Publications by authors named "Yutaro Kubota"

43 Publications

Characteristics of miRNA-SNPs in healthy Japanese subjects and non-small cell lung cancer, colorectal cancer, and soft tissue sarcoma patients.

Noncoding RNA Res 2021 Sep 27;6(3):123-129. Epub 2021 Jun 27.

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.

Single nucleotide polymorphisms in genes encoding microRNAs (miRNA-SNPs) may affect the maturation steps of miRNAs or target mRNA recognition, leading to changes in the expression of target mRNAs to cause gain- or loss-of-function changes. Several miRNA-SNPs are known to be associated with the risk of diseases such as cancer. The purpose of this study was to comprehensively determine the miRNA-SNPs in Japanese individuals to evaluate the differences in allele frequencies between ethnicities by comparing data from the global population in the 1000 Genomes Project and differences between healthy subjects and cancer patients. We performed next-generation sequencing targeting genes encoding 1809 pre-miRNAs. As a result, 403 miRNA-SNPs (146 miRNA-SNPs per subject on average) were identified in 28 healthy Japanese subjects. We observed significant differences in the allele frequencies between ethnicities in 33 of the 403 miRNA-SNPs. The numbers of miRNA-SNPs per subject in 44 non-small cell lung cancer (NSCLC), 33 colorectal cancer (CRC), and 15 soft tissue sarcoma (STS) patients were almost equal to those in healthy subjects. Significant differences in allele frequencies were observed for 14, 11, and 9 miRNA-SNPs in NSCLC, CRC, and STS patients compared with the frequencies in healthy subjects, suggesting that these SNPs can be biomarkers of risk for each type of cancer assessed. In summary, we comprehensively characterized miRNA-SNPs in Japanese individuals and found differences in allele frequencies of several miRNA-SNPs between ethnicities and between healthy subjects and cancer patients. Studies investigating a larger number of subjects should be performed to confirm the potential of miRNA-SNPs as biomarkers of cancer risk.
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http://dx.doi.org/10.1016/j.ncrna.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283029PMC
September 2021

Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure.

Cancer Chemother Pharmacol 2021 Sep 11;88(3):543-553. Epub 2021 Jun 11.

Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Purpose: SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan.

Methods: We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry.

Results: Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1.

Conclusion: The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.
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http://dx.doi.org/10.1007/s00280-021-04314-1DOI Listing
September 2021

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

Medicine (Baltimore) 2021 Jun;100(23):e25774

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine.

Introduction: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.

Patients Concerns: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.

Diagnosis: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.

Interventions: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.

Outcomes: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.

Conclusion: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
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http://dx.doi.org/10.1097/MD.0000000000025774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202549PMC
June 2021

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

In Vivo 2021 May-Jun;35(3):1865-1875

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background/aim: Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing.

Patients And Methods: Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared.

Results: Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio.

Conclusion: Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.
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http://dx.doi.org/10.21873/invivo.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193338PMC
June 2021

The Prognostic Impact of Eosinophils and the Eosinophil-to-Lymphocyte Ratio on Survival Outcomes in Stage II Resectable Pancreatic Cancer.

Pancreas 2021 02;50(2):167-175

Division of Medical Oncology, Department of Medicine, School of Medicine.

Objectives: The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection.

Methods: This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves.

Results: The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes.

Conclusions: Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.
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http://dx.doi.org/10.1097/MPA.0000000000001731DOI Listing
February 2021

A Case of Cerebral Infarction During Treatment With Rivaroxaban for Venous Thromboembolism.

Am J Ther 2020 Dec 28;Publish Ahead of Print. Epub 2020 Dec 28.

Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Shinagawa-ku, Tokyo Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo Division of Neurology, Department of Internal Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo Department of Pharmacy, Showa University Hospital, Shinagawa-ku, Tokyo.

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http://dx.doi.org/10.1097/MJT.0000000000001312DOI Listing
December 2020

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer.

Int J Oncol 2021 01 12;58(1):57-69. Epub 2020 Nov 12.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance‑related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient‑derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next‑generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug‑treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan‑Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.
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http://dx.doi.org/10.3892/ijo.2020.5147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721086PMC
January 2021

Nivolumab versus chemotherapy in Japanese patients with advanced esophageal squamous cell carcinoma: a subgroup analysis of a multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3).

Esophagus 2021 Jan 10;18(1):90-99. Epub 2020 Nov 10.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: The efficacy and safety of nivolumab versus chemotherapy was evaluated in the Japanese subpopulation from the overall intent-to-treat (ITT) population of the ATTRACTION-3 trial conducted in patients with advanced esophageal squamous cell carcinoma (ESCC) as second-line treatment.

Methods: Data from Japanese patients enrolled in the multicenter, randomized, open-label, phase 3 ATTRACTION-3 trial were analyzed. The primary endpoint was overall survival (OS). Secondary endpoints included duration of response (DOR), objective response rate (ORR), disease control rate (DCR), and safety. Exploratory subgroup analyses evaluated the association between OS and stratification factors/baseline variables.

Results: Overall, 274 (nivolumab, 136; chemotherapy, 138) of the 419 patients in ATTRACTION-3 were enrolled from Japan: response-evaluable population (107; 108) and safety population (135; 138). OS tended to be longer in the nivolumab group versus the chemotherapy group (median: 13.4 months vs. 9.4 months; HR, 0.77; 95% CI 0.59-1.01). Median DOR was longer in the nivolumab group (7.6 months) versus the chemotherapy group (3.6 months). ORRs were similar between the nivolumab [22.4% of patients (24/107)] and chemotherapy groups [22.2% (24/108); odds ratio, 0.98; 95% CI 0.52-1.87]. DCR was lower in the nivolumab group [41.1% (44/107)] versus the chemotherapy group [66.7% (72/108)]. OS in the exploratory analysis consistently favored the nivolumab group versus the chemotherapy group. Overall, nivolumab demonstrated favorable efficacy and safety versus chemotherapy in the Japanese subpopulation, and the trend was similar to that observed in the overall ATTRACTION-3 ITT population.

Conclusion: Nivolumab represents a new standard second-line treatment option for Japanese patients with advanced ESCC.
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http://dx.doi.org/10.1007/s10388-020-00794-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794205PMC
January 2021

A high number of PD-L1 CD14 monocytes in peripheral blood is correlated with shorter survival in patients receiving immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Feb 5;70(2):337-348. Epub 2020 Aug 5.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.

Purpose: Targeting of anti-programmed cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) is a standard therapeutic strategy for various cancers. The aim of the present study was to investigate the prognostic effect of pretreatment PD-L1 expression levels in peripheral blood mononuclear cell (PBMC) subsets for patients with several cancer types receiving anti-PD-1 blockade therapies.

Patients And Methods: Thirty-two patients undergoing anti-PD-L1 blockade therapy, including 15 with non-small cell lung cancer, 14 with gastric cancer, 1 with melanoma, 1 with parotid cancer, and 1 with bladder cancer, were recruited for the present study. PD-L1 expression levels in CD3, CD4, CD8, CD45RA and CCR7 T cells; CD20 B cells; CD14 and CD16 monocytes were measured via flow cytometry before treatment. The percentages of PD-L1 cells in respective PBMC subsets were compared with respect to different clinicopathological conditions and the association with overall survival (OS) was assessed.

Results: The percentages of PD-L1 with CD3, CD4 and CD8 T cells including naïve and memory T cell subsets, or CD20 B cells during pretreatment were not markedly correlated with the OS of patients (p > 0.05); however, the percentage of the PD-L1 CD14 monocyte subset was significantly correlated with OS (p = 0.0426).

Conclusion: Increase in pretreatment expression levels of PD-L1 on CD14 monocytes is associated with the OS of patients treated with immune checkpoint inhibitors. Further evaluation of large sample size and each specific cancer type might clarify the predictive role of PBMC in patients.
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http://dx.doi.org/10.1007/s00262-020-02686-6DOI Listing
February 2021

High expression levels of polymeric immunoglobulin receptor are correlated with chemoresistance and poor prognosis in pancreatic cancer.

Oncol Rep 2020 Jul 11;44(1):252-262. Epub 2020 May 11.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer has extremely poor prognosis, warranting the discovery of novel therapeutic and prognostic markers. The expression of polymeric immunoglobulin receptor (pIgR), a key component of the mucosal immune system, is increased in several cancers. However, its clinical relevance in pancreatic cancer remains unclear. In the present study, the prognostic value of pIgR in pancreatic cancer patients after surgical resection was assessed and it was determined that the expression of pIgR was correlated with poor prognosis. Ten pancreatic cancer patient‑derived xenograft (PDX) lines were established, followed by next‑generation sequencing of tumor tissues from these lines after standard chemotherapy. Immunohistochemical analysis of chemoresistance‑related molecules using 77 pancreatic cancer tissues was also performed. The expression of pIgR mRNA in the PDX group treated with anticancer drugs was higher than in the untreated group. High pIgR expression in tissue specimens from 77 pancreatic cancer patients was significantly associated with poor prognosis and was revealed to be an independent prognostic factor, predicting poor outcomes. High pIgR mRNA and protein levels were independent prognostic factors, indicating that pIgR could be a novel predictor for poor prognosis of pancreatic cancer patients.
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http://dx.doi.org/10.3892/or.2020.7610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251687PMC
July 2020

Variants of carboxylesterase 1 have no impact on capecitabine pharmacokinetics and toxicity in capecitabine plus oxaliplatin treated-colorectal cancer patients.

