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For patients with T1a muscularis mucosae (MM) esophageal squamous cell carcinoma (ESCC) with lymphovascular invasion (LVI) or T1b submucosal (SM) ESCC, endoscopic resection is non-curative, and adjuvant treatment entailing esophagectomy or definitive chemoradiotherapy is necessary. This is because about 30% of these cases have lymph node (LN) metastasis. The purpose of this study was to test the utility of a CRP genetic polymorphism test kit for determining the risk of LN metastasis with the aim of eliminating additional invasive adjuvant therapy.This is a retrospective, multi-institutional, observational study. The CRP 1846CT genetic polymorphisms were identified using a fully automated genotyping system. The primary end points were an 85% negative predictive value (NPV) for diagnosis of LN metastasis in pT1a (MM) and 80% NPV in pT1b (SM1) patients.A total of 742 ESCC (105 pMM, 166 pSM1 and 471 pSM2-3) patients who had received esophagectomy with 2- or 3-field LN dissection at 65 institutions were enrolled. According to this test, patients with the C/C and C/T genotypes were considered to be low risk. The NPVs using this test were 82.8% in pMM and 71.7% in pSM1 patients.CRP 1846CT genetic polymorphism is not a useful diagnostic indicator for determining the risk of LN metastasis; however, the possibility that CRP gene polymorphisms are involved in the mechanism of lymph node metastasis in solid tumors still remains.

Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography. We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed. In patients who were receiving regorafenib 40–160 mg/day, the Ctrough values of regorafenib, M2, and M5 were 318–9467, 34–3594, and 38–3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification. The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.

Platinum agents are taken up into cells by copper transporter (CTR) 1 (gene code: SLC31A1) and are excreted from cells by copper-transporting P-type adenosine triphosphatase (ATP7B) and multidrug resistance-associated protein (MRP) 2 (gene code: ABCC2). In addition, glutathione S transferase (GST) P1 is involved in the metabolism of platinum agents. The present study aimed to determine whether the rate of grade 3-4 hematological toxicity associated with platinum plus 5-fluorouracil (5-FU) therapy in 239 patients with esophageal cancer was affected by the SLC31A1 rs10981694AC and rs12686377GT, ATP7B rs9535828AG, GSTP1 rs1695AG, and ABCC2 -24CT polymorphisms.Chemotherapy consisted of protracted infusion of 5-FU (800 mg/mA total of 82 of 239 patients developed grade 3-4 hematological toxicity after chemotherapy. Univariate analysis showed that ABCC2 -24C/T + T/T genotypes (P = 0.038), radiation therapy (P = 0.013), baseline white blood cell count 6000/μL (P = 0.003), and baseline neutrophil count 3900/μL (P = 0.021) were statistically significant predictors of grade 3-4 hematological toxicity. Multivariate analysis revealed that ABCC2 -24C/T + T/T genotypes (P = 0.036), radiation therapy (P = 0.005), and baseline white blood cell count 6000/μL (P 0.001) were significant risk factors.We determined that ABCC2 -24CT is significantly associated with grade 3-4 hematological toxicity after platinum plus 5-FU therapy. These findings might contribute to improved treatment strategies for patients with esophageal cancer.

The relationship between the SLC31A1 (protein: copper transporter 1) rs10981694 A > C and ATP7B (protein: P-type adenosine triphosphatase 7B) rs9535828 A > G polymorphisms on the overall survival and disease-free survival of 104 Japanese patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemoradiotherapy (CRT) was investigated. Chemotherapy consisted of protracted infusion of 5-fluoracil (800 mg/m2/day) on days 1–5 and cisplatin or nedaplatin (80 mg/m2/day) on day 1. The median (range) follow-up was 47 (6–127) months. The 5-year overall and disease-free survival rates were 71.2% and 60.6%, respectively. The 5-year overall survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (91.7% vs. 65.0%, P = 0.018). The 5-year disease-free survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (79.2% vs. 55.0%, P = 0.043). In addition, univariate and multivariate analyses showed the SLC31A1 rs10981694 A > C polymorphism to be a significant prognostic factor affecting 5-year overall survival after neoadjuvant CRT. However, the overall and disease-free survival rates after surgery did not differ significantly among the ATP7B rs9535828 genotypes. In conclusion, only the SLC31A1 rs10981694 A/A genotype was an independent predictor of a poorer 5-year overall survival. Therefore, in neoadjuvant CRT for ESCC patients, the effect of platinum was affected by the SLC31A1 rs10981694 A > C polymorphism. The presence of this polymorphism should be considered when devising neoadjuvant CRT regimens or treatment strategies for ESCC.

