Naoko Chayahara

Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese.

Objectives:This study was performed to find the genetic factors predictive of clinical outcome to a 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT) in Japanese patients with locally advanced esophageal squamous cell carcinoma (ESCC). Materials and Methods:Thirty-one patients with stage I-IVa ESCC (I/II/III/IVa = 7/7/14/3) were enrolled in this study. One course of treatment consisted of protracted venous infusions (PVIs) of 5-FU (400 mg/m2/24 hours for days 1–5 and 8–12), CDDP (40 mg/m2/3 hours on days 1 and 8) and radiation (2 Gy/d on days 1–5, 8–12, and 15–19), and a 2nd course was successively repeated after a 2-week interval. A total of 8 measurements of the plasma concentration of 5-FU were made using high performance liquid chromatography. Genetic polymorphisms examined herein included those in the genes coding thymidylate synthase (TS), glutathione S-transferase P1 (GSTP1), multidrug resistant transporter MDR1/P-glycoprotein, and intercellular adhesion molecule-1, and in a circadian rhythm-relating gene, CLOCK. Results:The CR rate depended on stage (P = 0.001), but the analysis was not sufficiently powered to reach a level of statistical significance for the 2-year survival rate (P = 0.061). For stage II/III patients, to have 2 or 3 polymorphisms of 3R/3R of 5′-TSER, a 6 bp of 3′-TSUTR, and GSTP1-Ile105Val resulted in an extensively longer survival (P = 0.020), although no difference was found between 2 groups, with respect to the plasma concentrations of 5-FU and clinicopathologic characteristics. Conclusions:The prognostic index may allow predictions of the clinical outcome of a 5-FU/CDDP-based CRT in stage II/III ESCC patients.

Lenvatinib for Anaplastic Thyroid Cancer

Background Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results At data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7–12.9], the median OS was 10.6 months (95% CI: 3.8–19.8), and the objective response rate was 24%. Conclusion In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC. ClinicalTrials.gov NCT01728623.

VEGF G-1154A is Predictive of Severe Acute Toxicities during Chemoradiotherapy for Esophageal Squamous Cell Carcinoma in Japanese Patients

This study was conducted to evaluate the association between systemic exposure to 5-fluorouracil (5-FU) and genetic polymorphisms of vascular endothelial growth factor (VEGF) with clinical outcomes to a 5-FU/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma (ESCC). Forty-nine patients with ESCC (I/II/III/IVa = 11/9/17/7, with 5 postoperative recurrences) were enrolled into this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m2/24 hr for day 1-5 and 8-12) and cisplatin (40 mg/m2/3 hr on day 1 and 8), and radiation (2 Gy/day on day 1-5, 8-12, and 15-19); a second course was repeated after a 2 week interval. A total of eight measurements of the plasma concentration of 5-FU were made per patient to evaluate its systemic exposure as area under the concentration time curve for 480 hours (AUC480h), and VEGF genotypes of T-1498C, G-1154A, C-634G, C-7T, C936T, and G1612A were evaluated. The mean value of AUC480h in the patients with a complete response was 58.7 ± 16.8 mg*h/L, which was higher than that in the others, 49.0 ± 10.9 mg*h/L (P = 0.029), whereas no such association was found for severe acute toxicities. VEGF genotype was not associated with the clinical response, whereas VEGF G-1154A resulted in severe acute leukopenia (P = 0.042) and severe acute cheilitis (P = 0.025). In conclusion, VEGF G-1154A was a predictor of severe acute toxicities during 5-FU/cisplatin-based chemoradiotherapy in Japanese ESCC patients, whereas the AUC480h value of 5-FU was predictive of the clinical response.

Metabolomics evaluation of serum markers for cachexia and their intra-day variation in patients with advanced pancreatic cancer.

Purpose Cancer cachexia is a multifactorial syndrome characterized by progressive loss of weight and muscle atrophy. Using metabolomics, we investigated serum markers and their intra-day variation in advanced pancreatic cancer patients with cachexia. Methods Patients were enrolled in two groups: those with or without cachexia. Blood samples collected at 6:30 AM, 11:30 AM, 4:30 PM, and 9:30 PM were analyzed using metabolomics, and serum levels of IL-6, TNF-α, and leptin were measured and compared between the two groups. Intra-day variation was then evaluated. Results Twenty-one patients were enrolled in total. In the cachexia group (n = 9), median body weight loss rate over 6 months was greater, performance status was poorer, and anorexia was more severe than in the non-cachexia group (n = 12). Each metabolites level showed substantial intra-day variation, and some of them displayed significant differences between the two groups. Levels of paraxanthine remained markedly lower in the cohort with cachexia at all measurement points. Besides, median IL-6 and TNF-α levels appeared higher and leptin concentration appeared lower in the cachexia group, albeit without statistical significance. Conclusion Some metabolites and some serological marker levels were affected by cancer cachexia. Although paraxanthine levels were consistently lower in patients with cachexia, we identified that many metabolites indicated large intra- and inter-day variation and that it might be necessary to pay attention to intra-day variation in metabolomics research.

A Microarray-Based Gene Expression Analysis to Identify Diagnostic Biomarkers for Unknown Primary Cancer

Background The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. Methods Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). Results Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2–p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. Conclusions The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.

