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1.  Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients 
Journal of Clinical Oncology  2013;32(2):121-128.
Purpose
Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.
Patients and Methods
We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.
Results
This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.
Conclusion
These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
doi:10.1200/JCO.2013.50.8556
PMCID: PMC4062710  PMID: 24323028
2.  High-throughput profiling identifies clinically actionable mutations in salivary duct carcinoma 
Background
Salivary duct carcinoma (SDC) is a highly aggressive subtype of salivary gland cancers and there is no established standard therapy for this disease. Thus, development of molecular markers for SDC will be important to guide the diagnosis and therapy of this aggressive tumor.
Methods
We performed next-generation sequencing using the Ion Torrent AmpliSeq cancer panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes, and we analyzed copy number variations (CNVs) of 21 genes by NanoString nCounter for 37 patients with SDC. Fluorescent in situ hybridization was also conducted to confirm ERBB2 gene amplification. Clinical records and tumor histopathology of the patients were retrospectively reviewed.
Results
Genetic alterations were detected in 29 of 37 (78.3%) tumors, including mutations in PIK3CA (N = 9, 24.3%), ERBB2 (N = 4, 10.8%), and EGFR (N = 4, 10.8%). To our knowledge, this is the first time that ERBB2 mutations have been reported in this tumor type. Both PIK3CA and ERBB2 mutation status were associated with poor overall survival, but without statistical significance. ERBB2 amplification was strong and common in SDC and almost all cases also exhibited EGFR and ERBB3 amplifications.
Conclusions
This study reports the largest and most comprehensive analysis of DNA aberrations in SDC. Our results show that PIK3CA and/or ERBB2 alterations in the development of SDC might be a useful diagnostic tool and could serve as a potential therapeutic target.
doi:10.1186/s12967-014-0299-6
PMCID: PMC4216375  PMID: 25343854
Salivary duct carcinoma; Next-generation sequencing; Molecular markers; PIK3CA; ERBB2; EGFR
3.  The Effect of N/P Ratio on the In Vitro and In Vivo Interaction Properties of PEGylated Poly(2-(dimethylamino)ethyl methacrylate)-Based siRNA Complexes 
Macromolecular bioscience  2013;13(8):1059-1071.
In this study, we employed poly(ethylene glycol)-poly(n-butyl acrylate)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PnBA-PDMAEMA) triblock copolymer micelles as well as a PEG-PDMAEMA diblock copolymer as model systems for studying the role of N/P ratio on the in vivo behaviors of PEGylated siRNA carriers in mice. Through various in vitro assays, we identified the presence of a free/uncomplexed polymer population coexisting with siRNA complexes, the extent of which was found to be an increasing function of the N/P ratio. Contrary to what one might expect, however, we found that for both the diblock and triblock-based siRNA carrier systems, a change in the N/P ratio exerts insignificant influence on the in vivo biodistribution and ex vivo blood chemistry properties of the respective systems at < ~ 6 hours after systemic injection in mice. On the other hand, histological analysis of major organs at a longer time point (≈ 16 hours) indicates that the presence of uncomplexed polymer elicits toxicity to the organ that is associated with the clearance of the siRNA complexes from the circulation system. This effect can be eliminated by working at N/P ratios near the charge-neutralization point of the complexes.
doi:10.1002/mabi.201300046
PMCID: PMC4121118  PMID: 23828845
biodistribution; blood toxicity; N/P ratio; polyplex; siRNA
4.  Phase II Study of Afatinib as Third-Line Treatment for Patients in Korea With Stage IIIB/IV Non-Small Cell Lung Cancer Harboring Wild-Type EGFR 
The Oncologist  2014;19(7):702-703.
Background.
This phase II single-arm trial evaluated afatinib, an irreversible inhibitor of the ErbB receptor family as third-line treatment of Korean patients with advanced non-small cell lung cancer (NSCLC) and tumors with wild-type EGFR. Currently, no standard therapy exists for these patients.
Methods.
Eligible patients had stage IIIB/IV wild-type EGFR lung adenocarcinoma and had failed to benefit from two previous lines of chemotherapy but had not received anti-EGFR treatment. Patients received oral afatinib at 40 mg per day until disease progression or occurrence of intolerable adverse events (AEs). The primary endpoint was confirmed objective tumor response (OR) rate (confirmed complete response [CR] or partial response [PR]). Secondary endpoints included disease control rate (DCR; OR or stable disease for ≥6 weeks), progression-free survival (PFS), and safety.
Results.
Forty-two patients received afatinib treatment, and 38 of those were included in efficacy analyses. No confirmed CRs or PRs were reported. DCR was 24% (9 of 38 patients), with a median disease control duration of 19.3 weeks. Median PFS was 4.1 weeks (95% confidence interval: 3.9–8.0). Frequently reported AEs (mainly grades 1 and 2) were rash/acne (88%), diarrhea (62%), and stomatitis (57%).
Conclusion.
Heavily pretreated patients with wild-type EGFR NSCLC treated with afatinib monotherapy did not experience an objective response and only 24% had disease stabilization lasting more than 6 weeks. AEs were manageable and consistent with the expected safety profile.
doi:10.1634/theoncologist.2013-0419
PMCID: PMC4077442  PMID: 24868099
5.  Prognostic value of volumetric metabolic parameters measured by [18F]Fluorodeoxyglucose-positron emission tomography/computed tomography in patients with small cell lung cancer 
Cancer Imaging  2014;14(1):2.
Background
We evaluated the prognostic value of volume-based metabolic positron emission tomography (PET) parameters in patients with small cell lung cancer (SCLC) compared with other factors.
Methods
The subjects were 202 patients with pathologically proven SCLC who underwent pretreatment 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT). Volumetric metabolic parameters of intrathoracic malignant hypermetabolic lesions, including maximum and average standardized uptake value, sum of metabolic tumor volume (MTV), and sum of total lesion glycolysis (TLG) were measured.
Results
164 patients had died during follow-up (median 17.4 months) and median overall survival was 14 months. On univariate survival analysis, age, stage, treatment modality, sum of MTV (cutoff = 100 cm3), and sum of TLG (cutoff = 555) were significant predictors of survival. There was a very high correlation between the sum of MTV and the sum of TLG (r = 0.963, P < 0.001). On multivariate survival analysis, age (HR = 1.04, P < 0.001), stage (HR = 2.442, P < 0.001), and sum of MTV (HR = 1.662, P = 0.002) were independent prognostic factors. On subgroup analysis based on limited disease (LD) and extensive disease (ED), sum of MTV and sum of TLG were significant prognostic factors only in LD.
Conclusion
Both sum of MTV and sum of TLG of intrathoracic malignant hypermetabolic lesions are important independent prognostic factors for survival in patients with SCLC, in addition to age and clinical stage. However, it may be more useful in limited disease rather than in extensive disease.
doi:10.1186/1470-7330-14-2
PMCID: PMC4212529  PMID: 25609313
Small cell lung cancer; [18F]FDG-PET/CT; Metabolic tumor volume; Total lesion glycolysis; Prognosis
6.  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
7.  Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung Cancer 
PLoS ONE  2013;8(5):e64816.
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.
doi:10.1371/journal.pone.0064816
PMCID: PMC3665805  PMID: 23724098
8.  High Dose Involved Field Radiation Therapy as Salvage for Loco-Regional Recurrence of Non-Small Cell Lung Cancer 
Yonsei Medical Journal  2012;53(6):1120-1127.
Purpose
To determine the effectiveness of salvage radiation therapy (RT) in patients with loco-regional recurrences (LRR) following initial complete resection of non-small cell lung cancer (NSCLC) and assess prognostic factors affecting survivals.
Materials and Methods
Between 1994 and 2007, 64 patients with LRR after surgery of NSCLC were treated with high dose RT alone (78.1%) or concurrent chemo-radiation therapy (CCRT, 21.9%) at Samsung Medical Center. Twenty-nine patients (45.3%) had local recurrence, 26 patients (40.6%) had regional recurrence and 9 patients (14.1%) had recurrence of both components. The median RT dose was 54 Gy (range, 44-66 Gy). The radiation target volume included the recurrent lesions only.
Results
The median follow-up time from the start of RT in survivors was 32.0 months. The rates of in-field failure free survival, intra-thoracic failure free survival and extra-thoracic failure free survival at 2 years were 52.3%, 33.9% and 59.4%, respectively. The median survival after RT was 18.5 months, and 2-year overall survival (OS) rate was 47.9%. On both univariate and multivariate analysis, the interval from surgery till recurrence and CCRT were significant prognostic factors for OS.
Conclusion
The current study demonstrates that involved field salvage RT is effective for LRR of NSCLC following surgery.
doi:10.3349/ymj.2012.53.6.1120
PMCID: PMC3481375  PMID: 23074111
Concurrent chemo-radiation therapy; locoregional recurrence; non-small cell lung cancer; radiation therapy; salvage treatment
9.  Dual-Energy CT in Patients Treated with Anti-Angiogenic Agents for Non-Small Cell Lung Cancer: New Method of Monitoring Tumor Response? 
Korean Journal of Radiology  2012;13(6):702-710.
Objective
To evaluate tumor responses in patients treated with anti-angiogenic agents for non-small cell lung cancer (NSCLC) by assessing intratumoral changes using a dual-energy CT (DECT) (based on Choi's criteria) and to compare it to traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Materials and Methods
Ten NSCLC patients treated with bevacizumab underwent DECT. Tumor responses to anti-angiogenic therapy were assessed and compared with the baseline CT results using both RECIST (size changes only) and Choi's criteria (reflecting net tumor enhancement). Kappa statistics was used to evaluate agreements between tumor responses assessed by RECIST and Choi's criteria.
Results
The weighted κ value for the comparison of tumor responses between the RECIST and Choi's criteria was 0.72. Of 31 target lesions (21 solid nodules, 8 lymph nodes, and two ground-glass opacity nodules [GGNs]), five lesions (16%) showed discordant responses between RECIST and Choi's criteria. Iodine-enhanced images allowed for a distinction between tumor enhancement and hemorrhagic response (detected in 14% [4 of 29, excluding GGNs] of target lesions on virtual nonenhanced images).
Conclusion
DECT may serve as a useful tool for response evaluation after anti-angiogenic treatment in NSCLC patients by providing information on the net enhancement of target lesions without obtaining non-enhanced images.
doi:10.3348/kjr.2012.13.6.702
PMCID: PMC3484290  PMID: 23118568
Targeted therapy; Tumor response assessment; Response criteria; Guideline; Non-small cell lung cancer; Dual energy CT
10.  The Influence of Nano-Carrier Architecture on In Vitro siRNA Delivery Performance and In Vivo Biodistribution: Polyplexes vs. Micelleplexes 
ACS Nano  2011;5(5):3493-3505.
Micelle-based siRNA carriers (“micelleplexes”) were prepared from the A-B-C triblock copolymer, poly(ethylene glycol)-poly(n-butyl acrylate)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PnBA-PDMAEMA), and their in vitro performance and in vivo biodistribution properties were compared with the benchmark PEGylated and basic polycation systems, PEG-PDMAEMA and PDMAEMA, respectively. The micelle architecture, incorporating increased PEG shielding and a larger particle size (~50 nm) than polycation-based complexes (polyplexes; ~10 nm), enhances siRNA delivery performance in two important aspects: in vitro gene silencing efficiency, and in vivo tumor accumulation. The in vitro gene silencing efficiency of the micelleplexes (24% in HeLa cells) was significantly better than the statistically-insignificant levels observed for PDMAEMA and PEG-PDMAEMA polyplexes under identical conditions. This enhancement is linked to the different mechanisms by which micelleplexes are internalized (i.e., caveolar, etc.) compared to PDMAEMA and PEG-PDMAEMA polyplexes. Folate-functionalization significantly improved micelleplex uptake but had negligible influence on gene silencing efficiency, suggesting that this parameter is not limited by cellular internalization. In vivo biodistribution analysis revealed that siRNA delivered by micelleplexes was more effectively accumulated and retained in tumor tissues than that delivered by PEGylated polyplexes. Overall, the micelle particle size and architecture appear to improve in vitro and in vivo delivery characteristics without significantly changing other properties, such as cytotoxicity and resistance to enzymes and dissociation. The self-assembled nature of micelleplexes is expected to enable incorporation of imaging modalities inside the hydrophobic micelle core, thus combining therapeutic and diagnostic capabilities. The findings from the present study suggest that the micelleplex-type carrier architecture is a useful platform for potential theranostic and tumor-targeting applications.
doi:10.1021/nn102540y
PMCID: PMC3381331  PMID: 21456626
nano-carrier; siRNA delivery; in vitro performance; in vivo biodistribution; polyplex; micelleplex
11.  The Effectiveness of Maintenance Pharmacotherapies for Non-Small Cell Lung Cancer 
Although current recommendations for the treatment of advanced non-small cell lung cancer (NSCLC) include a maximum of six cycles of platinum-based combination therapy as a first-line approach, most patients experience progression within 3–4 months. Therefore, a new treatment strategy, maintenance therapy, has been proposed, and several large randomized prospective controlled trials have shown benefits with maintenance therapy. Maintenance therapy can be classified as either continuation maintenance, which is defined as a prolongation of a part of the first-line chemotherapy or molecularly targeted agent until progression, or switch-maintenance, which is defined as the administration of a different cytotoxic chemotherapy or molecularly targeted agent immediately after induction therapy. In this article, recent results from large randomized phase III trials regarding maintenance therapy are reviewed in order to evaluate the role of maintenance therapy in NSCLC.
