bluuebunny/crossref_metadata_2025 huggingface dataset:
A Distinct Metabolite Signature in Military Personnel Exposed to Repetitive Low-Level Blasts
Authors: Miller Michael R. , DiBattista Alicia , Patel Maitray A. , Daley Mark , Tenn Catherine , Nakashima Ann , Rhind Shawn G. , Vartanian Oshin , Shiu Maria Y. , Caddy Norleen , Garrett Michelle , Saunders Doug , Smith Ingrid , Jetly Rakesh , Fraser Douglas D.
Published: April 2022

Military Breachers and Range Staff (MBRS) are subjected to repeated sub-concussive blasts, and they often report symptoms that are consistent with a mild traumatic brain injury (mTBI). Biomarkers of blast injury would potentially aid blast injury diagnosis, surveillance and avoidance. Our objective was to identify plasma metabolite biomarkers in military personnel that were exposed to repeated low-level or sub-concussive blast overpressure. A total of 37 military members were enrolled (18 MBRS and 19 controls), with MBRS having participated in 8–20 breaching courses per year, with a maximum exposure of 6 blasts per day. The two cohorts were similar except that the number of blast exposures were significantly higher in the MBRS, and the MBRS cohort suffered significantly more post-concussive symptoms and poorer health on assessment. Metabolomics profiling demonstrated significant differences between groups with 74% MBRS classification accuracy (CA). Feature reduction identified 6 metabolites that resulted in a MBRS CA of 98%, and included acetic acid (23.7%), formate (22.6%), creatine (14.8%), acetone (14.2%), methanol (12,7%), and glutamic acid (12.0%). All 6 metabolites were examined with individual receiver operating characteristic (ROC) curve analyses and demonstrated areas-under-the-curve (AUCs) of 0.82–0.91 (P≤ 0.001) for MBRS status. Several parsimonious combinations of three metabolites increased accuracy of ROC curve analyses to AUCs of 1.00 (P< 0.001), while a combination of volatile organic compounds (VOCs; acetic acid, acetone and methanol) yielded an AUC of 0.98 (P< 0.001). Candidate biomarkers for chronic blast exposure were identified, and if validated in a larger cohort, may aid surveillance and care of military personnel. Future point-of-care screening could be developed that measures VOCs from breath, with definitive diagnoses confirmed with plasma metabolomics profiling.
Detection to Hospital Door: Gender Differences of Patients With Acute Stroke Symptoms
Authors: Walter Silke , Phillips Daniel , Wells Brittany , Moon Robert , Bertsch Thomas , Grunwald Iris Q. , Fassbender Klaus
Published: April 2022

Although prehospital stroke management is challenging, it is a crucial part of the acute stroke chain to enable equal access to highly specialised stroke care. It involves a critical understanding of players usually not specialized in acute stroke treatments. There is contradictory information about gender inequity in prehospital stroke detection, dispatch, and delivery to hospital stroke centers. The aim of this narrative review is to summarize the knowledge of gender differences in the first three stages of acute stroke management. Information on the detection of acute stroke symptoms by patients, their relatives, and bystanders is discussed. Women seem to have a better overall knowledge about stroke, although general understanding needs to be improved. However, older age and different social situations of women could be identified as reasons for reduced and delayed help-seeking. Dispatch and delivery lie within the responsibility of the emergency medical service. Differences in clinical presentation with symptoms mainly affecting general conditions could be identified as a crucial challenge leading to gender inequity in these stages. Improvement of stroke education has to be applied to tackle this inequal management. However, specifically designed projects and analyses are needed to understand more details of sex differences in prehospital stroke management, which is a necessary first step for the potential development of substantially improving strategies.
Sleep Misperception and Associated Factors in Patients With Anxiety-Related Disorders and Complaint of Insomnia: A Retrospective Study
Authors: Liang Yingjie , Zhao Xu , Zhang Changyong , Liu Guangya , Lu Baili , Han Li , Tong Fang , Luo Xinyu , Hu Chuang , Liu Hui
Published: April 2022

Purpose

Data on sleep parameters by polysomnography (PSG) in patients with anxiety-related disorders are limited. Although the disturbance and risk factors of sleep misperception have been implicated in psychopathology, its role in anxiety-related disorders remains unclear. This retrospective study aimed to explore the characteristics and sleep parameters in patients with anxiety-related disorders and different sleep perception types, and to explore the associated factors for sleep misperception.

Methods

Patients with anxiety-related disorders who had complaint of insomnia for more than 3 months were collected at Wuhan Mental Health Center between December 2019 and July 2021. Patients underwent a two-night PSG monitoring and completed a self-reported sleep questionnaire. Behaviors were assessed using 30-item Nurses' Observation Scale for Inpatient Evaluation (NOSIE-30). Patients were divided into normal sleep perception (NSP), positive sleep perception abnormality [PSPA; overestimation of total sleep time (TST) >60 min], and negative sleep perception abnormality (NSPA; underestimation of TST >60 min) groups. PSG indicators and NOSIE-30 scores were compared among groups using the one-way analysis of variance and the Kruskal-Wallis test. Multiple linear regression analysis was performed to determine the associated factors for misperception index.

Results

The subjective and objective TST were 5.5 ± 1.9 h and 6.4 ± 1.7 h in 305 patients, respectively. Sixty-nine (22.6%) had PSPA, 80 (26.2%) had NSP, and 156 (51.1%) had NSPA. Subjective TST and objective sleep parameters were significantly different among groups. No statistical differences in NOSIE-30 subscale and total scores were observed among groups. Sex, rapid eye movement (REM)/TST (%), sleep efficiency, number of awakenings, Non-rapid eye movement of stage 2 sleep (NREM)/TST (%), REM spontaneous arousal times, sleep latency, diagnosis, social competence, and manifest psychosis were associated with sleep misperception.

Conclusion

Sleep misperception is common in patients with anxiety-related disorders. Various sleep perception types have different PSG profiles, but similar personal and social behaviors. These data may be helpful to conduct personalized treatment.
Erdheim-Chester Disease Revealed by Central Positional Nystagmus: A Case Report
Authors: Weckel Alexandra , Gallois Yohann , Debs Rachel , Escude Bernard , Tremelet Laurent , Varenne Fanny , Biotti Damien , Chauveau Dominique , Bonneville Fabrice
Published: April 2022

Erdheim-Chester disease (ECD) is a rare histiocytic disorder, recently recognized to be neoplastic. The clinical phenotype of the disease is extremely heterogeneous, and depends on the affected organs, with the most frequently reported manifestations being bone pain, diabetes insipidus and neurological disorders including ataxia. In this article, we report on a case of a 48-year-old woman, whose initial symptom of gait instability was isolated. This was associated with positional nystagmus with central features: nystagmus occurring without latency, clinically present with only mild symptoms, and resistant to repositioning maneuvers. The cerebral MRI showed bilateral intra-orbital retro-ocular mass lesions surrounding the optic nerves and T2 hyperintensities in the pons and middle cerebellar peduncles. A subsequent CT scan of the chest abdomen and pelvis found a left “hairy kidney”, while 18 F-FDG PET-CT imaging disclosed symmetric 18F-FDG avidity predominant at the diametaphyseal half of both femurs. Percutaneous US-guided biopsy of perinephric infiltrates and the kidney showed infiltration by CD68(+), CD1a(-), Langerin(-), PS100(-) foamy histiocytes with BRAFV600E mutation. The combination of the different radiological abnormalities and the result of the biopsy confirmed the diagnosis of ECD. Many clinical and radiological descriptions are available in the literature, but few authors describe vestibulo-ocular abnormalities in patients with ECD. Here, we report on a case of ECD and provide a precise description of the instability related to central positional nystagmus, which led to the diagnosis of ECD.
Therapeutic Prospects of Polysaccharides for Ovarian Cancer
Authors: Wang Kaili , Cai Mengcheng , Sun Shuai , Cheng Wen , Zhai Dongxia , Ni Zhexin , Yu Chaoqin
Published: April 2022

Ovarian cancer (OC) is ranked as the leading cause of death among cancers of the female reproductive tract. First-line platinum treatment faces the severe challenges associated with the patient relapse and poor prognosis. Thus, it is imperative to develop natural antitumor drugs for OC with high efficacy. Natural polysaccharides have significant biological activities and antitumor effects. Our work has demonstrated that polysaccharides play key roles by inhibiting the cell proliferation and growth, regulating the tumor cell cycle, inducing apoptosis, suppressing the tumor cell migration and invasion, improving the immunomodulatory activities, and enhancing the efficacy of chemotherapy (cisplatin) in OC, which provide powerful evidence for the application of polysaccharides as novel anticancer agents, supplementary remedies, and adjunct therapeutic agents alone or in combination with cisplatin for preventing and treating the OC.
Percentage of Tumor Invasion at Pretreatment High-Resolution Magnetic Resonance Imaging: Associating With Aggressive and Tumor Response in Chinese T3 Rectal Cancer-Preliminary Results
Authors: Hu Xiaoxin , Li Jianwen , Sun Yinan , Sun Yiqun , Tong Tong
Published: April 2022

Purpose

The purpose of the study was to assess the ability of percentage of tumor invasion (PTI) of T3 rectal cancer on pretreatment MRI as an imaging biomarker to reflect aggressiveness and to predict tumor response after neoadjuvant chemoradiation (NCRT) in Chinese population.

Methods

A total of 107 Chinese rectal cancer patients who underwent pretreatment MRI staging as T3 were included. The extramural depth of tumor invasion (EMD), the distance between outer border of muscularis propria (MP) and mesorectal fascia (MRF) we called “thickness of the mesorectum (TM)”) at the same slice and direction were measured at pretreatment MRI, and PTI was equal to EMD/TM, was calculated. The EMD and PTI of subgroups based on pretreatment CEA, CA19-9 levels; N category and pathological complete response (pCR) were compared. The parameters, which described tumor invasion, were compared between pCR and non-pCR group. Student t-tests and logistic analysis were applied.

Results

The pretreatment PTI was higher in CEA ≥5.2 ng/ml patients (58.52% ± 27.68%) than in CEA <5.2 ng/ml patients (47.27% ± 24.15%) (p = 0.034). The pretreatment EMD in non-pCR group (7.21 ± 2.85 mm) was higher than in pCR group (6.14 ± 3.56 mm) (p = 0.049). The pretreatment PTI in non-pCR group (57.4% ± 26.4%) was higher than in pCR group (47.3% ± 29.1%) (p = 0.041). Compared with patients with PTI ≥50%, MRF (+), more patients with PTI <50%, MRF (−) showed pCR (OR = 8.44, p = 0.005; OR = 6.32, p = 0.024).

Conclusion

The PTI obtained at pretreatment MRI may serve as an imaging biomarker to reflect tumor aggressiveness and predict which T3 rectal cancer patients may benefit from NCRT in Chinese population.
Machine Learning-Based Prediction of Pathological Upgrade From Combined Transperineal Systematic and MRI-Targeted Prostate Biopsy to Final Pathology: A Multicenter Retrospective Study
Authors: Zhuang Junlong , Kan Yansheng , Wang Yuwen , Marquis Alessandro , Qiu Xuefeng , Oderda Marco , Huang Haifeng , Gatti Marco , Zhang Fan , Gontero Paolo , Xu Linfeng , Calleris Giorgio , Fu Yao , Zhang Bing , Marra Giancarlo , Guo Hongqian
Published: April 2022

Objective

This study aimed to evaluate the pathological concordance from combined systematic and MRI-targeted prostate biopsy to final pathology and to verify the effectiveness of a machine learning-based model with targeted biopsy (TB) features in predicting pathological upgrade.

Materials and Methods

All patients in this study underwent prostate multiparametric MRI (mpMRI), transperineal systematic plus transperineal targeted prostate biopsy under local anesthesia, and robot-assisted laparoscopic radical prostatectomy (RARP) for prostate cancer (PCa) sequentially from October 2016 to February 2020 in two referral centers. For cores with cancer, grade group (GG) and Gleason score were determined by using the 2014 International Society of Urological Pathology (ISUP) guidelines. Four supervised machine learning methods were employed, including two base classifiers and two ensemble learning-based classifiers. In all classifiers, the training set was 395 of 565 (70%) patients, and the test set was the remaining 170 patients. The prediction performance of each model was evaluated by area under the receiver operating characteristic curve (AUC). The Gini index was used to evaluate the importance of all features and to figure out the most contributed features. A nomogram was established to visually predict the risk of upgrading. Predicted probability was a prevalence rate calculated by a proposed nomogram.

Results

A total of 515 patients were included in our cohort. The combined biopsy had a better concordance of postoperative histopathology than a systematic biopsy (SB) only (48.15% vs. 40.19%, p = 0.012). The combined biopsy could significantly reduce the upgrading rate of postoperative pathology, in comparison to SB only (23.30% vs. 39.61%, p < 0.0001) or TB only (23.30% vs. 40.19%, p < 0.0001). The most common pathological upgrade occurred in ISUP GG1 and GG2, accounting for 53.28% and 20.42%, respectively. All machine learning methods had satisfactory predictive efficacy. The overall accuracy was 0.703, 0.768, 0.794, and 0.761 for logistic regression, random forest, eXtreme Gradient Boosting, and support vector machine, respectively. TB-related features were among the most contributed features of a prediction model for upgrade prediction.

Conclusion

The combined effect of SB plus TB led to a better pathological concordance rate and less upgrading from biopsy to RP. Machine learning models with features of TB to predict PCa GG upgrading have a satisfactory predictive efficacy.
Macrophage and T-Cell Infiltration and Topographic Immune Cell Distribution in Non-Melanoma Skin Cancer of the Head and Neck
Authors: Frohwitter Gesche , Kerta Marie , Vogl Christoph , Geppert Carol Immanuel , Werry Jan-Erik , Ries Jutta , Kesting Marco , Weber Manuel
Published: April 2022

Non-melanoma skin cancer (NMSC) is a heterogeneous tumor entity that is vastly determined by age and UV-light exposure leading to a great mutational burden in cancer cells. However, the success of immune checkpoint blockade in advanced NMSC and the incidence and disease control rates of NMSC in organ transplant recipients compared to immunologically uncompromised patients point toward the emerging importance of the immunologic activity of NMSC. To gain first insight into the role of T-cell and macrophage infiltration in NMSC of the head and neck and capture their different immunogenic profiles, which appear to be highly relevant for the response to immunotherapy, we conducted a whole slide analysis of 107 basal cell carcinoma (BCC) samples and 117 cutaneous squamous cell carcinoma (cSCC) samples. The CD8+ and CD68+ immune cell expression in both cancer types was evaluated by immunohistochemistry and a topographic distribution profile, and the proportion of both cell populations within the two tumor entities was assessed. The results show highly significant differences in terms of CD8+ T-cell and CD68+ macrophage infiltration in BCC and cSCC and indicate cSCC as a highly immunogenic tumor. Yet, BCC presents less immune cell infiltration; the relation between the immune cells compared to cSCC does not show any significant difference. These findings help explain disparities in local aggressiveness, distant metastasis, and eligibility for immune checkpoint blockade in both tumor entities and encourage further research.
Dual-Branch Convolutional Neural Network Based on Ultrasound Imaging in the Early Prediction of Neoadjuvant Chemotherapy Response in Patients With Locally Advanced Breast Cancer
Authors: Xie Jiang , Shi Huachan , Du Chengrun , Song Xiangshuai , Wei Jinzhu , Dong Qi , Wan Caifeng
Published: April 2022

The early prediction of a patient’s response to neoadjuvant chemotherapy (NAC) in breast cancer treatment is crucial for guiding therapy decisions. We aimed to develop a novel approach, named the dual-branch convolutional neural network (DBNN), based on deep learning that uses ultrasound (US) images for the early prediction of NAC response in patients with locally advanced breast cancer (LABC). This retrospective study included 114 women who were monitored with US during pretreatment (NAC pre) and after one cycle of NAC (NAC1). Pathologic complete response (pCR) was defined as no residual invasive carcinoma in the breast. For predicting pCR, the data were randomly split into a training set and test set (4:1). DBNN with US images was proposed to predict pCR early in breast cancer patients who received NAC. The connection between pretreatment data and data obtained after the first cycle of NAC was considered through the feature sharing of different branches. Moreover, the importance of data in various stages was emphasized by changing the weight of the two paths to classify those with pCR. The optimal model architecture of DBNN was determined by two ablation experiments. The diagnostic performance of DBNN for predicting pCR was compared with that of four methods from the latest research. To further validate the potential of DBNN in the early prediction of NAC response, the data from NAC pre and NAC1 were separately assessed. In the prediction of pCR, the highest diagnostic performance was obtained when combining the US image information of NAC pre and NAC1 (area under the receiver operating characteristic curve (AUC): 0.939; 95% confidence interval (CI): 0.907, 0.972; F1-score: 0.850; overall accuracy: 87.5%; sensitivity: 90.67%; and specificity: 85.67%), and the diagnostic performance with the combined data was superior to the performance when only NAC pre (AUC: 0.730; 95% CI: 0.657, 0.802; F1-score: 0.675; sensitivity: 76.00%; and specificity: 68.38%) or NAC1 (AUC: 0.739; 95% CI: 0.664, 0.813; F1-score: 0.611; sensitivity: 53.33%; and specificity: 86.32%) (p<0.01) was used. As a noninvasive prediction tool, DBNN can achieve outstanding results in the early prediction of NAC response in patients with LABC when combining the US data of NAC pre and NAC1.
Choline Kinase Alpha2 Promotes Lipid Droplet Lipolysis in Non-Small-Cell Lung Carcinoma
Authors: Zhu Rongxuan , Yang Yannan , Shao Fei , Wang Juhong , Gao Yibo , He Jie , Lu Zhimin
Published: April 2022

Background

Rapid tumor growth inevitably results in energy stress, including deficiency of glutamine, a critical amino acid for tumor cell proliferation. However, whether glutamine deficiency allows tumor cells to use lipid droplets as an energy resource and the mechanism underlying this potential regulation remain unclear.

Methods

We purified lipid droplets from H322 and H358 human non-small-cell lung cancer (NSCLC) cells under glutamine deprivation conditions and performed immunoblotting to determine the binding of choline kinase (CHK) α2 to lipid droplets. Immunofluorescence was used to quantify lipid droplet numbers and sizes. Immunoprecipitation and immunoblotting were performed to examine AMPK activation and CHKα2 phosphorylation. Cellular fatty acid levels, mitochondrial acetyl coenzyme A and ATP production, and cell apoptosis and proliferation were measured. Immunohistochemical analyses were performed to determine the expression levels of ACC pS79 and CHKα2 pS279 in tumor specimens from NSCLC patients. The prognostic value of ACC pS79 and CHKα2 pS279 was assessed using the Kaplan-Meier method and Cox regression models.

Results

Glutamine deficiency induces AMPK-mediated CHKα2 S279 phosphorylation, which promotes the binding of CHKα2 to lipid droplets, resulting in recruitment of cytosolic lipase ATGL and autophagosomes and subsequent lipolysis of lipid droplets to sustain tumor cell survival and proliferation. In addition, the levels of ACC pS79 and CHKα S279 were much higher in human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other. Notably, ACC pS79 and CHKα pS279 expression levels alone were associated with poor prognosis of NSCLC patients, and combined values of both phosphorylation levels were correlated with worse prognosis of the patients.

Conclusion

CHKα2 plays a critical role in lipolysis of lipid droplets in NSCLC. ACC pS79 and CHKα2 pS279 alone or in combination can be used as prognostic markers in NSCLC.
Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance
Authors: Mahfoudhi Emna , Ricordel Charles , Lecuyer Gwendoline , Mouric Cécile , Lena Hervé , Pedeux Rémy
Published: April 2022

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are currently recommended as first-line treatment for advanced non-small-cell lung cancer (NSCLC) with EGFR-activating mutations. Third-generation (3rd G) EGFR-TKIs, including osimertinib, offer an effective treatment option for patients with NSCLC resistant 1st and 2nd EGFR-TKIs. However, the efficacy of 3rd G EGFR-TKIs is limited by acquired resistance that has become a growing clinical challenge. Several clinical and preclinical studies are being carried out to better understand the mechanisms of resistance to 3rd G EGFR-TKIs and have revealed various genetic aberrations associated with molecular heterogeneity of cancer cells. Studies focusing on epigenetic events are limited despite several indications of their involvement in the development of resistance. Preclinical models, established in most cases in a similar manner, have shown different prevalence of resistance mechanisms from clinical samples. Clinically identified mechanisms include EGFR mutations that were not identified in preclinical models. Thus, NRAS genetic alterations were not observed in patients but have been described in cell lines resistant to 3rd G EGFR-TKI. Mainly, resistance to 3rd G EGFR-TKI in preclinical models is related to the activation of alternative signaling pathways through tyrosine kinase receptor (TKR) activation or to histological and phenotypic transformations. Yet, preclinical models have provided some insight into the complex network between dominant drivers and associated events that lead to the emergence of resistance and consequently have identified new therapeutic targets. This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies.
Core Needle Biopsy Can Early and Precisely Identify Large Thyroid Masses
Authors: Matrone Antonio , De Napoli Luigi , Torregrossa Liborio , Aghababyan Aleksandr , Papini Piermarco , Ambrosini Carlo Enrico , Cervelli Rosa , Ugolini Clara , Basolo Fulvio , Molinaro Eleonora , Elisei Rossella , Materazzi Gabriele
Published: April 2022

Background

Large thyroid masses, particularly if rapidly growing, are often characterized by compression and infiltration of the vital structures of the neck. Therefore, an early and precise diagnosis, not only of malignancy but also of histotype, is mandatory to set up the right therapy. The aim of this study was to evaluate the diagnostic performance of fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) in this setting.

Patients and Methods

We prospectively evaluated 95 patients with large and rapidly growing thyroid masses admitted to the University Hospital of Pisa between April 2014 and January 2020. All patients were submitted to FNAC and CNB in the same session. The ability of both procedures to diagnose the malignancy of the lesions, particularly the histotype, and to obtain sufficient material to perform molecular analysis was evaluated.

Results

FNAC obtained adequate tumor sample to reach a diagnosis in 76 of 95 (80%) patients, while a higher percentage was obtained with CNB (92/95, 96.8%). FNAC was able to identify the malignancy of the lesion in 74 of 95 (77.9%) cases, but only in 16 of 74 (21.6%) cases was it able to define the histotype. CNB was able to define the malignancy of the lesion in all but three cases (92/95, 96.8%), and in all specimens, the histotype was identified. Moreover, in all cases, the material extracted from CNB was optimal to perform molecular analysis. No surgery-related complications were experienced with both procedures.

Conclusions

CNB is a rapid and safe procedure with higher performance compared to FNAC in identifying the histotype of large and rapidly growing thyroid masses. Moreover, adequate material can be obtained to characterize the molecular profile for the treatment of potentially lethal cancers. In the era of precision medicine, CNB should be introduced in routine clinical practice as a key procedure for an early diagnosis and therapy of these diseases.
Pyrotinib-Containing Neoadjuvant Therapy in Patients With HER2-Positive Breast Cancer: A Multicenter Retrospective Analysis
Authors: Mao Xiaoyun , Lv Pengwei , Gong Yiping , Wu Xiujuan , Tang Peng , Wang Shushu , Zhang Dianlong , You Wei , Wang Ouchen , Zhou Jun , Li Jingruo , Jin Feng
Published: April 2022

Background

Pyrotinib, a small-molecule tyrosine kinase inhibitor, has been investigated as a component of neoadjuvant therapy in phase 2 trials of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study aimed to evaluate the effectiveness and safety of pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer in the real-world setting.

Methods

Data of 97 patients with HER2-positive breast cancer from 21 centers across China treated with pyrotinib-containing neoadjuvant therapy were reviewed. Neoadjuvant therapy consisted of taxane/carboplatin/trastuzumab plus pyrotinib (TCbH+Py, 30 [30.9%]), anthracycline/cyclophosphamide followed by taxane/trastuzumab plus pyrotinib (AC-TH+Py) or taxane followed by anthracycline/cyclophosphamide/trastuzumab plus pyrotinib (T-ACH+Py, 29 [29.9%]), taxane/trastuzumab plus pyrotinib (TH+Py, 23 [23.7%]), and other pyrotinib-containing neoadjuvant treatment (15 [15.5%]). The primary outcome was breast pathological complete response (bpCR, ypT0/is) rate. Secondary outcomes included total pathological complete response (tpCR, ypT0/is ypN0) rate, objective response rate (ORR), and the incidence of preoperative adverse events.

Results

The ORR of pyrotinib-containing neoadjuvant therapy was 87.6% (85/97). The bpCR and tpCR rates were 54.6% (95% confidence interval [CI], 44.2%-64.7%) and 48.5% [95% CI, 38.2%-58.8%], respectively. The most common grade 3 or 4 treatment-related adverse events included diarrhea (15 [15.5%]), decreased hemoglobin (nine [9.3%]), and decreased neutrophil count (eight [8.2%]). No treatment-related deaths occurred.

Conclusion

Pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer shows favorable effectiveness with manageable toxicity in the real-world setting. Trastuzumab plus pyrotinib may be a novel option of dual HER2-targeted blockade.
A Low Membrane Hsp70 Expression in Tumor Cells With Impaired Lactate Metabolism Mediates Radiosensitization by NVP-AUY922
Authors: Schwab Melissa , Multhoff Gabriele
Published: April 2022

As overexpression and membrane localization of stress proteins together with high lactate levels promote radioresistance in tumor cells, we studied the effect of the Hsp90 inhibitor NVP-AUY922 on the cytosolic and membrane expression of heat shock proteins (HSPs) and radiosensitivity in murine melanoma (B16F10) and human colorectal (LS174T) wildtype (WT) and lactate dehydrogenases A/B double knockout (LDH−/−) tumor cells. Double knockout for LDHA/B has been found to reduce cytosolic as well as membrane HSP levels, whereas treatment with NVP-AUY922 stimulates the synthesis of Hsp27 and Hsp70, but does not affect membrane Hsp70 expression. Despite NVP-AUY922-inducing elevated levels of cytosolic HSP, radiosensitivity was significantly increased in WT cells and even more pronounced in LDH−/− cells. An impaired lipid metabolism in LDH−/− cells reduces the Hsp70 membrane-anchoring sphingolipid globotriaosylceramide (Gb3) and thereby results in a decreased Hsp70 cell surface density on tumor cells. Our results demonstrate that the membrane Hsp70 density, but not cytosolic HSP levels determines the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in LDH−/− cells.
Development and External Validation of a Simple-To-Use Dynamic Nomogram for Predicting Breast Malignancy Based on Ultrasound Morphometric Features: A Retrospective Multicenter Study
Authors: Zhang Qingling , Zhang Qinglu , Liu Taixia , Bao Tingting , Li Qingqing , Yang You
Published: April 2022

Background

With advances in high-throughput computational mining techniques, various quantitative predictive models that are based on ultrasound have been developed. However, the lack of reproducibility and interpretability have hampered clinical use. In this study, we aimed at developing and validating an interpretable and simple-to-use US nomogram that is based on quantitative morphometric features for the prediction of breast malignancy.

Methods

Successive 917 patients with histologically confirmed breast lesions were included in this retrospective multicentric study and assigned to one training cohort and two external validation cohorts. Morphometric features were extracted from grayscale US images. After feature selection and validation of regression assumptions, a dynamic nomogram with a web-based calculator was developed. The performance of the nomogram was assessed with respect to calibration, discrimination, and clinical usefulness.

Results

Through feature selection, three morphometric features were identified as being the most optimal for predicting malignancy, and all regression assumptions of the prediction model were met. Combining all these predictors, the nomogram demonstrated a good discriminative performance in the training cohort and in the two external validation cohorts with AUCs of 0.885, 0.907, and 0.927, respectively. In addition, calibration and decision curves analyses showed good calibration and clinical usefulness.

Conclusions

By incorporating US morphometric features, we constructed an interpretable and easy-to-use dynamic nomogram for quantifying the probability of breast malignancy. The developed nomogram has good generalization abilities, which may fit into clinical practice and serve as a potential tool to guide personalized treatment. Our findings show that quantitative morphometric features from different ultrasound machines and systems can be used as imaging surrogate biomarkers for the development of robust and reproducible quantitative ultrasound dynamic models in breast cancer research.
Trends in the Incidence and Survival Rates of Primary Ovarian Clear Cell Carcinoma Compared to Ovarian Serous Carcinoma in Korea
Authors: Kim Se Ik , Ha Hyeong In , Eoh Kyung Jin , Lim Jiwon , Won Young-Joo , Lim Myong Cheol
Published: April 2022

Objective

To compare the incidence and survival rates of primary ovarian clear cell carcinoma (OCCC) and ovarian serous carcinoma (OSC) from a nationwide collected database.

Methods

We extracted information of patients with primary OCCC and OSC from the Korea Central Cancer Registry recorded between 1999 and 2018, including age at diagnosis and the Surveillance, Epidemiology, and End Results summary stage. Age-standardized incidence rates (ASRs) and annual percent changes (APCs) were calculated. Baseline characteristics and overall survival (OS) were compared between the OCCC and OSC groups.

Results

Overall, the incidence rate of primary OCCC increased markedly from 1999 (ASR, 0.16/100,000) to 2018 (0.76/100,000) (APC, 7.85%; P<0.0001). Patients with OCCC were significantly younger and had early-stage disease more frequently than those with OSC. Patients diagnosed with OCCC before the age of 50 showed better OS than those diagnosed after the age of 50 (P=0.0048). The 5-year OS of the OCCC group did not differ by study period [73.5% (1999–2008) vs. 75.4% (2009–2018), P=0.3187], whereas the 5-year OS of the OSC group improved from 54.4% to 58% (P=0.0003).

Conclusions

Our nationwide registry-based study demonstrated that the incidence of OCCC in Korea increased significantly from 1999 to 2018. Early-stage OCCC had a relatively good prognosis, but advanced-stage OCCC had a worse OS than advanced-stage OSC. Therefore, the development of optimal treatment strategies for OCCC is warranted.
Impact of Infant Thoracic Non-cardiac Perioperative Critical Care on Homotopic-Like Corpus Callosum and Forebrain Sub-regional Volumes
Authors: Kagan Mackenzie Shea , Mongerson Chandler R. L. , Zurakowski David , Bajic Dusica
Published: April 2022

Previously, we reported quantitatively smaller total corpus callosum (CC) and total forebrain size in critically ill term-born and premature patients following complex perioperative critical care for long-gap esophageal atresia (LGEA) that included Foker process repair. We extended our cross-sectional pilot study to determine sub-regional volumes of CC and forebrain using structural brain MRI. Our objective was to evaluate region-specific CC as anin-vivomarker for decreased myelination and/or cortical neural loss of homotopic-like sub-regions of the forebrain. Term-born (n= 13) and premature (n= 13) patients, and healthy naïve controls (n= 21) <1-year corrected age underwent non-sedated MRI using a 3T Siemens scanner, as per IRB approval at Boston Children's Hospital following completion of clinical treatment for Foker process. We used ITK-SNAP (v.3.6) tomanuallysegment six sub-regions of CC and eight sub-regions of forebrain as per previously reported methodology. Group differences were assessed using a general linear model univariate analysis with corrected age at scan as a covariate. Our analysis implicates globally smaller CC and forebrain with sub-region II (viz. rostral body of CC known to connect to pre-motor cortex) to be least affected in comparison to other CC sub-regions in LGEA patients. Our report of smaller subgenual forebrain implicates (mal)adaptation in limbic circuits development in selected group of infant patients following LGEA repair. Future studies should include diffusion tractography studies of CC in further evaluation of what appears to represent global decrease in homotopic-like CC/forebrain size following complex perioperative critical care of infants born with LGEA.
A Long-Term Study of Alignment Correction Following Proximal Femoral Varus Osteotomy and Pemberton Osteotomy in Children With Legg–Calvé–Perthes Disease and Developmental Dysplasia of the Hip
Authors: Liu Kuei-Yu , Wu Kuan-Wen , Lee Chia-Che , Lin Sheng-Chieh , Kuo Ken N. , Chang Jia-Feng , Wang Ting-Ming
Published: April 2022

Proximal femoral varus osteotomy (PFVO) is a common procedure performed in children with developmental dysplasia of the hip (DDH) and Legg–Calvé–Perthes disease (LCPD). However, the long-term effect on angular deformities of the knees and ankles following PFVO remains controversial. This study investigated the relationship between PFVO and alignment changes in the knee and ankle after the procedure. Twenty-five patients undergoing PFVO procedure with a minimum 4-year evaluation period were enrolled in the study, including 14 unilateral LCPD and 11 unilateral DDH. The standing scanogram examinations were collected before the operation, immediately following surgery, after a 1-year follow-up, after a 3-year follow-up, and at the final visit to the clinic. The radiographic parameters included leg length, femoral neck-shaft angle (FNSA), femorotibial angle (FTA), mechanical axis deviation (MAD), tibiotalar angle (TTA), and mechanical lateral distal femoral angle (mLDFA). At the final examination, FNSA demonstrated insignificant change between the operative and non-operative limbs in the DDH group. Compared with the postoperative result, FNSA significantly improved in the LCPD group (p = 0.039). Both groups did not develop statistical significance in TTA, mLDFA, MAD, and leg length discrepancy after more than a 5-year follow-up. From a biomechanical perspective that the foot passes more medial to the knee under the center of leg mass, varus knee was prone to develop. In order to correct the mechanical axis, the knee reverted to a valgus position gradually. Our study indicates that patients with LCPD or DDH receiving PFVO and Pemberton osteotomy narrow the gap of angular growth in knees and ankles between the operative and non-operative limbs after a long-term follow-up.
Clinical and Microbial Etiology Characteristics in Pediatric Urinary Tract Infection
Authors: Lu Jiandong , Liu Xiaozhu , Wei Yi , Yu Chengjun , Zhao Jie , Wang Ling , Hu Yang , Wei Guanghui , Wu Shengde
Published: April 2022

Background

Urinary tract infection (UTI) is a common occurrence in children. UTI and urological malformations are intimately linked. However, whether urinary tract malformations affect the clinical features of pediatric UTI remains unclear. The purpose of this study was to characterize the clinical features and microbial etiology of UTI in children.

Methods

We retrospectively reviewed the records of 741 patients with UTI treated at the Chongqing Medical University Affiliated Children's Hospital between 2015 and 2020. Patients with and without urological malformations were compared using propensity score matching (PSM).

Results

Escherichia coli was the most common causative microorganism of UTI, accounting for 40.5% of infections. One hundred twenty-two patients (16.5%) had urological malformations. PSM identified 122 matched pairs of patients with or without urological malformations. The proportion of patients with UTI caused by atypical microorganisms was significantly higher in patients with urological malformations (P = 0.048). Children with urological malformations showed longer duration of intravenous antibiotic treatment (P = 0.010), higher cost of treatment (P < 0.001), and higher prevalence of recurrence (23.8 vs. 10.7%, P < 0.001), compared with the normal group.

Conclusion

Children with urological malformations are more likely to develop UTI with atypical microorganisms. Appropriate imaging examination and urine culture are strongly recommended for the diagnosis and management of pediatric UTI.
Rhamnose Is Superior to Mannitol as a Monosaccharide in the Dual Sugar Absorption Test: A Prospective Randomized Study in Children With Treatment-Naïve Celiac Disease
Authors: Holtz Lori R. , Hoffmann Julie , Linneman Laura , He Mai , Smyrk Thomas C. , Liu Ta-Chiang , Shaikh Nurmohammad , Rodriguez Cynthia , Dyer Roy B. , Singh Ravinder J. , Faubion William A.
Published: April 2022

Background and Aim

We sought to correlate two different measures of gut permeability [lactulose:mannitol (L:M) and lactulose:rhamnose (L:R)] to the severity of duodenal histopathology in children with and without elevated antibodies to tissue transglutaminase (tTG). A secondary objective was to correlate gut permeability with celiac disease (CD) serology and indices of inflammation and bacterial product translocation.

Methods

We prospectively randomized children undergoing endoscopy with abnormal (n = 54) and normal (n = 10) concentrations of circulating antibodies to tTG, to either L:M or L:R. Biopsies underwent modified Marsh scoring to measure mucosal injury. Circulating anticore Escherichia coli lipopolysaccharide (LPS) IgG, α-1 acid glycoprotein, LPS-binding protein, and C-reactive protein concentrations were measured by enzyme immunoassays.

Results

Of the 54 cases with positive celiac serology, 31 and 69% had modified Marsh 0/1 scores or ≥3a, respectively. Circulating tTG IgA correlated with the modified Marsh score (p = 0.03). L:R, but not L:M or percent L excreted, differed according to modified Marsh scores (p = 0.01). There was no significant association between any systemic marker of inflammation or gut injury, and modified Marsh scores. Concerningly, most participants had evidence of urinary M before the challenge sugar was administered.

Conclusions

L:R, but not L:M, is associated with modified Marsh scores in children undergoing small bowel biopsy for suspected CD. Despite increased intestinal permeability, we see scant evidence of systemic exposure to gut microbes in these children. Gut permeability testing with L:R may predict which patients with abnormal celiac serology will have biopsy evidence for celiac disease and reduce the proportion of such patients undergoing endoscopy whose Marsh scores are ≤1. M should not be used as a monosaccharide for permeability testing in children.
Preoperative MRI Evaluation of Hand Vessels in Children With Congenital Syndactyly Malformation by a Contrast-Enhanced Three-Dimensional Water-Selective Cartilage Scan
Authors: Liu Bo , Cai Jinhua , Tian Xiaofei , Huang Kaiping , Liu Daisong , Zheng Helin , Wang Longlun , Yang Jing , Xu Hongrong
Published: April 2022

Background

It is crucial to preoperatively assess the arteries of the hands in congenital syndactyly malformation (CSM) patients because this information can affect the therapeutic outcome and prognosis.

Objective

To investigate the value of a contrast-enhanced three-dimensional water-selective cartilage scan for the preoperative evaluation of CSM in children.

Materials and Methods

Contrast-enhanced three-dimensional water-selective cartilage scan 3.0 T magnetic resonance imaging (MRI) performed in 16 clinically diagnosed CSM patients with 17 affected hands. The arteries of the hands were displayed with a focus on the bifurcation position of the common palmar digital arteries (CPDAs) and the maturity of the proper palmar digital arteries (PPDAs). The MRI results were interpreted by consensus between two experienced pediatric radiologists with 10 years of MRI experience each. The MRI findings were compared with the operation results.

