bluuebunny/crossref_metadata_2025_split huggingface dataset:
An optimized ultra-deep massively parallel sequencing with unique molecular identifier tagging for detection and quantification of circulating tumor DNA from lung cancer patients.
Authors: Pham Hong-Anh Thi , Tran Le Son , Tran Uyen Vu , Tran Thanh-Truong , Nguyen Hoai-Nghia , Giang Hoa , Dang Anh-Thu Huynh , Le Dinh-Thong Vu , Nguyen Son-Lam Vu , Nguyen Ngoc-Vu Vu , Nguyen Vu Trieu , Vo Binh Thanh , Nguyen Nguyen Huu , Nguyen Chu Van , Pham Cam Phuong , Dang-Mai Anh Tuan , Dinh-Nguyen Thien Kim , Phan Van Hieu , Do Thuy Thanh , Dinh Kiet Truong 
Published: October 2019

55 Background: The identification and quantification of actionable mutations are of critical importance for effective genotype-directed therapies, prognosis and drug response monitoring in patients with non-small-cell lung cancer (NSCLC). Although tumor tissue biopsy remains the gold standard for diagnosis of NSCLC, the analysis of plasma circulating tumor DNA (ctDNA), known as liquid biopsy, has recently emerged as an alternative and noninvasive approach for exploring tumor genetic constitution. In this study, we developed a mutation detection approach for liquid biopsy using ultra-deep massively parallel sequencing (MPS) with unique molecular identifier (UID) tagging and evaluated its performance for the identification and quantification of tumor-derived mutations from plasma of patients with advanced NSCLC. Methods: Tissue biopsy and plasma samples were collected from a total of 58 patients diagnosed with NSCLC in Vietnam. Genetic alterations in four driver genes including EGFR, KRAS, NRAS and BRAF were identified by using ultra-deep MPS combined with UID tagging. Subsequently, the concordance rate of mutation testing between matched plasma and tissue samples was assessed. Additionally, a commercially available ddPCR (Bio-rad) assay was used to conduct a cross-platform comparison with ultra-deep MPS for the detection and quantification of the three most common actionable EGFR mutations (del19, L858R and T790M). Results: Compared to the mutations detected in paired tissue samples, the plasma based ultra-deep MPS achieved high concordance rate of 87.5%. Cross-platform comparison with droplet digital PCR demonstrated comparable detection performance (91.4% concordance, Cohen's kappa coefficient of 0.85 with 95% CI = 0.72 – 0.97) and great reliability in quantification of mutation allele frequency (Intraclass correlation coefficient of 0.96 with 95% CI = 0.90 – 0.98). Conclusions: Our results highlight the potential application of liquid biopsy using ultra-deep MPS as a routine assay in clinical practice for both detection and quantification of actionable mutation landscape in NSCLC patients.
Pancreatic cancer: Assessment of neoadjuvant chemotherapy outcome based on radiomics of pretreatment computed tomography.
Authors: Li Xiang , Tang Tianyu , Liang Tingbo , Bai Xueli 
Published: October 2019

56 Background: To evaluate contrast enhanced-computed tomography (CE-CT) features to predicting treatment response and survival after neoadjuvant chemotherapy (NAC) for patients with borderline resectable and locally advanced pancreatic cancer. Methods: Sixty-one patients with pancreatic cancer receiving NAC were enrolled and underwent pre-treatment abdominal CE-CT. The patients were divided into groups according to post-treatment tumor size changes. Based on the pretreatment CE-CT images, 396 radiomic features were extracted from three-dimensional regions of interest. The optimal features were selected and three supervised machine learning classifiers were developed. Finally, univariate and multivariate analyses were performed to evaluate the ability of the selected features to predict the histopathological response and outcome. Results: Nine, seven, and five radiomic features, respectively, were selected as optimal features in three experiments. Two features, Haralick Entropy and Histogram Entropy, were consistent among the experiments and both were higher in patients with enlarged tumors. Moreover, a lower Histogram Entropy score was significantly associated with a better histopathological response (p = 0.008) and smaller tumor size (p = 0.041) in patients after tumor resection. In univariate Cox regression analysis, lower Histogram Entropy (p = 0.006) and lower Haralick Entropy (p = 0.001) predicted a better prognosis. Meanwhile, lower Haralick Entropy (p = 0.048) was an independent predictor of longer survival time in multivariate Cox regression analysis. Conclusions: Radiomic features are strongly correlated with NAC treatment response and prognosis in pancreatic cancer, suggesting the potential of imaging radiomics to help tailor the treatment of pancreatic cancer in the era of personalized medicine.
Analysis of serum by Raman spectroscopy finds changes in blood metabolites of cancer patients in 45 seconds.
Authors: Ito Hiroaki , Miyazaki Tomokazu , Uragami Naoyuki , Yokoyama Noboru , Inoue Haruhiro 
Published: October 2019