Lenvatinib is a substrate of cytochrome P450 (CYP) 3A and ATP-binding cassette (ABC) transporters. In this study, we aimed to evaluate how CYP3A4/5 and ABC transporter polymorphisms affected the mean steady-state dose-adjusted plasma trough concentrations (C0) of lenvatinib in a cohort of 40 Japanese patients with thyroid cancer. CYP3A4 20230G > A (*1G), CYP3A5 6986A > G (*3), ABCB1 1236C > T, ABCB1 2677G > T/A, ABCB1 3435C > T, ABCC2 −24C > T, and ABCG2 421C > A genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. In univariate analysis, there were no significant differences in the mean dose-adjusted C0 values of lenvatinib between the ABCB1, ABCG2, and CYP3A5 genotypes. However, the mean dose-adjusted C0 values of lenvatinib in patients with the CYP3A4*1/*1 genotype and ABCC2 −24T allele were significantly higher than those in patients with the CYP3A4*1G allele and −24C/C genotype, respectively (P = 0.018 and 0.036, respectively). In multivariate analysis, CYP3A4 genotype and total bilirubin were independent factors influencing the dose-adjusted C0 of lenvatinib (P = 0.010 and 0.046, respectively). No significant differences were found in the incidence rates of hypertension, proteinuria, and hand-foot syndrome following treatment with lenvatinib between the genotypes of CYP3A4/5 and ABC transporters. Lenvatinib pharmacokinetics were significantly influenced by the CYP3A4*1G polymorphism. If the target plasma concentration of lenvatinib for efficacy or toxicity is determined, elucidation of the details of the CYP3A4*1G genotype may facilitate decision-making related to the appropriate initial lenvatinib dosage to achieve optimal plasma concentrations.

A simple, highly sensitive and specific high-performance liquid chromatography (HPLC) method was developed for the simultaneous quantitation of regorafenib, N-oxidemetabolite (M-2) and the desmethyl N-oxide metabolite (M-5) in human plasma. Regorafenib, M-2, M-5 and the internal standard sorafenib were separated using a mobile phase of 0.5% KH2 PO4 (pH 3.5)-acetonitrile (30:70, v/v), on a Capcell PAK MG II column at a flow rate of 0.5 mL/min and measurement at UV 260 nm. The lower limits of quantification for regorafenib, M-2 and M-5 were 10 ng/mL for each analyte. A procedure using solid-phase extraction required only a small amount of plasma (100 μL) for one analysis while providing high extraction recovery (>81% for all compounds) and good selectivity. Coefficients of variation for intra- and inter-day assays were

A reliable marker of the sensitivity of esophageal cancer to chemoradiotherapy (CRT) as well as a personal biomarker predictive of adverse events during treatment has long been sought. The purpose of the present study was to test whether there is an association between interleukin-6 (IL-6) and/or monocyte chemoattractant protein-1 (MCP-1) polymorphisms and CRT-induced bone-marrow suppression––i.e., reductions in white blood cell and/or platelet counts. The study participants were 103 Japanese patients treated with definitive or pre-operative CRT for squamous cell esophageal cancer at Akita University Hospital. The patients were divided into two groups, with or without adverse events during or up to 1 month after CRT. Patient backgrounds––i.e., white blood cell and platelet counts before CRT and doses of chemotherapy and irradiation––did not differ between groups. However, there was a significantly higher incidence of grade 2–4 platelet count reductions ( G and MCP-1 −2518A>G polymorphisms were significantly associated with grade 2–4 platelet count reductions following CRT. These polymorphisms may thus be clinically relevant and should be taken into consideration when devising CRT regimens or treatment strategies for esophageal cancer.

