Sei Joong Kim

TrkC binds to the type II TGF- β receptor to suppress TGF- β signaling

Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner of the Tel-TrkC (ETV6-NTRK3) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages. Recently, we have shown that ETV6-NTRK3 suppresses transforming growth factor-β (TGF-β) signaling by directly binding to the type II TGF-β receptor (TβRII). Here, we report that expression of TrkC also suppresses TGF-β-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-β-induced Smad2/3 phosphorylation and restored TGF-β growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-β transcriptional activation. Moreover, we show that TrkC directly binds to the TβRII, thereby preventing it from interacting with the type I TGF-β receptor (TβRI). These results indicate that TrkC is an inhibitor of TGF-β tumor suppressor activity.

Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast

Despite strong possibility that endothelial cells (ECs) of tumors and normal tissues may differ in various aspects, most previous studies on ECs have used normal cells. Here, we purified ECs from tumorous and normal human breast tissues, and studied the effect of radiation on angiogenesis and relevant molecular mechanisms in these cells. We found that in normal tissue-derived ECs (NECs), 4 Gy irradiation increased tube formation, matrix metalloproteinase 2 (MMP-2) expression and extracellular signal-regulated kinase (ERK) pathway activation. In cancer-derived ECs (CECs), however, 4 Gy irradiation significantly reduced tube formation, increased the production of angiostatin and interleukin-6 (IL-6), and upregulated AKT and c-Jun N-terminal kinase (JNK) pathway activation. Knockdown experiments showed that siMMP-2 efficiently inhibited tube formation by irradiated NECs, whereas siPlasminogen effectively attenuated the radiation-induced suppression of tube formation and the upregulation of angiostatin in CECs. Moreover, siIL-6 clearly inhibited the radiation-induced generation of angiostatin in CECs. Inhibition of ERK with a pharmacological inhibitor or small interfering RNAs (siRNAs) markedly suppressed the radiation-induced tube formation and MMP-2 upregulation in NECs, whereas the inhibition of either AKT or JNK with pharmacological inhibitor or siRNA treatment of CECs markedly attenuated the inhibition of tube formation and the upregulation of angiostatin and IL-6 caused by 4 Gy irradiation. These observations collectively demonstrate that there are distinct differences in the radiation responses of NECs and CECs, and might provide important clues for improving the efficacy of radiation therapy.

Left Paraduodenal Hernia Presenting with Atypical Symptoms

Paraduodenal hernias are a rare congenital malformation, but they are the most common internal hernias. They develop secondary to a failure in midgut rotation, which may lead to small bowel obstruction or other clinical manifestations. The authors recently experienced a case of a left paraduodenal hernia presenting with unusual symptoms of left flank pain and vomiting.

Low bone density in breast cancer survivors in Korea: Prevalence, risk factors and associations with health-related quality of life

PURPOSE To examine the prevalence and risk factors of low bone density and identify associations with health-related quality of life (HRQOL) in breast cancer survivors in Korea. METHODS This study was a cross-sectional descriptive study design. A total of 136 women with breast cancer who had completed their therapy were recruited at one university-based cancer center in Korea. Bone mineral density (BMD), health behaviors (physical activity, diet/nutrition behaviors, smoking, alcohol consumption, sunlight exposure), and HRQOL were measured. RESULTS Among the 136 breast cancer survivors, 49 women (36.0%) had osteopenia and six women (4.4%) had osteoporosis. Univariate analyses revealed that older age, low education level, low monthly income, tamoxifen therapy, aromatase inhibitor therapy, calcium supplement intake, and past or current smoking were associated with low bone density (BMD T-score < -1.0). In multivariate analyses, low economic status (OR = 2.22, p = 0.050) and past or current smoking (OR = 3.77, p = 0.039) were final risk factors of low bone density. In addition, women who had low bone density reported worse role function (p = 0.022) than women who did not. CONCLUSIONS Women of lower economic status or who are past or current smokers warrant monitoring and treatment strategies to reduce bone loss risk. Nurses may play a crucial role in screening this high-risk group for low bone density and in educating patients on the importance of healthy lifestyle changes.

Effect of multiple invasive foci on breast cancer outcomes according to the molecular subtypes: a report from the Korean Breast Cancer Society

BACKGROUND In this study, the prognostic impact of the presence of the multifocal or multicentric tumor (MMT) and its association with molecular subtypes were investigated. PATIENTS AND METHODS We investigated the breast cancer metastasis and survival in patients with multifocal or multicentric invasive foci in the same breast. The study population includes 2882 patients in the Seoul National University Hospital Breast Care Center (SNUHBCC) dataset and 41 179 patients in Korean Breast Cancer Registry (KBCR) dataset. RESULTS From SNUHBCC dataset, we observed a significant role of MMT in developing distant metastasis and death when the tumors were triple-negative subtype. This subtype-specific prognostic importance of MMT in overall survival was also seen in KBCR dataset (HR, 1.32; 95% CI, 1.02-1.69). In tumors <2 cm, the hazard ratios (HRs) for node metastasis and death were similar along the tumor size change in triple-negative subtype, while other subtypes showed a stepwise increment, suggesting the biologic importance of small invasive foci in this subtype. CONCLUSIONS Our results demonstrate the prognostic importance of MMT in patients with triple-negative breast cancers. Small additional invasive foci in triple-negative breast cancer patients should be considered as clinically relevant tumor deposits.

Huge cystic lymphangioma involving the entire breast.

