Yosuke Sugiyama

Background: Combination therapy with immune checkpoint inhibitors and tyrosine kinase inhibitors (IO–TKI) is a key treatment option for metastatic renal cell carcinoma (mRCC), but distinguishing immune‐related adverse events (irAEs) from TKI‐related adverse events (TKI‐AEs) is challenging because of overlapping clinical features. We aimed to evaluate whether eosinophil counts can help differentiate between them. Methods: In this retrospective multicenter study, 123 patients with mRCC treated with IO–TKI therapy were analyzed. Patients were classified into an irAE group ( n = 64) and a TKI‐AE group ( n = 59). Changes in eosinophil counts from baseline to the start of the second treatment cycle were compared. Receiver operating characteristic (ROC) and logistic regression analyses were performed to assess associations with irAE occurrence. Results: Baseline eosinophil counts did not differ between groups. Eosinophil counts at the start of the second treatment cycle were higher in the irAE group than those in the TKI‐AE group (269.6 vs. 189.6 eosinophils/μL; p < 0.05). No significant differences were observed in other blood parameters, including neutrophil, lymphocyte, monocyte, and platelet counts, the neutrophil‐to‐lymphocyte ratio, or the platelet‐to‐lymphocyte ratio. Although the overall discriminatory performance was modest (area under the ROC curve = 0.57, sensitivity = 0.30, specificity = 0.94), eosinophil counts ≥ 380/μL were associated with irAEs in both univariate (odds ratio = 7.21) and multivariable (odds ratio = 8.39; p < 0.05) analyses. Conclusions: Early increases in eosinophil counts were associated with irAEs and may help distinguish irAEs from TKI‐AEs during IO–TKI therapy. Given their high specificity but limited sensitivity, eosinophil counts may have utility as an adjunctive rather than stand‐alone marker, and prospective validation is warranted.

Introduction: Immune‐related adverse events (irAEs) frequently occur during combination immune checkpoint inhibition. However, their prognostic impact may vary according to organ involvement and severity. In this study, we exploratorily evaluated whether severe non‐endocrine irAEs represent a temporally distinct and prognostically unfavorable clinical phenotype in patients with metastatic renal cell carcinoma (mRCC) treated with ipilimumab plus nivolumab. Patients and Methods: We analyzed 63 patients with mRCC treated with ipilimumab plus nivolumab who were followed for at least 5 years. Patients were categorized into non‐irAE, non‐severe + severe endocrine irAE, and severe non‐endocrine irAE groups. Overall survival (OS) was assessed. Multistate modeling was used to evaluate the transitions between treatment, irAE occurrence, and death. Landmark analyses were performed at 8 and 12 weeks to address immortal time bias. Results: The severe non‐endocrine irAE group was associated with inferior OS. The multistate analysis revealed a potentially increased risk of direct transition from ipilimumab plus nivolumab to death in the severe non‐endocrine irAE group. A significantly higher proportion of patients in the severe non‐endocrine irAE group experienced irAEs within 30 days. No significant association was observed in the 8‐ and 12‐week landmark analyses. Conclusion: In this exploratory retrospective study, severe non‐endocrine irAEs showed an association with early onset and potentially unfavorable clinical outcomes in patients with mRCC receiving ipilimumab plus nivolumab. Given the limited sample size, these findings should be interpreted cautiously and require confirmation in larger independent cohorts.

Background: Combination therapy comprising immune checkpoint inhibitors (ICIs) and chemotherapy is standard treatment for many cancer types. However, the management of adverse events (AEs) induced by combination therapy is more complicated than that of AEs induced by ICI monotherapy. Although immune‐related AEs (irAEs) induced by ICIs and AEs induced by chemotherapy require distinct therapeutic approaches, distinguishing between them can be challenging. Therefore, in this exploratory study, we aimed to investigate whether lymphocyte proportion could serve as a candidate biomarker associated with the occurrence of irAEs in patients receiving ICI plus chemotherapy combination therapy. Patients and Methods: We categorized 122 patients into the irAE group (those who experienced irAEs), chemo‐AE group (those with chemotherapy‐induced AEs), and non‐AE group (those without AEs) and analyzed their lymphocyte proportions before one course (baseline sample) and two courses (two‐course sample) of treatment. Results: Lymphocyte proportions of the baseline samples did not differ between the non‐AE, chemo‐AE, and irAE groups. The lymphocyte proportion of the two‐course sample of the irAE group was significantly higher than that of the non‐AE group (25.8% vs. 21.9%; p < 0.05). The lymphocyte proportion of the two‐course sample of the irAE group was significantly higher than that of the chemo‐AE group (25.8% vs. 19.6%; p < 0.05). The multivariate logistic regression analysis showed that a lymphocyte proportion ≥ 23.9% in the two‐course sample significantly increased the risk of irAEs (odds ratio = 3.04; p < 0.05). Conclusions: An increased lymphocyte proportion before the two courses of treatment was associated with the occurrence of irAEs and may serve as a candidate biomarker.

