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AimsProgesterone receptor (PR) is a crucial prognostic marker in breast cancer. However, achieving consistent results in PR immunohistochemistry (IHC) remains challenging due to the lack of well-defined low-positive controls. This study aimed to identify benign tissues with consistent low-level PR expression to serve as ideal controls for IHC.MethodsWe evaluated PR expression in the squamous epithelium of the uterine cervix, nipple smooth muscle and pancreatic islets. QuPath digital image analysis was employed to compare the intensity and quantity of PR staining in target cells within a 2×2 mm area.ResultsThe squamous epithelium of the secretory phase cervix, nipple smooth muscle and pancreatic islets displayed appreciable weak PR expression, with mean values of 73, 55 and 60 cells, respectively. Notably, 62% (8/13) of the 2×2 mm areas in the atrophic cervix were completely negative for PR expression. The coefficients of variation for weak PR-expressing cells in pancreatic islets (57.4%) and nipple smooth muscle (65.0%) were lower than those observed in the cervix (96.2%–222.0%). The squamous epithelium of the cervix, especially during the secretory phase, exhibited weak positivity confined to the basal layers, providing another viable control option. However, variations in PR expression may be influenced by physiological factors, such as hormonal fluctuations.ConclusionsPancreatic islets and nipple smooth muscle, with their consistent low-level PR expression, offer a promising solution to the challenges associated with PR IHC. This approach may help minimise variations resulting from differing staining methods across laboratories.

BackgroundThe aim of this study was to investigate the role of IL-17A in the cancer microenvironment and the recurrence of triple negative breast cancer (TNBC).MethodsUsing human TNBC cell lines, the role of IL17-A was investigated by knocked down of IL-17A (ΔIL-17A) and by administration of IL-17A into the culture medium. Cell proliferation assays, migration assays, as well as Western blot analysis and real-time PCR, were used to evaluate IL-17A-related signaling. Three types of 4T1 cells were implanted into BALB/c mice, namely wild type (WT), ΔIL-17A, and WT + neutralizing IL-17 antibody (WT + Ab) cells. Tumor weight, necrosis area, and the number of circulating tumor cells (CTCs) were measured. Immunohistochemistry and Western blotting were used to analyze expression of CD34, CD8, and TGF-β1 as well as anoikis resistance. The Kaplan–Meier’s method was used to correlate IL-17A expression and patient outcome, including disease-free survival (DFS) and overall survival (OS).ResultsOur results demonstrated that IL-17A was able to stimulate the migratory activity, but not the growth rate, of MDA-MB-231/468 cells. In vivo, for the ΔIL-17A group, there was an increase in necrosis area, a decrease in tumor CD34 expression and a reduction in the number of CTCs. Furthermore, in WT + Ab group, there was a decreased in tumor expression of CD34, fewer CD8 ( +) cells, and fewer CTCs, but an increase in expression of TGF-β1 expression. Both of the above were compared to the WT group. Knockdown of IL-17A also decreased anoikis resistance in human TNBC and the murine 4T1 cell lines. Kaplan–Meier analysis disclosed a negative correlation between tumor expression of IL-17A and OS in TNBC patients.ConclusionWe conclude that IL-17A promotes migratory and angiogenic activity in tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment such changes favor cancer metastasis.

There is good evidence that the tumor microenvironment plays an important role in cancer metastasis and progression. Our previous studies have shown that brain-derived neurotrophic factor (BDNF) participates in the process of metastasis and in the migration of cancer cells. The aim of this study was to investigate the role of BDNF on the tumor cell microenvironment, namely, the cancer cell-endothelial cell interaction of TNBC cells. We conducted oligoneucleotide microarray analysis of potential biomarkers that are able to differentiate recurrent TNBC from non-recurrent TNBC. The MDA-MB-231 and human endothelial HUVEC lines were used for this study and our approaches included functional studies, such as migration assay, as well as Western blot and real-time PCR analysis of migration and angiogenic signaling. In addition, we analyzed the survival outcome of TNBC breast cancer patients according to their expression level of BDNF using clinical samples. The results demonstrated that BDNF was able to bring about autocrinal (MDA-MB-231) and paracrinal (HUVECs) regulation of BDNF-TrkB gene expression and this affected cell migratory activity. The BDNF-induced migratory activity was blocked by inhibitors of ERK, PI3K and TrkB when MDA-MB-231 cells were examined, but only an inhibitor of ERK blocked this activity when HUVEC cells were used. Furthermore, decreased migratory activity was found for △BDNF and △TrkB cell lines. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed that BDNF is a key factor that is able to regulate a network made up of metalloproteases and calmodulin. Protein expression levels in a tissue array of tumor slices were found to be correlated with patient prognosis and the results showed that there was significant correlation of TrkB expression, but not of BDNF. expressionwith patient DFS and OS. Our study demonstrates that up-regulation of the BDNF signaling pathway seems tobe involved in the mechanism associated with early recurrence in triple negative breast cancer cell. In addition, BDNF can function in either an autocrine or a paracrine manner to increase the migration ability of both MDA-MB-231 cells and HUVEC cells. Finally, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients.

Sequencing of the T-cell receptor (TCR) repertoire can reflect immune status and monitor treatment responses. Here, we aimed to characterize the TCRβ repertoire and its correlation with clinical and prognostic significance in breast cancer. A total of 856 peripheral blood samples were collected from female breast cancer patients for TCR sequencing. At baseline, TCR clonality was elevated in patients with stage IV disease compared with earlier-stage breast cancer, and higher clonality within the stage IV cohort was associated with poorer overall survival. Compared with the luminal A subtype, luminal B2 breast cancer exhibited lower baseline TCR Shannon diversity. Following both adjuvant and neoadjuvant chemotherapy, we observed increased TCR convergence and clonality accompanied by reduced Shannon diversity. Remarkably, these repertoire changes were most evident in patients treated with taxane or anthracycline plus taxane regimens in the adjuvant setting, and with anthracycline plus taxane or platinum-based regimens in the neoadjuvant setting. Notably, trastuzumab was associated with increased clonality and reduced diversity in HER2-enriched tumors, but not in Luminal B2. Lower TCR richness in post-treatment blood samples was associated with patients achieving pathologic complete response in the neoadjuvant setting. This study provides comprehensive circulating TCR repertoire metric profiles across the heterogeneous population of breast cancer patients.

Background Circulating tumor cells (CTCs) are detectable in early-stage cancer and may enable early cancer detection. We evaluated a CTC-based assay as a complementary biomarker for breast cancer detection in an Asian population with a high prevalence of dense breast tissue. Methods In this single-center, prospective, blinded study, peripheral blood from Taiwanese women with breast cancer and healthy controls was analyzed using a CTC-enumeration platform (CMx) based on biomarker expression (cytokeratin 18 [CK18], mammaglobin [MGB], CD45), cell morphometry, and nuclear features. A machine-learning model integrating CTC biomarkers with age, white blood cell (WBC) count, and platelet count was developed to assess classification performance, providing proof-of-concept for combining CTC-derived and routine blood parameters in breast cancer risk assessment. Results A total of 228 breast cancer patients and 170 healthy controls were included. Age and CK18- and MGB-positive CTC counts differed significantly between groups, whereas WBC and platelet counts did not. An ensemble linear support vector machines model incorporating age and CTC features achieved an area under the curve of 0.85 (95% CI, 0.73–0.96) in the independent test cohort, with high sensitivity (0.93), positive predictive value (0.74), and negative predictive value (0.86), but modest specificity (0.57). In the exploratory BI-RADS 3/4 subgroup, the model identified all cancer cases (sensitivity 1.00), with a specificity of 0.44 and overall accuracy of 0.79. Conclusions This study demonstrates the feasibility of combining CTC enumeration with machine learning for breast cancer detection and supports the need for future large-scale, multicenter, multiethnic prospective external validation.

PurposeDeleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. MethodsWe evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. ResultsAmong 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. ConclusionsThe prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.

Serious complications may arise during the onset and management of intraoperative bradycardia. This study aimed to investigate several factors that may reduce the incidence of intraoperative bradycardia in adult patients undergoing general anaesthesia for various ophthalmic procedures. A total of 947 adult patients who underwent general anaesthesia for different ophthalmic surgeries in 2020 were initially included. Following the exclusion of 104 cases, 843 patients were eligible for analysis. Patients received either cisatracurium with neostigmine (n = 388) or rocuronium with sugammadex (n = 455) as neuromuscular blocking and reversal agents, respectively. Quantitative neuromuscular monitoring was applied in all cases, while depth of anaesthesia was monitored using the bispectral index (BIS) in selected cases. The primary outcome was the incidence of intraoperative bradycardia, defined as a heart rate of fewer than 60 beats per minute. The group receiving rocuronium and sugammadex demonstrated a significantly lower incidence of intraoperative bradycardia (p < 0.001). This reduction was further supported by logistic regression analysis, both in univariate (OR, 0.07; 95% CI, 0.02-0.24; p = 0.001) and multivariate models (OR, 0.08; 95% CI, 0.02-0.94; p = 0.001). Additionally, this group exhibited a significantly higher rate of BIS monitoring during surgery, alongside a significant reduction in total opioid (p = 0.039) and sevoflurane consumption (p < 0.001). The use of rocuronium is associated with a significant reduction in the incidence of intraoperative bradycardia in adult patients undergoing ophthalmic surgery under general anaesthesia.

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 (g BRCA1/2 ) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (s BRCA1/2 ) 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.

Amina M Illias, Department of Anaesthesiology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan, Tel +886-975366367, Email aminailliasma@gmail.com

There is still no definite answer regarding the most advantageous patient positioning during total hip replacement (THR). We compared whether patient position (lateral vs supine) incur a difference on hospital length of stay (LOS) after primary THR. This retrospective cohort study included primary THR patients at a single tertiary center (2017-2022). THR patients prepared in the lateral decubitus position were compared to those in the supine position. Propensity score matching at a 1:4 ratio was applied to minimize selection bias. Matching covariates included age, sex, body weight, comorbidities (hypertension, diabetes), anesthesia time, and intraoperative tranexamic acid use. After matching, 990 patients were analyzed (792 lateral; 198 supine). In supine group, the median LOS (5 days, IQR: 4-6) was shorter than the lateral group (5 days, IQR: 5-6; <0.001). More supine patients were discharged before day 5 (45.5% vs 22.7%, <0.001). Multivariate analysis revealed supine position as the strongest protective factor against long hospitalization (OR: 0.32, 95% CI: 0.23-0.46, <0.001). Other notable predictors of long LOS included ASA ≥III (OR: 1.74), longer anaesthesia duration (OR: 1.78), and higher IV fluid administration (OR: 1.08). Patient positioning did not notably predict blood transfusion risk (OR: 1.32, =0.144). THR patients in supine positioning have a substantial reduction in hospital LOS compared to patients in lateral decubitus positioning, with supine position providing a 68% reduction in risk of long hospitalization. The two groups showed no difference in blood transfusion requirements.