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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Here, the expression of LSM1 mRNA in breast cancer was estimated using The Cancer Genome Atlas (TCGA), Oncomine, TIMER and bc-GenExMiner databases. We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in breast cancer (BRCA) patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease-free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.

To report the clinical outcomes of vasospasm embolization technique in treating lower gastrointestinal bleeding (LGIB).Fifty LGIB patients (32 men and 18 women; mean age, 70.4 years) with positive contrast extravasation on multidetector computed tomography were treated with pharmaco-induced vasospasm embolization by semiselective catheterization technique. Distal rectal bleeding was excluded. The bleedings in three patients were considered to be tumor related. Eighteen underwent regular hemodialysis, and 22 showed unstable hemodynamic at intervention.Forty-two bleeders were found in superior mesenteric territory and eight in the inferior mesenteric territory. Successful, immediate hemostasis was achieved in 49 (98%) patients. Early recurrent bleeding (30 days) was found in 13 (26.5%) patients with 6 local rebleeding (12.2%), 5 new-foci bleeding (10.2%), and 2 uncertain foci bleeding (4.1%). Repeated vasospasm embolization therapy was given to five patients, with successful hemostasis in four. All the three tumor-related bleeding patients undergoing vasospasm embolization had ceased bleeding and discharged. Patient-based primary and overall clinical successes were achieved in 73.5% and 83.7%, and lesion-based primary and overall clinical successes were 83.0% and 86.7%, respectively. The 30-day mortality rate was 21.3%, and the 1- and 2-year survival rates were 51.5% and 43.8%. No major procedure-related complications (eg, bowel ischemia) were encountered.This study confirmed our prior preliminary conclusion that pharmaco-induced vasospasm embolization is easy, safe, and effective for LGIB. This treatment may be considered the first-line alternative approach for LGIB, especially for patients of advanced age with complex medical problems and/or when vasa rectal embolization isn't feasible.

This study aimed to investigate the effectiveness of neoadjuvant chemotherapy in patients with breast cancer in different age groups and evaluate the impact of age group on survival outcome according to different treatment responses. Data were retrospectively collected from the cancer registry database of Kaohsiung Medical University Hospital in Taiwan under an approved protocol. Overall, 96 elder patients (aged >50 years) and 96 younger controls (aged ≤50 years) who received neoadjuvant chemotherapy and breast surgical treatment were examined after 1:1 matching. Logistic regression analysis was used to investigate the effectiveness of treatment response in patients of different age groups. Additionally, the Kaplan-Meier estimator and log-rank test were performed to evaluate the effect of age group and treatment response on disease-free and overall survival (OS). Although no direct significant association was found between age group and treatment response, several significant results were found in treatment response stratification analysis. Among 16 pathological complete response (pCR) patients, elder patients showed significantly greater 5-year disease-free survival (DFS) than younger patients (DFS rate, 85.7% vs. 0%, p = 0.041). However, in 176 non-pCR patients, elder patients showed poor DFS compared to younger patients (DFS rate, 16.6% vs. 32.3%; log-rank test, p = 0.031). With limited sample size and study design, our study results demonstrate that patients aged >50 years who achieved pCR after neoadjuvant chemotherapy could obtain better survival outcome than younger patients. However, the younger patients showed no survival benefits regardless of pCR status.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy, which is caused by mutations mainly in genes encoding BBSome complex and IFT complex. Here, we reported a 21-year-old female with BBS characterized by three primary features including obesity, retinitis pigmentosa sine pigmento and bilateral renal cysts. She also had some secondary features such as diabetes mellitus, nonalcoholic fatty liver disease, subclinical hypothyroidism and mild conductive hearing damage. Whole exome sequencing revealed two compound heterozygous mutations in exon 2 of the BBS12 gene (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) in this patient. Sanger sequencing showed that her father and mother carried c.188delC (p.T63fs) and c.1993_1995del (p.665_665del) variants, respectively, while her parents were free of BBS-related symptoms. In conclusion, this case reported two novel mutations (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) of the BBS12 gene in a girl presented with BBS, which provides novel genetic resources for studies of the disease. Meanwhile, the BBS case shows the entire development progress from her birth to adulthood, which helps facilitate clinicians' understanding of BBS.Bardet-Biedl综合征(Bardet-Biedl syndrome, BBS)是一种罕见的常染色体隐性遗传的纤毛相关疾病,其病因主要与编码BBS蛋白复合体BBSome、鞭毛内运输复合体等基因突变有关。本文报道了1例21岁的女性BBS患者,该患者具有肥胖、视网膜色素变性、双肾囊肿的典型特征,还存在2型糖尿病、非酒精性脂肪肝、亚临床甲状腺功能减退症、轻度传导性听力下降等不典型表现。全外显子组测序发现该患者的BBS12基因2号外显子存在复合杂合突变(c.188delC, p.T63fs和c.1993_1995del, p.665_665del)。进一步通过Sanger测序发现患者的父亲和母亲分别携带c.188delC(p.T63fs)和c.1993_1995del(p.665_665del)突变,但均无相关症状。综上所述,本病例报告发现了BBS12基因的两个新的突变位点(c.188delC, p.T63fs和c.1993_1995del, p.665_665del),为该疾病的研究提供了新的遗传资源,同时该病例还展示了患者从出生到成人期间的整个疾病发展过程,能够帮助临床医生更好地理解BBS。.

In Western countries, breast cancer tends to occur in older postmenopausal women. However, in Asian countries, the proportion of younger premenopausal breast cancer patients is increasing. Increasing evidence suggests that the gut microbiota plays a critical role in breast cancer. However, studies on the gut microbiota in the context of breast cancer have mainly focused on postmenopausal breast cancer. Little is known about the gut microbiota in the context of premenopausal breast cancer. This study aimed to comprehensively explore the gut microbial profiles, diagnostic value, and functional pathways in premenopausal breast cancer patients. Here, we analyzed 267 breast cancer patients with different menopausal statuses and age-matched female controls. The α-diversity was significantly reduced in premenopausal breast cancer patients, and the β-diversity differed significantly between breast cancer patients and controls. By performing multiple analyses and classification, 14 microbial markers were identified in the different menopausal statuses of breast cancer. Bacteroides fragilis was specifically found in young women of premenopausal statuses and Klebsiella pneumoniae in older women of postmenopausal statuses. In addition, menopausal-specific microbial markers could exhibit excellent discriminatory ability in distinguishing breast cancer patients from controls. Finally, the functional pathways differed between breast cancer patients and controls. Our findings provide the first evidence that the gut microbiota in premenopausal breast cancer patients differs from that in postmenopausal breast cancer patients and shed light on menopausal-specific microbial markers for diagnosis and investigation, ultimately providing a noninvasive approach for breast cancer detection and a novel strategy for preventing premenopausal breast cancer., Breast cancer: gut microbes before and after menopause Women developing breast cancer before the menopause have less diverse gut microbe populations than their healthy peers, and significantly different gut microbial profiles than postmenopausal breast cancer patients. There is increasing evidence of a link between gut microbes and breast cancer, but most studies have focused on women after the menopause. The incidence of breast cancer in premenopausal women is increasing, especially in Asia. Researchers in Taiwan led by Chih-Po Chiang at Kaohsiung Medical University Hospital compared gut microbial populations in 267 breast cancer patients at different menopausal stages to matched controls. The results suggest that gut microbe profiling might offer a novel and noninvasive method for diagnosing and monitoring breast cancer. It may also lead to new strategies for prevention and treatment, as evidence emerges of a link between gut microbes and cancer.

Introduction Pituitary growth hormone-secreting (GH) pituitary adenomas (PAs) cause mass effects and dysregulated hypersecretion of GH. However, somatic mutation burden is low in PAs. While progress has been made in identifying the epigenetic changes involved in GH-PA initiation, the precise details of its tumorigenesis in GH-PA patients remains to be elucidated. As N6-methyladenosine (m6A) has been shown to often play a critical role in various tumors, it represents a possible initiation point for the tumorigenesis of pituitary adenomas. However, the role of RNA methylation in GH adenomas remains unclear. Methods Protein expression of m6A regulators was measured by immunohistochemistry. Global levels and distribution of m6A methylation were separately analyzed by m6A enzyme-linked immunosorbent assay and m6A sequencing (m6A-seq). RNA interference and lentivirus knockdown system were used to investigate the role of methyltransferase-like 3 (METTL3) and its m6A- dependent regulatory mechanism in tumor progression and GH secretion. Results We show that both METTL3 messenger RNA and protein expression are elevated in GH-PA samples when compared with both normal pituitary tissue specimens and nonsecreting pituitary adenomas. Levels of m6A modification increased in GH-PAs, and hypermethylated RNAs are involved in hormone secretion and cell development. Knockdown of METTL3 in GH3 cell line resulted in decreased cell growth and GH secretion. Importantly, we found that GNAS and GADD45γ act as the downstream targets in this process. Conclusion Our findings strongly suggest that m6A methyltransferase METTL3 promotes tumor growth and hormone secretion by increasing expression of GNAS and GADD45γ in a m6A-dependent manner. Thus, METTL3 and the methylated RNAs constitute suitable targets for clinical treatment of GH-PAs.

Inflammatory bowel disease (IBD) has a close association with transketolase (TKT) that links glycolysis and the pentose phosphate pathway (PPP). However, how TKT functions in the intestinal epithelium remains to be elucidated. To address this question, we specifically delete TKT in intestinal epithelial cells (IECs). IEC TKT-deficient mice are growth retarded and suffer from spontaneous colitis. TKT ablation brings about striking alterations of the intestine, including extensive mucosal erosion, aberrant tight junctions, impaired barrier function, and increased inflammatory cell infiltration. Mechanistically, TKT deficiency significantly accumulates PPP metabolites and decreases glycolytic metabolites, thereby reducing ATP production, which results in excessive apoptosis and defective intestinal barrier. Therefore, our data demonstrate that TKT serves as an essential guardian of intestinal integrity and barrier function as well as a potential therapeutic target for intestinal disorders.

Background We, herein, propose an algorithm for correction of oral incontinence or/and color/texture mismatch after oromandibular reconstruction, by means of serial excision. To the best of our knowledge, this is the first case series presenting serial excision for complete removal of the free flap skin paddle to improve functional and aesthetic outcomes after free flap reconstruction of oromandibular through-and-through defects. Methods Single-centre retrospective study of all patients who underwent serial excision of the whole skin paddle, for correction of oral incontinence or/and color and texture mismatch after free flap reconstruction, in a 9-year period. We propose a treatment algorithm, based on the lip defect size. Patients with small defects undergo primary commissuroplasty, simultaneously with the free flap reconstruction and, if necessary, subsequent serial excision in local anesthesia for the color/texture mismatch. Patients with large defects undergo secondary commissuroplasty in general anesthesia. They are left to heal and, subsequently, undergo staged excision in 4-6-month intervals in local anesthesia. Results Sixteen patients were analyzed. Thirteen patients (81%) had mild oral incontinence. Eight patients (50%) required two stages of serial excision, six patients (38%) underwent three serial excisions and two patients (12%) had to be operated four times. Skin paddle surface ranged from 4 × 4 cm to 10 × 6 cm. No complications were observed and all patients were satisfied with the final outcome. Conclusion We conclude that the algorithm-based serial excision, can significantly improve the functional and aesthetic outcomes in patients with oral incontinence and color/texture mismatch after free tissue transfer for through-and-through cheek defects, involving the oral commissure.

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future.

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high‐risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the only curative option for patients suffering from high‐risk AML/MDS. However, many patients relapse after allo‐HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL‐2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft‐versus‐host disease (GVHD) and boost the graft‐versus‐leukemia (GVL) effect post‐transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low‐dose decitabine (LDEC) plus VEN to prevent relapse after allo‐HSCT for high‐risk AML/MDS patients. Twenty patients with high‐risk AML (n = 17) or high‐risk MDS (n = 3) post‐transplantation were recruited. Approximately day 100 post‐transplantation, all patients received LDEC (15 mg/m2 for 3 d) followed by VEN (200 mg) on d 1‐21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event‐free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo‐HSCT. Survival outcomes were assessed using Kaplan‐Meier analysis. The median follow‐up was 598 (149‐1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2‐y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2‐y EFS time was 525 (149‐1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo‐HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high‐risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high‐risk AML/MDS patients., The results of the current study suggest that maintenance treatment with LDEC combined with VEN introduced nearly 3 mo after allo‐HSCT is efficacious, with an acceptable toxicity profile and impressive long‐term disease control.