Enfortumab vedotin (EV) is a crucial treatment for patients with metastatic urothelial carcinoma (mUC). However, a significant proportion of patients experience adverse events (AEs). The identification of biomarkers for AEs is imperative for the detection and treatment of AEs at an early stage. In this exploratory study, we aimed to identify biomarkers of AEs in patients with mUC treated with EV. We retrospectively examined 10 factors identified from the data of 116 patients with mUC treated with EV to identify biomarkers (age, body mass index, C‐reactive protein level, Eastern Cooperative Oncology Group performance status, eosinophil proportion, history of diabetes, lymphocyte proportion, neutrophil proportion, neutrophil‐to‐lymphocyte ratio, and platelet count) associated with the occurrence of AEs of any grade. The candidate biomarkers were measured at the start of EV treatment. The least absolute shrinkage and selection operator method was used to select the most useful parameters for predicting AE occurrence. Among the 10 factors, eosinophil proportion was identified as the only potential biomarker. The optimal cutoff value for eosinophil proportion against the occurrence of AEs of any grade was 2.5% (area under the curve = 0.625). Univariable logistic regression analyses showed that an eosinophil proportion of ≥ 2.5% was a risk factor for AE development (odds ratio = 4.35, 95% confidence interval = 1.35–14.0). Therefore, the results of this exploratory study indicated that an eosinophil proportion of ≥ 2.5% at the start of EV treatment may be a candidate biomarker for the occurrence of AEs of any grade.

There is an unmet need to predict immune‐related adverse events (irAEs) in patients receiving immune checkpoint inhibitors. This study aimed to examine whether eosinophils can predict irAEs in metastatic urothelial carcinoma (mUC). In this multicenter cohort study, we retrospectively examined eosinophil before (baseline sample) and 3 weeks after treatment (3‐week sample) in 124 patients with mUC treated with pembrolizumab between January 2018 and October 2024. We divided the patients into two groups depending on whether they had experienced an irAE (irAE group) or not (non‐irAE group). The variation in eosinophil proportion from baseline to 3 weeks was significantly higher in the irAE group than in the non‐irAE group (non‐irAE, 2.4%–3.1%; irAE, 2.2%–4.3%; p < 0.05). Notably, the variation in eosinophils from baseline to 3 weeks in patients with bladder cancer was significantly higher in the irAE group than in the non‐irAE group (non‐irAE, 2.5%–2.8%; irAE, 1.9%–4.1%; p < 0.05), but not in upper urinary tract urothelial cancer (non‐irAE, 2.2%–3.7%; irAE, 2.8%–4.4%; p = 0.97). The optimal cutoff value for eosinophils in patients with bladder cancer against the occurrence of any‐grade irAEs was 5.0% (area under the curve = 0.655). Multivariable analyses showed that eosinophil levels ≥ 5.0% increased the risk of any‐grade irAEs in patients with bladder cancer (odds ratio 3.61, 95% confidence interval, 1.00–13.0). An eosinophil proportion ≥ 5.0% may be an effective biomarker for evaluating pembrolizumab‐induced irAEs in patients with mUC, particularly those with bladder cancer.