Results

Of 51 CPDAs in the 17 affected hands, MRI showed that 30 had an abnormal bifurcation position and 20 had a normal position, and of the 102 PPDAs, 14 were shown to have an abnormal maturity and 85 a normal state, which were confirmed by surgery. The accuracy, sensitivity and specificity for determining the bifurcation position of the CPDAs based on MR maximum intensity projection reconstructed images were 98.04% (50/51), 96.77% (30/31) and 100% (20/20), respectively. The maturity of the PPDAs was judged by MR maximum intensity projection reconstructed images with an accuracy, sensitivity and specificity of 97.06% (99/102), 82.35% (14/17) and 100% (85/85), respectively.

Conclusion

Contrast-enhanced three-dimensional water-selective cartilage scan has excellent performance in displaying the bifurcation position of the CPDAs and the maturity of the PPDAs and is of high value for the preoperative evaluation of CSM in children.
Comparative Efficacy of Chinese Herbal Injections for Septic Shock: A Bayesian Network Meta-Analysis of Randomized Controlled Trials
Authors: Huang Peiying , Chen Yan , Zhang Haobo , Chen Bojun , Zhao Shuai , Feng Yuchao , Lei Sisi , Wu Qihua
Published: April 2022

Background: Septic shock is associated with high morbidity and mortality. Studies have reported that Chinese herbal injections (CHIs) in combination with Western medicine (WM) were more favorable. However, the debate on optimal CHIs is ongoing. The objective of this study is to explore the comparative effectiveness of CHIs for septic shock.

Methods: We retrieved data from the English and Chinese databases with retrieval time from database inception to 30 September 2021. Network meta-analysis was performed, with evaluation of methodological quality among the included studies and assessment of strength of evidence among the outcomes.

Results: A total of 77 RCTs with 5,647 patients were included. All the studies were rated as some concerns. In terms of 28-days-mortality, Yiqifumai injection (YQFM)+WM, Shuxuetong injection (SXT)+WM, Xuebijing injection (XBJ)+WM, and Shenfu injection (SF)+WM were better than WM; YQFM + WM and SXT + WM were superior for Shenmai injection (SM)+WM; YQFM + WM was superior for SF + WM; YQFM + WM ranked first. Regarding ICU length of stay, SF + WM and XBJ + WM were better than WM; XBJ + WM was superior for SF + WM; XBJ + WM ranked first. Concerning hospital length of stay, Shenqifuzheng injection (SQFZ)+WM, Shengmai injection (SGM)+WM, and XBJ + WM had greater potential than WM and SF + WM; SQFZ + WM ranked first. As for SOFA score at 7-days, XBJ + WM and SF + WM were superior for WM; XBJ + WM was superior for SF + WM; XBJ + WM ranked first. Regarding procalcitonin level at 7-days, SF + WM, SM + WM, and Xiyanping injection (XYP)+WM were better than WM; XYP + WM was superior for SF + WM, SGM + WM, SM + WM, Danshen injection (DS)+WM, and XBJ + WM; XYP + WM ranked first. Concerning serum lactate level at 7-days, SF + WM and SM + WM were more effective than XBJ + WM and WM; SM + WM ranked first. The comparisons were rated as moderate (15.05%), low (40.86%), and very low quality (44.09%); the strength of evidence of ranking probability for hospital length of stay was low whereas the remaining outcomes were rated as very low.

Conclusions: CHIs combined with WM might have higher efficacies for septic shock than WM alone. YQFM, XBJ, SQFZ, XYP, SM, SGM, and SF may be the potential optimal CHIs for septic shock. More and better evidence is needed to validate the conclusions.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42021282958.
Goofballing of Opioid and Methamphetamine: The Science Behind the Deadly Cocktail
Authors: Hazani Hanis Mohammad , Naina Mohamed Isa , Muzaimi Mustapha , Mohamed Wael , Yahaya Mohamad Fairuz , Teoh Seong Lin , Pakri Mohamed Rashidi Mohamed , Mohamad Isa Mohd Fadzli , Abdulrahman Sundus Mansoor , Ramadah Ravi , Kamaluddin Mohammad Rahim , Kumar Jaya
Published: April 2022

Globally, millions of people suffer from various substance use disorders (SUD), including mono-and polydrug use of opioids and methamphetamine. Brain regions such as the cingulate cortex, infralimbic cortex, dorsal striatum, nucleus accumbens, basolateral and central amygdala have been shown to play important roles in addiction-related behavioral changes. Clinical and pre-clinical studies have characterized these brain regions and their corresponding neurochemical changes in numerous phases of drug dependence such as acute drug use, intoxication, craving, withdrawal, and relapse. At present, many studies have reported the individual effects of opioids and methamphetamine. However, little is known about their combined effects. Co-use of these drugs produces effects greater than either drug alone, where one decreases the side effects of the other, and the combination produces a prolonged intoxication period or a more desirable intoxication effect. An increasing number of studies have associated polydrug abuse with poorer treatment outcomes, drug-related deaths, and more severe psychopathologies. To date, the pharmacological treatment efficacy for polydrug abuse is vague, and still at the experimental stage. This present review discusses the human and animal behavioral, neuroanatomical, and neurochemical changes underlying both morphine and methamphetamine dependence separately, as well as its combination. This narrative review also delineates the recent advances in the pharmacotherapy of mono- and poly drug-use of opioids and methamphetamine at clinical and preclinical stages.