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Pegylated liposomal doxorubicin (PLD) has been proven to be an effective antitumor drug for metastatic breast cancer, with less toxicity than conventional anthracycline. Our objective was to evaluate the efficacy and safety of PLD-based adjuvant chemotherapy compared to conventional chemotherapy for patients with stages I-III Triple-negative breast cancer (TNBC).A total of 162 patients, histologically proven to have TNBC at stages I-III between 2003 and 2010, were enrolled to evaluate the impact of PLD- and non-PLD-based adjuvant chemotherapy by using the end-pint of overall survival (OS) and relapse-free survival (RFS).Forty-nine (30.2%) patients received PLD-based adjuvant chemotherapy and 113 (69.8%) a non-PLD regimen, including 84 (52%) patients receiving non-PLD anthracycline. The Kaplan-Meier calculation indicated no differences in RFS and OS between the PLD and non-PLD groups. Multivariate analysis adjusted for tumor size and lymph node status also revealed similar RFS (HR=0.86, 95% CI=0.43-1.73, p=0.678) and OS (HR=0.86, 95% CI=0.41-1.79, p=0.692) for PLD-based chemotherapy compared with non-PLD-based. Patients receiving PLD-based chemotherapy had a relatively lower incidence of grade 3-4 neutropenia (25% vs. 41.6%, respectively; p=0.054) and significantly higher incidence of hand-foot syndrome (16.3% vs. 4.4%, respectively; p=0.010).PLD-based adjuvant chemotherapy was as effective as conventional chemotherapy for patients with TNBC. PLD is an alternative for patients with TNBC when conventional anthracycline is inappropriate.

Addition of cetuximab showed trend, but not significantly, to improve the therapeutic effects of gemcitabine and oxaliplatin combination for advanced biliary tract cancer in current randomized phase II trial. The trend of improvement did not correlate with KRAS mutation status. Biomarkers finding for selecting patients who will benefit most from anti-EGFR targeted therapy is warranted. Background Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. Patients and methods ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). Results The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Conclusions Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. Clinical Trials number This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

The influence of hepatitis C virus (HCV) infection on the outcome of patients with diffuse large B cell lymphoma (DLBCL) treated with rituximab-based chemotherapy is controversial. We retrospectively analyzed the characteristics and clinical outcomes of 168 patients with DLBCL diagnosed between January 2005 and December 2011. Twenty-nine patients who were HCV-positive before lymphoma treatment were compared with 139 patients who did not have HCV infection. The median follow-up duration was 3.0 (0.07-8.02) years. HCV infection resulted in more hepatic toxicity in both univariate (p=0.001) and multivariate (p=0.003) analyses. In addition, HCV-positive DLBCL patients were more likely to have treatment delay (20.1% vs. 0.7%, p

Background: Honoring patients’ treatment preferences is a key component of high-quality end-of-life care. Connecting clinical practices to patients’ preferences requires effective communication. However, few cancer patients reported discussing end-of-life-care preferences with their physicians. Aim: To identify correlates of physician–patient end-of-life-care discussions and to investigate associations of physician–patient end-of-life-care discussions with patient end-of-life-care preferences. Design: A cross-sectional survey from April 2011 through November 2012. Setting/participants: A convenience sample of 2467 cancer patients (89.3% participation rate) whose disease was diagnosed as terminal and unresponsive to current curative cancer treatment was recruited from 23 teaching hospitals throughout Taiwan. Results: Only 7.8% of respondents reported discussing end-of-life-care preferences with their physicians. Physicians were more likely to discuss end-of-life-care preferences with cancer patients who accurately understood their prognosis but less likely to do so if patients were married or received care in a hospital with an inpatient hospice unit. Furthermore, physician–patient end-of-life-care discussions were significantly, positively associated with the likelihood of preferring comfort-oriented care and hospice care, but negatively associated with preferences for receiving cardiopulmonary resuscitation when life is in danger and aggressive life-sustaining treatments at end of life, including intensive care unit admission, cardiac massage, intubation, and mechanical ventilation support. Conclusion: Physician–patient end-of-life-care discussions are correlated with accurate prognostic awareness, marital status, and institutional characteristics and negatively associated with terminally ill cancer patients’ preferences for aggressive end-of-life care. Interventions should be developed to facilitate timely end-of-life-care discussions between at-risk patients and their physicians, thus honoring patients’ end-of-life-care preferences and possibly avoiding futile life-sustaining treatments.

Purpose A phase II trial was conducted to evaluate the therapeutic efficacy and safety profiles of frontline concurrent chemoradiotherapy (CCRT) plus consolidation chemotherapy for patients with stage I/II nasal natural killer/T-cell lymphoma (NKTCL). Patients and methods Patients with newly diagnosed, measurable stage I/II nasal NKTCL were eligible. The CCRT included two cycles of the DEP regimen (dexamethasone, etoposide, and cisplatin) every 4 wk with concurrent 5040 cGy radiation in 28 fractions for 5 wk. Patients without disease progression after CCRT were subjected to two cycles of DVIP consisted of dexamethasone, etoposide, ifosphamide, mesna, and cisplatin every 4 wk. The primary endpoint was tumor response rate, and secondary endpoints were survival and toxicities. This phase II study has been registered in the ClinicalTrials.gov (NCT00292695). Results Thirty-three patients received CCRT, and 29 patients received two cycles of consolidation DVIP after CCRT. Among the 32 evaluable patients, 20 achieved complete response and 6 achieved partial response. The overall and complete response rate was 81% (95% CI, 68–95%) and 63% (95% CI, 46–79%), respectively. The 2-yr and 5-yr progression-free survival rate for intention-to-treat population was 64% (95% CI, 47–80%) and 60% (95% CI, 39–73%), respectively; while the corresponding overall survival rate was 73% (95% CI, 57–88%) and 66% (95% CI, 50–83%), respectively. The most common treatment-related grade 3/4 adverse event was leukopenia (85%). Conclusion Frontline CCRT plus consolidation chemotherapy is feasible and effective for treating localized nasal NKTCL.

Background Colorectal cancer is the third most commonly diagnosed cancer worldwide. Few studies have addressed the causes and risks of treatment refusal in a universal health insurance setting. Methods We examined the characteristics and survival associated with treatment refusal in patients with newly diagnosed colorectal cancer in Taiwan during 2004–2008. Treatment refusal was defined as not undergoing any cancer treatment within 4 months of confirmed cancer diagnosis. Patient data were extracted from four national databases. Factors associated with treatment refusal were identified through logistic regression using the generalized estimating equation method, and survival analysis was performed using the Cox proportional hazards model. Results Of the 41,340 new colorectal cancer cases diagnosed, 3,612 patients (8.74%) refused treatment. Treatment refusal rate was higher in patients with less urbanized areas of residence, lower incomes, preexisting catastrophic illnesses, cancer stages of 0 and IV, and diagnoses at regional and district hospitals. Logistic regression analysis revealed that patients aged >75 years were the most likely to refuse treatment (OR, 1.87); patients with catastrophic illnesses (OR, 1.66) and stage IV cancer (OR, 1.43) had significantly higher refusal rates. The treatment refusers had 2.66 times the risk of death of those who received treatment. Factors associated with an increased risk of death in refusers included age ≥75 years, insured monthly salary ≥22,801 NTD, low-income household or aboriginal status, and advanced cancer stage (especially stage IV; HR, 11.33). Conclusion Our results show a lower 5-year survival for colorectal patients who refused treatment than for those who underwent treatment within 4 months. An age of 75 years or older, low-income household status, advanced stages of cancer, especially stage IV, were associated with higher risks of death for those who refused treatment.

Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist and lipid-lowering agent, has been used worldwide for treatment of hyperlipidemia. The clinical trials demonstrate that fenofibrate possesses multiple pharmacological activities, including antitumor effects. However, the precise mechanisms in oral squamous cell carcinoma (OSCC) remain unclear. In this study, we investigated the anticancer effects of fenofibrate on the migration and invasion of human oral cancer CAL 27 cells. Fenofibrate inhibited the cell migration and invasion of CAL 27 cells by the wound healing and Boyden chamber transwell assays, respectively. In addition, fenofibrate reduced the protein expressions of MMP-1, MMP-2, MMP-7, and MMP-9 by Western blotting and inhibited enzyme activities of MMP-2/-9 using gelatin zymography assay. Results from immunoblotting analysis showed that the proteins of p-LKB1 (Ser428), LKB1, p-AMPKα (Thr172), p-AMPKα1/α2 (Ser425/Ser491), p-AMPKβ1 (Ser108), and AMPKγ1 were upregulated by fenofibrate; the levels of p-IKKα/β (Ser176) and p-IκBα were reduced in fenofibrate-treated cells. Also, fenofibrate suppressed the expressions of nuclear NF-κB p65 and p50 by immunoblotting and NF-κB DNA binding activity by EMSA assay. The anti-invasive effect of fenofibrate was attenuated by compound C [an adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibitor] or dominant negative form of AMPK (DN-AMPKα1). Thus, fenofibrate considerably inhibited metastatic behaviors of CAL 27 cells might be mediated through blocking NF-κB signaling, resulting in the inhibition of MMPs; these effects were AMPK-dependent rather than PPARα signaling. Our findings provide a molecular rationale, whereby fenofibrate exerts anticancer effects and additional beneficial effects for the treatment of cancer patients. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 866-876, 2016.

The relationship of Epstein-Barr virus (EBV), type I human T-cell lymphotropic virus (HTLV-I), and parvovirus B19 to histiocytic necrotizing lymphadenitis was studied prospectively in 10 Taiwanese patients using materials obtained by fine-needle aspiration and lymph node biopsy. The presence of EBV was detected by in situ hybridization for EBV-encoded RNA expression. Immunocytochemistry was used to detect virus-encoded protein for EBV and parvovirus B19. DNA in situ hybridization and polymerase chain reaction were performed to determine the existence of HTLV-I provirus. Expressions of EBV-encoded RNA and Fas ligand were detected in all cases. Expression of EBV-encoded protein was identified in only 1 case. Neither HTLV-I nor parvovirus B19 was detected in any case.

Protein C deficiency is one of the causes of curable or preventable portal vein thrombosis. We report two patients of portal vein thrombosis associated with hereditary protein C deficiency. The first patient presented with continuous right upper quadrant pain and high fever. The abdominal sonography revealed normal liver parenchyma but portal vein and superior mesenteric vein thrombosis. Based on a 55% (normal 70-140%) plasma protein C level, he was diagnosed as having protein C deficiency. A trace of his family history showed that his elder brother also had protein C deficiency with a 50% plasma C level. Both patients received anticoagulant therapy. The younger brother showed good response. Unfortunately, the elder one suffered from recurrent episodes of variceal bleeding and received a life-saving splenectomy and devascularization. We herein remind clinicians that early screening and therapy are helpful in preventing late complications of protein C deficiency with portal vein thrombosis.

BACKGROUND The association of Epstein-Barr virus (EBV) with Hodgkin's disease (HD) is intimately related to socioeconomic status. The proportion of HD patients with EBV is high in developing countries but low in developed countries. The aim of this study was to delineate the association of EBV with HD in Taiwan. METHODS Tissues from 70 consecutive cases of HD were examined for the presence of EBV, for the latent membrane protein (LMP-1) by immunohistochemistry, and for EBER-1 by in situ hybridization. RESULTS There were 53 males and 17 females, with a mean age of 42 years (range, 7-75 years). Histologic subtypes included nodular sclerosis in 36 cases (51.4%), mixed cellularity in 26 (37.1%), lymphocyte predominance in 6, and lymphocyte depletion in 2. Overall, EBV was expressed in 44 cases (62.9%), with EBER-1 expression detected in 40 (57.1%) and LMP-1 detected in 38 (54.3%). The following histologic subtypes were associated with EBV: lymphocyte predominance in 1 of 6 cases (16.7%), nodular sclerosis in 23 of 36 cases (63.9%), mixed cellularity in 18 of 26 cases (69.2%), and lymphocyte depletion in 2 of 2 cases (100%). CONCLUSIONS EBV association with HD is relatively high in Taiwan. Although EBV was detected in all subtypes and at all ages in this study, the low endemic incidence of HD in Taiwan suggests that other factors, besides EBV, play a role in the pathogenesis of HD. Cancer 1998;83:367-371. © 1998 American Cancer Society.

Mesenchymal stem cells can be easily isolated from bone marrow of patients with various haematological malignancies but the surface antigens expression may be changed after prolonged ex vivo culture

Background: Concurrent chemoradiation has become the standard of treatment in locally advanced nasopharyngeal carcinoma. However, the exact magnitude of the benefits of adjuvant chemotherapy is still unclear. Materials & methods: This is a retrospective assessment of 181 patients with newly diagnosed, locally advanced nasopharygeal carcinoma who received concurrent chemoradiation followed by adjuvant chemotherapy with cisplatin plus fluorouracil in one institution between 2004 and 2010. Results: The median follow-up period was 40 months (range: 2.1–96.6 months). The estimated 5-year survival rate of patients with and without adjuvant chemotherapy were 83.6 and 66.7%, respectively (p = 0.027). Patients receiving two to three cycles of adjuvant chemotherapy had improved outcomes compared with those without adjuvant chemotherapy or who had received one cycle. Multivariate analysis showed that both advanced stage and suboptimal treatment of adjuvant chemotherapy were adverse risk factors in terms of overall survival and disease-specific survival. Conclusion: Adjuvant chemotherapy with two to three cycles of cisplatin plus fluorouracil improved the survival of nasopharyngeal carcinoma patients.

The primary aim of this study was to evaluate the efficacy of palonosetron combined with dexamethasone in the prevention of vomiting, and especially nausea, in patients receiving allogeneic stem cell transplantation.Palonosetron 0.25 mg was given to 27 patients receiving allogeneic transplantation on the first day of conditioning, and then every other day during the entire conditioning period. Dexamethasone was given daily also during conditioning. Vomiting and nausea were recorded daily according to CTCAE version 4.0 from the start of conditioning to Day 7 after transplantation. In addition, MASCC antiemetic tool (MAT) was also used in parallel to evaluate the intensity of nausea.The treatment was well tolerated; 25.9 and 40.7 % of the patients had grade 2/3 vomiting and nausea respectively during conditioning. The incidences of grade 2/3 vomiting and nausea were even higher in the first week after transplantation (40.7 and 51.8 %, respectively). The score of MAT correlated well with the grade of CTCAE. However, the difference in the mean intensity of nausea between period of conditioning and the first week after HSCT was significant only by using MAT (0.96 ± 1.829 vs. 3.81 ± 3.386, p=0.001) but not CTCAE (1.26 ± 0.903 vs. 1.63 ±0.967, p=0.152).Palonosetron combined with dexamethasone is effective in preventing vomiting during conditioning. However, more effort should be made to alleviate nausea during conditioning and both nausea and vomiting in the first week after transplantation. Furthermore, MAT has a higher discriminant power than CTCAE in assessing the intensity of nausea in patients receiving allogeneic transplantation.

Adequate knowledge of prognosis is a prerequisite for planning appropriate end-of-life (EOL) care. However, questions remain about whether the association between prognostic understanding and EOL-care intensity reflects terminally ill cancer patients' preferences for EOL care. This study investigated the associations between accurate prognostic understanding and EOL-care preferences, and identified correlates of accurate prognostic understanding.A cross-sectional survey of 2452 terminally ill cancer patients from 23 hospitals throughout Taiwan.Nearly half the participants (49.80%) accurately understood their prognosis. These patients were significantly more likely to prefer comfort-oriented care as their goal for EOL care, but less likely to prefer life-prolonging treatments. Accurately understanding prognosis decreased the likelihood of preferring intensive care unit care, cardiac pulmonary resuscitation, cardiac massage, intubation, and mechanical ventilation support, but increased preference for hospice care. Participants were significantly more likely to accurately understand their prognosis if they were male, younger, better educated, with a stronger preference for physicians to disclose their prognosis to them, and receiving care at a hospital accredited as a medical center and in northwest Taiwan. The likelihood of accurate prognostic understanding was lower for patients recently (≤ 12 months) diagnosed with cancers with better prognosis and hematologic malignancies than for lung cancer patients.Accurately understanding prognosis is associated with fewer preferences for life-sustaining treatments and is correlated with both patient and institutional characteristics. Interventions should be developed to improve accurate prognostic understanding, thus facilitating informed EOL-care decisions that may limit the use of aggressive interventions.

As GPR30 has been implicated in mediating cancer cell proliferation, this study aimed to examine the antitumor effect of the GPR30 antagonist G15 in human oral squamous cell carcinoma (OSCC). G15 induced dose-dependent cytotoxicity, apoptosis and G2/M cell cycle arrest in a panel of OSCC cells. The results showed that G15 could inhibit the growth of the oral cancer cells with IC50 value 11.2 μM for SCC4, 15.6 μM for SCC9, and 7.8 μM for HSC-3, respectively. Flow cytometric analysis and Comet assay indicated that G15 suppressed the viability of SCC4 and HSC-3 cells by inducing apoptosis and G2/M arrest. In addition, G15 down regulated the expression of Akt, cell cycle-related proteins, and mitogen-activated protein kinases, but increased the levels of LC3B-II and the accumulation of autophagosomes. Inhibition of autophagy by chloroquine does not affect the G15-induced apoptosis in SCC4 cells. Mechanistic evidence indicated that the antiproliferative effect was mediated through the downregulation of cdc2, cdc25c and NF-κB expression. Taken together, our findings suggest the potential of G15 in treating OSCC.

Among the signaling pathways implicated in the tumorigenesis of oral squamous cell carcinoma (OSCC) is the extracellular signal-regulated kinase mitogen-activated protein kinase pathway, a downstream target of which is a family of serine/threonine kinases known as the 90 kDa ribosomal S6 kinases (RSKs). This study aims to investigate the role of BI-D1870, a specific inhibitor of p90 RSKs, in a panel of OSCC cell lines.The antitumor effects and mechanisms of BI-D1870 were assessed by MTT assays, flow cytometry, Western blotting, transfection, and confocal microscopy.BI-D1870 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound inhibited the downstream RSK target YB-1 and caused apoptosis as evidenced by PARP cleavage, activation of the caspase cascade, and the presence of pyknotic nuclei in the 4,6-diamidino-2-phenylindole assay. In addition, BI-D1870 also induced G2/M arrest by modulating the expression of p21 and other cell cycle regulators. Other newly discovered anticancer attributes of BI-D1870 included the generation of reactive oxygen species and increases in endoplasmic reticulum stress and autophagy.Together, these results suggest the translational value of BI-D1870 in oral squamous cell carcinoma therapy.

A growing body of evidence indicates that caveolin-1 (CAV1) may influence the development of human cancer. However, the exact role of CAV1 in childhood leukemia is still controversial. We investigated six novel polymorphic variants of CAV1, namely C521A (rs1997623), G14713A (rs3807987), G21985A (rs12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992), and analyzed the association of each specific genotype with susceptibility to childhood leukemia.In total, 266 patients with childhood leukemia and 266 age-matched healthy controls, recruited from two major medical centers in Taiwan, were genotyped investigating the association of these polymorphisms with childhood leukemia.We found that there were significant differences between childhood leukemia and control groups in the distributions of their genotypes (p=4.1×10(-8) and 0.0167) and allelic frequencies (p=4.9×10(-10) and 3.7×10(-3)) in the CAV1 G14713A and T29107A polymorphisms, respectively. As for the haplotype analysis, those who had GG/AT or GG/AA at CAV1 G14713A/T29107A had a reduced risk of childhood leukemia compared to those with GG/TT, while those with any other combinations were at increased risk.The A allele of CAV1 G14713A is risky, while the A allele of CAV1 T29107A is protective for the development of childhood leukemia and these may be novel useful genomic markers for the early detection of childhood leukemia.

Fatal hepatitis B virus (HBV) reactivation in lymphoma patients with “resolved” HBV infection (hepatitis B surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) can occur, but the true incidence and severity remain unclear. From June 2009 to December 2011, 150 newly diagnosed lymphoma patients with resolved HBV infection who were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy were prospectively followed. HBV DNA was checked at baseline, at the start of each cycle of chemotherapy, and every 4 weeks for 1 year after completion of rituximab-CHOP chemotherapy. Patients with documented HBV reactivation were treated with entecavir at a dosage of 0.5 mg/day for 48 weeks. HBV reactivation was defined as a greater than 10-fold increase in HBV DNA, compared with previous nadir levels, and hepatitis flare was defined as a greater than 3-fold increase in alanine aminotransferase (ALT) that exceeded 100 IU/L. Incidence of HBV reactivation and HBV-related hepatitis flares was 10.4 and 6.4 per 100 person-year, respectively. Severe HBV-related hepatitis (ALT >10-fold of upper limit of normal) occurred in 4 patients, despite entecavir treatment. Patients with hepatitis flare exhibited significantly higher incidence of reappearance of HBsAg after HBV reactivation (100% vs. 28.5%; P = 0.003). Conclusion: In lymphoma patients with resolved HBV infections, chemotherapy-induced HBV reactivation is not uncommon, but can be managed with regular monitoring of HBV DNA and prompt antiviral therapy. Serological breakthrough (i.e., reappearance of HBsAg) is the most important predictor of HBV-related hepatitis flare. (Hepatology 2014;59:2092–2100)

Although the antitumor activity of the crude extract of wild bitter gourd (Momordica charantiaL.) has been reported, its bioactive constituents and the underlying mechanism remain undefined. Here, we report that 3β,7β-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC), a cucurbitane-type triterpene isolated from wild bitter gourd, induced apoptotic death in breast cancer cells through peroxisome proliferator-activated receptor (PPAR)γactivation. Luciferase reporter assays indicated the ability of DMC to activate PPARγ, and pharmacological inhibition of PPARγprotected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPARγ-targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-κB, and estrogen receptorα, and induced endoplasmic reticulum stress, as manifested by the induction of GADD153 and GRP78 expression. Moreover, DMC inhibited mTOR-p70S6K signaling through Akt downregulation and AMPK activation. The ability of DMC to activate AMPK in liver kinase (LK) B1-deficient MDA-MB-231 cells suggests that this activation was independent of LKB1-regulated cellular metabolic status. However, DMC induced a cytoprotective autophagy presumably through mTOR inhibition, which could be overcome by the cotreatment with the autophagy inhibitor chloroquine. Together, the ability of DMC to modulate multiple PPARγ-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.

e16139Background: The benefit of adjuvant chemotherapy (AC) for upper tract urothelial cancer (UTUC) is controversial. Pathologic characteristics such as lymphovascular invasion (LVI) and squamous ...

417 Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.

134 Background: Our preclinical studies showed that AUY922 treatment could induce downregulation of KIT protein and apoptosis in both imatinib-sensitive and -resistant GIST cells (Autophagy 2013). This prospective, phase II trial evaluated the efficacy and safety of AUY922 in patients with metastatic GISTs after failure or intolerance to imatinib and sunitinib in an Asian population. Methods: Based on the MTD defined in previous phase I study, infusion 70 mg/m2 of AUY922 was given once weekly, 4 weeks as a cycle. The primary endpoint was disease control rate (DCR, objective response + stable disease ≥ 16 weeks), assessed by computed tomography (CT) scan according to RECIST v1.1 every 8 weeks. Metabolic response was assessed by positron emission tomography (PET)-CT scans performed at baseline and after 4 weeks of treatment. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: Between 2011.10 and 2015.01, 25 evaluable patients were enrolled. DCR at 16 weeks was 20% but none had partial response. According to the EORTC-defined PET response criteria, ten patients (40%) had metabolic partial response ( > 25% decrease of SUV from baseline) at 4 weeks after AUY922 treatment. At a median follow-up time of 7.8 months (range, 2.0-33.4 months), median progression-free survival (PFS) was 2.4 months (95% confidence interval (CI), 1.6-3.2 months) and median overall survival was 9.6 months (95% CI, 0-21.1 months). Metabolic partial responders had a trend of better PFS (3.8 vs. 1.9 months in non-responders, P = 0.09). The common adverse events (AEs) were fatigue (82%), visual disturbances (70%), diarrhea (55%). Grade 3/4 AEs included visual field darkening (3.7%), blurred vision (7.4%) and diarrhea (7.4%). Treatment interruption and dose modification were frequently required (62%) in patients with more than 8 weeks of treatment because of grade 2-3 visual field darkening. Conclusions: AUY922 showed modest antitumor activity in heavily pretreated GIST patients. Clinical relevant ocular toxicity was unexpectedly high in current study cohort; its correlation with PK will be further explored. Clinical trial information: NCT 01389583.

Objective: An increased risk of serious adverse effects related to bevacizumab has been observed in many Western studies for metastatic colorectal cancer. To evaluate the safety of bevacizumab in Chinese patients, a safety study was conducted in Taiwan. Methods: Bevacizumab was provided by the Expanded Access Program in combination with first-line chemotherapy per investigator's choice. The primary objective is the safety profile, particularly the targeted adverse events such as proteinuria, bowel perforation, hypertension, wound healing complication, thromboembolism and bleeding. The second objectives include time to disease progression and overall survival time. Patients with major surgical procedure performed within the 28 days of bevacizumab were excluded from this study. Results: Forty patients were eligible for intent-to-treat analysis. The overall rate of objective response and disease control was 55.2 and 81.6%. The median time to disease progression and overall survival were 11.9 and 22.9 months. The actuarial 2-year survival was 46.6%. Regarding toxicity, 7 subjects (17.5%) had serious adverse effects related to study treatment. None of the patients in this cohort had arterial thrombotic events and bowel perforation. Conclusions: Bevacizumab demonstrates a similar activity and safety profile in Chinese patients. Life-threatening bowel complications were avoided in this study by excluding patients with major surgery within the first 28 days.

The FLT3 gene with internal tandem duplication (ITD) is a poor prognostic factor in patients with acute myeloid leukemia (AML), and the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for AML patients with FLT3-ITD is controversial. We examined 122 AML patients; 34 patients had FLT3-ITD and 39 patients received allogeneic HSCT. The median overall survival (OS) of patients with wtFLT3/nonHSCT, wtFLT3/HSCT, FLT3-ITD/nonHSCT and FLT3-ITD/HSCT was 40.7 months, 53.4 months, 9.8 months and not reached, respectively (p=0.006). Compared to the wtFLT3/nonHSCT patients, the hazard ratio (95% CI) of OS for wtFLT3/HSCT, FLT3-ITD/nonHSCT and FLT3-ITD/HSCT was 1.39 (0.61-3.18), 3.57 (1.58-8.10) and 0.40 (0.11-1.59), respectively, after adjustment of age, sex, WBC, LDH, karyotype, NPM, and FAB classification. This result indicated that patients with FLT3-ITD/nonHSCT had a significantly worse outcome, but allogeneic HSCT improved the prognosis for patients with FLT3-ITD.

The aim of this study was to document the clinical and pathological features of a single institutional series of Asian patients with phyllodes tumors, and to determine the prognosis, the adequate management and the predictive histological features. The clinical data were retrospectively studied from the medical records and the pathological data from the Department of Pathology were utilized to identify 33 patients diagnosed with phyllodes tumors between 2003 and 2010. Eight patients had benign tumors, 13 borderline and 12 malignant. Nine patients (27 %) had recurrence. No patients classified as benign phyllodes tumors had recurrence, but those with malignant phyllodes tumors had a high recurrence rate (41 %). The 5-year disease-free survival was 59 %. The 5-year overall survival was 81 %. The width of surgical margin was not related to disease recurrence and stromal overgrowth was the only prognostic factor in terms of disease-free survival and overall survival. The phyllodes tumors of borderline and malignant classification in Asian patients had a high recurrence rate. Clinical and pathological factors, except for stromal overgrowth, cannot predict disease recurrence. Further molecular research is warranted.

The ataxia telangiectasia mutated (ATM) gene plays a major role in repairing the double-strand breaks and maintaining the genome stability. In this case-control study, associations of seven ATM single-nucleotide polymorphisms (rs600931, rs189037, rs652311, rs624366, rs228589, rs227092 and rs227060) with risks in childhood leukemia in a Taiwanese population were investigated. Two hundred and sixty-six patients with childhood leukemia and 266 age-matched healthy controls recruited were genotyped and analyzed. The P-values of the distributions of the genotypic frequencies in the seven ATM polymorphisms were 0.8925, 0.2835, 0.5772, 0.8731, 0.3641, 0.9181 and 0.5071, respectively. The Pvalues of the distributions of the allelic frequencies in the seven ATM polymorphisms were 0.6158, 0.1179, 0.6971, 0.7944, 0.1887, 0.6605 and 0.2747, respectively. Although the results did not indicate that ATM polymorphism is directly associated with childhood leukemia, the gene-gene and gene-environment interactions of ATM with other factors is worthy of further investigation in the future.

There is little evidence to demonstrate the importance of the Sonic hedgehog homolog (Shh) pathway to differentiation therapy in the treatment of hematological neoplasms. Here we characterize the changes in acute myelogenous leukemia (HL-60) cells after blocking the Shh pathway by an antagonist of Smoothened, cyclopamine. Cyclopamine induces apoptosis of HL-60 cells in a dose- and time-dependent manner with increased G0/G1 cycle fraction. Treatment with cyclopamine increases the expression of monocytic cell markers CD11b and CD14, but the expression of CD13, CD33 and CD38 is unchanged. The monocytic differentiation of HL-60 cells induced by cyclopamine is also evidenced by an increase in Egr-1 expression. Importantly, cyclopamine down-regulates the phosphorylation of Akt and ERK, but activates AMP-activated protein kinase (AMPK) signaling. Further investigations should determine the clinical application of modulating the Shh pathway in the treatment of hematological malignancies.

Caveolin-1 (Cav-1), which has been proposed as a candidate tumor suppressor, plays a regulatory role in several signaling pathways. High expression of Cav-1 in nasopharyngeal carcinoma (NPC) may enhance tumor cell migration and correlate with poor prognosis of the patients, while the genetic alterations of Cav-1 during nasopharyngeal carcinogenesis are still largely unknown. The aim of this study was to evaluate the association between NPC susceptibility and Cav-1 genotypes.One hundred and seventy six patients with NPC and 176 age- and gender-matched healthy controls recruited in Taiwan were genotyped and analyzed by PCR-restriction fragment length polymorphism.There were significant differences between the NPC and control groups in the distributions of the genotypic (p=0.0019) and allelic frequencies (p=2.5 10(-4)) in the Cav-1 T29107A (rs7804372) polymorphism.In this first report of Cav-1 involvement in NPC the A allele of Cav-1 T29107A is found to be protective against the development of NPC and may be a novel useful genomic marker for early screening and prediction of NPC.

Capsaicin, a pungent compound found in hot chili peppers, has been reported to have antitumor activities in many human cancer cell lines, but the induction of precise apoptosis signaling pathway in human nasopharyngeal carcinoma (NPC) cells is unclear. Here, we investigated the molecular mechanisms of capsaicin-induced apoptosis in human NPC, NPC-TW 039, cells. Effects of capsaicin involved endoplasmic reticulum (ER) stress, caspase-3 activation and mitochondrial depolarization. Capsaicin-induced cytotoxic effects (cell death) through G0/G1 phase arrest and induction of apoptosis of NPC-TW 039 cells in a dose-dependent manner. Capsaicin treatment triggered ER stress by promoting the production of reactive oxygen species (ROS), increasing levels of inositol-requiring 1 enzyme (IRE1), growth arrest and DNA-damage-inducible 153 (GADD153) and glucose-regulated protein 78 (GRP78). Other effects included an increase in cytosolic Ca2+, loss of the mitochondrial transmembrane potential (ΔΨ m), releases of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9 and -3. Furthermore, capsaicin induced increases in the ratio of Bax/Bcl-2 and abundance of apoptosis-related protein levels. These results suggest that ER stress- and mitochondria-mediated cell death is involved in capsaicin-induced apoptosis in NPC-TW 039 cells.

BACKGROUND: CD4(+)interferon (IFN)-γ(+) T cell (Th1) and CD4(+)interleukin (IL)-4(+) T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real world situation remains unknown. METHODOLOGY: Peripheral blood was collected every week prospectively from Day 0 to Day 210 (patients without GVHD) or Day 300 (patients with chronic GVHD) after allogeneic peripheral blood stem cell transplantation in consecutive 27 patients. The frequencies of Th1 and Th2 within CD4(+) T cells were determined by flow cytometry and pplasma IFN-γ, IL-12, IL-4, and IL-10 were determined by ELISA. PRINCIPAL FINDINGS: Kinetics of Th1, Th2 frequency, and the plasma IL-10 and IFN-γ more commonly coincided with, rather than predicted, the activity of GVHD. These markers are significantly higher when acute or chronic GVHD developed. The kinetics of IL-10 is especially correlated well with the activity of GVHD during clinical course of immunosuppressive treatment. For patients with hepatic GVHD, there is a positive correlation between plasma IL-10 levels and the severity of hepatic injury. The frequency of Th2 is also significant higher in acute GVHD and tends to be higher in chronic GVHD. Interestingly, there is a very good positive correlation between the frequency of Th1 and Th2 (r = 0.951, p

Drug resistance and associated immune deregulation limit use of current therapies in chronic lymphocytic leukaemia (CLL), thus warranting alternative therapy development. Herein we demonstrate that OSU-DY7, a novel D-tyrosinol derivative targeting p38 mitogen-activated protein kinase (MAPK), mediates cytotoxicity in lymphocytic cell lines representing CLL (MEC-1), acute lymphoblastic leukaemia (697 cells), Burkitt lymphoma (Raji and Ramos) and primary B cells from CLL patients in a dose- and time-dependent manner. The OSU-DY7-induced cytotoxicity is dependent on caspase activation, as evidenced by induction of caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage and rescue of cytotoxicity by Z-VAD-FMK. Interestingly, OSU-DY7-induced cytotoxicity is mediated through activation of p38 MAPK, as evidenced by increased phosphorylation of p38 MAPK and downstream target protein MAPKAPK2. Pretreatment of B-CLL cells with SB202190, a specific p38 MAPK inhibitor, results in decreased MAPKAPK2 protein level with concomitant rescue of the cells from OSU-DY7-mediated cytotoxicity. Furthermore, OSU-DY7-induced cytotoxicity is associated with down regulation of p38 MAPK target BIRC5, that is rescued at protein and mRNA levels by SB202190. This study provides evidence for a role of OSU-DY7 in p38 MAPK activation and BIRC5 down regulation associated with apoptosis in B lymphocytic cells, thus warranting development of this alternative therapy for lymphoid malignancies.

Until now, the cancer was examined by diagnosing the pathological changes of tumor. If the examination of cancer can diagnose the tumor before the cell occur the pathological changes, the cure rate of cancer will increase. This research develops a human-machine interface for hyper-spectral microscope. The hyper-spectral microscope can scan the specific area of cell and records the data of spectrum and intensity. These data is helpful to diagnose tumor. This research aims to develop a new system and a human-machine interface to control the hyper-spectral microscope. The interface can control the moving speed of motor, the exposure-time of hyper-spectrum, real-time focus, image of fluorescence, and record the data of spectral intensity and position.

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients’ Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

Prostate cancer is the most common cause of cancer death in men and is a major health problem worldwide. Methylene tetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is also an important source of DNA methylation and DNA synthesis (nucleotide synthesis). To assess the association and interaction of genotypic polymorphisms in MTHFR and lifestyle factors with prostate cancer in Taiwan, we investigated two well-known polymorphic variants of MTHFR, C677T (rs1801133) and A1298C (rs1801131), analyzed the association of specific genotypes with prostate cancer susceptibility, and discussed their joint effects with individual habits on prostate cancer risk. In total, 218 patients with prostate cancer and 436 healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped for these polymorphisms with prostate cancer susceptibility. We found the MTHFR C677T but not the A1298C genotype was differently distributed between the prostate cancer and control groups. The T allele of MTHFR C677T conferred a significantly (p=0.0011) decreased risk of prostate cancer. As for the A1298C polymorphism, there was no difference in distribution between the prostate cancer and control groups. Gene interactions with smoking were significant for MTHFR C677T polymorphism. The MTHFR C677T CT and TT genotypes in association with smoking conferred a decreased risk of 0.501 (95% confidence interval=0.344-0.731) for prostate cancer. Our results provide the first evidence that the C allele of MTHFR C677T may be associated with the development of prostate cancer and may be a novel useful marker for primary prevention and anticancer intervention.

To evaluate the association between the polymorphisms of the ERCC6 DNA repair gene, which plays an important role in maintaining genome stability, and the risk of bladder cancer in Taiwan.In this hospital-based case-control study, the association of ERCC6 codon 399, 1097 and 1413 polymorphisms with bladder cancer risk in a Central Taiwanese population was first investigated. In total, 288 patients with bladder cancer and 288 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped.A significantly different distribution was found in the frequency of the ERCC6 codon 399 genotypes, but not the ERCC6 codon 1097 or 1413 genotypes, between the bladder cancer and control groups. Those who had homozygous A/A or heterozygous A/G at ERCC6 codon 399 showed a 1.97- and 1.04-fold (95% confidence interval=1.29-3.01 and 0.71-1.53, respectively) increased risk of bladder cancer compared to those with G/G. As for ERCC6 codon 1097 or 1413, there was no difference in distribution between the bladder cancer and control groups.The first evidence that the homozygous A allele of the ERCC6 codon 399 may be associated with the development of bladder cancer and may be a novel useful marker for primary prevention and anticancer intervention is provided.

To evaluate the association between the genotypes of the heterodimeric DNA-binding component, Ku80 gene and the breast cancer risk in Taiwan.In this hospital-based case-control study, the association of Ku80 G-1401T rs828907, Ku80 C-319T rs11685387 and Ku80 intron19 rs9288518 polymorphisms with breast cancer risk in a Taiwanese population was investigated. In total, 1272 patients with breast cancer and the same number of age- and gender-matched healthy controls were genotyped.A significantly different distribution was found in the frequency of the Ku80 G-1401T genotype, but not the Ku80 C-319T or intron 19 genotypes, between the breast cancer and control groups. The T allele Ku80 G-1401T conferred a significant (p=0.0069) increased risk of breast cancer. Gene interactions with smoking, but not with breastfeeding, were significant for the Ku80 G-1401T polymorphism. The Ku80 G-1401T GT and TT genotypes in association with smoking conferred an increased risk of 3.162 (95% confidence interval=2.275-4.393) for breast cancer.The T allele of Ku80 G-1401T may be associated with the development of breast cancer and may be a novel useful marker for breast cancer detection and prediction.

The aim of the present study was to evaluate the association between the polymorphisms of the EXO1 gene and the risk of breast cancer in central Taiwan.In this hospital-based study, the association of EXO1 A1419G (rs3754093), C908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with breast cancer risk in a central Taiwanese population was investigated. In total, 1,272 patients with breast cancer and 1,272 age- and gender-matched healthy controls recruited from the China Medical University Hospital were genotyped.A significantly different distribution was found in the frequency of the EXO1 K589E genotype, but not the other genotypes, between the breast cancer and control groups. The A allele EXO1 K589E conferred a significantly (p=0.000025) increased risk of breast cancer. As for the rest of the polymorphisms, there was no difference in distribution between the breast cancer and control groups.Our results provide evidence that the A allele of EXO1 K589E may be associated with the development of breast cancer and may be a useful biomarker for breast cancer detection and primary prevention.

Non-homologous end-joining (NHEJ) system is a major route in repairing double strand breaks (DSBs), and is important in maintaining the genome stability. The gene XRCC4 is a central role of the NHEJ system, and it is critical in carcinogenesis. In order to reveal the association between XRCC4 and lung cancer, we recruited 164 lung cancer patients and 649 healthy controls from central Taiwan, investigated seven novel polymorphic variants of XRCC4, includes C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317), and analyzed the association of specific genotype with lung cancer susceptibility. The results showed that the XRCC4 G-1394T is significant in Taiwanese lung cancer and the GT genotype of G-1394T is an obvious risk factor of lung cancer susceptibility (P = 0.0049), and the G allele is a risky factor (P = 0.0087). As for XRCC4 C-1622T (rs7727691), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317) polymorphism sites, there was no difference in the distribution between the lung cancer and control groups. The analyzing results of joint effect for smoking habit and XRCC4 G-1394T polymorphism was that people with GT genotype and smoking habit present the highest risk of lung cancer than other groups (OR = 2.31, 95% CI = 1.43-3.72). The G allele of the XRCC4 G-1394T may be responsible for lung carcinogenesis and maybe useful in early detection and prevention of lung cancer.

The DNA repair gene XRCC4, a member of NHEJ for double strand breaks, is very important in maintaining the overall genome stability, and may play an important role in carcinogenesis. To reveal the relationship between XRCC4 and bladder cancer, seven polymorphic variants of XRCC4, including C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317) were investigated and analyzed for their association with bladder cancer susceptibility.In this case-control study, the association of these variants of XRCC4 with bladder carcinogenesis in Taiwan was investigated. Bladder cancer patients (158) and 158 age- and gender-matched healthy controls were recruited and their genotypes were analyzed by PCR-based restriction fragment length polymorphism method.It was found that XRCC4 G-1394T is a significant SNP in bladder carcinogenesis after analyzing the frequencies of each variant in both bladder cancer and control groups. The data indicated that the heterogeneous G of G-1394T is an obvious risk factor of bladder cancer susceptibility (p=0.005) and the data of G allele also showed a similar situation (p=0.0099). As for the other six polymorphisms, there was no difference between the bladder cancer and control groups.These findings suggest that the G allele of XRCC4 G-1394T may be involved in bladder carcinogenesis and useful in early detection of bladder cancer.

To evaluate the association between the polymorphisms of the Exo1 gene and the risk of lung cancer in central Taiwan.In this hospital-based study, the association of Exol A-1419G (rs3754093), C-908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with lung cancer risk in a central Taiwanese population was investigated. In total, 358 patients with lung cancer and 358 age- and gender-matched healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped.A significantly different distribution was found in the frequency of the Exo1 K589E genotype, but not the other genotypes, between the lung cancer and control groups. The A allele Exo1 K589E conferred a significantly (p = 0.0097) increased risk of lung cancer. As for the rest of the polymorphisms, there was no difference in distribution between the lung cancer and control groups. Gene environment interactions with smoking were significant for Exo1 K589E polymorphism. The Exo1 K589E AG and AA genotype in association with smoking conferred an increased risk of 1.7208 (95% confidence interval = 1.2188-2.4295) for lung cancer.Our results provide the first evidence that the A allele of Exo1 K589E may be associated with the development of lung cancer and may be a novel useful marker for primary prevention and anticancer intervention.

A patient with pathologically proven acrometastasis of his left thumb presented 3 months after esophagectomy for esophageal squamous cell carcinoma. Interestingly, there was indeed a faint uptake in his left thumb that was initially considered an artifact in the whole body bone scan taken before esophagectomy. Physicians must be aware of the possibility of acrometastasis, even if there is no other concomitant metastatic area.

The DNA repair gene XRCC4, an important caretaker of overall genome stability, is thought to play a major role in the development of human carcinogenesis. However, the association of the polymorphic variants of XRCC4 with oral cancer susceptibility has never been reported.In this hospital-based case-control study, the association of XRCC4 codon 247 (rs3734091), G-1394T (rs6869366), intron 7 (rs28360317) and intron 7 (rs1805377) polymorphisms with oral cancer risk in a Central Taiwanese population was investigated. In total, 318 patients with oral cancer and 318 age- and gender-matched healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped.A significantly different distribution was found in the frequency of the XRCC4 codon 247 genotype, but not the XRCC4 G-1394T or intron 7 genotypes, between the oral cancer and control groups. A/C heterozygosity at XRCC4 codon 247 conferred a significant (2.04-fold) increased risk of oral cancer. As for XRCC4 G-1394T and intron 7 polymorphisms, there was no difference in distribution between the oral cancer and control groups. Gene-environment interactions with smoking, but not with betel quid chewing or alcohol consumption, were significant for XRCC4 codon 247 polymorphism. The XRCC4 codon 247 A/C genotype in association with smoking conferred an increased risk of 3.44 (95% confidence interval = 1.24-9.60) for oral cancer.Our results provide the first evidence that the heterozygous A allele of the XRCC4 codon 247 may be associated with the development of oral cancer and may be a novel useful marker for primary prevention and anticancer intervention.

The DNA repair gene X-ray cross-complementing group 4 (XRCC4), a member of the non-homologous end-joining (NHEJ) repair system, plays a major role in the repair of the double-strand breaks of the DNA sequence. This gene is critical to the maintenance of overall genome stability, and is also thought to play a key role in human carcinogenesis. In this case-control study, several novel polymorphic variants of XRCC4, including C-1622T (rs7727691), G-1394T (rs6869366), C-571T (rs2075686) and intron3 DIP (rs28360071), were investigated, and the correlation of these variants to prostate cancer susceptibility in a Taiwanese population was observed. A total of 134 prostate cancer patients were recruited along with 134 age-matched healthy controls, and the association of their selected genotypes with susceptibility to prostate cancer was determined. The G-1394T variant of XRCC4 proved, after analysis of the frequencies of each variant in the prostate cancer and control groups, to be a significant single nucleotide polymorphism (SNP) in prostate carcinogenesis. Our data clearly indicate that the heterogeneous G of G-1394T increases the risk of suceptibility to prostate cancer (P=0.0106), while no difference in distribution of XRCC4 C-1622T (rs7727691), C-571T (rs2075686) or intron3 DIP (rs28360071) between the prostate cancer and control groups was found. In conclusion, our findings suggest that the G allele of XRCC4 G-1394T may be responsible for prostate carcinogenesis, and could be useful in the early detection and prevention of the disease.

This study was designed to determine the efficacy and safety of biweekly oxaliplatin in combination with infusional 5-fluouracil (5-FU) and leucovorin in patients with advanced gastric cancer (AGC). Fifty-five eligible patients with measurable or assessable M/AGC (median age 62 and 90% of patients presented with metastasis) received oxaliplatin (85 mg/m 2 ) intravenous infusion for 2 h, followed by intravenous infusion of 5-FU (3000 mg/m 2 ) and leucovorin (100 mg/m 2 ) for 46 h every 14 days until the patient's disease was either in progression, unacceptable toxicity, patient's withdrawal or the investigators' decision to discontinue treatment. Of the 55 enrolled patients, 48 were evaluable for response. Three patients (5.4%) showed complete remission and 20 patients (36.4%) achieved partial response. The overall response rate was 47.9%. Nineteen patients (34.5%) had stable disease and six patients (10.9%) showed progressive disease. The median time to progression was 5.6 months and the median overall survival was 10.8 months. Grade 3/4 toxicities included leucopenia (12.7%), thrombocytopenia (5.4%), diarrhoea (3.6%) and vomiting (9.1%). Peripheral neuropathy was noted in 61.8% of the patients (grade 1/2: 54.5%; grade 3: 7.3%). Our study confirmed that the combination of oxaliplatin and continuous infusion of 5-FU/leucoverin without bolus 5-FU as first-line chemotherapy is active for patients with AGC and relatively safe with lower haematological toxicity.