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Vitamin K plays a role in controlling cell growth. Anti-angiogenic effects of sorafenib lead to impairment of vitamin K uptake and induction of des-γ-carboxyprothrombin release by hepatocellular carcinoma (HCC) cells. We examined sorafenib and vitamin K individually and in combination regarding their ability to suppress migration and metastatic potential of HCC cells. HepG2 cells (HCC cell line) were treated with hepatocyte growth factor (HGF). E-Cadherin expression, phospho-MET (p-MET), and phospho-extracellular signal-regulated kinase (p-ERK) levels and cell migration were evaluated. HGF-stimulated HepG2 cells, which were treated with a combination of sorafenib and vitamin K, showed significantly increased expression of E-cadherin and impairment of migration ability compared to when treated with either agent alone. This combination therapy also induced marked inhibition of epithelial-mesenchymal transition phenotype; inhibition of HGF-stimulated cell proliferation, invasion and migration; and inhibition of HGF/c-MET signaling pathway. Levels of p-MET and p-ERK were also significantly reduced by this combination. Our experimental study demonstrated that sorafenib and vitamin K can function synergistically to inhibit the migration and proliferation of HCC cells. Combination therapy with sorafenib and vitamin K appears to be worthy of clinical trial with expectation of synergistic therapeutic effects., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Sorafenib increases survival of patients with advanced hepatocellular carcinoma (HCC) by inhibiting RAF kinase and receptor tyrosine kinase activity, but involvement of sorafenib in fibrosis and epithelial-mesenchymal transition (EMT) remains unclear. To elucidate effects of sorafenib on EMT progression and matrix metalloproteinase (MMP) activity, levels of E-cadherin, N-cadherin, and MMPs were evaluated in HepG2 human HCC cells induced by hepatocyte growth factor (HGF). Scratching cell migration assay, matrigel cell invasion assay, and immuno histochemistry were performed to examine effects of sorafenib on tumor metastasis and MMP expression. Sorafenib inhibited HGF-induced EMT and suppressed cell migration and invasion. Treatment with sorafenib significantly reduced HGF-enhanced expression of MMPs, suggesting that inhibition of MMP activity contributes to suppression of cellular motility and invasiveness of HepG2 cells. Neutralization of MMP activity by antibodies to MMP2/9, broad-spectrum MMP inhibitor or selective gelatinase inhibitor resulted in significant suppression of HGF-induced EMT and cell migration/invasion. Sorafenib treatment and MMP inactivation inhibited HGF-induced c-MET and MEK/ERK pathways. Sorafenib reduced MMP activity in this HGF-induced tumorigenic model of HCC. These findings provide in vitro evidence that sorafenib suppresses HGF-induced EMT and cell migration/invasion, as well as HGF-induced c-MET and MEK/ERK pathways., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Backgrounds/aims: Vitamin K may plays a role in controlling hepatocellular carcinoma (HCC) cell growth. In this study, we intended to present 5-year experience of 72 patients receiving oral vitamin K with or without sorafenib. Its end-point was to evaluate the safety of combination therapy using sorafenib and vitamin K., Methods: An interim analysis was performed as a single-arm cross-sectional study, including 72 HCC patients who underwent liver resection or transplantation and administered oral vitamin K2 alone (n=47) or with sorafenib (n=25)., Results: In all patients, administration of vitamin K2 analog 45 mg/day did not show any noticeable adverse side-effect during vitamin K therapy of 23.3±10.6 months, except for one patient who experienced skin rash at the third day of vitamin K therapy. In 25 patients receiving sorafenib and vitamin K for 6 months or longer, any noticeable adverse side-effect suspected of vitamin K origin was not identified yet. A small proportion of patients showed unexpectedly favorable anti-tumor effects after use of vitamin K with or without sorafenib., Conclusions: Because add-on of oral vitamin K did not increase the adverse side-effects of sorafenib, a combination therapy with these two agents appears to be worthy of further clinical trial with an expectation of synergistic therapeutic effects.

Background: Although benefits of surgical resection of residual gastrointestinal stromal tumors (GISTs) after imatinib therapy have been suggested, those benefits over imatinib alone have not been proven. We compared the clinical outcomes of surgical resection of residual lesions after imatinib treatment (S group) with imatinib treatment alone (NS group) in patients with recurrent or metastatic GISTs., Methods: A total of 134 patients (42 in the S group, 92 in the NS group) with recurrent or metastatic GIST who had stable disease for more than 6 months after responding to imatinib were included., Results: There were no statistically significant differences in the baseline characteristics of the S and NS groups except for age and number of peritoneal metastases. The median follow-up period was 58.9 months. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the S group compared with the NS group (median PFS: 87.7 vs. 42.8 months, p = 0.001; median OS: not reached vs. 88.8 months, p = 0.001). Multivariate analysis revealed that S group, female sex, KIT exon 11 mutations, and low initial tumor burden were associated with longer PFS, and S group and low initial tumor burden were associated with a longer OS. Even after applying inverse probability of treatment weighting adjustment, the S group demonstrated significantly better outcomes in terms of PFS (HR 2.326; 95 % confidence interval [CI] 1.034-5.236; p = 0.0412) and OS (HR 5.464; 95 % CI 1.460-20.408; p = 0.0117)., Conclusion: Surgical resection of residual lesions after disease control with imatinib is likely to be beneficial to patients with recurrent or metastatic GISTs.

Background: Gastric neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs) are aggressive tumours but the prognostic significance of a neuroendocrine component in <30% of the tumour remains unclear. Here, the implication of neuroendocrine components in gastric carcinomas was assessed according to proportion., Methods: Surgically resected primary gastric carcinomas with neuroendocrine morphology (NEM; n=88) from 2000 to 2012 at Asan Medical Center were retrospectively reviewed. Neuroendocrine differentiation (NED) was defined as immunopositivity for one of three neuroendocrine markers (synaptophysin, chromogranin or CD56) within the NEM area. To validate the prognostic significance of NED, these cases were compared with 650 randomly selected gastric adenocarcinomas without NEM from the same time period., Results: Gastric carcinomas with NEM were reclassified as NEC (⩾70% NED, n=47), MANEC (30-70% NED, n=10), gastric carcinoma with 10-30% NED (GCNED, n=8) and carcinoma with <10% NED (n=23). The survival rates of patients with ⩾10% NED were significantly poorer than those with <10% NED but no survival difference was observed between NEC and MANEC. In univariate analyses, older age (⩾60years), larger tumour size (⩾4cm), advanced stage group, ⩾10% NED and lymphovascular or perineural invasion were indicative of a poor prognosis. Stage group and ⩾10% NED remained as independent prognostic factors by multivariate analysis., Conclusions: A minor proportion (10-30%) of NED should not be overlooked in gastric carcinomas with NEM. NED should be carefully evaluated to predict patient outcomes and plan optimal additional therapies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Therapeutic approaches to marginal zone B-cell lymphoma (MZL) continue to evolve. Localized MZL responds favorably to local treatments, including surgery and/or local radiation therapy. However, MZL manifests as a disseminated disease in one-third of the cases at diagnosis. Moreover, relapses involving distant sites after local therapy have been reported previously. Therefore, the search for effective forms of systemic therapy is a critical issue. We conducted this multi-center, phase II trial to assess the efficacy and safety of gemcitabine single chemotherapy for patients with stage III/IV MZL., Methods: Patients received gemcitabine 1250 mg/m(2) on days 1 and 8 of each cycle. The treatment was repeated every 3 weeks and continued for 6 cycles until disease progression, withdrawal due to toxicity, or withdrawal of consent., Results: Between Sep. 2006 and Sep. 2008, a total of 16 patients were enrolled (with informed consent) into this trial from 6 institutes in Korea. Among these patients, 4 patients dropped out without evaluation. The median age of the 12 (9 males, 3 females) evaluated patients was 62 (range 25-73) years. Seven patients (58%) evidenced involvement of extranodal sites. All patients received previous treatment for MZL. The patients received a total of 69 cycles of gemcitabine chemotherapy (range 3-6 [median 6] cycles/person). There were 2 PR (17%; 95% Confidence Interval [CI], 0.0-41%), 9 SD (75%), and 1 PD (8%). There were 8/69 cycles (12%) of grade 3/4 neutropenia. Non-hematologic toxicities were mild and tolerable. There were 5 cycles (8%) of delayed chemotherapy (median 1 week) owing to neutropenia. Dose reduction was required in 12 cycles. However, no treatment-related death occurred in this study. The median TTP was 10.2 months (95% CI, 5.3-15.1). As the response rate in stage I did not justify progressing to stage II (> or = 8/15), this study had to be discontinued, in accordance with the established protocols., Conclusion: Gemcitabine as a single agent, in this dosage and at this schedule, evidenced minimal clinical activity in cases of advanced MZL.

Background: The objective of this study was to investigate the efficacy of belotecan, a new camptothecin analog, combined with cisplatin for the treatment of chemotherapy-naive patients with extensive-disease small cell lung cancer (ED SCLC)., Methods: Treatment consisted of belotecan 0.5 mg/m(2) daily on Days 1 through 4 and cisplatin 60 mg/m(2) on Day 1 of a 3-week cycle for up to 6 cycles unless there was disease progression, unacceptable toxicity, or patient refusal. Response assessment was done every 2 cycles using the Response Evaluation Criteria in Solid Tumors, and toxicity assessment was done every cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0., Results: Between September 2006 and March 2008, 30 patients participated in the study. Among them, 21 patients achieved a partial response, and the response rate was 70% (95% confidence interval [CI], 50.6%-85.3%); and, after a median follow-up of 20.2 months, the median progression-free survival was 6.9 months (95% CI, 6.3-7.5 months), and the overall survival was 19.2 months (95% CI, 13.3-25.2 months). Grade 3 and 4 adverse events included neutropenia in 23 patients, thrombocytopenia in 8 patients, febrile neutropenia in 9 patients, nausea in 3 patients, and pneumonia in 3 patients. There was 1 treatment-related death from pneumonia. However, nonhematologic toxicity generally was mild and manageable., Conclusions: The belotecan and cisplatin combination that was studied demonstrated promising response rates and survival outcomes with a manageable toxicity profile for chemotherapy-naive patients who had ED SCLC. The authors concluded that the combination warrants further randomized trials., (Copyright 2010 American Cancer Society.)

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1alpha expression. In our data, treatment of gefitinib suppressed induced HIF-1alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1alpha mRNA. The effect of gefitinib on down-regulation of HIF-1alpha was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1alpha expression. In addition, the suppression of HIF-1alpha using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.

Ionizing radiation including I(131) might produce chromosomal translocation, causing hematologic malignancy. The incidence of leukemia following radioactive iodine treatment for thyroid cancer has been reported to be approximately 0.1 to 2.0% in Western countries, whereas fewer cases have been reported in Korea. We hereby report four cases of secondary hematologic malignancy, who received iodine therapy for thyroid cancer after thyroidectomy: two cases of acute lymphoblastic leukemia with t(9;22)(q34;q11.2), a case of MDS with 5q deletion, and a case of MDS with normal karyotype. Three cases of hematologic malignancy have developed after cumulative dosage of less than 800 mCi. The treatment intervals in two cases were less than 12 months, and the other two cases had I(131) therapy only once. Assessment of causality using the Naranjo probability scale for adverse drug reactions showed that a 'possible' relationship existed between the use of I(131) and secondary hematologic malignancy in all of the four cases in this report.

Purpose: The therapeutic strategy for relapsed or refractory patients with diffuse large B-cell lymphoma (DLBL) remains challenging yet. Salvage therapy has been tried for these patients according to their clinical status. We studied ICD (irinotecan, cisplatin and dexamethasone) regimen as salvage chemotherapy for DLBL patients previously treated with RCHOP., Methods: Between February 2005 and May 2006, 15 patients were treated prospectively with ICD chemotherapy; irinotecan 65 mg/m(2)/day on days 1 and 8, cisplatin 30 mg/m(2)/day on days 1 and 8, and dexamethasone 40 mg/day on days 1-2 and 8-9. This schedule was planned to repeat every 3 weeks until disease progression, severe toxicity or stem cell transplantation., Results: Of the 14 patients evaluable for response, 3 patients achieved CR, 7 patients PR, with 1 SD and 3 PD; overall response rate 71% (10/14; 95% confidence interval, 47-95%). The median progression free survival (PFS) and event free survival (EFS) were 113 (range 21-493+) and 77 (range 21-324+) days, respectively. The median overall survival was 267 (range 31-493+) days. Grade 3/4 neutropenia and grade 3 neutropenic fever were observed in 67% (22/33) and 18% (6/33) of cycles, respectively. There were 20% of grade 3/4 nausea and diarrhea observed., Conclusions: The ICD regimen with current schedule showed high response rate for DLBL patients previously treated with RCHOP. But the high incidence of neutropenia led to delay of subsequent cycles causing dose intensity reduced, which seems to be related with short PFS and EFS.

This study evaluated the potential role of (18)F-fluoro-2-deoxy-glucose (FDG) uptake by primary tumors and N2 nodes on positron emission tomography (PET) in patients with stage IIIA N2 non-small-cell lung cancer (NSCLC). We retrospectively analyzed PET scans of 57 NSCLC patients who received surgical resection and proved pathologically to have stage IIIA N2 disease between January 2000 and April 2005. On each patient's PET scan, FDG uptake by the primary tumor and N2 nodes was evaluated using the maximum standardized uptake value (SUV). The SUV of the primary tumor (SUVt) and the highest value of the N2 nodes (SUVn) in each patient were treated as continuous variables for initial analysis. The SUVn and T stage (T1-2 vs. T3) were significant prognostic factors in univariate analysis (P=0.004 and 0.017, respectively), but the SUVt was not. Adjusted for the size of the N2 node (1cm), SUVt, and T stage (T1-2 vs. T3), the SUVn was associated with survival (P=0.019). Patients were divided into those with a low and high SUVn using a cutoff value. Controlling for the size of N2 nodes and T stages, patients with a low SUVn showed a tendency for prolonged survival (P=0.053). These results suggest that FDG uptake by the N2 node may predict survival of patients with stage IIIA N2 NSCLC.

Purpose: The present study evaluated baseline patient- or tumor-related prognostic factors in patients with advanced gastric adenocarcinoma., Patients and Methods: A total of 304 consecutive patients with newly diagnosed metastatic or recurrent gastric cancer treated with one or more cycles of cisplatin-based chemotherapy at the Korea Cancer Center Hospital were enrolled in the current study., Results: Among the original 304 patients, only 4 patients were alive at the time of this analysis. The median survival for all patients was 7.3 (95% CI, 6.3-8.2) months. Five independent prognostic factors were identified by a multivariate analysis: poor performance status (hazard ratio [HR], 1.46; 95% CI, 1.32-2.92), elevated total bilirubin (HR, 2.04; 95% CI, 1.73-2.35), presence of peritoneal metastasis (HR, 1.73; 95% CI, 1.57-1.90), presence of bone metastasis (HR, 3.11; 95% CI, 2.69-3.53), and more than 1 metastatic site (HR, 1.22; 95% CI, 1.06-1.38). A prognostic index was constructed that divided the patients into a good (n = 162), moderate (n = 82), or poor (n = 60) risk group. The 1-year survival rates for the good, moderate, and poor risk groups were 34.6, 20.7, and 1.7%, respectively, and the survival differences among the groups were highly significant (P < 0.0001)., Conclusion: Five prognostic factors were identified from patients receiving first-line cisplatin-based chemotherapy for advanced gastric cancer. A simple prognostic index was then developed that produced distinct survival rates among the different risk groups. Therefore, this prognostic model could help clinicians and patients in clinical decision-making and treatment tailoring based on the estimated prognosis.

We assessed the quality of life (QOL) at least one year after sequential chemoradiotherapy for the treatment of localized gastric diffuse large B-cell lymphoma (DLBCL). We used the EORTC Quality of Life Questionnaire for Stomach Cancer (EORTC QLQ-STO22). Among the 45 patients available at the one-year follow-up after radiation therapy, 40 patients completed the EORTC QLQ-STO22 questionnaire. Their median age was 54.5 (range, 20-70 years). Social functioning was most adversely affected among the respondents with a score of 59, whereas other functions and the global scales were preserved above a score of 70 by linearly transformed values. Fatigue, the financial impact and specific emotional problems such as "thinking about their illness" (STO-ANX) and "worry about weight loss or future health" (STO-BI) were persistently bothersome for some patients. Other stomach-related symptoms such as dysphagia, pain, or reflux were negligible at 1 year after treatment. Therefore, this organ-preserving combined approach was effective for the maintenance of the QOL and minimization of stomach abnormalities in patients with gastric lymphoma.

The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL. Two-hundred and five patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression-free survival (PFS), and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI. According to our multivariate analysis, nodal MZL, ECOG performance > or = 2, and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low-risk group, score 1 as an intermediate risk group, and score 2 as a high-risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI (P=0.0007) evidenced a more discriminated pattern than IPI (P=NS) or FLIPI (P=0.0044). MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI.

Intestinal marginal zone B-cell lymphoma of the MALT type (I-MZL) is a relatively uncommon form of lymphoma. Twenty-seven patients with histologically-confirmed I-MZL were analyzed. The patients initially presented with abdominal pain (62.9%), and diarrhea (22.2%). The most common involved site was the ileo-caecal area (40.7%). Musshoff's stage I(E), II(E)1, II(E)2, III(E) and IV were present in 44%, 15%, 11%, 7.4% and 22% respectively. Sixty-three percent were in the low-risk group according to the Follicular Lymphoma International Prognostic Index. Complete response and partial response were achieved in 82% and 4% patients. The estimated 5-year overall survival (OS) and progression-free survival (PFS) rates were 86% and 54%. Stage > or = II(E)2 was determined to be a poor prognostic factor for PFS and OS. I-MZL commonly manifests in an early-stage, low-risk state and tends to respond well to local and systemic treatment with favorable prognosis. I-MZL tends to be an indolent disease - characterized by prolonged survival with frequent relapses, similarly to other site MZLs.

The present study aimed to evaluate the clinicopathologic features and treatment outcomes of patients with primary thyroid lymphoma (PTL). The patients included 14 women and four men with a median age of 50 years (range 31 - 82 years). Thirteen cases involved the thyroid alone (stage IE) and five cases involved the regional lymph nodes (stage IIE). Histopathologic studies revealed marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) in 13 patients and diffuse large B-cell lymphoma (DLBCL) in three patients. The other two patients showed features of both MALT and DLBCL. Surgery and chemotherapy with or without radiotherapy were performed. All patients achieved complete remission. All 18 patients were alive with a median follow-up period of 55 months. The prognosis of patients with primary thyroid lymphoma appears to be favourable.

Objectives: We conducted a clinical risk factors analysis to define a prognostic model for high-grade primary gastric lymphoma (HG-PGL)., Methods and Results: The median event-free survival and overall survival of 214 HG-PGL patients were 54 and 104.5 months, respectively, after a median follow-up duration of 60 months. According to the prognostic factor analysis, survival, advanced age, male gender, higher LDH levels and the presence of ascites were identified as independent prognostic factors for HG-PGL. We identified four groups at different risk: group 1, no adverse effect; group 2, one factor; group 3, two factors; group 4, three or four factors. The new prognostic model showed excellent prognostic capacity to differentiate subgroups according to their risk stratification., Conclusions: The proposed new prognostic model for HG-PGL demonstrated a balanced distribution of patients into four groups with good prognostic capacity.

Burkitt lymphoma/leukemia (BL) is a highly aggressive non-Hodgkin's lymphoma (NHL) often presenting in extranodal sites or as an acute leukemia. Because of the shared molecular and genetic features, the World Health Organization classification of lymphoid diseases recognizes the lymphomatous and leukemic phases of BL as a single entity: a mature B cell neoplasm, subtype Burkitt lymphoma/Burkitt cell leukemia. Because BL frequently appears in the stomach, we investigated the clinical presentation and outcome of gastric BL. We discovered 21 patients with gastric BL through a survey of our NHL registry, and retrospectively analyzed the distinct features of BL, including the St Jude/Murphy staging, other extranodal involvement, morphology and immunophenotype, response to treatment, and clinical outcome. The patients' median age was 48 years (range, 7-75), and the male-to-female ratio was 2.5. Stage 1 was found in five patients, stage 2 in five patients, and stage 4 in 11 patients. The stomach body and antrum were most frequently involved. All 21 patients were treated with systemic intensive chemotherapy, producing a 71% (15/21) rate of complete response (CR) to chemotherapy. Both the 2-year disease-free and overall survival rates were 55%. All ten patients in BL stages 1 and 2 showed outstanding outcomes, and nine of the ten patients exhibited CR and long-term survival. These data show that a high proportion of patients with gastric BL have a localized disease that is limited to stage 1 and 2, and that these localized BLs have outstanding outcomes. These findings suggest that these BLs could represent a distinct subtype that might have a different biology, which needs to be defined.

A phase II study was conducted to assess the efficacy and tolerability of capecitabine in combination with irinotecan (CAPIRI) in advanced colorectal cancer. Forty-seven patients with previously untreated metastatic or unresectable colorectal adenocarcinoma received capecitabine 1000 mg/m2 twice daily on days 2-15 and intravenous irinotecan 100 mg/m2 on days 1 and 8, every 21 days. A total of 268 cycles of chemotherapy (median 6: range 1-11) were administered. According to an intent-to-treat analysis, the overall response rate was 49% (95% CI, 35-63%). Median time to progression and overall survival were 7.5 months (95% CI, 4.8-10.2) and 19.5 months (95% CI, 15.7-23.8), respectively. The most common grade 3/4 adverse events were diarrhea (24%) and neutropenia (11%). There were no treatment-related deaths. These results indicate that CAPIRI has comparable activity and tolerability to FOLFIRI as first-line treatment for advanced colorectal cancer.