Background Bypass grafting is the standard of care for chronic aorto-iliac occlusive disease (AIOD, aka Leriche Syndrome) but is associated with mortality rates of up to 25% if surgical re-intervention is necessary. Despite a recent shift towards an endovascular-first strategy for TransAtlantic InterSociety Consensus II (“TASC II”) C and D lesions, reports from Leriche Syndrome are still limited. Patients and methods 15 high-risk patients (11 male, 4 female), mean age of 60.6 years, with chronic aorto-iliac occlusive disease were retrospectively reviewed. Retrograde approaches via the bilateral femoral arteries for aortic occlusion less than 4 cm in length and/or antegrade fashion from the brachial artery for juxtarenal type lesions were made. For the latter, thrombolysis prior to angioplasty was also performed. Intraluminal or if necessary, subintimal angioplasty was performed with deployment of either bare metal stents or stentgrafts in a kissing-stent fashion. Results A total of 28 iliac arteries and 14 occluded abdominal aorta were treated with 100% technical success, of which 25% success were achieved by using subintimal technique. Two minor complications occurred, including vascular rupture and distal emboli in one patient apiece, which were successfully managed via endovascular fashion. There were no complications of renal artery emboli. Primary and secondary patency rates at 1, 3 and 5 years were 92.3% and 100%; 83.9% and 100%; and 83.9% and 100%, respectively. Conclusion Endovascular therapy for chronic aorto-iliac occlusion has a high technical success rate, with good short- and mid-term primary and secondary patency rates and may provide a valid alternative to surgery for high-risk patients.

Context The resection plan of pituitary adenoma (PA) needs preoperative observation of the sellar region. Radiomics prediction requires high-quality segmentations. Manual delineation is time-consuming and subject to rater variability. Objective This work aims to create an automated segmentation method for the sellar region, several tools to extract invasiveness-related features, and evaluate their clinical usefulness by predicting the tumor consistency. Methods Patients included were diagnosed with pituitary adenoma at Peking Union Medical College Hospital. A deep convolutional neural network, called gated-shaped U-net (GSU-Net), was created to automatically segment the sellar region into 8 classes. Five magnetic resonance imaging (MRI) features were extracted from the segmentation results, including tumor diameters, volume, optic chiasma height, Knosp grading system, and degree of internal carotid artery contact. The clinical usefulness of the proposed methods was evaluated by the diagnostic accuracy of the tumor consistency. Results A total of 163 patients with confirmed pituitary adenoma were included as the first group and were randomly divided into a training data set and test data set (131 and 32 patients, respectively). Fifty patients with confirmed acromegaly were included as the second group. The Dice coefficient of pituitary adenoma in important image slices was 0.940. The proposed methods achieved accuracies of more than 80% for the prediction of 5 invasive-related MRI features. Methods derived from the automatic segmentation showed better performance than original methods and achieved areas under the curve of 0.840 and 0.920 for clinical models and radiomics models, respectively. Conclusion The proposed methods could automatically segment the sellar region and extract features with high accuracy. The outstanding performance of the prediction of the tumor consistency indicates the methods’ clinical usefulness for supporting neurosurgeons in judging patients’ conditions, predicting prognosis, and other downstream tasks during the preoperative period.

Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis., Human ribonuclease 1 (hRNase 1) regulates innate immunity, hemostasis and RNA clearance. Here, the authors report an alternative function of hRNase 1 as a secretory ligand of Eph receptor EphA4 to enhance breast cancer stemness and promote breast tumour initiation.

Background The main purpose of this study was to describe the all-inside arthroscopic technique for repairing anterior talofibular ligament (ATFL) avulsion fractures at the attachment points of the fibula and talus, and to evaluate the functional outcomes during long-term follow-up. Methods The data of 78 patients with ATFL avulsion fracture treated in our hospital from August 2013 to November 2016 were analyzed retrospectively. All patients underwent surgery. Patients were divided into two groups according to whether they had undergone all-inside arthroscopic treatment or open treatment. The American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Foot and Ankle Outcome Score (FAOS) and a 36-item Short Form Health Survey questionnaire (SF-36) were used to evaluate functional outcomes. Results The postoperative follow-up period was 24–48 months. All patients reported subjective improvements to ankle stability without any nerve, blood vessel or tendon complications. At the final follow-up, there was no significant difference in the AOFAS, SF-36 or sport participation rate between the arthroscopic group and the open group; however, the KAFS and FAOS were significantly higher in the arthroscopic group than in the open group. Conclusions For ATFL avulsion fractures, the all-inside ankle arthroscopic procedure produced better outcomes than did the open procedure. The all-inside ankle arthroscopic procedure provides a minimally invasive technique with acceptable long-term functional outcomes.

The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy.

Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.

Objectives Blood–brain barrier (BBB) disruption is a critical pathological process involved in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterized the profile of five cell adhesion molecules in patients with NMOSD. Methods We measured levels of cell adhesion molecules, including ICAM‐1, ICAM‐2, VCAM‐1, PECAM‐1, and NCAM‐1, in the serum of 28 patients with NMOSD, 24 patients with multiple sclerosis (MS), and 25 healthy controls (HCs). Results ICAM‐2 levels (median: 394.8 ng/mL) were increased in patients with NMOSD compared with MS (267.1 ng/mL, P = 0.005) and HCs (257.4 ng/mL, P = 0.007), and VCAM‐1 and ICAM‐1 levels were higher in patients with NMOSD (641.9 ng/mL and 212.7 ng/mL, respectively) compared with HCs (465 ng/mL [P = 0.013] and 141.8 ng/mL [P = 0.002], respectively). However, serum PECAM‐1 levels were lower in patients with NMOSD (89.62 ng/mL) compared with MS (106.9 ng/mL, P = 0.015) and HCs (107.2 ng/mL, P = 0.007). Receiver operating characteristic curve analysis revealed that PECAM‐1 (area under the curve (AUC): 0.729) and ICAM‐2 (AUC: 0.747) had adequate abilities to distinguish NMOSD from MS, and VCAM‐1 (AUC: 0.719), PECAM‐1 (area under the curve: 0.743), ICAM‐1 (AUC: 0.778), and ICAM‐2 (AUC: 0.749) exhibited potential to differentiate NMOSD and HCs. Serum levels of PECAM‐1 also demonstrated a negative correlation with Kurtzke Expanded Disability Status Scale scores in patients with NMOSD. Interpretation Our results reveal possible BBB breakdown signals specifically observed in NMOSD and highlight the potential role of cell adhesion molecules as biomarkers of this disease.

Background The undertreatment of cancer pain is a global issue although many international guidelines and various studies bloom to explore the approaches in pain management. However, there is no standard care for cancer pain in routine practices. To set up a standardized procedure for improving cancer pain management in Taiwan, the Good Pain Management (GPM) program is explored to provide treatments following the US National Cancer Care Network (NCCN) Adult Cancer Pain Guideline. Method Patients diagnosed with moderate-to-severe cancer pain were eligible and randomized into the GPM or control arm and observed the first 48 h to evaluate the effects of pain management between 2 arms. Pain control, adequacy of treatments, patient satisfaction, and quality of life (QoL) of eligible patients were analyzed. Ad hoc analyses based on the pain medication category were also conducted. Result Fifty-one patients were enrolled, with 26 and 25 assigned to the GPM and control arms, respectively. Significant differences among the GPM and control arms were found including a greater decrease in the mean numerical rating scale (NRS) score in the GPM arm (− 4.6 vs. − 2.8), a lower proportion of moderate-to-severe pain in the GPM arm (23.2% vs. 39.8%), and a higher pain management index (PMI) score in the GPM arm (0.64 points vs. 0.33 points) (all p Conclusion In summary, our study demonstrated that the implementation of a standardized pain assessment and management approach (GPM ward program) showed significant improvements on pain relief, decreased the portion of moderate-to-severe cancer pain, and increased patient satisfaction in the 1st 48 h after admission. The implementation of the GPM approach in the cancer ward may provide sooner and better improvement of cancer pain management for patients who suffered moderate-to-severe cancer pain. Trial registration ClinicalTrials.gov (Identifier: NCT03155516)

Objective With the increasing incidence of breast cancer in young women, its side effects have extended into the sexual lives of women. However, an appropriate tool to measure the sexual function is nonexistent. The aim of this study was to develop a suitable tool to measure sexual function in women with breast cancer. Materials and methods After conducting literature reviews regarding the sexual function characteristics of women with breast cancer, this study designed a set of integrated sexual function questionnaires, which included pertinent information and three scales. The validity of the scales was examined under the guidance of three gender studies experts and two gynecologists who are also professors. Regarding the construct validity, researchers conducted exploratory factor analysis on the measurement results of 196 women with breast cancer. Results The integrated sexual function questionnaires included the following three scales: “Breasts' Role Self-Checklist,” “Scales for Breasts' Role in the Foreplay,” and “Female Sexual Function Scale for BCSs.” The questionnaire tool consisted of the longitudinal time change, patients' and their partners' situation, information related to the recovery process, participants' perspective toward objectification of women's breasts, the role of breasts in foreplay during sexual activities, sexual desire, sexual satisfaction, sexual obstacle, and other self-evaluations. We first derived one factor from six questions in “Breasts' Role Self-Checklist” and named it as “The Importance of Breasts for Women.” The other two factors were obtained from eight questions in “Scales for Breasts' Role in the Foreplay” and named as “Sexual Attraction to Breasts” and “Function of Breasts in Foreplay.” In addition, three factors were derived from 16 questions in “Female Sexual Function Scale for BCSs” and named as “Sexual Desire,” “Sexual Satisfaction,” and “Sexual Obstacle.“ Conclusion This study determined that these integrated scales for breast cancer survivors are suitable due to their content validity, construct validity, and high internal consistency reliability, with a Cronbach's alpha of higher than 0.9 for all the three scales.

Mitochondrial unfolding protein are abundant in breast cancer cells, but the mechanism by which breast cancer cells resist apoptosis is still not fully elucidated. In this study, we explored the role of mitochondrial unfolded protein response (mtUPR)-related proteins in four types of breast cancer tissues. Mitochondrial fractions were taken from four breast cancer tissues (luminal A, luminal B, Her2 –overexpression, and TNBC) and the expression of mitochondrial polyubiquitinated proteins was observed by western blot and ELISA. In addition, the expression of hsp10, hsp60, and clpp in mitochondria was observed by western blot in breast cancer tissues and adjacent tissues, and confirmed by ELISA. The expression levels of hsp10 and hsp60 were correlated with clinicopathological parameters in 114 breast cancer patients. We found an increase in the performance of mitochondrial polyubiquitinated proteins in breast cancer tissues of luminal A, luminal B, Her2-overexpression, and TNBC. The mitochondrial hsp10, hsp60, and clpp are abundantly expressed in breast cancer tissues rather than adjacent noncancerous tissues. The expression levels of mitochondrial hsp10 and hsp60 were highest in histological grade 3 breast cancer tissues. Additionally, mitochondria with high hsp60 expression were more present in Her2-positive tumors. We observed that mtUPR was specifically activated in breast cancer tissues but inactivated in normal mammary tissue. MtUPR had also exhibited a particular increase in Her2-overexpression tumors but not in ER- or PR-positive tumors. Taken together, we suggested that mtUPR may act as a potential candidate for developing novel Her2-overexpression breast cancer therapy.

