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  • 1
    Online Resource
    Online Resource
    経口分子標的薬の個別化投与設計に向けて
    Pharmaceutical Society of Japan ; 2019
    In:  YAKUGAKU ZASSHI Vol. 139, No. 6 ( 2019-6-1), p. 911-915
    Details
    In: YAKUGAKU ZASSHI, Pharmaceutical Society of Japan, Vol. 139, No. 6 ( 2019-6-1), p. 911-915
    Type of Medium: Online Resource
    ISSN: 0031-6903 , 1347-5231
    URL: Article
    DOI: 10.1248/yakushi.18-00213-2
    Language: English
    Publisher: Pharmaceutical Society of Japan
    Publication Date: 2019
    detail.hit.zdb_id: 2131241-2
    SSG: 15,3
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  • 2
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    Predictive model for recurrence of renal cell carcinoma by comparing pre‐ and postoperative urinary metabolite concentrations
    Wiley ; 2022
    In:  Cancer Science Vol. 113, No. 1 ( 2022-01), p. 182-194
    Details
    In: Cancer Science, Wiley, Vol. 113, No. 1 ( 2022-01), p. 182-194
    Abstract: To improve treatment outcomes in real practice, useful biomarkers are desired when predicting postoperative recurrence for renal cell carcinoma (RCC). We collected data from patients who underwent definitive surgery for RCC and for benign urological tumor at our department between November 2016 and December 2019. We evaluated the differences in pre‐ and postoperative urinary metabolites with our precise quantitative method and identified predictive factors for RCC recurrence. Additionally, to clarify the significance of metabolites, we measured the intracellular metabolite concentration of three RCC cell lines. Among the 56 patients with RCC, nine had a recurrence (16.0%). When comparing 27 patients with T1a RCC and 10 with benign tumor, a significant difference was observed between pre‐ and postoperative concentrations among 10 urinary metabolites. In these 10 metabolites, multiple logistic regression analysis identified five metabolites (lactic acid, glycine, 2‐hydroxyglutarate, succinic acid, and kynurenic acid) as factors to build our recurrence prediction model. The values of area under the receiver operating characteristic curve, sensitivity, and specificity in this predictive model were 0.894%, 88.9%, and 88.0%, respectively. When stratified into low and high risk groups of recurrence based on this model, we found a significant drop of recurrence‐free survival rates among the high risk group. In in vitro studies, intracellular metabolite concentrations of metastatic tumor cell lines were much higher than those of primary tumor cell lines. By using our quantitative evaluation of urinary metabolites, we could predict postoperative recurrence with high sensitivity and specificity. Urinary metabolites could be noninvasive biomarkers to improve patient outcome.
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.v113.1
    DOI: 10.1111/cas.15180
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 3
    Online Resource
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    Accurate quantification of urinary metabolites for predictive models manifest clinicopathology of renal cell carcinoma
    Wiley ; 2020
    In:  Cancer Science Vol. 111, No. 7 ( 2020-07), p. 2570-2578
    Details
    In: Cancer Science, Wiley, Vol. 111, No. 7 ( 2020-07), p. 2570-2578
    Abstract: Using surgically resected tissue, we identified characteristic metabolites related to the diagnosis and malignant status of clear cell renal cell carcinoma (ccRCC). Specifically, we quantified these metabolites in urine samples to evaluate their potential as clinically useful noninvasive biomarkers of ccRCC. Between January 2016 and August 2018, we collected urine samples from 87 patients who had pathologically diagnosed ccRCC and from 60 controls who were patients with benign urological conditions. Metabolite concentrations in urine samples were investigated using liquid chromatography‐mass spectrometry with an internal standard and adjustment based on urinary creatinine levels. We analyzed the association between metabolite concentration and predictability of diagnosis and of malignant status by multiple logistic regression and receiver operating characteristic (ROC) curves to establish ccRCC predictive models. Of the 47 metabolites identified in our previous study, we quantified 33 metabolites in the urine samples. Multiple logistic regression analysis revealed 5 metabolites ( l ‐glutamic acid, lactate, d ‐sedoheptulose 7‐phosphate, 2‐hydroxyglutarate, and myoinositol) for a diagnostic predictive model and 4 metabolites ( l ‐kynurenine, l ‐glutamine, fructose 6‐phosphate, and butyrylcarnitine) for a predictive model for clinical stage III/IV. The sensitivity and specificity of the diagnostic predictive model were 93.1% and 95.0%, respectively, yielding an area under the ROC curve (AUC) of 0.966. The sensitivity and specificity of the predictive model for clinical stage were 88.5% and 75.4%, respectively, with an AUC of 0.837. In conclusion, quantitative analysis of urinary metabolites yielded predictive models for diagnosis and malignant status of ccRCC. Urinary metabolites have the potential to be clinically useful noninvasive biomarkers of ccRCC to improve patient outcomes.
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.v111.7
    DOI: 10.1111/cas.14440
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 4
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    Importance of Therapeutic Drug Monitoring to Detect Drug Interaction between Pazopanib and Warfarin: A Case Report
    Frontiers Media SA ; 2020
    In:  Journal of Pharmacy & Pharmaceutical Sciences Vol. 23 ( 2020-05-13), p. 200-205
    Details
    In: Journal of Pharmacy & Pharmaceutical Sciences, Frontiers Media SA, Vol. 23 ( 2020-05-13), p. 200-205
    Abstract: Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time-international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.
    Type of Medium: Online Resource
    ISSN: 1482-1826 , 1482-1826
    URL: Article
    DOI: 10.18433/jpps30868
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 1422972-9
    SSG: 15,3
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  • 5
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    Clinical Importance of Plasma Drug Concentration of Oral Molecular Targeted Drugs for Renal Cell Carcinoma
    Frontiers Media SA ; 2021
    In:  Journal of Pharmacy & Pharmaceutical Sciences Vol. 24 ( 2021-03-16), p. 127-136
    Details
    In: Journal of Pharmacy & Pharmaceutical Sciences, Frontiers Media SA, Vol. 24 ( 2021-03-16), p. 127-136
    Abstract: Purpose: Therapeutic drug monitoring (TDM) is widely used in clinical practice to maximize drug efficacy and minimize toxicities. Currently, it is also practiced in the use of oral molecular targeted drugs. The objective of this study was to assess the clinical importance of measuring the systemic concentration of oral molecular targeted drugs used to treat renal cell carcinoma (RCC). Methods: The systemic concentrations of the oral molecular targeted drugs sorafenib, sunitinib, axitinib, pazopanib, and everolimus used for RCC were useful for therapeutic interventions, and clinical outcomes were evaluated retrospectively. Results: The interventional use of systemic drug concentration was confirmed in 26 of 87, and their categories are presented. The systemic concentration of sunitinib was useful in dose reduction and/or discontinuation (n = 10), dose escalation (n = 3), and adherence monitoring (n = 2). Nine of the 10 patients whose dose was reduced showed reduced adverse event. Two patients who were intervened in adherence monitor showed improved adherence. For axitinib, dose reduction and/or discontinuation (n = 1) and dose escalation (n = 6) were confirmed. For pazopanib, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, both of them were confirmed to have reduced adverse events. For everolimus, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, a patient with reduced dose recovered from adverse events. Interventions for sorafenib were not identified. Conclusions: This study demonstrated that systemic concentrations of oral molecular targeted drugs for RCC were considered to be clinically useful for dose adjustment, monitoring of treatment adherence, and the detection of drug interactions. Moreover, this information could be successfully used to guide individualized therapy to maximize the antitumor effects of these drugs.
    Type of Medium: Online Resource
    ISSN: 1482-1826
    URL: Article
    DOI: 10.18433/jpps31816
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 1422972-9
    SSG: 15,3
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  • 6
    Online Resource
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    Value of global metabolomics in association with diagnosis and clinicopathological factors of renal cell carcinoma
    Wiley ; 2019
    In:  International Journal of Cancer Vol. 145, No. 2 ( 2019-07-15), p. 484-493
    Details
    In: International Journal of Cancer, Wiley, Vol. 145, No. 2 ( 2019-07-15), p. 484-493
    Abstract: What's new? Clinically relevant biomarkers are needed to advance renal cell carcinoma (RCC) diagnosis and assessments of therapeutic response. Here, using a liquid chromatograph‐mass spectrometer‐based global metabolomics protocol, RCC tissues were examined for metabolites relevant to RCC early diagnosis and malignant status. In total, 58 metabolites were found to be elevated in surgically resected RCC tissues. Of these, 34 metabolites, primarily from the glutathione, glycoglycerolipid, carnitine, tocopherol, and glycolysis pathways, were associated with early diagnosis of RCC. Most other metabolites identified in RCC tissues were from the tricarboxylic acid cycle, nucleotide sugar, and inositol pathways and were characteristic of malignant status.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v145.2
    DOI: 10.1002/ijc.32115
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 7
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    Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry
    Wiley ; 2018
    In:  Biomedical Chromatography Vol. 32, No. 6 ( 2018-06)
    Details
    In: Biomedical Chromatography, Wiley, Vol. 32, No. 6 ( 2018-06)
    Abstract: An analytical method using high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry has been developed and validated for simultaneous measurement of four tyrosine kinase inhibitors used for renal cell carcinoma and their metabolites in human plasma. Despite their similar structures, it is difficult to measure plasma levels of these compounds simultaneously using optimal MS parameters for each compound because a quantitative range exceeding 50,000‐fold is required. To overcome this problem, we used a linear range shift technique using in‐source collision‐induced dissociation. Linearity ranges of sorafenib, sorafenib N ‐oxide, sunitinib, N ‐desethyl sunitinib, axitinib and pazopanib were 100–10,000, 10–1,000, 1–100, 1–100, 1–100 and 500–50,000 ng/mL, respectively. The intra‐ and inter‐day precision and accuracy were high, and coefficients of variation and relative error were 〈 10.3% and within ±11.8%, respectively. The matrix effects of all analytes ranged from 87.7 to 114.8%. Extraction recoveries and overall recoveries showed small extraction loss ( 〈 15.0%) for all analytes. Moreover, all cancer patient samples used in this study were successfully quantified and fell within the linear range of measurement. Therefore, this novel analytical system using in‐source collision‐induced dissociation has sufficient performance to measure plasma concentrations of these four tyrosine kinase inhibitors and their metabolites for therapeutic drug monitoring.
