Efficacy and safety of subsequent molecular targeted therapy after immuno-checkpoint therapy, retrospective study of Japanese patients with metastatic renal cell carcinoma (AFTER I-O study).

OBJECTIVES: Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear. METHODS: Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs. RESULTS: Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3-4 events in 51% of patients, and no treatment-related deaths occurred. CONCLUSIONS: TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit.

[Risk Classification and Nivolumab plus Ipilimumab Combination Therapy for Treatment of Renal Cell Carcinoma].

The International Metastatic Renal Cell Carcinoma Database Consortium(IMDC)classification is often used to predict the prognosis of patients treated with molecularly targeted agents. In this review, the authors describe the prognostic value of the neutrophil-lymphocyte ratio and C-reactive protein for Japanese patients with renal cell carcinoma. Both markers may help identify which patients are likely to have a poor prognosis despite molecularly targeted therapy. In these circumstances, the CheckMate 214 trial showed that nivolumab plus ipilimumab combination therapy was superior to sunitinib for the treatment of patients with intermediate/poor prognosis. As a consequence, the combination of nivolumab plus ipilimumab is now positioned as standard first-line treatment for renal cell carcinoma, and the IMDCclassification is recommended as an aid in treatment decisions. Although careful management of immune-related adverse events is necessary, nivolumab plus ipilimumab combination therapy is expected to improve the outcomes of renal cell carcinoma for which the prognosis is otherwise generally poor.

Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: a propensity score-matched analysis.

BACKGROUND: The average age of patients diagnosed with renal cell carcinoma (RCC) is increasing, but a limited number of reports have described therapy of tyrosine kinase inhibitor for elderly RCC patients. Hence, we analysed the efficacy and safety of sorafenib in elderly patients aged ≥75 years with advanced RCC. METHODS: Data were extracted from <75-year-old and ≥75-year-old patient groups, matching those demographics considered to affect prognosis. Differences in patients' characteristics, dose modification, adverse events, tumour response, progression-free survival, and renal function (glomerular filtration) were evaluated between the groups. RESULTS: From 2536 and 703 patients aged <75 and ≥75 years, respectively, 397 pairs were matched. Median daily dose was higher and duration of treatment longer in patients <75 years; however, progression-free survival and tumour response were similar in both age groups. Incidence of all adverse events was not significantly different between groups. The proportion of patients discontinuing treatment was higher in patients ≥75 years, but there was no significant difference between groups in the number patients discontinuing due to adverse events. CONCLUSIONS: For patients aged ≥75 years, sorafenib treatment had minimal additional negative impact compared to younger patients and showed similar efficacy and safety without reducing renal function.

Little Impact on Renal Function in Advanced Renal Cell Carcinoma Patients Treated with Sorafenib--Analyses of Postmarketing Surveillance in Japan in over 3,200 Consecutive Cases.

BACKGROUND: To assess the effect of sorafenib on renal function in patients with advanced renal cell carcinoma (RCC) included in a postmarketing surveillance. METHODS: All patients in Japan with advanced RCC treated with sorafenib between February 2008 and September 2009 were followed for 12 months. Baseline characteristics, renal function, survival, safety, and dosage were stratified according to baseline estimated glomerular filtration rate (eGFR): G1 (eGFR≥90), G2 (eGFR≥60-<90), G3a (eGFR≥45-<60), G3b (eGFR≥30-<45), G4 (eGFR≥15-<30), and G5 (eGFR<15). A total of 3,255 and 3,171 patients were included in this analysis for safety and efficacy, respectively. RESULTS: The mean eGFRs (mL/min/1.73 m2) were not substantially changed for each group at baseline and 12 months, respectively. Median daily doses of sorafenib were 726 mg (G1), 522 mg (G2), 524 mg (G3a), 517 mg (G3b), 483 mg (G4), and 400 mg (G5). Renal failure, reported as an adverse event, occurred more frequently in the G4 and G5 groups (9%and 3%, respectively) than in other groups. Objective response rates for each subgroup were as follows: G1, 23%; G2, 28%; G3a, 29%; G3b, 26%; G4, 24%; and G5, 18%. One-year survival was higher in the G3a and G3b groups (82% and 78%, respectively) and lower in the G1 group (50%). CONCLUSIONS: This study demonstrated little impact of sorafenib on renal function in advanced RCC patients during the observational period. Patients showed sufficient clinical response and safety irrespective of baseline eGFR value.

When should icodextrin be started to improve atherosclerosis in peritoneal dialysis patients?

Icodextrin-based peritoneal dialysis (PD) has many advantages over glucose-based PD. The present study aimed to investigate when icodextrin should be started for better management of cardiovascular status (as defined by echocardiography findings) and residual renal function (RRF). We retrospectively analyzed 40 patients treated with continuous ambulatory PD or automated PD. The patients were divided into these groups: Group A: started icodextrin within 2 weeks after PD onset. Group B: started icodextrin 1 year after PD onset. Group C: started icodextrin 2 years after PD onset. Group D: never used icodextrin during the study period. At the start of PD, we observed no significant difference in left ventricular mass index (LVMI) or urine volume (UV) between the groups. At 4 years, LVMI and UV were both significantly improved in group A compared with group D. The amelioration in LVMI was negatively associated with phosphate elimination. Our study showed that icodextrin preserved RRF and ameliorated left ventricular hypertrophy. Moreover, the timing of icodextrin introduction in PD patients influenced the clinical effects, including progression of cardiac hypertrophy and RRF.

Icodextrin eliminates phosphate and ameliorates cardiac hypertrophy and valvular calcification in patients with end-stage renal disease and diabetes mellitus undergoing peritoneal dialysis.

Among end-stage renal disease (ESRD) patients, cardiovascular disease is a common comorbidity and one of most important factors affecting clinical prognosis. Calcium deposition has been reported to correlate with plasma phosphate. Icodextrin (Ico)-based peritoneal dialysis (PD) has many advantages over glucose (Glu)-based PD. We aimed to identify factors that suppress arteriosclerosis and valvular disease in patients with ESRD and diabetes mellitus (DM) undergoing Ico-based PD. In this retrospective study, we evaluated the effects of Ico-based PD (n = 20) on phosphate elimination and cardiovascular disease progression in patients with ESRD andDM, and we compared the results with those for Glu-based PD (n = 20). Left ventricular mass index (LVMI) and aortic valve calcification (AVC) score were significantly decreased and daily phosphate elimination was significantly increased in the Ico group compared with the Glu group. Furthermore, mean daily phosphate elimination was significantly and negatively correlated with the amelioration in LVMI and AVC score. Our study suggests that, compared with glucose, icodextrin has the ability to eliminate more phosphate from the body, indicating that phosphate elimination might potentially be a means of controlling cardiovascular disease in PD patients with DM.

Favorable Management of Repeated Serous Retinal Detachment with Continued Tumor Response in a Patient with Intrahepatic Cholangiocarcinoma during Treatment with Pemigatinib.

Pemigatinib is a fibroblast growth factor receptor inhibitor (FGFRi) approved for the treatment of patients with previously treated biliary tract cancer with FGFR2 fusion. Although infrequent, ocular toxicity manifested as serous retinal detachment (SRD) has been observed and is regarded as a serious side effect. We herein report the case of a 54-year-old woman with unresectable cholangiocarcinoma-initiated pemigatinib after failure of gemcitabine plus S-1 (GS). Although the patient experienced repeated SRD after pemigatinib, dose interruption and dose reduction of pemigatinib from 13.5 mg to 9 mg, and from 9 mg to 4.5 mg led to complete recovery of SRD, and continued tumor shrinkage.

Zinc is a novel intracellular second messenger.

Zinc is an essential trace element required for enzymatic activity and for maintaining the conformation of many transcription factors; thus, zinc homeostasis is tightly regulated. Although zinc affects several signaling molecules and may act as a neurotransmitter, it remains unknown whether zinc acts as an intracellular second messenger capable of transducing extracellular stimuli into intracellular signaling events. In this study, we report that the cross-linking of the high affinity immunoglobin E receptor (Fcepsilon receptor I [FcepsilonRI]) induced a release of free zinc from the perinuclear area, including the endoplasmic reticulum in mast cells, a phenomenon we call the zinc wave. The zinc wave was dependent on calcium influx and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation. The results suggest that the zinc wave is involved in intracellular signaling events, at least in part by modulating the duration and strength of FcepsilonRI-mediated signaling. Collectively, our findings indicate that zinc is a novel intracellular second messenger.

[Pharmacological characteristics and clinical study results of Pemigatinib (Pemazyre® Tablets), a selective fibroblast growth factor receptor (FGFR) inhibitor].

Pemigatinib (Pemazyre® Tablets 4.5 mg) is a novel fibroblast growth factor receptor (FGFR) inhibitor, created by Incyte Corporation. The product was approved in March 2021 and was launched in June 2021 for the treatment of patients with locally advanced or metastatic biliary tract cancer (BTC) with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that has progressed after at least one prior line of systemic therapy. Pemigatinib was shown to selectively inhibit kinase activity of FGFR1～3 (IC50; 0.39～1.2 nM). In cultured cells, pemigatinib inhibited the phosphorylation of FGFR1 and its downstream signals, ERK1/2 and STAT5 in a concentration-dependent manner. Pemigatinib also potently inhibited the growth of various types of cell lines with FGFR 1～3 gene alteration. Pemigatinib was shown to induce concentration-dependent tumor regression in a tumor xenograft model mice in which tumor tissue sections from patients with cholangiocarcinoma (CCA) harboring FGFR2 gene fusions were transplanted. Pemigatinib was well tolerated in Japanese and overseas Phase1 studies (INCB 54828-101 and 202). In the global phase2 study (INCB 54828-202) conducted in CCA patients with FGFR2 gene fusions or rearrangements, significant improvement in the overall response rate was observed. Although several adverse reactions were observed which was based on the mechanism of action of pemigatinib, the safety profile and management of the adverse reactions were favorable. Pemigatinib is expected to contribute to second-line drug treatment after failure of standard therapies in biliary tract cancer.

