have been developing peptidic low-nanomolar-affinity PBD-binding inhibitors. However, these peptides do not show significant cytotoxicity, due to their low cell membrane permeability. To obtain cell-active Plk1 inhibitors, I applied a bivalent approach designed to simultaneously engage both KD and PBD regions of Plk1 for enhancing the potency, selectivity and lipophilicity. Here, I developed bivalent Plk1 inhibitors, in which the PBD-binding peptides are conjugated with the known KD-binding inhibitors BI2536 or wortmannin using PEG linkers. These bivalent inhibitors exhibit up to 100-fold enhanced Plk1 affinity relative to the best monovalent PBD-binding ligands, higher selectivity for tested kinases compared to BI2536, and significant cytotoxicity against HeLa cells.

In cancer drug therapy involving anti-epidermal growth factor receptor (EGFR) antibody drugs, skin disorders such as acneiform rash are frequently observed and often progress to severe forms, resulting in treatment discontinuation. The severity of these skin disorders has been reported to correlate with therapeutic efficacy. Therefore, appropriate management is essential to avoid interruption of treatment due to severe dermatological toxicity. Identifying patients at risk of developing serious skin disorders at the start of anti-EGFR antibody drug therapy is necessary to enable prophylactic or early intervention. However, risk factors for skin disorders induced by anti-EGFR antibody drugs remain poorly understood, and predicting the severity of these conditions is challenging. This review highlights findings from retrospective and prospective observational studies conducted to predict the severity of skin disorders associated with anti-EGFR antibody drugs.

Non-clinical pharmacological safety studies are conducted using cells and animals to ensure the safety of pharmaceuticals in humans. Following these studies, drug candidates are administered to humans during clinical trials. Safety must be sufficiently confirmed in non-clinical studies to ensure that test participants suffer no adverse health effects. However, due to species differences, low ability to extrapolate from in vitro to in vivo evaluation methods, and other problems, health hazards may unfortunately still occur. Therefore, sophisticated in vitro evaluation systems using human cells are actively being pursued. The main challenge remains the lack of a reliable methodology for extrapolating in vitro results to in vivo settings. We have attempted to extract parameters that can be predictably translated from in vitro [contractile evaluation in three-dimensional (3D) heart tissue] to in vivo (guinea pig echocardiography) conditions, using cardiac contractile dysfunction induced by anticancer drugs as an example. In this review, we introduce the in vitro methods developed to date to evaluate this cardiac contractile dysfunction, analyze the factors enabling highly accurate prediction of torsades de pointes in humans based on past proarrhythmic risk prediction methods using human induced pluripotent stem cell-derived cardiomyocytes, and apply them to evaluate cardiac contractile dysfunction caused by anticancer drugs using three-dimensional heart tissue. We also introduce the proposed strategy for this evaluation method in this section.

Diterpenoid alkaloids are major pharmaceutically active constituents of Aconitum plants. In phytochemical investigations on Aconitum japonicum subsp. subcuneatum, Aconitum yesoense var. macroyesoens, and Delphinium elatum cv. Pacific Giant (Ranunclaceae), the structures of isolated C19- and C20-diterpenoid alkaloids were elucidated. Three aconitine-type C19-diterpenoid alkaloids, jesaconitine, aconitine, and mesaconitine, which are main components of A. japonicum subsp. subcuneatum, are significantly toxic to the central nervous system. However, lycoctonine-type C19-diterpenoid alkaloids and C20-diterpenoid alkaloids are less toxic. Several diterpenoid alkaloids from the genera Aconitum and Delphinium and their derivatives exhibited slight cytotoxic activity against several human tumor cell lines [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. In our course of studies on synthetic derivatives of the C19-diterpenoid alkaloids delcosine and delpheline and the C20-diterpenoid alkaloids lucidusculine, pseudokobusine, and kobusine, we found several derivatives showing significant cytotoxic activity and, thus, providing promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells. Among non-cytotoxic synthetic analogues, several lycoctonine-type C19-diterpenoid alkaloid derivatives effectively and significantly sensitized MDR cells to three anticancer drugs, paclitaxel, vincristine, and doxorubicin.

Ixazomib (IXA) is a convenient oral anticancer drug; however, due to its fixed dosage, IXA tolerability among elderly Japanese individuals may be reduced. Therefore, this study aimed to clarify the difference in relative dose intensity (RDI) of IXA in IRd therapy in elderly patients. Between October 2018 and September 2023, patients who underwent IRd therapy (IXA, lenalidomide, and dexamethasone combination treatment) at Ogaki Municipal Hospital were enrolled in the study and categorized into two age groups: ≥75 years (group O, n=16) and <75 years (group Y, n=6). We retrospectively analyzed RDI of IXA, in IRd therapy. In addition, we evaluated the reasons for dose reduction or delayed treatment. The median initial IXA dose was 3 mg (range: 2.3-4 mg) and 4 mg (range: 3-4 mg) in group O and Y, respectively (p=0.122). The median RDI in group O (65.8%, range: 51.1-91.7%) was significantly lower than in group Y (93.3%, range: 80.5-100.0%) (p=0.002). Among them, anorexia was more common in group O than in group Y (p=0.049). In group O, dose adjustments were made due to anorexia (n=10), diarrhea (n=5), nausea (n=2), and fatigue (n=2). In group Y, adjustments were made due to diarrhea (n=2) and thrombocytopenia (n=1). Upon IXA (4 mg) administration, the rate of dose adjustments due to gastrointestinal symptoms were 75% and 17% in group O and Y, respectively (p=0.051). Overall, RDI was lower in group O owing to gastrointestinal symptoms. This suggests that the fixed IXA dosage (4 mg) is less tolerable in older individuals.

Many anticancer drugs, including anthracycline drugs, pose a risk of cardiovascular damage as an adverse reaction. This can detrimentally impact the prognosis and quality of life of patients, potentially leading to the interruption of cancer chemotherapy and compromising cancer treatment. Recently, onco-cardiology (or cardio-oncology) has developed as a new interdisciplinary field that focuses on the prevention and treatment of cardiovascular toxicity of anticancer drugs. In this review, we explore the mechanism underlying the cardiotoxicity of anthracyclines and examine pharmacological agents that safeguard the heart from anthracycline-induced damage. Anthracycline-induced cardiotoxicity primarily involves oxidative stress, characterized by radical production in mitochondria and subsequent apoptosis in cardiomyocytes. While various antioxidant agents, such as resveratrol, vitamin E, and melatonin have demonstrated efficacy in reducing anthracycline-induced cardiotoxicity in animal models, their clinical effectiveness remains inconclusive. Alternatively, dexrazoxane, an intracellular iron chelator, along with standard heart failure medications, such as β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, reduce anthracycline cardiotoxicity and prevent subsequent heart failure in both animal and human studies. Additionally, statins [hydroxymethylglutaryl (HMG)-CoA reductase inhibitors] and ranolazine have emerged as potential candidates for attenuating anthracycline-induced cardiotoxicity in clinical settings. Notably, recent in vitro findings suggest that everolimus, an autophagy/mitophagy-inducing antitumor drug, may protect cardiomyocytes from anthracycline-induced toxicity without reducing the antitumor effects of anthracycline. Although promising, further clinical research is warranted to validate the potential of everolimus as a safer and more effective anthracycline chemotherapeutic strategy.

(Purpose) We performed a clinical retrospective study on the evaluation of pembrolizumab treatment results for advanced urothelial cancer in our hospital. (Materials and Methods) Twenty-seven patients diagnosed with advanced or metastatic urothelial carcinoma who received pembrolizumab between April 2018 and December 2021 were included. We retrospectively reviewed medical records to examine treatment outcomes, immune-related adverse event (irAE), and prognostic factors. (Results) The median age of patients was 76 years, and the median number of pembrolizumab doses was 6. The median overall survival was 8.8 months, and the best treatment response according to RECIST version 1.1 was complete response 1, partial response 7, stable disease 5, and progression disease 14. Pre-pembrolizumab risk factors related to overall survival include the presence of liver metastasis, LDH ≥200 IU/L, and TSH <4 μIU/mL in univariate analysis. Grade 3 irAE was type 1 diabetes in only 1 case, and grade 2 were hypothyroidism in 4 cases, type 1 diabetes in 1 case, interstitial pneumonia in 1 case, and skin disorder in 1 case. Nine patients had a TSH of 4 μIU/mL or higher at the start of pembrolizumab, and four of them had hypothyroidism requiring oral levothyroxine, and none of the patients in the low TSH group required hormone replacement (p =0.013). (Conclusion) High TSH level before pembrolizumab administration for advanced urothelial cancer was associated with hypothyroidism, suggesting the possibility of improved prognosis.

This is a personal review of my chemistry research on retirement from Teikyo University. Under the guidance of Prof. Masaji Ohno of the Faculty of Pharmaceutical Sciences, The University of Tokyo, my research career started with the synthesis of water-soluble basic natural compounds, including the first artificial bleomycin showing potent molecular-oxygen activation effects and DNA binding abilities. While studying abroad at Eidgenössische Technische Hochschule (ETH) under the guidance of Prof. Albert Eschenmoser, I studied the formation of ribose under prebiotic conditions. The condensation reaction between formaldehyde and glycolaldehyde phosphate produced ribose in far greater yield than the formose reaction. In the School of Pharmacy, Showa University, I conducted research in nucleic acid chemistry to synthesize, for example, anomeric spiro-nucleosides using radical chemistry and oligonucleotides that interacted with the κB motif. After moving to Teikyo University in 1999, I engaged in studies on the synthesis of vitamin D derivatives, included in fat-soluble vitamins, with selective biological activities without calcemic side-effects, and discovered, for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D3 (MART-10), which exhibits potent anticancer activity in vivo, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (AH-1), which shows greater bone-forming effects than natural active vitamin D3 in vivo, and the A-ring-converted vitamin D derivative KK-052, which is an in vivo selective inhibitor of sterol regulatory-element binding protein (SREBP), a master transcription factor of lipogenesis, independent of the vitamin D canonical activity through a vitamin D receptor.

A 75-year-old female who was referred to our hospital with dizziness as the main complaint. Computed tomographic (CT) and positron emission tomography-CT scans indicated the presence of generalized lymphadenopathy and a 10 cm tumor in her left kidney. Further evaluation led to a diagnosis of Hodgkin’s lymphoma and left renal cell carcinoma. Due to her poor general condition secondary to the lymphoma, she was referred to our institution where chemotherapy was promptly initiated. After one year, metastases to the sternum and right hilar lymph nodes from the renal cancer were detected. Therefore, treatment for the lymphoma was discontinued, and combination therapy with Pembrolizumab and Axitinib for the renal carcinoma was started. Eight months after starting treatment for kidney cancer, the patient developed gastritis as an immune-related adverse event (irAE), which improved with high-dose steroid therapy. Subsequently, severe thrombocytopenia developed following the initiation of steroid therapy but improved upon discontinuation of Axitinib. Currently, treatment is ongoing with Cabozantinib without recurrence of either gastritis or thrombocytopenia.

The adverse chapter of cancer chemotherapy negatively impact QOL, and pharmacists play a key role in improving QOL by providing optimal drug therapy through pharmaceutical interventions. Although outpatient cancer chemotherapy is now common, the impact of pharmaceutical interventions from a QOL perspective has not been thoroughly studied. Therefore, this study investigated the impact and cost-effectiveness of pharmaceutical interventions on QOL using the EuroQol 5 Dimension (EQ-5D) and Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The study was conducted between 2013 and 2015 on 39 patients who underwent their first outpatient chemotherapy for breast cancer at Gifu Municipal Hospital. The results showed that pharmaceutical interventions improved social relationship QOL in patients experiencing fatigue during the first cycle and enhanced psychological QOL in patients with adverse events of nausea during the second cycle. Furthermore, the maximum incremental cost-effectiveness ratio (ICER) was found to be 1.3 million yen per quality-adjusted life years (QALY) according to cost utility analysis. The pharmaceutical interventions by pharmacists in outpatient cancer chemotherapy improve QOL, and the ICER remains well below the Japanese threshold, signifying clear medical and economic benefits.

This survey aimed to reveal the actual preventing exposure for handling of clothing and sweat of patients treated with anticancer drugs, following the publication of "Guideline for Preventing Occupational Exposure in Cancer Chemotherapy Drugs, 2019 Edition" (Guideline 2019). A survey was conducted among nurses working at 95 hematopoietic stem cell transplantation promotion base hospitals from September 1, 2023 to October 31, 2023. The response rate was 84.2% (80 facilities). Of the respondents, 45% wore gloves when touching patients' skin to administer anticancer drugs. Almost the nurses identified "urine" and "feces" as fluids on contaminated linen, while 14.1% also identified "sweat." For new staff, the results for preventing exposure education on "if touching the patients' skin" and "if handling clothing and linen" were 23.8% and 34.9%, respectively. This survey shows that nurses may not be following the Guideline 2019 for use of personal protective equipment and handling of clothes. Medical institutions handling anticancer drugs need to educate their staff for preventing occupational exposure.

The administration of cabazitaxel for patients with castration-resistant prostate cancer (CRPC) requires prior docetaxel therapy. Sequential chemotherapy may have to be discontinued due to docetaxelassociated side effects. This study investigated the relationship between treatment outcome of docetaxel and cabazitaxel and their associated side effects. We retrospectively analyzed 69 patients with CRPC who had been administered docetaxel withand without subsequent cabazitaxel at Toyonaka Municipal Hospital from October 2014 to June 2022. Twenty-eight patients (41%) discontinued docetaxel because of side effects, and the median number of docetaxel cycles at discontinuation was 2 (range : 1-11). Fourteen of these patients received no treatment following docetaxel. A comparison of the 28 patients who had discontinued docetaxel due to side effects with 41 patients who had not revealed a significant difference in the total numbers of chemotherapy cycles (2.5 vs 9 ; P＜0.001) and time to treatment failure (56 days vs 301 days ; P＝ 0.001), with a trend toward shorter overall survival from the start of docetaxel treatment (259 days vs 512 days ; P＝0.06). Multivariate analysis identified discontinuation of docetaxel due to side effects (OR＝0.07 ; P＜0.001) and lower hemoglobin (OR＝0.01 ; P＝0.001) as significant factors inhibiting the introduction of cabazitaxel. Reducing the side effects of docetaxel, including early drug switching, may allow more CRPC patients to be reached with cabazitaxel. Consequently, the resulting taxane-based chemotherapy may contribute to an additional survival advantage.

A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan-Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.

Recent advances in cancer therapy have significantly improved the survival rate of patients with cancer. In contrast, anti-cancer drug-induced adverse effects, especially cardiotoxicity, have come to affect patients' prognosis and quality of life. Therefore, there is a growing need to understand the anti-cancer drug-induced cardiotoxicity. Human induced pluripotent stem (iPS) cell-derived cardiomyocytes (hiPSC-CMs) have been used to assess drug-induced cardiotoxicity by improving the predictability of clinical cardiotoxicity and the principles of the 3Rs (replacement, reduction and refinement). To predict the anti-cancer drug-induced cardiotoxicity, we developed a novel method to assess drug-induced proarrhythmia risk using hiPSC-CMs by participating in the international validation. In addition, we established the chronic contractility toxicity assessment by image-based motion analysis. The compound BMS-986094, which was withdrawn from clinical trials, inhibited contractility velocity and relaxation velocity in hiPSC-CMs. Currently, we are trying to investigate the predictability of the contractility assay by comparing the hiPSC-CM data with adverse events reports from real-world database. In this review, we would like to introduce the novel imaging-based contractility method using hiPSC-CMs and future perspectives in anti-cancer drug-induced cardiotoxicity.

Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase. Treating colon cancer cells with a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC), led to elevated expression levels of CYP1B1 and CYP3A4 through demethylation of the promoter regions of related genes. Furthermore, the administration of DAC and the histone deacetylase inhibitor depsipeptide [(DEP), an anti-cancer drug romidepsin] significantly increased the cellular sensitivities of human colon cancer cells to CPT-11 and 5-FU, respectively. Remarkably, DAC treatment also increased colon cancer cell sensitivity to SN-38, an active metabolite of CPT-11, through the suppression of the anti-apoptotic protein Bcl-2. DEP increased colon cancer cell sensitivity to 5-FU in association with increased expressions of tumor-suppressor p21 and major histocompatibility complex class II genes. Another facet of my research is centered around understanding the gene regulatory mechanisms of the CYP1 family through aryl hydrocarbon receptors (AhR)s under glucose-deprivation stress and in three-dimensional (3D) culture systems of human solid tumor cells. In the 3D culture of human liver cancer cells, I found Pregnane X Receptor being implicated in the regulation of CYP1A2, which aligns with the in vivo mode of CYP1A2 expression.

Immune checkpoint inhibitors (ICIs) provide excellent benefits to the treatment of various cancer types, including urothelial carcinoma. Conversely, they can cause immune-related adverse events (irAEs), and some of them are severe or fatal. Furthermore, evidence on the safety and effectiveness of the readministration of ICIs after the occurrence of irAEs is limited. In this case report, a 78-year-old man who suffered from metastatic right renal pelvic cancer was treated with pembrolizumab. He had a partial response to pembrolizumab, but he developed grade 3 myasthenia gravis. The myasthenia gravis symptoms were immediately relieved by corticosteroids and intravenous immunoglobulin therapy. When the disease rapidly progressed, he was treated again with pembrolizumab. After 5 days, a chest radiograph showed shrinkage of pulmonary metastases. Unfortunately, he died of multiple brain infarctions 7 days after the readministration. We report this case with a literature review on the efficacy and safety of the readministration of ICIs after the occurrence irAEs including myasthenia gravis.

Danger-associated molecular patterns (DAMPs) derived from damaged or dying cells elicit inflammation and potentiate antitumor immune responses. We found that treatment of cancer cells with the antitumor agent topotecan (TPT), an inhibitor of topoisomerase I (TOP1), induces DAMP secretion that triggers dendritic cell activation and cytokine production. TPT administration inhibits tumor growth in tumor-bearing mice, which is accompanied by infiltration of activated DCs and CD8+ T cells. These effects are abrogated in mice lacking stimulator of interferon genes (STING), an essential molecule in cytosolic DNA-mediated innate immune responses. Furthermore, we identified ribosomal protein L15 (RPL15), a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited pre-ribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. RPL15 knockdown induced DAMP secretion and increased the cytotoxic T lymphocyte (CTL) population but decreased the T-regulatory cell (Treg) population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against programmed death receptor-1(PD-1) blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.

We investigated the clinical characteristics of patients who developed kidney injury after starting treatment with immune checkpoint inhibitors (ICI) for urologic malignancies. The study included 118 patients who were treated with ICI at our hospital. They consisted of 65 with renal cell carcinoma, 52 with urothelial carcinomas and 1 with adrenocortical carcinoma with high-frequency microsatellite instability. Immune-related kidney injury was observed in 13 patients (11.0%), including stage 1, 2 and 3 kidney injuries in 9, 0 and 4 patients, respectively. In univariate analyses, ≥stage 4 chronic kidney disease (CKD) before ICI treatment and proton pump inhibitor use were significantly associated with all stages of kidney injury, whereas ≥stage 4 CKD and ICI combination therapy were significantly associated with kidney injury at ≥ stage 2. Of the 4 patients who developed ≥stage 2 kidney injury, histological examination was done only for 2 because renal biopsy was contraindicated in the other 2 due to prior nephrectomy. Steroid pulse therapy was performed for 3 patients but provided complete recovery only in 1. We should be aware of the risk for immune-related kidney injury in patients with baseline CKD (≥stage 4) and receiving ICI combination therapy. Precise diagnosis by histological examination can often be challenging due to a history of nephrectomy.