    Type of Medium: Online Resource
    ISSN: 0269-3879 , 1099-0801
    URL: Issue
    URL: Article
    DOI: 10.1002/bmc.v32.6
    DOI: 10.1002/bmc.4184
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1479945-5
    SSG: 12
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  • 8
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    Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
    MDPI AG ; 2020
    In:  Metabolites Vol. 11, No. 1 ( 2020-12-22), p. 1-
    Details
    In: Metabolites, MDPI AG, Vol. 11, No. 1 ( 2020-12-22), p. 1-
    Abstract: Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo11010001
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662251-8
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  • 9
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    Trough blood levels of sunitinib for Asian (Japanese) patients with metastatic renal cell carcinoma and therapeutic drug monitoring.
    American Society of Clinical Oncology (ASCO) ; 2016
    In:  Journal of Clinical Oncology Vol. 34, No. 2_suppl ( 2016-01-10), p. 508-508
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 2_suppl ( 2016-01-10), p. 508-508
    Abstract: 508 Background: The optimal blood concentration of total Sunitinib (SU) (SU + its active metabolite) is reportedly 50-100 ng/ml at trough levels according to the product literature. This is, however, based on models optimally calculated for Caucasians; hence, the desirable blood concentration for Asian patients, including Japanese, is unclear. We examined trough SU levels in Japanese patients with metastatic renal cell carcinomas (mRCC), to determine the preferred concentration of total SU and its doses. We also evaluated the efficacy and dependability of therapeutic drug monitoring (TDM) through the duration of therapy. Methods: Patients with mRCC scheduled for targeted therapy were prospectively recruited between November 2011 and August 2015. TDM of trough levels for patients treated with SU was performed on a regular basis. For this, blood samples were obtained immediately before administering SU on day 8 and day 15 after the initial administration day. Pre-therapeutic characteristics and post-therapeutic outcomes were evaluated. Relationships between pre-therapeutic characteristics, the dose of SU administered, adverse events (AEs) and total SU concentration at trough levels were determined. Results: Twenty of a total of 31 eligible patients were analyzed. Median patient age was 64 years (52-82), median BMI was 23.58 kg/m 2 (17.7-32.78), and the average duration of SU therapy was 5 months (1-40). Seventeen patients were treated with SU as first-line therapy and 3 patients as second-line therapy after interferons. Patients with trough SU levels of over 80 ng/ml following the first course needed to discontinue SU due to AEs. All of the patients who obtained long-term stable disease (SD) or partial response (PR) without any AE 〉 grade 2 were those with trough SU levels of 40-60 ng/ml. Conclusions: Our study suggests that trough total SU levels of 50-100 ng/ml are too high for Japanese people. And 40-80 ng/ml seems to be the preferable trough blood concentration of total SU after the first course of SU therapy in Japanese patients. TDM appears to be effective for the management of patients, to obtain optimal benefits of SU without AEs during therapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2016.34.2_suppl.508
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Severe toxicity induced by accumulation of active sunitinib metabolite in a Japanese patient with renal cell carcinoma: a case report
    Springer Science and Business Media LLC ; 2017
    In:  Journal of Medical Case Reports Vol. 11, No. 1 ( 2017-12)
    Details
    In: Journal of Medical Case Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2017-12)
    Type of Medium: Online Resource
    ISSN: 1752-1947
    URL: Article
    DOI: 10.1186/s13256-016-1185-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2269805-X
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