Search

Background/aims: Distal mean nocturnal baseline impedance (MNBI) measuring via pH-impedance may be valuable in diagnosing patients with suspected laryngopharyngeal reflux (LPR). However, its wide adoption is hindered by cost and invasiveness. This study investigates whether baseline impedance measured during high-resolution impedance manometry (HRIM-BI) can predict pathological MNBI., Methods: A cross-sectional study in Taiwan included 74 subjects suspected of LPR, who underwent HRIM (MMS) and pH-impedance testing (Diversatek), after stopping proton pump inhibitors for more than 7 days. Subjects with grade C or D esophagitis or Barrett's esophagus were excluded. The cohort was divided into 2 groups: those with concomitant typical reflux symptoms (CTRS, n = 28) and those with isolated LPR symptoms (ILPRS, n = 46). HRIM-BI measurements focused on both distal and proximal esophagi. Pathological MNBI was identified as values below 2065 Ω, measured 3 cm above the lower esophageal sphincter., Results: In all subjects, distal HRIM-BI values correlated weakly with distal MNBI(r = 0.34-0.39, P < 0.005). However, in patients with ILPRS, distal HRIM-BI corelated moderately with distal MNBI(r = 0.43-0.48, P < 0.005). The areas under the receiver operating characteristic curve was 0.78 ( P = 0.001) with a sensitivity of 0.83 and a specificity of 0.68. No correlation exists between distal HRIM-BI and distal MNBI in patients with CTRS, and between proximal HRIM-BI and proximal MNBI in both groups., Conclusions: Distal HRIM-BI from HRIM may potentially predict pathological MNBI in patients with ILPRS, but not in those with CTRS. Future outcome studies linked to the metric are warranted.

Background: Diagnosing laryngopharyngeal reflux (LPR) is challenging due to overlapping symptoms. While proton pump inhibitors (PPIs) are commonly prescribed, reliable predictors of their responsiveness are unclear. Reflux monitoring technologies like dual potential of hydrogen (pH) sensors and multichannel intraluminal impedance-pH (MII-pH) could improve diagnosis. Research suggests that a composite pH parameter, defined by ≥ 2 pharyngeal acid reflux (PAR) episodes and/or excessive esophageal acid reflux (EAR), predicts PPI efficacy. The criteria for PAR episodes, a pharyngeal pH drop of ≥ 2 units to < 5 within 30 seconds during esophageal acidification, showed strong interobserver reliability. We hypothesized that PAR episodes alone might also predict PPI responsiveness., Aim: To investigate whether PAR episodes alone predict a positive response to PPI therapy., Methods: Patients suspected of having LPR were prospectively recruited from otolaryngologic clinics in three Taiwanese tertiary centers. They underwent a 24-hour esophagopharyngeal pH test using either 3-pH-sensor or hypopharyngeal MII-pH catheters while off medication, followed by a 12-week esomeprazole course (40 mg twice daily). Participants were categorized into four groups based on pH results: PAR alone, EAR alone, both pH (+), and both pH (-). The primary outcome was a ≥ 50% reduction in primary laryngeal symptoms, with observers blinded to group assignments., Results: A total of 522 patients (mean age 52.3 ± 12.8 years, 54% male) were recruited. Of these, 190 (mean age 51.5 ± 12.4 years, 61% male) completed the treatment, and 89 (47%) responded to PPI therapy. Response rates were highest in the PAR alone group (73%, n = 11), followed by EAR alone (59%, n = 68), both pH (+) (56%, n = 18), and both pH (-) (33%, n = 93). Multivariate analysis adjusting for age, sex, body mass index, and endoscopic esophagitis showed that participants with PAR alone, EAR alone, and both pH (+) were 7.4-fold ( P = 0.008), 4.2-fold ( P = 0.0002), and 3.4-fold ( P = 0.03) more likely to respond to PPI therapy, respectively, compared to the both pH (-) group. Secondary analyses using the definition of ≥ 1 PAR episode were less robust., Conclusion: In the absence of proven hypopharyngeal predictors, this post-hoc analysis found that baseline ≥ 2 PAR episodes alone are linked to PPI responsiveness, suggesting the importance of hypopharyngeal reflux monitoring., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: This pre-post intervention study aimed to assess the relationship between baseline dietary quality and the efficacy of a dietitian-guided weight reduction program, which has not been thoroughly documented to date., Methods: Ninety-two consecutive obese or overweight patients visiting a tertiary center clinic for weight reduction were enrolled in this study. Participants received a dietitian-guided weight reduction education program aimed at reducing daily caloric intake by 500 kcal and improving adherence to the Mediterranean diet for 3 months. Baseline dietary quality was assessed using the 14-item Taiwanese Mediterranean Diet Adherence Screener (T-MEDAS), where a higher T-MEDAS score reflects greater adherence to the Mediterranean diet. Additional covariates, including dietary behaviors, lifestyle factors, and comorbidities were also recorded. The primary outcome was the percentage of weight reduction at 3 months, analyzed using restricted cubic spline models and generalized estimating equations (GEE) to account for the correlation between weight change and the baseline T-MEDAS scores., Results: Thirty-nine participants were excluded due to major illnesses, use of anti-obesity medications, or loss to follow-up. Among the remaining 53 participants (mean age 41.2 ± 12.8 years, 56.6% female), the average weight reduction was 3.9 ± 3.3% from a baseline weight of 98.5 ± 12.8 kg. Participants who did not achieve a weight reduction of more than 5% had higher baseline T-MEDAS scores compared to those who did (5.4 ± 1.7 vs. 4.1 ± 1.8, p = 0.026). A restricted cubic spline model, adjusted for covariates including age, gender, diabetes mellitus (DM), dyslipidemia, and smoking, revealed a significant inverse relationship between higher baseline T-MEDAS scores and weight loss. After controlling for various confounders, GEE analysis demonstrated that higher baseline T-MEDAS scores were significantly associated with less weight loss (beta: -4.1, 95% CI: -5.6 to -2.6, p < 0.001)., Conclusions: Higher baseline dietary quality was associated with reduced effectiveness of a dietitian-guided weight reduction program. This suggests that additional strategies may be required to improve the success of weight loss interventions in individuals with higher baseline dietary quality., Competing Interests: Declarations Competing interests The authors declare no competing interests. Institutional review board statement The study protocol was approved by the ethics committee of Taichung Veterans General Hospital Institutional Review Board (IRB No. CE21192B) and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. Consent to participate All participants provided written informed consent for the study. Consent to publication Not applicable. Conflict of interest The authors declare no conflicts of interest., (© 2024. The Author(s).)

Background: Although tumor cells undergoing epithelial-mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored., Methods: We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma., Results: Our primary culture revealed carcinoma cells expressing diverse epithelial-mesenchymal traits, consistent with epithelial-mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal-epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT., Conclusions: Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma., (© 2024. The Author(s).)

Background: Immunohistochemistry (IHC) and in situ hybridization (ISH) remain standard biomarkers for therapeutic decisions in human epidermal growth factor 2 (HER2)-positive breast cancers (BCs); however, they are insufficient to explain the heterogeneous anti-HER2 response., Methods: We aimed to investigate the correlation of in situ HER2 RNA expression (isHRE), using RNAscope, with HER2 biomarkers and the impact of isHRE on the pathological complete response (pCR) rates of 278 patients with HER2 IHC/fluorescence ISH (FISH)-positive BC receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment (NCTT)., Results: We validated HER2 RNAscope scoring as a semiquantitative method to determine isHRE and showed a positive correlation between RNAscope scores and pCR rates, with particularly different rates between patients with a score of 5 versus 1-4 BCs (66.7% vs. 15.9%, p < 0.0001). There were higher RNAscope scores and pCR rates in patients with HER2 IHC 3 + versus IHC 2+/FISH + BCs and HER2 RNAscope scores and pCR rates showed similar non-linear positive correlations with HER2 copy numbers and HER2/centromere 17 ratios. Moreover, in each HER2-positive IHC/FISH category, higher pCR rates were observed in patients with RNAscope scores of 5 versus 1-4 BC. Patients achieving pCR had BCs with notably higher HER2 RNAscope scores. Multivariate analysis identified HER2 RNAscope 5 as a strong pCR predictor [odds ratio = 10.865, p < 0.001]. The combined impact of multivariate analysis-defined pCR predictors demonstrated that a higher pCR rate was observed in patients with a score of 5 versus a score of 1-4 BCs regardless of the status of hormone receptor and mono-or dual anti-HER2 blockade., Concusions: Our results demonstrated that high isHRE (RNAscope score 5) is a strong pCR predictor in patients with HER2-positive BCs receiving NCTT, highlighting the complementary role of isHRE in stratifying HER2 status in tissue. Such stratification is relevant to anti-HER2 therapeutic efficacy, particularly using the cutoff of score 1-4 versus 5., (© 2024. The Author(s).)

Context.—: RNA sequencing study has demonstrated that human epidermal growth factor receptor 2 (HER2) RNA levels influence anti-HER2 therapeutic efficacy. However, in situ HER2 RNA expression (isHRE), which evaluates HER2 RNA expression in tissue, has remained unclear in breast cancers (BCs) of various HER2 immunohistochemistry (IHC)/in situ hybridization (ISH) categories., Objective.—: To correlate isHRE with all HER2 IHC/fluorescence ISH (FISH) categories in BC., Design.—: Formalin-fixed, paraffin-embedded tissue sections from 259 BCs, covering all IHC/FISH categories, were analyzed for isHRE by RNAscope., Results.—: We validated HER2 RNAscope scoring as a semiquantitative method to evaluate isHRE and demonstrated significantly higher RNAscope scores in IHC 3+ than in IHC 2+ cases, and in IHC 2+ than in IHC 0/1+ cases. Among the 5 IHC 2+/FISH groups, group 1 (G1) cases had the highest scores. The scores in G3 cases were higher than those in G2, but not significantly different from those in G4 and G5. G4 cases had significantly higher scores than those in G2. Higher HER2 copy numbers and HER2:CEP 17 (centromere 17) copy number ratios were significantly correlated with higher isHRE in G1 cases, but not in G2 to G5 cases. RNAscope scores were significantly lower in HER2-negative (IHC 0) than in HER2-low (IHC 2+/FISH- and IHC 1+) BCs but were not different between IHC 0 and 1+ BCs when analyzed separately., Conclusions.—: We demonstrate the HER2 RNA expression status among BCs of various HER2 IHC/FISH categories in tissue. Such information may be relevant for anti-HER2 treatment decisions considering the role of HER2 RNA expression in predicting anti-HER2 therapeutic efficacy., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: Estrogen receptor (ER) testing performed using immunohistochemistry (IHC) is a critical predictive tool for breast cancer treatment. This study aimed to investigate the use of tonsil control for monitoring ER staining and hypothesize that optimal staining would reduce interlaboratory variations., Methods: A proficiency test for ER IHC was conducted using 21 tissue cores. The staining quality was centrally reviewed based on tonsil ER staining., Results: We found that 64.9% of participant samples demonstrated optimal or good staining quality. Poor staining quality was significantly associated with the use of Ventana autostainers and concentrated antibodies. Although the concordance rate did not show significant differences across staining quality levels, interparticipant agreement declined as staining quality deteriorated. Among the 19 discordant responses, 63.2% could be attributed to staining problems, whereas 36.8% could be due to misinterpretation. Poor staining quality due to inadequate staining was the primary reason for undercalls, which can lead to false-negative results. Misinterpretations of nonspecific faint staining that was weaker than the staining of the tonsil control were the cause of most overcalls., Conclusion: Tonsil tissue is an ideal control for monitoring ER staining and can serve as a reference for determining the lower bound for ER positivity. Optimal ER staining and appropriate references for ER positivity can further improve ER IHC quality., Competing Interests: Conflicts of Interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Background: Percutaneous endoscopic gastrostomy (PEG) is commonly chosen for long-term enteral nutrition support. However, common complications of PEG include wound infection, leakage, obstruction, bleeding, dislodgement, pneumonia, peritonitis, and more. The anticipation of these complications by both patients and their family caregivers underscores the essential requirement of ongoing technical guidance for the daily care of PEG and the adoption of preventative strategies., Objective: This study aimed to establish and compare a health education program utilizing a tracking system for PEG using a mobile app (PEG app) and instant messaging software versus a paper-based health education program with instant messaging software. Their effectiveness in preventing complications, avoiding hospital readmissions, improving self-care practices, and enhancing quality of life outcomes was assessed., Methods: A randomized controlled trial design was used, and the study sample consisted of patients from a medical center in central Taiwan who underwent thoracic surgery or gastroenterology procedures. Inclusion criteria were being a new case undergoing his or her first gastric tube insertion and having the ability to operate a smartphone. Exclusion criteria were cases requiring tube replacement or nasogastric tubes. A total of 74 participants were enrolled, with 37 participants in the experimental group and 37 participants in the control group. Data collection took place from hospitalization until 1 month after discharge. The experimental group received care using the gastric tube tracking system (PEG app) and the Line app that included phone, text, and photo capture capabilities, while the control group received routine nursing care and used the Line app., Results: The experimental group demonstrated a significant reduction in the occurrence of complications compared with the control group (χ 2 1 =12.087, P=.001). Specifically, the occurrence of leakage events was significantly lower in the experimental group than in the control group (χ 2 1 =12.906, P=.001). However, the experimental group exhibited superior self-care ability compared with the control group (t 72 =2.203, P=.03). There was no significant difference in overall quality of life scores between the experimental and control groups (t 72 =1.603, P=.11). However, the experimental group showed better social aspects of quality of life than the control group (t 72 =2.164, P=.03)., Conclusions: Integration of the PEG app with instant messaging can enhance self-care ability, improve social aspects of quality of life, and reduce complications. The study results suggest that the PEG app could be used as an adjunct tool to promote patients' self-directed management of their gastric tube at home, particularly for patients who have undergone their first PEG placement and are being discharged from the hospital., Trial Registration: Chinese Clinical Trial Registry ChiCTR2300071271; https://tinyurl.com/4vvy584e., (©Bi-Lian Chen, Han-Chung Lien, Shyh-Sheng Yang, Shiao-Chi Wu, Hsien-Hsien Chiang, Li-Chan Lin. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 20.10.2023.)

Laryngopharyngeal reflux (LPR) is a variant of gastroesophageal reflux disease (GERD) in which gastric refluxate irritates the lining of the aerodigestive tract and causes troublesome airway symptoms or complications. LPR is a prevalent disease that creates a significant socioeconomic burden due to its negative impact on quality of life, tremendous medical expense, and possible cancer risk. Although treatment modalities are similar between LPR and GERD, the diagnosis of LPR is more challenging than GERD due to its non-specific symptoms/signs. Due to the lack of pathognomonic features of endoscopy, mounting evidence focused on physiological diagnostic testing. Two decades ago, a dual pH probe was considered the gold standard for detecting pharyngeal acidic reflux episodes. Despite an association with LPR, the dual pH was unable to predict the treatment response in clinical practice, presumably due to frequently encountered artifacts. Currently, hypopharygneal multichannel intraluminal impedance-pH catheters incorporating two trans-upper esophageal sphincter impedance sensors enable to differentiate pharyngeal refluxes from swallows. The validation of pharyngeal acid reflux episodes that are relevant to anti-reflux treatment is, therefore, crucial. Given no diagnostic gold standard of LPR, this review article aimed to discuss the evolution of objective diagnostic testing and its predictive role of treatment response.

Background/aims: Diagnosis of isolated laryngopharyngeal reflux symptoms (ILPRS), ie, without concomitant typical reflux symptoms (CTRS), remains difficult. Mean nocturnal baseline impedance (MNBI) reflects impaired mucosal integrity. We determined whether esophageal MNBI could predict pathological esophagopharyngeal reflux (pH+) in patients with ILPRS., Methods: In this cross-sectional study conducted in Taiwan, non-erosive or low-grade esophagitis patients with predominant laryngopharyngeal reflux symptoms underwent combined hypopharyngeal multichannel intraluminal impedance-pH monitoring when off acid suppressants. Participants were divided into the ILPRS (n = 94) and CTRS (n = 63) groups. Asymptomatic subjects without esophagitis (n = 25) served as healthy controls. The MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES) and the proximal esophagus were measured., Results: Distal but not proximal esophageal median MNBI values were significantly lower in patients with pH+ than in those with pH- (ILPRS in pH+ vs pH-: 1607 Ω vs 2709 Ω and 1885 Ω vs 2563 Ω at 3 cm and 5 cm above LES, respectively; CTRS in pH+ vs pH-: 1476 vs 2307 Ω and 1500 vs 2301 Ω at 3 cm and 5 cm above LES, respectively, P < 0.05 for all). No significant differences of any MNBI exist between any pH- subgroups and healthy controls. The areas under the receiver operating characteristic curve in the ILPRS group were 0.75 and 0.80, compared to the pH- subgroup and healthy controls ( P < 0.001 for both), respectively. Interobserver reproducibility was good (Spearman correlation 0.93, P < 0.0001)., Conclusion: Distal esophageal MNBI predicts pathological reflux in patients with ILPRS.

Background/aims: Hypopharyngeal multichannel intraluminal impedance-pH (HMII-pH) technology incorporating 2 trans-upper esophageal sphincter impedance channels has been developed to detect pharyngeal reflux. We used the HMII-pH technique to validate the candidate pharyngeal acid reflux (PAR) episodes based on the dual-pH tracings and determined the interobserver reproducibility., Methods: We conducted a cross-sectional study in tertiary centers in Taiwan. Ninety patients with suspected laryngopharyngeal reflux and 28 healthy volunteers underwent HMII-pH test when off acid suppressants. Candidate PAR episodes were characterized by pharyngeal pH drops of at least 2 units and reaching a nadir pH of 5 within 30 seconds during esophageal acidification. Two experts manually independently identified candidate PAR episodes based on the dual-pH tracings. By reviewing the HMII-pH tracings, HMII-pH-proven PAR episodes were subsequently confirmed. The consensus reviews of HMII-pH-proven PAR episodes were considered to be the reference standard diagnosis. The interobserver reproducibility was assessed., Results: A total of 105 candidate PAR episodes were identified. Among them 84 (80.0%; 95% CI, 71.0-87.0%) were HMII-pH-proven PAR episodes (82 in 16 patients and 2 in 1 healthy subject). Patients tended to have more HMII-pH-proven PAR episodes than healthy controls (median and percentile values [25th, 75th, and 95th percentiles]: 0 [0, 0, 3] vs 0 [0, 0, 0], P = 0.067). The concordance rate in diagnosing HMII-pH-proven PAR episodes between 2 independent observers was 92.2%., Conclusion: Our preliminary data showed that 80.0% (71.0-87.0%) of the proposed candidate PAR episodes were HMII-pH-proven PAR episodes, among which the interobserver reproducibility was good.

Background: Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. Although previous transcriptomic and proteomic studies have reported subtype-related heterogeneity, the intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear., Methods: Fifty-nine NST components and paired metaplastic components (spindle carcinomatous [SPS], matrix-producing, rhabdoid [RHA], and squamous carcinomatous [SQC] components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling using the NanoString Breast Cancer 360 Panel on a NanoString nCounter FLEX platform. BC360-defined signatures were scored using nSolver software., Results: Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial-mesenchymal transition and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlaps in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. Finally, the EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis., Conclusions: We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs., (© 2023. The Author(s).)

Background: Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis-related portal hypertension (pHTN). This study defined evident pHTN by the presence of esophageal or gastric varices and compared patients' outcomes of metastatic breast cancer with imaging-diagnosed pseudocirrhosis with or without varices., Methods: The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Survival outcomes were compared based on endoscopic evidence of esophageal or gastric varices., Results: Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eighty-one (76%) had initial metastases in both hepatic lobes, and 32 (30%) had esophageal or gastric varices. The median overall survival (OS) was 5 and 13 months in patients with and without varices (P = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative subtype was 16, 9, and 2 months, respectively (P = .001). Patients with varices usually had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with varices had OS exceeding 1 year. In multivariate analysis, evident varices (P = .007) and triple-negative subtype (P = .013) were associated with poor OS., Conclusions: Patients with pseudocirrhosis and evident varices had a significantly shorter median OS, and were usually associated with clinical cirrhosis-related complications. To maximize OS, early identification and meticulous supportive care are warranted., (© The Author(s) 2022. Published by Oxford University Press.)

Aim: Hepatocellular carcinoma (HCC) is one of the most common cancers. Tyrosine kinase inhibitors (TKIs), including sorafenib (SOR) and lenvatinib (LEN), as well as immune checkpoint inhibitors (ICIs), including nivolumab (NIVO) and pembrolizumab (PEMBRO), have been approved for the treatment of advanced HCC. The aim of the study is to determine whether advanced-stage HCC patients should receive a combination of TKI and ICI as first-line therapy., Methods: Data for subjects with BCLC stage C HCC, who were receiving combining TKI and ICI as first-line therapy at Taichung Veterans General Hospital from April 2019 to July 2021, were evaluated. The general and therapeutic outcome data were collected and analyzed., Results: A total of 33 patients were enrolled (8 SOR/NIVO, 4 SOR/PEMBRO, 11 LEN/NIVO, and 10 LEN/PEMBRO). All cases belonged to Child-Pugh class A. The objective response rate was 48.5%, and disease control rate was 72.7%. The average progression-free survival (PFS) and overall survival (OS) of all patients was 9.2 and 17.0 months, respectively. The use of PEMBRO, when compared with NIVO, had a significantly positive impact towards achieving an objective response, defined as either complete response or partial response (OR 5.54, p = 0.045). PFS and OS between the different TKIs or ICIs had no differences. The most adverse event was fatigue (36.4%), and most cases were mild and manageable., Conclusion: Combining TKI and ICI provides an acceptable antitumor efficacy in first-line therapy for advanced-stage HCC patients. The survival outcomes between different TKIs or ICIs display no differences.

Background: Transarterial chemoembolization (TACE) is a recommended treatment for patients with intermediate stage hepatocellular carcinoma (HCC) but with variable treatment outcomes., Aim: To determine factors for predicting outcomes of TACE in patients with intermediate stage B HCC., Methods: Patients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC who underwent TACE as the primary treatment were enrolled at Taichung Veterans General Hospital from January 2005 to December 2009. Patients were assigned to either the objective responder (OR) group or the non-OR group according to mRECIST criteria. Clinical and radiological characteristics were compared between the 2 groups. The overall survival of enrolled subjects was analyzed., Results: In 128 enrolled patients, 66 (51.6%) were in the OR group and 62 (48.4%) in the non-OR group. Compared with the non-OR group, the OR group had a significantly smaller HCC size (6.55 cm vs 9.50 cm, P = 0.001) and was within the up-to-7 criteria (50% vs 26.7%, P = 0.001). After multivariable analyses, these significant associations still existed. Overall survival rate of all the subjects averaged 20.65 ± 13.26 mo. The survival rate at 1-year was 64.8%, 2-year was 46.9%, and 3-year was 31.2%. For those patients with OR to TACE, smaller tumor size and within up-to-7 criteria were associated with significantly better overall survival. Those patients with subgroup B1 had the highest OR ratio (75%) and better overall survival (26.70 ± 12.07 mo) after TACE., Conclusion: BCLC stage B HCC patients with smaller tumor size or within up-to-7 criteria had better survival outcomes to TACE. BCLC stage B subgroup is useful to predict refractoriness to TACE., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Joint analysis of multiple protein expressions and tissue morphology patterns is important for disease diagnosis, treatment planning, and drug development, requiring cross-staining alignment of multiple immunohistochemical and histopathological slides. However, cross-staining alignment of enormous gigapixel whole slide images (WSIs) at single cell precision is difficult. Apart from gigantic data dimensions of WSIs, there are large variations on the cell appearance and tissue morphology across different staining together with morphological deformations caused by slide preparation. The goal of this study is to build an image registration framework for cross-staining alignment of gigapixel WSIs of histopathological and immunohistochemical microscopic slides and assess its clinical applicability. To the authors' best knowledge, this is the first study to perform real time fully automatic cross staining alignment of WSIs with 40× and 20× objective magnification. The proposed WSI registration framework consists of a rapid global image registration module, a real time interactive field of view (FOV) localization model and a real time propagated multi-level image registration module. In this study, the proposed method is evaluated on two kinds of cancer datasets from two hospitals using different digital scanners, including a dual staining breast cancer data set with 43 hematoxylin and eosin (H&E) WSIs and 43 immunohistochemical (IHC) CK(AE1/AE3) WSIs, and a triple staining prostate cancer data set containing 30 H&E WSIs, 30 IHC CK18 WSIs, and 30 IHC HMCK WSIs. In evaluation, the registration performance is measured by not only registration accuracy but also computational time. The results show that the proposed method achieves high accuracy of 0.833 ± 0.0674 for the triple-staining prostate cancer data set and 0.931 ± 0.0455 for the dual-staining breast cancer data set, respectively, and takes only 4.34 s per WSI registration on average. In addition, for 30.23% data, the proposed method takes less than 1 s for WSI registration. In comparison with the benchmark methods, the proposed method demonstrates superior performance in registration accuracy and computational time, which has great potentials for assisting medical doctors to identify cancerous tissues and determine the cancer stage in clinical practice., (© 2022. The Author(s).)

Breast cancer is the leading cause of death for women globally. In clinical practice, pathologists visually scan over enormous amounts of gigapixel microscopic tissue slide images, which is a tedious and challenging task. In breast cancer diagnosis, micro-metastases and especially isolated tumor cells are extremely difficult to detect and are easily neglected because tiny metastatic foci might be missed in visual examinations by medical doctors. However, the literature poorly explores the detection of isolated tumor cells, which could be recognized as a viable marker to determine the prognosis for T1NoMo breast cancer patients. To address these issues, we present a deep learning-based framework for efficient and robust lymph node metastasis segmentation in routinely used histopathological hematoxylin−eosin-stained (H−E) whole-slide images (WSI) in minutes, and a quantitative evaluation is conducted using 188 WSIs, containing 94 pairs of H−E-stained WSIs and immunohistochemical CK(AE1/AE3)-stained WSIs, which are used to produce a reliable and objective reference standard. The quantitative results demonstrate that the proposed method achieves 89.6% precision, 83.8% recall, 84.4% F1-score, and 74.9% mIoU, and that it performs significantly better than eight deep learning approaches, including two recently published models (v3&#95;DCNN and Xception-65), and three variants of Deeplabv3+ with three different backbones, namely, U-Net, SegNet, and FCN, in precision, recall, F1-score, and mIoU (p<0.001). Importantly, the proposed system is shown to be capable of identifying tiny metastatic foci in challenging cases, for which there are high probabilities of misdiagnosis in visual inspection, while the baseline approaches tend to fail in detecting tiny metastatic foci. For computational time comparison, the proposed method takes 2.4 min for processing a WSI utilizing four NVIDIA Geforce GTX 1080Ti GPU cards and 9.6 min using a single NVIDIA Geforce GTX 1080Ti GPU card, and is notably faster than the baseline methods (4-times faster than U-Net and SegNet, 5-times faster than FCN, 2-times faster than the 3 different variants of Deeplabv3+, 1.4-times faster than v3&#95;DCNN, and 41-times faster than Xception-65).

Medical resources are limited for hepatitis C virus (HCV) elimination in rural indigenous areas of Taiwan. This study aimed to investigate liver disease risk and conduct a HCV elimination program in two rural indigenous townships. A program of village-by-village screening tests was conducted including hepatitis B virus surface antigen (HBsAg), antibody to HCV (anti-HCV) and gamma-glutamyl transferase (GGT), linking to outreach hepatology care at two indigenous townships (Laiyi and Mudan). Adult residents were invited to join this program. One hepatology specialist assessed liver disease risk, provided HCV treatment counselling and initiated direct acting antivirals (DAA) at an outreach hepatology clinic in primary health centers. A total of 3503 residents attended this program with a screening coverage of 73.5%. The prevalence of HBsAg, anti-HCV, and high GGT level was 8.2%, 10.0% and 19.5%, respectively. Laiyi had significantly higher prevalence of anti-HCV than Mudan. While males had significantly higher prevalence of HBsAg and high GGT in both townships, females in Laiyi had higher anti-HCV prevalence. HBsAg and high GGT prevalence peaked at 40-59 years of age and anti-HCV prevalence increased significantly with age. Two hundred and sixty-three residents visited the outreach hepatology clinic for HCV treatment evaluation, with 121 (46%) residents having active HCV, while 116 received DAA, with 111 (95.7%) achieving HCV elimination. For rural indigenous townships in southern Taiwan, HCV infection and alcohol consumption were two major liver disease risks. While HCV infection was predominant in old females, chronic hepatitis B virus infection and habitual alcohol consumptions predominated in middle-aged males. HCV elimination was achieved by the village-by-village screening model and linked to outreach hepatology care.

Aim: Currently, atezolizumab combined with bevacizumab is the standard first-line treatment for unresectable hepatocellular carcinoma (HCC), but lenvatinib or sorafenib are still recommended for these patients for some reasons. The aim of the study was to determine the outcomes of Taiwanese patients with advanced-stage HCC who received lenvatinib or sorafenib., Methods: Data on patients with BCLC stage C HCC who were receiving lenvatinib or sorafenib as the first-line therapy from May 2018 to August 2020 was collected. The individuals with lenvatinib and sorafenib were propensity score-matched at a ratio of 1:2., Results: A total of 22 patients with lenvatinib and 44 patients with sorafenib were enrolled. The ORR (36.4% vs. 11.4%, p = 0.023) and DCR (81.9% vs. 56.9%, p = 0.039) were both higher in the lenvatinib group compared with the sorafenib group. The median overall survival (OS) of the lenvatinib group and the sorafenib group was 9.36 months and 8.36 months, respectively. The best median OS was detected in patients receiving lenvatinib and having an objective tumor response (11.29 months), with a significant difference ( p = 0.031) compared with the other groups., Conclusion: Lenvatinib, compared to sorafenib, had better ORR and DCR, but similar OS, in Taiwanese patients with advanced-stage HCC. The patients with an objective tumor response had a better OS.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC., (© 2021. The Author(s).)

Background: Current guidelines recommend harvesting ≥3 sentinel nodes if sentinel lymph node biopsy (SLNB) alone is considered after neoadjuvant therapy (NAT) for initially node-positive (cN+) breast cancer. We attempted to investigate factors predicting one or two sentinel lymph nodes harvested to be accepted for SLNB alone after NAT in initially cN + patients., Methods: Overall, 157 patients who received NAT (clinically T1-3/N1-2/M0) and underwent SLNB were identified from a prospectively maintained database. Significant factors were identified using a multiple logistic regression model., Results: The overall SLN identification rate was 83.4%. Failed SLN identification was associated with a 2-day protocol using a single tracer (odds ratio: 0.331 [95% confidence interval {CI}: 0.132-0.830], p = 0.018), age >52 years (0.345 [0.131-0.913], p = 0.032), and lobular histology (0.156 [0.026-0.944], p = 0.043). The overall false-negative SLNB rate was 14.7%. Its increased risk was associated with radioactivity count >530 for any SLN during SLNB (96.4 [4.00-2320], p = 0.005), age ≥57 years (34.2 [1.92-610], p = 0.016), and taxane use (105 [1.02-10700], p = 0.049); its decreased risk was associated with more harvested SLNs (0.191 [0.054-0.669], p = 0.01) and dual tracers (0.101 [0.012-0.843], p = 0.034). A predictive model using these factors achieved an area under the curve of 0.935 (95% CI: 0.878-0.991)., Conclusion: When taxane was administered during NAT, the false-negative rate was predicted at <5% for patients aged <57 years, if 1-2 SLNs were harvested using dual tracers, and when the count of every SLN was lower than 530 after NAT in cN + breast cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Both stromal tumor-infiltrating lymphocytes (sTILs) and programmed death-ligand 1 (PD-L1) affect responses to immunotherapy; however, the extent of sTIL and PD-L1 expression within various metaplastic components in metaplastic breast carcinoma (MBC), which are critical for the characterization of immune microenvironments, remains unreported. We profiled sTIL infiltration and PD-L1 expression in different metaplastic components of specimens from 82 MBC patients. The overall positivity for high or intermediate (H/I) sTIL, immune cell-PD-L1 (IcPD-L1), and tumor cell-PD-L1 (TcPD-L1) was 34.1%, 47.6%, and 17.1%, respectively, but differences specific to MBC subtypes and each metaplastic component existed. Squamous cell carcinoma exhibited the highest positivity rates of sTIL(H/I) (50.0%) and IcPD-L1 (66.7%), while matrix-producing carcinoma had the lowest respective rates (14.3% and 28.6%). The positivity rates of sTIL(H/I) and IcPD-L1 were the highest in squamous component (Sq) and the lowest in chondroid component (Ch). All cases that had discordant sTIL categories between carcinoma of no special type (NST) and metaplastic components showed sTIL(H/I) positivity higher in Sq, but lower in spindled component (Sp) and Ch. While there was no pattern of higher IcPD-L1-positivity in Sp, six of the seven cases that were TcPD-L1-discordant between NST and Sp were TcPD-L1-positive in Sp, suggesting a trend for higher TcPD-L1 in Sp. The diagnostic predictability of total tumor IcPD-L1 positivity based on IcPD-L1 positivity in Sq and Ch was 95.2% and 33.3%, respectively. Multivariate analysis showed that sTIL(H/I) positivity, but not PD-L1 positivity, correlated with better survival. Our data implicate distinct immune microenvironments in different metaplastic components in MBC, which may have immunopathologic, diagnostic, and therapeutic significance.

Objective: Transarterial chemoembolization (TACE) is the treatment modality for intermediate, or Barcelona Clinic Liver Cancer stage B, hepatocellular carcinoma (HCC), but its beneficial effect on outcomes is still unsatisfactory. This study aimed to assess the outcomes of combined TACE and sorafenib for patients with intermediate HCC., Methods: Patients with intermediate HCC who were receiving TACE alone (the monotherapy group), or combined TACE and sorafenib (the combined therapy group) from January 2013 to June 2018 were enrolled., Results: Altogether 64 patients were enrolled, of whom 34 were assigned to the monotherapy group and 30 to the combined therapy group. A prolonged time-to-progression (TTP) (mean 14.46 mo vs 6.39 mo, P = 0.001) was noted in the combined therapy group compared with the monotherapy group. Overall survival (OS) (mean 18.96 mo vs15.44 mo, P = 1.000) between the two groups did not differ significantly. After adjustment, there were no significant differences in the 12-18 month mortality rate between the two groups., Conclusion: Patients with intermediate HCC receiving combined TACE and sorafenib had a better TTP, but not OS, than those receiving TACE alone., (© 2020 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Aims: Although Ki67 labelling index (LI) is a prognostic and predictive marker in breast cancer, its accuracy and reproducibility must be validated before its clinical application. We aimed to evaluate the agreement of Ki67 LI in clinical practice in Taiwan., Methods: We conducted a Ki67 immunohistochemistry (IHC) proficiency test. The participants performed the Ki67 IHC test and measured the Ki67 LI of 10 cases of breast cancer tissue on a microarray slide. The staining quality was centrally reviewed based on the Ki67 staining of the tonsil surface epithelium., Results: Ki67 staining and counting methods are diverse in Taiwan. The reproducibility of Ki67 LI was poor to good (intraclass correlation coefficient: 0.581, 95% CI 0.354 to 0.802). The reproducibility and agreement in the high staining quality group were significantly higher than those in the low staining quality group. The majority of the Ki67 LIs derived from the low staining quality group were underestimated. Different counting methods did not reveal significant differences when determining Ki67 LI with microarray sections., Conclusions: We suggest using the surface epithelium of the tonsil as external control and achieving optimal staining results that consist of a high positive parabasal layer, a low positive intermediate layer and a negative superficial layer. Good Ki67 staining quality can minimise the staining variations among different laboratories, and it is essential for the reproducibility of Ki67 LI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Patients with isolated laryngopharyngeal reflux symptoms (LPRS) defined as those without concomitant typical reflux symptoms (CTRS) are clinically challenging to manage due to unclear pathophysiology. We investigated esophageal physiology in patients with isolated LPRS and their response to proton-pump inhibitors (PPI) therapy., Methods: This is a multi-center observational study conducted in referral hospitals in Taiwan. Patients with predominant LPRS, but without common non-reflux causes, underwent esophageal manometry, 24-hr ambulatory esophagopharyngeal pH testing, and Bernstein test, followed by a 12-week esomeprazole 40 mg twice-daily treatment. Participants with pathological reflux were divided into the isolated LPRS group (ie, LPRS without CTRS, n = 40) and the CTRS group (ie, LPRS with CTRS, n = 66). Participants without pathological reflux or esophagitis (n = 132) served as the nonreflux controls., Results: The PPI-responsiveness was similar between the isolated LPRS group and CTRS group (63% vs 57%, P = .8), but lower in the nonreflux controls (32%, P = .005). Despite similar distal esophageal acid exposure time (P = .7) when compared to those with CTRS, the isolated LPRS group had a lower prevalence of both positive Bernstein test (P = .001) and ineffective esophageal motility disorder (P = .03), and fewer pharyngeal acid reflux episodes (P < .0001)., Conclusions: Our findings indicate similar distal esophageal acid exposure and PPI-responsiveness between LPRS patients with and without CTRS. The lack of CTRS in the isolated LPRS group is likely due to esophageal acid hyposensitivity and fewer pharyngeal acid reflux episodes, thus implicating distinct pathophysiology of isolated LPRS from those with CTRS., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls., Competing Interests: Competing interestsA.E. is on the Roche advisory board and has reported honoraria from Amgen, Novartis and Roche. A.J.L. is a consultant for BMS, Merck, AZ/Medimmune, and Genentech. R.S. reports research funding from Roche, Puma, Merck; advisory board and consultancy for BMS; travel funding from Roche, Merck, and Astra Zeneca. S.G. reports Lab research funding from Lilly, Clinical research funding from Eli Lilly and Novartis and is a Paid advisor to Eli Lilly, Novartis, and G1 Therapeutics. J.v.d.L. is member of the scientific advisory boards of Philips, the Netherlands and ContextVision, Sweden and receives research funding from Philips, the Netherlands and Sectra, Sweden. S.A. reports Research funding to institution from Merck, Genentech, BMS, Novartis, Celgene and Amgen and is an uncompensated consultant /steering committee member for Merck, Genentech and BMS. T.O.N. has consulted for Nanostring and received compensation and has intellectual property rights/ownership interests from Bioclassifier LLC [not related to the subject material under consideration]. S.L. receives research funding to institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer and Eli Lilly, has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and acted as consultant (paid to her institution) to Aduro Biotech. S.R.L. has received travel and educational funding from Roche/Ventana. A.M. is an equity holder in Elucid Bioimaging and in Inspirata Inc., a scientific advisory consultant for Inspirata Inc, has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck, has sponsored research agreements with Philips and Inspirata Inc, is involved in a NIH U24 grant with PathCore Inc, and 3 different R01 grants with Inspirata Inc. and his technology has been licensed to Elucid Bioimaging and Inspirata Inc. G.C. is on the advisory boards of Roche, BMS, Pfizer, Seattle Genetics and Ellipsis, and reports personal fees from Roche, BMS, Pfizer, Seattle Genetics, and Ellipsis, outside of the submitted work. J.H. is the director and owner of Vivactiv Ltd. J.H. is the director and owner of Slide Score B.V. F.P.L. reports funding from Astrazeneca, BMS, Roche, MSD, Pfizer, Novartis, Sanofi, Eli Lilly. J.B. reports consultancies from Insight Genetics, BioNTech AG, Biotheranostics, Pfizer, RNA Diagnostics and OncoXchange, research funding from Thermo Fisher Scientific, Genoptix, Agendia, NanoString Technologies, Stratifyer GmbH and Biotheranostics, applied for patents, including Jan 2017: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility—15/325,472; EPO—15822898.1; Canada—not yet assigned; Jan 2017: Systems, Devices and Methods for Constructing and Using a Biomarker, US utility—15/328,108; EPO—15824751.0; Canada—not yet assigned; Oct 2016: Histone gene module predicts anthracycline benefit, PCT/CA2016/000247; Dec 2016: 95‐Gene Signature of Residual Risk Following Endocrine Treatment, PCT/CA2016/000304; Dec 2016: Immune Gene Signature Predicts Anthracycline Benefit, PCT/CA2016/000305. M.A.S. reports consulting work for Achilles Therapeutics. C.S. reports receipt of grants/research support from Pfizer, AstraZeneca, BMS and Ventana; receipt of honoraria, consultancy, or SAB Member fees from Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Sarah Canon Research Institute, Genentech, Roche-Ventana, GRAIL, Medicxi; Advisor for Dynamo Therapeutics; Stock shareholder in Apogen Biotechnologies, Epic Bioscience, GRAIL; Co-Founder & stock options in Achilles Therapeutics. A.H.B. is the co-founder and CEO of PathAI. J.K. is an employee of PathAI. D.D. is on the advisory board for Oncology Analytics, Inc, and a consultant for Novartis. D.L.R. is on the advisory board of Amgen, Astra Zeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, NanoString, Perkin Elmer, Ventana, Ultivue; receives research support from Astra Zeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, Ultivue; instrument support from Ventana, Akoya/Perkin Elmer, NanoString; paid consultant for Biocept; received travel honoraria from BMS, founder and equity holder for PixelGear and received royalty from Rarecyte. A.T. reports benefits from ICR’s Inventors Scheme associated with patents for one of PARP inhibitors in BRCA1/2 associated cancers, as well as honoraria from Pfizer, Vertex, Prime Oncology, Artios, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics and Merck Serono. This work includes contributions from, and was reviewed by, individuals at the FDA. This work has been approved for publication by the agency, but it does not necessarily reflect official agency policy. Certain commercial materials and equipment are identified in order to adequately specify experimental procedures. In no case does such identification imply recommendation or endorsement by the FDA, nor does it imply that the items identified are necessarily the best available for the purpose. This work includes contributions from, and was reviewed by, individuals who received funding from the National Institutes of Health, the U.S. Department of Veterans Affairs and the Department of Defense. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government., (© The Author(s) 2020.)

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Competing Interests: Competing interestsJ.T. is funded by Visiopharm A/S, Denmark. A.M. is an equity holder in Elucid Bioimaging and in Inspirata Inc. He is also a scientific advisory consultant for Inspirata Inc. In addition he has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck. He also has sponsored research agreements with Philips and Inspirata Inc. His technology has been licensed to Elucid Bioimaging and Inspirata Inc. He is also involved in an NIH U24 grant with PathCore Inc, and three different R01 grants with Inspirata Inc. S.R.L. received travel and educational funding from Roche/Ventana. A.J.L. serves as a consultant for BMS, Merck, AZ/Medimmune, and Genentech. He is also provides consulting and advisory work for many other companies not relevant to this work. FPL does consulting for Astrazeneca, BMS, Roche, MSD Pfizer, Novartis, Sanofi, and Lilly. S.Ld.H., A.K., M.K., U.K., and M.B. are employees of Roche. J.M.S.B. is consultant for Insight Genetics, BioNTech AG, Biothernostics, Pfizer, RNA Diagnostics, and OncoXchange. He received funding from Thermo Fisher Scientific, Genoptix, Agendia, NanoString technologies, Stratifyer GmBH, and Biotheranostics. L.F.S.K. is a consultant for Roche and Novartis. J.K.K. and A.H.B. are employees of PathAI. D.L.R. is on the advisory board for Amgen, Astra Xeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, Nanostring, Perking Elmer, Roche/Ventana, and Ultivue. He has received research support from Astrazeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, Ultivue, Roche/Ventana, Akoya/Perkin Elmer, and Nanostring. He also has financial conflicts of interest with BMS, Biocept, PixelGear, and Rarecyte. S.G. is a consultant for and/or receives funding from Eli Lilly, Novartis, and G1 Therapeutics. J.A.W.M.vdL. is a member of the scientific advisory boards of Philips, the Netherlands and ContextVision, Sweden, and receives research funding from Philips, the Netherlands and Sectra, Sweden. S.A. is a consultant for Merck, Genentech, and BMS, and receives funding from Merck, Genentech, BMS, Novartis, Celgene, and Amgen. T.O.N. has consulted for Nanostring, and has intellectual property rights and ownership interests from Bioclassifier LLC. S.L. receives research funding to her institution from Novartis, Bristol Meyers-Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer and Eli Lilly. She has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech. J.H. is director and owner of Slide Score BV. M.M.S. is a medical advisory board member of OptraScan. R.S. has received research support from Merck, Roche, Puma; and travel/congress support from AstraZeneca, Roche and Merck; and he has served as an advisory board member of BMS and Roche and consults for BMS., (© The Author(s) 2020.)

We conducted a systemic search of several databases for randomized controlled trials (RCTs) that reported efficacy and safety outcomes of drugs for left-sided and right-sided metastatic colorectal cancer (mCRC), to identify the best available treatment. A network meta-analysis with mixed comparisons was created to interpret the best treatment option using the surface under the cumulative ranking curve. In the left-sided rat sarcoma (RAS) wild-type (WT) mCRC patients, bevacizumab, panitumumab, or cetuximab with chemotherapy groups showed a significantly better objective response rate than the chemotherapy alone group. The progression-free survival (PFS) and overall survival were better with panitumumab or cetuximab with chemotherapy than with chemotherapy alone. In the right-sided RAS WT mCRC patients, PFS for bevacizumab with chemotherapy was significantly better than that for cetuximab with chemotherapy. Cetuximab, closely followed by panitumumab, is the most effective treatment in left-sided RAS WT mCRC. Bevacizumab is more effective in right-sided mCRC., Competing Interests: Declaration of Competing Interest The authors declare no competing interests for this work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Bats are natural reservoirs of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV). Scotophilus bat CoV-512 demonstrates potential for cross-species transmission because its viral RNA and specific antibodies have been detected in three bat species of Taiwan. Understanding the cell tropism of Scotophilus bat CoV-512 is the first step for studying the mechanism of cross-species transmission. In this study, a lentivirus-based pseudovirus was produced using the spike (S) protein of Scotophilus bat CoV-512 or SARS-CoV as a surface protein to test the interaction between coronaviral S protein and its cell receptor on 11 different cells. Susceptible cells expressed red fluorescence protein (RFP) after the entry of RFP-bound green fluorescence protein (GFP)-fused S protein of Scotophilus bat CoV-512 (RFP-Sco-S-eGFP) or RFP-SARS-S pseudovirus, and firefly luciferase (FLuc) activity expressed by cells infected with FLuc-Sco-S-eGFP or FLuc-SARS-S pseudovirus was quantified. Scotophilus bat CoV-512 pseudovirus had significantly higher entry efficiencies in Madin Darby dog kidney epithelial cells (MDCK), black flying fox brain cells (Pabr), and rat small intestine epithelial cells (IEC-6). SARS-CoV pseudovirus had significantly higher entry efficiencies in human embryonic kidney epithelial cells (HEK-293T), pig kidney epithelial cells (PK15), and MDCK cells. These findings demonstrated that Scotophilus bat CoV-512 had a broad host range for cross-species transmission like SARS-CoV.

Background: Epibulbar complex choristoma, a rare congenital epibulbar tumor, has many diverse forms. Reviewing the literature, it can present clinically as either a circumferential or isolated epibulbar mass, limbal tumor, lateral canthal mass, aggregate of ectopic cilia in the upper eyelid, eyelid mass mimicking chalazion, or lacrimal caruncle mass. The management depends on the extent of involvement, the risk of amblyopia, and cosmetic concerns. Here, we report an atypical presentation of epibulbar complex choristoma with simultaneous eyelid involvement., Case Presentation: A 1-month-old full-term boy was brought to our clinic with congenital epibulbar mass of the right eye with simultaneous eyelid involvement. Dilated fundus examination was unremarkable. Survey for linear nevus sebaceous Jadassohn was negative. Due to concerns of possible amblyopia and cosmetics, lamellar keratectomy, sclerotomy, and conjunctivoplasty were performed to remove the epibulbar lesion. The eyelid defect was reconstructed with 6-0 Vicryl sutures. Histopathological examination reported complex choristoma. Upon three-year follow-up, low astigmatism and favorable cosmetics results were achieved., Conclusions: Congenital complex choristoma can present clinically as an epibulbar mass with eyelid involvement. The management depends on the extent of involvement, the risk of amblyopia, and cosmetic concerns. The method of eyelid reconstruction should be tailored according to the residual eyelid defect.

TGF-β induces epithelial-mesenchymal transition (EMT), which is involved in tumour progression. This study aims to identify and characterise novel factors potentially related to TGF-β-mediated tumour aggression in breast cancer. We treated the human mammary epithelial cell line MCF10A with TGF-β and observed TGF-β-dependent upregulation of FBN1, involving demethylation of CpG sites, in MCF10A cells undergoing EMT. The biological importance of fibrillin-1, encoded by FBN1, was evaluated through immunohistochemistry on 225 breast cancer specimens of various subtypes. Fibrillin-1 expression was observed only in metaplastic carcinoma of the breast (MCB) (51.7%), and the expression was observed in spindle sarcomatous metaplasia (SSM), but not in other metaplasia, including matrix-producing, pleomorphic, and squamous metaplasia, and carcinomatous components of both MCB and non-MCB. Fibrillin-1 expression was also restricted to the SSM of non-mammary carcinosarcomas of various organs. Overall, fibrillin-1 expression was enriched in MCB and non-mammary carcinosarcoma with SSM (93.7% and 93.3%, respectively), but not in MCBs and non-mammary carcinosarcoma without SSM. FBN1 knockdown in MDA-MB-231 cells with high FBN1 expression did not compromise migration, invasion, and tumourigenesis, and did not alter the expression of other EMT-related markers. In conclusion, fibrillin-1 is a novel TGF-β-induced marker. Fibrillin-1 expression in SSM, but not in other metaplasia and carcinomatous components, in both MCBs and non-mammary carcinosarcomas, together with the inability of FBN1-knockdown to compromise migration and invasion, indicates that fibrillin-1 is a marker induced solely in spindle metaplasia during EMT and does not induce EMT nor lead to tumour aggressiveness., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Objectives/hypothesis: To evaluate the prediction value of saliva pepsin detection for an 8-week proton pump inhibitor (PPI) response in patients with a Reflux Symptoms Index (RSI) score ≥13, which indicates possible laryngopharyngeal reflux., Study Design: Prospective individual single-cohort study., Methods: Patients were recruited who had experienced chronic laryngopharyngeal symptoms (RSI score ≥13) for more than 3 months after excluding other etiologies. The patients received PPI (40 mg of esomeprazole once daily) treatment for 8 weeks. Prior to treatment, the patients submitted saliva/sputum samples that were collected during the time symptoms were observed. The samples were taken for pepsin detection, and performed using the commercially available Peptest lateral flow device. The association of the Peptest results and PPI response were statistically analyzed with the χ 2 test., Results: Seventy-four patients completed the study, and upon completion of PPI treatment, the mean RSI score was significantly reduced from 19.22 ± 5.18 to 8.99 ± 5.69. Forty-four (59.5%) patients exhibited a good response as defined by an RSI score reduction ≥50%. The results of the Peptest were semiquantitatively graded as 0, 1, 2, 3 (negative, weak positive, moderate positive and strong positive, respectively) based upon the visual intensity of the test sample line as compared to the control line. Twenty-four patients (32.4%) exhibited grade 3 strong positive results. The Peptest strong positive results (P < .05) were significantly associated with a good PPI response, with the positive predictive value being 79.2%., Conclusions: Analysis of strong positive results for pepsin detection in saliva/sputum samples may be a useful, noninvasive method for predicting better PPI response in patients with suspected reflux induced chronic laryngopharyngeal symptoms., Level of Evidence: 2 Laryngoscope, 129:709-714, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To identify whether a certain group of breast ductal carcinoma-in-situ (DCIS) patients can be treated with breast-conserving surgery (BCS) alone; to analyze the clinicopathologic features of DCIS and tamoxifen administration in patients treated with BCS who developed ipsilateral breast tumor recurrence (IBTR)., Patients and Methods: Data for 375 women with breast DCIS who underwent BCS at our institute between June 2003 and October 2010 were analyzed. The patients were divided into different categories according to the recurrence risk predicted using the California/Van Nuys Prognostic Index (USC/VNPI) score (4-6, 7-9, and 10-12), Eastern Cooperative Oncology Group (ECOG) E5194 criteria, or combined risk features with USC/VNPI score and ECOG E5194 criteria. The IBTR and disease-free survival (DFS) rates were calculated by the Kaplan-Meier method. The prognostic effects of age, tumor size, tumor grade, margin width, estrogen receptor status, USC/VNPI score, low-risk characteristics, and tamoxifen use were evaluated by log-rank tests., Results: Of the patients, 168 were treated with breast irradiation after BCS and 207 were not. The patients who were treated with radiotherapy (RT) tended to be younger (< 40 years), to have higher USC/VNPI scores (7-9), and to meet the ECOG E5194 non-cohort 1 criteria. The 7-year risk of IBTR was 6.2% (n = 11) in the patients who received irradiation and 9.0% (n = 22) in those who did not. DFS rates were better in the patients who underwent RT than in those who did not (93.3% vs. 88.5%, P = .056). Among the patients who underwent BCS alone, age ≥ 40 years, margin width > 10 mm, USC/VNPI scores 4-6, ECOG E5194 cohort 1 criteria, estrogen receptor-positive status, and tamoxifen use predicted lower IBTR and better DFS rates. In the multivariate analysis, combined low-risk characteristics (USC/VNPI scores 4-6 and meeting the ECOG E5194 cohort 1 criteria) were identified as an independent prognostic factor of lower IBTR (P = .028) and better DFS (P = .005)., Conclusion: RT reduces the risk of IBTR after BCS for DCIS of the breast. Patients with combined low-risk characteristics (USC/VNPI scores 4-6 and meeting the ECOG E5194 cohort 1 criteria) may be adequately treated with BCS alone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To investigate the benefits of the Seattle protocol in the diagnosis of Chinese individuals with Barrett's esophagus., Methods: Subjects enrolled were patients from one center with endoscopically-suspected esophageal metaplasia. These patients first received narrow-band imaging-targeted biopsy, and later, the Seattle protocol-guided biopsy, within a period from October 2012 to December 2014. Those cases without initial pathologic patterns of intestinal metaplasia (IM) and then appearance or loss of IM tissue were designated as Group A or B, respectively. Those with initial pathologic patterns of IM, which then persisted or were lost were designated as Group C or D, respectively., Results: The number of cases for each group was as follows: A: 20, B: 78, C: 31 and D: 14. The distribution of the Prague criteria M levels of Group A was significantly higher than Group B ( P = 0.174). Among these groups, Group C had the highest proportions of hiatus hernia (54.8%), long segment Barrett's esophagus (29%), and also the highest Prague criteria M levels. The sensitivity of IM detection was 69.2% for the narrow-band imaging-targeted biopsy and 78.5% for the Seattle protocol-guided biopsy. The difference was not significant ( P = 0.231). The number of detectable dysplasias increased from one case via the NBI-target biopsy to five cases via the Seattle protocol-guided biopsy, including one case of adenocarcinoma., Conclusion: The Seattle protocol improved the IM detection in our subjects with higher Prague criteria M levels and disclosed more cases with dysplastic tissues., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this study.

Introduction: Trimethylation of histone H3K36 (H3K36me3), an epigenetic marker of transcription-associated histone modification and stem cell regulation, is expressed in a variety of human cancers. This study elucidated the prognostic significance of H3K36me3 in patients with resectable hepatocellular carcinoma (HCC)., Methods: Expression of H3K36me3 was retrospectively evaluated through immunohistochemistry in 152 surgically resected primary HCCs., Results: In nontumorous liver parenchyma, H3K36Me3 was detected in bile ducts but not in hepatocytes. H3K36me3 was positive in 104 (68.4%) of the HCCs. Positivity for H3K36me3 was associated with high level of serum α-fetoprotein (>200 ng/mL, P = 0.0148), high tumor grade (P = 0.0017), and high tumor stage (P = 0.0008). Patients with H3K36me3-positive tumors were more likely to have lower 5-year disease-free survival and 5-year overall survival than those with H3K36me3-negative tumors (P = 0.0484 and P = 0.0213, respectively). Multivariate analysis showed that H3K36me3 positivity was an independent predictor of high tumor grade (P = 0.0475) and high tumor stage (P = 0.0114) and thus contributed to poor prognosis. Furthermore, H3K36me3 positivity was significantly correlated with the expression of biliary markers cytokeratin 19 (CK19) and hepatocyte nuclear factor 1β (HNF1β) (P < 0.0001 and P = 0.0005, respectively). Combinatorial analysis revealed that CK19 and HNF1β expression individually exerted additive prognostic adverse effects on HCCs with H3K36me3 positivity., Conclusions: Our study indicates that H3K36me3 positivity is associated with the expression of biliary markers and is a crucial predictor of poor prognosis in resectable HCC., Competing Interests: The authors have declared that no competing interests exist.

Background: Barrett's esophagus (BE) is a disorder more often found in obese men. Differences between the two genders are not known in the Asian countries. Here, we studied their gender differences in the Taiwanese population in terms of risk factors and clinical presentations., Methods: Data from Taichung Veteran General Hospital were prospectively collected during an approximately two year-period (October 2012 to December 2014). Patients all underwent endoscopic surveillance, and BE was diagnosed based on the typical pattern of intestinal metaplasia. The patient characteristics were compared between the two genders., Results: We enrolled 152 BE patients: 103 men and 49 women. We found in the males, when compared with the females, significantly older mean age, higher waist circumference, greater BMI (ratio of obesity BMI ≧25 kg/m 2 ), and more cases with dyslipidemia and hiatus hernia. Long-segment BE and high-grade dysplasia/adenocarcinoma appeared only in males. Self-reported reflux symptoms were noted 80.6% in men and 89.8% in women. In those with dysplastic BE, we found these patients having higher ratios of obesity, hiatus hernia, alcohol drinking, cigarette smoking and reflux symptom., Conclusion: Gender differences were found in our BE patients, males were older in age, more obese, and suffered more serious signs from BE in terms of both endoscopic and pathologic presentations., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Aim: The aim of this study was to investigate the incidence of dysplastic transformation of Barrett's esophagus (BE) in a Chinese population., Method: Data from nondysplastic BE patients at Taichung Veterans General Hospital were collected from May 2008 to June 2017. The enrolled individuals received regular upper gastrointestinal (UGI) endoscopy during follow up. The pathological transformations, including low-grade dysplasia (LGD), high-grade dysplasia (HGD), or esophageal adenocarcinoma (EAC), were collected prospectively until June 2017. Rates of progression were calculated in cases with a diagnosis of dysplasia or EAC., Results: There were 51 subjects who met the inclusion criteria, with a mean follow up of 3.71 years (SD, 1.61) and a total follow up of 189.1 patient-years. Eight cases (15.7%) developed LGD, with a calculated incidence rate of 2.9% per year. The mean time to development of LGD was 3.26 years (SD, 2.68-3.84). One subject (2%) developed EAC, with a calculated incidence rate of 0.4% per year. No case with HGD was detected., Conclusion: In a Chinese population with nondysplastic BE, 15.7% of cases developed LGD, with an incidence rate of 2.9% per year, and 2% of cases developed EAC, with an incidence rate of 0.4% per year.

Introduction: Whole brain (WB) re-irradiation for breast cancer patients with progressive brain metastasis after first-course WB radiotherapy (WBRT) is controversial. In this study, we sought to investigate the association between the molecular sub-classifications and breast-specific Graded Prognostic Assessment (GPA, which includes the Karnofsky performance status, molecular subtypes, and age as its indices) and the outcomes of breast cancer patients who received WB re-irradiation., Methods: Twenty-three breast cancer patients who received WB re-irradiation for relapsed and progressive intracranial lesions after first-course WBRT between 2004 and 2016 were retrospectively reviewed. Patients were divided according to the 4 molecular subtypes of luminal A/B (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), luminal HER2 (HR+/HER2+), HER2 (HR-/HER2+), and triple negative (HR-/HER2-). The clinical and radiological responses and survival rates after WB re-irradiation were analyzed., Results: At 1 month after WB re-irradiation, 13 of 23 patients (56.5%) exhibited disappearance or alleviation of neurological symptoms. The median survival time after WB re-irradiation was 2.93 months (95% confidence interval [CI], 1.79-4.08). After WB re-irradiation, patients with HER2-negative tumors had poorer median survival times than those with HER2-positive tumors (2.23 vs. 3.0 months, respectively; p = 0.022). Furthermore, patients with high breast GPA scores (2.5-4.0, n = 11) had longer median survivals than those with low-scores (0-2.0, n = 12) after WB re-irradiation (4.37 vs. 1.57 months, respectively; p < 0.005)., Conclusions: WB re-irradiation may be a feasible treatment option for certain breast cancer patients who develop brain metastatic lesions after first-course WBRT when these lesions are ineligible for radiosurgery or surgery.

Background: The aim of this study was to investigate the expression of transforming growth factor β (TGF-β) in the different stages of Barrett's esophagus (BE)., Methods: Paired endoscopic esophageal biopsy samples were obtained from patients with BE prospectively. Subjects were classified into three groups: BE, BE with dysplasia, and adenocarcinoma (AC) arising from BE. Biopsy specimens over normal esophageal epithelium and gastric cardiac epithelium of limited cases were done. Four cell lines, HETA1 (human esophageal epithelium), CA-A and CP-C (non-dysplastic metaplasia), and OE33 (AC) were analyzed for quantitative mRNA and Western blotting of TGF-β., Results: All 30 subjects with BE were enrolled. Expression of TGF-β mRNA in BE were significantly (P < 0.01) lower than that in the normal esophagus and cardiac epithelium. The BE tissue showed a lower positive ratio of TGF-β immunohistochemical (IHC) stain than the cardiac epithelium. The expression of TGF-β mRNA in the cell lines CA-A, CP-3, OE-33, was significantly (P < 0.05) lower than that in the cell line HETA-1. The Western blotting result showed lower TGF-β protein expression of the cell lines CA-A, CP-3, and OE-33., Conclusions: The expression of TGF-β was lower in the tissue of BE.

Aim: The aim of this study was to investigate health-related quality of life (HRQoL) of a Chinese population with Barrett's esophagus (BE)., Methods: Data from subjects with BE from a single hospital were prospectively collected from October 2012 to December 2014. The exclusion criteria included total esophagectomy, severe cardiopulmonary deficiency, malignancy, or other unsuitable conditions for scope. All the enrolled cases were asked to complete the Reflux Disease Questionnaire (RDQ), the short form-12, (SF-12), and the Hospital Anxiety and Depression Scale (HADS)., Results: In total, 139 subjects were enrolled, and the mean age of the cases was 61.85 years old. Most subjects had short-segment BE (SSBE) (92.8%) and non-dysplastic BE tissue (94.2%). The mean physical and mental composite scores, PCS and MCS, of SF-12 were 44.14 and 45.53, respectively. The SF-12 scores in BE individuals were similar in men and women, elderly and non-elderly, LSBE and SSBE, coexisting EE and no-EE, and dysplastic and non-dysplastic. The appearance of reflux symptoms tended to decrease SF-12 scores in affected individuals, especially heartburn. The rates of anxiety and depression accounted for 25.2% and 17.3% of these cases, respectively., Conclusion: Our study found HRQoL in BE patients was strongly associated with presentation of reflux symptoms.

Background/aims: The aim of this study was to investigate the associations between obesity and erosive esophagitis (EE) or Barrett's esophagus (BE) in a Chinese population., Methods: Data from subjects were retrospectively collected from 2006 to 2009. Individuals with BE were identified and age- and sex-matched at a 1:2 ratio with normal esophagocardial junction and EE patients. The subjects were stratified into two groups: the normal weight group and overweight/ obesity group (body mass index ≥25 mg/m²) or the normal waist group and abdominal obesity group (waist circumference ≥90 cm for men and ≥80 cm for women)., Results: Overall, 45%, 72%, and 52% were overweight/obese and 23%, 65%, and 18% had abdominal obesity in the normal, EE, and BE groups, respectively. Positive associations were identified between EE and overweight/obesity (odds ratio [OR], 3.14; 95% confidence interval [CI], 1.75 to 5.66) and abdominal obesity (OR, 6.22; 95% CI, 3.34 to 11.57); however, the associations were nonsignificant between BE and overweight/obesity (OR, 1.32; 95% CI, 0.67 to 2.61) or abdominal obesity (OR, 0.73; 95% CI, 0.31 to 1.73). Female BE patients had a significantly increased rate of being overweight/obese., Conclusions: Obesity is a contributing factor in EE. The association of BE and obesity was not significant, with the exception of female BE cases.

Background: Upper gastrointestinal (GI) malignancies are an uncommon cause of dyspepsia but of great concern. The aim of this study was to determine the association between alarm features and each type and stage of upper GI malignancies., Methods: Patients who underwent endoscopy for symptoms of dyspepsia between January 2008 and December 2009 were retrospectively collected. Alarm features studied in this study were dysplasia, body weight loss and GI bleeding. Patients were classified according to the findings of endoscopy and histological reports., Results: A total of 3,926 patients were included in the study, with 82 (2.1%) cases with GI malignancies. The specificity and negative predictive value of alarm features ranged from 93.8% to 99.8%, but the sensitivity and positive predictive value ranged from 11.6% to 29.3%. The only variable with a positive predictive value was dysphagia (66.7%). The patients with esophageal cancers and upper gastric cancers had the highest ratio of alarm features, most body weight loss and dysphagia. There was a positive correlation between alarm features and advanced stages of gastric cancers, with the exception of GI bleeding sign., Conclusion: Although alarm features had a low sensitivity in identifying patients with upper GI malignancies, the presence of alarm features did help diagnose esophageal or upper gastric cancer and the sign of GI bleeding for early gastric cancer. In addition, dysphagia and weight loss are associated with higher stages of gastric cancer.

Background: Gastroesophageal reflux disease (GERD) is a chronic disease with a negative impact on the quality of life. The aim of this study was to investigate the reflux symptoms and the health-related quality of life in a population with GERD., Methods: Data from patients with GERD, according to the Montreal definition, were collected between January and December 2009. The enrolled patients were classified by different reflux symptoms according to the modified Chinese GERDQ. The general demographic data, the modified GERD impact scores and the SF-36 questionnaire scores of these groups of patients were analyzed., Results: A total of 173 patients were enrolled, and the general data, endoscopic findings and lifestyle habits of the participants with different severity of heartburn or regurgitation were all similar. The patients with moderate severity of reflux symptoms had significant lower SF-36 scores than those with mild severity. The cases with advanced heartburn severity owned the lowest scores among all cases. The impact on the daily activity of each affected individual had a positive association with the stronger severity of reflux symptom., Conclusion: The life quality of a population with GERD achieved the meaningful declination in participants with the moderate severity of heartburn or regurgitation. The severity of the reflux symptoms had a greater impact on the normal daily activity of the patients with GERD. The cases with advanced severity of heartburn had the worst well-being.

In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12.3%) had died. Multiple-adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals for distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS) in association with the genotypes of 34 SNPs from the above-mentioned 16 genes were evaluated, using the stepwise selection Cox model. We found that the SNP, ESR1-codon325 rs1801132 (G/G+G/C), was associated with a longer DDFS, whereas UGT1A1 rs4148323 (A/A+A/G), and HCN1 rs981782 (A/A+A/C) were significantly associated with poorer DDFS. MAP3K1 rs889312 (C/C) and CYP2B6 rs3211371 (T/C) were significantly associated with poor DFS, DDFS and OS. Among premenopausal women, MAP3K1 rs889312 (C/C), CYP2B6 rs3211371 (T/C), CYP2B6 rs4802101 (T/T), ABCB1 rs2032582 (C/C), and ALDH3A1 rs2231142 (G/G) were significantly associated with poor DDFS, DFS, or OS. Our results provide additional evidence that genetic polymorphisms observed in SNPs are associated with the prognoses of patients with HR-positive breast cancers; this may indicate different treatment strategies for these patients.

Objective: Asymptomatic erosive esophagitis (AEE) is commonly found in men, and might be a risk factor of developing esophageal adenocarcinoma. We aimed to determine if specific dietary habits increase the risk of AEE in asymptomatic Taiwanese men., Methods: We recruited male adults undergoing upper gastrointestinal endoscopy for health check. We excluded subjects with reflux symptoms, or taking anti-reflux medications or drugs that potentially impair lower esophageal sphincter function or cause mucosal injury. The frequency of consuming reflux-provoking diets including alcohol, tea, coffee, tomato/citric juice, chocolate, sweet food, and spicy food was assessed. The erosive esophagitis was diagnosed based on the Los Angeles Classification after endoscopy. Frequent consumption of a specific diet was defined as ≥4 days/week of consuming that diet., Results: A total of 1256 participants were recruited. After excluding 424 ineligible subjects, AEE was identified in 180 (22%) among 832 asymptomatic subjects. The risk of AEE increased with the number of days per week of consuming alcohol or tea: nondrinkers (19%, 17%), occasional drinkers (<1 day/week; 19%, 15%), regular drinkers (1-3 days/week; 26%, 21%), frequent drinkers (4-6 days/week; 32%, 22%), and daily drinkers (42%, 28%), respectively (trend test P < 0.001 for both). Multivariate analysis showed that hiatus hernia (adjusted odds ratio (aOR) 5.0, 95% confidence interval (CI) 2.6-9.6), drinking alcohol ≥4 days/week (aOR 2.3, 95% CI 1.3-4.0), and drinking tea ≥4 days/week (aOR 1.6, 95% CI 1.1-2.3) are independent risk factors of AEE. The risk of AEE was 3.8 times greater for those drinking both alcohol and tea ≥4 days/week than the non-drinkers., Conclusions: Frequent alcohol and tea consumption increased the risk of AEE in Taiwanese men.

Background: Metabolic syndrome has been highlighted as a risk factor for several gastrointestinal diseases, including gastroesophageal reflux disease and Barrett's esophagus (BE). The aim of this study was to investigate the association of metabolic syndrome with erosive esophagitis (EE) and BE., Methods: Data were retrospectively collected from patients who visited the Medical Screening Center at Taichung Veterans General Hospital, Taichung, Taiwan from January 2006 to December 2009. All patients underwent an open-access transoral upper gastrointestinal endoscopy, and serum laboratory data were collected. The exclusion criteria included prior gastric surgery, or presence of esophageal varices or peptic ulcers. These patients were assigned to groups according to their endoscopic findings as follows: (1) normal group; (2) EE group; and (3) BE group. Metabolic syndrome was diagnosed based on the International Diabetes Federation criteria., Results: There were 560/6499 (8.6%) patients, 214/1118 (9.6%) patients, and 19/95 (20%) patients with metabolic syndrome in the normal, EE, and BE groups, respectively. There was a significantly higher percentage of cases with hypertriglyceridemia in the EE group (67%) compared with the other groups. The BE group had significantly higher rates of central obesity (33%) and hypertension (29.5%) compared with rates in the normal and EE groups. After adjusting for confounders, the positive association with metabolic syndrome still existed in both the EE group (adjusted odds ratio=2.43; 95% confidence interval=1.02-3.44) and the BE group (adjusted odds ratio=2.82; 95% confidence interval=2.05-3.88)., Conclusion: Our research indicated that in fact there is a greater risk of concurrent metabolic syndrome in patients with EE or BE., (Copyright © 2016 The Authors. Published by Elsevier Taiwan LLC.. All rights reserved.)