A Multicentre Retrospective Study of Nivolumab Plus Ipilimumab for Untreated Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: To evaluate the effectiveness and safety of nivolumab plus ipilimumab for untreated metastatic renal cell carcinoma in real-world clinical practice in Japan based on 1-year follow-up results. PATIENTS AND METHODS: This multicentre, retrospective study analysed 45 metastatic renal cell carcinoma patients who received nivolumab plus ipilimumab between August 2018 and January 2019 in Japan. Data were extracted from patients' medical records. Subgroup analyses were performed based on baseline demographic data and treatment history. RESULTS: The objective response rate was 42.5% (complete response rate: 10.0%). The 12-month overall survival rate was 81.4% and the progression-free survival rate was 56.1%. Thirty-five patients (77.8%) showed any grade treatment-related adverse events and 17 (37.8%) showed grade ≥3 treatment-related adverse events, with no significant difference in safety between subgroups. CONCLUSION: The effectiveness and safety of nivolumab plus ipilimumab in real-world clinical practice with 1-year follow-up were comparable with those of the CheckMate 214 trial.

Fc{epsilon}RI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane.

The aggregation of high affinity IgE receptors (Fcepsilon receptor I [FcepsilonRI]) on mast cells is potent stimulus for the release of inflammatory and allergic mediators from cytoplasmic granules. However, the molecular mechanism of degranulation has not yet been established. It is still unclear how FcepsilonRI-mediated signal transduction ultimately regulates the reorganization of the cytoskeleton and how these events lead to degranulation. Here, we show that FcepsilonRI stimulation triggers the formation of microtubules in a manner independent of calcium. Drugs affecting microtubule dynamics effectively suppressed the FcepsilonRI-mediated translocation of granules to the plasma membrane and degranulation. Furthermore, the translocation of granules to the plasma membrane occurred in a calcium-independent manner, but the release of mediators and granule-plasma membrane fusion were completely dependent on calcium. Thus, the degranulation process can be dissected into two events: the calcium-independent microtubule-dependent translocation of granules to the plasma membrane and calcium-dependent membrane fusion and exocytosis. Finally, we show that the Fyn/Gab2/RhoA (but not Lyn/SLP-76) signaling pathway plays a critical role in the calcium-independent microtubule-dependent pathway.

B-cell linker protein prevents aneuploidy by inhibiting cytokinesis.

Aneuploidy is a hallmark of human cancers. Although the maintenance of genomic integrity by p53 is important in preventing aneuploidy, its mechanism remains to be elucidated. Here we report evidence that B-cell linker protein (BLNK) mediates the inhibition of cytokinesis, which generates tetraploidy but prevents aneuploidy. We identified BLNK as a transcriptional target of p53. Surprisingly, ectopic expression of exogenous BLNK inhibited cytokinesis, resulting in the formation of tetraploid cells. Indeed, BLNK was involved in the generation of spontaneously arising binucleate tetraploid cells. Interestingly, cytokinesis after DNA damage was inhibited in p21(-/-) and p53+/+ cells, but not in p53(-/-) cells. BLNK knockdown in p53+/+ and p21(-/-) cells enhanced cytokinesis after DNA damage, leading to the generation of aneuploid cells. In addition, a BLNK-downregulated human pre-B leukemia cell line showed increased cytokinesis and aneuploidy after DNA damage compared with two other pre-B leukemia cell lines expressing higher levels of BLNK. These results suggest that BLNK acts as a mediator of p53 in the inhibition of cytokinesis, which prevents aneuploidy. We propose that the inhibition of cytokinesis is crucial for the maintenance of genomic integrity.

Efficacy and safety of sorafenib for advanced renal cell carcinoma: real-world data of patients with renal impairment.

