Cancer Research and Treatment

Original Articles

Lymphoma

Forkhead Box C1 (FOXC1) Expression in Stromal Cells within the Microenvironment of T and NK Cell Lymphomas: Association with Tumor Dormancy and Activation: Ji Hae Nahm, Woo Ick Yang, Sun Och Yoon; Cancer Res Treat. 2020;52(4):1273-1282. Published online July 3, 2020; DOI: https://doi.org/10.4143/crt.2020.032

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Purpose
Forkhead box C1 (FOXC1) is critical for maintaining bone marrow microenvironments during hematopoiesis, but its role in hematological malignancies remains obscure. Here, we investigated whether FOXC1 regulates tumor dormancy and activation in the microenvironments of T and natural killer (NK) cell lymphomas.
Materials and Methods
One hundred and twenty cases of T and NK cell lymphomas were included; the immunohistochemical expression of FOXC1 was investigated in stromal cells, and numbers of FOXC1⁺ stromal cells were counted. Furthermore, the expression of phosphorylated p38 (p-p38) and phosphorylated ERK1/2 (p-ERK1/2) in tumor cells was investigated using immunohistochemistry.
Results
FOXC1 was variably expressed in C-X-C motif chemokine 12–associated reticular stromal cells, histiocytes, (myo)fibroblasts, and endothelial cells. The phenotypes of cases were categorized as dormant (high p-p38/low p-ERK1/2; n=30, 25.0%), active (high p-ERK1/2/low p-p38; n=25, 20.8%), or intermediate (others; n=65, 54.2%). Lower FOXC1⁺ stromal cell infiltration was associated with the dormant phenotype, the precursor T lymphoblastic leukemia/lymphoma subtype, and inferior overall survival rates, whereas higher FOXC1⁺ stromal cell infiltration was associated with the active phenotype and favorable patient prognosis (p < 0.05 for all).
Conclusion
These results suggested that FOXC1⁺ stromal cells within the microenvironments of T and NK cell lymphomas might be related to tumor phenotypes.

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Mechanisms of lymphoma-stromal interactions focusing on tumor-associated macrophages, fibroblastic reticular cells, and follicular dendritic cells
Rintaro Ohe
Journal of Clinical and Experimental Hematopathology.2024; 64(3): 166. CrossRef

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Incidence and Survival of Pediatric Soft Tissue Sarcomas: Comparison between Adults and Children: Sun Min Lim, Cheol Joo Yoo, Jung Woo Han, Yong Jin Cho, Soo Hee Kim, Joong Bae Ahn, Sun Young Rha, Sang Joon Shin, Hyun Cheol Chung, Woo Ick Yang, Kyoo-Ho Shin, Jae Kyung Rho, Hyo Song Kim; Cancer Res Treat. 2015;47(1):9-17. Published online August 21, 2014; DOI: https://doi.org/10.4143/crt.2013.157

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Purpose
Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors. Materials and Methods We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS. Conclusion Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children.

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Grace Guzman, Megan R. Reed, Kevin Bielamowicz, Brian Koss, Analiz Rodriguez
Current Oncology Reports.2023; 25(5): 479. CrossRef
Clinicopathological and treatment response characteristics of updated rhabdomyosarcoma histomolecular subtypes: An Asian population‐based study
Guo Yuan How, Chik Hong Kuick, Min Hwee Yong, Shui Yen Soh, Esther XY Hee, Meng Kang Wong, Richard Quek, Mohd Farid Harunal, Sathiyamoorthy Selvarajan, Kesavan Sittampalam, Chetan Anil Dhamne, Victor Lee, Kenneth TE Chang, Amos HP Loh
Asia-Pacific Journal of Clinical Oncology.2023;[Epub] CrossRef
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Peter M. Fantozzi, Gina Sprint, Anna Marie Medina
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Vassiliki Lyra, Sofia Chatziioannou, Maria Kallergi
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Desmoplastic Small Round Cell Tumors With EWS-WT1 Transcript Expression: Should We Consider Children and Adult Patients Differently?
Laura Olivier-Gougenheim, Daniel Orbach, Vincent Atallah, Perrine Marec-Berard, Amandine Bertrand
Journal of Pediatric Hematology/Oncology.2022; 44(3): e637. CrossRef
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Antonio Juan Ribelles, Pablo Gargallo, Pablo Berlanga, Vanessa Segura, Yania Yáñez, Bárbara Juan, Marta Salom, Margarita Llavador, Jaime Font de Mora, Victoria Castel, Adela Cañete
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Ewing Sarcoma
Hee Young Ju
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Emerging trends in immunotherapy for pediatric sarcomas
Kyle A. Dyson, Brian D. Stover, Adam Grippin, Hector R. Mendez-Gomez, Joanne Lagmay, Duane A. Mitchell, Elias J. Sayour
Journal of Hematology & Oncology.2019;[Epub] CrossRef

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Clinical Value of Ezrin Expression in Primary Osteosarcoma: Chan Kim, Eunah Shin, Soojung Hong, Hong Jae Chon, Hye Ryun Kim, Jung Ryun Ahn, Min Hee Hong, Woo Ick Yang, Jae Kyung Roh, Sun Young Rha; Cancer Res Treat. 2009;41(3):138-144. Published online September 28, 2009; DOI: https://doi.org/10.4143/crt.2009.41.3.138

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Purpose

Ezrin is a membrane cytoskeletal linker protein and it is known to be associated with metastasis of primary osteosarcoma. The aim of this study is to determine the relationship between an ezrin expression and several key clinical parameters and to elucidate its potential prognostic value for patients with osteosarcoma.

Materials and Methods

Seventy patients with histologically confirmed osteosarcoma and who had no distant metastasis were enrolled between 1995 and 2005 at Yonsei Cancer Center, Severance Hospital, Korea. The clinical parameters were retrospectively reviewed and immunohistochemical staining (IHC) for ezrin was performed using the surgically resected specimens.

Results

Of the 70 tumor specimens, 39 (55.7%) revealed an ezrin expression. More of an osteoblastic histology and an elevated initial ALP level were observed in the ezrin positive patients than in the ezrin negative patients (p=0.008 and 0.001, respectively). The proportion of patients who favorably responded to neoadjuvant chemotherapy (≥90% necrosis) was significantly higher in the group of ezrin positive patients than that in the group of ezrin negative patient (72.2% vs 45.2%, respectively, p=0.024). The ezrin positive patients showed more frequent recurrence than did the ezrin negative patients (64.1% vs 35.5%, respectively, p=0.017). The patients with an ezrin expression also demonstrated poorer survival than did those patients without ezrin expression (5-year EFS: 31.7% vs 61.3%, respectively, p=0.023, 5-year OS: 53.4% vs 71.0%, respectively, p=0.022). When comparing EFS according to both an ezrin expression and chemoresponsiveness, there were trends that the ezrin negative/chemoresponsive group showed the best 5-year EFS (71.4%), followed by the ezrin negative/chemoresistant group (52.9%), the ezrin positive/chemoresponsive group (38.1%) and the ezrin positive/chemoresistant group (13.6%). These trends were statistically significant (p=0.036).

Conclusion

The expression of ezrin by IHC staining was found in 55.7% of the patients with metastasis-free osteosarcoma. Immunoreactivity to ezrin is a negative prognostic factor for survival for the patients suffering with osteosarcoma. Identifying an ezrin expression might offer a valuable piece of information when treating patients with primary osteosarcoma.

Citations

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Mass Spectrometric-Based Proteomics for Biomarker Discovery in Osteosarcoma: Current Status and Future Direction
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International Journal of Molecular Sciences.2022; 23(17): 9741. CrossRef
Ezrin is a prognostic biomarker in patients with clear cell metastatic renal cell carcinoma receiving sunitinib
Bulent Cetin, Ipek Isik Gonul, Ozge Gumusay, Baris Afsar, Irem Bilgetekin, Ahmet Ozet, Aytug Uner
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The clinical prognostic significance of ezrin in patients with bone and soft tissue sarcomas: a meta‐analysis
Feng Wang, Tao Yu, Chengbin Ma, Haifei Zhang, Zhiyu Zhang
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Efficacy of Pre- and Postoperative Chemotherapy in Patients with Osteosarcoma of the Extremities: Joo Hyuk Sohn, Sun Young Rha, Hei Cheul Jeung, Hyun Joon Shin, Young Suck Goo, Hyun Cheol Chung, Woo Ick Yang, Soo Bong Hahn, Kyu Ho Shin, Jin Sik Min, Byung Soo Kim, Jae Kyung Roh, Woo Ick Jang; Cancer Res Treat. 2001;33(6):520-526. Published online December 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.6.520

Abstract PDF

PURPOSE
We evaluated the treatment efficacy including survival and recurrence, and factors associated with recurrence in osteosarcoma patients treated with preoperative chemotherapy, surgery, and adjuvant chemotherapy.
MATERIALS AND METHODS
Forty nine patients with osteosarcoma were treated with preoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion for 3 cycles, followed by surgery. According to the pathologic response, if tumor was necrotized more than 90%, the same adjuvant chemotherapy was reintroduced for 3 cycles, and if the response was not enough, then the salvage regimen was introduced. Plain chest film and chest CT scan were taken monthly and every 3 months, respectively. When tumor recurred, the metastasectomy was performed whenever possible.
RESULTS
Forty three patients were evaluable with amedian follow up of 53 months. Five-year disease-free and overallsurvival rate was 47.0% and 66.9%, respectively. The recurrence was observed in 22 patients (51.2%) with median time of 12.5 months. Baseline alkaline phosphatase (ALP) was the only significant factor for recurrence (p=0.03) and the patients with the possibility of metastasectomy recurrence showed higher post-relapse survival compared to other treatment modalities (26 momths vs 5~12 months).
CONCLUSION
These results indicates that pre- and postoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion showed comparable treatment efficacy and acceptable toxicities.

Citations

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Loading comparison of two structures in the moving tube of a non-invasive prosthesis
Jie Zhang, Ping Ye, Lizheng Zhang, Hongliu Wu, Tianxi Chi, Zhaohua Chang
Technology and Health Care.2021; 29(5): 1001. CrossRef
The multidisciplinary treatment of osteosarcoma of the proximal tibia: a retrospective study
Junqi Huang, Wenzhi Bi, Gang Han, Jinpeng Jia, Meng Xu, Wei Wang
BMC Musculoskeletal Disorders.2018;[Epub] CrossRef
Expression change of ezrin as a prognostic factor in primary osteosarcoma
Yao Fei Wang, Jing Nan Shen, Xian Biao Xie, Jin Wang, Gang Huang
Medical Oncology.2011; 28(S1): 636. CrossRef
Comparison of Long-Term Outcome between Doublet and Triplet Neoadjuvant Chemotherapy in Non-Metastatic Osteosarcoma of the Extremity
Soojung Hong, Sang Joon Shin, Minkyu Jung, Jaeheon Jeong, Young Joo Lee, Kyoo-Ho Shin, Jae Kyung Roh, Sun Young Rha
Oncology.2011; 80(1-2): 107. CrossRef
Clinical Value of Ezrin Expression in Primary Osteosarcoma
Chan Kim, Eunah Shin, Soojung Hong, Hong Jae Chon, Hye Ryun Kim, Jung Ryun Ahn, Min Hee Hong, Woo Ick Yang, Jae Kyung Roh, Sun Young Rha
Cancer Research and Treatment.2009; 41(3): 138. CrossRef
Carboxypeptidase-G2 Rescue in a Patient with High Dose Methotrexate-induced Nephrotoxicity
Eun Sil Park, Kyung Hee Han, Hyoung Soo Choi, Hee Young Shin, Hyo Seop Ahn
Cancer Research and Treatment.2005; 37(2): 133. CrossRef

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Clinical Significance of Apoptosis and p53 Protein Expression in Stage IIB Squamous Cell Carcinoma of the Cervix Treated with Radiotherapy Alone: Eun Ji Chung, Gwi Eon Kim, Jinsil Seong, Woo Ick Yang, Young Tae Kim, Chang Ok Suh; J Korean Cancer Assoc. 2000;32(3):638-646.

Abstract PDF: PURPOSE
The purpose was to investigate the spontaneous apoptotic index (SAI) and p53 protein expression and to identify the role of SAI and p53 protein positivity.
MATERIALS AND METHODS
Forty six patients with squamous cell carcinoma of the cervix, FIGO stage IIB, treated with curative radiotherapy alone between 1990 and 1993 were included in this study. Definitive radiotherapy including external beam and high-dose-rate brachytherapy was given. Pretreatment paraffin-embedded biopsy specimens of those patients were scored for apoptosis and p53 protein expression using mouse mondegrees Clonal antibody (DO-7) by immuno staining. Clinicopathologic characteristics were also studied in relation to SAI and p53 protein expression, and as prognostic factors for clinical outcome.
RESULTS
SAI and p53 were not related to any clinical characteristics. The range of the SAI was 0.2~4.7% (median 1.1%, mean 1.5%). The rate of p53 protein expression was 65.2% (30/46). Patients whose tumors had high SAI and low p53 protein positivity had better treatment outcome than those with lower SAI. There was also a significant correlation between the SAI and p53 protein expression.
CONCLUSION
The pretreatment SAI and p53 oncoprotein expression are clinically useful in predicting the clinical outcome of FIGO stage IIB squamous cell carcinoma of the uterine cervix patients treated with definitive radiotherapy.

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Clinical Significance of Urokinase - type Plasminogen Activator Receptor ( uPAR ) Expression in Breast Cancer Tissues: Soo Jung Gong, Sun Young Rha, Hei Chul Jung, Joon Oh Park, Nae Choon Yoo, Jae Kyung Roh, Woo Ick Yang, Kyong Sik Lee, Jin Sik Min, Byung Soo Kim, Hyun Cheol Chung; J Korean Cancer Assoc. 2000;32(1):53-59.

Abstract PDF: PURPOSE
Cancer invasion is induced by several proteolytic enzyme systems associated with the destruction of basement membrane and extracellular matrix. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been reported as prognostic factors in breast cancer patients and plasminogen activation is regulated by various factor such as uPAR and growth factor. So we examined the tissue levels of urokinase-type plasminogen activator receptor (uPAR) in breast cancer patients.
MATERIALS AND METHODS
Tissue uPAR levels were measured by ELISA assay in 268 breast cancer patients.
RESULTS
The median and mean values of tissue uPAR level in breast cancer were 3.5 ng/mg and 4.8+-3.6 ng/mg cytosol protein, respectively. Tissue uPAR level was the highest in T1 stage, but there was no statistical significance between T stage (p >0.05). In nodal stage, there was also no difference in the value of uPAR according to progression. And the value of uPAR expression was not associated with estrogen and progesteron receptor status, number of involved node and percent of node involvement. In TNM stage, tissue uPAR levels were higher in patients with stage I-II than in patients with stage III-IV (p=0.027). In univariate analysis, nodal factor (p=0.0023) and TNM stage (p=0.0004) were significantly associated with overall survival. But, multivariate analysis showed that TNM stage was the only significant prognostic factor (p=0.0002). CONCLUSION: These results suggest that uPAR is mainly associated with initial tumor invasion and other factors might be involved in later stages of cancer progression.

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Clinical Relevance of Urokinase-type Plasminogen Activator ( uPA ) , uPA Receptor , Plasminogen Activator Inhibitor-1 Co-expression from Tissue and Serum of Breast Cancer as Targets of Biotherapy: Sun Young Rha, Joon Oh Park, Soo Jung Gong, Se Ho Park, Nae Choon Yoo, Woo Ick Yang, Jae Kyung Roh, Jin Sik Min, Kyong Sik Lee, Byung Soo Kim, Hyun Cheol Chung; J Korean Cancer Assoc. 1999;31(2):256-266.

Abstract PDF: PURPOSE
We measured and compared the uPA, plasminogen activator inhibitor-1 (PAI-1) and uPA receptor (uPAR) levels in breast cancer tissues and blood of the patients to evaluate their clinical relevance for biotherapy.
MATERIALS AND METHODS
uPA, PAI-1 (Monozyme, Netherland), uPAR (American Diagnostics, USA) levels were measured by ELISA assay in 192 breast cancer tissues, in 18 normal breast tissues and in 163 blood from breast cancer patients. RESULTS: There was a tendency of uPA increment from ductal carcinoma in situ while increment of PAI-1 and uPAR occurred from Ti. With the progression of cancer, uPA, PAI-1, uPAR tended to decrease; however, the uPA/uPAR, uPA/PAI-1 ratios remained unchanged. There was a correlation of uPA expression between normal and cancer tissues ( r(2)= 0.49). Correlation of uPA and PAI-1 was found in normal tissue and stage I cancer tissue while correlation of uPAR and PAI-1 was found with cancer progression. Between cancer tissue and blood significant correlations were found in uPA, PAI-1, uPAR levels.
CONCLUSION
uPA, PAI-1, uPAR levels in cancer tissue elevated from the early stage maintaining correlative expressions with cancer progression. A positive correlation between cancer tissue and blood level suggested the applicability of the levels of uPA, PAI-1 or uPAR for detecting patients for biotherapy.

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The Efficacy of Pre - operative Chamotherapy with Intra-arterial Cisplatin and Intravenous Adriamycin for High Grade Osteosarcoma: Sun Young Rha, Soo Jung Gong, Hee Cheol Chung, Kwang Yong Shim, Joong Bae Ahn, Nae Choon Yoo, Hyn Cheol Chung, Joo Hang Kim, Hae Kyung Roh, Jin Sik Min, Byung Soo Kim, Kyu Ho Shin, Woo Ick Yang, Chong In Lee; J Korean Cancer Assoc. 1999;31(1):134-143.

Abstract PDF: PURPOSE
Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment [pre-operative chemotherapy + surgery (limb salvage or amputation) + adjuvant chemotherapy] had improved the overall survival and quality of life. To improve the local control rate, we introduced pre-operative chemotherapy combined with intra-arterial (IA) cisplatin and continuous intravenous infusion (CI) of adriamycin. We evaluated the efficacy and feasibility, such as limb salvage rate, recurrence pattern and the survival impact, based on the histologic response of pre-operative chemotherapy.
MATERIALS AND METHODS
Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1996. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72hrs CI, was administered for 3 cycles with 3 week interval, followed by surgery. Post-operative chemotherapy was applied by the tumor necrosis rate. If the tumor necrosis of the specimen was more than 90%, the same regimen af the preoperative one was administered for 3 cycles. A salvage regimen (Ifosfamide 7.5 gm/m2/5d IV + high dose MTX 10 gm/m2 IV VP-16 360 mg/m2/3d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%.
RESULTS
Of 41 patients, 37 were evaluable for efficacy and toxicities, because 4 refused further chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 female, with the median age of 16 years (8-41). The tumor locations were as follows: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (10 with grade III, 27.8%; 17 with grade IV, 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lungs. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive care.
CONCLUSION
Pre-operative chemotherapy combined with IA cisplatin and CI adriamycin induced higher good response rate without survival benefits. To improve the survival rate, the design of good salvage chemotherapy with a non-cross resistant regimen should be considered.

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Microsatellite Instability Correlate with a Prognosis in Breast Cancer: Hwa Young Lee, Chengshi Quan, Soo Jung Gong, Joon Oh Park, Joong Bae Ahn, Kwang Yong Shim, Sun Young Rha, Nae Choon Yoo, Woo Ick Yang, Joo Hang Kim, Jae Kyung Roh, Kyong Sik Lee, Byung Soo Kim, Hyun Cheol Chung; J Korean Cancer Assoc. 1998;30(5):914-920.

Abstract PDF: PURPOSE
Microsatellite instability in patients with defects in the mismatch repair system resulting in RER has a high risk of accumulating mutations in oncogene and tumor suppressor gene. In this study, we evaluated the incidence of microsatellite instability in breast cancer by comparing PCR-amplified sequences from frozen samples of normal and tumor tissue fram affected patients. We also investigated whether RER was associated with TGF-beta RII mutation.
MATERIALS AND METHODS
Fifty surgically resected breast cancer specimens from Jan. 1996 to June, 1997 were used for study. Microsatellite instability(referred to as replication error, RER) at three loci with BAT 26, BAT 40, TA10 was analyzed by polymerase chain reaction and the results were compared with clinicopathologic characteristics.
RESULTS
Of the 50 breast cancer patients, 14(28%) were RER(+) at one or more microsatellite loci, and 4(8%) showed TGF-beta RII mutation. Microsatellite instability was significantly correlated with lymph node involvement(especially in case of 4 or more lymph nodes involvement). But we could not find any correlation between RER and other prognostic factors including tumor size, tumor grade, hormone receptor status and pathology. One of fourteen tumors with RER(+) showed TGF-beta RII mutstion. There was no signiticant correlation between RER(+) and TGF-beta type II receptor gene mutation.
CONCLUSION
The findings suggest that microsatellite instability would be useful prognostic factor in unilateral breast cancer patients, and the role of targeting to gene mutation will be explored in future studies.

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