Background/Objectives: Nivolumab plus ipilimumab (IO–IO) provides durable clinical benefit in metastatic renal cell carcinoma (mRCC), yet long-term real-world data focusing on progression-free and treatment-free (PF–TF) survival remain limited. This study aimed to evaluate the long-term outcomes of IO–IO with a particular focus on the frequency and clinical characteristics of PF–TF. Methods: We retrospectively analyzed 63 patients with mRCC treated with first-line IO–IO across eight institutions with a minimum potential follow-up of five years. Progression-free survival (PFS), PFS2, and overall survival (OS) were assessed. PF–TF was defined as absence of disease progression and any cancer-directed therapy at the five-year landmark. Clinical and treatment-related factors were compared between patients with and without PF–TF. Results: The median PFS, PFS2, and OS were 7.5 (95% confidence interval [CI], 5.1–13.3), 26.2 (95% CI, 13.6–46.6), and 47.4 months (95% CI, 29.3–not reached), respectively. At 5 years, 11 patients (17%) achieved PF–TF. Baseline characteristics, IMDC risk classification, and peripheral blood biomarkers were not predictive of PF–TF. PF–TF was associated with the absence of bone metastases, presence of lymph node metastases, and occurrence of immune-related adverse events (irAEs), as well as the delayed onset of irAEs. No PF–TF patients required corticosteroid pulse therapy, and durable PF–TF was observed even after early treatment discontinuation due to adverse events. Conclusions: IO–IO demonstrated sustained long-term efficacy in real-world practice, with a subset achieving durable PF–TF. These findings highlight IO–IO as a strategy capable of providing long-term disease control with reduced treatment burden in selected patients with mRCC.

Background: While opioid analgesics are widely used to manage moderate-to-severe cancer-related pain, dosing is mostly based on subjective pain reports rather than objective physiological indicators, potentially contributing to inconsistent dosing and suboptimal pain control. This study investigated whether model-predicted oxycodone serum concentrations could guide opioid dosing and whether wearable-derived heart rate and step count, combined with these predictions, could complement conventional numerical rating scale (NRS) pain assessments. Methods: Sixteen patients with advanced genitourinary cancer receiving oxycodone were prospectively monitored. Clinically collected serum concentrations were used to simulate individual pharmacokinetic profiles. Pain intensity was assessed using the NRS, and physiological parameters were recorded using wearable devices. Linear mixed-effects models were constructed to evaluate the associations between simulated serum oxycodone concentrations, NRS, and physiological variables. Results: In the linear mixed-effects model, simulated serum oxycodone concentrations were significantly associated with lower NRS scores (β = −0.26, P = .0177). Although neither heart rate nor step count independently predicted NRS, incorporating heart rate into the model improved the overall fit. Thus, heart rate may capture pain-related physiological responses not fully explained by oxycodone concentration alone, thereby enhancing the explanatory power of the model. Conclusions: Model-based simulated serum oxycodone concentrations may serve as an objective reference for individualized pain assessment and opioid titration. Combining wearable-derived physiological signals, particularly heart rate, with model-predicted oxycodone concentrations may further improve the precision and adaptability of pain management in palliative care.

We have established a highly stable and reproducible patient derived xenograft model that exclusively and robustly retains the morphological, functional, and proliferative characteristics of human yolk sac tumor of the testis. This model might provide an invaluable in vivo platform for accelerating the discovery and validation of novel therapeutic strategies for this aggressive malignancy, with the ultimate aim of improving the prognosis for affected patients.

Introduction: Avelumab (Ave) is approved for metastatic urothelial carcinoma (mUC) maintenance therapy and prolongs overall survival (OS). We explored trends related to Ave treatment of mUC patients. Methods: A total of 72 patients with mUC treated with first-line chemotherapy, from January 2019 to November 2022, at our affiliated institutions, were analyzed. We compared clinical parameters and the prognosis of patients treated with Ave (n = 43) because of progression during first-line chemotherapy, with untreated patients (Ave-untreated; n = 29). Among the Ave-treated group, we classified patients showing a complete or partial response or stable disease in their best response to Ave maintenance therapy as Ave-suitable patients; these were retrospectively analyzed. Potential prognostic factors, including the Geriatric Nutritional Risk Index (GNRI) for determining patients suitable for Ave, were evaluated. Results: The basic clinical parameters of patients when first-line treatment was initiated were not statistically different between the two groups. The Ave-suitable group (median 26.6 months, 95% confidence interval [CI]: 19.4–not reached [NR]) showed significantly longer median OS after first-line treatment than the Ave-untreated group (median 12.0 months, 95% CI: 7.5–NR) with tolerable adverse events. The cut-off values of prognostic factors were set by the receiver operating characteristic curve. Low age and GNRI sustainability were revealed as significant prognostic factors for being Ave-suitable both in univariate and multivariate analysis. Conclusion: In mUC, Ave maintenance prolonged OS within tolerable safety profiles. GNRI sustainability may be used as a biomarker to predict being Ave-suitable.

Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC.