Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin's lymphoma: an in vitro and in vivo study.

Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin's lymphoma patients.

Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer.

Clinical implications of KRAS mutations in advanced non-small cell lung cancer remain unclear. We retrospectively evaluated the prognostic and predictive value of KRAS mutations in patients with advanced NSCLC. Among 484 patients with available results for both KRAS and EGFR mutations, 39 (8%) had KRAS and 182 (38%) EGFR mutations, with two cases having both mutations. The median overall survivals for patients with KRAS mutations, EGFR mutations, or both wild types were 7.7, 38.0, and 15.0 months, respectively (P<0.001). The KRAS mutation was an independent poor prognostic factor in the multivariate analysis (hazard ratio = 2.6, 95% CI: 1.8-3.7). Response rates and progression-free survival (PFS) for the pemetrexed-based regimen in the KRAS mutation group were 14% and 2.1 months, inferior to those (28% and 3.9 months) in the KRAS wild type group. KRAS mutation tended to be associated with inferior treatment outcomes after gemcitabine-based chemotherapy, while there was no difference regarding taxane-based regimen. Although the clinical outcomes to EGFR tyrosine kinase inhibitors (TKIs) seemed to be better in patients with KRAS wild type than those with KRAS mutations, there was no statistical difference in response rates and PFS according to KRAS mutation status when EGFR mutation status was considered. Two patients with both KRAS and EGFR mutations showed partial response to EGFR TKIs. Although G12D mutation appeared more frequently in never smokers, there was no difference in clinical outcomes according to KRAS genotypes. These results suggested KRAS mutations have an independent prognostic value but a limited predictive role for EGFR TKIs or cytotoxic chemotherapy in advanced NSCLC.

Gemcitabine alone and/or containing chemotherapy is efficient in refractory or relapsed NK/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKL) has a dismal prognosis. Although L-asparaginase has shown promising efficacy as a frontline therapy, currently there are no treatment options after progression to an L-asparaginase-containing regimen. We report the results of gemcitabine-containing therapy in patients with relapsed or refractory ENKL. We retrospectively reviewed 20 patients with refractory or relapsed ENKL who received a gemcitabine-containing regimen between 2005 and 2011. The overall response rate was 40% (8 of 20 patients) with a complete response (CR) rate of 20% (n = 4) and a partial response (PR) rate of 20% (n = 4). Four complete responders had a disease-free status for more than 7 months including two patients received autologous stem cell transplantation consolidation and L-aspraginase maintenance, respectively. The median progression-free survival of the 20 patients was 2.3 months; however, it was 7.3 months for eight responders (CR and PR). The median overall survival of the eight responders had not been reached at the time of analysis. Gemcitabine was effective in a subset of pretreated ENKL patients and can be considered as a salvage option.

A prospective multicentre phase II study of cisplatin and weekly docetaxel as first-line treatment for recurrent or metastatic nasopharyngeal cancer (KCSG HN07-01).

BACKGROUND: The purpose of this phase II study was to determine the efficacy and toxicity of cisplatin and weekly docetaxel combination chemotherapy as a first-line treatment in patients with recurrent or metastatic nasopharyngeal cancer. PATIENTS AND METHODS: Recurrent or metastatic nasopharyngeal cancer patients were enrolled and received a combination of weekly docetaxel (35 mg/m(2) on Day1 and Day8) and cisplatin (70 mg/m(2) D1) every 21 days, for up to a maximum of 6 cycles. The primary endpoint was objective response rate, and the secondary endpoints included toxicity of combination chemotherapy, progression-free survival, overall survival and 1-year survival rate. RESULTS: In total, 47 patients were enrolled and analysed, and 46 patients (97.9%) completed the planned protocol. In an intent-to-treat analysis, 6 patients (12.8%) achieved complete response (CR) and 27 patients (57.4%) showed partial response (PR), with an objective response rate of 70.2%. The median progression-free survival and overall survival were 9.6 months (95% C.I. 5.7-13.5 months) and 28.5 months (95% C.I. 16.9-40.1 months), respectively, and the 1-year survival rate was 89.9%. The common grade 3 adverse events were stomatitis (1.2%), neutropenia (0.8%), anaemia (0.8%), infection (0.8%) and diarrhoea (0.8%). Grade 4 adverse events were not observed in this study. CONCLUSIONS: The combination chemotherapy of cisplatin and weekly docetaxel is highly effective and shows favourable toxicity as a first-line chemotherapy in patients with recurrent or metastatic nasopharyngeal cancer.

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation.

PURPOSE: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined. METHODS: We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR. RESULTS: Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4 %). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n = 6) or erlotinib (n = 6). The most common mutation was exon 19 deletion (n = 7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75 %, respectively. The median PFS was 3.67 months (95 % CI: 1.34-5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53 months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83 months) who were treated with EGFR TKIs. CONCLUSIONS: The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.

The impact of baseline and interim PET/CT parameters on clinical outcome in patients with diffuse large B cell lymphoma.

Taking a step forward from the IPI, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification in patients with aggressive non-Hodgkin's lymphoma (NHL). Here, we analyzed the predictive value of various PET/CT parameters in patients with DLBCL. Particularly, we were interested in patients with an IPI score of 1, 2, or 3, whose prognosis are confusing. Between Jul 2008 and Feb 2010, a total of 100 patients (including 57 patients with an IPI score of 1-3) who were treated with R-CHOP for DLBCL, and had assessable PET/CT parameters were analyzed in this study. Absolute value of SUVmax, SUVsum(sum of SUVmax) and TLGsum(SUVmean x Volumemeta) from baseline and interim PET/CT, and ΔSUVsum, ΔSUVmax, and ΔTLGsum between baseline and interim PET/CT were selected as PET/CT parameters. The median number of R-CHOP cycles was 6, and interim PET/CT was performed after 2 or 3 cycles. None of the parameters which showed percentile change between initial and interim PET/CT were associated with prognosis. Instead, absolute value of SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were significantly relevant to PFS in all patients, and in patients with an IPI score of 1­3.

Implications of different CA 15-3 levels according to breast cancer subtype at initial diagnosis of recurrent or metastatic breast cancer.

BACKGROUND: CA 15-3 is derived from proteolytic shedding of the extracellular domain of mucin 1 (MUC1) glycoprotein. Luminal subtype breast cancer shows a higher expression in MUC1 genes, and a positive relationship between MUC1 expression and estrogen receptor (ER) expression has been reported. In this study, we attempted to determine the difference of CA 15-3 level according to the subtype of breast cancer. METHODS: From January 2000 to December 2009, a total of 707 patients who were diagnosed with metastatic or recurrent breast cancer at Samsung Medical Center were included in this study. Among these, 536 patients with available clinical data including pretreatment CA 15-3 and immunohistochemistry for ER, progesterone receptor (PgR) and hormone receptor 2 (HER2) were analyzed in this study. Patients were classified into 3 groups according to their receptor status: ER-positive (ER+) and/or PgR+ irrespective of HER2 (HR+), ER-/PgR-/HER2+ (HER2-enriched) and ER-/PgR-/HER2- (triple negative, TN). RESULTS: The supranormal values of CA 15-3 were frequently observed in HR+ breast cancer compared to other types (45.6% for HR+, 24.4% for HER2-enriched and 28.8% for TN; p < 0.001). The increase of marker levels differed significantly among the 3 groups (24 U/ml for HR+, 13 U/ml for HER2-enriched and 18 U/ml for TN; p < 0.001). CONCLUSIONS: The increase of both marker levels and the frequency of supranormal values of CA 15-3 were more frequently observed in HR+ breast cancer, which is positively associated with MUC1 expression. These results could potentially serve as a basis for expanding the clinical implications of CA 15-3 in the field of clinical trials for novel targeted therapies in breast cancer.