In 1944, Harold Kirby described microorganisms living within nuclei of the protists Trichonympha in guts of termites; however, their taxonomic assignment remains to be accomplished. Here, we identified intranuclear symbionts of Trichonympha agilis in the gut of the termite Reticulitermes speratus. We isolated single nuclei of T. agilis, performed whole-genome amplification, and obtained bacterial 16S rRNA genes by PCR. Unexpectedly, however, all of the analyzed clones were from pseudogenes of 16S rRNA with large deletions and numerous sequence variations even within a single-nucleus sample. Authentic 16S rRNA gene sequences were finally recovered by digesting the nuclear DNA; these pseudogenes were present on the host Trichonympha genome. The authentic sequences represented two distinct bacterial species belonging to the phylum Verrucomicrobia, and the pseudogenes have originated from each of the two species. Fluorescence in situ hybridization confirmed that both species are specifically localized, and occasionally co-localized, within nuclei of T. agilis. Transmission electron microscopy revealed that they are distorted cocci with characteristic electron-dense and lucent regions, which resemble the intranuclear symbionts illustrated by Kirby. For these symbionts, we propose a novel genus and species, 'Candidatus Nucleococcus trichonymphae' and 'Candidatus Nucleococcus kirbyi'. These formed a termite-specific cluster with database sequences, other members of which were also detected within nuclei of various gut protists, including both parabasalids and oxymonads. We suggest that this group is widely distributed as intranuclear symbionts of diverse protists in termite guts and that they might have affected the evolution of the host genome through lateral gene transfer.

Background: The individual and collective contributions of genetic polymorphisms in drug transporter genes in human renal proximal tubules to cisplatin-induced nephrotoxicity are still unclear. Methods: In this study, we investigated the effects of polymorphisms in SLC22A2 (808G>T), SLC31A1 (rs10981694A>C, rs12686377G>T, rs7851395A>G), SLC47A1 (rs2289669G>A), ABCB1 (1236C>A, 2677G>T/A, 3435C>T), ABCC2 (-24C>T), and ABCG2 (421C>A) on cisplatin-induced nephrotoxicity in 131 patients with esophageal cancer receiving 5-fluorouracil and cisplatin (FP) chemotherapy. The change rate of the estimated glomerular filtration rate (eGFR) was calculated according to the following formula: eGFR before FP chemotherapy-lowest eGFR during first cycle after FP chemotherapy)/eGFR before FP chemotherapy. Results: In univariate analysis, there was a significant correlation between patient age and the change rate of the eGFR by cisplatin (P = 0.021). However, there were no significant differences in the change rate of the eGFR by cisplatin between SLC22A2, SLC47A1, SLC31A1, ABCB1, ABCC2, and ABCG2 polymorphisms. Multivariate analysis revealed that only age was an independent variable predicting a higher risk of cisplatin-induced acute renal dysfunction. Conclusion: In FP chemotherapy for esophageal cancer patients, cisplatin-induced nephrotoxicity was not affected by polymorphisms in the uptake transporters OCT2 and Ctr1 or efflux transporters MATE1, P-glycoprotein, MRP2, and BCRP. Since degradation of renal function due to aging reduces cisplatin clearance, the cisplatin dosage should be carefully chosen in elderly patients.

Endometrial cancer (EC) rates are rising in Japan. Lymph node (LN) metastasis is an important prognostic factor in EC, and its risk is increased with higher tumor grade, deep myometrial invasion, larger tumor size, and lymphovascular space invasion (LVSI). Current methodologies to assess these factors are unreliable. We previously showed the association between C-reactive protein (CRP) 1846C>T (rs1205) polymorphism and LN metastasis in esophageal, non-small cell lung, and breast cancers. The CRP gene is located on chromosome 1q21-q23, and the polymorphism in the noncoding region (1846C>T) of this gene decreases serum CRP levels. We investigated the relationship between CRP 1846C>T genetic polymorphism and LN metastasis or LVSI in 130 EC patients using polymerase chain reaction-restriction fragment length polymorphism. The CRP 1846C/T genotype was C/C in 11 patients, C/T in 58 patients and T/T in 61 patients. The patients were divided into two groups based on their CRP 1846 genotypes: "C/C" and "C/T + T/T". Nine (7%) and 18 (13%) patients, all with the polymorphism, had LN metastasis and moderate or prominent lymphatic invasion, respectively. LN metastasis and/or severe lymphatic invasion were observed in the C/T + T/T group, while patients with the C/C genotype had no LN metastases or severe lymphatic invasion. Univariate and multivariate logistic regression models revealed that the C/T + T/T patients had a significant likelihood of developing LN metastasis and/or severe lymphatic invasion. Our results suggest that CRP genetic polymorphism is a novel risk predictor of LN metastasis and/or lymphatic invasion in EC.