Evaluating clinical efficacy of hospital-based surveillance with mammography and ultrasonography for breast cancer.

Periodic mammography and/or sonography examinations are conducted across numerous hospitals nationalwidely, especially for antedees with a positive mammography screening. Despite the regular practice, clinical efficacy of hospital-based breast cancer surveillance remains unclear. Specifically, the impact of surveillance interval upon survival and prognostic surrogates stratified by menopausal status, as well as malignant transition rate should be deciphered. We retrieved cancer registry to ascertain 841 breast cancers with surveillance history through administration data. Healthy controls underwent breast surveillance and were concurrently free of cancer. More benign diseases rather than cancers were identified from premenopausal women (age ≤50 years) with sonography alone within one year, as well as older women (age >50) with both mammography and sonography one to two years before a cancer or benign diagnosis. Among breast cancers, mammography alone during the antecedent one to two years had a protective effect for diagnosing carcinoma in situ rather than invasive cancer (age-adjusted odds ratio: 0.048, P = 0.016). Three-state time homogeneous Markov model showed that hospital-based breast surveillance within 2 years of disease onset reduced the malignant transition rate by 65.16% (59.79-76.74%). The clinical efficacy of breast cancer surveillance was evidenced.

Colorectal cancer concurrent gene signature based on coherent patterns between genomic and transcriptional alterations.

BACKGROUND: The aim of the study was to enhance colorectal cancer prognostication by integrating single nucleotide polymorphism (SNP) and gene expression (GE) microarrays for genomic and transcriptional alteration detection; genes with concurrent gains and losses were used to develop a prognostic signature. METHODS: The discovery dataset comprised 32 Taiwanese colorectal cancer patients, of which 31 were assayed for GE and copy number variations (CNVs) with Illumina Human HT-12 BeadChip v4.0 and Omni 25 BeadChip v1.1. Concurrent gains and losses were declared if coherent manners were observed between GE and SNP arrays. Concurrent genes were also identified in The Cancer Genome Atlas Project (TCGA) as the secondary discovery dataset (n = 345). RESULTS: The "universal" concurrent genes, which were the combination of z-transformed correlation coefficients, contained 4022 genes. Candidate genes were evaluated within each of the 10 public domain microarray datasets, and 1655 (2000 probe sets) were prognostic in at least one study. Consensus across all datasets was used to build a risk predictive model, while distinct relapse-free/overall survival patterns between defined risk groups were observed among four out of five training datasets. The predictive accuracy of recurrence, metastasis, or death was between 61 and 86% (cross-validation area under the receiver operating characteristic (ROC) curve: 0.548-0.833) from five independent validation studies. CONCLUSION: The colorectal cancer concurrent gene signature is prognostic in terms of recurrence, metastasis, or mortality among 1746 patients. Genes with coherent patterns between genomic and transcriptional contexts are more likely to provide prognostication for colorectal cancer.

The extended concurrent genes signature for disease-free survival in breast cancer.

BACKGROUND/PURPOSE: Previously we had identified concurrent genes, which highlighted the interplay between copy number variation (CNV) and differential gene expression (GE) for Han Chinese breast cancers. The merit of the approach is to discovery biomarkers not identifiable by conventional GE only data, for which phenotype-correlation or gene variability is the criteria of gene selection. MATERIALS AND METHODS: Thirty-one comparative genomic hybridization (CGH) and 83 GE microarrays were performed, with 29 breast cancers assayed from both platforms. Potential targets were revealed by Genomic Identification of Significant Targets in Cancer (GISTIC) from CGH arrays. Concurrent genes and genes with significant GISTIC scores were used to derive the extended concurrent genes signature, which was consensus from leading edge analysis across all studies and a supervised partial least square (PLS) regression predictive model of disease-free survival was constructed. RESULTS: There were 1584 concurrent genes from 29 samples with both CGH and GE microarrays. Enriched concurrent genes sets for disease-free survival were identified independently from 83 GE arrays and another one with Han Chinese origin as well as three studies of Western origin. For five studies with disease-free survival follow up, prognostic discrepancy was observed between predicted high-risk and low-risk group patients. CONCLUSION: We concluded that through parallel analyses of CGH and GE microarrays, the proposed extended concurrent gene expression signature can identify biomarkers with prognostic values.

Deciphering Genetic Alterations of Taiwanese Patients with Pancreatic Adenocarcinoma through Targeted Sequencing.

Pancreatic adenocarcinoma (PAC) is the 8th leading cause of cancer-related deaths in Taiwan, and its incidence is increasing. The development of PAC involves successive accumulation of multiple genetic alterations. Understanding the molecular pathogenesis and heterogeneity of PAC may facilitate personalized treatment for PAC and identify therapeutic agents. We performed tumor-only next-generation sequencing (NGS) with targeted panels to explore the molecular changes underlying PAC patients in Taiwan. The Ion Torrent Oncomine Comprehensive Panel (OCP) was used for PAC metastatic lesions, and more PAC samples were sequenced with the Ion AmpliSeq Cancer Hot Spot (CHP) v2 panel. Five formalin-fixed paraffin-embedded (FFPE) metastatic PAC specimens were successfully assayed with OCP, and KRAS was the most prevalent alteration, which might contraindicate the use of anti-EGFR therapy. One PAC patient harbored a FGFR2 p. C382R mutation, which might benefit from FGFR tyrosine kinase inhibitors. An additional 38 samples assayed with CHP v2 showed 100 hotspot variants, collapsing to 54 COSMID IDs. The most frequently mutated genes were TP53, KRAS, and PDGFRA (29, 23, 10 hotspot variants), impacting 11, 23, and 10 PAC patients. Highly pathogenic variants, including COSM22413 (PDGFRA, FATHMM predicted score: 0.88), COSM520, COSM521, and COSM518 (KRAS, FATHMM predicted score: 0.98), were reported. By using NGS with targeted panels, somatic mutations with therapeutic potential were identified. The combination of clinical and genetic information is useful for decision making and precise selection of targeted medicine.

Residual risk stratification of Taiwanese breast cancers following curative therapies with the extended concurrent genes signature.

INTRODUCTION: The aim of the study was to perform digital RNA counting to validate a gene expression signature for operable breast cancers initially treated with curative intention, and the risk of recurrence, distant metastasis, and mortality was predicted. METHODS: Candidate genes were initially discovered from the coherent genomic and transcriptional alternations from microarrays, and the extended concurrent genes were used to build a risk stratification model from archived formalin-fixed paraffin-embedded (FFPE) tissues with the NanoString nCounter. RESULTS: The extended concurrent genes signature was prognostic in 144 Taiwanese breast cancers (5-year relapse-free survival: 89.8 and 69.4% for low- and high-risk group, log-rank test: P = 0.004). Cross-platform comparability was evidenced from significant and positive correlations for most genes as well as equal covariance matrix across 64 patients assayed for both microarray and digital RNA counting. DISCUSSION: Archived FFPE samples could be successfully assayed by the NanoString nCounter. The purposed signature was prognostic stratifying breast cancer patients into groups with distinct survival patterns, and clinical applicability of the residual risk model was proved.

A comprehensive study comparing tack and glue mesh fixation in laparoscopic total extraperitoneal repair for adult groin hernias.

BACKGROUND: Glue mesh fixation is thought to cause less pain compared to tack mesh fixation during laparoscopic total extraperitoneal inguinal hernia repair (TEP). However, the clinical benefits of glue mesh fixation are still controversial. This study aimed to evaluate the acute pain, chronic pain, and recurrence rate between these two fixation methods. METHODS: After reviewing all patients in our prospective hernia repair database from February 2008 to December 2017, we identified 583 patients who underwent TEP with tack mesh fixation and 70 patients with glue fixation by a single surgeon. Acute post-operative pain and activity level were evaluated using a Visual Analog Score (VAS) and the modified Medical Outcome Study (MOS) score. The primary endpoint was chronic pain 6 months after TEP. The secondary endpoints were acute pain, activity level, complications, and recurrence. RESULTS: After adjustment for potential confounding factors, the glue mesh fixation had significant lower VAS at 2 h post operation during rest and coughing and on the first day after surgery during coughing (p = 0.005, p < 0.001, and p = 0.011). The modified MOS on the first day was higher in the glue group (p < 0.001). There were no reduced risk of chronic pain or increased risk of recurrence for the glue group compared to the tack group [Odds ratio (OR) = 0.237, p = 0.169; OR = 2.498, p = 0.299]. In the sub-group analysis for recurrent hernia repair, glue fixation is associated with better modified MOS (p = 0.031) on first day and lower VAS on the operative day and first day at rest (p = 0.003 and p = 0.024) after surgery. CONCLUSIONS: Glue fixation method was superior to tack fixation method in acute post-operative pain and early post-operative activity level after laparoscopic TEP repair. However, both fixation methods had similar incidence of chronic pain-, recurrence-, and procedure-related complications after laparoscopic TEP repair.

Validation of the Taiwan Chinese version of the EORTC QLQ-CR29 to assess quality of life in colorectal cancer patients.

BACKGROUND: The increasing incidence of colorectal cancer in Taiwan has generated a need for a disease-specific quality-of-life measuring instrument. We aimed to validate the Taiwan Chinese version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29. METHODS: A total of 108 patients were interviewed. Convergent and discriminant validity, Cronbach's alpha coefficient, test-retest reliability, and known-groups comparisons were used to examine the reliability and validity. RESULTS: We found good internal consistency reliability for multi-item scales of the QLQ-C30 and QLQ-CR29, except for the cognitive function and pain scale of the QLQ-C30. Patients in the active treatment group reported compromised functional scale scores (global health status/quality of life, QLQ-C30) and worse symptoms (blood and mucus in stool, QLQ-CR29) than those in the follow-up group. Similar results were found in comparisons based on Eastern Cooperative Oncology Group (ECOG) Performance Status and Bristol Stool Scale: higher physical function/sexual interest, less fatigue/urine frequency symptoms for patients with the lowest ECOG Performance Status (Grade 0), and borderline worse stool frequency scores from Types 5 and 6 patients on the Bristol Stool Scale. CONCLUSION: The study validated the Taiwan Chinese version of the EORTC QLQ-C30 and QLQ-CR29. The clinical applicability warrants further studies with greater number of participants.

Conceptual structure of the Taiwan Chinese version of the EORTC QLQ-C30.

OBJECTIVE: This study aimed to evaluate the conceptual structure of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) by analyzing data collected from patients with major cancers in Taiwan. The conceptual structure underlying QLQ-C30, including higher-order factors, was explored by structural equation modeling (SEM). METHODS: The Taiwan Chinese version of the EORTC QLQ-C30 was used as the measuring instrument. Higher-order models, including mental health/physical health, mental function/physical burden, symptom burden/function, single latent health-related quality of life, formative symptom burden/function, and formative health-related quality of life, were tested. RESULTS: Study subjects included 283 patients with breast, lung, and nasopharyngeal cancers. The original QLQ-C30 multi-factorial structure demonstrated poor composite reliability of the cognitive function subscale. The formative symptom/burden model was favored by model fit indices, further supporting causal-indicator duality, but was compromised by unexpected associations between symptomatic subscales and latent factors. The formative health-related quality of life was proposed with a single second-order latent factor where symptomatic subscales remained formative. Two additional symptom measures from the formal cognitive function subscale with the formative health-related quality-of-life model were proposed as the alterative conceptual structure for the Taiwan Chinese QLQ-C30. CONCLUSIONS: Results of the current study represent the complete SEM approach for the EORTC QLQ-C30. The formative health-related quality-of-life model with elimination of cognitive function enhances the conceptual structure of the Taiwan Chinese version with parsimonious fit and interpretability.

Refinement of breast cancer risk prediction with concordant leading edge subsets from prognostic gene signatures.

Several prognostic signatures have been identified for breast cancer. However, these signatures vary extensively in their gene compositions, and the poor concordance of the risk groups defined by the prognostic signatures hinders their clinical applicability. Breast cancer risk prediction was refined with a novel approach to finding concordant genes from leading edge analysis of prognostic signatures. Each signature was split into two gene sets, which contained either up-regulated or down-regulated genes, and leading edge analysis was performed within each array study for all up-/down-regulated gene sets of the same signature from all training datasets. Consensus of leading edge subsets among all training microarrays was used to synthesize a predictive model, which was then tested in independent studies by partial least squares regression. Only a small portion of six prognostic signatures (Amsterdam, Rotterdam, Genomic Grade Index, Recurrence Score, and Hu306 and PAM50 of intrinsic subtypes) was significantly enriched in the leading edge analysis in five training datasets (n = 2,380), and that the concordant leading edge subsets (43 genes) could identify the core signature genes that account for the enrichment signals providing prognostic power across all assayed samples. The proposed concordant leading edge algorithm was able to discriminate high-risk from low-risk patients in terms of relapse-free or distant metastasis-free survival in all training samples (hazard ratios: 1.84-2.20) and in three out of four independent studies (hazard ratios: 3.91-8.31). In some studies, the concordant leading edge subset remained a significant prognostic factor independent of clinical ER, HER2, and lymph node status. The present study provides a statistical framework for identifying core consensus across microarray studies with leading edge analysis, and a breast cancer risk predictive model was established.

Efficacy of a self-management program on quality of life in colorectal cancer patients: A randomized controlled trial.

PURPOSE: To test the efficacy of a self-management program based on acceptance and commitment therapy on quality of life, emotional distress, fatigue, physical activity, and fruit and vegetable intake in patients with colorectal cancer. METHODS: The study was a randomized controlled trial. A sample of 156 patients with colorectal cancer (stage I-III) was recruited by convenience sampling and participants were allocated randomly assigned to control or intervention groups. The intervention included a colorectal cancer self-management information booklet, two personal skills training sessions, and 12 follow-up telephone calls. The control group received health education leaflets. Outcome variables were assessed in both groups at baseline and every two months thereafter during the six-month follow-up period. RESULT: The mean age of participants was 62 years (range: 30-89 years). Generalized estimation equations analyses revealed significant differences over time in changes in anxiety (ß = -2.22, p = 0.001), depression (ß = -1.48, p = 0.033), fatigue (ß = 4.46, p = 0.001), physical and functional measures (ß = 6.16, p = 0.005), and colorectal-cancer-specific quality of life (ß = 7.45, p = 0.012). However, there were no significant differences in changes in physical activity or fruit and vegetable intake over time. CONCLUSION: The self-management skills provided by oncology nurses, including symptom management, psychological adjustment, and relaxation exercises, help colorectal cancer patients to overcome the challenges of cancer survivorship, accelerate their recovery, and improve their quality of life. THE TRIAL NUMBER: NCT03853278 registered on ClinicalTrials.gov.

Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway.

The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (ß-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 µM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor > normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal > tumor, N > T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of ß-APN (300 µM) and magnolol (25 µM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of ß-APN.

Prediction consistency and clinical presentations of breast cancer molecular subtypes for Han Chinese population.

BACKGROUND: Breast cancer is a heterogeneous disease in terms of transcriptional aberrations; moreover, microarray gene expression profiles had defined 5 molecular subtypes based on certain intrinsic genes. This study aimed to evaluate the prediction consistency of breast cancer molecular subtypes from 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50) as well as clinical presentations of each molecualr subtype in Han Chinese population. METHODS: In all, 169 breast cancer samples (44 from Taiwan and 125 from China) of Han Chinese population were gathered, and the gene expression features corresponding to 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50) were retrieved for molecular subtype prediction. RESULTS: For Sørlie 500 and Hu 306 intrinsic gene set, mean-centring of genes and distance-weighted discrimination (DWD) remarkably reduced the number of unclassified cases. Regarding pairwise agreement, the highest predictive consistency was found between Hu 306 and PAM50. In all, 150 and 126 samples were assigned into identical subtypes by both Hu 306 and PAM50 genes, under mean-centring and DWD. Luminal B tended to show a higher nuclear grade and have more HER2 over-expression status than luminal A did. No basal-like breast tumours were ER positive, and most HER2-enriched breast tumours showed HER2 over-expression, whereas, only two-thirds of ER negativity/HER2 over-expression tumros were predicted as HER2-enriched molecular subtype. For 44 Taiwanese breast cancers with survival data, a better prognosis of luminal A than luminal B subtype in ER-postive breast cancers and a better prognosis of basal-like than HER2-enriched subtype in ER-negative breast cancers was observed. CONCLUSIONS: We suggest that the intrinsic signature Hu 306 or PAM50 be used for breast cancers in the Han Chinese population during molecular subtyping. For the prognostic value and decision making based on intrinsic subtypes, further prospective study with longer survival data is needed.

Clinical practice guidelines for patients with gastrointestinal stromal tumor in Taiwan.

For many years, the understanding of gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, has been very limited. However, it is now possible to provide a more precise definition through the use of pathology classification and molecular techniques. Coupled with the advancement of clinical practice, especially the development of targeted therapy, there is now a much better insight into its treatment. At present, organizations such as the National Comprehensive Cancer Network in the USA and the European Society for Medical Oncology in Europe have established a consensus and drawn up guidelines for the diagnosis, treatment, and follow-up of GISTs.With experts coming from various districts in Taiwan and combining the most recent clinical data and experiences, the Taiwan Surgical Society of Gastroenterology drafted the first national GIST treatment guidelines after a consensus meeting in 2007. Following subsequent advances in GIST diagnosis and treatment, further revisions and modifications have been made to the original guidelines. We present here the updated consensus and recommendations of the Taiwan Surgical Society of Gastroenterology for the diagnosis and treatment of GIST. We hope these guidelines can help enhance the quality of diagnosis, treatment, and care of patients with GIST in Taiwan.

Long-term Follow-up of Patients With Hernia Using the Hernia-Specific Quality-of-Life Mobile App: Feasibility Questionnaire Study.

BACKGROUND: Hernia repair is one of the most common surgical procedures; however, the long-term outcomes are seldom reported due to incomplete follow-up. OBJECTIVE: The aim of this study was to examine the use of a mobile app for the long-term follow-up of hernia recurrence, complication, and quality-of-life perception. METHODS: A cloud-based corroborative system drove a mobile app with the HERQL (Hernia-Specific Quality-of-Life) questionnaire built in. Patients who underwent hernia repair were identified from medical records, and an invitation to participate in this study was sent through the post. RESULTS: The response rate was 11.89% (311/2615) during the 1-year study period, whereas the recurrence rate was 1.0% (3/311). Causal relationships between symptomatic and functional domains of the HERQL questionnaire were indicated by satisfactory model fit indices and significant regression coefficients derived from structural equational modeling. Regarding patients' last hernia surgeries, 88.7% (276/311) of the patients reported them to be satisfactory or very satisfactory, 68.5% (213/311) of patients reported no discomfort, and 61.1% (190/311) of patients never experienced mesh foreign body sensation. Subgroup analysis for the most commonly used mesh repairs found that mesh plug repair inevitably resulted in worse symptoms and quality-of-life perception from the group with groin hernias. CONCLUSIONS: The mobile app has the potential to enhance the quality of care for patients with hernia and facilitate outcomes research with more complete follow-up.

Nutritional Status and Related Factors in Patients with Gastric Cancer after Gastrectomy: A Cross-Sectional Study.

Patients after gastrectomy for gastric cancer are at risk of malnutrition, and poor nutritional status negatively affects patients' clinical outcomes. Knowledge of the factors influencing patients' nutritional status can inform interventions for improving patients' nutrition. A cross-sectional study was conducted to describe nutritional status and related factors in gastric cancer patients after gastrectomy. A convenience sample of gastric cancer patients with gastrectomy was recruited from general surgery or oncology clinics of a medical center in northern Taiwan. Data were collected with self-reported questionnaires, including the Functional Assessment Cancer Therapy­Gastric Module version 4, the Concerns in Meal Preparation scale, the Center for Epidemiologic Studies Depression Scale, and the Mini Nutrition Assessment. One hundred and one gastric cancer patients participated in the study. There were 81 cases of subtotal gastrectomy and 20 cases of total gastrectomy. Most patients (52.5%) were malnourished or at risk. Linear regression showed that symptom severity (ß = −0.43), employment status (ß = 0.19), and difficulty in diet preparation (ß = −0.21) were significant predictors of nutritional status. Together, these three variables explained 35.8% of the variance in patient nutritional status (F = 20.3, p < 0.001). More than 50% of our participants were malnourished or at risk for malnutrition, indicating a need for continued monitoring and support after discharge from hospitals. Special attention should be given to patients with severe symptoms, unemployment, and difficulties in diet preparation.

Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces α9-nicotinic acetylcholine receptor expression in human breast cancer cells.

The primary aim of this study was to elucidate the role of the estrogen receptor (ER), a transcription factor involved in the nicotine- and 17ß-estradiol (E2)-mediated up-regulation of α9-nAChR gene expression. A real-time polymerase chain reaction (PCR) assay was used to quantify the α9-nAChR mRNA expression levels of surgically isolated (n=339) and laser-capture microdissected tissues (ER+ versus ER-, n= 6 per group). Chromatin immunoprecipitation (ChIP) and luciferase-promoter activity assays were used to investigate the ER-mediated transcriptional regulation of α9-nAChR gene expression. We observed that breast tumors with higher α9-nAChR mRNA expression levels (i.e., a mean fold ratio in the tumor/normal-paired samples of greater than tenfold) were associated with the lowest 5-year disease-specific survival rate (50%, dead/alive= 4/4, total = 8 patients, P= 0.006), in contrast to breast tumors with low levels (i.e., a mean fold ratio of less than onefold) of α9-nAChR expression (88%, dead/alive= 3/22, total= 25 patients). Furthermore, higher α9-nAChR mRNA expression levels were preferentially detected in ER+ tumor tissues in comparison to ER- tumor tissues (ER+ versus ER- patients: n=160 vs. 72; mean fold ratios of α9-nAChR expression = 11 ± 3 vs. 6.7 ± 2.3 fold, respectively). In vitro promoter-binding assays demonstrated that the ER is a major transcription factor that mediates nicotine- and E2-induced up-regulation of α9-nAChR gene expression in MCF-7 cells. In conclusion, our data indicate that the ER plays a central role in mediating α9-nAChR gene up-regulation in response to either nicotine or E2 stimulation.

Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins.

Previous studies have demonstrated that the persistent exposure of human bronchial epithelial cells to nicotine (Nic) through nicotinic acetylcholine receptors increases cyclin D1 promoter activity and protein expression. The main purpose of this study is to elucidate the carcinogenic role of cyclin D3, which is involved in breast tumorigenesis when induced by Nic. Real-time PCR analysis revealed that cyclin D3 is highly expressed at the mRNA level in surgically dissected breast tumor tissue, compared to the surrounding normal tissue (tumor/normal fold ratio = 17.93, n = 74). To test whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells, the transformed cell line MCF-10A-Nic (DOX) was generated from normal breast epithelial cells (MCF-10A) with inducible α9-nAChR gene expression, using the adenovirus tetracycline-regulated Tet-off system. Tet-regulated overexpression of α9-nAChR in MCF-10A-Nic (DOX) xenografted BALB/c-nu/nu mice resulted in a significant induction of cyclin D3. In contrast, cyclin D3 expression was down-regulated in α9-nAChR knock-down (siRNA) MDA-MB-231-xenografted tumors in NOD.CB17-PRKDC(SCID)/J(NOD-SCID) mice. Furthermore, we found that Nic-induced human breast cancer (MDA-MB-231) cell proliferation was inhibited by 1 µM of garcinol (Gar), isolated from the edible fruit Garcinia indica, through down-regulation of α9-nAChR and cyclin D3 expression. These results suggest that α9-nAChR-mediated cyclin D3 overexpression is important for nicotine-induced transformation of normal human breast epithelial cells. The homeostatic regulation of cyclin D3 has the potential to be a molecular target for antitumor chemotherapeutic or chemopreventive purposes in clinical breast cancer patients.

Choledochal cysts in infants and children: experiences over a 20-year period at a single institution.

This analysis was undertaken to compare the clinicopathological features of infants with choledochal cysts to those of older children with these entities and to evaluate the surgical outcomes for both subject groups. The medical records of all children admitted to the Cathay General Hospital with choledochal cysts over a 20-year period were retrospectively reviewed. Twenty-five subjects were included and divided into the infant (<1 year at presentation; 8 subjects) and classical pediatric (1-18 years at presentation; 17 subjects) groups. Anatomical subtypes were: IA (16), IC (6), and IVA (3). The median biliary amylase value was markedly elevated for the pediatric group but not for the infant group. Most (82.4%) patients in the pediatric group, but none in the infant group, presented with abdominal pain. Jaundice and clay-colored stool were present in all patients in the infant group but only 35% of those in the pediatric group. All patients underwent choledochocystectomy and Roux-en-Y hepaticojejunostomy with good outcomes. Neonates/infants with choledochal cysts present differently from older children with these entities. Amylase measurements may serve to distinguish biliary atresia with cystic dilatation from choledochal cyst in neonates/infants. Prognosis following radical cyst excision and reconstruction with Roux-en-Y hepaticojejunostomy is excellent.

Primary malignant melanoma of the esophagogastric junction: A case report.

RATIONALE: Most gastrointestinal melanomas are metastatic from an oculocutaneous primary lesion; however, primary gastrointestinal melanomas have been found in all levels of the gastrointestinal tract. We present the case of Primary malignant melanoma of the esophagus and discuss the diagnostic methods, differentiation from metastatic lesions and treatment options. PATIENT CONCERNS: A 78-year-old male patient presented with fresh blood vomiting and tarry stools for 1 day. DIAGNOSES: Esophagogastroduodenoscopy of this patient revealed a tumor ∼4 cm in size at the cardia side of the esophagogastric junction with dark-red and gray pigmentation. Immunohistochemical stains of the biopsy specimens were positive for S-100 and HMB-45, which are specific markers of melanoma. INTERVENTIONS: Laparotomy with proximal gastrectomy was performed by the surgeon. Histological examination of the surgical specimen revealed the tumor arose from the distal esophagus with invasion of the proximal stomach. Primary malignant melanoma of the esophagus was diagnosed after a full skin and ophthalmic examination and positron emission tomography, which revealed no lesions elsewhere in the body. OUTCOMES: No tumor recurrence was noted at the 1-year follow-up. LESSONS: Primary malignant melanoma of the esophagus is an extremely rare but highly aggressive tumor. The special pattern of pigmentation should be recognized while performing endoscopy. Early detection and radical resection of the tumor are critical to ensure favorable outcomes.

Targeted Sequencing of Taiwanese Breast Cancer with Risk Stratification by the Concurrent Genes Signature: A Feasibility Study.

Breast cancer is the most common female malignancy in Taiwan, while conventional clinical and pathological factors fail to provide full explanation for prognostic heterogeneity. The aim of the study was to evaluate the feasibility of targeted sequencing combined with concurrent genes signature to identify somatic mutations with clinical significance. The extended concurrent genes signature was based on the coherent patterns between genomic and transcriptional alterations. Targeted sequencing of 61 Taiwanese breast cancers revealed 1036 variants, including 76 pathogenic and 545 likely pathogenic variants based on the ACMG classification. The most frequently mutated genes were NOTCH, BRCA1, AR, ERBB2, FANCA, ATM, and BRCA2 and the most common pathogenic deletions were FGFR1, ATM, and WT1, while BRCA1 (rs1799965), FGFR2 (missense), and BRCA1 (rs1799949) were recurrent pathogenic SNPs. In addition, 38 breast cancers were predicted into 12 high-risk and 26 low-risk cases based on the extended concurrent genes signature, while the pathogenic PIK3CA variant (rs121913279) was significantly mutated between groups. Two deleterious SH3GLB2 mutations were further revealed by multivariate Cox's regression (hazard ratios: 29.4 and 16.1). In addition, we identified several significantly mutated or pathogenic variants associated with differentially expressed signature genes. The feasibility of targeted sequencing in combination with concurrent genes risk stratification was ascertained. Future study to validate clinical applicability and evaluate potential actionability for Taiwanese breast cancers should be initiated.