doi:10.4137/CMO.S8001
PMCID: PMC3382338  PMID: 22745566
non-small cell lung cancer; maintenance therapy
12.  A Single Nucleotide Polymorphism in the Phospholipase D1 Gene is Associated with Risk of Non-Small Cell Lung Cancer 
Phospholipase D (PLD) has an important role in various biological functions including vesicular transport, endocytosis, exocytosis, cell migration, and mitosis. These cellular biological processes are deregulated in the development of various human tumors. In order to explore the relationship between the PLD1 gene and risk of non-small cell lung cancer (NSCLC), single nucleotide polymorphisms (SNP) in the PLD1 exon region were surveyed in 211 NSCLC patients and 205 normal controls. In this study, we identified six SNPs at exon 23 in the PLD1 gene. Among the six SNPs, the most notable was a heterozygous A to C transition at nucleotide 2698 (A2698C, p<0.001). In addition, the genotype frequencies of A2744C (AC+CC) and A2756C (AC+CC) were associated with gender (female, A2744C and A2756C: p=0.071) in NSCLC patients. Interestingly, although the SNP A2698C did not cause change in amino acid, correlation between odd ratio of NSCLC patients and the SNP A2698C was observed to be statistically significant.
PMCID: PMC3614861  PMID: 23675264
biomarker; DGGE; lung cancer; NSCLC; phospholipase D; single nucleotide polymorphism
13.  INSPIRE: A phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer 
BMC Cancer  2011;11:430.
Background
Previous research suggests the therapeutic cancer vaccine L-BLP25 potentially provides a survival benefit in patients with locally advanced unresectable stage III non-small cell lung carcinoma (NSCLC). These promising findings prompted the phase III study, INSPIRE, in patients of East-Asian ethnicity. East-Asian ethnicity is an independent favourable prognostic factor for survival in NSCLC. The favourable prognosis is most likely due to a higher incidence of EGFR mutations among this patient population.
Methods/design
The primary objective of the INSPIRE study is to assess the treatment effect of L-BLP25 plus best supportive care (BSC), as compared to placebo plus BSC, on overall survival time in East-Asian patients with unresectable stage III NSCLC and either documented stable disease or an objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria following primary chemoradiotherapy. Those in the L-BLP25 arm will receive a single intravenous infusion of cyclophosphamide (300 mg/m2) 3 days before the first L-BLP25 vaccination, with a corresponding intravenous infusion of saline to be given in the control arm. A primary treatment phase of 8 subcutaneous vaccinations of L-BLP25 930 μg or placebo at weekly intervals will be followed by a maintenance treatment phase of 6-weekly vaccinations continued until disease progression or discontinuation from the study.
Discussion
The ongoing INSPIRE study is the first large study of a therapeutic cancer vaccine specifically in an East-Asian population. It evaluates the potential of maintenance therapy with L-BLP25 to prolong survival in East-Asian patients with stage III NSCLC where there are limited treatment options currently available.
Study number
EMR 63325-012
Trial Registration
Clinicaltrials.gov reference: NCT01015443
doi:10.1186/1471-2407-11-430
PMCID: PMC3203100  PMID: 21982342
14.  Molecular profiles of EGFR, K-ras, c-met, and FGFR in pulmonary pleomorphic carcinoma, a rare lung malignancy 
Background
Pulmonary pleomorphic carcinoma (PPC) is a rare type of lung cancer characterized by the poor response to conventional chemotherapy and subsequent disappointing outcomes. Therefore, it is paramount to delineate the molecular characteristics of this disease entity.
Methods
In this study, we retrospectively examined the surgical specimens of 61 patients who underwent lung surgery. Mutational or gene amplification statuses of epidermal growth factor receptor (EGFR), k-ras, c-kit, c-met, and fibroblast growth factor receptor (FGFR) were examined using genomic DNA sequencing, real-time PCR and/or fluorescence in situ hybridization (FISH).
Results
The median age was 61 years, and 50 patients were men and 11 were women. In the histologic review of epithelial component, adenocarcinoma were in 44 cases (72%), squamous cell carcinoma in 15 (25%) and large cell carcinoma in 2 patients (3%). Overall, 30 cases (49%) had any molecular alterations. Nine patients (15%) possessed EGFR deletion in exon 19 (n = 8) or L858R mutations in exon 21 (n = 1), while 3 other cases having atypical EGFR mutations. Six patients (9.8%) had k-ras mutations in exon 12, and 3 had c-kit mutations. High gene copy number of c-met was found in 11 patients (18.0%) and that of FGFR was in 6 patients (9.8%). No significant relationships were identified among the occurrence and type of mutations and patient survival or any other clinicopathological variables.
Conclusions
Given the diverse repertoire of mutational profiles observed in PPC samples, clinical trials based on accurate cancer-genotyping should be considered as a legitimate treatment scheme for this rare disease entity in the future.
doi:10.1007/s00432-011-0986-0
PMCID: PMC3133705  PMID: 21626008
Lung cancer; Pulmonary pleomorphic carcinoma; EGFR; k-ras; c-kit; c-met; FGFR
15.  Molecularly Targeted Therapy Using Bevacizumab for Non-Small Cell Lung Cancer: a Pilot Study for the New CT Response Criteria 
Korean Journal of Radiology  2010;11(6):618-626.
Objective
We wanted to compare the efficacy of the new CT response evaluation criteria for predicting the tumor progression-free survival (PFS) with that of RECIST 1.1 in non-small cell lung cancer (NSCLC) patients who were treated with bevacizumab.
Materials and Methods
Sixteen patients (M:F = 11:5; median age, 57 years) treated with bevacizumab and combined cytotoxic chemotherapeutic agents were selected for a retrospective analysis. The tumor response was assessed by four different methods, namely, by using RECIST 1.1 (RECIST), RECIST but measuring only the solid component of tumor (RECISTsolid), the alternative method reflecting tumor cavitation (the alternative method) and the combined criteria (the combined criteria) that evaluated both the changes of tumor size and attenuation. To evaluate the capabilities of the different measurement methods to predict the patient prognosis, the PFS were compared, using the log rank test, among the responder groups (complete response [CR], partial response [PR], stable disease [SD] and progressive disease [PD]) in terms of the four different methods.
Results
The overall (CR, PR or SD) response rates according to RECIST, RECISTsolid, the alternative method and the combined criteria were 81%, 88%, 81% and 85%, respectively. The confirmed response rates (CR or PR) were 19%, 19%, 50% and 54%, respectively. Although statistically not significant, the alternative method showed the biggest difference for predicting PFS among the three response groups (PR, SD and PD) (p = 0.07). RECIST and the alternative method showed a significant difference for predicting the prognosis between the good (PR or SD) and poor overall responders (p = 0.02).
Conclusion
The response outcome evaluations using the three different CT response criteria that reflect tumor cavitation, the ground-glass opacity component and the attenuation changes in NSCLC patients treated with bevacizumab showed different results from that with using the traditional RECIST method.
doi:10.3348/kjr.2010.11.6.618
PMCID: PMC2974223  PMID: 21076587
Targeted therapy; Tumor response assessment; Response criteria; Guideline, Non-small cell lung cancer
16.  Modest Anti-Cancer Activity of a Bile Acid Acylated Heparin Derivative in a PC14PE6 Induced Orthotopic Lung Cancer Model 
Purpose
A novel chemically modified heparin derivative, heparin-deoxycholic acid nano-particles, has lower anticoagulant activity, and was recently reported to have significant anti-tumor effects on squamous head and neck cancer cells. Therefore, the aim of this study was to evaluate the anti-tumor effects of heparin-deoxycholic acid nano-particles in a human lung adenocarcinoma cell line.
Materials and Methods
An orthotopic lung cancer model in 16 mice was developed using intra-thoracic injections of 0.5×106 PC14PE6 cells. Ten days after inoculation, the mice were divided into two groups. PBS and Heparin-DOCA particles were injected once a day every 3 days in the tail vein, for a total of 5 injections. The body weight and survival of each mouse were monitored and the tumor size in the lung was measured by SPECT-CT before and after heparin-DOCA nano-particle treatment.
Results
IThe HD particles had no significant cytotoxicity when the PC9 cells were treated in vitro. There was no statistical difference in tumor size, body weight and survival between the HD treated and control groups in vivo. Furthermore, there was no difference in the amount of CD31 between tumor tissues in the two study groups.
Conclusion
HD synthesized with unfractionated heparin had no apparent inhibitory effects on tumor growth in a PC14PE6 cell induced orthotopic lung cancer mouse model. The HD particles did not significantly inhibit tumor-induced angiogenesis at the tumor sites.
doi:10.4143/crt.2009.41.2.80
PMCID: PMC2731213  PMID: 19707505
Lung; Adenocarcinoma; Mouse; Heparin; Derivatives; Angiogenesis
17.  FDG PET/CT and Mediastinal Nodal Metastasis Detection in Stage T1 Non-Small Cell Lung Cancer: Prognostic Implications 
Korean Journal of Radiology  2008;9(6):481-489.
Objective
We aimed to compare the prognoses of patients with pathologically true negative (P-TN) N2 and PET/CT false negative (FN) results in stage T1 non-small cell lung cancer (NSCLC).
Materials and Methods
Our institutional review board approved this retrospective study with a waiver of informed consent. The study included 184 patients (124 men and 60 women; mean age, 59 years) with stage T1 NSCLC who underwent an integrated PET/CT and surgery. After estimating the efficacy of PET/CT for detecting N2 disease, we determined and compared disease-free survival (DFS) rates in three groups (P-TN [n = 161], PET/CT FN [n = 12], and PET/CT true positive [TP, n = 11]) using the Kaplan-Meier analysis and log-rank test.
Results
Pathologic N2 disease was observed in 23 (12%) patients. PET/CT had an N2 disease detection sensitivity of 48% (11 of 23 patients), a specificity of 95% (153 of 161), and an accuracy of 89% (164 of 184). The 3-year DFS rate in the PET/CT FN group (31%, 95% confidence interval [CI]; 13.6-48.0%) was similar to that of the TP group (16%, 95% CI; 1.7-29.5%) (p = 0.649), but both groups had significantly shorter DFS rates than the P-TN group (77%, 95% CI; 72.0-81.2%) (p < 0.001).
Conclusion
The PET/CT shows a high specificity, but low sensitivity for detecting N2 disease in stage T1 NSCLC. Patients with PET/CT FN N2 disease have survival rates similar to PET/CT TP N2 disease patients, which are both substantially shorter than the survival rate of P-TN patients.
doi:10.3348/kjr.2008.9.6.481
PMCID: PMC2627243  PMID: 19039263
Lung neoplasms; Lung neoplasms, CT; Lung neoplasms, PET; Lung neoplasms, staging
18.  Clinical evaluation of incadronate in korean patients with malignancy-associated hypercalcemia: An open-label, multicenter study 
Abstract
Background:
Incadronate has been found to lessen the increase in corrected serum calcium levels in malignancy-associated hypercalcemia (MAH) in a Phase III study in Japan. The drug is currently used to treat MAH in Japan.
Objective:
The purpose of this study was to assess the clinical usefulness of incadronate in patients with MAH.
Methods:
This open-label study was conducted at 3 medical institutions in Korea. Korean patients with MAH (corrected serum calcium levels ≥11.0 mg/dL) were given a single 10-mg IV infusion of incadronate over 2 to 4 hours in 500 to 1000 mL of normal saline. Corrected calcium levels were determined and subjective symptoms and objective findings (ie, bone pain, spontaneous pain, pain from contusion, tenderness, other pain, loss of appetite, nausea and/or vomiting, thirst, constipation, fatigue, and disturbance of consciousness) were used to monitor the effectiveness of the drug for 6 days after the infusion. Symptoms were evaluated using a 4-point scale (0 = none to 3 = severe). Adverse events (AEs) were identified by patients' reports, and adverse drug events (ADEs) were assessed by the investigators throughout the study.
Results:
Twenty-four Korean patients (18 [75%]male, 6 [25%]female; mean age, 56.5 years) were included in the study; data from 22 and 24 patients were used to assess effectiveness and tolerability, respectively. Corrected serum calcium level was significantly decreased on day 6 after treatment compared with pretreatment on day 0 (baseline) (9.51 [0.89] mg/dL vs 11.83 [0.89] mg/dL; P < 0.001). The antihypercalcemic effect of incadronate became apparent as an inhibition of bone absorption a few days after infusion. Corrected serum calcium level was significantly decreased on days 2 to 6 (P < 0.001) after treatment compared with pretreatment at baseline. Evaluation of symptoms showed significant improvement in the incadronate-treated group (mean total score [range] at baseline, 8 [1–23] and day 6, 5.5 [1–17]; P = 0.001). Eight (33.3%) of the patients were found to have ADEs. Some of the 8 patients experienced >1 ADE (mild and transient fever [13 events], chills [3], headache [1], and myalgia [1]). AEs were observed in 19 (79.2%) of 24 patients. The most frequently reported AE was fever (14 events).
Conclusion:
In this small, open-label study, Korean subjects with MAH treated with incadronate experienced significant improvement in symptoms and calcium levels from baseline.
doi:10.1016/j.curtheres.2007.06.004
PMCID: PMC3967285  PMID: 24683210
incadronate; bisphosphonate; malignancy-associated hypercalcemia; Korea
19.  Orbital Infiltration as the First Site of Relapse of Primary Testicular T-cell Lymphoma 
A 43-year-old male presented with a painless left testicular mass. The pathologic diagnosis of the radical orchiectomy specimen was peripheral T-cell lymphoma, unspecified (PTCL-u). According to the Ann Arbor staging system, his initial stage was III because of the right nasopharyngeal involvement. After first-line chemotherapy with four courses of the CHOP regimen and this was followed by involved-field radiotherapy, he achieved complete remission. Two months later, disease recurred to the left ciliary body of the left eye without evidence of involvement at other sites. Although the patient received intensive chemotherapy with autologous hematopoietic stem cell transplantation, he ultimately died of leptomeningeal seeding. Because both the central nervous system (CNS) and the orbit are sanctuary sites for chemotherapy, orbital infiltration of lymphoma should prompt physicians to evaluate involvement of the CNS and to consider performing prophylactic intrathecal chemotherapy as a treatment option.
doi:10.4143/crt.2007.39.1.40
PMCID: PMC2739356  PMID: 19746228
Non-Hodgkin's lymphoma; T cell lymphoma; Testes; Eye neoplasm
20.  Paclitaxel with Cisplatin as Salvage Treatment for Patients with Previously Treated Advanced Transitional Cell Carcinoma of the Urothelial Tract 
Neoplasia (New York, N.Y.)  2007;9(1):18-22.
Abstract
BACKGROUND
This study was performed to evaluate the safety and efficacy of paclitaxel with cisplatin as salvage therapy in patients previously treated with gemcitabine and cisplatin (G/C) for advanced transitional cell carcinoma (TCC) of the urothelial tract.
METHODS
Twenty-eight patients with metastatic or locally advanced TCC who had received prior G/C chemotherapy were enrolled. All patients received paclitaxel (175 mg/m2) and cisplatin (60 mg/m2) every 3 weeks for eight cycles or until disease progression.
RESULTS
The median age was 61 years (range, 43–83 years), and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0–2). The overall response rate was 36% [95% confidence interval (95% CI) = 18–54], with three complete responses and seven partial responses. The median time to progression was 6.2 months (95% CI = 3.9–8.5), and the median overall survival was 10.3 months (95% CI = 6.1–14.1). The most common Grade 3/4 nonhematologic and hematologic toxicities were emesis (10 of 28 patients; 36%) and neutropenia (5 of 110 cycles; 5%).
CONCLUSIONS
Salvage chemotherapy with paclitaxel and cisplatin displayed promising results with tolerable toxicity profiles in patients with metastatic or locally advanced TCC who had been pretreated with G/C.
PMCID: PMC1804323  PMID: 17325740
Paclitaxel; cisplatin; transitional cell carcinoma; salvage therapy; urothelium
21.  Mouse Orthotopic Lung Cancer Model Induced by PC14PE6 
Purpose
This study was undertaken to investigate in detail the xenograft mouse orthotopic lung cancer model induced by PC14PE6 adenocarcinoma cells.
Materials and Methods
Three cell doses (0.5×106; 1×106; 2×106) of PC14PE6 cells were injected into the lungs of male BALB/c nude mice by the intrathoracic injection method. The lung and other organs, including brain, liver, spleen, kidney, muscle, adrenal gland, and lymph node on knee, were removed and stained with H/E to detect the presence of tumor cells.
Results
The reliable tumorigenicity time in the PC14PE6 adenocarcinoma cell-inoculated BALB/c nude mouse was 10 days after intrathoracic injection. The average life span of the three groups after inoculation was 14 days in the 2×106 cells inoculum group; 25 days in the 1×106 cells inoculum group; and 32 days in the 0.5×106 cells inoculum group. The PC14PE6 adenocarcinoma cells induced orthotopic lung cancer limited within the thorax.
Conclusions
This orthotopic lung cancer model is an efficient cancer model with easy inoculation methods, rapid and high tumorigenicity, and simple monitoring methods for metastasis.
doi:10.4143/crt.2006.38.4.234
PMCID: PMC2741646  PMID: 19771249
Orthotopic; PC14PE6; Lung cancer; Animal model
22.  Prognosis of Non-Small Cell Lung Cancer with Synchronous Brain Metastases Treated with Gamma Knife Radiosurgery 
Journal of Korean Medical Science  2006;21(3):527-532.
The clinical outcome and prognostic factors of patients with synchronous brain metastases from non-small cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKS) were analyzed. A total of 35 patients with NSCLC underwent GKS as an initial treatment for metastatic brain lesions of synchronous onset. The period of survival and various prognostic factors such as age, gender, performance status, multiplicity of the brain lesions, intracranial tumor volume, and extent of the primary tumor were analyzed. The overall median survival time for this series was 12 months (range 0.75 to 43 months) from the diagnosis. Of the 21 patients who were no longer alive at the conclusion of this study, only 7 (33.3%) died of neurological causes. Multivariate analysis of these data revealed that N stage, whole-brain radiotherapy (WBRT), and chemotherapy were significant predictors for survival (p<0.05). Survival of patients with NSCLC and synchronous brain metastases is mainly dependent upon the progression of the systemic disease, provided that the cerebral lesions are treated adequately with local treatment modalities including radiosurgery. Application of radiosurgery as an initial treatment option and aggressive local and systemic modalities to control extracranial disease may improve survival.
doi:10.3346/jkms.2006.21.3.527
PMCID: PMC2729962  PMID: 16778400
Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Radiosurgery
23.  Pulmonary Complications After Hematopoietic Stem Cell Transplantation 
Journal of Korean Medical Science  2006;21(3):406-411.
Despite advanced effective prophylaxes, pulmonary complications still occur in a high proportion of all hematopoietic stem cell recipients, accounting for considerable morbidity and mortality. The aim of our study was to describe the causes, incidences and mortality rates secondary to pulmonary complications and risk factors of such complications following hematopoietic stem cell transplantation (HSCT). We reviewed the medical records of 287 patients who underwent either autologous or allogeneic HSCT for hematologic disorders from February 1996 to October 2003 at Samsung Medical Center (134 autografts, 153 allografts). The timing of pulmonary complications was divided into pre-engraftment, early and late period. The spectrum of pulmonary complications included infectious and non-infectious conditions. 73 of the 287 patients (25.4%) developed pulmonary complications. Among these patients, 40 (54.8%) and 29 (39.7%) had infectious and non-infectious conditions, respectively. The overall mortality rate from pulmonary complications was 28.8%. Allogeneic transplant, grade II-IV acute graft-versus-host disease (GVHD) and extensive chronic GVHD were the risk factors with statistical significance for pulmonary complications after HSCT. The mortality rates from pulmonary complications following HSCT were high, especially those of viral and fungal pneumonia, diffuse alveolar hemorrhage and idiopathic pneumonia syndrome.
doi:10.3346/jkms.2006.21.3.406
PMCID: PMC2729942  PMID: 16778380
Infection; Hematopoietic Stem Cell Transplantation; Graft vs. Host Disease
24.  Preoperative Concurrent Radiochemotherapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer 
Journal of Korean Medical Science  2006;21(2):229-235.
This is to examine whether aggressive multimodality therapy improves the treatment outcomes in stage IIIA non-small cell lung cancer (NSCLC). Fifty-three consecutive NSCLC patients with N2 disease, confirmed by mediastinoscopic biopsy, received preoperative thoracic radiation therapy (45 Gy/5 weeks) concurrent with two cycles of oral etoposide and intravenous cisplatin and surgery. Postoperative radiation therapy (PORT, 18 Gy/2 weeks) was optionally recommended for those with the risk factors of loco-regional recurrence based on the surgical and pathological findings. Surgical resection was performed in 38 patients (71.7%), and down-staging was achieved in 19 patients (50%). The median survival period was 27 months in 38 patients who underwent resection, and the rates at 3-yr of overall survival, loco-regional control, distant metastasis-free survival, and disease-free survival were 44.3%, 87.9%, 32.9%, and 29.3%. Significantly favorable factor regarding overall survival was achieving p0/I stage by the multivariate analysis. PORT was successful in reducing locoregional recurrences in patients with the risk factors. Current preoperative concurrent radiochemotherapy and surgery by the authors resulted in comparable survival with other reports, however, further refinement of multimodality approach may be warranted for more effective reduction of distant metastasis.
doi:10.3346/jkms.2006.21.2.229
PMCID: PMC2733996  PMID: 16614506
Carcinoma, Non-Small Cell Lung; Preoperative, Radiotherapy; Drug Therapy; Surgery
25.  Three Cases of Synchronous Solid Tumor and Multiple Myeloma 
The association between a multiple myeloma and a secondary solid tumor is not well established. Some reports showed an increased risk of secondary solid neoplasms in multiple myeloma patients, but others have not. Three cases of the synchronous occurrence of multiple myelomas and solid tumors, namely, a small cell carcinoma of the lung, an adenocarcinoma of the colon and a squamous carcinoma of the pyriform sinus were experienced at our hospital. Therefore, herein is reported the clinical courses and treatment results. The stage of multiple myeloma was Durie-Salmon stage I in all of three cases; therefore, the solid tumors were treated as a primary target because the prognosis of early stage multiple myeloma is generally better than that of advanced solid tumor, while a smoldering or stage I myeloma do not need primary therapy until progression of the multiple myeloma. Two patients died of their solid tumors, but one patient is alive.
doi:10.4143/crt.2004.36.5.338
PMCID: PMC2843872  PMID: 20368825
Multiple myeloma; Synchronous neoplasm; Second neoplasm

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