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Kobayashi K.,Head and Neck Surgery | Kobayashi K.,University of Tokyo | Takenouchi S.,Head and Neck Surgery | Mitani H.,The Cancer Institute Hospital | Yoshida T.,Head and Neck Surgery
Auris Nasus Larynx | Year: 2014

Objective: Risk-based treatment represents the optimal management strategy for papillary thyroid carcinoma; however, the optimal extent of thyroidectomy and neck dissection remains controversial. This study aims to clarify the pattern of recurrence after conservative surgery in patients with papillary thyroid carcinoma. Methods: We retrospectively reviewed 93 patients with papillary thyroid carcinoma treated with conservative surgery. We analyzed recurrence rate, recurrence pattern, risk factors for recurrence, salvage treatment, and disease-free survival (DFS) in patients stratified according to risk. Results: The recurrence rate was significantly lower in the low-risk group compared with the high-risk group (14% vs 34%; p<. 0.01). The recurrence pattern also differed between the two groups, with ipsilateral lateral neck recurrence being more common in the low-risk group (9%), while contralateral lateral neck recurrence was more common in the high-risk group (18%). Patients with contralateral thyroid lobe metastasis and/or direct contralateral thyroid lobe invasion showed a significantly higher rate of contralateral lateral neck metastasis than patients negative for both these features. The overall 5-year DFS was 81% in all patients. Advanced T and N classification, large primary tumor (≥4. cm), extrathyroidal invasion, and high-risk group were significantly associated with poorer 5-year DFS in univariate analysis. Conclusion: Conservative surgery may represent a good treatment option for patients with low-risk papillary thyroid carcinoma. Tumor recurrence patterns differ between risk groups, with contralateral thyroid lobe lesions and direct contralateral lobe invasion being risk factors for contralateral lateral neck recurrence. © 2014 Elsevier Ireland Ltd.

Yoshioka H.,Kurashiki Central Hospital | Azuma K.,Kurume University | Yamamoto N.,Wakayama Medical University | Takahashi T.,Shizuoka Cancer Center | And 13 more authors.
Annals of Oncology | Year: 2015

Background: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). Methods: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. Results: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). Conclusions: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Izumiyama-Shimomura N.,Tokyo Metropolitan University | Nakamura K.-I.,Tokyo Metropolitan University | Aida J.,Tokyo Metropolitan University | Ishikawa N.,Tokyo Metropolitan University | And 10 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2014

Purpose: Evaluation of the relationships existing among 3 histologic types of urothelial tumors, chromosomal instability, and telomere length. Patients and methods: We examined 37 consecutive cases of papillary urothelial neoplasm, from which 26 (70.3%) were suitable for karyotype analysis, comprising 7 papillary urothelial neoplasms of low malignant potential (PUNLMPs), 10 low-grade papillary urothelial carcinomas (PUCs), and 9 high-grade PUCs. We performed karyotype and anaphase bridge analyses, and measured telomere lengths by quantitative fluorescence in situ hybridization. Results: PUNLMPs were always diploid and had anaphase bridges. Low-grade PUCs showed diploidy (n = 2), hypoploidy (n = 4) and polyploidy (n = 4), and high-grade PUCs showed diploidy (n = 1) and polyploidy (n = 8); both had anaphase bridges. The incidence of anaphase bridges did not differ significantly between PUNLMPs and high-grade PUCs (P = 0.105). The telomere lengths of PUNLMP, low-grade PUC, and high-grade PUC, expressed as mean telomere fluorescence units (TFU)±SD, were 7906±3197, 4893±1567, and 3299±1406, respectively. The differences among the 3 groups were significant. However, 42.9% of the PUNLMPs had shorter telomeres than the mean value for low-grade PUCs, and 30.0% of the low-grade PUCs had shorter telomeres than those for high-grade PUCs. There was an inverse correlation between telomere length and the incidence of anaphase bridges. Conclusions: PUNLMP appears to progress to low-grade PUC and high-grade PUC in association with telomere shortening and chromosomal instability. Our data suggest that critically shortened telomeres cause chromosomal instability during progression of papillary urothelial neoplasms. © 2014 Elsevier Inc.

Kabeya M.,The Cancer Institute | Kabeya M.,Niigata University | Furuta R.,The Cancer Institute | Kawabata K.,The Cancer Institute Hospital | And 2 more authors.
Cancer Science | Year: 2012

The carcinogenetic role of human papillomavirus (HPV) in mobile tongue cancer remains unclear because of conflicting results reported in the literature. This disparity is likely to be due to variations in the samples and methods used. Furthermore, despite a tendency for increased prevalence of mobile tongue cancer in young adults, only a few reports specifically in young patients have been published. In the present study on 32 patients, including six in their 20s, we genotyped the prevalence of HPV using a highly sensitive detection tool in fresh-frozen samples from surgical specimens and a novel detection device with electrochemical DNA chip and loop-mediated isothermal amplification. In addition, we confirmed HPV prevalence by in situ hybridization and immunohistochemistry for the p16 INK4a protein, regarded as a biomarker of HPV-associated cancers. The frequency of 13 genotypes of high-risk HPV was 0/32 (0%), which was further confirmed by in situ hybridization. Overexpression of p16 INK4a protein was observed in six of the 32 patients (19%), with four (67%) also overexpressing p53. Because there is usually a lack of p53 overexpression in HPV-associated cancer, it is unlikely that p16 INK4a protein overexpression is correlated with HPV infection. Consequently, it is unlikely that HPV infection plays an important role in mobile tongue carcinogenesis, in particular in young adults. In addition, our data suggest that the overexpression of p16 INK4a protein is not an appropriate biomarker for HPV association in mobile tongue carcinogenesis. © 2011 Japanese Cancer Association.

Takahashi K.,Molecular Therapeutics | Takahashi K.,Jichi Medical University | Takahashi K.,The Cancer Institute Hospital | Saga Y.,Jichi Medical University | And 6 more authors.
Cancer Science | Year: 2011

Controlling lymph node metastasis is currently a key issue in cancer therapy. Lymph node metastasis is one of the most important prognostic factors in various types of cancers, including endometrial cancer. Vascular endothelial growth factor-C (VEGF-C) plays a crucial role in lymphangiogenesis, and is implicated to play an important role in lymph node metastasis. To evaluate the role of VEGF-C in lymph node metastasis, we developed an animal model by using an endometrial cancer cell line, HEC1A. This cell line is not invasive by nature and secretes moderate amounts of VEGF-C; intrauterine injection of HEC1A cells into Balb/c nude mice resulted in uterine cancer with lymph node metastasis after 8weeks. To analyze the contribution of VEGF-C to lymph node metastasis, its corresponding gene was stably introduced into HEC1A cells (HEC1A/VEGF-C), which then produced more than 10 times the amount of VEGF-C. The number of lymph node metastases was significantly higher in HEC1A/VEGF-C cells than in HEC1A cells (3.2 vs 1.1nodes/animal, respectively). Augmented lymphangiogenesis was observed within tumors when HEC1A/VEGF-C cells were inoculated. These results indicate that VEGF-C plays a critical role in lymph node metastasis, in addition to serving as a platform to test the efficacy of various therapeutic modalities against lymph node metastasis. © 2011 Japanese Cancer Association.

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