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Abstract Background Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that is three times deadlier than melanoma. In 2008, it was found that 80% of MCC cases are caused by the genomic integration of a novel polyomavirus, Merkel Cell Polyomavirus (MCPyV), and the expression of its small and truncated large tumor antigens (ST and LT-t, respectively). MCPyV belongs to a family of human polyomaviruses; however, it is the only one with a clear association to cancer. Methods To investigate the role and mechanisms of various polyomavirus tumor antigens in cellular transformation, Rat-2 and 293A cells were transduced with pLENTI MCPyV LT-t, MCPyV ST, TSPyV ST, HPyV7 ST, or empty pLENTI and assessed through multiple transformation assays, and subcellular fractionations. One-way ANOVA tests were used to assess statistical significance. Results Soft agar, proliferation, doubling time, glucose uptake, and serum dependence assays confirmed ST to be the dominant transforming protein of MCPyV. Furthermore, it was found that MCPyV ST is uniquely transforming, as the ST antigens of other non-oncogenic human polyomaviruses such as Trichodysplasia Spinulosa-Associated Polyomavirus (TSPyV) and Human Polyomavirus 7 (HPyV7) were not transforming when similarly assessed. Identification of structural dissimilarities between transforming and non-transforming tumor antigens revealed that the uniquely transforming domain(s) of MCPyV ST are likely located within the structurally dissimilar loops of the MCPyV ST unique region. Of all known MCPyV ST cellular interactors, 62% are exclusively or transiently nuclear, suggesting that MCPyV ST localizes to the nucleus despite the absence of a canonical nuclear localization signal. Indeed, subcellular fractionations confirmed that MCPyV ST could achieve nuclear localization through a currently unknown, regulated mechanism independent of its small size, as HPyV7 and TSPyV ST proteins were incapable of nuclear translocation. Although nuclear localization was found to be important for several transforming properties of MCPyV ST, some properties were also performed by a cytoplasmic sequestered MCPyV ST, suggesting that MCPyV ST may perform different transforming functions in individual subcellular compartments. Conclusions Together, these data further elucidate the unique differences between MCPyV ST and other polyomavirus ST proteins necessary to understand MCPyV as the only known human oncogenic polyomavirus.

Background: Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose ((18)F-FDG) has been studied in thymic epithelial tumors. We evaluated the usefulness of (18)F-FDG PET for monitoring after treatment in unresectable thymic epithelial tumors. Method: Twelve patients with unresectable/metastatic thymic epithelial tumors underwent PET study with (18)F-FDG before and after chemotherapy or radiotherapy. Response and survival were analyzed according to the ratio of the peak standardized uptake value (SUV) of the tumor to the mean SUV of the mediastinum (T/M ratio). Results: Partial response (PR) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) was noted in 4 (33%) of 12 patients, and partial metabolic response (PMR) was observed in 6 (50%) of 12 patients. PR was observed in 4 of 6 patients with PMR. In 6 patients with any response, the T/M ratio at post-treatment was significantly lower than at baseline (p = 0.0017). In 6 patients with stable disease (SD), stable metabolic disease (SMD) was observed in 5 by use of (18)F-FDG PET. No statistically significant difference of (18)F-FDG uptake between at baseline and post-therapy was observed in 6 patients with SD (p = 0.4157) and SMD (p = 0.8419). Although the overall survival after treatment showed no statistically significant difference between PMR and SMD or progressive metabolic disease in the whole group of patients including thymoma, a statistically significant difference in the overall survival was observed between 5 patients with PMR and 5 patients with non-PMR (p = 0.0280). Conclusion: Our preliminary study suggests that (18)F-FDG PET is useful for monitoring response and outcome after treatment in unresectable thymic epithelial tumors. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) metastases caused by small-cell lung cancer (SCLC) are incurable and therefore fatal. Although such metastases are usually treated with chemotherapy or radiotherapy, their sensitivity to these treatment measures is unclear. Amrubicin appears to be a promising agent for relapsed SCLC, but its effectiveness in CNS metastases originating from SCLC is unknown., Methods: Between April 2002 and December 2009, 110 SCLC patients with CNS metastasis were treated at Shizuoka Cancer Center. Of these, we retrospectively reviewed 8 consecutive cases with CNS metastases originating from relapsed SCLC that were treated with amrubicin as a second-line therapy., Results: We recorded three sensitive relapses and five refractory cases. Amrubicin yielded a CNS response rate of 50 % (2 partial responses and 2 complete response; 95 % CI, 21.5-78.5\ %) and the disease control rate for CNS lesions was 87.5 % (95 % CI, 52.9-97.8 %). All of the sensitive relapse patients achieved a partial response. The median time to progression for CNS metastases was 150.5 days (95 % CI, 9-171 days), and the median survival time from the start of amrubicin administration was 230.5 days (95 % CI, 89-619 days). We also report a dramatic improvement in one patient's radiological result of intramedullary spinal cord metastasis and alleviation of her symptoms following amrubicin monotherapy including this case series., Conclusions: The results of this study suggest that amrubicin is active in patients with CNS metastases originating from SCLC.

Background: It remains unclear whether thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) expressions are associated with the pathogenesis of thymic epithelial tumors. Therefore, we investigated the expression of TS, OPRT and DPD in thymic epithelial tumors., Patients and Methods: Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for TS, OPRT, DPD, microvessel density (MVD) determined by CD34, and p53. We also conducted in vitro study of TS, OPRT and DPD expression using thymic carcinoma, thymic tumor and thymic fibroblast cell lines., Results: TS, OPRT and DPD were expressed in 61%, 48% and 41%, respectively. High grade malignancy is significantly associated with higher expression of TS, OPRT and DPD in thymic epithelial tumors. These biomarkers were closely associated with p53 and MVD, and the overexpression of TS and DPD was a prognostic marker for predicting poor outcome in univariate analysis. Our in vitro study showed that marked overexpression of TS and OPRT was observed in thymic carcinoma cells, but not in thymic tumor cells, or thymic fibroblast cells., Conclusions: The expression of TS, OPRT and DPD was closely related to the grade of malignancy in thymic epithelial tumors. A positive expression of TS, DPD and OPRT might be an important factor in predicting the effectiveness of 5-FU based chemotherapy in this disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Based on previous reports, patients who experience isolated central nervous system (CNS) failure may not have systemic acquired resistance to EGFR-TKI therapy. However, because there are few articles that have reported on the clinical efficacy of continuous EGFR-TKI administration following progressive disease (PD) in isolated CNS metastasis, we retrospectively investigated the possibility of using the treatment., Patients and Methods: From July 2002 to December 2009, 17 non-small cell lung cancer patients showed isolated CNS failure after clinical benefit (partial response or stable disease longer than 6 months) from EGFR-TKIs and continuously received EGFR-TKIs following radiotherapy (whole brain radiotherapy or stereotactic radiotherapy) to the CNS metastases., Results: The response rate and the disease control rate of CNS lesions were 41% and 76%, respectively. The median progression free survival, extracranial progression free survival and the median overall survival time were 80 days, 171 days and 403 days, respectively. The toxicities which were observed during the first EGFR-TKI treatments were sustained, but did not worsen during this study period. The acute toxicities caused by radiotherapy to the CNS were controllable. There were no remarkable late toxicities related to the treatment., Conclusions: Continuous administration of EGFR-TKI following radiotherapy after PD in isolated CNS metastasis appears to be a valid treatment option., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The efficacy of gefitinib for patients with non-adenocarcinoma non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non-adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non-adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty-seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large-cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty-one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression-free survival (mPFS) was 27%, 67-70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non-adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67-70%vs 92-93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations., (© 2011 Japanese Cancer Association.)

Background: We investigated the clinical significance of excision repair cross-complementation group 1 (ERCC1), breast cancer susceptibility 1 (BRCA1), and class III β-tubulin (TUBB3) expression in thymic epithelial tumors., Method: Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for ERCC1, BRCA1, TUBB3, microvessel density, and p53., Results: ERCC1, BRCA1, and TUBB3 were expressed in 48%, 50%, and 27%, respectively. The expression of ERCC1, BRCA1, and TUBB3 was significantly correlated with the grade of malignancy in thymic epithelial tumors. These biomarkers were closely associated with p53 and microvessel density and were a prognostic marker for predicting poor outcome. We also found that overexpression of ERCC1 and TUBB3 was associated with resistance to platinum- and taxane-based chemotherapy., Conclusion: An expression of ERCC1, BRCA1, and TUBB3 was correlated strongly with each other and was significantly associated with a poor outcome in thymic epithelial tumors. High-ERCC1 and TUBB3 expressions might be associated with resistance to platinum- and taxane-based chemotherapy, respectively.

Background: Elevated levels of N-telopeptide of type I collagen (NTX) are associated with skeletal-related events and death. However, it is unclear whether NTX is useful for monitoring therapeutic response in non-small cell lung cancer (NSCLC) patients with bone metastases., Patients and Methods: Urinary NTX levels were assessed at baseline and after one cycle of chemotherapy in 30 NSCLC patients with bone metastases. NTX levels were categorized as normal (NTX <64 nmol/mmol creatinine) or high (NTX ≥64 nmol/mmol creatinine)., Results: In 30 patients, the median NTX level at 1 month was significantly lower than that at baseline (P = 0.0016). The NTX levels after treatment were significantly lower than those at baseline in 20 patients with partial response (n = 2) or stable disease (n = 18). However, no significant difference of the NTX levels was observed in 10 patients with progressive disease. Sixteen (53.3%) of 30 patients had high baseline NTX levels. Ten patients had normal NTX levels after one cycle of chemotherapy, whereas 6 patients also had high NTX levels after treatment. The 10 patients with normal NTX levels had significantly better prognosis than the 6 patients with high NTX levels., Conclusion: Urinary NTX levels at 1 month after chemotherapy may be useful for predicting therapeutic response in NSCLC patients with bone metastases. Normalization of elevated baseline NTX at 1 month after chemotherapy was associated with survival benefits.

Purpose: The use of erlotinib after gefitinib failure in patients with non-small cell lung cancer (NSCLC) is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of erlotinib after failure of gefitinib., Methods: We searched published reports including erlotinib and gefitinib. Eleven reports were identified (published between November 2004 and December 2008). Advanced NSCLC who documented progressive disease (PD) for gefitinib 250 mg/day, received erlotinib 150 mg once daily., Results: A total of 106 patients were pooled from these studies. Asian was observed in 70.8%, women in 72.6%, adenocarcinoma in 85.1%, never smoker in 75.3%. In erlotinib therapy, there was observed in 9.9% in partial response (PR), 18.9% in stable disease (SD) and 70.8% in PD. Disease control (DC) rate for gefitinib and erlotinib was 71.7% and 29.2%, respectively. No significant difference of disease control rate (37.5% vs 21.7%, p=0.1503) and response rate (6.3% vs 8.7%, p=1.000) was observed between patients with EGFR mutations and those with wild type EGFR. The significantly different response on erlotinib therapy was observed in patients who had shown SD for gefitinib therapy (p=0.0095) and those who had a PFS of more than 6 months during gefitinib treatment (p=0.0261). The common toxicities were skin rash and diarrhea., Conclusion: Erlotinib may produce clinical benefits in patients who had shown long SD on prior gefitinib therapy. Moreover, EGFR mutations were not positive predictors for erlotinib response after gefitinib failure., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: No investigation of S-1 monotherapy in previously treated advanced non-small-cell lung cancer (NSCLC) patients has yet been reported. We conducted a retrospective study to evaluate the efficacy and tolerability of S-1 in patients with failure of second- or further-line chemotherapy., Patients and Methods: The records of NSCLC patients who had received S-1 monotherapy between January 2005 and November 2006 with the following eligibility criteria were reviewed: previously treated with at least two regimens including platinum and docetaxel in the case of nonadenocarcinoma patients, and including platinum, docetaxel and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in the case of adenocarcinoma patients. S-1 was administered for 28 consecutive days, followed by a 14-day drug-free period (42 days in one course). The drug was administered in two divided doses daily at 80 mg/day for patients with a body surface area <1.25 m(2), 100 mg/day for those with a body surface area of 1.25-1.5 m(2), and 120 mg/day for those with a body surface area > or = 1.5 m(2)., Results: Thirty-five patients were registered. The median number of courses administered per patient was 2 (range 1-9). The toxicity profile was mild, and grade 3 or more severe toxicity was rare. The overall response and disease control rates were 5.7% and 40%, respectively. The median survival time was 208 days., Conclusion: S-1 exhibits modest activity and acceptable toxicity when used as a third or subsequent line of chemotherapy in patients with advanced NSCLC.