Metastasis-Free Interval Is Closely Related to Tumor Characteristics and Has Prognostic Value in Breast Cancer Patients with Distant Relapse

PURPOSE: We investigated the relationships between metastasis-free interval (MFI) and tumor characteristics, and assessed the prognostic value of MFI for survival after metastasis in patients with metastatic breast cancer. Furthermore, we compared MFI among the subtypes. METHODS: We identified 335 patients with postoperative tumor recurrence at distant site(s). All patients underwent curative resection and had a MFI of at least 6 months. MFI was categorized as short (<2 years), intermediate (≥2 years and <5 years), or long (≥5 years). Overall survival after metastasis (OSM) was estimated. RESULTS: Patients with a shorter MFI were younger, more likely to have initial metastasis to visceral organs, and had a larger tumor with a higher stage and grade as well as a higher rate of nodal involvement at initial diagnosis. Among 136 patients with known disease subtypes, shorter MFI was associated with the triple-negative subtype while longer MFI was associated with the hormone receptor-positive/human epidermal growth factor receptor 2 negative subtype. Mortality after metastasis declined sharply with increasing MFI up to approximately 2 years, and continued gradually declining between 2 and 5 years. An MFI longer than 5 years did not add any survival benefit. MFI was a significant prognostic factor for OSM independent of nodal status, stage, metastatic site, and hormone receptor status of the metastasized cancer. CONCLUSION: MFI is closely related to biological characteristics of both primary tumors and their metastases, and has a prognostic value for survival after metastasis. We therefore suggest investigation into treatments targeting improvement of MFI as a potential novel strategy.ope

Clinical and anatomical approach using Sihler's staining technique (whole mount nerve stain).

Sihler's staining allows visualization of the nerve distribution within soft tissues without extensive dissection and does not require slide preparation, unlike traditional approaches. This technique can be applied to the mucosa, muscle, and organs that contain myelinated nerve fibers. In particular, Sihler's technique may be considered the best tool for observing nerve distribution within skeletal muscles. The intramuscular distribution pattern of nerves is difficult to observe through manual manipulation due to the gradual tapering of nerves toward the terminal end of muscles, so it should be accompanied by histological studies to establish the finer branches therein. This method provides useful information not only for anatomists but also for physiologists and clinicians. Advanced knowledge of the nerve distribution patterns will be useful for developing guidelines for clinicians who perform operations such as muscle resection, tendon transplantation, and botulinum toxin injection. Furthermore, it is a useful technique to develop neurosurgical techniques and perform electrophysiological experiments. In this review, Sihler's staining technique is described in detail, covering its history, staining protocol, advantages, disadvantages, and possible applications. The application of this technique for determining the arterial distribution pattern is also described additionally in this study.ope

Risk Factors for a False-Negative Result of Sentinel Node Biopsy in Patients with Clinically Node-Negative Breast Cancer

Purpose: Although sentinel lymph node biopsy (SLNB) can accurately represent the axillary lymph node (ALN) status, the false-negative rate (FNR) of SLNB is the main concern in the patients who receive SLNB alone instead of ALN dissection (ALND). Materials and Methods: We analyzed 1,886 patientswho underwent ALND after negative results of SLNB,retrospectively. A logistic regression analysis was used to identify risk factors associated with a falsenegative (FN) result. Cox regression model was used to estimate the hazard ratio of factors affecting disease-free survival (DFS). Results: Tumor located in the upper outer portion of the breast, lymphovascular invasion, suspicious node in imaging assessment and less than three sentinel lymph nodes (SLNs) were significant independent risk factors for FN in SLNB conferring an adjusted odds ratio of 2.10 (95% confidence interval [CI], 1.30 to 3.39), 2.69 (95% CI, 1.47 to 4.91), 2.59 (95% CI, 1.62 to 4.14), and 2.39 (95% CI, 1.45 to 3.95), respectively. The prognostic factors affecting DFS were tumor size larger than 2 cm (hazard ratio [HR], 1.86; 95% CI, 1.17 to 2.96) and FN of SLNB (HR, 2.51; 95% CI, 1.42 to 4.42) in SLN-negative group (FN and true-negative), but in ALN-positive group (FN and true-positive), FN of SLNB (HR, 0.64; 95% CI, 0.33 to 1.25) did not affect DFS. Conclusion: In patients with risk factors for a FN such as suspicious node in imaging assessment, upper outer breast cancer, less than three harvested nodes, we need attention to find another metastatic focus in non-SLNs during the operation. It may contribute to provide an exact prognosis and optimizing adjuvant treatments.ope

Standardized uptake value of ¹⁸F-fluorodeoxyglucose positron emission tomography for prediction of tumor recurrence in breast cancer beyond tumor burden.

