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Volume 45(4); December 2013
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Review Article
Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges
Melissa M. Phillips, Michael T. Sheaff, Peter W. Szlosarek
Cancer Res Treat. 2013;45(4):251-262.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.251
AbstractAbstract PDFPubReaderePub
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.

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Original Articles
Effect of Dose Escalation with Single Opioid, Fentanyl Matrix in Patients Not Controlling Cancer Pain: A Multicenter, Prospective, Observational Study in Korea
Sung Ae Koh, Kyung Hee Lee, Mi Jung Kim, Kyu Taek Lee, Seung Woo Park, Seung Hyun Nam, Hun Mo Ryoo
Cancer Res Treat. 2013;45(4):263-269.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.263
AbstractAbstract PDFPubReaderePub
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.
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Trends in the Aggressiveness of End-of-Life Care for Advanced Stomach Cancer Patients
Ji Hyung Hong, Sang-Young Rho, Young Seon Hong
Cancer Res Treat. 2013;45(4):270-275.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.270
AbstractAbstract PDFPubReaderePub
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.

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    Yun Jin Jeong, Do Yeun Kim
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    Medical Oncology.2014;[Epub]     CrossRef
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Clinical Prognostic Factors for Locally Advanced Esophageal Squamous Carcinoma Treated after Definitive Chemoradiotherapy
Dae-Eun Kim, Uh-Jin Kim, Won-Young Choi, Mi-Young Kim, Seung-Hun Kim, Min-Jee Kim, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung, Taek-Keun Nam, Kook-Joo Na, Sang-Hee Cho
Cancer Res Treat. 2013;45(4):276-284.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.276
AbstractAbstract PDFPubReaderePub
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.

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Nomogram to Predict Treatment Outcome of Fluoropyrimidine/Platinum-Based Chemotherapy in Metastatic Esophageal Squamous Cell Carcinoma
Hyun Ae Jung, Antoine Adenis, Jeeyun Lee, Se Hoon Park, Chi Hoon Maeng, Silvia Park, Hee Kyung Ahn, Young Mog Shim, Nicolas Penel, Young-Hyuck Im
Cancer Res Treat. 2013;45(4):285-294.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.285
AbstractAbstract PDFPubReaderePub
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> or =2), weight loss (10% of the weight loss for 3 months), low albumin level (< or =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.

Citations

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    Peng Luo, Jie Wu, Xiankai Chen, Yafan Yang, Ruixiang Zhang, Xiuzhu Qi, Yin Li
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    Hyun Ae Jung, Antoine Adenis, Jeeyun Lee, Se Hoon Park, Chi Hoon Maeng, Silvia Park, Hee Kyung Ahn, Young Mog Shim, Nicolas Penel, Young-Hyuck Im
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Predictive Factors for Radiation Pneumonitis in Lung Cancer Treated with Helical Tomotherapy
Youngkyong Kim, Seong Eon Hong, Moonkyoo Kong, Jinhyun Choi
Cancer Res Treat. 2013;45(4):295-302.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.295
AbstractAbstract PDFPubReaderePub
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 > or =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.

Citations

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    Shin-Hyung Park, Jae-Kwang Lim, Min Kyu Kang, Jongmoo Park, Chae Moon Hong, Chang Ho Kim, Seung Ick Cha, Jaehee Lee, Seoung-Jun Lee, Jae-Chul Kim
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Immunogenicity of Influenza Vaccine in Colorectal Cancer Patients
Dong Ho Kim, Yun Yong Lee, Ui Sup Shin, Sun Mi Moon
Cancer Res Treat. 2013;45(4):303-312.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.303
AbstractAbstract PDFPubReaderePub
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.

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Effects of Polymorphisms of Innate Immunity Genes and Environmental Factors on the Risk of Noncardia Gastric Cancer
Jeongseon Kim, Young Ae Cho, Il Ju Choi, Yeon-Su Lee, Sook-Young Kim, Jung-Ah Hwang, Soo-Jeong Cho, Myeong-Cherl Kook, Chan Gyoo Kim, Young-Woo Kim
Cancer Res Treat. 2013;45(4):313-324.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.313
AbstractAbstract PDFPubReaderePub
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.

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Clinical Implications of VEGF, TGF-beta1, and IL-1beta in Patients with Advanced Non-small Cell Lung Cancer
Ji-Won Kim, Youngil Koh, Dong-Wan Kim, Yong-Oon Ahn, Tae Min Kim, Sae-Won Han, Do-Youn Oh, Se-Hoon Lee, Seock-Ah Im, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang
Cancer Res Treat. 2013;45(4):325-333.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.325
AbstractAbstract PDFPubReaderePub
PURPOSE
Vascular endothelial growth factor (VEGF)-A, VEGF165b, interleukin (IL)-1beta, and transforming growth factor (TGF)-beta1 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-beta1 and IL-1beta levels were associated with shorter progression-free survival, and high VEGF-A and IL-1beta 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-1beta, 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-beta1 (p=0.020) levels.
CONCLUSION
Serum VEGF-A, TGF-1beta, and IL-1beta 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-beta1 levels.

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Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041
Jin Ho Kim, Il Han Kim, Jin Hee Shin, Hak Jae Kim, In Ah Kim
Cancer Res Treat. 2013;45(4):334-342.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.334
AbstractAbstract PDFPubReaderePub
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-naive 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.

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Case Reports
Tumor Lysis Syndrome in a Solid Tumor: A Case Report of a Patient with Invasive Thymoma
Ji Yun Lee, Sung Hee Lim, Ji Young Lee, Ji Hoon Kim, Ki Hong Choi, Keunchil Park, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn
Cancer Res Treat. 2013;45(4):343-348.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.343
AbstractAbstract PDFPubReaderePub
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.

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    Larry E Nyanti, Andy Sing Ong Tang, Adam Malik b Ismail, Lee Ping Chew, Tze Shin Leong
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  • Tumor Lysis Syndrome in Patients With Solid Tumors: A Systematic Review of Reported Cases
    Riyadh M Alqurashi , Husam H Tamim, Ziyad D Alsubhi, Alyazid A Alzahrani, Emad Tashkandi
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    Aibek E. Mirrakhimov, Alaa M. Ali, Maliha Khan, Aram Barbaryan
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Sunitinib Treatment for Metastatic Renal Cell Carcinoma in Patients with Von Hippel-Lindau Disease
Ho Cheol Kim, Jung Su Lee, Sang Hyung Kim, Hoon Sub So, Chang Yoon Woo, Jae Lyun Lee
Cancer Res Treat. 2013;45(4):349-353.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.349
AbstractAbstract PDFPubReaderePub
Von Hippel-Lindau (VHL) disease is an autosomal dominant disease that produces a variety of tumors and cysts in the central nervous system and visceral organs, including renal cell carcinoma (RCC). RCC in patients with VHL disease does not frequently metastasize, therefore, the response to treatment and prognosis of metastatic RCC developed in patients with VHL disease has not been reported. Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity. Here, we report on four patients with metastatic RCC in VHL disease who received sunitinib and achieved partial responses that have lasted for a prolonged period of time.

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Sarcoidosis Mimicking Cancer Metastasis Following Chemotherapy for Ovarian Cancer
Mi Hyun Kim, Kwangha Lee, Ki Uk Kim, Hye-Kyung Park, Min Ki Lee, Dong Soo Suh
Cancer Res Treat. 2013;45(4):354-358.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.354
AbstractAbstract PDFPubReaderePub
We report on a rare case of sarcoidosis that developed after chemotherapy for ovarian cancer, and mimicked a cancer metastasis. A 52-year-old female diagnosed with stage III ovarian cancer underwent curative surgery and postoperative chemotherapy. Four months later, her whole-body positron emission tomography and computed tomography (CT) scan showed high uptake in the mediastinal lymph nodes, and ovarian cancer recurrence was suspected. Biopsy of the mediastinal lymph nodes and subcutaneous nodules revealed noncaseating granulomas. These lesions resolved spontaneously without treatment; however, newly developed perilymphatic and centrilobular nodules were observed on follow-up chest CT. Surgical biopsy of these lesions also showed noncaseating granulomas. She was finally diagnosed with sarcoidosis.

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