Cancer Chemother Pharmacol 2020 06 26;85(6):1119-1128. Epub 2020 May 26.

Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Purpose: Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects of CES1 variants on pharmacokinetics and toxicity of capecitabine.

Methods: We enrolled postoperative colorectal cancer (CRC) patients administered with adjuvant capecitabine plus oxaliplatin (CapeOX) and metastatic CRC patients receiving CapeOX. The pharmacokinetic analysis of the first capecitabine dose (1000 mg/m) was done on day 1, and oxaliplatin administration was shifted to day 2. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-FU were analyzed by high-performance liquid chromatography. CES1 polymorphisms (rs3217164, rs2244614, rs2244613, rs7187684, and rs11861118) and the functional CES1 genes (1A1, var1A1, 1A2, and pseudo 1A3) in their diplotype configurations were analyzed by direct sequencing.

Results: Thirty-seven patients were enrolled from September 2017 to February 2020. Patients with a higher area under the plasma concentration-time curve to capecitabine dose ratio (AUC/dose) of 5'-DFUR than its mean showed a higher frequency of overall ≥ grade 3 toxicity and lower relative dose intensity (RDI) of capecitabine than those with a lower ratio. Higher CES1 activity expressed as a metabolic ratio (AUC of capecitabine/sum of three AUCs of each metabolite) lower than its mean was associated with higher 5'-DFUR AUC/dose and lower RDI, indicating essential roles of CES1 in capecitabine activation to produce 5'-DFUR. However, the association between CES1 variants and capecitabine pharmacokinetics and toxicity was not significant.

Conclusion: CES1 variants are not associated with capecitabine pharmacokinetics and toxicity.
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http://dx.doi.org/10.1007/s00280-020-04087-zDOI Listing
June 2020

Association between the findings of metachronous secondary primary malignancies and the number of Lugol-voiding lesions.

Dis Esophagus 2020 Sep;33(9)

Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan.

This study was designed to evaluate the relation between dysplastic squamous epithelium in the esophageal mucosa and the development of metachronous secondary primary malignancies (mSPM) other than esophagus after endoscopic resection (ER) in patients with early esophageal squamous cell carcinoma (SCC). We studied 330 patients with early esophageal SCC who underwent ER as a post hoc analysis of a prospective multicenter cohort study (UMIN Clinical Trials Registry ID UMIN000001676). Lugol-voiding lesions (LVL) were graded into 3 categories (A = no lesion; B = 1 to 9 lesions; C ≥ 10 lesions). The following variables were studied: (i) the incidences of mSPM other than esophagus; (ii) the standardized incidence ratios (SIRs) of mSPM; (iii) the cumulative incidence and total number of mSPM other than esophagus; and (iv) predictors of mSPM other than esophagus on analysis with a multivariate Cox proportional-hazards model. After a median follow-up of 46.6 months, mSPM other than esophagus was diagnosed in a total of 73 patients (90 lesions). Among the 106 patients in group C, 37 patients had mSPM (51 lesions), including head and neck cancer in 14 patients (24 lesions) and gastric cancer in 12 patients (16 lesions). The SIR of mSPM was 3.61 in this study subjects. An increase in the LVL grade (A to B to C) was associated with a progressive increase in the cumulative incidence rate of mSPM other than esophagus (P = 0.017 for A vs. C, P = 0.023 for B vs. C). An increase in the LVL grade (A to B to C) was also associated with a progressive increase in the total number of mSPM other than esophagus per 100 person-years (primary events, relative risk [RR] = 1.66 and 3.24 for grades B and C, respectively, vs. A, P = 0.002 for trend; all events, RR = 1.81 and 4.66 for grades B and C, respectively, vs. A, P < 0.0001 for trend). LVL grade C was a strong predictor of mSPM other than esophagus (RR = 3.41 for A vs. C). LVL grade may be a useful predictor of the risk of mSPM other than esophagus after ER in patients with early esophageal SCC.
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http://dx.doi.org/10.1093/dote/doz110DOI Listing
September 2020

Higher Systemic Exposure to Unbound Active Metabolites of Regorafenib Is Associated With Short Progression-Free Survival in Colorectal Cancer Patients.

Clin Pharmacol Ther 2020 09 10;108(3):586-595. Epub 2020 Mar 10.