995PDPHASE II STUDY OF LENVATINIB (LEN), A MULTI-TARGETED TYROSINE KINASE INHIBITOR, IN PATIENTS (PTS) WITH ALL HISTOLOGIC SUBTYPES OF ADVANCED THYROID CANCER (DIFFERENTIATED, MEDULLARY AND ANAPLASTIC)

palmar-plantar erythrodysesthesia syndrome (74%; 6%), fatigue (71%; 3%), decreased appetite (69%; 9%), proteinuria (51%; 0%), stomatitis (51%; 0%), diarrhea (43%; 11%), nausea (40%; 6%) and dysphonia (31%; 0%). Almost all (34/35) subjects required dose reduction, however, no subjects required study drug withdrawal due to AEs. 34 pts were evaluable for efficacy, including 21 pts with RR-DTC, 4 pts with MTC, and 9 pts with ATC. The objective response rate (ORR) based on the investigator assessment was 47.6% in RR-DTC, 25.0% in MTC, and 33.3% in ATC, respectively. Median PFS was 6.5 mo (95% CI: 5.6 - 7.3) in MTC and 5.5 mo (95% CI: 1.4 -) in ATC, respectively. Median PFS has not been determined in RR-DTC. Conclusions: AE profiles were generally similar to the data from previous clinical studies of lenvatinib with manageable toxicity with dose reduction and interruption. LEN demonstrated promising activity in all histologic subtypes of advanced thyroid cancer. Three of 9 pts with ATC have received administration of LEN for more than 6 month, which should be noteworthy. Disclosure: S. Takahashi, M. Tahara and N. Kiyota: Advisory Board: Eisai. All other authors have declared no conflicts of interest.

Prediction of Glomerular Filtration Rate in Cancer Patients by an Equation for Japanese Estimated Glomerular Filtration Rate

BACKGROUND Assessment of renal function is important for safe cancer chemotherapy, and eligibility criteria for clinical trials often include creatinine clearance. However, creatinine clearance overestimates glomerular filtration rate, and various new formulae have been proposed to estimate glomerular filtration rate. Because these were developed mostly in patients with chronic kidney disease, we evaluated their validity in cancer patients without kidney disease. METHODS Glomerular filtration rate was measured by inulin clearance in 45 Japanese cancer patients, and compared with creatinine clearance measured by 24-h urine collection as well as that estimated by the Cockcroft-Gault formula, Japanese estimated glomerular filtration rate developed in chronic kidney disease patients, the Modification of Diet in Renal Disease study equation and the Chronic Kidney Disease Epidemiology Collaboration equation. The Modification of Diet in Renal Disease study and Chronic Kidney Disease Epidemiology Collaboration equations were adjusted for the Japanese population by multiplying by 0.808 and 0.813, respectively. RESULTS The mean inulin clearance was 79.2 ± 18.7 ml/min/1.73 m(2). Bias values to estimate glomerular filtration rate for Japanese estimated glomerular filtration rate, the Cockcroft-Gault formula, creatinine clearance measured by 24-h urine collection, the 0.808 × Modification of Diet in Renal Disease study equation and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation were 0.94, 9.75, 29.67, 5.26 and -0.92 ml/min/1.73 m(2), respectively. Precision (root-mean square error) was 14.7, 22.4, 39.8, 16.0 and 14.1 ml/min, respectively. Of the scatter plots of inulin clearance versus each estimation formula, the Japanese estimated glomerular filtration rate correlated most accurately with actual measured inulin clearance. CONCLUSION The Japanese estimated glomerular filtration rate and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation estimated glomerular filtration rate with lower bias and higher precision than the other formulae. We therefore propose Japanese estimated glomerular filtration rate for the estimation of glomerular filtration rate in Japanese cancer patients.

Left atrial extension of metastatic lung tumor via pulmonary vein: report on the first case of Ewing sarcoma

Extension of metastatic lung tumors into the left atrium via pulmonary veins is rare. Here, we report the first case of Ewing sarcoma exhibiting such extension. A 31-year-old man with pulmonary metastasis from Ewing sarcoma presented with a mass in the left lung, extending to the left atrium through the left inferior pulmonary vein. As the patient was considered to be at risk of tumor embolism, the mass was excised surgically.

Role of metallothionein in Helicobacter pylori-positive gastric mucosa with or without early gastric cancer and the effect on its expression after eradication therapy

Background and Aim:  Metallothionein (MT) has a proven relationship with various kinds of cancer and reduces tissue damage. Helicobacter pylori (H. pylori) infection is associated with the alteration of gastric epithelial cell cycle events, a condition implicated in the initiation and development of gastric cancer. This study investigates the role of MT in H. pylori‐induced gastritis with or without early gastric cancer (ECG) and evaluates the effect on MT expression after eradication therapy.

Randomized trial of standard pain control with or without gabapentin for pain related to radiation-induced mucositis in head and neck cancer

OBJECTIVE Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT. METHODS HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC+G). Gabapentin was maintained at 900mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events. RESULTS Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC+G (n=11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC+G arm (47 in SPC vs. 74 in SPC+G, p=0.517; 215mg vs. 745.3mg, p=0.880; and 1260mg vs. 1537.5mg, p=0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC+G arm for weight gain (p=0.005). Adverse events related to gabapentin were manageable. CONCLUSIONS This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted.