Seung Sook Lee

Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: A multicentre, single-arm, phase 2 trial

BACKGROUND We performed a phase II study to evaluate the efficacy of bortezomib in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas (PTCLs) based on our phase I study results. METHODS Patients received bortezomib on days 1 and 8 at a dose of 1.6 mg/m(2) in addition to CHOP every 3 weeks for a total of six cycles. RESULTS Forty-six patients were enrolled: PTCL, not otherwise specified (PTCL-NOS, n=16), extranodal NK/T-cell lymphoma, nasal type (ENKTL, n=10), angioimmunoblastic T-cell lymphoma (AITL, n=8), ALK-negative anaplastic large-cell lymphoma (ALCL, n=6), cutaneous T-cell lymphoma (CTCL, n=5) and hepatosplenic T-cell lymphoma (n=1). Thirty patients achieved complete response (CR, 65%) and the overall response rate was 76% (35/46). Although the CR rate of ENKTL was only 30% (3/10), three subtypes of PTCLs (PTCL-NOS, AITL and ALCL) showed 87% of overall response rate (ORR) (26/30) and 73% of CR rate (22/30). However, the 3-year overall survival and progression-free survival were 47% and 35%, respectively due to frequent relapse after remission. Grade 3/4 leucopenia was the most frequent toxicity whereas neurotoxicity was tolerable: grade 1 or 2 of peripheral neuropathy. CONCLUSIONS The combined treatment of bortezomib and CHOP is an effective and feasible regimen for advanced-stage PTCLs other than ENKTL, with acceptable toxicity. However, future studies exploring new drug combinations are warranted to overcome relapse after remission.

The Role of MET Activation in Determining the Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Resistant cells also showed MET activation, although gene amplification was not detected. Furthermore, the induction of MET activity was not found to be associated with sensitivity to EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib or erlotinib caused MET activation, but this did not affect sensitivity to EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by hepatocyte growth factor did not modulate the cellular effects of gefitinib or erlotinib. Rather, activated MET enhanced migration and invasion abilities. Summarizing, MET activation may be acquired during cancer cell proliferation and enhances migratory and invasive abilities without affecting cellular sensitivity to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused by factors other than MET gene amplification is not a suitable surrogate marker of resistance to EGFR-TKIs. (Mol Cancer Res 2009;7(10):1736–43)

Alteration of signal-transducing molecules in tumor-infiltrating lymphocytes and peripheral blood T lymphocytes from human colorectal carcinoma patients

Abstract Tumor development or growth is accompanied by impaired immune responses, such as a poor proliferative response or down-regulated cytolytic T lymphocyte activity. Although recent reports have suggested that modification of the signal-transducing molecule is responsible for impaired immune responses in tumor-bearing hosts, the causes of defective immune function are not yet completely understood. Furthermore, the clinical significance of the findings is not yet clear. In this study, we investigated the alteration of several signal-transducing molecules in peripheral blood T lymphocytes (T-PBL) as well as in tumor-infiltrating lymphocytes (TIL) from human colorectal carcinoma patients and their relationship with the impaired host immune responses. A greater reduction in CD3ζ chain level was observed in TIL than in T-PBL from tumor-bearing hosts. CD3ζ chain reduction in T-PBL correlated with the clinicopathological stage of a tumor, especially with the status of lymph node metastasis. The levels of p56lck and p59fyn protein tyrosine kinase in T-PBL were also compared between tumor-bearing hosts and normal healthy volunteers. In T-PBL from tumor-bearing hosts, expression of protein tyrosine kinase p59fyn was significantly lower than that of p56lck. However, the level of CD3ζ chain expression did not correlate with T lymphocyte functions such as T lymphocyte proliferative response or allogeneic target cell lysis.

Molecular characterization of epstein-barr virus and oncoprotein expression in nasopharyngeal carcinoma in Korea

We evaluated the characteristics of nasopharyngeal carcinoma in Korea, including its clinical, pathologic, and molecular features, especially emphasizing on the EBV strains involved, latent membrane protein 1 (LMP1) expression, and the alterations of matrix metalloproteinase 9 (MMP9) and E‐cadherin expression.

Lymph Node to Primary Tumor Suv Ratio by 18f-fdg Pet/ct and the Prediction of Axillary Lymph Node Metastases in Breast Cancer

Purpose The authors evaluated the usefulness of axillary lymph node (ALN) to primary breast tumor SUV ratio (determined by 18F-FDG PET/CT) for predicting the presence of ALN metastasis in breast cancer. Methods One hundred thirty-six consecutive female patients with breast cancer were enrolled in this retrospective study between January 2009 and November 2012. All patients underwent surgical resection without neoadjuvant chemotherapy, and ALN metastases were histologically confirmed by ALN dissection (n = 75) or sentinel lymph node (LN) biopsy (n = 61). The maximum SUVs of FDG-avid ALNs (SUVLN) and of primary breast tumors were measured on preoperative 18F-FDG PET/CT images, and ALN to primary breast tumor SUV ratios (LN/T ratios) were calculated. In a subgroup of patients with FDG-avid ALNs, optimal cutoff values for SUVLN and LN/T ratio were determined by receiver operating characteristic curve analysis for predicting the presence of ALN metastasis. Subsequently, the diagnostic performances of visual analysis (presence of FDG-avidity), SUVLN, and LN/T ratio for the prediction of ALN metastasis were determined. Results In a subgroup of patients with FDG-avid ALNs (n = 65), the area under the curve and the optimal criteria of SUVLN for detecting ALN metastasis were 0.655 and greater than 2.1, and those of LN/T ratio were 0.739 and greater than 0.2, respectively. For these criteria, the sensitivity, specificity, and diagnostic accuracy of detecting ALN metastasis were 71.4%, 77.3%, and 74.3%, respectively, for visual analysis; 47.1%, 93.9%, and 69.9%, respectively, for SUVLN; and 62.9%, 92.4%, and 77.2%, respectively, for LN/T ratio in all patients. The specificity of LN/T ratio was significantly higher than that of visual analysis (P = 0.0259). Although the sensitivity of LN/T ratio was higher than that of SUVLN, it did not reach a statistical significance (P = 0.0874). Conclusions The LN/T ratio better predicts the presence of ALN metastasis than visual analysis or SUVLN in breast cancer.

Prognostic Significance of Pretreatment 18F-FDG PET/CT in Patients with Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma Treated by Radioimmunotherapy Using 131I-Rituximab

Aims: It was the aim of this paper to identify prognostic factors in patients with relapsed or refractory B-cell non-Hodgkins lymphomas, treated by radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti-CD20 monoclonal antibody rituximab (131I-rituximab). Methods: Twenty-four patients were enrolled prospectively and were treated with unlabeled rituximab 70 mg and a therapeutic activity (median 7.3 GBq) of 131I-rituximab. Contrast-enhanced 18F-FDG PET/CT scans were performed before and after 1 month of RIT. Tumor sizes and maximum standardized uptake values (SUVmax) of scans were measured. Results: Four of the 24 patients survived. High SUVmax in a pretreatment scan was found to be related to poorer overall survival (OS) and progression-free survival (p = 0.04 and 0.02, respectively). Furthermore, a large tumor size in a pretreatment scan was associated with poorer OS but not with progression-free survival (p < 0.01 and p = 0.07, respectively). By multivariate analyses, a high SUVmax, a large tumor size in a pretreatment scan and diffuse large B-cell lymphoma histology were significantly associated with poorer OS [p = 0.04/hazard ratio (HR) = 3.54, p < 0.01/HR = 5.52, and p = 0.02/HR = 3.38, respectively). Conclusion: SUVmax and tumor size determined by a pretreatment 18F-FDG PET/CT result as significant predictors of OS in patients with relapsed or refractory B-cell non-Hodgkins lymphoma treated by RIT.

Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma.

Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation.

Radiation-induced eosinophilic, polymorphic, and pruritic eruption in a pig skin model

Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy (EPPER) can occur in cancer patients after irradiation. In this study, we characterized the clinical and histopathological features of pig skin that developed widespread polymorphic and pruritic skin lesions following localized 50 Gy gamma-irradiation. The pigs developed pruritus 5-7 weeks after irradiation, and infiltration of the dermis by eosinophils was detected 4-7 weeks after irradiation. The irradiated animals also showed transiently increased numbers of peripheral eosinophils 5-7 weeks after treatment. Irradiation induced desquamation after 2-4 weeks, which and the desquamation gradually resolved after 7 weeks. These pathological changes correspond to those seen in irradiated human skin, indicating that this model could be useful for elucidating the pathogenesis of EPPER and for developing therapeutic and prophylactic methods.

A Case of Severe Protein-losing Enteropathy as a Late Complication of Pelvic Irradiation

Protein-losing enteropathy is the manifestation of a diverse set of disorders, and it is characterized by the excessive loss of plasma proteins into the affected portions of the gastrointestinal tract, and this results in hypoalbuminemia. We report here on a case of severe protein-losing enteropathy with the typical clinical features of hypoalbuminemia, dependent edema and increased alpha 1-antitrypsin (α1-AT) clearance, as measured by using 24hr stool testing. The associated disorder with the protein-losing enteropathy of our case was radiation enterocolitis and lymphatic obstruction that was due to radiation treatment and lymph node dissection in the remote past for the treatment of uterine cervical carcinoma. Our case suggests that chronic radiation enterocolitis can result in irreversible injury to the intestinal mucosa and a protein-losing enteropathy, which can bring about a very poor quality of life and even the loss of life.

A Proposal for Creating a Guideline for Cancer Registration of the Fibromatosis, PEComa Group, Malignant Lymphoma In Situ and Dendritic Cell Tumors (III)

Background Understanding the biologic behavior of a tumor is a prerequisite for tumor registration code assignment. The aim of this report was to propose appropriate behavior codes of the International Classification of Disease Oncology 3 (ICD-O3) to rare, yet pathologically interesting hematopoietic and soft tissue tumors. Methods The Study Group for Hematopathology, the Bone and Soft Tissue Pathology Study Group, and the Cancer Registration Committee prepared the questionnaire containing provisional behavior codes of selected diseases. Results In situ lesions of mantle cell and follicular lymphomas, dendritic cell tumors, and neoplasms with perivascular epithelioid cell differentiation (PEComa), not otherwise specified were classified as malignant (-/3). The fibromatosis group, with the exception of lipofibromatosis, was proposed as benign (-/0). Lipofibromatosis and several diseases that belong to the PEComa group were proposed as uncertain malignant potential (-/1). For the hematologic and soft tissue tumors, 274 and 288 members of the Korean Society of Pathologists, respectively, provided opinions through questionnaire, and most responders showed agreement with the provisional behavior code proposed. Conclusions The determination of behavior codes for the rare diseases described in this study, especially those of the PEComa group or malignant lymphoma, could be viewed as impractical and premature, but this study provides the basis for future research on this topic.