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.

Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006).

PURPOSE: In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels. METHODS: In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3-4, 5-6, and 7-8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate. RESULTS: Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8-96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively (p = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively (p = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity. CONCLUSION: Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01069211.

The Practice Patterns and Perceptions of Korean Surgeons Regarding Margin Status after Breast-Conserving Surgery.

Two consecutive surveys for breast surgeons in Korea were conducted to comprehend the practice patterns and perceptions on margin status after breast-conserving surgery. The surveys were conducted online in 2014 (initial) and 2016 (follow-up). A total of 126 and 88 responses were obtained in the initial and follow-up survey, respectively. More than 80% of the respondents replied to routinely apply frozen section biopsy for intraoperative margin assessment in both surveys. Re-excision recommendations of the margin for invasive cancer significantly changed from a close margin to a positive margin over time (p=0.033). Most of the respondents (73.8%) defined a negative margin as "no ink on tumor" in invasive cancer, whereas more diverse responses were observed in ductal carcinoma in situ cases. The influence of guideline establishment for negative margins has been identified. A high uptake rate of intraoperative frozen section biopsy was noted and routine use needs reconsideration.

Development of individual survival estimating program for cancer patients' management.

OBJECTIVES: The goal of this report is to present an individual patient's survival estimation curve using the each institution's survival data after Cox proportional hazard analysis. METHODS: The program was developed in three parts: input of basic data from Cox proportional hazard analysis, input of individual patient's covariates, and presentation of individual patient's survival curve. In the first part, the average survival rates with each survival time were entered as the means of covariates using the results of Cox proportional hazard analysis. In the second part, the individual patient's values of each covariate were entered for the calculation of survival estimation. In the third part, the survival curve was displayed according to the input data. RESULTS: The data of 2,652 breast cancer patients were analyzed. Cox regression analysis was conducted using the covariates of age, tumor size, N stage, and M stage. The individual patient's survival curve was presented using the basic data and covariate factors. In the breast cancer patients, the program presented survival curves according to each patient's age, tumor size, N stage, and M stage. The data of 251 thyroid cancer patients were analyzed by a similar method. CONCLUSIONS: We developed a program to present individual survival curves of cancer patients. This program will be useful for clinicians to assist their decision-making and discussion with patients.

Validation of risk assessment models for predicting the incidence of breast cancer in korean women.

PURPOSE: The Gail model is one of the most widely used tools to assess the risk of breast cancer. However, it is known to overestimate breast cancer risk for Asian women. Here, we validate the Gail model and the Korean model using Korean data, and subsequently update and revalidate the Korean model using recent data. METHODS: We validated the modified Gail model (model 2), Asian American Gail model, and a previous Korean model using screening patient data collected between January 1999 and July 2004. The occurrence of breast cancer was confirmed by matching the resident registration number with data from the Korean Breast Cancer Registration Program. The expected-to-observed (E/O) ratio was used to validate the reliability of the program, and receiver operating characteristics curve analysis was used to evaluate the program's discriminatory power. There has been a rapid increase in the incidence of breast cancer in Korea, and we updated and revalidated the Korean model using incidence and mortality rate data from recent years. RESULTS: Among 40,229 patients who were included in the validation, 161 patients were confirmed to have developed breast cancer within 5 years of screening. The E/O ratios and 95% confidence intervals (CI) were 2.46 (2.10-2.87) for the modified Gail model and 1.29 (1.11-1.51) for the Asian American Gail model. The E/O ratio and 95% CI for the Korean model was 0.50 (0.43-0.59). For the updated Korean model, the E/O ratio and 95% CI were 0.85 (0.73-1.00). In the discriminatory power, the area under curve and 95% CI of the modified Gail model, Asian American Gail model, Korean model and updated Korean model were 0.547 (0.500-0.594), 0.543 (0.495-0.590), 0.509 (0.463-0.556), and 0.558 (0.511-0.605), respectively. CONCLUSION: The updated Korean model shows a better performance than the other three models. It is hoped that this study can provide the basis for a clinical risk assessment program and a future prospective study of breast cancer prevention.

A multi-institutional study of the prevalence of BRCA1 and BRCA2 large genomic rearrangements in familial breast cancer patients.

BACKGROUND: Large genomic rearrangements (LGRs) in the BRCA1/2 genes are frequently observed in breast cancer patients who are negative for BRCA1/2 small mutations. Here, we examined 221 familial breast cancer patients from 37 hospitals to estimate the contribution of LGRs, in a nationwide context, to the development of breast cancer. METHODS: Direct sequencing or mutation scanning followed by direct sequencing was performed to screen small mutations. BRCA1/2 small mutation-negative patients were screened for the presence of LGRs using a multiple ligation-dependent probe amplification (MLPA) assay. RESULTS: Using a combined strategy to detect the presence of small mutations and LGRs, we identified BRCA1/2 small mutations in 78 (35.3%) out of 221 familial breast cancer patients and BRCA1 LGRs in 3 (2.1%) out of 143 BRCA1/2 small mutation-negative patients: the deletion of exons 11-13, the deletion of exons 13-15, and whole gene deletion of exons 1-24. The novel deletion of exons 11-13 is thought to result from a non-homologous recombination event mediated by a microhomology sequence comprised of 3 or 4 base pairs: c.3416_4357 + 1863delins187 (NG_005905.2: g.33369_44944delins187). CONCLUSIONS: In this study, we showed that LGRs were found in 3.7% (3/81) of the patients who had mutations in BRCA1 or BRCA2, and 7.5% (3/40) of patients with mutations in BRCA1. This suggests that the contribution of LGRs to familial breast cancer in this population might be comparable to that in other ethnic populations. Given these findings, an MLPA to screen for mutations in the BRCA1 gene is recommended as an initial screening test in highly selective settings.

Development and validation of web-based nomograms to predict postoperative invasive component in ductal carcinoma in situ at needle breast biopsy.

OBJECTIVES: Although sonography-guided core needle biopsy is a highly targeted method, there is a possibility of an invasive component after surgical excision of ductal carcinoma in situ (DCIS) of the breast. This study was performed to develop and validate nomograms to predict the postoperative invasive component in DCIS at core needle biopsy. METHODS: Two nomograms were developed using the data of previous meta-analysis and multivariate analysis. Nomograms were validated externally using the data of the authors' affiliation. The accuracy was validated by the expected-to-observed ratio and the Hosmer-Lemeshow goodness-of-fit test. Discrimination was validated by the area under the curve (AUC) of receiver operating characteristic (ROC) curve analysis. RESULTS: The nomogram using the meta-analysis study data was developed at http://dcis-m.surgery.kr.pe/, and the nomogram using the multivariate analysis study data was developed at http://dcis-k.surgery.kr.pe/. The Hosmer-Lemeshow goodness-of-fit test showed that the nomogram using multivariate analysis data (p = 0.131) was better calibrated than that using meta-analysis data (p < 0.001). ROC curve analysis showed statistically significant power of discrimination in both nomograms (AUC = 0.776, 0.751). CONCLUSIONS: Both nomograms showed statistically significant discriminatory power, but the nomogram using the data of multivariate analysis was simpler and more reliable. These would be useful for the prediction of invasive cancer and the need for sentinel node biopsy in DCIS at core needle biopsy.

Korean risk assessment model for breast cancer risk prediction.

PURPOSE: We evaluated the performance of the Gail model for a Korean population and developed a Korean breast cancer risk assessment tool (KoBCRAT) based upon equations developed for the Gail model for predicting breast cancer risk. METHODS: Using 3,789 sets of cases and controls, risk factors for breast cancer among Koreans were identified. Individual probabilities were projected using Gail's equations and Korean hazard data. We compared the 5-year and lifetime risk produced using the modified Gail model which applied Korean incidence and mortality data and the parameter estimators from the original Gail model with those produced using the KoBCRAT. We validated the KoBCRAT based on the expected/observed breast cancer incidence and area under the curve (AUC) using two Korean cohorts: the Korean Multicenter Cancer Cohort (KMCC) and National Cancer Center (NCC) cohort. RESULTS: The major risk factors under the age of 50 were family history, age at menarche, age at first full-term pregnancy, menopausal status, breastfeeding duration, oral contraceptive usage, and exercise, while those at and over the age of 50 were family history, age at menarche, age at menopause, pregnancy experience, body mass index, oral contraceptive usage, and exercise. The modified Gail model produced lower 5-year risk for the cases than for the controls (p = 0.017), while the KoBCRAT produced higher 5-year and lifetime risk for the cases than for the controls (p<0.001 and <0.001, respectively). The observed incidence of breast cancer in the two cohorts was similar to the expected incidence from the KoBCRAT (KMCC, p = 0.880; NCC, p = 0.878). The AUC using the KoBCRAT was 0.61 for the KMCC and 0.89 for the NCC cohort. CONCLUSIONS: Our findings suggest that the KoBCRAT is a better tool for predicting the risk of breast cancer in Korean women, especially urban women.

The prevalence of BRCA mutations among familial breast cancer patients in Korea: results of the Korean Hereditary Breast Cancer study.

The primary aim of this study was to estimate the prevalence of BRCA1/2 mutations among familial breast cancer (BC) patients in Korea. We analyzed 775 familial BC patients who were enrolled in the Korean Hereditary Breast Cancer (KOHBRA) study and treated at 36 institutions between May 2007 and May 2010. Patients with familial BC were defined as BC patients with family histories of BC or ovarian cancer (OC) in any relatives. All probands received genetic counseling and BRCA genetic testing was performed after obtaining informed consent. The mean age of BC diagnosis was 43.6 years. The numbers of probands with family histories of BC only and OC only were 682 and 93, respectively. The overall prevalence of the BRCA mutation among familial BC patients was 21.7 % (BRCA1 9.3 % and BRCA2 12.4 %). Subgroup analyses observed prevalences of the BRCA mutation as follows: 19.6 % among patients with BC family history only (BRCA1 7.6 % and BRCA2 12.0 %) and 36.6 % among patients with OC family history only (BRCA1 21.5 % and BRCA2 15.1 %). Most of the subgroups satisfied the 10 % probability criteria to undergo BRCA testing. However, the prevalence of the BRCA mutations among subgroups that had 2 BC patients in a family with both age at diagnosis of more than 50 years old did not reach the 10 % criteria (4.1 %). Korean familial BC patients are good candidates for BRCA testing even when they have family histories of single breast cancers. However, proband age at diagnosis should be carefully considered when selecting patients for testing.

Estimating the risks and benefits of tamoxifen for prophylactic breast cancer chemoprevention in Korea.

PURPOSE: According to the National Surgical Adjuvant Breast and Bowel Project P1 (NSABP-P1) study, tamoxifen can prevent 49% of invasive breast cancers in patients who have a 5-year risk of 1.67% or more. Because tamoxifen is associated with both adverse effects (endometrial cancer, stroke, pulmonary embolism) and protective effect (fracture prevention), it is necessary to weigh the risks and benefits of using tamoxifen for prevention in Korean women. This study weighed those risks and benefits. METHODS: Data were reviewed on the incidences of breast cancer, hip fracture, endometrial cancer and stroke in the absence of tamoxifen treatment in Korean women. We also reviewed NSABP-P1 data on the effects of tamoxifen on these outcomes. A risk-benefit index was calculated according to age and specific risk of breast cancer. Sensitivity analyses were performed with assumptions regarding the effects of tamoxifen. RESULTS: Compared to U.S. women, the numbers of hip fractures and endometrial cancers were lower, but the number of strokes was much higher. The net benefit of tamoxifen was reduced with increasing age because of a high risk of stroke in older women. Older Korean women had more risk than benefit from tamoxifen chemoprevention. Only women younger than age 40 had a positive risk-benefit index with an average 5-year risk of breast cancer in Korea. Sensitivity analysis showed that this result was robust. CONCLUSION: Women under the age 40 had more benefit than risk from tamoxifen chemoprevention. Tamoxifen chemoprevention should be limited to Korean women younger than age 40.

Oncologic manifestations of neurofibromatosis type 1 in Korea.

PURPOSE: The aim of this study was to investigate the incidence and spectrum of malignant tumors in Korean neurofibromatosis type 1 (NF1) patients. METHODS: We retrospectively reviewed 125 patients who were diagnosed with NF1 at a single institution from 1995 to 2010. The incidence, location, histologic type, and radiologic findings of malignant tumors as well as development of multiple primary tumors were analyzed. RESULTS: Eighteen malignant tumors occurred in 16 patients (12.8%) among 125 Korean NF1 patients; 9 carcinomas, 8 sarcomas and 1 central nervous system (CNS) tumor. Five tumors were of nervous system origin and 13 were non-nervous system tumors. The locations of the tumors were as follow: 1 CNS, 2 lung, 3 breast, 3 stomach, 3 small bowel, 1 colon, 1 liver, 1 uterus, 1 neck, and 2 in extremities. Three malignant peripheral nerve sheath tumors (MPNSTs) occurred at the neck and extremity, and one in the liver. All three gastrointestinal stromal tumors (GISTs) had multiple tumors in the jejunum, and one MPNST and one pheochromocytoma were accompanied in two GISTs. Multiple primary tumors, benign or malignant were reported in 4 patients (25.0%), synchronously or metachronously. CONCLUSION: Korean NF1 patients had a high risk of developing malignant tumors. The common malignant tumors in Koreans such as breast, lung and stomach cancers developed frequently in addition to the NF1-related tumors such as MPNST or GIST.

Bilateral adrenal pheochromocytoma with a germline L790F mutation in the RET oncogene.

About ten percent of pheochromocytomas are associated with familial syndrome. Hereditary pheochromocytoma has characteristics of early onset, multifocality and bilaterality. We experienced a case of 44-year-old man with bilateral pheochromocytoma without evidence of medullary thyroid cancer. Genetic test detected a L790F germline mutation of RET oncogene. The author found a necessity for genetic tests in cases of young-age, bilateral pheochromocytoma.

Modification of hydroxyapatite/gelatin nanocomposite using polyacrylamide.

A hydroxyapatite (HAp)/gelatin (GEL) nanocomposite was mixed with mineralized polyacrylamide (PAM) to produce a macrocomposite. The mineralization of PAM was carried out by solution-precipitation using Ca(OH)(2) and H(3)PO(4). The crystal growth of HAp in PAM was moderately changed from amorphous-like nanocrystalline to crystalline with the increase of PAM. The dry body of HAp/PAM nanocomposite cracked after the immersion test in water, but the cross-linked sample using glutaraldehyde did not crack. The macrocomposite of HAp/GEL nanocomposite and HAp/PAM nanocomposite showed good toughness, but cracked after the immersion test in water. The cross-linked macrocomposite sample did not crack after the immersion test in water.

Calcium phosphate formation in gelatin matrix using free ion precursors of Ca2+ and phosphate ions.

OBJECTIVES: Hydroxyapatite (HAp)/gelatin (GEL) nanocomposite has been developed as a bone substitute. The nanocomposite formation in the GEL matrix is greatly affected by the reaction between Ca(2+) and phosphate ions. The mineralization of GEL macromolecules was investigated through a co-precipitation of calcium phosphates (Ca-P) by using free ions of Ca(2+) and phosphate ions, Pi. The purpose of this study was to prepare a dense HAp/GEL nanocomposite through a free ion production process. METHODS: Free ionic calcium, Ca(2+), was produced through electrodialysis process using a cation membrane (CMV). Triprotic acid ions were diffused through an anion membrane (AMV) from an aqueous solution of H(3)PO(4). The HAp/GEL nanocomposite was prepared by the co-precipitation process. As a reference material for comparison, Ca(OH)(2) and H(3)PO(4) were used for the preparation of a HAp/GEL nanocomposite. RESULTS: The dense compact body of dried Ca-P/GEL nanocomposite was obtained through the fine chemical reaction of Ca(2+) and Pi. The free calcium ion Ca(2+), diffused from the CMV of the cation reactor greatly affected the formation of Ca-P phase. Phosphate ion species diffused through the AMV in the anion reactor definitely influenced the reaction with Ca(2+). For the formation of the Ca-P phase in the GEL matrix, the organic-inorganic interaction was analyzed using FT-IR. The crystal growth of HAp in the GEL matrix increased with the increase of GEL from XRD, FT-IR and TEM. SIGNIFICANCE: The mineralization reaction in GEL macromolecules was critically influenced by the free ions of Ca(2+) and inorganic phosphate ions, Pi. The interaction between Ca(2+) and Pi in the GEL matrix was very fine compared to the HAp/GEL nanocomposite prepared from Ca(OH)(2) and H(3)PO(4) with the GEL. The dense compact body of HAp/GEL nanocomposite was obtained for an artificial bone application.

Organic-inorganic interaction between hydroxyapatite and gelatin with the aging of gelatin in aqueous phosphoric acid solution.

Hydroxyapatite (HAp)/gelatin (GEL) nanocomposite was prepared by the solution-precipitation process using Ca(OH)(2) in water and aqueous solution of H(3)PO(4) in GEL. Before the co precipitation process the GEL powders were dissolved in the aqueous phosphoric acid solution for the phosphorylation of GEL molecules. The chemical variation of the phosphorylated GEL macromolecules was investigated by using attenuated total reflection (ATR) measurement. The crystal growth of HAp became bigger with the long-time aging of the GEL molecules in the phosphoric acid solution, and it resulted from the reduction of length scale of the GEL molecules. The degree of the organic-inorganic interaction was decreased because of the degradation of the GEL macromolecules.

Fluoride incorporation in hydroxyapatite/gelatin nanocomposite.

The incorporation of fluoride ion into hydroxyapatite (HAp)/gelatin (GEL) nanocomposite was investigated. The F(-) ion incorporation into OH(- )site of HAp phase was an energetically active process, which could be confirmed from the spray solution reaction. The precursors of Ca(2+) in water and phosphates in aqueous gelatin were mixed in the humidified air chamber by air spray, and then the precipitates were aged in a reactor. The F(-) ion precursor was dissolved in the starting solution of Ca(OH)(2) in water, and the resulted Ca(OH, F)(2) complex droplets induced the formation of stable fluoroapatite (F, OH)Ap. The reaction kinetics could be assumed from TEM morphology with ED, XRD and FT-IR analysis.

Cross-linkage of hydroxyapatite/gelatin nanocomposite using imide-based zero-length cross-linker.

Hydroxyapatite [HAp]/Gelatin [GEL] nanocomposite was prepared at 37 and 48 degrees C through coprecipitation process. The HAp/GEL nanocomposite slurries were cross-linked by imide-based zero-length cross-linking agent such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS). The chemical bond formation and microstructure in HAp/GEL nanocomposite was investigated as a function of cross-linking agents and temperature. The single addition of EDC into the composite slurries resulted in a tougher microstructure in both samples prepared at 37 and 48 degrees C. However, in the case of the simultaneous addition of EDC and NHS the sample prepared at 48 degrees C showed a coarse microstructure. These results were consistent with the fact that the chemical reactivity of NHS is degraded at 48 degrees C whereas the reactivity of EDC increases up to 80 degrees C.

Organic-inorganic interaction and the growth mechanism of hydroxyapatite crystals in gelatin matrices between 37 and 80 degrees C.

The crystal development of hydroxyapatite[HAp] phase in gelatin[GEL] matrices was investigated in the temperature range 37 to 80 degrees C by using X-ray diffraction, scanning electron microscopy(SEM), thermoanalytical measurement(DT/TGA), Fourier-Transformed Infra-Red(FT-IR) spectroscopy, and transmission electron microscopy(TEM) with electron diffraction(ED). It was found that during the coprecipitation of apatite phase in GEL matrices and the next aging process the crystallites were formed and developed through the two reaction mechanisms of organic-inorganic interaction between apatite phase and GEL molecules, and thermodynamic reaction for the crystal growing. The analytical evidences showed that there was a definite competition between these two mechanisms with the reaction temperature. Below 50 degrees C the crystal development of HAp was greatly suppressed by the existence of the GEL molecules, indicating the heterogeneous nucleation by the supposed number of carboxyl groups in GEL. Above 50 degrees C the effective organic components as a template for the heterogeneous nucleation of apatite crystallites were greatly degraded and so more amount of inorganic ions could be favorably accredited on the preexisting crystallites in virtue of the limited nucleation chance, finally resulting in the crystal growth. At higher temperature pretty big HAp crystals were developed with the depletion of the organics to be bound with crystallites in the slurry solution. Presumably it is believed that the poisoning of the functional groups in GEL molecules was vigorously occurred in the phosphoric acid environment above approximately 50 degrees C.

RET oncogene expression of papillary thyroid carcinoma in Korea.

PURPOSE: To identify the prevalence of RET/PTC oncogene expression in Korea, and to investigate the correlation between RET/PTC oncogene expression and the known prognostic factors of papillary thyroid carcinoma (PTC) in 22 patients. METHODS: We performed reverse transcription-polymerase chain reaction (RT-PCR) for RET/PTC1, RET/PTC2, and RET/PTC3 rearrangements and immunohistochemical staining for the RET gene. Patient information was obtained from medical records. The chi(2) test, independent sample t-test, and logistic regression were used for statistical analysis. RESULTS: The mean age of the patients was 44.4 years. RET/PTC rearrangement by RT-PCR was positive in only 2 (9.1%) of the 22 patients, and RET/PTC1 and RET/PTC3 were positive in 1 patient each (4.5%). Immunohistochemical staining revealed positive RET oncogene expression in 8 patients (36.3%). RET oncogene expression was marginally related to recurrence ( P = 0.05), but without significance by multivariate analysis. CONCLUSION: It is possible that a rare form of rearrangement exists in Korean papillary thyroid carcinoma, but this study failed to prove that RET oncogene expression is associated with alleged prognostic factors.