57 Background: Cancer is an important disease that accounts for many of the causes of death worldwide, and early diagnosis is important for improving treatment results. In medical care, blood test is a simple and excellent test method, but there is still no cancer blood diagnosis method with high accuracy that can be performed in general hospitals. We are trying to detect cancer patients by analyzing serum using Raman spectroscopy. Methods: Among the outpatients who underwent upper gastrointestinal endoscopy or colonoscopy, 236 subjects who agreed to participate in the study were included. Raman scattering spectra were measured by irradiating a 1064 nm wavelength laser for 15 seconds with serum collected from the subject before endoscopic examination. The average value measured a total of three times was taken as the measured value, and the three measured values were averaged to obtain the value of each examinee. In the obtained Raman scattering spectra, the scattering spectral intensities of the wavelength originating in the specific molecules were analyzed. Results: We were able to obtain clear Raman scattering spectra of all serum samples. When comparing the Raman scattering spectral intensities of the wavelength originating in specific molecules, a large number of serum measurement values were gathered at the center, and the measurement values of the cancer patients' serum were over low or high. By setting the appropriate cutoff line, cancer patients (gastric cancer or colon cancer) and non-cancerous persons could be relatively clearly distinguished (sensitivity, 100%; Specificity, 75%). Conclusions: Our micro Raman system is able to acquire Raman scattering spectra of serum samples. Furthermore, it has been suggested that cancer diagnosis using serum could be possible by comparing the scattering spectral intensities caused by specific molecules. Clinical trial information: UMIN000034306.
Plasma circulating tumor DNA-based genetic profiling of lung cancer patients in Vietnam using ultra-deep massive parallel sequencing with unique identifier tagging.
Authors: Do Huy Phuoc , Nguyen Thao Thanh Tran , Tran Uyen Vu , Tran Thanh-Truong , Dang Anh-Thu Huynh , Nguyen Vu Trieu , Nguyen Chu Van , Do Han Ngoc , Phan Minh-Duy , Tran Le Son , Nguyen Hoai-Nghia , Giang Hoa 
Published: October 2019

58 Background: Lung cancer is by far the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Genotype-directed therapy becomes a promising method for cancer treatment beside surgery and chemo-radiotherapy. Liquid biopsy using massive parallel sequencing has emerged as a non-invasive alternative procedure in profiling cancer driver mutations. In this study, we report the spectrum of clinically actionable mutations in plasma circulating tumor DNA of 299 non-small cell lung cancer patients using ultra-deep massive parallel sequencing with unique identifier tagging. Methods: Plasma circulating tumor DNA was extracted, ligated with unique identifier (Swift Bioscience), enriched of the target coding regions of EGFR, KRAS, NRAS, BRAF and the breakpoints of ALK, ROS1 (IDT) and sequenced using NextSeq 550 (Illumina) at mean coverage depth of 20,000X. Results: Out of 299 patients tested, 128 (42,8%) carried driver mutations. Genetic alterations were identified in EGFR (79 samples, 26,4%), KRAS (30 samples, 10%), ALK (7 samples, 2,34%), ROS1 (6 samples, 2%), BRAF (3 samples, 1%). There was no sample with NRAS mutation. In 79 EGFR-cases, there were 23 carry two pathogenic variants. 28 mutation types of EGFR were found including 19 indels and 9 missense variants L858R and T790M were the major ones. One case was found with concomitant EGFR and BRAF. Our study showed the spectrum and frequency of the cancer driver mutations detected in liquid biopsy was correlated to those detected in tissue biopsy samples. Conclusions: For the first time the spectrum of mutation types in liquid biopsy of Vietnamese NSCLC patients were investigated and showed the correlation with those detected in tissue biopsy samples.
Body mass index in non-small cell lung cancer patients treated with anti-PD-1 immune checkpoint inhibitors.
Authors: Tateishi Akiko , Horinouchi Hidehito , Masuda Ken , Jo Hitomi , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Yamamoto Noboru , Ohe Yuichiro 
Published: October 2019