BACKGROUND: We retrospectively analysed the efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with renal impairment. METHODS: Patients were divided into two groups by an estimated glomerular filtration rate (eGFR) cut-off of 45 mL/min/1.73 m2. Background factors considered to affect prognosis were well balanced by propensity score matching between the groups. Demographics, dose modification, adverse events, tumour response, progression-free survival, and renal function (eGFR) were evaluated. RESULTS: Among 935 and 2008 patients with an eGFR of <45 and ≥45, respectively, 613 pairs were matched. The mean starting dose was significantly lower in patients with an eGFR of <45; however, the mean daily dose, median treatment duration, progression-free survival, and tumour response were similar between the groups. In terms of safety, no significant differences were found in serious adverse events, although cytopaenia (16.6% vs 10.6%) and renal dysfunction (4.4% vs 0.7%) were higher in patients with an eGFR of <45 than ≥45 in all adverse events. There were also no differences in dose modification, including dose reduction, dose interruption, and treatment discontinuation. CONCLUSION: Throughout the 12-month observation period, sorafenib in patients with an eGFR of <45 and ≥45 showed similar safety and efficacy, and treatment was continued without affecting renal function.

Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

BACKGROUND: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC. METHODS: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%. CONCLUSIONS: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

A Pilot Study Examining the Effects of Tolvaptan on Residual Renal Function in Peritoneal Dialysis for Diabetics.

BACKGROUND: For patients with end-stage renal disease (ESRD), peritoneal dialysis (PD) serves as a possible renal replacement therapy. However, most PD patients, particularly those with ESRD and diabetes mellitus, reportedly discontinue PD early, resulting in shorter survival periods and poorer prognosis because of overhydration. Recently, the vasopressin-2 receptor antagonist tolvaptan was approved for volume control in patients with heart failure. The present study aimed to identify the effects of tolvaptan in diabetic PD patients. METHODS: In this pilot study, the tolvaptan group (n = 12) were treated with 15 mg/day of tolvaptan 2 weeks after PD initiation and were prospectively analyzed for 1 year, and patients in the control group (n = 12) did not receive tolvaptan and were retrospectively analyzed for 1 year. In addition to the biochemical tests, echocardiograms, serum atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels, peritoneal Kt/V, and creatinine clearance (CCr) were examined at baseline and at 6 and 12 months after PD initiation. RESULTS: In the control group, the urine volume, renal Kt/V, and renal CCr levels consistently decreased; however, these parameters were stably maintained during the study period in the tolvaptan group. Atrial natriuretic peptide, CRP levels and the left ventricular mass index of the tolvaptan-treated group were significantly lower than those in the control group, whereas total protein and albumin levels were significantly higher at 6 and 12 months in the tolvaptan group. There were no obvious adverse effects. CONCLUSIONS: These data suggest that tolvaptan may preserve residual renal function and improve volume control in PD patients with diabetes mellitus.

Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria.

Maintenance of healthy mitochondria prevents aging, cancer, and a variety of degenerative diseases that are due to the result of defective mitochondrial quality control (MQC). Recently, we discovered a novel mechanism for MQC, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria). However, a large part of the mechanisms for MQC remains unknown. Here, we report additional mechanisms for Mieap-regulated MQC. Reactive oxygen species (ROS) scavengers completely inhibited MALM. A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. Deficiency of NIX also completely impaired MALM. When MALM was inhibited, Mieap induced vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulfed and degraded the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impaired both MALM and MIV generation, leading to accumulation of unhealthy mitochondria. These results suggest that (1) mitochondrial ROS and NIX are essential factors for MALM, (2) MIV is a novel mechanism for lysosomal degradation of mitochondria, and (3) the p53-Mieap pathway plays a pivotal role in MQC by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively.

Zinc is required for Fc epsilon RI-mediated mast cell activation.

Zinc (Zn) is an essential nutrient, and its deficiency causes growth retardation, immunodeficiency, and neuronal degeneration. However, the precise roles and molecular mechanism(s) of Zn function in immune response have not been clarified. Mast cells (MCs) are granulated cells that play a pivotal role in allergic reactions and inflammation. The granules of MCs contain various chemical mediators and inflammatory cytokines that are released upon FcepsilonRI cross-linking. In this study, we report that Zn is essential for MC activation both in vitro and in vivo. We showed that a Zn chelator, N,N,N,N-tetrakis (2-pyridylmethyl) ethylenediamine, inhibited in vivo allergic reactions such as PCA and PSA. Consistent with this, N,N,N,N-tetrakis (2-pyridylmethyl) ethylenediamine significantly inhibited the FcepsilonRI-induced degranulation and cytokine production. We found that Zn was required for FcepsilonRI-induced translocation of granules to the plasma membrane, a process that we have shown to be important for MC degranulation. In addition, we showed that Zn was essential for plasma membrane translocation of protein kinase C and subsequent nuclear translocation of NF-kappaB, leading to cytokine production, such as IL-6 and TNF-alpha. These results revealed that Zn was involved in multiple steps of FcepsilonRI-induced MC activation and required for degranulation and cytokine production.