We report a case of a 31-year-old female who required mastectomy with the diagnosis of cystic lymphangioma of the entire left breast. We tried operative management that is not mastectomy since it was not malignant, but finally mastectomy was needed. In reduction mammaplasty patients, plastic surgeons should consider cystic lymphangioma as a differential diagnosis of unilateral large breasts.

The radiosensitivity of endothelial cells isolated from human breast cancer and normal tissue in vitro

We developed a novel method for harvesting endothelial cells from blood vessels of freshly obtained cancer and adjacent normal tissue of human breast, and compared the response of the cancer-derived endothelial cells (CECs) and normal tissue-derived endothelial cells (NECs) to ionizing radiation. In brief, when tissues were embedded in Matrigel and cultured in endothelial cell culture medium (ECM) containing growth factors, endothelial cells grew out of the tissues. The endothelial cells were harvested and cultured as monolayer cells in plates coated with gelatin, and the cells of 2nd-5th passages were used for experiments. Both CECs and NECs expressed almost the same levels of surface markers CD31, CD105 and TEM-8 (tumor endothelial marker-8), which are known to be expressed in angiogenic endothelial cells, i.e., mitotically active endothelial cells. Furthermore, both CECs and NECs were able to migrate into experimental wound in the monolayer culture, and also to form capillary-like tubes on Matrigel-coated plates. However, the radiation-induced suppressions of migration and capillary-like tube formations were greater for CECs than NECs from the same patients. In addition, in vitro clonogenic survival assays demonstrated that CECs were far more radiosensitive than NECs. In summary, we have developed a simple and efficient new method for isolating endothelial cells from cancer and normal tissue, and demonstrated for the first time that endothelial cells of human breast cancer are significantly more radiosensitive than their normal counterparts from the same patients.

Identifying long-term survivors among metastatic breast cancer patients undergoing primary tumor surgery

PurposeThe prognostic role of primary tumor surgery in women with metastatic breast cancer at diagnosis is contentious. A subset of patients who will benefit from aggressive local treatment is needed to be identified. Using a nationwide database, we developed and validated a predictive model to identify long-term survivors among patients who had undergone primary tumor surgery.MethodsA total of 150,043 patients were enrolled in the Korean Breast Cancer Registry between January 1990 and December 2014. Of these, 2332 (1.6%) presented with distant metastasis at diagnosis. Using Cox proportional hazards regression, we developed and validated a model that predicts survival in patients who undergo primary tumor surgery, based on the clinicopathological features of the primary tumor.ResultsA total of 2232 metastatic breast cancer patients were reviewed. Of these, 1541 (69.0%) patients had undergone primary tumor surgery. The 3-year survival rate was 62.6% in this subgroup. Among these patients, advanced T-stage, high-grade tumor, lymphovascular invasion, negative estrogen receptor status, high Ki-67 expression, and abnormal CA 15-3 and alkaline phosphatase levels were associated with poor survival. A prediction model was developed based on these factors, which successfully identified patients with remarkable survival (score 0–3, 3-year survival rate 87.3%). The clinical significance of the model was also validated with an independent dataset.ConclusionsWe have developed a predictive model to identify long-term survivors among women who undergo primary tumor surgery. This model will provide guidance to patients and physicians when considering surgery as a treatment modality for metastatic breast cancer.

The Effect on Bone Outcomes of Adding Exercise to Supplements for Osteopenic Breast Cancer Survivors: A Pilot Randomized Controlled Trial.

Background: Cancer treatment–induced bone loss is an important long-term effect in breast cancer survivors, but evidence regarding lifestyle interventions for preventing cancer treatment–induced bone loss is lacking. Objective: The aim of this study was to investigate the feasibility, safety, and effects of a 6-month combined home-based exercise and calcium and vitamin D supplements (EX + SUPP) intervention compared with calcium and vitamin D supplements alone (SUPP) on bone health of osteopenic breast cancer survivors. Methods: In this pilot randomized controlled trial, we enrolled 43 women with breast cancer who were diagnosed as osteopenic through bone mineral density screening. Women were randomly assigned to the EX + SUPP group (n = 23) or the SUPP group (n = 20). Results: The rates of participant retention (90.7%) and of counseling calls delivered to the EX + SUPP group (90.3%) were high. The average exercise adherence rate was 69.5% for weight-bearing exercise and 48.5% for resistance exercise. The EX + SUPP group reported no injuries or adverse events. Despite positive findings of adherence and safety, no significant group differences were observed for bone mineral density, bone turnover marker, or physical performance. Conclusions: A home-based exercise program for bone health among osteopenic breast cancer survivors is feasible and safe. There was no significant additive effect of exercise on bone outcomes under the conditions studied, however, suggesting the need for a larger trial. Implications for Practice: Effective exercise intervention may require more intensive components such as higher loading forces and longer duration for improving bone health among this population.

Ectopic Hidradenoma Papilliferum of the Breast: Ultrasound Finding

Hidradenoma papilliferum (HP) is a benign neoplasm arising from mammary-like glands which typically involves the dermal layer of the female anogenital area. The prognosis for HP is good. Recurrence is unusual and is typically attributed to incomplete excision of the primary tumor. Malignant transformation is rare and HP of the breast has not yet been reported. Ectopic HP is usually solitary, small, and asymptomatic. It appears as a well-circumscribed, complex cystic mass in the dermis on ultrasound. We present a case of HP arising from the axillary tail of the breast.