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Abstract Background Physician burnout is rising, especially among academic physicians facing pressures to increase their clinical workload, lead administrative tasks and committees, and be active in research. There is a concern this could have downstream effects on learners’ experiences and academic physician’s ability to teach learners on the team. Methods A 29-question RedCap survey was electronically distributed to 54 attending physicians within an academic learning health system who oversaw the General Medicine inpatient teaching services during the 2022–2023 academic year. The aims were to assess this cohort of attending physicians’ experiences, attitudes, and perceptions on their ability to effectively teach learners on the team, feeling valued, contributors to work-life balance and symptoms of burnout, Fisher’s Exact Tests were used for data analysis. Results Response rate was 56%. Attendings splitting time 50% inpatient / 50% outpatient felt that team size and type of admissions model affected their ability to effectively teach learners (p = 0.022 and p = 0.049). Attendings with protected administrative time felt that non-patient care obligations affected their ability to effectively teach the learners (p = 0.019). Male attendings and attendings with ≤ 5 years of General Medicine inpatient teaching experience felt less valued by residency leadership (p = 0.019 and p = 0.026). 80% of attendings experienced emotional exhaustion, and those with > 10 weeks on a General Medicine inpatient teaching service were more likely to experience emotional exhaustion (p = 0.041). Attendings with > 10 weeks on a General Medicine inpatient teaching service and those who were a primary caregiver were more likely to experience depersonalization (p = 0.012 and p = 0.031). 57% of attendings had reduced personal achievement. Conclusions Institutions should seek an individual and organizational approach to professional fulfillment. Special attention to these certain groups is warranted to understand how they can be better supported. Further research, such as with focus groups, is needed to address these challenges.

Abstract Mammographic screening has contributed to a significant reduction in breast cancer mortality. Several studies have highlighted the correlation between breast density, as detected through mammography, and a higher likelihood of developing breast cancer. A polygenic risk score (PRS) is a numerical score that is calculated based on an individual's genetic information. This study aims to explore the potential roles of PRS as candidate markers for breast cancer development and investigate the genetic profiles associated with clinical characteristics in Asian females with dense breasts. This is a retrospective cohort study integrated breast cancer screening, population genotyping, and cancer registry database. The PRSs of the study cohort were estimated using genotyping data of 77 single nucleotide polymorphisms based on the PGS000001 Catalog. A subgroup analysis was conducted for females without breast symptoms. Breast cancer patients constituted a higher proportion of individuals in PRS Q4 (37.8% vs. 24.8% in controls). Among dense breast patients with no symptoms, the high PRS group (Q4) consistently showed a significantly elevated breast cancer risk compared to the low PRS group (Q1–Q3) in both univariate (OR = 2.25, 95% CI 1.43–3.50, P

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.

Background: We introduced an adapted Lyman normal-tissue complication probability (NTCP) model, incorporating clinical risk factors and censored time-to-event data, to estimate the risk of major adverse cardiac events (MACE) following left breast cancer radiotherapy (RT). Materials and methods: Clinical characteristics and MACE data of 1100 women with left-side breast cancer receiving postoperative RT from 2005 to 2017 were retrospectively collected. A modified generalized Lyman NTCP model based on the individual left ventricle (LV) equivalent uniform dose (EUD), accounting for clinical risk factors and censored data, was developed using maximum likelihood estimation. Subgroup analysis was performed for low-comorbidity and high-comorbidity groups. Results: Over a median follow-up 7.8 years, 64 patients experienced MACE, with higher mean LV dose in affected individuals (4.1 Gy vs. 2.9 Gy). The full model accounting for clinical factors identified D50 = 43.3 Gy, m = 0.59, and n = 0.78 as the best-fit parameters. The threshold dose causing a 50 % probability of MACE was lower in the high-comorbidity group (D50 = 30 Gy) compared to the low-comorbidity group (D50 = 45 Gy). Predictions indicated that restricting LV EUD below 5 Gy yielded a 10-year relative MACE risk less than 1.3 and 1.5 for high-comorbidity and low-comorbidity groups, respectively. Conclusion: Patients with comorbidities are more susceptible to cardiac events following breast RT. The proposed modified generalized Lyman model considers nondosimetric risk factors and addresses incomplete follow-up for late complications, offering comprehensive and individualized MACE risk estimates post-RT.

Abstract Background The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. Methods A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. Results Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. Conclusion Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

Abstract Background/aim Breast cancer is the most common female malignancy in the world. Nearly ninety percent of screening-detected breast cancers were diagnosed with earlier stages of 0 to II in Taiwan. It’s widely acknowledged that mammography screening of breast cancer can achieve the goal of early diagnosis and treatment in terms of preventive task while neglected interval cancers are associated with unfavorable tumor characteristics and worse outcomes. The purpose of this study was to explore the characteristics of screening-detected breast cancers in Taiwan. Materials and methods Both screening and diagnostic mammography examinations with accompanied BI-RADS (breast imaging-reporting and data system) classification were extracted from the health information system and linked to cancer registry in Taiwan. Enrolled population included those attending their first mammography between 2012 and 2016, excluding subjects with previous breast cancer, or with missing or incomplete data. We compared treatment outcomes between breast cancers with either initial screening or diagnostic mammography (control group), and investigated the compositions of breast cancers detected by screening mammography through direct chart reviews. Results A total of 84,246 screening and 61,230 diagnostic mammography sessions were performed from 2010 to 2020. More positive results (BI-RADS 0, 3, 4 and 5) were observed for those attending the first diagnostic than the first screening mammography (43.58% versus 16.12%, p

Neoadjuvant chemotherapy (NACT)-induced pathologic complete response (pCR) is associated with a favorable prognosis for breast cancer. Prior research links tumor-infiltrating lymphocytes with breast cancer chemotherapy response, suggesting the tumor-immune microenvironment's role. The aim of this study was to evaluate the immune-related genes that exhibit associations with the response to NACT. In this study, we analyzed a total of 37 patients (aged 27–67) who received NACT as the first-line treatment for primary breast cancer, followed by surgery. This group consisted of nine patients (24.3 %) with estrogen receptor (ER)-positive/HER2-negative status, ten patients (27.0 %) with ER-positive/HER2-positive status, five patients (13.5 %) with ER-negative/HER2-positive status, and thirteen patients (35.1 %) with triple-negative breast cancer (TNBC). Among these patients, twelve (32.4 %) achieved a pCR, with eight (66.6 %) having HER2-positive tumors, and the remaining four having TNBC. To identify immune-related genes linked with pCR in subjects with breast cancer prior to NACT, we collected fresh tissues for next-generation sequencing. Patients with pCR had higher expressions of eight genes, KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4, compared to non-pCR patients. The 8-gene signature was associated with good prognosis and linked to better relapse-free survival in patients receiving chemotherapy. The expression of these genes was involved in better drug response, displaying a positive correlation with the infiltration of immune cells. In conclusion, we have identified eight immune-related genes that are associated with a favorable prognosis and positive responses to drugs. This 8-gene signature could potentially provide prognostic insights for breast cancer patients undergoing NACT.

The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.

BackgroundBreast cancer is the most common cancer type that affects women. In hormone receptor–positive (HR+), human epidermal growth factor receptor 2−negative (HER2–) advanced breast cancer (ABC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of PIK3CA mutations in the Taiwanese breast cancer population.MethodologyThis is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of PIK3CA mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment.ResultsPIK3CA mutations were identified in 278 of 728 patients (38%). PIK3CA mutations were reported in 43% of patients with HR−/HER2+ subtype and 42% of patients with HR+/HER2– postmenopausal status. A lower prevalence of PIK3CA mutations was observed in triple-negative (27%) and HR+/HER2– premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the PIK3CA mutation cohort and 16 months (95% CI: 11-23 months) in the PIK3CA wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the PIK3CA mutation cohort and 6 months (95% CI: 2-9 months) in the PIK3CA wild-type cohort.ConclusionA high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes.

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.

Abstract 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.

In this study, we evaluated the concordance of targeted sequencing between paired ctDNA and matched tumor samples from early breast cancers treated with curative intention. Molecular profiling was performed using the Oncomine Comprehensive Assay v3 and the Oncomine Breast cfDNA Assay v2. The liquid biopsy detection rate was 39% (all-stage breast cancers, n = 612). Among 246 early-stage patients assayed for both ctDNA and matched tumor, the cfDNA assay detected 73 (29.6%) and the comprehensive assay detected 201 (81.7%) breast cancers with at least one alteration (χ2 test, p = 0.001). In total, 67 (25.6%) cases tested positive on both platforms, while the cfDNA and comprehensive assays detected an additional 10 (4%) and 138 (56%) cases, respectively. The most prevalent mutant genes were TP53 (68.3%) and KRAS (53.5%), while the PIK3CA (39.4%), AKT1 (45.9%), and ERBB2 (17.1%) mutations constituted biomarkers for FDA-approved therapeutics. Our study showed that tumor tissue should be the source of actionable mutation detection for early breast cancers, considering that the concordance rate between tumor and liquid biopsy was only one-quarter.

BackgroundHernia repair is one of the most common surgical procedures; however, the long-term outcomes are seldom reported due to incomplete follow-up. ObjectiveThe 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. MethodsA 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. ResultsThe 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. ConclusionsThe mobile app has the potential to enhance the quality of care for patients with hernia and facilitate outcomes research with more complete follow-up.

Taxanes-containing chemotherapy constitutes an essential backbone for both early and metastatic breast cancer (mBC). However, the two major taxane drugs—paclitaxel and docetaxel—have distinct safety profiles. In this review, we summarize the safety outcome and management following treatment with both taxanes from selected clinical trials. We utilized PubMed to perform literature search before April 2021. Five phase III randomized controlled trials with reports of individual taxane adverse events (AEs) were included in this review. Grade 3/4 AEs were summarized and discussed extensively. The rates of grade 3/4 neutropenia were higher with docetaxel than with paclitaxel. For non-hematologic grade 3/4 AEs, peripheral neuropathy was more frequent with paclitaxel while fluid retention was more frequent with docetaxel. Compared to paclitaxel, docetaxel had a higher rate of grade 3/4 gastrointestinal AEs. Grade 3/4 myalgia were generally comparable between the two taxanes. Except for neutropenia, the incidence rate of grade 3/4 AEs of taxanes was generally manageable. Peripheral neuropathy was more common with paclitaxel while grade 3/4 neutropenia was more common with docetaxel.

Wu, Hsieh et al. analyze Taiwanese breast cancer patient samples using whole-exome sequencing to examine the heterogeneity and homogeneity in the timing and dependencies of somatic aberrations across disease subtypes. The authors focus on somatic alterations and related features that correlate with whole genome doubling, including homologous recombination deficiencies.

The present study aimed to develop an AI-based system for the detection and classification of polyps using colonoscopy images. A total of about 256,220 colonoscopy images from 5000 colorectal cancer patients were collected and processed. We used the CNN model for polyp detection and the EfficientNet-b0 model for polyp classification. Data were partitioned into training, validation and testing sets, with a 70%, 15% and 15% ratio, respectively. After the model was trained/validated/tested, to evaluate its performance rigorously, we conducted a further external validation using both prospective (n = 150) and retrospective (n = 385) approaches for data collection from 3 hospitals. The deep learning model performance with the testing set reached a state-of-the-art sensitivity and specificity of 0.9709 (95% CI: 0.9646–0.9757) and 0.9701 (95% CI: 0.9663–0.9749), respectively, for polyp detection. The polyp classification model attained an AUC of 0.9989 (95% CI: 0.9954–1.00). The external validation from 3 hospital results achieved 0.9516 (95% CI: 0.9295–0.9670) with the lesion-based sensitivity and a frame-based specificity of 0.9720 (95% CI: 0.9713–0.9726) for polyp detection. The model achieved an AUC of 0.9521 (95% CI: 0.9308–0.9734) for polyp classification. The high-performance, deep-learning-based system could be used in clinical practice to facilitate rapid, efficient and reliable decisions by physicians and endoscopists.

Abstract Glycoprotein non-metastatic B (GPNMB) is a transmembrane protein overexpressed in numerous cancers including triple-negative breast cancers (TNBC). It has been linked to promote cancer aggressiveness and implicated as a novel target for GPNMB-expressing cancers. In current study, we aimed to explore the clinical significance of GPNMB in TNBC. Among 759 specimens, immunohistochemistry (IHC) exhibited GPNMB expressions were variable in different subtypes and significantly higher in TNBC. Kaplan–Meier analysis revealed GPNMB overexpression in TNBC was associated with worse prognosis especially distant metastasis (P = 0.020, HR = 2.515, CI 1.154–5.480). Multivariate analysis showed GPNMB expression was an independent prognostic factor in terms of recurrence and distant metastasis (P = 0.008, HR = 3.22, CI 1.36–7.61; P = 0.017, HR = 3.08, CI 1.22–7.74). In silico analysis showed high mRNA expression of GPNMB was associated with distant metastasis and GPNMB was overexpressed in TNBC. Furthermore, GPNMB positively correlated with epithelial–mesenchymal transition (EMT) regulators, mesenchymal marker vimentin, MMP and integrins. The protein levels of Twist and MMP2 were upregulated by GPNMB overexpression in TNBC cells. GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC.

Abstract Background Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) targeted panel. Methods The study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo Fisher™ Oncomine™ Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT). Results A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes (all variants combined within each sample) were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%). Conclusion Targeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.

Tumor metastasis or recurrence often occurs in patients with curative resection of colorectal cancer (CRC). Placental-specific 8 (PLAC8), which has increased expression in stool, may be associated with CRC recurrence. Insights into the role of PLAC8 in CRC recurrence and its clinical significance may support to develop strategies for preventing CRC recurrence and deterioration. Clinical tissues, cell and animal models were used to clarify the roles of PLAC8 in CRC tumorigenesis, invasion, and migration. Next-generation sequencing of 16S ribosomal DNA has been used to assess the gut microbiota in stool of CRC patients. We found that PLAC8 was upregulated in tissues from patients with late-stage CRC. In our in vitro studies, PLAC8 was dynamically regulated in mitotic cells. Overexpressed PLAC8 was nucleated at the centrosome during mitosis, and therefore, PLAC8 overexpression might increase cell growth and migration (all p

We proposed a highly versatile two-step transfer learning pipeline for predicting the gene signature defining the intrinsic breast cancer subtypes using unannotated pathological images. Deciphering breast cancer molecular subtypes by deep learning approaches could provide a convenient and efficient method for the diagnosis of breast cancer patients. It could reduce costs associated with transcriptional profiling and subtyping discrepancy between IHC assays and mRNA expression. Four pretrained models such as VGG16, ResNet50, ResNet101, and Xception were trained with our in-house pathological images from breast cancer patient with recurrent status in the first transfer learning step and TCGA-BRCA dataset for the second transfer learning step. Furthermore, we also trained ResNet101 model with weight from ImageNet for comparison to the aforementioned models. The two-step deep learning models showed promising classification results of the four breast cancer intrinsic subtypes with accuracy ranging from 0.68 (ResNet50) to 0.78 (ResNet101) in both validation and testing sets. Additionally, the overall accuracy of slide-wise prediction showed even higher average accuracy of 0.913 with ResNet101 model. The micro- and macro-average area under the curve (AUC) for these models ranged from 0.88 (ResNet50) to 0.94 (ResNet101), whereas ResNet101_imgnet weighted with ImageNet archived an AUC of 0.92. We also show the deep learning model prediction performance is significantly improved relatively to the common Genefu tool for breast cancer classification. Our study demonstrated the capability of deep learning models to classify breast cancer intrinsic subtypes without the region of interest annotation, which will facilitate the clinical applicability of the proposed models.

PurposeThe present study aimed to assign a risk score for breast cancer recurrence based on pathological whole slide images (WSIs) using a deep learning model.MethodsA total of 233 WSIs from 138 breast cancer patients were assigned either a low-risk or a high-risk score based on a 70-gene signature. These images were processed into patches of 512x512 pixels by the PyHIST tool and underwent color normalization using the Macenko method. Afterward, out of focus and pixelated patches were removed using the Laplacian algorithm. Finally, the remaining patches (n=294,562) were split into 3 parts for model training (50%), validation (7%) and testing (43%). We used 6 pretrained models for transfer learning and evaluated their performance using accuracy, precision, recall, F1 score, confusion matrix, and AUC. Additionally, to demonstrate the robustness of the final model and its generalization capacity, the testing set was used for model evaluation. Finally, the GRAD-CAM algorithm was used for model visualization.ResultsSix models, namely VGG16, ResNet50, ResNet101, Inception_ResNet, EfficientB5, and Xception, achieved high performance in the validation set with an overall accuracy of 0.84, 0.85, 0.83, 0.84, 0.87, and 0.91, respectively. We selected Xception for assessment of the testing set, and this model achieved an overall accuracy of 0.87 with a patch-wise approach and 0.90 and 1.00 with a patient-wise approach for high-risk and low-risk groups, respectively.ConclusionsOur study demonstrated the feasibility and high performance of artificial intelligence models trained without region-of-interest labeling for predicting cancer recurrence based on a 70-gene signature risk score.

Background: A 23-gene classifier has been developed based on gene expression profiles of Taiwanese luminal-like breast cancer. We aim to stratify risk of relapse and identify patients who may benefit from adjuvant chemotherapy based on genetic model among distinct clinical risk groups. Methods: There were 248 luminal (hormone receptor-positive and human epidermal growth factor receptor II-negative) breast cancer patients with 23-gene classifier results. Using the modified Adjuvant! Online definition, clinical high/low-risk groups were tabulated with the genetic model. The primary endpoint was a recurrence-free interval (RFI) at 5 years. Results: There was a significant difference between the high/low-risk groups defined by the 23-gene classifier for the 5-year prognosis of recurrence (16 recurrences in high-risk and 3 recurrences in low-risk; log-rank test: p < 0.0001). Among the clinically high-risk group, the 5-year RFI of high risk defined by the 23-gene classifier was significantly higher than that of the low-risk group (15 recurrences in high-risk and 2 recurrences in low-risk; log-rank test: p < 0.0001). Conclusion: This study showed that 23-gene classifier can be used to stratify clinically high-risk patients into distinct survival patterns based on genomic risks and displays the potentiality to guide adjuvant chemotherapy. The 23-gene classifier can provide a better estimation of breast cancer prognosis which can help physicians make a better treatment decision.

The function of small G protein signalling modulators (SGSM1/2/3) in cancer remains unknown. Our findings demonstrated that SGSM2 is a plasma membrane protein that strongly interacted with E-cadherin/β-catenin. SGSM2 downregulation enhanced the phosphorylation of focal adhesion kinase (FAK; Y576/577), decreased the expression of epithelial markers such as E-cadherin, β-catenin, and Paxillin, and increased the expression of Snail and Twist-1, which reduced cell adhesion and promoted cancer cell migration. Oestrogen and fibronectin treatment was found to promote the colocalization of SGSM2 at the leading edge with phospho-FAK (Y397). The BioGRID database showed that SGSM2 potentially interacts with cytoskeleton remodelling and cell-cell junction proteins. These evidences suggest that SGSM2 plays a role in modulating cell adhesion and cytoskeleton dynamics during cancer migration.

Hospitals are continuously facing pressures to mitigate the gap between patient’s expectations and the quality of services provided. Now with Medicare reimbursements tied to Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores, institutions are attempting interventions to increase satisfaction scores. However, a standard framework to understand patient values and perceptions and subsequently translate it into reliable measures of patient satisfaction does not exist, particularly in the inpatient settings. This article highlights opportunity for the addition of qualitative customer value research to augment the information providers gain from HCAHPS scores and provide additional indicators that can be used in improving the patient experience. In this article, patient laddering interviews and hierarchical value mapping are reviewed as methodologies to understand patient core satisfaction values during their hospital stay. A systematic literature search was performed to identify articles addressing laddering interviews and hierarchical value mapping as applied to health care. Inclusion criteria involved studies relating to health care and using laddering interviews. Exclusion criteria included non-health-care studies. Only 3 studies were found eligible for this review. Our systematic review of literature revealed only few studies which may help to guide us to improve patient experience using laddering interviews. These interviews can help compose a personalized bedside survey which may be more meaningful than current widely used HCAHPS survey.

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.

Abstract 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.

Some patients with thyroid cancer develop a second primary cancer. Defining the characteristics of patients with double primary cancers (DPCs) is crucial and needs to be followed. In this study, we examine molecular profiles in DPC. We enrolled 71 patients who received thyroid cancer surgery, 26 with single thyroid cancer (STC), and 45 with DPC. A retrograde cohort was used to develop immunohistochemical expressions of mismatch repair (MMR) proteins and cell-cycle-related markers from tissue microarrays to produce an equation for predicting the occurrence of DPC. The multivariate logistic model of 67 randomly selected patients (24 with STC and 43 with DPC) identified that the expression of deficient MMR (dMMR) (odds ratio (OR), 10.34; 95% confidence interval (CI), 2.17–49.21) and pRb (OR, 62.71; 95% CI, 4.83–814.22) were significantly associated with a higher risk of DPC. In contrast, the expression of CDK4 (OR, 0.19; 95% CI, 0.04–0.99) and CDK6 (OR, 0.03; 95% CI, 0.002–0.44) was significantly associated with a lower risk of DPC. Collectively, dMMR, pRb, CDK4, and CDK6 have a sensitivity of 88.9% (95% CI, 75.1–95.8) and a specificity of 69.2% (95% CI, 48.1–84.9) for occurrence of DPC in all 71 patients. This is the first report to demonstrate the molecular differentiation of STC and DPC. Overall, the integral molecular profile performed excellent discrimination and denoted an exponential function to predict the probability of DPC.

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.

The evolutionary trajectories that drive clinical and therapeutic consequences in localized breast cancers (BCs) with ipsilateral breast tumor relapse (IBTR) remain largely unknown. Analyses of longitudinal paired whole-exome sequencing data from 10 localized BC patients with IBTR reveal that, compared to primary breast tumors, homologous recombination (HR) deficiency, inactivation of the HR pathway, chromosomal instability, and somatic driver mutations are more frequent. Furthermore, three major models of evolution in IBTR are summarized, through which relative contributions of mutational signatures shift, and the subclonal diversity expansions are shown. Optimal treatment regimens are suggested by the clinically relevant molecular features, such as HR deficiency (20%) or specific alterations (30%) with sensitivity to available FDA-approved drugs. Finally, a rationale for the development of the therapeutic management framework is provided. This study sheds light on the complicated evolution patterns in IBTR and has significant clinical implications for future improvement of treatment decisions.

Bolivian sex workers were more likely than other employed women to report tuberculosis screening only if they reported HIV screening. Of all women with household tuberculosis exposure,

Among all cancers in women, breast cancer has the highest incidence. The mortality of breast cancer is highly associated with metastasis. Migration and malignant transformation of cancer cells have been reported to be modulated by store-operated calcium (SOC) channels, which control calcium signaling and cell proliferation pathways. Stromal interaction molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum, triggering the activation of store-operated calcium signaling. However, the clinical relevance of STIM1 in breast cancer is still unclear. Here, we recruited 348 breast cancer patients and conducted a genetic association study to address this question. Four tagging germline single nucleotide variants (SNVs) in STIM1 were selected and RNA sequencing data of 525 breast cancer samples from The Cancer Genome Atlas (TCGA) database were evaluated. The results show that rs2304891 and rs3750996 were correlated with clinical stage of breast cancer. Expression quantitative trait loci (eQTL) analysis indicated that risk G allele of STIM1 contributed to the higher expression of STIM1. In addition, we found an increased risk of rs2304891 G allele and rs3750996 A allele in estrogen receptor (ER) positive and progesterone receptor (PR) positive patients. In conclusion, our results suggest that germline SNV, rs2304891 and rs3750996 as well as STIM1 expression are important biomarkers for the prediction of clinical outcomes in breast cancer patients.

The growth arrest-specific 2 (GAS2) was cloned and found to be upregulated in the feces of recurrent CRC patients. This overexpressed GAS2 induced different patterns of gene expressions in CRC cells. Briefly, one cell proliferation marker, Ki-67 antigen (Ki-67), was upregulated in the cells with overexpressed GAS2, “Correlation between proliferation markers: PCNA, Ki-67, MCM-2 and antiapoptotic protein Bcl-2 in colorectal cancer” [1]. Whereas, the expression of another cell proliferation marker, proliferating cell nuclear antigen (PCNA), changed insignificantly [1]. In addition, the mRNA level of one cyclin involving in both cell cycle G1/S and G2/M transitions was also not affected by GAS2 overexpression, “Cdc20 and Cks direct the spindle checkpoint-independent destruction of cyclin A” [2]. The experimental design and procedures in this article can be helpful for understanding the molecular significance of GAS2 in SW480 and SW620 CRC cells.

Surgery is the most effective treatment for breast cancer patients. However, some patients developed recurrence and distant metastasis after surgery. Adjuvant therapy is considered for high-risk patients depending on several prognostic markers, and lymphovascular invasion has become one of such prognostic markers that help physicians to identify the risk for distant metastasis and recurrence. However, the mechanism of lymphovascular invasion in breast cancer remains unknown. This study aims to unveil the genes and pathways that may involve in lymphovascular invasion in breast cancer. In total, 108 breast cancer samples were collected during surgery and microarray analysis was performed. Significance analysis of the microarrays and limma package for R were used to examine differentially expressed genes between lymphovascular invasion–positive and lymphovascular invasion–negative cases. Network and pathway analyses were mapped using the Ingenuity Pathway Analysis and the Database for Annotation, Visualization and Integrated Discovery. In total, 86 differentially expressed genes, including 37 downregulated genes and 49 upregulated genes were identified in lymphovascular invasion–positive patients. Among these genes, TNFSF11, IL6ST , and EPAS1 play important roles in cytokine–receptor interaction, which is the most enriched pathway related to lymphovascular invasion. Moreover, the results also suggested that an imbalance between extracellular matrix components and tumor micro-environment could induce lymphovascular invasion. Our study evaluated the underlying mechanisms of lymphovascular invasion, which may further help to assess the risk of breast cancer progression and identify potential targets of adjuvant treatment.

With the development of prosthetic mesh and tension free techniques, the recurrence rate following inguinal hernia repair has been reduced, and hernia outcomes research should focus on post-operative quality of life and potential complications.A novel hernia quality of life assessment instrument, HERQL, was developed. The HERQL questionnaire comprises a 4-item summative pain score measuring pain and discomfort resulting from various strenuous activities. Symptomatic and functional domains, as well as post-operative satisfaction are evaluated as well.A total of 386 HERQL surveys were completed by 183 patients with inguinal hernias. Internal consistency reliability of the summative pain score was satisfactory, with a Cronbach's alpha of 0.85. Criterion validity was examined by concomitant assessment of the pain/discomfort and health impact subscales of the EQ-5D questionnaire, with substantial to moderate correlations. Pre-operative patients reported more severe hernia protrusion, more pain during mild to heavy exercise, and worse activity restriction and health impairment than the follow-up patients, indicating clinical validity. The conceptual structure of the HERQL demostrated the causal relationship between the formative symptomatic subscales and the reflective functional status indicators. Repeated measurement of the summative pain scores revealed an estimated time effect of -1.63, which was the rate of change in the summative pain score across the pre-operative, immediately post-operative, and follow-up 3-month periods suggesting the clinical responsiveness of the HERQL.This study will facilitate inguinal hernia outcomes research and enhance the quality of care for this common disease by providing a validated HERQL instrument with enhanced sensitivity.

Breast cancer is the most common female malignancy in Taiwan; however, quality of life (QOL) following breast cancer therapy remains rarely studied. The aim of the present study was to evaluate QOL among Taiwanese breast cancer patients with and without breast-conserving therapy. Methods: A total of 130 women with breast cancer (37 with breast-conserving therapy and 93 with modified radical mastectomy) were enrolled between August, 2004 and December, 2007 in a single center. Patients who underwent breast-conserving therapy were younger, less likely to be married, had a higher educational level, and were at an earlier clinical stage than those who underwent modified radical mastectomy. The traditional Chinese version of the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 questionnaires were used as measuring instruments. Structural equation modeling with mean structural analysis, which evaluates configuration invariance and compares groups for latent functional/symptomatic factors, was constructed using a multi-indicators approach. Results: Patients with breast-conserving therapy reported worse global QOL status and role function scores and higher symptomatic scores for fatigue, pain, dyspnea, insomnia, appetite loss, breast and arm problem subscales than those without conserving therapy. In addition, age, marital status, hormone manipulation and postoperative adjuvant therapy were significant confounders for QOL. Measurement invariance was ascertained and the same QOL construct could be applied to Taiwanese subjects with and without breast-conserving therapy. Conclusion: Our study suggests that breast-conserving therapy might be associated with worse perceived QOL for Taiwanese breast cancer survivors.

Inflammatory myofibroblastic tumour is a rare solid tumour mimicking malignancy with locally aggressive growth and recurrence even after complete resection. We report the case of a 10-year-old girl with an intra- abdominal inflammatory myofibroblastic tumour. This clinical and pathological entity should be differentiated from other malignant sarcomatous lesions when encountered intraoperatively. It is almost impossible to differentiate inflammatory myofibroblastic tumour from other malignancies preoperatively; the diagnosis is often confirmed by careful microscopic examination or immunohistochemical markers after surgical resection. Total excision of the tumour with life-time follow-up is needed because of the risk of recurrence.

The interplay between copy number variation (CNV) and differential gene expression may be able to shed light on molecular process underlying breast cancer and lead to the discovery of cancer-related genes. In the current study, genes concurrently identified in array comparative genomic hybridization (CGH) and gene expression microarrays were used to derive gene signatures for Han Chinese breast cancers. We performed 23 array CGHs and 81 gene expression microarrays in breast cancer samples from Taiwanese women. Genes with coherent patterns of both CNV and differential gene expression were identified from the 21 samples assayed using both platforms. We used these genes to derive signatures associated with clinical ER and HER2 status and disease-free survival. DISTRIBUTIONS OF SIGNATURE GENES WERE STRONGLY ASSOCIATED WITH CHROMOSOMAL LOCATION: chromosome 16 for ER and 17 for HER2. A breast cancer risk predictive model was built based on the first supervised principal component from 16 genes (RCAN3, MCOLN2, DENND2D, RWDD3, ZMYM6, CAPZA1, GPR18, WARS2, TRIM45, SCRN1, CSNK1E, HBXIP, CSDE1, MRPL20, IKZF1, and COL20A1), and distinct survival patterns were observed between the high- and low-risk groups from the combined dataset of 408 microarrays. The risk score was significantly higher in breast cancer patients with recurrence, metastasis, or mortality than in relapse-free individuals (0.241 versus 0, P