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John Wen-Cheng Chang,1 Yen-Lin Huang,2 Yao-Yu Chang,3 Yung-Feng Lo,4 Tsung-Ying Ho,5 Yi-Ting Huang,6 Huan-Wu Chen,7 Chiao-En Wu1 1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 2Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 3Department of Dermatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 4Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 5Department of Nuclear Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 6Department of Radiology Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 7Department of Medical Imaging & Intervention, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, TaiwanCorrespondence: Chiao-En WuDivision of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, 5, Fushing St., Gueishan Township, Taoyuan 333, TaiwanTel +886-3-328-1200 ext 8825Email jiaoen@gmail.comPurpose: Sentinel lymph node biopsy (SLNB) is the standard management for clinically node-negative cutaneous melanoma patients. This study aimed to evaluate the role of SLNB in Taiwanese melanoma patients and in particular, patients with acral lentiginous melanoma (ALM).Patients and methods: We retrospectively analyzed the clinicopathological characteristics and survival outcomes of the patients who underwent primary surgery followed by either SLNB or nodal observation at the Linkou Chang Gung Memorial Hospital from January 2000 to December 2011.Results: Among the total of 209 patients, 127 underwent SLNB and 51 underwent nodal observation only after primary surgery. There were no significant differences in clinicopathological features between the two groups except that patients who underwent SLNB were older and had a higher rate of ALM than those under nodal observation. The median follow-up time was 43.5 months until July 2013. The patients who underwent SLNB had significantly better disease-free survival (DFS) (57.1 vs 18.7 months, p < 0.01) and melanoma-specific survival (MSS) (112.4 vs 45.2 months, p < 0.01) than those under observation. Improvement in DFS (HR: 0.51, p < 0.01) and MSS (HR: 0.60, p = 0.03) was observed even after adjusting for age and disease pathology by multivariate analysis. This benefit of clinical outcomes persisted in patients with ALM, Breslow thickness ≤2 mm, or no ulceration, but not in patients with non-ALM, Breslow thickness >2 mm, or ulceration.Conclusion: SLNB was associated with favorable outcomes in patients with clinically node-negative cutaneous melanoma, particularly in Taiwanese patients with ALM, Breslow thickness ≤2 mm, and nonulcerated melanoma.Keywords: cutaneous melanoma, sentinel lymph node biopsy, acral lentiginous melanoma, nodal observation

Purpose: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients., Methods: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF., Results: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38 + HLADR + CD8 + T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects., Conclusion: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are implicated in the pathogenesis of Cryptococcus gattii (C. gattii) infection and pulmonary alveolar proteinosis (PAP). Their presence has also been noted in nocardiosis cases, particularly those with disseminated disease. This study delineates a case series characterizing clinical features and specificity of anti-GM-CSF Abs in nocardiosis patients., Methods: In this study, eight patients were recruited to determine the presence or absence of anti-GM-CSF Abs. In addition to the detailed description of the clinical course, we thoroughly investigated the autoantibodies regarding the characteristics, isotypes, subclasses, titers, and neutralizing capacities by utilizing the plasma samples from patients., Results: Of eight patients, five tested positive for anti-GM-CSF Abs, all with central nervous system (CNS) involvement; patients negative for these antibodies did not develop CNS nocardiosis. Distinct from previously documented cases, none of our patients with anti-GM-CSF Abs exhibited PAP symptoms. The titer and neutralizing activity of anti-GM-CSF Abs in our cohort did not significantly deviate from those found in C. gattii cryptococcosis and PAP patients. Uniquely, one individual (Patient 3) showed a minimal titer and neutralizing action of anti-GM-CSF Abs, with no relation to disease severity. Moreover, IgM autoantibodies were notably present in all CNS nocardiosis cases investigated., Conclusion: The presence of anti-GM-CSF Abs suggests an intrinsic immunodeficiency predisposing individuals toward CNS nocardiosis. The presence of anti-GM-CSF Abs helps to elucidate vulnerability to CNS nocardiosis, even with low titer of autoantibodies. Consequently, systematic screening for anti-GM-CSF Abs should be considered a crucial diagnostic step for nocardiosis patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Due to the presence of other comorbidities and multi-therapeutic modalities in breast cancer, renally cleared chemotherapeutic regimens may cause nephrotoxicity. The aim of this retrospective study is to compare the chemotherapy types and outcomes in breast cancer patients with or without chronic renal disease., Patients and Methods: We retrospectively enrolled 62 female patients with breast cancer and underlying late stages (stage 3b, 4, and 5) of chronic kidney disease (CKD) treated from 2000 to 2017. They were propensity score-matched 1:1 with patients in our database with breast cancer and normal renal function (total n = 124)., Results: The main subtype of breast cancer was luminal A and relatively few patients with renal impairment received chemotherapy and anti-Her-2 treatment. The breast cancer patients with late-stage CKD had a slightly higher recurrent rate, especially at the locally advanced stage. The 5-year overall survival was 90.1 and 71.2% for patients without and with late-stage CKD, but the breast cancer-related mortality rate was 88.9 and 24.1%, respectively. In multivariate analyses, dose-reduced chemotherapy was an independent negative predictor of 5-year recurrence-free survival and late-stage CKD was associated with lower 5-year overall survival rate., Conclusions: Breast cancer patients with late-stage CKD may receive insufficient therapeutic modalities. Although the recurrence-free survival rate did not differ significantly by the status of CKD, patients with breast cancer and late-stage CKD had shorter overall survival time but a lower breast cancer-related mortality rate, indicated that the mortality was related to underlying disease., (© 2023. The Author(s).)

Purpose: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are a predisposing factor for pulmonary alveolar proteinosis (PAP) and Cryptococcus gattii cryptococcosis. This study aimed to investigate clinical manifestations in anti-GM-CSF Ab-positive patients with C. gattii cryptococcosis and analyze the properties of anti-GM-CSF Abs derived from these patients and patients with PAP., Methods: Thirty-nine patients diagnosed with cryptococcosis (caused by C. neoformans or C. gattii) and 6 with PAP were enrolled in the present study. Clinical information was obtained from medical records. Blood samples were collected for analysis of autoantibody properties. We also explored the National Health Insurance Research Database (NHIRD) of Taiwan to investigate the epidemiology of cryptococcosis and PAP., Results: High titers of neutralizing anti-GM-CSF Abs were identified in 15 patients with cryptococcosis (15/39, 38.5%). Most anti-GM-CSF Ab-positive cryptococcosis cases had central nervous system (CNS) involvement (14/15, 93.3%). Eleven out of 14 (78.6%) anti-GM-CSF Ab-positive CNS cryptococcosis patients were confirmed to be infected with C. gattii, and PAP did not occur synchronously or metachronously in a single patient from our cohort. Exploration of an association between HLA and anti-GM-CSF Ab positivity or differential properties of autoantibodies from cryptococcosis patients and PAP yielded no significant results., Conclusion: Anti-GM-CSF Abs can cause two diseases, C. gattii cryptococcosis and PAP, which seldom occur in the same subject. Current biological evidence regarding the properties of anti-GM-CSF Abs cannot provide clues regarding decisive mechanisms. Further analysis, including more extensive cohort studies and investigations into detailed properties, is mandatory to better understand the pathogenesis of anti-GM-CSF Abs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adequate axillary lymph node (ALN) staging is critical for patients with invasive breast cancer. However, neoadjuvant chemotherapy (NAC) was associated with a lower risk of ALN metastasis compared with those who underwent primary surgery among clinically node-negative (cN0) patients. This study aimed to investigate the factors associated with ALN status among patients with cN0 breast cancer undergoing NAC. A total of 222 consecutive patients with cN0 breast cancer undergoing NAC between January 2012 and December 2021 were reviewed. Univariate and multivariate analyses were performed to compare factors associated with positive ALN status. Seventeen patients (7.7%) had ALNs metastases. Here, 90 patients (40.5%) achieved pathologic complete response in the breast (breast-pCR), and all had negative ALN status. Lymphovascular invasion (odds ratio: 29.366, p < 0.0001) was an independent risk predictor of ALN metastasis in all study populations. Among patients without breast-pCR, mastectomies were performed more frequently in patients with ALN metastasis (52.9%) than in those without metastasis (20.9%) (p = 0.013). Our findings support the omission of axillary surgery in patients who achieve breast-pCR. Prospective studies are needed to confirm the feasibility of a future two-stage surgical plan for breast-conserving surgery in patients who are likely to achieve breast-pCR during clinical evaluation.

Anti-interferon (IFN)-γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10-9 M) binding to IFN-γ, but only eight neutralized IFN-γ-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1-IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ-responsive cells., (© 2022 Shih et al.)

Triple-negative breast cancer (TNBC) is treated with neoadjuvant chemotherapy (NAC). The response to NAC, particularly the probability of a complete pathological response (pCR), guides the surgical approach and adjuvant therapy. We developed a prediction model using a nomogram integrating blood tests and pre-treatment ultrasound findings for predicting pCR in patients with stage II or III operable TNBC receiving NAC. Clinical data before and after the first cycle of NAC collected from patients between 2012 and 2019 were analyzed using univariate and multivariate analyses to identify correlations with pCR. The coefficients of the significant parameters were calculated using logistic regression, and a nomogram was developed based on the logistic model to predict the probability of pCR. Eighty-eight patients were included. Five parameters correlated with the probability of pCR, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte (PLR) ratio, percentage change in PLR, presence of echogenic halo, and tumor height-to-width ratio. The discrimination performance of the nomogram was indicated by an area under the curve of 87.7%, and internal validation showed that the chi-square value of the Hosmer-Lemeshow test was 7.67 ( p = 0.363). Thus, the integrative prediction model using clinical data can predict the probability of pCR in patients with TNBC receiving NAC.

Background: Sentinel lymph node biopsy (SLNB) is the standard axillary staging approach for early breast cancer with clinically negative axillary involvement. Adequate SLNB should include the removal of not only radioactive tracer-labeled lymph nodes (hot nodes or SLNs) but also suspicious unlabeled nodes (non-hot nodes or non-SLNs). However, the biopsy of non-hot nodes is highly dependent on the surgeons' experiences. This article aims to facilitate the surgeon's decision making by elucidating parameters that correlate with non-hot node metastasis., Methods: From 2013 to 2016, clinically node-negative (cN0) breast cancer patients receiving axillary SLNB using single Tc-99m tracer method at our institute were recruited. Patients were excluded if they had received prior neoadjuvant chemotherapy. Among them, cases that have at least one non-isotope-hot node biopsied were retrospectively reviewed with a particular focus on patients with pathologically negative isotope-hot SLNs. The correlation of clinicopathological data with metastasis to axillary lymph nodes and sentinel lymph nodes was analyzed with the Chi-squared test, Fisher's exact test, and multivariate logistic regression. Receiver operating curve (ROC) was applied for continuous variables that predicted non-hot node metastasis; relapse-free survival (RFS) and locoregional relapse-free survival (LRRFS) were compared by Kaplan-Meier analysis., Results: In 632 isotope-hot SLN negative patients, T stage showed a correlation with non-isotope-hot SLN metastasis (p = 0.035, odds ratio (OR) 9.65). Tumors larger than 2.5 cm best predict non-isotope-hot SLN metastasis (area under curve (AUC) = 0.71). With a median follow up of 41.80 months, locoregional relapse-free survival was significantly worse in cases with non-hot node metastasis (66.2% vs. 69.0%, p = 0.001)., Conclusion: In the setting of SLNB using single radioisotope tracer, non-hot node metastasis in cases with negative hot SLN still carries a higher locoregional recurrence rate (13.3%). For early breast cancer larger than 2.5 cm, removal of suspicious non-hot nodes should be included for a precision therapy., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

In this work, we propose applying a time-varying electric field to a time-slotted molecular communication system with ionized message particles to combat inter-symbol interference (ISI) and enhance the transmission performance. Firstly, the solution to the Nernst-Planck equation, which describes the motion of ions under the electric field, is derived. With the derived solution, the bit error probability (BEP) and the receiver operating characteristic (ROC) curve are analyzed. Then, the time-varying electric field is optimized by the proposed algorithms to respectively minimize the error probability (MinEP), maximize the signal-to-interference ratio (MaxSIR), and maximize the sensing probability (MaxSP). For solving the MinEP and MaxSIR problems, algorithms based on the approximate gradient descent method are proposed. In addition, an efficient algorithm is proposed for solving the MaxSP problem. The proposed MinEP and MaxSIR schemes are shown to effectively mitigate ISI, and the proposed MaxSP scheme delivers the near-optimal performance with low complexity, demonstrating that the performance of molecular communications can be significantly enhanced by applying the time-varying electric field.

We retrospectively enrolled 139 patients who developed metachronous isolated supraclavicular lymph node metastasis (miSLNM) from 8129 consecutive patients who underwent primary surgery between 1990 and 2008 at a single medical center. The median age was 47 years. The median follow-up time from date of primary tumor surgery was 73.1 months, and the median time to the date of neck relapse was 43.9 months in this study. Sixty-one (43.9%) patients underwent selective neck dissection (SND). The 5-year distant metastasis-free survival (DMFS), post-recurrence survival, and overall survival (OS) rates in the SND group were 31.1%, 40.3%, and 68.9%, respectively, whereas those of the no-SND group were 9.7%, 32.9%, and 57.7%, respectively ( p = 0.001). No SND and time interval from primary tumor surgery to neck relapse ≤24 months were the only significant risk factors in the multivariate analysis of DMFS (hazard ratio (HR), 1.77; 95% confidence interval (CI), 1.23-2.56; p = 0.002 and HR, 1.76, 95% CI, 1.23-2.52; p = 0.002, respectively) and OS (HR, 1.77; 95% CI, 1.22-2.55; p = 0.003 and HR, 3.54, 95% CI, 2.44-5.16; p < 0.0001, respectively). Multimodal therapy, including neck dissection, significantly improved the DMFS and OS of miSLNM. Survival improvement after miSLNM control by intensive surgical treatment suggests that miSLNM is not distant metastasis.

The prevailing view is that the ClC-Ka chloride channel (mouse Clc-k1) functions in the thin ascending limb to control urine concentration, whereas the ClC-Kb channel (mouse Clc-k2) functions in the thick ascending limb (TAL) to control salt reabsorption. Mutations of ClC-Kb cause classic Bartter syndrome, characterized by renal salt wasting, with perinatal to adolescent onset. We studied the roles of Clc-k channels in perinatal mouse kidneys using constitutive or inducible kidney-specific gene ablation and 2D and advanced 3D imaging of optically cleared kidneys. We show that Clc-k1 and Clc-k2 were broadly expressed and colocalized in perinatal kidneys. Deletion of Clc-k1 and Clc-k2 revealed that both participated in NKCC2- and NCC-mediated NaCl reabsorption in neonatal kidneys. Embryonic deletion of Clc-k2 caused tubular injury and impaired renal medulla and TAL development. Inducible deletion of Clc-k2 beginning after medulla maturation produced mild salt wasting resulting from reduced NCC activity. Thus, both Clc-k1 and Clc-k2 contributed to salt reabsorption in TAL and distal convoluted tubule (DCT) in neonates, potentially explaining the less-severe phenotypes in classic Bartter syndrome. As opposed to the current understanding that salt wasting in adult patients with Bartter syndrome is due to Clc-k2 deficiency in adult TAL, our results suggest that it originates mainly from defects occurring in the medulla and TAL during development.

Few studies have analyzed the discrepancy between breast pathologic complete response (B-pCR) and axillary node pCR (N-pCR) rates and their impact on survival outcomes in different intrinsic subtypes of early breast cancer after neoadjuvant chemotherapy (NAC). We retrospectively reviewed B-pCR, N-pCR, and total (breast and axillary node) pCR (T-pCR) after NAC to assess the discrepancy and outcomes between 2005 and 2017. A total of 968 patients diagnosed with cT1-4c, N1-2, and M0 breast cancer were enrolled in the study. The median age was 49 years and the median follow-up time was 45 months. Of these patients, 213 achieved T-pCR, 31 achieved B-pCR with axillary node pathologic non-complete response (N-non pCR), 245 achieved N-pCR with breast pathologic non-complete response (B-non pCR), and 479 achieved total (breast and axillary node) pathologic non-complete response (T-non pCR) after NAC. The highest B-pCR and N-pCR rates were found in the hormone receptor-negative, human epidermal growth factor receptor 2-positive HR(-)HER2(+) subtype, while the lowest B-pCR rate was found in the HR(+)HER2(-) subtype. The N-pCR rate was correlated to the B-pCR rate (P<0.001), but was higher than the B-pCR rate in all subtypes. The 5-year overall survival (OS) rates for patients with T-pCR, B-pCR, and N-pCR were 91.2%, 91.7%, and 91.9%, respectively. For non-pCR, non-pCR, and non-pCR, the 5-year OS rates were 73.6%, 78.9%, and 74.7%, respectively (P<0.0001). B-non pCR patients had a lower risk of recurrence than T-non pCR or N-non-pCR patients, although there were no differences in OS among them. In conclusion, the N-pCR rate was higher than the B-pCR rate after NAC in all intrinsic subtypes, and N-non pCR or T-non pCR patients had the worst outcomes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). Locoregional recurrence (LRR) rate is still high after NAC. The aim of this study was to determine predictive factors for LRR in breast cancer patients in association with the operation types after NAC., Methods: Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence., Results: The median follow-up time was 59.2 months (range 3.13-186.75 months). The mean initial tumor size was 4.89 cm (SD ± 2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41.3% and 58.7%, respectively. One hundred four patients developed LRR (9.9%). Comparing between patients who underwent BCS and those who underwent mastectomy revealed no significant difference in the overall LRR rate of the two groups, 8.8% in BCS group vs 10.7% in mastectomy group (p = 0.303). Multivariate analysis indicated that independent factors for the prediction of LRR included clinical N2 status, negative estrogen receptor (ER), and failure to achieve pCR. In subgroups of multivariate analysis, only negative ER was the independent factor to predict LRR in mastectomy group (p = 0.025) and hormone receptor negative/human epidermal growth factor receptor 2 positive (HR-/HER2 +) subtype (p = 0.006) was an independent factor to predict LRR in BCS patients. Further investigation according to the molecular subtype showed that following BCS, non-pCR group had significantly increased LRR compared with the pCR group, in HR-/HER2 + subtype (25.0% vs 8.3%, p = 0.037), and HR-/HER2- subtype (20.4% vs 0%, p = 0.002)., Conclusion: Clinical N2 status, negative ER, and failure to achieve pCR after NAC were independently related to the risk of developing LRR. Operation type did not impact on the LRR. In addition, the LRR rate was higher in non-pCR hormone receptor-negative patients undergoing BCS comparing with pCR patients.

Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti-IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti-IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti-IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti-IFN-γ autoantibody-associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Guo et al.)

This in vitro study evaluated the shear bond strength (SBS), failure mode and microleakage of fissure sealing materials in relation to different etching times on aprismatic and prismatic enamel. Ninety-six healthy human third molars were randomly allocated to the following groups: 1) prismatic or aprismatic enamel; 2) etching: 15, 30, 45, 60 s. After 5,000-fold thermocycling SBS, failure mode and microleakage were measured. Statistical evaluation included Mann-Whitney-U-test and linear regression analysis. In the aprismatic enamel group, an increasing etching time resulted in higher SBS. The linear regression model revealed that 60 s of etching time led to a significant increase in SBS. Microleakage was found to be low in all test groups. This study indicated that 60 s of etching time showed to a significantly better SBS. When considering the small differences of SBS, failure modes and microleakage between 30 and 60 s etching time, 30 s acid etching seems to also be justifiable.

Objective: This systematic literature review and meta-analysis compared the clinical retention of primed or adhesively bonded sealants to that of conventional sealant materials., Methods: A search of the MEDLINE, EMBASE and CENTRAL databases identified 3707 abstracts published prior to 12/31/2017, of which 335 clinical publications were analysed in detail. A total of 67 studies included information about sealant retention after 24, 36, or 60 months of follow-up. A meta-analysis using a random effects model was conducted to calculate the pooled estimate of the retention rates for the five groups of sealants. Subgroup moderator analysis was performed to compare the pooled retention rate estimate (RRE) of primed sealants against those of the other groups., Results: Primed sealants had a 2-year pooled RRE of 43.2% (95% CI: 30.5-55.8), which was significantly inferior to those of auto-polymerizing (80.8%, 95% CI: 72.2-89) and light-polymerizing sealants (68.4%, 95% CI: 60.2-76.7). Fluoride-releasing and light-polymerizing sealants had the highest 3-year pooled RREs (86.4%, 95% CI: 73.4-99.3 and 83.1%, 95% CI: 75.6-90.7, respectively)., Significane: The results of this meta-analysis suggest that primed sealants cannot be fully recommended for clinical practice due to their moderate survival rates. Auto-polymerizing, light-polymerizing and fluoride-releasing sealants continue to be considered the reference standards for pit and fissure sealants. However, future generations and developments of primed sealant materials may change this position., (Copyright © 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to identify the factors that predict distant recurrence and survival outcome after patients with primary positive hormone receptor-positive (HR+) invasive breast cancer undergo complete excision for isolated local recurrence (ILR)., Methods: From January 2000 to December 2009, we performed a retrospective review of our database and identified 51 patients with HR + invasive breast cancer who underwent complete excision for ILR as a component of salvage therapy. The distant metastasis-free survival (DMFS) and overall survival (OS) from the time of ILR were calculated using the Kaplan-Meier method, and a Cox regression model was used for multivariate analysis., Results: Of the 51 cases of ILR, 28 were of ipsilateral breast tumor recurrence and 23 were of chest wall recurrence. By receiver operating characteristic curve analyses, the cut-off time point for time to ILR was determined to be 29 months. According to time to ILR (≤29 vs. >29 months) and primary tumor size (≤2 vs. >2 cm), patients were divided into four risk groups as variables for analysis. On multivariate analysis, two independent prognostic factors for DMFS and OS after ILR were identified: risk groups (ILR≤29 months with primary tumor size >2 cm vs. ILR>29 months with primary tumor size ≤ 2 cm, HR = 8.53 for DMFS and HR = 11.18 for OS) and primary tumor grade (2/3 vs. 1, HR = 6.10 for DMFS and 4.27 for OS)., Conclusion: We demonstrated that poor DMFS and OS are associated with high risk group defined as short time to ILR (≤29 months) with primary tumor size (>2 cm) and higher primary tumor grade (2/3) among patients with HR + invasive breast cancer treated with complete excision for ILR. Therapeutic strategies for ILR based on hormone therapy with new agents should be explored in future prospective studies, especially for patients with poor outcome., (Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

To assess the feasibility of using contrast-enhanced spectral mammography (CESM) for operative planning of patients with breast cancers who were initially diagnosed by sonographic guided biopsy.With the approval of the Institutional Review Board of our hospital, we retrospectively reviewed the data on patients with breast cancers who underwent CESM and contrast-enhanced magnetic resonance imaging (CE-MRI) prior to operation and were followed up for at least 5 years postoperatively. The patients with breast cancer diagnosed by sonographic guided biopsy without mammography were included for analysis. The size and number of cancers on low-energy mammograms (LE-MG), recombined subtracted mammograms (RSM), and CE-MRI were recorded and compared with microscopic histopathologic data and at least 5 years of clinical follow-up data.Fifty-one cancerous breasts of 46 patients were included in the analysis. All the principal cancers could be detected by RSM or CE-MRI; however, only 45 were by LE-MG. The Pearson correlation coefficients for the size on microscopy were 0.44 for LE-MG, 0.77 for RSM, and 0.84 for CE-MRI (all P-values ≤.001). Regarding the microscopic reports, RSM or CE-MRI had sensitivities of 100% and a positive predictive value of 63.6% for multicentric cancers. One breast cancer with partial mastectomy recurred after 3 years of follow-up.CESM was feasible for assessing the cancer extension and multicentric cancers as secondary examination in patients with diagnosed breast cancers after sonographic biopsy.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin. The available reports of MCC in Asia are limited; in this study, we report the largest series of MCC in Taiwan to date.The series is composed by 24 pathologically proven MCC cases, which were retrospectively reviewed in Chang Gung Memorial Hospital in Taiwan between 2000 and 2018.The tumor occurred predominantly in men (80%) and in the elderly (median 74.8 years). Twenty-one patients had locoregional MCC and 3 had metastatic MCC at the time of diagnosis. Patients with pathologically proven negative nodes by sentinel lymph node biopsy (SLNB) showed better survival time than those without SLNB in 16 clinically node-negative MCC cases undergoing primary surgery. Salvage surgery for loco-regional recurrence lengthened the survival time and possibly cured recurrent MCC. Palliative chemotherapy with cisplatin and etoposide showed a response rate of 25%, progression-free survival of 3.6 months, and overall survival of 14.8 months in 4 metastatic/recurrent MCC. Avelumab treatment was effective in 1 patient, who achieved a durable disease control.This observational cohort of MCC patients in Taiwan suggests aggressive surgical intervention including wide excision and lymph node management, salvage operation is critical for early MCC patients, and palliative chemotherapy and immunotherapy showed their efficacy for advanced MCC patients.

With-no-lysine (WNK) kinases regulate renal sodium-chloride cotransporter (NCC) to maintain body sodium and potassium homeostasis. Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII). X-ray crystal structure and in vitro studies reveal chloride ion (Cl - ) binds to a hydrophobic pocket within the kinase domain of WNKs to inhibit its activity. The mechanism is thought to be important for physiological regulation of NCC by extracellular potassium. To test the hypothesis that WNK4 senses the intracellular concentration of Cl - physiologically, we generated knockin mice carrying Cl - -insensitive mutant WNK4. These mice displayed hypertension, hyperkalemia, hyperactive NCC, and other features fully recapitulating human and mouse models of PHAII caused by gain-of-function WNK4. Lowering plasma potassium levels by dietary potassium restriction increased NCC activity in wild-type, but not in knockin, mice. NCC activity in knockin mice can be further enhanced by the administration of norepinephrine, a known activator of NCC. Raising plasma potassium by oral gavage of potassium inactivated NCC within 1 hour in wild-type mice, but had no effect in knockin mice. The results provide compelling support for the notion that WNK4 is a bona fide physiological intracellular Cl - sensor and that Cl - regulation of WNK4 underlies the mechanism of regulation of NCC by extracellular potassium., Competing Interests: The authors declare no conflict of interest.

Background: Neoadjuvant chemotherapy (NAC) is the standard approach for downstaging of locally advanced breast cancer and can improve breast conservation rates. A pathological complete response (pCR) after NAC associated with favorable long-term outcomes has been described. There is still a high locoregional recurrence (LRR) rate after NAC and the influence of age on LRR after NAC is unclear. This study analyzed the relationship between age and LRR after NAC., Methods: Two hundred and sixty-three patients with invasive breast cancer who received NAC followed by mastectomy or breast conserving surgery (BCS) were enrolled. Concurrent weekly epirubicin and docetaxel was the NAC regimen., Results: Twenty-nine patients (11%) achieved a pCR after NAC. In univariate analysis, age <50 years, luminal B (HER2 positive) subtype, HER2 overexpression subtype, and triple-negative subtype were factors to predict a pCR. In multivariate analysis, age <50 years, luminal B (HER2 positive) type, HER2 overexpression, and triple-negative subtype were the independent factors to predict a pCR. No patients in the pCR group developed LRR compared with 31 patients in the non-pCR group. Eleven patients (6.9%) in the younger group (age <50 years) developed LRR compared with 20 patients (19.4%) in the older group (age ≥50 years). In multivariate analysis, younger age (<50 years) was the only independent prognostic factor for a LRR-free survival., Conclusion: Younger age can predict a pCR and is an independent prognostic factor for LRR in locally advanced breast cancer patients after NAC as concurrent epirubicin and docetaxel., (Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background: Healthcare providers are facing the challenge of helping cancer patients cope with the impact of outpatient-based chemotherapy. A nurse-led care program was proposed to address this challenge., Objective: The aim of this study was to examine the effects of a nurse-led care program for patients receiving outpatient-based chemotherapy., Methods: This was a single-center, open-label, 2-arm parallel trial with equal randomization (NCT02228200). Breast cancer patients in Hong Kong were randomly allocated to the intervention arm or the control arm. The control arm received routine hospital care. The intervention arm received the nurse-led care plus the routine hospital care. The quality of life, self-efficacy, symptom distress levels, and satisfaction with care were evaluated with questionnaires before randomization (T0), in the middle of chemotherapy (T1), and 1 month after chemotherapy (T2). Individual interviews were conducted with some participants in the intervention arm at T2., Results: The intervention arm participants reported significantly lower distress levels from oral problems, fatigue, peripheral neuropathy, distressful feelings, and higher satisfaction with care. According to the satisfaction evaluation and the interviews, the participants stated that the service was helpful in providing information and communication opportunities, filling the service gap after drug administration, providing psychological support, relieving discomfort, and building confidence., Conclusion: Breast cancer patients received support from the provision of comprehensive, continuous, and individualized care., Implications for Practice: The nurse-led care program could be applied to breast cancer patients in other hospitals in Hong Kong. Exploring its applicability to cancer settings in other countries is recommended.

Purpose: This meta-analysis investigated the influence of different acid etching times on the retention rate of pit-and-fissure sealants based on clinical trials with a minimum duration of two years., Materials and Methods: A literature search was carried out in electronic databases along with hand searching to identify clinical trials that evaluated pit-and-fissure sealants in permanent molars. From 1280 identified abstracts, 195 studies were selected for full-text analysis, and 28 studies with 36 test groups were included in this meta-analysis. Test groups with etching times of 15 (n = 3), 20 (n = 2), 30 (n = 10), 40 (n = 1) and 60 s (n = 20) were found. Incidence rates of pit-and-fissure sealant losses were modelled using negative binomial regression., Results: The regression analysis did not reveal a significant influence of etching time on the survival of pit-and-fissure sealants based on the identified and included clinical trials., Conclusions: Due to the limited number of clinical data for 15 and 20 s, conclusions regarding very short acid etching times were not possible. On the basis of regression analysis, a minimum of 30-s acid etching might be sufficient prior to fissure sealing.

Purpose: To evaluate the cost-effectiveness of a nurse-led care program for breast cancer patients receiving outpatient-based chemotherapy., Method: An open-label, single-center randomized controlled trial was conducted. Patients receiving the nurse-led care and those receiving the routine care were compared in terms of quality of life, as well as in health service utilizations and total cost of care. A cost-utility analysis was conducted., Results: A total of 124 patients were recruited. The data of 116 subjects who completed the study were used for the cost-utility analysis. There were 81 unscheduled hospital visits and 43 hospital admissions. The common reasons for utilizing health services were infections and fevers, skin problems, digestive system problems, and mouth/teeth/throat problems. There were no differences in health service utilizations between the nurse-led and routine care groups for subjects receiving four-cycle chemotherapy. For those receiving six-cycle chemotherapy, the estimated number of emergency department visits was 2.188 times (95% Confidence Interval, 1.051 to 4.554) higher for the routine care group when compared with the nurse-led care group (p = .038). The incremental cost-utility ratios were £8856 and £18,936 per quality-adjusted life year gained for subjects receiving four-cycle and six-cycle chemotherapy, respectively., Conclusions: Cancer patients make unscheduled health service visits when receiving outpatient-based chemotherapy, which leads to increased health service costs. The nurse-led care reduces emergency departments visits made by breast cancer patients undergoing six-cycle adjuvant chemotherapy. For breast cancer patients undergoing four-cycle chemotherapy and six-cycle chemotherapy, the nurse-led care could be cost-effective., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To retrospectively analyze the quantitative measurement and kinetic enhancement among pathologically proven benign and malignant lesions using contrast-enhanced spectral mammography (CESM)., Methods: We investigated the differences in enhancement between 44 benign and 108 malignant breast lesions in CESM, quantifying the extent of enhancements and the relative enhancements between early (between 2-3 min after contrast medium injection) and late (3-6 min) phases., Results: The enhancement was statistically stronger in malignancies compared to benign lesions, with good performance by the receiver operating characteristic curve [0.877, 95% confidence interval (0.813-0.941)]. Using optimal cut-off value at 220.94 according to Youden index, the sensitivity was 75.9%, specificity 88.6%, positive likelihood ratio 6.681, negative likelihood ratio 0.272 and accuracy 82.3%. The relative enhancement patterns of benign and malignant lesions, showing 29.92 vs 73.08% in the elevated pattern, 7.14 vs 92.86% in the steady pattern, 5.71 vs 94.29% in the depressed pattern, and 80.00 vs 20.00% in non-enhanced lesions (p < 0.0001), respectively., Conclusion: Despite variations in the degree of tumour angiogenesis, quantitative analysis of the breast lesions on CESM documented the malignancies had distinctive stronger enhancement and depressed relative enhancement patterns than benign lesions. Advances in knowledge: To our knowledge, this is the first study evaluating the feasibility of quantifying lesion enhancement on CESM. The quantities of enhancement were informative for assessing breast lesions in which the malignancies had stronger enhancement and more relative depressed enhancement than the benign lesions.

The purpose of this study was to develop a principal component analysis-based adaptive minimum Euclidean distances (PAMED) approach to establish an optimal object reference frame for symmetrical alignment of the dental arch during computer-aided surgical simulation (CASS). It was compared with our triangular methods and the standard principal component analysis (PCA) method. Thirty sets of maxillary digital models were used. Midsagittal and occlusal planes were ranked by three experienced evaluators based on their clinical judgment. The results showed that for the midsagittal plane, all three evaluators ranked "ideal" for all 30 models with the PAMED method, 28 with the triangular method, and at least 11 with the PCA method. For the occlusal plane, one evaluator ranked all 30 models "ideal" with both the PAMED and the PCA methods while the other two evaluators ranked all 30 models "ideal" with the triangular method. However, the differences among the three methods were minimal. In conclusion, our PAMED method is the most reliable and consistent approach for establishing the object reference frame for the dental arch in orthognathic surgical planning. The triangular method should be used with caution because it can be affected by dental arch asymmetry. The standard PCA method is not recommended., (Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Key Points: The highly variable phenotypes observed in patients with classic Bartter's syndrome (BS) remain unsatisfactorily explained. The wide spectrum of functional severity of CLCNKB mutations may contribute to the phenotypic variability, and the genotype-phenotype association has not been established. Low-level expression of the human ClC-Kb channel in mammalian cells impedes the functional study of CLCNKB mutations, and the underlying cause is still unclear. The human ClC-Kb channel is highly degraded by proteasome in human embryonic kidney cells. The C-terminal in-frame green fluorescent protein fusion may slow down the proteasome-mediated proteolysis. Barttin co-expression necessarily improves the stability, membrane trafficking and gating of ClC-Kb. CLCNKB mutations in barttin-binding sites, dimer interface or selectivity filter often have severe functional consequences. The remaining chloride conductance of the ClC-Kb mutant channel significantly correlates with the phenotypes, such as age at diagnosis, plasma chloride concentration, and the degree of calciuria in patients with classic BS., Abstract: Mutations in the CLCNKB gene encoding the human voltage-gated chloride ClC-Kb (hClC-Kb) channel cause classic Bartter's syndrome (BS). In contrast to antenatal BS, classic BS manifests with highly variable phenotypes. The functional severity of the mutant channel has been proposed to explain this phenomenon. Due to difficulties in the expression of hClC-Kb in heterologous expression systems, the functional consequences of mutant channels have not been thoroughly examined, and the genotype-phenotype association has not been established. In this study, we found that hClC-Kb, when expressed in human embryonic kidney (HEK) cells, was unstable due to degradation by proteasome. In-frame fusion of green fluorescent protein (GFP) to the C-terminus of the channel may ameliorate proteasome degradation. Co-expression of barttin increased protein abundance and membrane trafficking of hClC-Kb and markedly increased functional chloride current. We then functionally characterized 18 missense mutations identified in our classic BS cohort and others using HEK cells expressing hClC-Kb-GFP. Most CLCNKB mutations resulted in marked reduction in protein abundance and chloride current, especially those residing at barttin binding sites, dimer interface and selectivity filter. We enrolled classic BS patients carrying homozygous missense mutations with well-described functional consequences and clinical presentations for genotype-phenotype analysis. We found significant correlations of mutant chloride current with the age at diagnosis, plasma chloride concentration and urine calcium excretion rate. In conclusion, hClC-Kb expression in HEK cells is susceptible to proteasome degradation, and fusion of GFP to the C-terminus of hClC-Kb improves protein expression. The functional severity of the CLCNKB mutation is an important determinant of the phenotype in classic BS., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Background: T1a,bN0 breast cancer is not easily detected. Before mammography became widespread, most cases were discovered only after the development of symptoms. The presence of ductal carcinoma in situ (DCIS) affects the detectability of associated invasive cancer; however, the prognostic value of concomitant DCIS is controversial. This study compared the characteristics of screening-detected and symptom-detected T1a,bN0 breast cancer, and investigated the impact of accompanying DCIS on detection and prognosis. Patients and Methods: Data were collected from a single hospital between 2000 and 2009. Of 5,690 primary breast cancers patients, 438 met the criteria for T1a,bN0M0. Logistic regression models were used to identify prognostic indicators and their association with the detection method. Survival analyses were performed to estimate distant relapse-free survival (DRFS) and breast cancer-specific survival (BCSS). Results: Tumors in 79 and 359 patients were detected by screening and development of symptoms, respectively. Symptomatic cancer patients were younger, more likely to receive a mastectomy, and had larger accompanying DCIS lesions; their 10-year DRFS rates were worse than those of patients with screening-detected tumors (91.1% vs. 100% respectively, p =0.049). Patients with large accompanying DCIS (≥2 cm) had markedly worse 10-year DRFS (77.1% vs. 97.4%, p <0.001) and BCSS (94.3% vs. 98.9%, p <0.001). Conclusion: T1a,bN0 breast cancers detected owing to symptoms are more likely to have larger accompanying DCIS. T1a,bN0 patients with large accompanying DCIS have worse DRFS and BCSS. It is important to consider associated DCIS size when evaluating prognosis in T1a,bN0 breast cancer patients., Competing Interests: Competing Interests: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have declared that no competing interests exist.

Introduction: Primary breast angiosarcoma with spontaneous intratumoral bleeding associating with Kasabach-Merritt Syndrome is rarely reported., Case Findings/patient Concerns: We herein present such a case in a 30-year-old pregnant woman who was initially diagnosed to hemangioma at her early gestation. However, the sudden rapid tumor growth was aware of the attention and intended for receiving the breast enhanced magnetic resonance imaging., Diagnoses and Interventions: The dynamic MRI enhancement showed inhomogenous enhancement at the periphery of the lobulated tumor on both early and delayed scans, otherwise a large hematoma was revealed at the center. Surgical resection was performed after baby delivery by Caeserean section, and histopathologic study confirmed breast angiosarcoma., Conclusion: Despite its rarity, clinicians should recognize the association of breast angiosacroma with Kasabach-Merritt Syndrome with suggestive finding of enhanced MRI in order to decide the surgical approach.

Background: Mammography screening is a cost-efficient modality with high sensitivity for detecting impalpable cancer with microcalcifications, and results in reduced mortality rates. However, the probability of finding microcalcifications without associated cancerous masses varies. We retrospectively evaluated the diagnosis and cancer probability of the non-mass screened microcalcifications by dual-energy contrast-enhanced spectral mammography (DE-CESM)., Patients and Methods: With ethical approval from our hospital, we enrolled the cases of DE-CESM for analysis under the following inclusion criteria: (1) referrals due to screened BI-RADS 4 microcalcifications; (2) having DE-CESM prior to stereotactic biopsy; (3) no associated mass found by sonography and physical examination; and (4) pathology-based diagnosis using stereotactic vacuum-assisted breast biopsy. We analyzed the added value of post-contrast enhancement on DE-CESM., Results: A total of 94 biopsed lesions were available for analysis in our 87 women, yielding 27 cancers [19 ductal carcinoma in situ (DCIS), and 8 invasive ductal carcinoma (IDC)], 32 pre-malignant and 35 benign lesions. Of these 94 lesions, 33 showed associated enhancement in DE-CESM while the other 61 did not. All 8 IDC (100%) and 16 of 19 DCIS (84.21%) showed enhancement, but the other 3 DCIS (15.79%) did not. Overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 88.89%, 86.56%, 72.72%, 95.08% and 87.24%, respectively. The performances of DE-CESM on both amorphous and pleomorphic microcalcifications were satisfactory (AUC 0.8 and 0.92, respectively). The pleomorphous microcalcifications with enhancement showed higher positive predictive value (90.00% vs 46.15%, p = 0.013) and higher cancer probability than the amorphous microcalcifications (46.3% VS 15.1%). The Odds Ratio was 4.85 (95% CI: 1.84-12.82)., Conclusion: DE-CESM might provide added value in assessing the non-mass screened breast microcalcification, with enhancement favorable to the diagnosis of cancers or lack of enhancement virtually diagnostic for non-malignant lesions or noninvasive subgroup cancers., Competing Interests: The authors have declared that no competing interests exist.

Overexpression of receptor tyrosine kinase-like orphan receptor (ROR1) in a variety of human malignancies is associated with aggressive behaviour. Therapeutic agents targeting ROR1 have shown promising results in vivo and in vitro studies. In breast cancer, high-level expression of ROR1 mRNA is associated with high-grade tumours and metastasis. We investigated the prevalence and prognostic significance of ROR1 expression in triple negative breast cancer (TNBC). ROR1 was immunohistochemically stained on full-face sections of 210 TNBC patient samples. Forty-seven TNBC cases (22.4 %) showed strong ROR1 expression, which was associated with shorter disease-free survival (DFS; P = 0.00015), distant metastasis-free survival (DMFS; P = 0.00013) and overall survival (OS; P = 0.026) in univariate analyses. Results were confirmed by multivariate analysis. Seventy TNBC cases (33.3 %) with medullary features showed longer OS (P = 0.00013). We divided the whole series into two subgroups based on the presence or absence of medullary features. Strong ROR1 expression retained a predictive value of shorter DFS and DMFS in both subgroups. Our study suggests that strong ROR1 expression might be an independent adverse prognostic factor in TNBC patients and may serve as a potential marker for patient selection in ROR1-targeted therapy. More large-scale studies are needed to clarify its potential usefulness.

Objective: To assess the utility of dual-energy contrast-enhanced spectral mammography (DE-CESM) for evaluation of suspicious malignant microcalcifications., Methods: Two hundred and fifty-six DE-CESMs were reviewed from 2012-2013, 59 cases fulfilled the following criteria and were enrolled for analysis: (1) suspicious malignant microcalcifications (BI-RADS 4) on mammogram, (2) no related mass, (3) with pathological diagnoses. The microcalcification morphology and associated enhancement were reviewed to analyse the accuracy of the diagnosis and cancer size measurements versus the results of pathology., Results: Of the 59 microcalcifications, 22 were diagnosed as cancers, 19 were atypical lesions and 18 were benign lesions. Twenty (76.9 %) cancers, three (11.55 %) atypia and three (11.55 %) benign lesions revealed enhancement. The true-positive rate of intermediate- and high-concern microcalcifications was significantly higher than that of low-concern lesions (93.75 % vs. 50 %). Overall, the diagnostic sensitivity of enhancement was 90.9 %, with 83.78 % specificity, 76.92 % positive predictive value, 93.94 % negative predictive value and 86.4 % accuracy. Performance was good (AUC = 0.87) according to a ROC curve and cancer size correlation with a mean difference of 0.05 cm on a Bland-Altman plot., Conclusions: DE-CESM provides additional enhancement information for diagnosing breast microcalcifications and measuring cancer sizes with high correlation to surgicohistology., Key Points: • DE-CESM provides additional enhancement information for diagnosing suspicious breast microcalcifications. • The enhanced cancer size closely correlates to microscopy by Bland-Altman plot. • DE-CESM could be considered for evaluation of suspicious malignant microcalcifications.

Background/purpose: Extended hormonal therapy with tamoxifen for > 5 years has improved disease-free survival (DFS) and overall survival (OS) in hormone receptor (HR)-positive breast cancer patients. The aim of this study was to identify the HR-positive breast cancer women who need adjuvant tamoxifen for > 5 years., Methods: Between 1990 and 2004, 1104 HR-positive breast cancer patients who had received tamoxifen treatment at our institution and had been disease free for at least 6 years were included in this analysis. Univariate and multivariate analyses of prognostic factors for late recurrence were performed using the binary logistic regression model., Results: During a median follow-up period of 10.9 years after surgery, 70 patients died and 99 showed recurrence. In multivariate analysis, age < 40 years (p < 0.001) and lymph node metastasis (p < 0.001) were associated with higher rates of recurrence. We stratified patients into high-risk (age < 40 years or positive lymph node status, 536 patients) and low-risk (age > 40 years and negative lymph node status, 566 patients) groups. The recurrence rates were 14.6% and 3.5% in the high-risk and low-risk groups, respectively. Patients in the high-risk group had poorer disease-free survival (p < 0.001) and overall survival (p = 0.010) than those in the low-risk group., Conclusion: Our findings suggest that HR-positive breast cancer women either aged < 40 years or with positive lymph node status were justified in continuing with tamoxifen therapy for > 5 years., (Copyright © 2015. Published by Elsevier B.V.)

Purpose: This study investigated the influence of several methodological details on the shear bond strength (SBS) testing of pit and fissure sealants. The following variables were considered: type of enamel surfaces, prismatic vs aprismatic enamel, etching time, and aging and shearing procedures., Materials and Methods: The surfaces of 180 healthy human third molars were divided into 4 different sections (mesial, distal, buccal, and oral). After tooth separation, the specimens were randomly allocated to the following groups: 1) enamel preparation: prismatic vs aprismatic; 2) etching: 30 s vs 60 s; 3) aging: 1 day or 3 months vs 5000 thermocycles; 4) shearing: notched-edge method (ISO 29022:2013) vs knife-edge method. After following each protocol, SBS was determined using a universal testing machine, followed by failure mode analysis. Data were analysed using Mann-Whitney U-tests and regression analyses., Results: In the aprismatic enamel group, the longer etching time resulted in slightly, not statistically significantly higher SBS. When aging sealants on aprismatic enamel with different procedures, significantly lower SBS was found for 5000 thermocycles. In the case of aprismatic enamel etched for 60 s and sheared with the notched-edge blade, there was no significant difference between the aging procedures. Failure mode analysis showed adhesive failures to be predominant. Simple linear regression revealed that all of the included factors significantly influenced SBS. In a multiple linear regression model, the variables "aprismatic enamel" and "distal surface" were associated with a higher SBS; "5000 thermocycles" reduced SBS significantly., Conclusion: Enamel grinding, aging method, and type of enamel surface significantly influenced the SBS.

Presence of microcalcifications within the specimens frequently signifies a successful attempt of stereotactic vacuum-assisted breast biopsy (VABB) in obtaining a pathologic diagnosis of the breast microcalcifications. In this study, the authors aimed to assess and compare the accuracy and consistency of calcified or noncalcified specimens obtained from same sites of sampling on isolated microcalcifications without mass in diagnosing high-risk and malignant lesions. To the best of our knowledge, an individual case-based prospective comparison has not been reported.With the approval from institutional review board of our hospital (Chang Gung Memorial Hospital), the authors retrospectively reviewed all clinical cases of stereotactic VABBs on isolated breast microcalcifications without mass from our database. The authors included those having either surgery performed or had clinical follow-up of at least 3 years for analysis. All the obtained specimens with or without calcification were identified using specimen radiographs and separately submitted for pathologic evaluation. The concordance of diagnosis was assessed for both atypia and malignant lesions.A total of 390 stereotactic VABB procedures (1206 calcified and 1456 noncalcified specimens) were collected and reviewed. The consistent rates between calcified and noncalcified specimens were low for atypia and malignant microcalcifications (44.44% in flat epithelial atypia, 46.51% in atypical ductal hyperplasia, 55.73% in ductal carcinoma in situ, and 71.42% in invasive ductal carcinoma). The discordance in VABB diagnoses indicated that 41.33% of malignant lesions would be misdiagnosed by noncalcified specimens. Furthermore, calcified specimens showed higher diagnostic accuracy of breast cancer as compared with the noncalcified specimens (91.54 % versus 69.49%, respectively). The evaluation of both noncalcified specimens and calcified specimens did not show improvement of diagnostic accuracy as compared with evaluating calcified specimens alone (91.54% versus 91.54%, respectively).The high prevalence of diagnostic discordance between the calcified and noncalcified specimens indicated the higher value of calcified specimens in diagnosing atypia and malignant microcalcifications. Noncalcified specimens did not provide additional diagnostic benefit from this study. The separation of calcified and noncalcified specimens may facilitate more focused interpretation from pathologists among the large number of specimens.

Background: The increasing number of cancer patients and inadequate communication in clinics are posing challenges to cancer patients receiving outpatient-based chemotherapy and healthcare providers. A nurse-led care program was proposed as one way of dealing with at least some of these challenges., Objective: The objectives of the pilot study were to assess the feasibility of the subject recruitment, care, and data collection procedures and to explore the acceptability of this program., Methods: A pilot study with a 1-group pretest-posttest design was conducted. Five cancer patients receiving chemotherapy in a chemotherapy day center participated. Each patient had a nurse consultation before chemotherapy and received 2 telephone calls after the first and second cycles of chemotherapy. Four questionnaires were adopted to evaluate the subjects' quality of life, self-efficacy, symptom experiences, and satisfaction with care. Questionnaires were completed before the chemotherapy and after the second cycle. The subjects were also interviewed to understand their comments on the service., Results: The recruitment, care, and data collection procedures were completed smoothly. Slight changes were observed in quality of life and self-efficacy. All 5 subjects were highly satisfied with the care., Conclusions: The nurse-led care program is feasible and acceptable., Implications for Practice: The effect of the nurse-led care program will be evaluated in a single-center, open, randomized controlled trial. If the encouraging results can be confirmed, it may be an effective approach to improving the quality of ambulatory chemotherapy care. It would also shed light on the development of nurse-led care in other areas.

Background/purpose: Sentinel lymph node biopsy (SLNB) is a standard procedure in the management of clinically node-negative melanoma. However, few studies have been performed on SLNB in Asia, which is an acral melanoma-prevalent area. This study evaluated the clinicopathologic prognostic factors of disease-free survival (DFS) and overall survival (OS) in Taiwanese patients with cutaneous melanoma who received wide excision and SLNB. The prognosis of patients with false-negative (FN) SLNB was also evaluated., Methods: Malignant melanoma cases were reviewed for 518 patients who were treated between January 2000 and December 2011. Of these patients, 127 patients with node-negative cutaneous melanoma who received successful SLNB were eligible for inclusion in the study., Results: The SLNB-positive rate was 34.6%. The median DFS was 51.5 months, and the median OS was 90.9 months at the median follow-up of 36.6 months. Multivariate analysis revealed that patients whose melanoma had a Breslow thickness greater than 2 mm had a significantly shorter DFS than patients whose melanoma had a Breslow thickness of 2 mm or less [hazard ratio (HR), 3.421; p = 0.005]. Independent prognostic factors of OS were a Breslow thickness greater than 2 mm (HR, 4.435; p = 0.002); nonacral melanoma (HR, 3.048; p = 0.001); and an age older than 65 years (HR, 2.819; p = 0.036). During the follow-up period, 13 of 83 SLN-negative patients developed a regional nodal recurrence. The SLNB failure rate was 15.7% and the FN rate was 22.8%. Compared to patients with a true-positive SLNB, patients with FN SLNB had a significantly shorter DFS (p = 0.001) but no significant difference in OS (p = 0.262)., Conclusion: Except for the pathologic subtypes, prognostic factors in Taiwan are similar to those used in other melanoma-prevalent countries. Identifying and closely monitoring patients at risk of nodal recurrence after a negative SLNB is important., (Copyright © 2013. Published by Elsevier B.V.)

Flat epithelial atypia (FEA) and atypical ductal hyperplasia (ADH) are precursors of breast malignancy. Management of FEA or ADH after image-guided core needle biopsy (CNB) remains controversial. The aim of this study was to evaluate malignancy underestimation rates after FEA or ADH diagnosis using image-guided CNB and to identify clinical characteristics and imaging features associated with malignancy as well as identify cases with low underestimation rates that may be treatable by observation only. We retrospectively reviewed 2,875 consecutive image-guided CNBs recorded in an electronic data base from January 2010 to December 2011 and identified 128 (4.5%) FEA and 83 (2.9%) ADH diagnoses (211 total cases). Of these, 64 (30.3%) were echo-guided CNB procedures and 147 (69.7%) mammography-guided CNBs. Twenty patients (9.5%) were upgraded to malignancy. Multivariate analysis indicated that age (OR = 1.123, p = 0.002, increase of 1 year), mass-type lesion with calcifications (OR = 8.213, p = 0.006), and ADH in CNB specimens (OR = 8.071, p = 0.003) were independent predictors of underestimation. In univariate analysis of echo-guided CNB (n = 64), mass with calcifications had the highest underestimation rate (p < 0.001). Multivariate analysis of 147 mammography-guided CNBs revealed that age (OR = 1.122, p = 0.040, increase of 1 year) and calcification distribution were significant independent predictors of underestimation. No FEA case in which, complete calcification retrieval was recorded after CNB was upgraded to malignancy. Older age at diagnosis on image-guided CNB was a predictor of malignancy underestimation. Mass with calcifications was more likely to be associated with malignancy, and in cases presenting as calcifications only, segmental distribution or linear shapes were significantly associated with upgrading. Excision after FEA or ADH diagnosis by image-guided CNB is warranted except for FEA diagnosed using mammography-guided CNB with complete calcification retrieval., (© 2015 Wiley Periodicals, Inc.)

Purpose: To analyse the accuracy of dual-energy contrast-enhanced spectral mammography in dense breasts in comparison with contrast-enhanced subtracted mammography (CESM) and conventional mammography (Mx)., Materials and Methods: CESM cases of dense breasts with histological proof were evaluated in the present study. Four radiologists with varying experience in mammography interpretation blindly read Mx first, followed by CESM. The diagnostic profiles, consistency and learning curve were analysed statistically., Results: One hundred lesions (28 benign and 72 breast malignancies) in 89 females were analysed. Use of CESM improved the cancer diagnosis by 21.2 % in sensitivity (71.5 % to 92.7 %), by 16.1 % in specificity (51.8 % to 67.9 %) and by 19.8 % in accuracy (65.9 % to 85.8 %) compared with Mx. The interobserver diagnostic consistency was markedly higher using CESM than using Mx alone (0.6235 vs. 0.3869 using the kappa ratio). The probability of a correct prediction was elevated from 80 % to 90 % after 75 consecutive case readings., Conclusion: CESM provided additional information with consistent improvement of the cancer diagnosis in dense breasts compared to Mx alone. The prediction of the diagnosis could be improved by the interpretation of a significant number of cases in the presence of 6 % benign contrast enhancement in this study., Key Points: • DE-CESM improves the cancer diagnosis in dense breasts compared with mammography. • DE-CESM shows greater consistency than mammography alone by interobserver blind reading. • Diagnostic improvement of DE-CESM is independent of the mammographic reading experience.

Aim: Triple-negative breast cancer (TNBC) has a relatively poor prognosis compared to other molecular subtypes of breast cancer. This study aimed to evaluate the role of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-negative TNBC and to identify patients who could benefit from this therapy., Patients and Methods: We retrospectively reviewed the clinicopathological features and outcomes of patients with node-negative TNBC after surgery followed by either adjuvant chemotherapy with CMF or observation only., Results: Between January 2000 and December 2006, 276 patients with node-negative TNBC were eligible for inclusion in this study. The median follow-up time was 85.0 months by the end of 2010. The CMF (N=211) and observation (N=65) groups did not significantly differ with regard to T-stage, lymphovascular invasion (LVI), and tumour grade, but patients in the former group were on average younger (p<0.01). Adjuvant CMF was associated with favourable disease-free survival (DFS) (p=0.04). The CMF group also had a significantly lower locoregional recurrence rate than the observation group (0.4% vs. 9.2%, p=0.02). Subgroup analysis revealed that patients in the CMF group had significantly better DFS than those in the observation group among those with tumours larger than 2 cm (hazard ratio=0.38, p=0.02) and those who underwent partial mastectomy (hazard ratio=0.28, p=0.01)., Conclusion: Adjuvant CMF chemotherapy was effective in reducing locoregional recurrence rate and prolong DFS in patients with node-negative TNBC, particularly in those with tumours of more than 2 cm or who had undergone partial mastectomy.

The OMAHA System was adopted as the documentation system in an interventional study. To systematically record client care and facilitate data analysis, two Office Excel files were developed. The first Excel file (File A) was designed to record problems, care procedure, and outcomes for individual clients according to the OMAHA System. It was used by the intervention nurses in the study. The second Excel file (File B) was the summary of all clients that had been automatically extracted from File A. Data in File B can be analyzed directly in Excel or imported in PASW for further analysis. Both files have four parts to record basic information and the three parts of the OMAHA System. The computerized OMAHA System simplified the documentation procedure and facilitated the management and analysis of data.

Background: Re-excision is a necessary procedure in obtaining clean margins for breast-conserving surgery (BCS)-treated patients. Re-excision rates vary widely among different breast cancer management procedures. The aim of this study was to evaluate the efficacy of ultrasound (US)-guided BCS to decrease the re-excision rate in patients with US-detectable breast cancer, as well as the relationship between positive margins and ultrasonographic characteristics of tumor., Methods: Between 2008 and 2009, we identified consecutive patients who underwent initial US-guided BCS for breast in situ or invasive carcinoma, which was preoperatively detected using US examination and on the basis of image-guided biopsy findings. The margins achieved after BCS were separately assessed by performing frozen section analysis of shaved margins. The negative margin and positive margin groups were compared for clinicopathological features and ultrasonographic findings., Results: Of 381 patients undergoing US-guided BCS, 126 (33.1%) had palpable tumors and 255 (66.9%) had nonpalpable tumors. Positive margins were noted in 35 patients (9.2%). These patients underwent re-excision and were margin-free; no further surgery was required for these patients. There were no significant intergroup differences in clinicopathological features and ultrasonographic findings., Conclusion: Breast US is an effective modality for intraoperative tumor localization and can thus help obtain clean margins and reduce the re-excision rate in cases in which breast-conserving therapy has been performed. Furthermore, frozen section analysis of cavity shaved margins is a feasible method for minimizing the need for further surgery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: General anesthesia is used for most major surgeries, and the most common side effects include headache, nausea, vomiting, and sore throat. Major breast surgery is associated with a high incidence of postoperative nausea and vomiting (PONV). We compared the postoperative nausea and vomiting of propofol-based total intravenous anesthesia (TIVA) and sevoflurane (SEVO) anesthesia under auditory evoked potential (AEP) monitoring in female patients undergoing breast surgery., Methods: A total of 84 patients scheduled to undergo elective breast surgery from 1 to 4 h in duration from March 2011 to December 2011 were prospectively included in the study. All participants were randomly assigned to TIVA or SEVO group. The AEP index was maintained at 15-25. After completing the surgery, the duration of surgery, emergence time, and the side effects of PONV were recorded., Results: Patient characteristics, intraoperative and postoperative data, and the amounts of intraoperative analgesic drugs used were not significantly different between the TIVA and SEVO groups. The incidence of PONV was significantly higher in the SEVO group than in the TIVA group (50% and 14.3%, respectively; p < 0.001), and the total cost was significantly lower in the TIVA group than in the SEVO group (648 ± 185 and 850 ± 197, respectively)., Conclusion: We observed that when compared with sevoflurane, propofol given for the maintenance of general anesthesia improves the postoperative patient well-being and reduces the incidence of PONV. Furthermore, total intravenous anesthesia with propofol resulted in significant cost reductions.

Purpose: Little evidence can be found about the long-term outcome of breast cancer patients after axillary lymph node recurrence (ALNR) and its survival benefit after different kinds of management. The present study intends to evaluate the risk factors associated with axillary recurrence after definite surgery for primary breast cancer. The prognosis after ALNR and particularly outcome of different management methods also were studied., Methods: We retrospectively reviewed data from 4,473 patients who were diagnosed with primary breast cancer and received surgical intervention in a single institute from January 1990 to December 2002. Medical files were reviewed and data on survival were updated annually. Risk factors and prognosis of patients with axillary recurrence were analyzed. Breast-cancer-specific survival of patients with ALNR and outcomes after different management methods also were studied., Results: After a median follow-up of 70.2 months, axillary recurrence developed in 0.8% of patients. Factors associated with ALNR included: age younger than 40 years, medial tumor location, no initial standard level I & II axillary dissection, and not receiving hormonal therapy. The 5-year breast-cancer-specific survival after ALNR was 57.9%. For patients who received further axillary dissection, the 5-year survival rate was 82.5% compared with 44.9% for patients who did not receive further dissection., Conclusions: ALNR is a rare event in treating breast cancer. Young age at diagnosis and medially located tumor are associated with higher risk, but standardized initial axillary dissection to level II and adjuvant hormonal therapy is protective against ALNR. In patients with ALNR, the outcome is not dismal and survival may be improved if further axillary dissection is given.