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Regorafenib treatment improves survival of patients with metastatic colorectal cancer, but it is also characterized by detrimental side effects that may require modified dosing or interval schedules. Regorafenib is metabolized by cytochrome P450 3A4 in the liver to its active metabolites, M-2 and M-5. We examined area under the unbound plasma concentration-time curve (AUCu) to these compounds to establish pharmacokinetic bases for individualized dosing strategies. The plasma protein binding of M-2 and M-5 was approximately 10-fold lower than that of regorafenib, whereas AUCu values for active metabolites on both days 1 and 15 were significantly higher than that of regorafenib. Patients with higher AUCu values of M-2 or M-5 on day 1 showed significantly shorter progression-free survival than others, likely due, at least in part, to treatment discontinuation as a result of adverse events, especially occurred during first cycle.
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http://dx.doi.org/10.1002/cpt.1810DOI Listing
September 2020

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.

PLoS One 2020 10;15(1):e0226707. Epub 2020 Jan 10.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Tokyo, Japan.

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226707PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953839PMC
April 2020

Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.

Lancet Oncol 2019 11 30;20(11):1506-1517. Epub 2019 Sep 30.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma.

Methods: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing.

Findings: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).

Interpretation: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients.

Funding: ONO Pharmaceutical Company and Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(19)30626-6DOI Listing
November 2019

Plasma Levels of Soluble PD-L1 Correlate With Tumor Regression in Patients With Lung and Gastric Cancer Treated With Immune Checkpoint Inhibitors.

Anticancer Res 2019 Sep;39(9):5195-5201

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan

Background/aim: Cancer immune therapy by immune checkpoint inhibitors (ICIs) is a promising therapeutic strategy for various cancer types. Among ICIs, anti-programmed cell death protein-1 (PD1) and anti-programmed death-ligand 1 (PD-L1) antibodies have shown a remarkable clinical benefit. The present study aimed to address the functional and clinical significance of serum levels of soluble PD-L1 (sPD-L1) in patients.

Materials And Methods: A total of 21 patients, 11 with NSCLC, nine with gastric cancer and one with bladder cancer, who underwent anti-PD-1 therapy were evaluated for sPD-L1 concentration by ELISA analyses at diagnosis and after treatment.

Results: Pretreatment levels of sPD-L1 in patients who received ICIs were not remarkably correlated with the overall survival of these patients (r=0.3394, p=0.1323). Reduction of plasma sPD-L1 level was significantly correlated with tumor regression in patients administered four cycles of treatment (p<0.05).

Conclusion: sPD-L1 might be derived and secreted from tumors and might be useful to identify primary responders to ICIs at a relatively early treatment timepoint.
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http://dx.doi.org/10.21873/anticanres.13716DOI Listing
September 2019

Association between macrocytosis and metachronous squamous cell carcinoma of the esophagus after endoscopic resection in men with early esophageal squamous cell carcinoma.

Esophagus 2020 04 8;17(2):149-158. Epub 2019 Jul 8.

Department of Clinical Oncology, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Macrocytosis is associated with an increased risk of squamous cell carcinoma (SCC) arising in the esophagus in men. The aim of this study was to evaluate the association between macrocytosis and metachronous SCC of the esophagus after endoscopic resection (ER) of early esophageal SCC in men.

Methods: The study group comprised 278 men with early esophageal SCC after ER. The main study variables were as follows: (1) cumulative incidence and total number of metachronous SCC of the esophagus according to the presence or absence of macrocytosis (mean corpuscular volume ≥ 106 fl) and (2) predictors of metachronous SCC of the esophagus as assessed with a multivariate Cox proportional-hazards model.

Results: The median follow-up was 50.3 months. Macrocytosis was associated with a higher 2-year cumulative incidence of metachronous SCC of the esophagus (without macrocytosis vs. with macrocytosis: 11.4% vs. 38.1%, p = 0.002). Macrocytosis was also associated with a higher total number of metachronous SCC of the esophagus per 100 person-years (without macrocytosis vs. with macrocytosis: 7.7 vs. 31.5 per 100 person-years, p < 0.0001). In addition, macrocytosis was a significant predictor of metachronous SCC of the esophagus on multivariate Cox proportional-hazards analysis (relative risk 2.23).

Conclusion: Macrocytosis is a useful predictor of the risk of metachronous SCC of the esophagus after ER of early esophageal SCC in men.
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http://dx.doi.org/10.1007/s10388-019-00685-wDOI Listing
April 2020

Efficacy of Endoscopic Resection and Selective Chemoradiotherapy for Stage I Esophageal Squamous Cell Carcinoma.

Gastroenterology 2019 08 20;157(2):382-390.e3. Epub 2019 Apr 20.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address:

Background & Aims: Esophagectomy is the standard treatment for stage I esophageal squamous cell carcinoma (ESCC). We conducted a single-arm prospective study to confirm the efficacy and safety of selective chemoradiotherapy (CRT) based on findings from endoscopic resection (ER).

Methods: We performed a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC from December 2006 through July 2012; 176 patients underwent ER. Based on the findings from ER, patients received the following: no additional treatment for patients with pT1a tumors with a negative resection margin and no lymphovascular invasion (group A); prophylactic CRT with 41.4 Gy delivered to locoregional lymph nodes for patients with pT1b tumors with a negative resection margin or pT1a tumors with lymphovascular invasion (group B); or definitive CRT (50.4 Gy) with a 9-Gy boost to the primary site for patients with a positive vertical resection margin (group C). Chemotherapy comprised 5-fluorouracil and cisplatin. The primary end point was 3-year overall survival in group B, and the key secondary end point was 3-year overall survival for all patients. If lower limits of 90% confidence intervals for the primary and key secondary end points exceeded the 80% threshold, the efficacy of combined ER and selective CRT was confirmed.

Results: Based on the results from pathology analysis, 74, 87, and 15 patients were categorized into groups A, B, and C, respectively. The 3-year overall survival rates were 90.7% for group B (90% confidence interval, 84.0%-94.7%) and 92.6% in all patients (90% confidence interval, 88.5%-95.2%).

Conclusions: In a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC, we confirmed the efficacy of the combination of ER and selective CRT. Efficacy is comparable to that of surgery, and the combination of ER and selective CRT should be considered as a minimally invasive treatment option. UMIN-Clinical Trials Registry no.: UMIN000000553.
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http://dx.doi.org/10.1053/j.gastro.2019.04.017DOI Listing
August 2019

Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil.

Cancer Chemother Pharmacol 2019 06 9;83(6):1127-1135. Epub 2019 Apr 9.

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Purpose: Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites.

Methods: We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116).

Results: Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites.

Conclusion: Rabeprazole does not affect capecitabine pharmacokinetics.
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http://dx.doi.org/10.1007/s00280-019-03837-yDOI Listing
June 2019

Decreased Disposition of Anticancer Drugs Predominantly Eliminated via the Liver in Patients with Renal Failure.

Curr Drug Metab 2019 ;20(5):361-376

Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan.

Background: Evidence has revealed that renal impairment can affect the systemic exposure of drugs which are predominantly eliminated via the liver. The modulation of drug-metabolizing enzymes and transporters expressed in the liver and/or small intestine by diverse entities, including uremic toxins, in systemic circulation of patients with severe renal failure is considered as the cause of atypical pharmacokinetics, which sometimes induce undesirable adverse events that are especially critical for drugs with narrow therapeutic window such as anticancer drugs. A dosing strategy for anticancer drugs in these patients needs to be established.

Methods: The effects of renal impairment on the systemic exposure and safety of anticancer drugs were summarized. The proposed mechanisms for the alterations in the pharmacokinetics of these anticancer drugs were also discussed.

Results: Changes in pharmacokinetics and clinical response were reported in 9 out of 10 cytotoxic anticancer drugs investigated, although available information was limited and sometimes controversial. Systemic exposure of 3 out of 16 tyrosine kinase inhibitors was higher in patients with severe renal failure than that in patients with normal kidney function. An increase in systemic exposure of anticancer drugs in patients with renal impairment is likely to be observed for substrates of OATP1B1, despite the limited evidence.

Conclusion: The molecular basis for the effect of uremia on non-renal drug elimination still needed to be clarified with further studies to generate generalizable concepts, which may provide insights into establishing better clinical usage of anticancer drugs, i.e. identifying patients at risk and dose adjustment.
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http://dx.doi.org/10.2174/1389200220666190402143125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700602PMC
December 2019

Influx and Efflux Transporters Contribute to the Increased Dermal Exposure to Active Metabolite of Regorafenib After Repeated Oral Administration in Mice.

J Pharm Sci 2019 06 24;108(6):2173-2179. Epub 2019 Jan 24.

Department of Molecular Pharmacotherapeutics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kakuma-machi, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address:

The multikinase inhibitor regorafenib, which is a standard treatment for certain cancer patients after disease progression following other approved therapies, exhibits delayed-onset dermal toxicity. Here, we aimed to clarify the mechanisms that contribute to the increased dermal exposure to active metabolite M-5 of regorafenib after repeated oral administration. The dermal concentration of M-5 at 24 h after the last 5 oral administrations of regorafenib in mdr1a/1b/bcrp mice was more than 190 times that in wild-type mice. The skin-to-plasma concentration ratio of M-5 in mdr1a/1b/bcrp was also higher than in wild-type mice, suggesting possible involvement of P-glycoprotein and breast cancer resistance protein in regulating the dermal distribution. The area under the plasma concentration-time curve values of M-5 and its precursor M-2 in plasma of mdr1a/1b/bcrp were at most 26 and 3 times those in wild-type mice, respectively. Interestingly, repeated administration of regorafenib markedly increased the area under the plasma concentration-time curve of M-5 in plasma, but not liver, compared with a single dose. Intravenous administration of M-5 dose-dependently reduced the liver-to-plasma concentration ratio. Our results indicate that hepatic uptake of M-5 may partially explain the accumulation of M-5 in the systemic circulation, but multiple factors, including influx and efflux transporters, are involved in determining dermal exposure to M-5.
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http://dx.doi.org/10.1016/j.xphs.2019.01.018DOI Listing
June 2019

Lack of correlation between the costs of anticancer drugs and clinical benefits in Japan.

Cancer Sci 2018 Dec 27;109(12):3896-3901. Epub 2018 Nov 27.

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Both overall survival (OS) and progression-free survival (PFS) are primary endpoints of phase III studies of new anticancer drugs. Medical care expenditures, especially oncology drug prices, are rapidly increasing; however, the impact of oncology drug prices on OS and PFS is unclear. We analyzed the relationship between oncology drug prices and clinical outcomes in Japan. The costs of a full course or 1 year of treatment were estimated on the basis of the latest National Health Insurance Drug Price Standards, and the relationship between costs and improvements in OS or PFS obtained with each drug were analyzed. Cost-effectiveness was compared between new-class drugs and next-in-class drugs. We then developed a simple model for estimating the costs required to prolong OS and PFS by 1 day and used this model to compare cost-effectiveness. Drug costs were not significantly related to treatment outcomes in terms of PFS or OS. There was no significant difference in the median cost between novel drugs and the next-in-class drugs (P = 0.39). The oncology drug cost required to prolong PFS by 1 day was more expensive than the drug cost required for prolong OS by 1 day. Prices of oncology drugs should be decided on the basis of actual clinical benefits for cancer patients, and the drug price evaluation process should be disclosed in Japan.
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http://dx.doi.org/10.1111/cas.13831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272097PMC
December 2018

Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer.

Int J Clin Oncol 2019 Feb 22;24(2):222-230. Epub 2018 Sep 22.

Institute of Molecular Oncology, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Background: Cholinergic syndrome is an acute adverse event frequently observed in patients administered irinotecan, and can sometimes negatively affect their quality of life. In some manifestations of the syndrome such as bradycardia, careful monitoring of patients is advised. In this study, we retrospectively investigated the risk factors associated with irinotecan-induced cholinergic syndrome in Japanese patients with cancer.

Methods: Patients who received irinotecan-based chemotherapy between April 2014 and June 2018 were examined. Patient backgrounds and clinical data during the first cycle of an irinotecan-containing regimen, including cholinergic syndrome manifestation within 24 h after the start of treatment, were collected from medical records. Univariate and multivariate analyses were performed to assess the risk of irinotecan-induced cholinergic syndrome.

Results: Among 179 patients administered an irinotecan-containing regimen, 51 experienced cholinergic syndrome after the initiation of treatment. The most common symptom was sweating followed by diarrhea, abdominal pain, lacrimation, and nasal discharge. 42 patients developed symptoms of cholinergic syndrome during their first treatment with irinotecan. Multivariate analyses revealed that the incidences of cholinergic syndrome in patients administered 2 or 3 chemotherapeutic agents; i.e., irinotecan plus 1 or 2 other cytotoxic anticancer drug(s), were significantly higher than that in patients administered irinotecan alone [odds ratio (OR) 4.35, 95% confidence interval (CI) 1.5-12, p = 0.0053 and OR 4.50, 95% CI 1.5-14, p = 0.0093, respectively]. The addition of a molecularly targeted drug did not affect the incidence of cholinergic syndrome.

Conclusion: The incidence rate of irinotecan-induced cholinergic syndrome increased concomitantly with the addition of cytotoxic chemotherapeutic agents administered.
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http://dx.doi.org/10.1007/s10147-018-1347-7DOI Listing
February 2019

A phase II trial of 1st-line modified-FOLFOXIRI plus bevacizumab treatment for metastatic colorectal cancer harboring RAS mutation: JACCRO CC-11.

Oncotarget 2018 04 10;9(27):18811-18820. Epub 2018 Apr 10.

Division of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, 227-8501, Japan.

FOLFOXIRI plus bevacizumab is considered a standard initial therapy for metastatic colorectal cancer (mCRC). However, few prospective trials have evaluated triplet therapy plus bevacizumab in patients with RAS mutant mCRC. Patients with an age of 20 to 75 years, and unresectable, measurable tumors harboring RAS mutation were given first-line treatment with bevacizumab (5 mg/kg on day 1) plus modified-FOLFOXIRI (irinotecan 150 mg/m, oxaliplatin 85 mg/m, levofolinate 200 mg/m, and fluorouracil 2400 mg/m as a 46-h continuous infusion on day 1, repeated every 2 weeks). The primary endpoint was the objective response rate (ORR) as evaluated by an external review board. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Among 64 patients who were enrolled between October 2014 and August 2016, 62 were evaluable for efficacy (right-sided tumors in 27%). ORR and disease control rate were 75.8% (95% confidence interval [CI] 65.1-86.5) and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.2%. Median PFS was 11.5 (95% CI 9.5-14.0) months as of the cut-off date of September 2017. Adverse events of grade 3 or 4 were neutropenia (54%), hypertension (32%), diarrhea (13%), anorexia (11%), peripheral neuropathy (2%), and febrile neutropenia (5%). In conclusion, this prospective trial demonstrated for the first time that FOLFOXIRI plus bevacizumab is an active first-line treatment for patients with RAS mutant mCRC. Modified-FOLFOXIRI plus bevacizumab might become an alternative regimen of triplet chemotherapy for mCRC in Japan.
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http://dx.doi.org/10.18632/oncotarget.24702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922357PMC
April 2018

Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites.

J Pharm Sci 2017 09 4;106(9):2632-2641. Epub 2017 May 4.

Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kakuma-machi, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address:

Regorafenib is a multikinase inhibitor orally administered to colorectal cancer patients, and is known to often exhibit dermal toxicity. The purpose of this study is to clarify possible involvement of P-glycoprotein and breast cancer resistance protein (BCRP) in the dermal accumulation of regorafenib and its active metabolites M-2 and M-5. Following intravenous administration in triple knockout (Abcb1a/1b/bcrp; TKO) and wild-type (WT) mice, delayed plasma clearance of M-2 and M-5, but not regorafenib, was observed in TKO mice compared to WT mice. Elacridar, an inhibitor of both transporters, also caused delayed clearance of M-2 and M-5, suggesting that these transporters are involved in their elimination. Skin-to-plasma concentration ratios of regorafenib, M-2, and M-5 were significantly higher in TKO mice than in WT mice. Elacridar increased skin-to-plasma and epidermis-to-plasma concentration ratios of regorafenib. Basal-to-apical transport of M-2 and M-5 was observed in LLC-PK1-Pgp and MDCKII/BCRP/PDZK1 cells, which was inhibited by elacridar and the BCRP inhibitor Ko143, respectively. The present findings thus indicate that P-glycoprotein and BCRP are involved in the accumulation of regorafenib and its active metabolites in the skin, by affecting either their systemic exposure or their plasma distribution in the circulating blood.
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http://dx.doi.org/10.1016/j.xphs.2017.04.064DOI Listing
September 2017

Toxicities of Receptor Tyrosine Kinase Inhibitors in Cancer Pharmacotherapy: Management with Clinical Pharmacology.

Curr Drug Metab 2017 ;18(3):186-198

Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 1428555. Japan.

A number of molecularly targeted anticancer drugs that efficiently inhibit receptor tyrosine kinases, socalled receptor tyrosine kinase inhibitors (TKIs), have been developed. Although these receptor TKIs are generally well tolerated, unexpected toxicities sometimes occur in various organs. TKI-induced adverse events not only lower the quality of life of cancer patients but also reduce dose intensity, and sometimes result in treatment discontinuation. To reduce adverse drug events and increase treatment efficacy, oncologists and clinical pharmacologists have made efforts to establish strategies to treat patients via optimal selection and dosing of TKIs. Drug efficacy and safety are generally determined by the interplay of multiple processes that regulate pharmacokinetics and pharmacodynamics (toxicodynamics). In this review article, we first provide an overview of adverse events caused by receptor TKIs, focusing on gefitinib, erlotinib, sorafenib and sunitinib, followed by a discussion on the association between pharmacokinetics and toxicities induced by these TKIs, with a focus on establishing optimal personalized treatment strategies by controlling pharmacokinetic properties. Finally, we introduce new findings on the molecular mechanisms of TKIinduced toxicities, elucidated using a new strategy, systems toxicology.
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http://dx.doi.org/10.2174/1389200218666170105165832DOI Listing
May 2018

Cost-minimization analysis of adjuvant chemotherapy regimens given to patients with colorectal cancer in Japan.

J Pharm Health Care Sci 2016 9;2:30. Epub 2016 Nov 9.

Institute of Molecular Oncology, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan ; Division of Medical Oncology, Department of Internal Medicine, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan.

Background: Consideration of medical costs as well as effectiveness and adverse events is rapidly been becoming an important factor in the selection of chemotherapy regimens. However, practical data on the costs of chemotherapy are scarce. We clinically estimated the medical costs of 6 adjuvant chemotherapy regimens for colorectal cancer on the basis of clinical and cost-related data and compared their cost-effectiveness by cost-minimization analyses.

Methods: All patients who received adjuvant chemotherapy for colorectal cancer between April 2012 and May 2015 at four hospitals affiliated with Showa University were studied retrospectively. Clinical and cost data related to adjuvant chemotherapy were collected from medical records and medical fee receipt data, respectively. Six adjuvant chemotherapy regimens were studied: capecitabine and oxaliplatin (CapeOX); 5-fluorouracil (5-FU), ℓ-leucovorin (LV), and oxaliplatin (modified FOLFOX6 [mFOLFOX6]); 5-FU and LV (5-FU/LV); tegafur and uracil (UFT), and LV (UFT/LV); capecitabine; and tegafur, gimeracil and oteracil (S-1). The regimens were divided into 2 groups according to whether or not they contained oxaliplatin because of the difference in effectiveness. Cost-minimization analyses, where relative costs of regimens showing equivalent effectiveness were simply compared, were performed to evaluate the cost-effectiveness of the regimens in each group.

Results: A total of 154 patients with colorectal cancer received adjuvant chemotherapy during the study period. Fifty-seven patients were treated with CapeOX, 10 with mFOLFOX6, 38 with UFT/LV, 20 with capecitabine, and 29 with S-1. No patient received 5-FU/LV. The total costs of oxaliplatin-containing regimens were significantly higher than those of oxaliplatin non-containing regimens. The high cost of oxaliplatin, but not the costs of drugs or various tests for the treatment of adverse events, was the primary reason for the higher costs of the oxaliplatin-containing regimens. The cost-effectiveness of the oxaliplatin-containing regimens CapeOX and mFOLFOX6 were comparable. Among the oxaliplatin non-containing regimens, the cost-effectiveness of S-1 and capecitabine was superior to that of UFT/LV.

Conclusion: Thus, we provided the cost-effectiveness data of 5 adjuvant chemotherapy regimens for colorectal cancer based on practical clinical and cost data from Japanese patients. The results can be included as a factor in regimen selection because these results would represent the real world.

Trial Registration: This study is a retrospective observational study and does not include any health care interventions. Therefore, we did not register the protocol of this study.
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http://dx.doi.org/10.1186/s40780-016-0064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103437PMC
November 2016

Early tumor shrinkage as a predictor of favorable outcomes in patients with advanced pancreatic cancer treated with FOLFIRINOX.

Oncotarget 2016 Oct;7(41):67314-67320

Division of Medical Oncology, Showa University School of Medicine, Tokyo, Japan.

There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in pancreatic cancer. We therefore investigated whether the ETS will predict outcomes in 59 patients with advanced pancreatic cancer treated with FOLFIRINOX therapy. The association of ETS with progression-free survival (PFS) and overall survival (OS) was evaluated but also we addressed to the correlation between outcomes and DpR. ETS was defined as a reduction ≥ 20% of target lesions' diameters measured at 6 to 8 weeks from treatment start. DpR was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Among 47 evaluable patients for the ETS, 12 (25.5%) patients experienced ETS. The ETS was significantly associated with better PFS (9.0 vs. 4.2 months) as well as OS (24.0 vs. 9.1 months); moreover, the association had a statistically significance for PFS but a strong trend for OS in multivariate analysis. The DpR was statistically significantly but weakly associated with OS. In conclusion, this is the first report that the early response to chemotherapy may predict favorable outcomes in patients with advanced pancreatic cancer treated with FOLFIRINOX therapy.
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http://dx.doi.org/10.18632/oncotarget.12007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341877PMC
October 2016

Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer.

World J Gastroenterol 2015 Nov;21(43):12234-48

Ken-ichi Fujita, Yasutsuna Sasaki, Institute of Molecular Oncology, Showa University, Tokyo 1428555, Japan.

Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy.
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http://dx.doi.org/10.3748/wjg.v21.i43.12234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649109PMC
November 2015
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