ELOVL2-AS1 suppresses tamoxifen resistance by sponging miR-1233-3p in breast cancer.

Tamoxifen (Tam) has long been a top treatment option for breast cancer patients, but the challenge of eliminating cancer recurrence remains. Here, we identify a signalling pathway involving ELOVL2, ELOVL2-AS1, and miR-1233-3p, which contributes to drug resistance in Tam-resistant (TamR) breast cancer. ELOVL2-AS1, a long noncoding RNA, was significantly upregulated by its antisense gene, ELOVL2, which is known to be downregulated in TamR cells. Additionally, ELOVL2-AS1 underwent the most hypermethylation in MCF-7/TamR cells. Furthermore, patients with breast cancer who developed TamR during chemotherapy had significantly lower expression of ELOVL2-AS1 compared to those who responded to Tam. Ectopic downregulation of ELOVL2-AS1 by siRNA both stimulated cancer cell growth and deteriorated TamR. We also found that ELOVL2-AS1 sponges miR-1233-3p, which has pro-proliferative activity and elevates TamR, leading to the activation of potential target genes, such as MYEF2, NDST1, and PIK3R1. These findings suggest that ELOVL2-AS1, in association with ELOVL2, may contribute to the suppression of drug resistance by sponging miR-1233-3p in breast cancer.

An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer.

PURPOSE: Pegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support. MATERIALS AND METHODS: This was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE. RESULTS: Pegfilgrastim administration reduced FN by 11.8-1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%. CONCLUSION: The use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.

Accuracy of Digital Breast Tomosynthesis for Detecting Breast Cancer in the Diagnostic Setting: A Systematic Review and Meta-Analysis.

OBJECTIVE: To compare the accuracy for detecting breast cancer in the diagnostic setting between the use of digital breast tomosynthesis (DBT), defined as DBT alone or combined DBT and digital mammography (DM), and the use of DM alone through a systematic review and meta-analysis. MATERIALS AND METHODS: Ovid-MEDLINE, Ovid-Embase, Cochrane Library and five Korean local databases were searched for articles published until March 25, 2020. We selected studies that reported diagnostic accuracy in women who were recalled after screening or symptomatic. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate random effects model was used to estimate pooled sensitivity and specificity. We compared the diagnostic accuracy between DBT and DM alone using meta-regression and subgroup analyses by modality of intervention, country, existence of calcifications, breast density, Breast Imaging Reporting and Data System category threshold, study design, protocol for participant sampling, sample size, reason for diagnostic examination, and number of readers who interpreted the studies. RESULTS: Twenty studies (n = 44513) that compared DBT and DM alone were included. The pooled sensitivity and specificity were 0.90 (95% confidence interval [CI] 0.86-0.93) and 0.90 (95% CI 0.84-0.94), respectively, for DBT, which were higher than 0.76 (95% CI 0.68-0.83) and 0.83 (95% CI 0.73-0.89), respectively, for DM alone (p < 0.001). The area under the summary receiver operating characteristics curve was 0.95 (95% CI 0.93-0.97) for DBT and 0.86 (95% CI 0.82-0.88) for DM alone. The higher sensitivity and specificity of DBT than DM alone were consistently noted in most subgroup and meta-regression analyses. CONCLUSION: Use of DBT was more accurate than DM alone for the diagnosis of breast cancer. Women with clinical symptoms or abnormal screening findings could be more effectively evaluated for breast cancer using DBT, which has a superior diagnostic performance compared to DM alone.

Cordyceps militaris Induces Immunogenic Cell Death and Enhances Antitumor Immunogenic Response in Breast Cancer.

