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2.  Primary Follicular Lymphoma in a Male Breast: A Case Report 
Primary breast lymphoma (PBL) is a rare disease, particularly in males. Diffuse large B cell lymphoma is the most common PBL, while follicular lymphoma is less common. Furthermore, primary follicular lymphoma of a male breast is rarely reported. We report a male patient with primary follicular lymphoma of the breast and hepatocellular carcinoma (HCC). A 46-year-old man was diagnosed with liver cirrhosis secondary to chronic hepatitis B infection. Ten years later, he underwent segmentectomy of the liver due to HCC. Another 5 months later, he presented with a painless mass in the right chest wall. The mass was diagnosed as follicular lymphoma of the breast. The stage was IEA and he did not receive adjuvant therapy. Although only a few cases have been reported, lymphoma should be considered as a possible cause of breast mass, even in male patients.
doi:10.4143/crt.2014.46.1.104
PMCID: PMC3918521  PMID: 24520230
Breast; Follicular lymphoma; Hepatocellular carcinoma; Liver cirrhosis; Male
3.  A Randomized Double-Blind, Double-Dummy, Multicenter Trial of Azasetron versus Ondansetron to Evaluate Efficacy and Safety in the Prevention of Delayed Nausea and Vomiting Induced by Chemotherapy 
Purpose
This study was conducted to evaluate the efficacy and safety of azasetron compared to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting.
Materials and Methods
This study was a multi-center, prospective, randomized, double-dummy, double-blind and parallel-group trial involving 12 institutions in Korea between May 2005 and December 2005. A total of 265 patients with moderately and highly emetogenic chemotherapy were included and randomly assigned to either the azasetron or ondansetron group. All patients received azasetron (10 mg intravenously) and dexamethasone (20 mg intravenously) on day 1 and dexamethasone (4 mg orally every 12 hours) on days 2-4. The azasetron group received azasetron (10 mg orally) with placebo of ondansetron (orally every 12 hours), and the ondansetron group received ondansetron (8 mg orally every 12 hours) with placebo of azasetron (orally) on days 2-6.
Results
Over days 2-6, the effective ratio of complete response in the azasetron and ondansetron groups was 45% and 54.5%, respectively (95% confidence interval, -21.4 to 2.5%). Thus, the non-inferiority of azasetron compared with ondansetron in delayed chemotherapy-induced nausea and vomiting was not proven in the present study. All treatments were well tolerated and no unexpected drug-related adverse events were reported. The most common adverse events related to the treatment were constipation and hiccups, and there were no differences in the overall incidence of adverse events.
Conclusion
In the present study, azasetron showed inferiority in the control of delayed chemotherapy-induced nausea and vomiting compared with ondansetron whereas safety profiles were similar between the two groups.
doi:10.4143/crt.2014.46.1.19
PMCID: PMC3918522  PMID: 24520219
Vomiting; Vomiting/chemically induced; Vomiting/prevention and control; Antineoplastic agents; Serotonin antagonists; Azasetron; Ondansetron
4.  Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice 
Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.
doi:10.4143/crt.2014.46.1.2
PMCID: PMC3918523  PMID: 24520218
Curcumin; Nano-formulation; Biological availability; Metabolism; Anticancer
5.  Chemotherapy in Advanced Gastric Cancer Patients Associated with Disseminated Intravascular Coagulation 
Purpose
Little is known about the clinical features of advanced gastric cancer (AGC) combined with disseminated intravascular coagulation (DIC). The main objective of this study was to determine the clinical outcome of patients with AGC complicated by DIC.
Materials and Methods
We conducted a retrospective review of 68 AGC patients diagnosed with DIC at four tertiary medical centers between January 1995 and June 2010.
Results
Sixty eight patients were included. The median age was 55 years (range, 25 to 78 years). Nineteen patients received chemotherapy, whereas 49 patients received only best supportive care (BSC). The median overall survival (OS) of the 68 patients was 16 days (95% confidence interval [CI], 11 to 21 days). Significantly prolonged OS was observed in the chemotherapy group, with a median survival of 61 days compared to 9 days in the BSC group (p<0.001, log-rank test). Age and previous chemotherapy were another significant factors that were associated with OS in univariate analysis. In multivariate analysis, age (≥65 vs. <65; hazard ratio [HR], 0.38; 95% CI, 0.18 to 0.78; p<0.001), chemotherapy (BSC vs. chemotherapy; HR 0.31; 95% CI, 0.15 to 0.63; p<0.001), and previous chemotherapy (yes or no; HR, 0.49; 95% CI, 0.25 to 0.98; p<0.045) were consistently independent prognostic factors that impacted OS.
Conclusion
Our study showed that patients with AGC complicated by DIC had very poor OS, and suggested that chemotherapy might improve OS of these patients.
doi:10.4143/crt.2014.46.1.27
PMCID: PMC3918524  PMID: 24520220
Stomach neoplasms; Disseminated intravascular coagulation; Drug therapy
6.  The Role of Radiotherapy in the Treatment of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma 
Purpose
To assess radiotherapy for patients with early stage gastric mucosa-associated lymphoid tissue (MALT) lymphoma with respect to survival, treatment response, and complications.
Materials and Methods
Enrolled into this study were 48 patients diagnosed with gastric MALT lymphoma from January 2000 to September 2012. Forty-one patients had low grade and seven had mixed component with high grade. Helicobacter pylori eradication was performed in 33 patients. Thirty-four patients received radiotherapy alone. Ten patients received chemotherapy before radiotherapy, and three patients underwent surgery followed by chemotherapy and radiotherapy. One patient received surgery followed by radiotherapy. All patients received radiotherapy of median dose of 30.6 Gy.
Results
The duration of follow-up ranged from 6 to 158 months (median, 48 months). Five-year overall survival and cause-specific survival rates were 90.3% and 100%. All patients treated with radiotherapy alone achieved pathologic complete remission (pCR) in 31 of the low-grade and in three of the mixed-grade patients. All patients treated with chemotherapy and/or surgery prior to radiotherapy achieved pCR except one patient who received chemotherapy before radiotherapy. During the follow-up period, three patients developed diffuse large B-cell lymphoma in the stomach, and one developed gastric adenocarcinoma after radiotherapy. No grade 3 or higher acute or late complications developed. One patient, who initially exhibited gastroptosis, developed mild atrophy of left kidney.
Conclusion
These findings indicate that a modest dose of radiotherapy alone can achieve a high cure rate for low-grade and even mixed-grade gastric MALT lymphoma without serious toxicity. Patients should be carefully observed after radiotherapy to screen for secondary malignancies.
doi:10.4143/crt.2014.46.1.33
PMCID: PMC3918525  PMID: 24520221
Stomach; Marginal zone B-cell lymphoma; Radiotherapy
7.  A Distribution Weighted Prognostic Scoring Model for Node Status in Advanced Rectal Cancer 
Purpose
There are various lymph node-based staging systems. Nevertheless, there is debate over the use of parameters such as the number of involved lymph nodes and the lymph node ratio. As a possible option, the distribution of metastatic lymph nodes may have a prognostic significance in rectal cancer. This study is designed to evaluate the impact of distribution-weighted nodal staging on oncologic outcome in rectal cancer.
Materials and Methods
From a prospectively maintained colorectal cancer database of our institution, a total of 435 patients who underwent a curative low anterior resection for mid and upper rectal cancer between 1995 and 2004 were enrolled. Patients were divided into 3 groups according to the location of apical metastatic nodes. A location-weighted prognostic score was calculated by a scoring model using a logistic regression test for location based-statistical weight to number of lymph nodes. All cases were categorized in quartiles from lymph node I to lymph node IV using this protocol.
Results
The location of lymph node metastasis was an independent factor that was associated with a poor prognostic outcome (p<0.001). Based on this result, the location-weighted-nodal prognostic scoring model did not show lesser significant results (p<0.0001) in both overall survival and cancer-free survival analyses.
Conclusion
The location of apical nodes among the metastatic nodes does not have a lesser significant impact on oncologic result in patients with advanced rectal cancer. A location-weighted prognostic scoring model, which considered the numbers of involved lymph nodes as the rate of significance according to the location, may more precisely predict the survival outcome in patients with lymph node metastasis.
doi:10.4143/crt.2014.46.1.41
PMCID: PMC3918526  PMID: 24520222
Rectal neoplasms; Prognostic scoring model; Lymph nodes; Neoplasm staging
8.  Dose KRAS Mutation Status Affect on the Effect of VEGF Therapy in Metastatic Colon Cancer Patients? 
Purpose
Mutations affecting the KRAS gene are an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, the role of KRAS mutation as a biomarker for anti-vascular endothelial growth factor (VEGF) remains controversial.
Materials and Methods
We analyzed retrospective data from 32 CRC patients who were available for KRAS mutation status and received cytotoxic chemotherapy plus bevacizumab as a first-line therapy. Six of 32 patients received anti-EGFR therapies. We used KRAS mutation status as a predictive or prognostic factor in CRC patients receiving bevacizumab.
Results
We observed mutations in KRAS in 59.4% of patients. Bevacizumab was used in combination with oxaliplatin based regimens. There was no significant difference for progression free survival (PFS) and overall survival (OS) in patients with oxaliplatin based cytotoxic chemotherapy plus bevacizumab according to the status of KRAS mutation. After first-line therapy, 28 patients (87.5%) received second-line therapy. In univariate analysis, KRAS mutations did not have a major prognostic value for PFS (hazard ratio, 1.007; 95% confidence interval [CI], 0.469 to 2.162; p>0.05) or OS (hazard ratio, 0.548; 95% CI, 0.226 to 1.328; p>0.05). In addition, anti-EGFR therapies did not affect the impact on OS.
Conclusion
KRAS mutation is neither a predictive for bevacizumab nor a prognostic for OS in CRC patients receiving anti-VEGF therapy.
doi:10.4143/crt.2014.46.1.48
PMCID: PMC3918527  PMID: 24520223
KRAS; Vascular endothelial growth factor; Colonic neoplasms
9.  Combination of TRAP1 and ERCC1 Expression Predicts Clinical Outcomes in Metastatic Colorectal Cancer Treated with Oxaliplatin/5-Fluorouracil 
Purpose
The novel heat shock protein tumor necrosis factor receptor-associated protein 1 (TRAP1) is associated with multidrug resistance in colorectal cancer (CRC) cells in vitro. Excision repair cross-complementation group 1 (ERCC1) expression levels in tumor tissues also predict clinical outcomes in metastatic CRC patients receiving combination oxaliplatin and 5-fluorouracil treatment. We investigated whether TRAP1 and ERCC1 protein expression by immunohistochemistry predict clinical outcomes in CRC patients.
Materials and Methods
The study population consisted of 56 patients with metastatic CRC who received first-line oxaliplatin/5-fluorouracil therapy. Clinical response and overall survival (OS) by levels of the markers TRAP1 and ERCC1 were evaluated.
Results
The rates of TRAP1 and ERCC1 expression were 21% and 52%, respectively. Patients negative for ERCC1 expression showed a tendency to respond to chemotherapy (p=0.066). Median OS was significantly longer in patients negative for TRAP1 than those positive for TRAP1 (p=0.023). Patients negative for ERCC1 expression also had a better OS than those positive for ERCC1 (p=0.021). The median OS was 30.9 months for patients negative for TRAP1 and ERCC1 compared to 13.2 months for those positive for TRAP1 and/or positive for ERCC1 expression (p=0.006). The combination of TRAP1 and ERCC1 expression was significantly associated with the response to chemotherapy (p=0.046) and independently predicted median OS in multivariate analysis (hazard ratio, 2.98; 95% confidence interval, 1.18 to 7.49).
Conclusion
The present study demonstrates that the combination of TRAP1 and ERCC1 expression predicts the survival of metastatic CRC patients who were treated with oxaliplatin/5-fluorouracil.
doi:10.4143/crt.2014.46.1.55
PMCID: PMC3918528  PMID: 24520224
Colorectal neoplasms; ERCC1; Fluorouracil; Oxaliplatin; TRAP1
10.  Clinical Implications of Systemic Inflammatory Response Markers as Independent Prognostic Factors in Colorectal Cancer Patients 
Purpose
Cancer-related inflammation affects many aspects of malignancy. We confirm the effects of early postoperative systemic inflammation on cancer prognosis.
Materials and Methods
Six hundred consecutive patients underwent surgery for colorectal cancer from 2006 to 2009. Measurements of white blood cells, neutrophils, lymphocytes, monocytes, and platelet counts were performed preoperatively, daily until the fourth postoperative day, and subsequently every two days. Patients were divided into three groups based on the days spent on the leukocyte count to drop below 10,000/mm3 after surgery.
Results
Preoperative white blood cell (WBC) counts correlated with stage of disease. In univariate survival analyses, tumor, node, metastasis (TNM) stage, and monocyte count were associated with cancer-free survival. In addition, cancer-free survival outcomes were worse in patients who required more than four days for the normalization of WBC count. A TNM stage greater than II and the neutrophil lymphocyte ratio were associated with the duration of overall survival. In a multivariate analysis of these significant variables, TNM stage, an interval longer than four days for normalization of WBC counts and monocyte count independently associated with cancer-free survival.
Conclusion
Postoperative early inflammatory phase and preoperative monocyte count correlate with poor colon cancer prognosis. We can conclude that preoperative and postoperative inflammatory response and period unfavorably affect the metastatic microenvironment.
doi:10.4143/crt.2014.46.1.65
PMCID: PMC3918529  PMID: 24520225
Colorectal neoplasms; Inflammation; Perioperative period; Prognosis
11.  High-Dose-Rate Brachytherapy for the Treatment of Vaginal Intraepithelial Neoplasia 
Purpose
Vaginal intraepithelial neoplasia (VAIN), a rare premalignant condition, is difficult to eradicate. We assess the effectiveness of high-dose rate intracavitary brachytherapy (HDR-ICR) in patients with VAIN or carcinoma in situ (CIS) of the vagina after hysterectomy.
Materials and Methods
We reviewed 34 patients treated for posthysterectomy VAIN or CIS of the vagina by brachytherapy as the sole treatment. All patients underwent a coloposcopic-directed punch biopsy or had abnormal cytology, at least 3 consecutive times. All patients were treated with a vaginal cylinder applicator. The total radiation dose was mainly 40 Gy in 8 fractions during the periods of 4 weeks at a prescription point of the median 0.2 cm (range, 0 to 0.5 cm) depth from the surface of the vaginal mucosa.
Results
Acute toxicity was minimal. Seven patients had grade 1/2 acute urinary and rectal complications. There were 15 cases of late toxicity, predominantly vaginal mucosal reaction in 12 patients. Of these patients, two patients suffered from grade 3 vaginal stricture and dyspareunia continuously. After a median follow-up time of 48 months (range, 4 to 122 months), there were 2 recurrences and 2 persistent diseases, in which a second-line therapy was needed. The success rate was 88.2%. The average prescription point in failure patients was 1.1 mm from the surface of the vagina compared to an average of 2.6 mm in non-recurrent patients (p=0.097).
Conclusion
HDR-ICR is an effective treatment method in VAIN patients. In spite of high cure rates, we should consider issues regarding vaginal toxicity and radiation techniques to reduce the occurrence of failure and toxicity.
doi:10.4143/crt.2014.46.1.74
PMCID: PMC3918530  PMID: 24520226
Vaginal neoplasms; Carcinoma in situ; Radiotherapy; Brachytherapy
12.  Synergistic Effect of COX-2 Inhibitor on Paclitaxel-Induced Apoptosis in the Human Ovarian Cancer Cell Line OVCAR-3 
Purpose
Celecoxib, a highly selective cyclooxygenase-2 inhibitor, regulates apoptosis of several types of human cancer cells. The purpose of this study was to investigate whether celecoxib in combination with paclitaxel modulates apoptosis of ovarian cancer cells, and to identify the signal pathway by which celecoxib mediates apoptosis.
Materials and Methods
OVCAR-3 cells were exposed to paclitaxel (20 µM) in the absence or presence of celecoxib (10 µM). Cell viability was evaluated using a Cell Counting Kit-8 assay. Apoptosis was evaluated using Annexin-V/7-aminoactinomycin D staining and a cellular DNA fragmentation enzyme-linked immunosorbent assay. Caspase-3, -9, and cleavage of poly ADP-ribose polymerase (PARP) were determined by western blotting. Expression of nuclear factor-κB (NF-κB) and vascular endothelial growth factor (VEGF) and Akt activation were assessed using reverse transcriptase-polymerase chain reaction and western blotting.
Results
Celecoxib enhanced paclitaxel-induced growth inhibition of OVCAR-3 cells. Celecoxib significantly increased paclitaxel-induced apoptosis of OVCAR-3 cells. Pretreatment with celecoxib also increased activation of caspase-9, -3 and cleaved PARP following paclitaxel-treatment. Exposure of OVCAR-3 cells to celecoxib in combination with paclitaxel resulted in downregulation of NF-κB activation and VEGF expression. Furthermore, combining celecoxib and paclitaxel inhibited phosphorylation of Akt.
Conclusion
OVCAR-3 cells were sensitized to paclitaxel-induced apoptosis by celecoxib through downregulation of NF-κB and Akt activation, suggesting that celecoxib may work synergistically with paclitaxel to inhibit different targets and ultimately produce anticancer effects. Combining celecoxib with paclitaxel may prove beneficial in the clinical treatment of ovarian cancer.
doi:10.4143/crt.2014.46.1.81
PMCID: PMC3918531  PMID: 24520227
Ovarian neoplasms; Celecoxib; Paclitaxel; Apoptosis; NF-kappa B; Akt
13.  Adenoid Cystic Carcinoma of the Breast: A Case Series of Six Patients and Literature Review 
Adenoid cystic carcinoma (ACC) of the breast is a very rare and indolent tumor with a favorable prognosis, despite its triple-negative status. Due to its rarity, there has been no consensus regarding treatments, and treatment guidelines have not been established. Here, we report on six patients with ACC of the breast. All of the patients initially presented with localized disease and no axillary lymph node metastases. Although some of our patients developed local recurrence or distant metastases, all patients had a favorable clinical course, and to date, none of the patients has died from complications of her disease. Here, we described the clinicopathologic features of ACC of the breast and review the current literature.
doi:10.4143/crt.2014.46.1.93
PMCID: PMC3918532  PMID: 24520228
Adenoid cystic carcinoma; Breast neoplasms; Triple-negative breast carcinoma
14.  Pseudocirrhosis of Breast Cancer Metastases to the Liver Treated by Chemotherapy 
Pseudocirrhosis refers to a condition that shows changes in hepatic contour that mimic cirrhosis radiographically in the absence of the typical histopathological findings of cirrhosis. This condition has been observed in patients with cancer metastatic to the liver, both in those who have undergone prior systemic chemotherapy and those who have not. Pseudocirrhosis may cause difficulty in interpretation of the response to chemotherapy and hepatic decompression and complication of portal hypertension have a negative effect on the prognosis. We report on a case of breast cancer with liver metastases that showed cirrhotic changes during disease progression. Progression of liver metastases was confirmed by F18 fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT). We also performed ultrasound-guided liver biopsy and confirmed tumor infiltration with severe desmoplastic fibrosis. This case suggests the pathogenesis of pseudocirrhosis through histopathological findings and the role of PET-CT in evaluation of the response to chemotherapy in patients with pseudocirrhosis.
doi:10.4143/crt.2014.46.1.98
PMCID: PMC3918533  PMID: 24520229
Pseudocirrhosis; Breast neoplasms; Drug therapy
15.  Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges 
Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.
doi:10.4143/crt.2013.45.4.251
PMCID: PMC3893322  PMID: 24453997
Neoplasms; Arginine; Argininosuccinate synthetase; Argininosuccinate lyase; ADI-PEG20; Arginase; Drug combinations
16.  Effect of Dose Escalation with Single Opioid, Fentanyl Matrix in Patients Not Controlling Cancer Pain: A Multicenter, Prospective, Observational Study in Korea 
Purpose
End-of-dose failure (EOD) is a clinically common observation and many cancer patients increase the frequency of opioid administration. Fentanyl matrix use is known to be effective in patients with chronic cancer pain. To measure the effectiveness of increase in a single dose of fentanyl matrix in patients whose pain was not controlled sufficiently, we perform this study.
Materials and Methods
A multi-center, open-label, prospective, observational study was conducted in 30 hospitals in Korea, between August and December 2008.
Results
A total of 452 patients were enrolled; 404 patients completed the study. The mean pain intensity decreased from 5.27 at the first visit to 3.37 at the end of the trial. There was a significant difference in pain intensity (p < 0.001) between the first and last visits. The percentage of pain intensity difference was 30.1%. The prevalence of EOD at the first visit was 73% from the 452 enrolled patients. After the use of fentanyl patch, EOD decreased from 73% to 56%. Pain intensity of patients experiencing EOD was 5.64 at the baseline compared to 4.27 in patients without EOD. On final visit, pain intensity in patients with and without EOD was 4.02 and 2.54, respectively. The observed adverse events were mainly nausea, asthenia, constipation and diarrhea.
Conclusion
This study demonstrated that increasing dose of fentanyl patch decreased pain intensity and decreased the rate of patients experiencing EOD. Thus, fentanyl patch may be an effective modality in cancer patients whose pain was previously not controlled sufficiently; the side effects were as could be expected with an opioid.
doi:10.4143/crt.2013.45.4.263
PMCID: PMC3893323  PMID: 24453998
Fentanyl; Neoplasms; Pain
17.  Trends in the Aggressiveness of End-of-Life Care for Advanced Stomach Cancer Patients 
Purpose
It is important to balance the appropriateness of active cancer treatments and end-of-life care to improve the quality of life for terminally ill cancer patients. This study describes the treatment patterns and end-of-life care in terminal gastric cancer patients.
Materials and Methods
We retrospectively analyzed the records of 137 patients with advanced gastric cancer receiving chemotherapy and dying between June 1, 2006 and May 31, 2011. We recorded interval between last chemotherapy dose and death; frequency of emergency room visits or admission to the intensive care unit in the last month before death; rate of hospice referral and agreement with written do-not-resuscitate orders; and change in laboratory values in the last three months before death.
Results
During the last six months of life, 130 patients (94.9%) received palliative chemotherapy; 86 (62.7%) during the final two months; 41 (29.9%) during the final month. During the final month, 53 patients (38.7%) visited an emergency room more than once; 21 (15.3%) were admitted to the intensive care unit. Hospice referral occurred in 54% (74 patients) of the patients; 93.4% (128 patients) gave written do-not-resuscitate orders. Platelets, aspartate aminotransferase and creatinine changed significantly two weeks before death; total bilirubin, one month before; and C-reactive protein, between four and two weeks before death.
Conclusion
Our results demonstrated that a significant proportion of gastric cancer patients received palliative chemotherapy to the end of life and the patients who stopped the chemotherapy at least one month before death had a lower rate of intensive care unit admission and longer overall survival than those who sustained aggressive chemotherapy until the last months of their lives.
doi:10.4143/crt.2013.45.4.270
PMCID: PMC3893324  PMID: 24453999
End-of-life care; Aggressiveness; Palliative chemotherapy; Stomach neoplasms
18.  Clinical Prognostic Factors for Locally Advanced Esophageal Squamous Carcinoma Treated after Definitive Chemoradiotherapy 
Purpose
Locally advanced esophageal cancers are generally treated with neoadjuvant chemoradiotherapy, followed by surgery in operable candidates. However, even if the patients were diagnosed as operable disease, surgery could not be performed on patients with poor condition or other comorbidity. In this case, definitive chemoradiotherapy (dCRT) is the other option for localized esophageal cancer. Therefore, the purpose of this study was to evaluate the efficacy and clinical prognostic factors for dCRT in locally advanced esophageal cancer.
Materials and Methods
We conducted a review of patients who received dCRT for locally advanced squamous esophageal cancer from 2004 to 2010, focusing on stages III and IVa. All patients received at least two cycles of platinum-based chemotherapy during radiation, and all tumor burdens were included in the radiation field. The treatment results were analyzed for patterns of failure and prognostic factors associated with survival.
Results
In total, 63 patients were enrolled in this study. The overall response rate was 84.1%. Relief from dysphagia after dCRT was achieved in 48 patients. The most frequent failure was local recurrence. The median overall survival (OS) was 23.0 months, and the 2-year survival rate was 45.4%. Similar results were observed for elderly study patients. Significant prognostic factors for OS were duration of smoking, high grade of dysphagia (score of 3 or 4), and shorter duration of progression-free and dysphagia-free survival. Maintenance chemotherapy after dCRT did not influence OS. However, "good risk" patients receiving maintenance chemotherapy showed better OS than those who did not receive maintenance chemotherapy (30.4 months vs. 12.0 months, p=0.002).
Conclusion
dCRT has a major role in improving survival and palliation of dysphagia in inoperable advanced esophageal cancer, even in elderly patients. Maintenance chemotherapy after dCRT may be effective in prolonging survival in "good risk" patients.
doi:10.4143/crt.2013.45.4.276
PMCID: PMC3893325  PMID: 24454000
Esophageal squamous cell carcinoma; Chemoradiotherapy; Prognosis
19.  Nomogram to Predict Treatment Outcome of Fluoropyrimidine/Platinum-Based Chemotherapy in Metastatic Esophageal Squamous Cell Carcinoma 
Purpose
The degree of benefit from palliative chemotherapy differs widely among patients with metastatic esophageal squamous cell carcinoma (MESCC). The purpose of this study was to develop and validate a prognostic nomogram to predict survival and aid physicians and patients in the decision-making process regarding treatment options.
Materials and Methods
Clinicopathologic variables and treatment outcomes of 239 patients who were diagnosed with MESCC and received either fluorouracil/cisplatin (FP) or capecitabine/cisplatin (XP) as first-line chemotherapy were reviewed. A nomogram was developed as a prognostic scoring system incorporating significant clinical and laboratory variables based on a multivariate Cox proportional hazards regression model. An independent series of 61 MESCC patients treated with FP served as an independent data set for nomogram validation.
Results
No difference in response rate was observed between the FP group (44.8%) and the XP group (54.2%). Similarly, no significant differences in median progression-free survival and median overall survival were observed between regimen groups. Multivariate analysis showed that poor performance status (Eastern Cooperative Oncology Group [ECOG] status≥2), weight loss (10% of the weight loss for 3 months), low albumin level (≤3.5 g/dL), and absence of previous esophagectomy at the time of chemotherapy were significantly associated with low OS in both groups (p<0.05). Based on these findings, patients were classified into favorable (score, 0 to 90), intermediate (91-134), and poor (>135) prognostic groups. The median survival for those with a favorable ECOG was 13.8 months (95% confidence interval [CI], 10.8 to 18.6 months), for intermediate 11.2 months (95% CI, 8.7 to 11.9 months), and for poor, 7.0 months (95% CI, 3.6 to 10.0 months). External validation of the nomogram in a different patient cohort yielded significantly similar findings.
Conclusion
The nomogram described here predicts survival in MESCC patients and could serve as a guide for the use of FP/XP chemotherapy in MESCC patients.
doi:10.4143/crt.2013.45.4.285
PMCID: PMC3893326  PMID: 24454001
Esophageal squamous cell carcinoma; Prognostic factor; Nomograms
20.  Predictive Factors for Radiation Pneumonitis in Lung Cancer Treated with Helical Tomotherapy 
Purpose
Predictive factors for radiation pneumonitis (RP) after helical tomotherapy (HT) may differ from those after linac-based radiotherapy. In this study, we identified predictive factors for RP in patients with lung cancer treated with HT.
Materials and Methods
We retrospectively analyzed clinical, treatment-related and dosimetric factors from 31 patients with lung cancer treated with HT. RP was graded according to Common Terminology Criteria for Adverse Events version 4.0 and grade ≥2 RP was defined as a RP event. We used Kaplan-Meier methods to compute the actuarial incidence of RP. For univariate and multivariate analysis, the log-rank test and the Cox proportional regression hazard model were used. We generated receiver-operating characteristics (ROC) curves to define the cutoff values for significant parameters.
Results
The median follow-up duration was 6.6 months (range, 1.6 to 38.5 months). The 2-, 4-, and 6-month actuarial RP event rates were 13.2%, 58.5%, and 67.0%, respectively. There was no grade 4 or more RP. Ipsilateral V5, V10, V15, and contralateral V5 were related with RP event on univariate analysis. By multivariate analysis, ipsilateral V10 was factor most strongly associated with RP event. On the ROC curve, the cutoff values of ipsilateral V5, V10, V15, and contralateral V5 were 67.5%, 58.5%, 50.0%, and 55.5%, respectively.
Conclusion
In our study, ipsilateral V5, V10, V15, and contralateral V5 were significant predictive factors for RP after HT.
doi:10.4143/crt.2013.45.4.295
PMCID: PMC3893327  PMID: 24454002
Lung neoplasms; Radiation pneumonitis; Intensity-modulated radiotherapy; Risk factor
21.  Immunogenicity of Influenza Vaccine in Colorectal Cancer Patients 
Purpose
Although influenza is regarded as a major cause of morbidity and mortality in immunocompromised patients, vaccine coverage remains poor. We evaluated the immunogenicity of influenza vaccines in colorectal cancer patients.
Materials and Methods
In this study, 40 colorectal cancer patients who received an influenza vaccine at the Korea Cancer Center Hospital during the 2009-2010 and 2010-2011 influenza seasons were analyzed. The blood samples were collected at prevaccination and 30 days post vaccination, and antibody titers were measured using the hemagglutination-inhibition tests.
Results
In the 2009-2011 season, the seroprotection rate for H1N1 (94.7%) was significantly higher than that for H3N2 (42.1%) and B (47.3%). The seroconversion rate was 52.6%, 26.3%, and 36.8% for H1N1, H3N2, and B, respectively. Fold increase of geometric mean titer (MFI) was 3.86, 1.49, and 3.33 for H1N1, H3N2, and B, respectively. In the 2010-2011 season, the seroprotection rate for H1N1 (57.1%) was significantly higher than that for H3N2 (52.4%) and B (38.1%). The seroconversion rate was 52.4%, 47.6% and 33.3% for H1N1, H3N2, and B, respectively. MFI was 12.29, 3.62 and 4.27 for H1N1, H3N2, and B, respectively.
Conclusion
Our study cohort showed an acceptable immune response to an influenza vaccine without significant adverse effects, supporting the recommendation for annual influenza vaccination in colorectal cancer patients.
doi:10.4143/crt.2013.45.4.303
PMCID: PMC3893328  PMID: 24454003
Colorectal neoplasms; Human influenza; Influenza vaccines; Hemagglutination inhibition tests
22.  Effects of Polymorphisms of Innate Immunity Genes and Environmental Factors on the Risk of Noncardia Gastric Cancer 
Purpose
Increasing evidence suggests that polymorphisms in innate immunity genes are associated with Helicobacter pylori-induced inflammation and may influence susceptibility in developing noncardia gastric cancer. Therefore, we investigate the effect of polymorphisms of innate immunity genes and interactions with environmental factors in the Korean population.
Materials and Methods
We genotyped four polymorphisms of TLR2 (rs1898830), TLR4 (rs10983755 and rs10759932), and CD14 (rs2569190) in a case-control study of 487 noncardia gastric cancer patients and 487 sex- and age-matched healthy controls. Polytomous logistic regression models were used to detect the effects of genetic polymorphisms and environmental factors, which were stratified by the histological type of gastric cancer.
Results
TLR4 rs10983755 A carriers were found to have higher risk of intestinal-type noncarida gastric cancer than G homozygotes (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.01 to 1.97), but other genetic variants showed no association with the risk of noncardia gastric cancer. Among H. pylori-positive participants, smokers carrying TLR4 rs10983755 A had a higher risk of intestinal-type gastric cancer than nonsmoking TLR4 rs10983755 G homozygotes (OR, 4.28; 95% CI, 2.12 to 8.64). In addition, compared with tap water, other drinking water sources during childhood were found to be associated with the elevated risk of intestinal-type gastric cancer, and these associations were slightly stronger among TLR4 rs10983755 A carriers.
Conclusion
The genetic polymorphisms of innate immunity genes are associated with the development of intestinal-type noncardia gastric cancer and these associations may differ in accordance to an exposure to certain environmental factors.
doi:10.4143/crt.2013.45.4.313
PMCID: PMC3893329  PMID: 24454004
Noncardia gastric cancer; Innate immunity; Genetic polymorphisms; Smoking; Drinking water
23.  Clinical Implications of VEGF, TGF-β1, and IL-1β in Patients with Advanced Non-small Cell Lung Cancer 
Purpose
Vascular endothelial growth factor (VEGF)-A, VEGF165b, interleukin (IL)-1β, and transforming growth factor (TGF)-β1 are known to influence tumor angiogenesis. Clinical implications of these cytokines need to be elucidated.
Materials and Methods
Using clinical data and baseline serum samples of 140 consecutive patients with advanced non-small cell lung cancer who received platinum-based combination chemotherapy, we investigated the association among serum cytokine levels, treatment outcomes, as well as leukocyte and platelet counts.
Results
The median age of patients was 64 years (range, 26 to 86 years). The male to female ratio was 104:36. High TGF-β1 and IL-1β levels were associated with shorter progression-free survival, and high VEGF-A and IL-1β levels were associated with shorter overall survival in the univariate analysis. VEGF165b was not related to the treatment outcomes. Leukocytosis and thrombocytosis were associated with shorter overall survival. The multivariate analysis demonstrated that VEGF-A, IL-1β, and leukocytosis were significant prognostic factors (p=0.0497, p=0.047, and p<0.001, respectively). Leukocytosis was not associated with recent pneumonia (p=0.937) and correlated with VEGF-A (p<0.001) and TGF-β1 (p=0.020) levels.
Conclusion
Serum VEGF-A, TGF-1β, and IL-1β levels, in addition to leukocyte and platelet counts, are shown to be associated with clinical outcomes. Leukocyte and platelet counts are correlated with serum VEGF-A and TGF-β1 levels.
doi:10.4143/crt.2013.45.4.325
PMCID: PMC3893330  PMID: 24454005
Vascular endothelial growth factor; Interleukin-1beta; Transforming growth factor beta1; Leukocytes; Blood platelets; Non-small cell lung carcinoma
24.  Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041 
Purpose
This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation.
Materials and Methods
The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution.
Results
TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naïve cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest.
Conclusion
TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.
doi:10.4143/crt.2013.45.4.334
PMCID: PMC3893331  PMID: 24454006
Histone deacetylase inhibitors; Radiation-sensitizing agents; Preclinical drug evaluation
25.  Tumor Lysis Syndrome in a Solid Tumor: A Case Report of a Patient with Invasive Thymoma 
Tumor lysis syndrome (TLS) has rarely been observed in solid tumors. We report on a case of a patient with advanced invasive thymoma who developed tumor lysis syndrome after chemotherapy. The potential complications of TLS should be considered in treatment of extensive thymoma.
doi:10.4143/crt.2013.45.4.343
PMCID: PMC3893332  PMID: 24454007
Thymoma; Drug therapy; Tumor lysis syndrome; Hyperuricemia; Acute kidney injury

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