Characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma

BACKGROUND: A high incidence of severe hematological adverse events during sunitinib treatment complicates decision making on dose and treatment cycle. We identified the characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma (RCC). METHODS: Seventy-nine patients were treated with sunitinib as 6-week cycles of “4-week on 2-week off” schedule. To evaluate early-onset hematotoxicity, we compared patients with dose reduction during the first cycle (dose-reduced group, n = 57) and those who maintained the initial dose (dose-maintained group, n = 22). ABCG2 and FLT3 genotypes were analyzed for association between hematotoxicity and reported gene polymorphisms. RESULTS: Mean relative dose intensity (RDI) was similar in the two groups during the first 2 weeks of dosing in the first cycle, but was significantly lower in the dose-reduced group during the last 2 weeks. Lymphocytopenia and thrombocytopenia were observed in the dose-reduced group within the first 2 weeks. Genetic analysis indicated a significantly higher frequency of FLT3 738 T/C polymorphism in the dose-reduced group, but no significant difference in the ABCG2 421 C/A polymorphism. CONCLUSIONS: This study showed a high incidence of sunitinib-induced hematotoxicity in Japanese patients with RCC, many of whom need dose adjustment during the first cycle. Further studies should verify whether dose adjustment based on early-onset thrombocytopenia prolongs sunitinib treatment

Cancer Immunol Immunother

Purpose Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. Materials and Methods Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study. The patients received subcutaneous administration of the peptide as an emulsion form with Montanide ISA-51 VG once a week in a dose-escalation manner (doses of 0.5, 1.0, or 3.0 mg/body, 3 patients for each dose). The primary endpoint was safety, and the secondary endpoints were immunological and clinical responses. Results Vaccinations with HIG2-9-4 peptide could be well tolerated without any serious systemic adverse events. Peptide-specific cytotoxic T lymphocyte (CTL) responses were detected in eight of the nine patients. Doses of 1.0 or 3.0 mg/body seemed to induce a CTL response better than did a dose of 0.5 mg/body, although the number of patients was too small to draw a firm conclusion. The disease control rate (stable disease for ≥4 months) was 77.8 %, and the median progression-free survival time was 10.3 months. Conclusions HIG2-9-4 peptide vaccine treatment was tolerable and effectively induced peptide-specific CTLs in RCC patients. This novel peptide vaccine therapy for RCC is promising

PREDICTION SYSTEMS FOR BLADDER CANCER THERAPY

The present study established systems to predict the chemo‑sensitivity of muscle invasive bladder cancer (MIBC) for neoadjuvant chemotherapy (NAC) with methotrexate, vinblastine, doxorubicin plus cisplatin (M‑VAC) and carboplatin plus gemcitabine (CaG) by analyzing microarray data. The primary aim of the study was to investigate whether the clinical response would increase by combining these prediction systems. Treatment of each MIBC case was allocated into M‑VAC NAC, CaG NAC, surgery, or radiation therapy groups by their prediction score (PS), which was calculated using the designed chemo‑sensitivity prediction system. The therapeutic effect of the present study was compared with the results of historical controls (n=76 patients) whose treatments were not allocated using the chemo‑sensitivity prediction system. In addition, the overall survival between the predicted to be responder (positive PS) group and predicted to be non‑responder (negative PS) group was investigated in the present study. Of the 33 patients with MIBC, 25 cases were positive PS and 8 were negative PS. Among the 25 positive PS cases, 7 were allocated to receive M‑VAC NAC and 18 were allocated to receive CaG NAC according to the results of the prediction systems. Of the 8 negative PS cases, 3 received CaG NAC, 1 received surgery without NAC and 4 received radiation therapy. The total clinical response to NAC was 88.0% (22/25), which was significantly increased compared with the historical controls [56.6% (43/76) P=0.0041]. Overall survival of the positive PS group in the study was significantly increased compared with the negative PS group (P=0.027). In conclusion, the combination of the two prediction systems may increase the treatment efficacy for patients with MIBC by proposing the optimal NAC regimen. In addition, the positive PS group would have a better prognosis compared with the negative PS group. These results suggest that the two prediction systems may lead to the achievement of ‘precision medicine’

Analysis of Expression Patterns of MicroRNAs That Are Closely Associated With Renal Carcinogenesis

Background: MicroRNAs (miRNA) are frequently dysregulated in clear cell renal cell carcinoma (ccRCC).Objective: This study aimed to elucidate the role of miRNA expression patterns in renal carcinogenesis and to identify the specific miRNAs that exhibit expression patterns closely associated with patient outcomes.Methods: We examined the expression patterns of selected miRNAs, including miRNA-155-5p, miRNA-122-5p, miRNA-21-5p, miRNA-185-5p, miRNA-106a-5p, miRNA-106b-3p, miRNA-34b-3p, miRNA-210-3p, miRNA-141-3p, miRNA-200c-3p, miRNA-135a-5p, miRNA-30a-5p, miRNA-218-5p, miRNA-429, miRNA-200a-3p and miRNA-200b-3p, in 96 samples of ccRCCs using the TaqMan real-time PCR method. In addition, cluster analysis was performed to stratify expression patterns of multiple miRNAs.Results: In the present study, three distinct subgroups could be clearly stratified in ccRCCs. Subgroup 1 was characterized by upregulation of miRNA-155-5p, miRNA-122-5p, miRNA-21-5p, miRNA-185-5p, miRNA-106a-5p, miRNA-106b-3p, miRNA-34b-3p and miRNA-210-3p. Subgroup 2 was closely associated with downregulation of miRNA-141-3p, miRNA200c-3p, miRNA-30a-5p, miRNA-218-5p, miRNA-429, miRNA-200a-3p and miRNA-200b-3p. Moreover, significant lower expression of miRNA-135a-5p was a distinctive feature of subgroup 3, which was correlated with metachronous metastasis. Among the individual markers in subgroup 3, miRNA-135a-5p was retained in multivariate analysis. The cutoff value of miRNA-135a-5p expression to identify the association of an altered level of miRNA-135a-5p with metachronous metastasis in ccRCCs was determined and showed excellent specificity.Conclusion: We suggest that the expression pattern of the chosen miRNAs is useful to identify renal carcinogenesis and to help identify the association of such expression patterns with metachronous metastasis in ccRCCs. In addition, miRNA-135a-5p was an excellent marker for prediction of metachronous metastasis

Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC

Purpose: The present study compared the efficacy of sunitinib and sorafenib as first-line treatment of metastatic clear cell renal cell carcinoma (mCC-RCC) with favorable or intermediate Memorial Sloan Kettering Cancer Center (MSKCC) risk. Patients and methods: Treatment-naive patients with mCC-RCC were randomized to receive open-label sunitinib followed by sorafenib (SU/SO) or sorafenib followed by sunitinib (SO/SU). The primary endpoint was first-line progression-free survival (PFS). The secondary endpoints were total PFS and overall survival (OS). Results: Of the 124 patients enrolled at 39 institutions from February 2010 to July 2012, 120 were evaluated. The median first-line PFS duration was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.42-1.08). The total PFS and OS were not significantly different between the SU/SO and SO/SU groups (27.8 and 22.6 months; HR, 0.73; 95% CI, 0.428-1.246; and 38.4 and 30.9 months; HR, 0.934; 95% CI, 0.588-1.485, respectively). The subgroup analysis revealed that the total PFS with SU/SO was superior to the total PFS with SO/SU in the patients with favorable MSKCC risk and those with Conclusions: No statistically significant differences were found in first-line PFS, total PFS, or OS between the 2 treatment arms (ClinicalTrials.gov identifier, NCT01481870)

Fine-mapping of qRL6.1, a major QTL for root length of rice seedlings grown under a wide range of NH4+ concentrations in hydroponic conditions

Root system development is an important target for improving yield in cereal crops. Active root systems that can take up nutrients more efficiently are essential for enhancing grain yield. In this study, we attempted to identify quantitative trait loci (QTL) involved in root system development by measuring root length of rice seedlings grown in hydroponic culture. Reliable growth conditions for estimating the root length were first established to renew nutrient solutions daily and supply NH4+ as a single nitrogen source. Thirty-eight chromosome segment substitution lines derived from a cross between ‘Koshihikari’, a japonica variety, and ‘Kasalath’, an indica variety, were used to detect QTL for seminal root length of seedlings grown in 5 or 500 μM NH4+. Eight chromosomal regions were found to be involved in root elongation. Among them, the most effective QTL was detected on a ‘Kasalath’ segment of SL-218, which was localized to the long-arm of chromosome 6. The ‘Kasalath’ allele at this QTL, qRL6.1, greatly promoted root elongation under all NH4+ concentrations tested. The genetic effect of this QTL was confirmed by analysis of the near-isogenic line (NIL) qRL6.1. The seminal root length of the NIL was 13.5–21.1% longer than that of ‘Koshihikari’ under different NH4+ concentrations. Toward our goal of applying qRL6.1 in a molecular breeding program to enhance rice yield, a candidate genomic region of qRL6.1 was delimited within a 337 kb region in the ‘Nipponbare’ genome by means of progeny testing of F2 plants/F3 lines derived from a cross between SL-218 and ‘Koshihikari’

Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy

Background: Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant-based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. Methods: A total of 1336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants, and sequencing of 8 prostate cancer-associated genes was performed by multiplex polymerase chain reaction based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. Results: The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval = 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with prostate specific antigen 2-10 ng/mL who had prebiopsy magnetic resonance imaging, high PRS had an equivalent impact on biopsy positivity as a positive magnetic resonance imaging finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, respectively, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. Conclusions: Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings

Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites

The p300 and CBP histone acetyltransferases are recruited to DNA double-strand break (DSB) sites where they induce histone acetylation, thereby influencing the chromatin structure and DNA repair process. Whether p300/CBP at DSB sites also acetylate non-histone proteins, and how their acetylation affects DSB repair, remain unknown. Here we show that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DSB sites. Using in vitro acetylated RAD52, we identified 13 potential acetylation sites in RAD52 by a mass spectrometry analysis. An immunofluorescence microscopy analysis revealed that RAD52 acetylation at DSBs sites is counteracted by SIRT2- and SIRT3-mediated deacetylation, and that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, inhibition of ataxia telangiectasia mutated (ATM) protein by siRNA or inhibitor treatment demonstrated that the acetylation of RAD52 at DSB sites is dependent on the ATM protein kinase activity, through the formation of RAD52, p300/CBP, SIRT2, and SIRT3 foci at DSB sites. Our findings clarify the importance of RAD52 acetylation in HR and its underlying mechanism

Outcomes of axitinib versus sunitinib as first-line therapy to patients with metastatic renal cell carcinoma in the immune-oncology era

Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second-line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). This study was aimed at comparing the efficacy of two TKIs-axitinib and sunitinib-in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first-line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression-free survival (PFS), cause-specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab-treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first-line therapy in mRCC patients. Thus, from among VEGFR-TKIs, axitinib might be a possible option for application in the middle of IO drug-based treatment sequences