INTRODUCTION: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can reveal the metabolic activity of malignant tumors. Recent advances gained from molecular studies suggest that tumor biology can be a good predictor of prognosis in breast cancer. We compared the ability of maximum standardized uptake values (SUVmax) derived by FDG-PET with tumor burden in predicting tumor recurrence for patients with breast cancer. METHODS: 496 patients with breast cancer who underwent preoperative FDG-PET between April 2004 and May 2009 were retrospectively identified. SUVmax was obtained by FDG-PET, and the cutoff point was defined using a time-dependent receiver operating characteristic curve for recurrence-free survival (RFS). The primary endpoint was RFS. RESULTS: In multivariate analysis for RFS, SUVmax carried independent prognostic significance (hazard ratio, 2.39; 95% confidence interval, 1.20 to 4.76; P = 0.012). When the patients were classified into four groups according to the combined factors of tumor size (≤2 cm versus >2 cm) and SUVmax (<4 versus ≥4), RFS differed significantly (P < 0.001). Similarly, SUVmax had prognostic value in combination with nodal status (negative versus positive) or stage (I versus II and III) (P < 0.001 and P = 0.001, respectively). In hormone receptor-positive disease, SUVmax remained a significant prognostic factor for RFS based on multivariate analysis. CONCLUSIONS: Our results highlight the prognostic value of FDG-PET in prediction of tumor relapse for patients with breast cancer. Particularly in patients with hormone receptor-positive disease, the tumor metabolic information provided by FDG-PET is more significantly correlated with prognosis than tumor burden.ope

Local control of brain metastasis: treatment outcome of focal brain treatments in relation to subtypes

PURPOSE: To investigate treatment options for local control of metastasis in the brain, we compared focal brain treatment (FBT) with or without whole brain radiotherapy (WBRT) vs. WBRT alone, for breast cancer patients with tumor relapse in the brain. We also evaluated treatment outcomes according to the subtypes. METHODS: We conducted a retrospective review of breast cancer patients with brain metastasis after primary surgery. All patients received at least one local treatment for brain metastasis. Surgery or stereotactic radiosurgery was categorized as FBT. Patients were divided into two groups: the FBT group received FBT±WBRT, whereas the non-FBT group received WBRT alone. Subtypes were defined as follows: hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, and triple-negative (TN). We examined the overall survival after brain metastasis (OSBM), brain metastasis-specific survival (BMSS), and brain metastasis-specific progression-free survival (BMPFS). RESULTS: A total of 116 patients were identified. After a median follow-up of 50.9 months, the median OSBM was 11.5 months (95% confidence interval, 9.0-14.1 months). The FBT group showed significantly superior OSBM and BMSS. However, FBT was not an independent prognostic factor for OSBM and BMSS on multivariate analyses. In contrast, multivariate analyses showed that patients who underwent surgery had improved BMPFS, indicating local control of metastasis in the brain. FBT resulted in better BMPFS in patients with HR-negative/HER2-positive cancer or the TN subtype. CONCLUSION: We found that patients who underwent surgery experienced improved local control of brain metastasis, regardless of its extent. Furthermore, FBT showed positive results and could be considered for better local control of brain metastasis in patients with aggressive subtypes such as HER2-positive and TN.ope

Ex Vivo Shear-Wave Elastography of Axillary Lymph Nodes to Predict Nodal Metastasis in Patients with Primary Breast Cancer

Purpose: There is still a clinical need to easily evaluate the metastatic status of lymph nodes during breast cancer surgery. We hypothesized that ex vivo shear-wave elastography (SWE) would predict precisely the presence of metastasis in the excised lymph nodes. Methods: A total of 63 patients who underwent breast cancer surgery were prospectively enrolled in this study from May 2014 to April 2015. The excised axillary lymph nodes were examined using ex vivo SWE. Metastatic status was confirmed based on the final histopathological diagnosis of the permanent section. Lymph node characteristics and elasticity values measured by ex vivo SWE were assessed for possible association with nodal metastasis. Results: A total of 274 lymph nodes, harvested from 63 patients, were examined using ex vivo SWE. The data obtained from 228 of these nodes from 55 patients were included in the analysis. Results showed that 187 lymph nodes (82.0%) were nonmetastatic and 41 lymph nodes (18.0%) were metastatic. There was significant difference between metastatic and nonmetastatic nodes with respect to the mean (45.4 kPa and 17.7 kPa, p<0.001) and maximum (55.3 kPa and 23.2 kPa, p<0.001) stiffness. The elasticity ratio was higher in the metastatic nodes (4.36 and 1.57, p<0.001). Metastatic nodes were significantly larger than nonmetastatic nodes (mean size, 10.5 mm and 7.5 mm, p<0.001). The size of metastatic nodes and nodal stiffness were correlated (correlation coefficient of mean stiffness, r=0.553). The area under curve of mean stiffness, maximum stiffness, and elasticity ratio were 0.794, 0.802, and 0.831, respectively. Conclusion: Ex vivo SWE may be a feasible method to predict axillary lymph node metastasis intraoperatively in patients undergoing breast cancer surgery.ope

Odontogenic ameloblasts-associated protein (ODAM), via phosphorylation by bone morphogenetic protein receptor type IB (BMPR-IB), is implicated in ameloblast differentiation

To elucidate the function of the odontogenic ameloblast-associated protein (ODAM) in ameloblasts, we identified more than 74 proteins that interact with ODAM using protoarray. Of the identified proteins, bone morphogenetic protein receptor type-IB (BMPR-IB) was physiologically relevant in differentiating ameloblasts. ODAM and BMPR-IB exhibited similar patterns of expression in vitro, during ameloblast differentiation. ODAM and BMPR-IB interacted through the C-terminus of ODAM, which resulted in increased ODAM phosphorylation in the presence of bone morphogenetic protein 2 (BMP-2). Immunoprecipitation assays using Ser-Xaa-Glu (SXE) mutants of ODAM demonstrated that the phosphorylation of ODAM by BMPR-IB occurs at this motif, and this phosphorylation is required for the activation of MAPKs. ODAM phosphorylation was detected in ameloblasts during ameloblast differentiation and enamel mineralization in vitro and involved in the activation of downstream factors of MAPKs. Therefore, the BMP-2-BMPR-IB-ODAM-MAPK signaling cascade has important roles in ameloblast differentiation and enamel mineralization. Our data suggest that ODAM facilitates the progression of tooth development in cooperation with BMPR-IB through distinct domains of ODAM.ope

Studies on the metabolism of the larval stages of hookworm

의학과/박사Introduction: It has been recognized that ascaris eggs need oxygen for development(Brown 1928, Fairbairn 1957). Fairbairn(1957) found glycogen in the tissues of ascaris and measured it quantitatively. Passey and Fairbairn(1955) reported that the developing ascaris eggs consumed much oxygen, whereas the matured eggs almost cased to respire and the amount of glycogen and lipids was decreased. Kawazoe and his coworkers(1961) experienced that the content of glycogen in hatched larvae increased just after they migrated into the blood vessel and the blood sugar decreased reversely. This phenomenon may explain why the hatched larvae need to migrate into blood vessels for the supply of glycogen. Fernando and Wong(1964) studied the glucose metabolism and glycogen synthesis of adult hookworms. However, there have been no reports concerning the oxygen consumption of migrating hookworm larvae yet. In the present study, the author designed to measure the oxygen consumption and the amount of nutrition materials from rhabditoid to premature stage of hookworm in order to understand the reason for migration of hookworm larvae in the host. Materials and Methods: Larvae: a) Free living stages; The hookworm(Ancylostoma caninum) larvae were divided into five groups according to the age of the culture.Culture(days)b) Tissue stage in abnormal host; 1,000 filariform larvae were given each to mouse orally. The mice were sacrificed at 24 and 48 hours after the infection, and the larvae from muscle, liver and lung were collected by the modified Baermann's method. c) Preadult stage in proper host; Two dogs were infected with canine hookworm larvae 20,000 each, and the collected larvae from muscle, liver, lung and small intestine in 14 days after the infection were measured for respective purposes. Measurement: a) Body length: The larvae on the slide were killed by heating. 50 larvae were randomly sampled and the length measured with a micrometer following mathematic calculation, and ANOVA test was applied for significence. b) Oxygen consumption: The oxygen consumption of hookworm larvae was measured by Warburg's standard manometric techniques (Umbreit, Burris & Stauffer, 1949). c) Glycogen: Glycogen was isolated by the mothod of Good et al(1933) and glycogen was determined with anthrone reagent prepared according to Fales' method(1951). The optical densities were read in a Colemann spectrophotometer at 620 mμ. d) Lipids: Total lipids was determined by the method of Folch et al(1951). Results: 1) Free living stages; The length of the larvae was 452-479μ in rhabditoid stage and 596-647μ in filariform stage and no further development was observed. The amount of oxygen consumption was maximum, 919.7x10**-6 μl/hr./larva on the first day after infection with rhabditoid larvae, and then gradually decreased according to the culture age reaching to 337.3x10**-6 μl/hr./larva, but there was no much difference between 6 days and 10 days culture larvae. The glycogen amount was the highest, 1411.29x10**-8mg/larva, on the 2nd day of the rhabditoid larvae, and decreased gradually. There was no difference between the 6th day and 10th day of the filariform larvae. The amount of total lipids was highest, 1956.4x10**-8 mg/larva on the 2nd day of the rhabditoid larvae and showed similar undulation with glycogen amount. 2) Tissue stages; The length of the larvae from host tissue after 24 and 48 hours of the infection was almost the same as those of the filariform stages. There were no significant differences of body length of the larvae which were collected from muscle, liver, and lung. However the oxygen consumption showed the highest value in the larvae from muscle 24 and 48 hours after the infection; 3892/6x10**-6μl/hr./larva and 8497.3x10**-6μl/hr/larva. The larvae from lung 24 and 48 hours after the infection showed the minimum value, 103.3 10**-6 μl/hr./larva and 145.0x10**-6μl/hr./larva. The glycogen amount in the larvae of 24 and 48 hours after the infection showed also similar tendencies. The larvae from the muscle showed 400.67x10**-8 mg/larva and 583.18x10**-8 mg/larva, and from the lungs were 134.22x10**-5mg/larva and 74.65x10**-8mg/larva. The total lipids from the larvae of 48 hours in various organs were as follows: 698.76x10**-8 mg/larva in muscle, 564.26x10**-8 mg/larva in liver, and 258.84x10**-8 mg/larva in lung. 3) Pre-adult stage: The average body length of the young adult of Ancylostoma caninum(14 days after the infection) collected from the small intestine of two dogs was 12.7mm; male 10.2mm, female 15.1mm. The length of the young adult was almost 20 times that of the filariform stage. The average glycogen amount of the worm was 27x-10**3mg/worm(15x10**-3mg/worm in male and 3.8x10**-3mg/worm in female) and the average amount of total lipids of the worm was 0.77x10**-3 mg/worm (0.39x10**-3mg/worm in male and 1.15x10**-3 mg/worm in female). The oxygen consumption was 181.9 μl/hr./worm(125.4μl/hr./worm in male and 238.4 μl/hr./worm in femal)> which was as much as 600,0000 times that of the filariform larva. Summary and Conclusion: The body lengths, oxygen consumption rates, and the amounts of glycogen and lipids contents of free living and tissue migrating larvae of canine hookworm were examined. The following is a brief summary of the results: 1. The hatched larvae grew up rapidly until the reached to filariform stage, and significant manifestations of further development were observed neither in filariform stage nor tissue stages. 2. The developing rhabditoid larvae consummed much oxygen the filariform stage though the migrating larvae in muscle showed more than 10 times of oxygen consumption, compared with rhabditoid larvae and any other tissue stages. 3. The glycogen contents were the highest on the 2nd day rhabditoid larvae. The larvae from the muscle showed more less, though the amount was much higher than the value from liver and lung. 4. Lipids: The amount of total lipids was the highest on the 2nd day in rhabditoid larvae. The larvae from the muscle at 48 hours after the infection showed the highest amount of total lipids compared with from the liver and the lungs. Through the above results, it is considered that the rhabditoid hookworm larvae deposit glycogen and lipids for development and activities during the free living stage, and the larvae migrate into the tissues restoring the nutrients for further development for the adult stage.10〃 Ⅴ6filariform Ⅳ4〃 Ⅲ2rhabditoid Ⅱ1Stage larvaerestrictio

TMN 환경에서 분산관리지원을 위한 분산처리 기술

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