To evaluate the effect of electro-acupuncture (EA) in infertile patients with phlegm-dampness polycystic ovary syndrome-insulin resistance (PCOS-IR).Seventy-six PCOS-IR patients who underwnet in vitro fertilization and embryo transfer (IVF-ET) were equally assigned to two groups according to a random digital table: the EA group and the control group, with 38 cases in each group. Before undergoing IVF, the two groups were treated with EA or pseudo-acupuncture, respectively, for 3 menstrual cycles. The intervention was 25 min twice a week until the day of oocyte collection. The selected acupoints were Zhongwan (RN 12), Tianshu (ST 25), Daheng (SP 15), Daimai (GB 26), Qihai (CV 6), Guanyuan (CV 4), and bilateral points including Xuehai (SP 10), Fenglong (ST 40), Zusanli (ST 36), and Yinlingquan (SP 9). Evaluation of phlegm-dampness syndrome score and IR score were carried out before and after treatment. Additionally, the number of oocytes retrieved, transplantable embryo rate, high-quality embryo rate, clinical pregnancy rate and live birth rate were compared between the two groups. Real-time polymerase chain reaction analysis was used to monitor the mRNA expression of the insulin receptor substrate (IRS-1), phosphatidylinositiol 3-kinase (PI3K) and glucose transport factor 4 (GLUT4) in ovarian granulosa cells.EA treatment reduced the phlegm-dampness syndrome score as well as the IR scores compared with the control group (P0.05). No significant differences in the number of oocytes retrieved and clinical pregnancy rate between the two groups (P0.05). Moreover, the transplantable embryo rate [49.0% (284/580) vs. 41.9% (273/652)], high-quality embryo rate [36.6% (104/284) vs. 27.8% (76/273)], and live birth rate [50% (19/38) vs. 26.3% (10/38)] in the EA group were significantly higher than in the control group (P0.05). Gene expression analyses revealed significantly elevated IRS-1, PI3K and GLUT4 mRNA in ovarian granulosa cells of the EA group compared with the control group (P0.05).EA may ameliorate the effects of phlegm-dampness syndrome and ovarian IR in PCOS-IR patients. Mechanistically, this effect might be through an upregulation of the IRS-1/PI3K/GLUT4 signaling pathway, which may result in improved oocyte quality and embryonic development potential. (Registration No. ChiCTR1800015453).

Background: The all-inside arthroscopic Broström-Gould technique gained particular attention among clinicians and researchers due to its high rate of satisfactory results. Thus far, there is a lack of evidence regarding the differences in clinical outcomes between the use of 1 anchor and 2 anchors. The purpose of this study was to compare the differences in clinical function and activity levels in patients treated with 1 or 2 anchors in all-inside arthroscopic Broström-Gould surgery for chronic lateral ankle instability (CLAI). Methods: The data of 75 patients with CLAI (unilateral) admitted from May 2013 to July 2016 were retrospectively analyzed. All patients were treated with all-inside arthroscopic Broström-Gould surgery. The patients were divided into a single-anchor group ( n = 36) and double-anchor group ( n = 39) according to the number of anchors used. There was no statistical difference in general characteristics between the 2 groups before surgery. After 36 to 72 months of follow-up, the pain visual analog scale (VAS) score, American Orthopaedic Foot & Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), and Foot and Ankle Outcome Score (FAOS) were used to evaluate and compare the clinical function results between the 2 groups. Results: The incidence of wound complications; reaction to the suture; injury to the nerve, blood vessel, or tendon; and length of postoperative hospitalization were similar between the 2 groups. At the last follow-up, there was no significant difference in the VAS and AOFAS scores between single- and double-anchor groups, but the KAFS and FAOS in the double-anchor group were significantly higher than in the single-anchor group. Additionally, more patients in the double-anchor group returned to preinjury sports activities. Conclusion: All-inside arthroscopic Broström-Gould surgery for the treatment of CLAI yielded a better functional effect and better recovery to preinjury mobility when 2 anchors were used instead of a single anchor. Level of Evidence: Level III, comparative study.

Objective To evaluate the functional outcomes of arthroscopic anatomical repair of anterior talofibular ligament (ATFL) in the treatment of chronic lateral ankle instability (CLAI) during medium- and long-term follow-up. Methods From September 2014 to August 2017, the data of 37 patients (23 males, 14 females; 12 left ankles, 25 right ankles) aged between 21 and 56 years, with an average age of 32.17 ± 6.35 years, presenting with CLAI, was retrospectively analyzed. Among them, 32 injuries were caused by sprain and five injuries were caused by car accidents. The course of the disease lasted for 12 to 60 months, with an average of 26.07 ± 13.29 months. All patients had intact skin around the ankle and no skin lesions. All patients underwent arthroscopic anatomical repair of ATFL, with the fixation of one to two anchors. Pre- and post-operative visual analogue scales (VAS), the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS), and the Karlsson Ankle Functional Score (KAFS) were compared to evaluate the curative effect of the operation. Results The operation was successful in all 37 cases. The operation time ranged from 40 to 75 min, with an average of 51.25 ± 11.49 min. After surgery, all incisions healed in stage I and there were no complications such as nerve, blood vessel and tendon injury, implant rejection, or suture rejection. Hospital stays of postoperative patients were 3 to 5 days, with an average of 3.77 ± 1.36 days. All patients were followed for 24 to 45 months, averaging 33.16 ± 10.58 months. For three patients with CLAI combined with mild limitation of subjective ankle movement, joint activity was normal after rehabilitation function exercise and proprioceptive function training for 2 months. At the final follow-up, ankle pain had disappeared completely. The ankle varus stress test and ankle anterior drawer test were both negative. Range of joint motion was good. There was no lateral instability of the ankle and all patients returned to normal gait. The mean VAS score decreased to 1.12 ± 0.13, the AOFAS score increased to 92.53 ± 4.87, and the KAFS score increased to 93.36 ± 6.15. All the follow-up indexes were significantly different from those before surgery. Conclusion Arthroscopic anatomical repair of ATFL for CLAI is precise, with less surgical trauma and reliable medium- and long-term effect.

To elucidate the sleep quality characteristics and factors related to either good or poor sleep quality in acromegaly patients before surgery and to explore sleep quality changes after transsphenoidal surgery and the factors related to these changes.We prospectively enrolled 39 acromegaly patients and 78 patients with nonfunctioning pituitary adenomas. Scales for anxiety, depression, disease stigma and nasal condition were evaluated. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was administered before surgery as well as one month and three months after surgery.A higher percentage of acromegaly patients had poor sleep quality compared to controls (35.9% vs. 5.1%, p 0.001). In addition, acromegaly patients experienced worse subjective sleep quality, extended sleep latency, increased sleep disturbance and decreased daytime functioning. Higher scores for anxiety, disease stigma and sinonasal outcomes were correlated with worse sleep quality in acromegaly patients. At one month after transsphenoidal surgery, we found worse subjective sleep quality, extended sleep latency, shortened sleep duration, impaired sleep efficiency and increased sleep disturbance in acromegaly patients. At three months postoperatively, most impaired PSQI domains in acromegaly patients recovered to preoperative levels. The use of soluble gauze was related to decreased sleep quality at one month after surgery and severe anxiety and depression were related to improved sleep quality at three months after surgery.Sleep quality was reduced in acromegaly patients. Moreover, sleep quality initially worsened after surgery but later recovered. Emotional problems and the use of soluble gauze were related factors.None.

The objective of this study was to evaluate the efficacy of various daptomycin dosing regimens against Staphylococcus aureus and Enterococcus faecium in pediatric patients with proven/suspected gram-positive infection. Monte Carlo simulations (MCSs) were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. According to the results of the MCSs, currently approved pediatric dosage regimens were sufficient against Staphylococcus aureus with MIC ≤ 0.5 μg/mL for all pediatric patients, but poor when MIC ≥ 1 μg/mL except for adolescents (12-17 years) who need a dosage of ≥10 mg/kg/day at MIC = 1 μg/mL. For Enterococcus faecium with MIC ≤ 4 μg/mL, the recommended dosage of 8-12 mg/kg/day in adults was enough for adolescents, but not subjected to younger pediatric patients. Furthermore, based on MIC distributions obtained from the European Committee on Antimicrobial Susceptibility Testing, the approved high-dose regimen should be recommended for infants aged 3-12 months, children (2-11 years), and adolescents to achieve better clinical efficacy against methicillin-resistant Staphylococcus aureus. In addition, the dosage of 8-12 mg/kg/day was powerful against Enterococcus faecium for adolescents; however, only the highest dosage of 12 mg/kg/day was effective for infants aged 3-12 months and children. All the simulated regimens were not optimal for infants aged 13-24 months. These PK/PD-based simulations rationalize and optimize the dosage regimens of daptomycin against Staphylococcus aureus and Enterococcus faecium in pediatric patients.

Background The trend of women suffering from early-onset breast cancer is increasing in Taiwan. The association of early-onset breast cancer with body mass index (BMI), menarche, and menopausal status has focused interest on the field of cancer epidemiology; however, few studies have explored the interaction of these factors on early-onset risk. This study aimed to estimate the interaction effects of BMI, menarche, and menopausal status on 40-year-old early-onset breast cancer. Methods Breast cancer patients were recruited from Kaohsiung Medical University Chung-Ho Memorial Hospital from 2013 to 2020. Multivariable logistic regression was used to estimate odds ratios (ORs) for early-onset breast cancer risk associated with menarcheal age stratified by sociodemographic factors and for the interaction between BMI and menopausal status on early-onset risk. Results A total of 775 participants were divided into 131 early-onset cases (≤ 40 years) and 644 late-onset cases (> 40 years). Compared to the age of 13 years at menarche, the age ≤ 11 years was significantly positively associated (OR: 2.62, 95% CI: 1.38–4.97) and ≥ 16 years was negatively associated (OR: 0.13, 95% CI: 0.03–0.53) with 40-year-old early-onset breast cancer respectively. In an adjusted model, the status of BMI OR = 4.62, Pinteraction = 0.057). Compared to both BMI ≥ 24 and peri-/postmenopausal status, both the status of BMI Conclusions This study suggests that the status of BMI

The association between phthalate exposure and breast cancer remains controversial. We performed a prospective patient cohort design to explore the interaction between creatinine-corrected urinary phthalate metabolites and hormone receptors as well as body mass index (BMI) on recurrent breast cancer. In this follow-up study, 636 female breast cancer patients and 45 new recurrent cases diagnosed for a total of 1576.68 person-years of follow-up were recruited. Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively associated with breast cancer recurrence, with adjusted hazard ratio (aHR) 3rd vs. 1st quartile of 0.15 (95% CI 0.04–0.51). The MEOHP presented as a non-monotonic dose–response (NMDR) curve, being U-shaped. In the stratification of hormone receptors, MEOHP still exhibited a U-shaped dose–response curve. The third quartile of MEOHP showed significant lowest recurrent risk in the status of ER-positive (aHR 0.18, 95% CI 0.05–0.66), PR-negative (aHR 0.14, 95% CI 0.03–0.63), and HER2-negative (aHR 0.24, 95% CI 0.08–0.76). Whether in BMI pinteraction = 0.042). The association between MEOHP and recurrent breast cancer was modified by hormone receptors and BMI.

Background Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. Methods A total of 12,901 breast cancer cases and 12,583 controls from 12 case–control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15–55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. Results We did not observe associations between any HLA allele and breast cancer risk at P P = 1.08e−3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). Conclusions No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.

PurposeStudies on hyperprolactinemia and hypopituitarism in acromegaly are limited. We aimed to analyze the preoperative status, postoperative alterations, and correlated factors of hyperprolactinemia and hypopituitarism in acromegaly patients.MethodsThis is a single-center cohort study with long-term follow-up. We prospectively enrolled 529 acromegaly patients. Hyperprolactinemia and hypopituitarism were evaluated by testing hypothalamus-pituitary-end organ (HPEO) axes hormones before and after surgery.ResultsHyperprolactinemia (39.1%) and hypopituitarism (34.8%) were common in acromegaly. The incidences of axis-specific hypopituitarism varied (hypogonadism, 29.7%; hypothyroidism, 5.9%; adrenal insufficiency, 5.1%), and multiple HPEO axes dysfunction was diagnosed in 5.3% of patients. Patients with preoperative hyperprolactinemia [hazard ratio (HR)=1.39 (1.08-1.79); p=0.012], hypogonadism [HR=1.32 (1.01-1.73); p=0.047], and hypothyroidism [HR=3.49 (1.90-6.44); pConclusionHyperprolactinemia and hypopituitarism are common among acromegaly patients and predict worse surgical outcomes. After surgery, improvement and worsening of HPEO axes function co-exist. Correlated factors are identified for clinical management.

Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and found that Σ4MEHP (the sum of MEHP, MEHHP, MECPP and MEOHP concentrations) in urine was significantly higher (P = 0.018) in the recurrent breast cancer group compared with non-recurrent patients. Σ4MEHP-High was positively and significantly correlated with tumor stage (P = 0.005), lymph node status (P = 0.001), estrogen receptor status (P = 0.010), Her2/Neu status (P = 0.004), recurrence (P = 0.000) and tumor size (P = 0.002), as well as an independent prognostic marker (OR = 1.868; 95% CI = 1.424-2.451; P

Journal of orthopaedic surgery and research 17, 69 (2022). doi:10.1186/s13018-022-02968-y, Published by Biomed Central, London

Background The first dorsal metacarpal artery flap, including dorsal digital nerves with or without dorsal branches of the proper digital nerves, can be used to reconstruct thumb pulp defects with good results. However, it is still unclear whether there are differences in the sensory outcomes between preserving or not preserving the dorsal branches of the proper digital nerves. Methods This retrospective cohort study included 137 thumb pulp defect patients who underwent first dorsal metacarpal artery flap reconstruction procedure from October 2015 to June 2019. Patients were divided into two groups according to whether the dorsal branches of the proper digital nerves were preserved. In the non-preservation group (n = 80), the dorsal digital nerves were included in the flap for sensory reconstruction. In the preservation group (n = 57), the dorsal digital nerves and the dorsal branches of the proper digital nerves of the index finger were included in the flap. The stump of the proper digital nerves in the defect was coaptated to the donor nerves of the flap using the end-to-end fashion. At the last follow-up, static two-point discrimination, Semmes–Weinstein monofilament scores, pain, cold intolerance of the reconstructed finger, and patient satisfaction in both groups were compared. Results All patients were followed up for at least 17 months. No significant differences were found regarding pain of thumb pulp, static two-point discrimination, Semmes–Weinstein monofilament score, cold intolerance in the injured finger, and patient satisfaction. The non-preservation group presented slightly shorter operative times (p Conclusion There are no differences at 2 years in postoperative clinical outcomes when dorsal digital nerves are used to reconstruct flap sensation regardless of preservation of the dorsal branches of the proper digital nerves in the first dorsal metacarpal artery flap. Level of evidence: Level III, retrospective comparative study.

Background To date, no data on the effect of adjuvant postmastectomy radiotherapy (PMRT) on oncologic outcomes, such as all-cause death, locoregional recurrence (LRR), and distant metastasis (DM), are available in women with left-side breast invasive ductal carcinoma (IDC) and heart failure with reduced ejection fraction (HFrEF). Patients and methods We enrolled 646 women with left-breast IDC at clinical stages I–IIIC and HFrEF receiving radical total mastectomy (TM) followed by adjuvant PMRT or non-adjuvant PMRT. We categorized them into two groups based on their adjuvant PMRT status and compared their overall survival (OS), LRR, and DM outcomes. We calculated the propensity score and applied inverse probability of treatment weighting (IPTW) to create a pseudo-study cohort. Furthermore, we performed a multivariate analysis of the propensity score–weighted population to obtain hazard ratios (HRs). Results In the IPTW-adjusted model, adjuvant PMRT (adjusted HR [aHR]: 0.52; 95% confidence interval [CI]: 0.37–0.74) was a significant independent prognostic factor for all-cause death (P = 0.0003), and the aHR (95% CI) of LRR and DM for adjuvant PMRT was 0.90 (0.79–0.96; P = 0.0356) and 0.89 (0.54–1.50; P = 0.6854), respectively, compared with the nonadjuvant PMRT group. Conclusion Adjuvant PMRT was associated with a decrease in all-cause death, and LRR in women with left IDC and HFrEF compared with nonadjuvant PMRT.

PurposeCushing’s disease (CD) is a rare disease that contributes to 70–80% hypercortisolemia, which presents similarities and differences between pediatric and adult patients, and even between male and female patients. However, the comparative study of CD between different age groups and different genders is still insufficient. The aim of the study is to make a systematic comparison to reveal the gender differences in children and adult patients of CD, helping clinicians to provide optimal treatment for different groups of patients.MethodsWe conducted a retrospective research consisting of 30 pediatric and 392 adult CD patients in a single center in Peking Union Medical College Hospital. All 422 patients showed symptoms related to hypercortisolism and received adenoma excision surgery in the department of neurosurgery between 2014 and 2020.ResultsFor the accuracy of diagnosis, the sensitivity of BIPSS at baseline in pediatric patients was lower than in adults (75 vs. 91%, P = 0.054) but increased greatly after desmopressin stimulation (94 vs. 95%). However, the accuracy of lateralization for BIPSS was not preferred for prediction. As for clinical manifestations, growth retardation, weight gain, hirsutism, and acne were more prevalent for children, while for adults, hypertension, osteopenia, glucometabolic disorder, easy bruising, hair loss, and weight loss were more frequently seen. As previously reported, we observed a significant difference between the male prevalence of pediatric and adult patients (50 vs. 17%, P < 0.001), which was possibly caused by the more severe and earlier onset of a series of symptoms. Gender-related comparison showed greater morbidity of nephrolithiasis, hypokalemia, hypertension, easy bruising, osteopenia, and striae for male patients, while irregular menses, hirsutism, and hair loss were more common for female patients. Further analysis showed that the secretory activity of the PA axis was higher for males, presenting as the more remarkable alteration of laboratory parameters and contributing to the more severe clinical manifestations. For patients treated with transsphenoidal pituitary surgery (TSS), the immediate prognosis could be predicted by operation history, invasiveness, Ki-67, and information provided by MRI, including tumor size and Knosp grading. However, we still lack methods to predict long-term prognosis.ConclusionsOur study is the first detailed and systematic comparison between pediatric and adult CD patients. Further exploration of the impact of CD on different genders reveals a more severe and probably an earlier-onset pattern of CD for male patients.

ObjectivesTo identify plasma extracellular vesicles (EVs) associated with radiographic knee osteoarthritis (OA) progression.MethodsEVs of small (SEV), medium (MEV) and large (LEV) sizes from plasma of OA participants (n=30) and healthy controls (HCs, n=22) were profiled for surface markers and cytokine cargo by high-resolution flow cytometry. The concentrations of cytokines within (endo-) and outside (exo-) EVs were quantified by multiplex ELISA. EV associations with knee radiographic OA (rOA) progression were assessed by multivariable linear regression (adjusted for baseline clinical variables of age, gender, BMI and OA severity) and receiver operating characteristic (ROC) curve analysis.ResultsBased on integrated mean fluorescence intensity (iMFI), baseline plasma MEVs carrying CD56 (corresponding to natural killer cells) predicted rOA progression with highest area under the ROC curve (AUC) 0.714 among surface markers. Baseline iMFI of TNF-α in LEVs, MEVs and SEVs, and the total endo-EV TNF-α concentration, predicted rOA progression with AUCs 0.688, 0.821, 0.821, 0.665, respectively. In contrast, baseline plasma exo-EV TNF-α (the concentration in the same unit of plasma after EV depletion) did not predict rOA progression (AUC 0.478). Baseline endo-EV IFN-γ and exo-EV IL-6 concentrations were also associated with rOA progression, but had low discriminant capacity (AUCs 0.558 and 0.518, respectively).ConclusionsPlasma EVs carry pro-inflammatory cargo that predict risk of knee rOA progression. These findings suggest that EV-associated TNF-α may be pathogenic in OA. The sequestration of pathogenic TNF-α within EVs may provide an explanation for the lack of success of systemic TNF-α inhibitors in OA trials to date.

Whole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment. 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.

Objective: To analyze the blood test indicators of patients after infection of COVID-19 in Chongqing and analyze the clinical indicators of 8 patients with diarrhea. Materials and Methods: From January 26, 2019 to February 13, 2020, 70 patients diagnosed with 2019-nCoV according to the World Health Organization interim guidance for NCP and divided into diarrhea and non-diarrhea groups. The laboratory tests liver and kidney function, blood routine, coagulation function, and immune status. Results: The study population included 70 hospitalized patients with confirmed CONV-2019. NCP patients (43males and 27 females) with a mean age of 48.57±17.80 (9~82) years and only 4.3% of patients have lung-related diseases. The positive rate of ESR, CRP, PT, IL6, lymphocyte count, GGT, Prealbumin and CD4 was more than 50%. We further analyzed the differences between 8 diarrhea patients and 62 non-diarrhea patients. Among these indicators, only Lymphocyte, CRP, Prealbumin and Cystatin C positive rate is more than 50%. Although there is no statistical difference in GGT, 100% of the 7 patients tested decreased. Conclusion: Our data recommended that the ESR, CRP, PT, IL6, lymphocyte count, GGT, prealbumin and CD4 have important value in the diagnosis of COVID-19, and the decrease of GGT may be an important indicator for judging the intestinal dysfunction of patients.

Proliferative activity prediction is important for determining individual treatment strategies for patients with acromegaly, and tumor proliferative activity is usually measured by the expression of Ki-67. This study aimed to assess the value of a magnetic resonance imaging (MRI)-based radiomics approach in predicting the Ki-67 index of acromegaly patients. A total of 138 patients with acromegaly were retrospectively reviewed and randomly assigned to primary and validation cohorts. Radiomics features were extracted from MR images, and then the elastic net and recursive feature elimination algorithms were applied to determine critical radiomics features for constructing a radiomics signature. Subsequently, multivariable logistic regression analysis was used to select the most informative clinical features, and a radiomics nomogram incorporating a radiomics signature and selected clinical features was constructed for individual predictions. Twenty-five acromegaly patients were enrolled for multicenter model validation. Seventeen radiomics features were selected to construct a radiomics signature that achieved an area under the curve (AUC) value of 0.96 and 0.89 in the primary cohort and the validation cohort, respectively. A radiomics nomogram that incorporated the radiomics signature and eight selected clinical features was constructed and showed good discrimination and calibration, with an AUC of 0.94 in the primary cohort and 0.91 in the validation cohort. The radiomics signature in the multicenter validation achieved an accuracy of 88.2%. The analysis of the decision curve showed that the radiomics signature and radiomics nomogram were clinically useful for patients with acromegaly. The radiomics signature developed in this study could aid neurosurgeons in predicting the Ki-67 index of patients with acromegaly and could contribute to non-invasive measurement of proliferative activity, affecting individual treatment strategies.

Ectopic ACTH-secreting pituitary adenoma (EAPA) are a rare cause of Cushing’s disease. Due to the lack of consensus and experience in terms of the diagnosis and treatment of EAPAs, preoperative identification and optimal treatment remain challenging. To investigate the characteristics of EAPAs and offer some proposals for the diagnosis and management of this uncommon disease, the EAPA patients admitted to our center and all of the EAPA cases reported in the literature were reviewed. In a retrospective electronic medical chart review, 6 patients (0.39%) with EAPAs were identified from 1536 consecutive patients who were admitted to our hospital with a diagnosis of Cushing’s syndrome between January 2000 and August 2019. A literature review was performed on the online databases PubMed and EMBASE, and 52 cases conformed to the criteria. The data regarding biochemical tests, imaging examinations and follow-ups were analyzed. The mean age of patients with EAPAs was 37.7 years old, and an obvious female predominance (3.5: 1) was demonstrated. The most common location of EAPAs was the cavernous sinus (34.5%), followed by the sphenoid sinus (31.0%) and the suprasellar region (20.7%). No significant differences in the biochemical test results were found among tumors in different locations. Except for sex, no risk factors related to remission were found. Although no significant differences among different locations were found, the tumors in the cavernous sinus had a relatively higher rate of invisibility in terms of imaging and a higher non-remission rate than tumors in other locations. In patients with negative intrasellar findings, the uncommon disease of EAPA should be considered. Due to the endocrine similarity between intrasellar pituitary corticotrophin adenoma and EAPA, the preoperative identification of EAPA depends on a careful review of the imaging examinations. Locations such as the cavernous sinus, sphenoid sinus and suprasellar region should be considered first. Tumor resection is recommended when the diagnosis is confirmed.

BACKGROUND The epidermal growth factor receptor (EGFR) is a therapeutic target for non-small cell lung cancer (NSCLC), but knowledge on gene mutations that contribute to NSCLC development and persistence is lacking. In this study, we investigated genetic variations in EGFR and their association with the clinical and pathological factors of NSCLC. MATERIAL AND METHODS Clinical cases (331 patients) and The Cancer Genome Atlas (TCGA) cases (1040 patients) were selected and analyzed using the refractory mutation systems cBioPortal and the Tumor Immune Estimation Resource (TIMER). RESULTS EGFR mutation frequencies were 54.4% (180 of 331 patients) and 8.0% (83 of 1040 patients) in the clinical and TCGA cohorts, respectively. EGFR mutations were strongly associated with smoking and pathology (P≤0.05) in the clinical cohort, and with gender, smoking, and pathology (P=0.001, P