68 Background: Previous retrospective analyses have revealed higher response rates and a trend towards longer progression-free survival (PFS) and overall survival (OS) in response to immune checkpoint inhibitors (ICIs) in overweight patients. There are few reports concerning the association between the overweight state and the efficacy of ICIs specifically in non-small cell lung cancer (NSCLC) patients. We investigated the association between the body mass index (BMI) and the efficacy of ICIs in patients with NSCLC. Methods: Patients with advanced NSCLC who received ICI therapy (nivolumab or pembrolizumab) at the National Cancer Center Hospital from January 2016 to December 2018 were included in this retrospective cohort study. Based on their BMI, the patients were categorized into the overweight (A) group (BMI ≥25) and the non-overweight (B) group (BMI < 25). The PFS was compared between the two groups as the primary outcome. Results: Data of a total of 323 patients (median age, 63 years) were analyzed; 87 (26.9%)/43 (13.3%)/193 (59.8%) patients received pembrolizumab as 1st line therapy, pembrolizumab as 2nd line therapy, and nivolumab, respectively. Tumor proportion score was ≥50% in 58.4% (139/238) patients. The ECOG-PS was ≥2 in 37 patients (11.5%). The median body weight was 58.1, and the median BMI was 21.4. Of the 323 patients, 46 (14.2%) were categorized into group A (overweight) and 277 (85.8%) into group B (non-overweight). The median PFS and OS in two groups were as follows: A, 6.9 m/B, 5.6 m (HR 0.84, 95% CI [0.57-1.25], p = 0.38), and A, 22.3 m/B, 15.4 m (HR 0.90, 95% CI [0.56-1.43], p = 0.64), respectively. In accordance with the ICI regimen that the patients received, the PFS was A, 7.9 m/B, 7.8 m (HR 0.86, 95%CI [0.37-2.04], p = 0.74) in the patients who received pembrolizumab as 1st line therapy, A, 7.5 m/B, 5.3 m (HR 0.60, 95% CI [0.18-2.00], p = 0.40) in the patients who received pembrolizumab as 2nd line therapy, and A, 6.5 m/B, 4.4 m (HR 0.84, 95% CI [0.52-1.36], p = 0.48) in the patients who received nivolumab. Conclusions: Overweight NSCLC patients treated with ICIs showed a trend (non-statistically significant) towards a longer PFS as compared to non-overweight patients.
High throughput proteomic analysis and machine learning algorithm identifies DUOX2 (dual oxidase 2) as a novel biomarker for response prediction of concurrent chemoradiotherapy for locally advanced rectal cancer.
Authors: Lee Hyebin 
Published: October 2019

71 Background: Although many efforts to predict treatment response of concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer (LARC) have been made, no molecular has proved to be a robust biomarker. Methods: We performed mass spectrometry-based quantitative proteomic analysis of pretreatment Formalin-fixed, Paraffin-embedded (FFPE) biopsy samples of 13 patients with LARC, who were treated with CCRT followed by curative surgery. Based on pathologic report of surgical specimens, we divided thirteen patients as two response groups: complete response (CR) and non-complete response (nCR) groups. Results: A total of 3,637 proteins were identified and 498 proteins were confirmed as expressed at significantly different levels (DEPs; differently expressed proteins) between these two groups. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were also performed: the result showed that up-regulated DEPs enriched in biological processes (BP) were significantly different between two groups; immune response, cell migration & motility, protein transport in CR group; amide/peptide biosynthetic process, translation, posttranscriptional regulation of gene expression and detoxification in nCR group. To identify the best classifier to evaluate predictive power of signatures, we employed for different machine learning algorithms to classify samples between CR and nCR groups. As a result, we identified the predictive relevance of dual oxidase 2 (DUOX2) as the strongest predictive biomarker. Conclusions: This study identified a new biomarker, DUOX2, applicable to discrimination between CR and nCR after NACRT for LARC. To our knowledge, the present study provides the first identification of a clinical biomarker for response prediction based on in-depth proteomics and machine learning algorithms.
PDL-1 expression in oral squamous cell carcinoma and implications for treatment.
Authors: Srinivasalu Vijay Kumar , Subramaniam Narayana , Iyer Subramania , Nambiar Ajit , Koyakutty Manzoor , Thankappan Krishnakumar , Das Manjula , Dhar sujan Kumar , Balasubramanian Deepak 
Published: October 2019

82 Background: PDL-1 expression has been shown in multiple tumours to be a key factor in treatment response and immunogenicity. In oral squamous cell carcinoma (OSCC), its role is controversial; the expression levels, prognostic significance and therapeutic relevance are unclear. This study was performed to determine the incidence of PDL-1 expression in OSCC, and to determine its correlation with demographic, clinical and pathological features, recurrence and survival. Methods: PDL1 expression levels were determined by immunohistochemistry (DAKO kit) on 64 samples of OSCC obtained during resection on tumour (T) and tumour infiltrating lymphocytes (TILs). Statistical analysis was performed for corelation with clinicopathological features and survival. We also analysed PD1/PDL1 expression on the mRNA-seq data from The Cancer Genome Atlas (TCGA) (n = 527) and Gene Expression Omnibus (GEO) (n = 61) for validation. Results: PDL1 expression of < 1% was the most common for T (92%) and TILs (56%). Tumour PDL-1 expression < 1% had higher lymphovascular invasion (LVI) (p = 0.044) and bone invasion (p = 0.010). TIL PDL-1 expression < 1% was more common in patients < 45 years (p = 0.023) with more local recurrences (p = 0.020). For TCGA data, overall survival (OS) in the young ( < 45 years) was reduced in patients with low ( < 1%) PD1 expression (p = 0.010) while GEO data showed that older patients ( > 45 years) had a significantly higher PD1 expression level (p = 0.044). Conclusions: PDL1 expression in OSCC was low. Low TIL PDL1 expression was more common in patients with age < 45 years, with a higher chance of local recurrence. Genomic data also validated a potential link between PD1 expression and age. On the tumour, PD1 expression may be an important prognosticator, while on TILs, PDL1 is likely more relevant. Moreover PDL1 expression on the tumour is likely to be heterogeneous, so TIL PDL1 expression may be more representative of the tumour microenvironment and a better prognostic marker.
Glucocorticoid Receptor Polymorphisms Influence Muscle Strength in Cushing’s Syndrome
Authors: Müller Lisa Marie , Kienitz Tina , Deutschbein Timo , Riester Anna , Hahner Stefanie , Burger-Stritt Stephanie , Berr Christina M , Oßwald Andrea , Braun Leah , Rubinstein German , Reincke Martin , Quinkler Marcus 
Published: October 2019

Abstract

Context
An important clinical feature of Cushing’s syndrome (CS) is proximal muscle myopathy caused by glucocorticoid induced protein metabolism. However, interindividual differences cannot be explained solely by the pure extent of hypercortisolemia.

Objective
To evaluate the effects of glucocorticoid receptor (GR) polymorphisms (BclI, N363S, ER22/23EK and A3669G), which influence peripheral glucocorticoid sensitivity on muscular function in endogenous CS.

Methods
205 patients with proven endogenous CS (128 central, 77 adrenal) from 3 centers of the German Cushing’s Registry and 125 subjects, in whom CS was ruled out, were included. All subjects were assessed for grip strength (via hand grip dynamometer) and performed a chair-rising test (CRT). DNA samples were obtained from peripheral blood leukocytes for GR genotyping.

Results
In patients with active CS, normalized handgrip strength of the dominant and nondominant hand was higher in A3669G minor allele than in wildtype carriers (P = .006 and P = .021, respectively). CS patients in remission and ruled-out CS showed no differences in handgrip strength regarding A3669G minor allele and wildtype carriers. Male CS patients harboring the ER22/23EK wildtype presented lower hand grip strength than minor allele carriers (P = .049 dominant hand; P = .027 nondominant hand). The other polymorphisms did not influence handgrip strength. CRT showed no differences regarding GR polymorphisms carrier status.

Conclusion
Handgrip strength seems to be more susceptible to hypercortisolism in A3669G wildtype than in A3669G minor allele carriers. This might partially explain the inter-individual differences of glucocorticoid-induced myopathy in patients with endogenous CS. ER22/23EK polymorphism seems to exert sex-specific differences.
Impaired Respiratory Function in Women With PCOS Compared With Matched Controls From a Population-Based Study
Authors: Underdal Maria Othelie , Salvesen Øyvind , Henriksen Anne Hildur , Andersen Marianne , Vanky Eszter 
Published: October 2019

Abstract

Context
Increased prevalence of asthma has been reported from epidemiological studies in women with polycystic ovary syndrome (PCOS).

Objective
To investigate respiratory function in women with PCOS compared with controls in a clinical setting.

Design
An 8-year clinical follow-up study including self-reported asthma diagnoses and spirometry of women with PCOS randomized to metformin or placebo during pregnancy in the original studies (the Pilot and the PregMet-study), compared with matched controls from a population-based cohort study (The HUNT Study).

Setting
Secondary and tertiary care centers.

Participants
A total of 145 women with PCOS (54% of original cohort) were matched 1:3 to controls, on gender, age, and smoking-status.

Main outcomes and measures
Self-reported doctor-diagnosed asthma (DDA), percentage of predicted forced expiratory volume in the first second of expiration (FEV1 % predicted), percentage of predicted forced vital capacity (FVC % predicted).

Results
Women with PCOS reported more DDA compared with controls (19% vs 9%; P &lt; 0.01). Spirometry indicated a combined obstructive (FEV1 % predicted, 93.7 vs 102.0; P &lt; 0.01) and restrictive (FVC % predicted, 94.5 vs 103.7; P &lt; 0.01) respiratory impairment in PCOS compared with controls. Metformin in pregnancy did not affect respiratory function at follow-up.

Conclusion
Women with PCOS reported higher prevalence of DDA compared with controls matched for age and smoking status. In addition, respiratory function was decreased, with both obstructive and restrictive components. Further insight to the underlying pathogenesis of these observations is needed.

Clinical trial registration
ClinicalTrials.gov: The PregMet study: NCT00159536. The Pilot study: NCT03259919.
Effects of Pegvisomant and Pasireotide LAR on Vertebral Fractures in Acromegaly Resistant to First-generation SRLs
Authors: Chiloiro Sabrina , Giampietro Antonella , Frara Stefano , Bima Chiara , Donfrancesco Federico , Fleseriu Cara Maya , Pontecorvi Alfredo , Giustina Andrea , Fleseriu Maria , De Marinis Laura , Bianchi Antonio 
Published: October 2019

Abstract

Purpose
Osteopathy is an emerging complication of acromegaly. In somatostatin receptor ligands (SRL)-resistant patients, pegvisomant (PegV) and pasireotide LAR (Pasi) are used for acromegaly treatment, but their effect on skeletal health is still not defined.

Methods
In a longitudinal retrospective international study, we evaluated incidence of radiological vertebral fractures (VFs) in 55 patients with acromegaly resistant to first-generation SRL.

Results
At study entry, prevalent VFs occurred in 23 patients (41.8%). Biochemical acromegaly control was reached in 66.7% of patients on PegV and in 66.7% of patients on Pasi. During the follow-up, incident VFs (iVFs) were detected in 16 patients (29.1%). Occurrence of iVFs was associated with prevalent VFs (P = .002), persistence of active acromegaly (P = .01) and higher value of insulin-like growth factor 1 (IGF-1) during follow-up (P = .03). Among patients with active disease at last visit, iVFs occurred less frequently in patients on treatment with Pasi (25%) compared to PegV (77.8% P = .04), independently of the IGF-1 values (P = .90). In patients who reached biochemical control, 22.7% on PegV and 12.5% on Pasi had iVFs (P = .40). Among both treatment groups, the presence of pre-existent VFs was the main determinant for iVFs.

Conclusion
Our data show for the first time that patients with biochemically active disease treated with Pasi had lower risk of iVFs versus those treated with PegV. It also confirms that the presence of pre-existent VFs was the main determinant for iVFs. Additional studies on larger populations and with longer follow-up are needed to confirm our data and disclose the mechanisms underlying our findings.