Cordyceps militaris has been widely used as a traditional medicine in East Asia. Its effects against breast cancer have been reported previously. However, whether C. militaris-induced breast cancer cell death is immunogenic remains unelucidated. This study aimed to determine whether ethanolic extracts of C. militaris (CM-EE) could induce immunogenic cell death (ICD) in breast cancer immunotherapy to improve the efficacy of immune checkpoint inhibitors. Human and mouse breast cancer cells were treated with various concentrations of CM-EE for 72 h, and cytotoxicity was measured using the sulforhodamine B assay. Flow cytometry was used to assess cell death with annexin V/7-AAD staining and measure the surface exposure of damage-associated molecular pattern (DAMP) molecules including calreticulin, HSP70, and HSP90. Western blot for cleaved poly (ADP-ribose) polymerase (PARP) was used to confirm apoptotic cell death. The immunogenicity of CM-EE-induced dead cells was evaluated using the CFSE dilution assay. CM-EE reduced the viability of human (MCF7, MDA-MB-231, HS578T, and SKBR3) and mouse (4T1-neu-HA, TUBO-HA, and TUBO-P2J-HA) breast cancer cells. The IC50 was 25-50 µg/ml in human breast cancer cells and 10-50 µg/ml in mouse breast cancer cells at 72 h. CM-EE-treated breast cancer cells were positively stained by annexin V, cleaved PARP, and cleaved caspase 3/7 which were increased upon CM-EE treatment. Surface exposure of DAMP molecules was increased in dose- and time-dependent manners. The CFSE dilution assay revealed that dendritic cells fed with CM-EE-treated breast cancer cells successfully stimulated tumor-specific T cell proliferation without inhibiting DC function and T cell proliferation. The expression of PD-L1 mRNA and protein level was increased in dose-dependent manners. In addition, CM-EE also potentiated the cytotoxic activity of tumor-specific T cells. CM-EE can induce immunogenic and apoptotic cell death in breast cancer cells, and it is a good candidate for cancer immunotherapy and may improve the efficacy of immune checkpoint inhibitors.

Age-related risk factors associated with primary contralateral breast cancer among younger women versus older women.

PURPOSE: Contralateral prophylactic mastectomy is increasing, despite unclear evidence of improving survival. To investigate the age-related risk factors for contralateral breast cancer (CBC). METHODS: This study included 8716 patients diagnosed with non-metastatic unilateral invasive breast cancer between 1989 and 2008. Data on primary tumor size, node metastasis, grade and subtype using individual matching were used to adjust for differences in the primary tumor and treatment between younger and older age groups. CBC risk factors, CBC-free survival, and annual CBC risk were analyzed by age. RESULTS: The younger group included 652 patients aged under 35 years, and the older group included 2608 women aged 35 years or older. The median time to CBC development was 6.1 years. CBC was detected in 6.6% of the women in the younger group and 2.5% of those in the older group. Multivariable analysis revealed a relative CBC risk of 2.48 in younger women compared to older women. The risk was significantly higher among women with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors (hazard ratio [HR] 4.98), a family history of breast cancer (HR 7.79), and anti-hormone therapy (HR 3.46). In younger women with HER2-positive cancer, CBC occurrence peaked at 4.6 years after surgery, in those with hormone receptor-positive cancer, it peaked at 7.1 years after surgery, and in triple-negative disease cases, and it increased steadily over time. CONCLUSIONS: After adjusting for primary breast tumor characteristics, patients < 35 years old had 2.5 times the risk of CBC development compared to the older women. CBC occurrence peaked within 5 years after primary breast cancer in younger women with the HER2-positive subtype and after 5 years in cases with the hormone receptor-positive subtype.

Breast sparganosis: a case report.

A 57-year-old Korean female patient presented with a migrated palpable left breast mass. Physical examination revealed a 3-cm soft, non-tender mass in the upper inner quadrant of her left breast. Mammography showed 8.2-cm extended nodular and tortuous tubular masses in the upper portion of her left breast. Ultrasonography revealed a 5.8-cm extended nodular, tortuous tubular and hypoechoic to anechoic lesion in the subcutaneous mammary parenchymal layer. A lumpectomy was conducted and revealed a 30-cm live tapeworm. Histopathologic examination of the excised breast tissue revealed chronic granulomatous inflammation and eosinophilic infiltration by a parasitic organism, which was confirmed as a sparganum. After surgery, the patient was treated with a single dose of praziquantel and albendazole. Asian countries such as Korea, China and Japan are known to have high endemicity of sparganosis, mostly because of their dietary customs. When examining patients from these countries, sparganosis should be considered because of the unique dietary customs despite the high level of hygiene.

Assessment of Quality of Life and Safety in Postmenopausal Breast Cancer Patients Receiving Letrozole as an Early Adjuvant Treatment.

PURPOSE: There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. METHODS: Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. RESULTS: All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p<0.001). The mean serum cholesterol level increased significantly from 199 to 205 after 36 months (p=0.042). The mean BMD significantly decreased from -0.39 at baseline to -0.87 after 36 months (p<0.001). CONCLUSION: QoL gradually improved during letrozole treatment. BMD and serum cholesterol level changes were similar to those in Western countries, indicating that adjuvant letrozole treatment is well tolerated in Korean women, with minimal ethnic variation.

Metastatic Small Cell Carcinoma of the Breast from Cancer of the Uterine Cervix: A Case Report.

We report here on a case of 51-year-old woman with metastatic small cell carcinoma of the breast that came from her cancer of the uterine cervix. She underwent radical hysterectomy with bilateral salpingo-oophorectomy due to small cell carcinoma of the uterine cervix, and adjuvant radiotherapy was administered to the pelvis. Breast metastasis with a palpable mass then occurred 3 months after the primary surgery. Simple mastectomy and adjuvant chemotherapy were performed. She initially showed a good response to the therapy, yet she ultimately died of multiple metastases with a fulminating disease course. This is an extremely rare case, and only 1 similar case has been reported earlier, so we report on this case along with a review of the relevant literature.

Is a One Night Delay of Surgery Safe in Patients With Acute Appendicitis?

PURPOSE: With varied reports on the impact of time to appendectomy on clinical outcomes, the purpose of this study was to determine the effect of preoperative in-hospital delay on the outcome for patients with acute appendicitis. METHODS: A retrospective review of 1,076 patients who had undergone an appendectomy between January 2010 and December 2013 was conducted. RESULTS: The outcomes of surgery and the pathologic findings were analyzed according to elapsed time. The overall elapsed time from onset of symptoms to surgery was positively associated with advanced pathology, increased number of complications, and prolonged hospital stay. In-hospital elapsed time was not associated with any advanced pathology (P = 0.52), increased number of postoperative complications (P = 0.14), or prolonged hospital stay (P = 0.24). However, the complication rate was increased when the in-hospital elapsed time exceeded 18 hours. CONCLUSION: Advanced pathology and postoperative complication rate were associated with overall elapsed time from symptom onset to surgery rather than in-hospital elapse time. Therefore, a short-term delay of an appendectomy should be acceptable.

Effect of polylactic film (Surgi-Wrap) on preventing postoperative ileus after major hepato-pancreato-biliary surgery.

BACKGROUNDS/AIMS: Major hepato-pancreato-biliary (HPB) surgery is usually performed via an open method rather than a laparoscopic method. Postoperative ileus (POI) is a classic complication after open surgery. The purpose of this study was to determine whether polylactic film is useful in the prevention of POI. METHODS: A total of 179 patients who underwent major HPB surgery between 2005 and 2014, were retrospectively reviewed. A diagnosis of POI was made by a physical examination, laboratory, and radiological findings. Surgi-Wrap® polylactic film was preferentially used intraperitoneally by surgeons, just before wound closure. RESULTS: Major HPB surgery included pancreatoduodenectomy (n=48), distal or subtotal pancreatectomy (n=24), hepatectomy (n=67), other bile duct or gallbladder operations (n=35), and others (n=5). Although patients with polylactic film showed a significantly lower incidence of POI (n=3, 4.1% vs. n=14, 13.3%, p=0.041), they showed a significantly higher complication rate (n=20, 27.0% vs. n=19, 18.1%, p=0.004), particularly intra-abdominal fluid collection (n=7, 9.4% vs. n=2, 1.9%), and wound infections (n=6, 8.1% vs. n=3, 2.9%), than those who did not receive the film, respectively. CONCLUSIONS: Although the polylactic film prevented POI, more complications other than POI were observed. Well-designed randomized controlled trials, using this anti-adhesive product, are needed to evaluate its effect on POI after major HPB surgery.

Microdochectomy assisted by ultrasound-guided indigo carmine staining of intraductal lesions: a case report.

Spontaneous bloody nipple discharge from a single duct is a significant clinical problem. When performing preoperative marking of the discharging duct, it is sometimes difficult to identify the duct owing to intermittent discharge. Precise preoperative marking of the discharging duct and intraductal lesions is very important to avoid unnecessary wide excision of breast tissue or failure to remove the cause of nipple discharge. We herein present a case of preoperative ultrasound-guided indigo carmine staining in a patient with no discharge on the day of surgery. When a dilated duct is visualized on ultrasound, the targeted duct can be localized using indigo carmine staining, and it is possible to perform a precise minimal volume microdochectomy.

Primary fibrosarcoma of the breast: a case report.

A primary fibrosarcoma of the breast is a rare tumor. Here we report on a case of a primary fibrosarcoma of the breast that presented as a palpable left breast mass in a 47-year-old woman. The physical examination revealed a 3 cm sized, round mass in the left upper outer breast. The mammograms revealed a 3 cm sized, partially circumscribed and partially obscured, high density mass in the upper outer quadrant of the left breast. An ultrasonogram demonstrated a 3 cm sized, ovoid, circumscribed and hypoechoic mass with peripheral increased vascularity on Doppler imaging. Surgical excision was performed and the pathology revealed a low grade fibrosarcoma.

A case of monoclonal gammopathy in extranodal marginal zone B-cell lymphoma of the small intestine.

Monoclonal gammopathy occurs in one-third of the patients with mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). However, monoclonal gammopathy has been rarely reported in Korea. Paraprotenemia accompanying MALT lymphoma is strongly correlated with involvement of the bone marrow, and this involvement leads to the progression of the disease. Here, we present a case of a 66-yr-old man diagnosed with IgM monoclonal gammopathy and stage IV extranodal marginal zone lymphoma of the small intestine, with the involvement of the bone marrow.

Simultaneous adrenal pheochromocytoma and sarcoidosis.

A 48-year-old man presented for evaluation of general weakness. Because he had a history of excessive alcohol use, an abdominal computed tomography scan was obtained, which revealed a left adrenal mass. Hormonal evaluation showed elevated levels of urinary catecholamines. Bilateral hilar lymphadenopathy was detected on a chest radiograph. The suspected diagnosis was asymptomatic pheochromocytoma with sarcoidosis. We performed a mediastinoscopic lymph node biopsy, which was followed by endoscopic adrenalectomy. Histologic tissue analysis confirmed an adrenal pheochromocytoma and sarcoid granulomas in the mediastinal lymph nodes. This case highlights the difficulty in determining the appropriate work up of patients presenting with an adrenal incidentaloma and concomitant systemic disease.

Do very young Korean breast cancer patients have worse outcomes?

BACKGROUND: In general, Korean women with breast cancer are younger than white women. We have compared the clinicopathologic characteristics and prognosis in very young and less young premenopausal Korean women with breast cancer. METHODS: Of the breast cancer patients treated at the Asan Medical Center in Seoul, Korea, from 1989 to 2002, 381 (9.6%) were younger than 35 years of age (the "very young" group) and 2320 were 35 to 50 years of age (the "less young" group). We retrospectively compared the clinicopathologic factors and survival rates of these two groups. RESULTS: The very young group with lymph node metastases had poorer 5-year survival (69.9% vs. 82.7%, P = .0063) and disease-free survival (58.1% vs. 74.1%, P < .0001) rates than their older counterparts. In addition, the very young group had more advanced-stage disease (P = .001), higher T stage (P = .001), and more positive lymph nodes (P = .024) than did their older counterparts, as well as higher percentages of estrogen receptor-negative disease (48.2% vs. 42.1%, P = .047), progesterone receptor-negative disease (53.5% vs. 44.1%, P = .002), and grade 3 histology (52.1% vs. 43.5%, P = .011) tumors. CONCLUSIONS: Compared with older premenopausal Korean women with breast cancer, those younger than 35 years old had a poorer prognosis as a result of a higher rate of recurrence, a later stage at diagnosis, and more aggressive disease. Thus, in Korean breast cancer patients, age younger than 35 years was an independent predictor of recurrence.

BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations.

We analyzed the mutation spectrum of BRCA1 and BRCA2 genes in 354 Korean breast cancer patients. Overall, 40 patients carried 25 distinct BRCA1/2 mutations including 12 novel mutations. Seven district mutations were found in multiple unrelated patients, with the BRCA2 c.7480C>T mutation detected in eight unrelated patients, accounting for 50% of the mutations detected in BRCA2. The large number (25/40, 62.5%) of recurrent mutations suggests the possibility of developing a simple screening test for these mutations. The frequency of mutations was related to the number and kinds of risk factors, varying from 10.4 to 25% in the five major risk factor groups. The frequency of BRCA mutations in patients with two or more risk factors was markedly higher than that in patients with one risk factor.

Changing patterns in the clinical characteristics of Korean patients with breast cancer during the last 15 years.

HYPOTHESIS: Breast cancer has become the most common cancer in Korean women in recent years, with continuously increased incidence rates attributed to westernized lifestyles. DESIGN: Retrospective case series evaluating the changing patterns of clinical characteristics in breast cancer during the last 15 years. SETTING: Hospitalized patients with breast cancer in a university medical center. PATIENTS: A total of 5001 breast cancer patients who underwent surgery between July 1989 and March 2004 at the Asan Medical Center. MAIN OUTCOME MEASURE: Clinicopathologic data were collected using the online Korea Breast Cancer Registration Program, including factors such as age, symptoms, stage, surgery, reconstruction, risk factors, and survival. RESULTS: The median age of patients slightly increased from 44 years in 1991 to 46 years in 2003. The most frequent age group was the fifth decade (41.7%) and premenopausal women younger than 50 years (64.9%). The proportion of asymptomatic patients detected by screening mammography increased from 3.8% in 1991 to 21.0% in 2003 (P<.001). The proportion of early breast cancer (stages 0 and I) increased from 34.2% in 1991 to 48.8% in 2003 (P=.013). Breast-conserving surgery has increased continuously from 5.1% in 1991 to 39.1% in 2003 (P<.001). Twelve percent of all patients who underwent mastectomies had immediate reconstruction, and the proportion showed an increasing trend, especially in skin-sparing mastectomy and transverse rectus abdominis myocutaneous flap reconstruction. Five-year observed survival rates were 84.1%. Five-year survival rates according to stages were as follows: (1) 98.5%, stage 0; (2) 95.3%, stage I; (3) 86.0%, stage II; (4) 65.0%, stage III; and (5) 29.3%, stage IV. The number of patients with specific risk factors, such as early menarche and late first delivery, significantly increased. Of 263 high-risk patients examined for the BRCA mutation, mutations were found in 20 patients (7.6%), with 13 cases with BRCA1 and 7 cases with BRCA2. CONCLUSIONS: The present study showed a continuous increase in the number of patients with breast cancer; the proportion of young patients, asymptomatic patients, early breast cancer, breast-conserving surgery, and immediate reconstruction after mastectomy; and the number of patients with risk factors. These results suggest that the clinical characteristics of Korean breast cancer patients reflect the patterns of Western countries.

Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients.

The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer.