bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination therapy with vincristine, immunoglobulin and glucocorticosteroid (VIG regimen) is very effective for the management of grade 3/4 or steroid-refractory immune-related adverse events (irAE) secondary to PD-1 blockade.
Authors: Chen Zhan-Hong , Wei Li , Wang Tian-tian , Lin Qu , Wu Xiangyuan 
Published: June 2021

e14577 Background: The management of grade 3/4 or steroid-refractory immune related adverse events (irAE) is based on a paucity of retrospective data analysis. Our initial experience with the combination therapy with Vincristine (VCR), immunoglobulin (IVIG) and glucocorticosteroid (VIG regimen) showed clinical improvement in a wide variety of irAEs. As a result, we recommend the use of VIG regimen for the management of grade 3/4 or steroid-refractory irAEs. Methods: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The components of VIG regimens are as follows: Methylprednisolone (MP) 2-10mg/kg for 3days, VCR 1.4mg/m2 (≤2mg) continuous infusion for 4-8 hours on day 3 once a week with Immunoglobulin (IVIG) 0.4g/kg for 3-5 days. The dose of MP and IVIG will be reduced quickly after irAE improves. VCR 1.4mg/m2 once a week will be used for 1 to 3 times according to the improvement. Clinical improvement was defined as either: documentation of resolution of symptoms and normalisation of biochemical tests or hospital discharge within 14 days. Results: A total of 25 patients had grade3/4 or steroid-refractory irAEs after receiving immune checkpoint inhibitors and then received VIG regimen. Among them, 22 patients have been significantly improved, with an improvement rate of 88%. Twenty-three patents were treated in the inpatient setting (92%). The index grade 3/4 irAE was pneumonitis in 28%, immune mediated hepatotoxicity(IMH) in 28%, rash/SJS/TEN in 24%, cerebritis in 8 % and one case each of ITP, Near blindness and severe oral mucositis. In 7 patients with severe IMH, the range of total bilirubin was 80-481umol/L and ALT 35-5000u/L. Six patients with IMH recover well but one patient did not recover to normal due to IMH complicated with pneumonitis and TEN . Clinical improvement was noted in 22/25 patients (88%), 11 patients (44%) required a single dose, while 12 patients (48%) required two doses, 2 patients(8%) required three doses of VCR 1.4mg/m2 continuous infusion for 4-8 hours. What is impressive is that the two patients with encephalitis were significantly relieved within 2 weeks after using the VIG regimen. One patient with TEN (SCORETEN 3)was significantly improved and discharged from our hospital 11 days after using the VIG regimen. A patient with near-blind eyesight recovered to normal 3 days after using the VIG regimen. Conclusions: VIG regimen may be an effective therapeutic option for the management of grade3/4 or steroid-refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the efficacy and safety of VIG regimen.
Identification and analysis of immune microenvironment characterization and key signal pathways in liver metastasis.
Authors: Zhu Xiaoxia , Zheng Zhihao , Jiang Yuhang , Li Luyao 
Published: June 2021

e15004 Background: The liver represents a common site for metastatic disease, patients with advanced malignancies were usually associated with worse prognostic outcomes once liver metastasis has occurred. The aim of this study was to explore the immune microenvironment characterization and key signal pathways of liver metastasis in colorectal cancer (CRC) and breast cancer (BRCA), and to provide potential targets and decision-making basis for the diagnosis and treatment of patients with liver metastasis. Methods: Two datasets (GSE49355 and GSE58708) were downloaded from the Gene Expression Omnibus (GEO) database, and patients with primary tumors and paired liver metastases were enrolled. Data were processed by the limma and Deseq2 package and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG) and Reactome pathway analysis was performed using clusterProfiler package. Prognosis markers were identified via survival analysis of The Cancer Genome Atlas (TCGA) databases. CIBERSORT algorithm was used to calculate the proportions of 22 types of infiltrated immune cells. We used Spearman’s correlation analysis to describe the correlation between gene expression and microsatellite instability (MSI) or tumor mutational burden (TMB) score. Results: We investigated 16 patients with paired specimens (3 patients with BRCA and 13 patients with CRC). A total of 424 and 49 DEGs were identified in the BRCA and CRC samples. Only 26 DEGs were shared by the two kinds of cancers. The functional enrichment analysis suggested that the functions of DEGs were mainly related to cholesterol metabolism, complement and coagulation cascades, platelet activation etc. The survival analysis indicated that high expression levels of SERPINA3 was associated with a better prognosis in TCGA-BRCA (P = 0.01), while high ITIH2 and COLEC11 expression correlated with poor prognosis in TCGA-COAD (P = 0.045 and P = 0.013, respectively). CIBERSORT analysis revealed a significantly increased proportion of M2-macrophages and decreased proportion of activated mast cells in liver metastases. The Spearman correlation analysis showed that the SERPINA3 expression had a significantly negative relationship with the TMB (r = -0.26, P＜0.001) in TCGA-BRCA, but not significantly associated with the MSI (r = -0.02, P = 0.520), while the COLEC11 expression was significantly correlate negatively with the MSI and TMB (r = -0.15, P < 0.001 and r = -0.23, P < 0.001, respectively) in TCGA-COAD. Conclusions: The immune microenvironment of liver metastases exhibits a significant increase in the proportion of M2-macrophages and a significant decrease in the proportion of activated mast cells, and the key signal pathways implicate cholesterol metabolism and platelet activation. The specific mechanism needs to be further elucidated. Support: 81972853, 81572279, LC2019ZD009.
MosaicNeedles: A tool for multi-omic liquid biopsy sensitivity and specificity enhancement.
Authors: Quan Qimin , Wilkinson Joe , Ritchey Joshua , Kaiser Alaina , Geanacopoulos John , Boyce John 
Published: June 2021

e15019 Background: Liquid biopsy has evolved to be an important method complementary to tissue biopsy. It is not only non-invasive, but also has the potential to detect cancer in its earliest stages and monitor patients in remission. The integration of proteomics into liquid biopsy may transform the molecular diagnostics of cancer and accelerate basic and clinical oncology research. A recent study showed that adding just 8 protein biomarkers to a panel of circulating DNA biomarkers increased the diagnostic accuracy up to 98% sensitivity and 99% specificity. Proteomics also bridges the gaps of functional information lost due to post-transcriptional and post-translational modifications in the genomic approach. However, the proteogenomic approach normally requires the use of multiple different assay technologies and laboratory workflows, including mass spectrometry. Methods: NanoMosaic’s Tessie platform employs a densely integrated nanoneedle sensor array (thus named MosaicNeedles) which can be used to detect both nucleic acids and proteins in a single assay process with reduced workflow complexity, without the need for mass spectrometry. Results: The NanoMosaic platform is a label-free, digital, single molecule counting technology using nanoneedles. It achieves sub-pg/ml (̃fM) level sensitivity with 7 logs of dynamic range. An array of nanoneedles is densely integrated and manufactured with CMOS-compatible nanofabrication processes. Each nanoneedle is a single molecule biosensor that is functionalized with capture probes. The capture probe can be either an antibody for protein detection or an oligonucleotide with a specific target sequence to a DNA fragment, mRNA, or miRNA of interest. The scattering spectrum of each nanoneedle changes when an analyte binds to its surface. At low abundance, analytes that are captured can be quantitated by counting the presence or absence of a color change on each individual nanoneedle in a binary fashion. As an analyte concentration increases the binding events increase accordingly and achieve saturation. In this range, an analog analysis on the spectrum shift will be performed, thus providing a wider dynamic range, up to 7 logs. Ultrahigh level multiplex can be achieved by parallelizing each analyte specific sensing area without loss of sensitivity or dynamic range. A 10,000-plex study can be achieved with a total of 2.5 billion nanoneedles on a 50mm by 50mm consumable. In this consumable, a 2,000-plex proteome and 8,000 cell-free DNA fragments can be detected. Conclusions: In conclusion, a full proteogenomic quantification can be performed on the NanoMosaic platform in one reaction, with higher sensitivity, lower cost and higher throughput than is currently possible by traditional methods. In addition, the high-plexibility of the NanoMosaic platform allows the discovery of new biomarkers across the whole proteome without the need for mass spectrometry.
Polydatin reduces cardiotoxicity of tyrosine kinase inhibitor sunitinib by decreasing pro-oxidative stress, pro-inflammatory cytokines and NLRP3 inflammasome expression.
Authors: Berretta Massimiliano , Quagliariello Vincenzo , Buccolo Simona , Iovine Martina , De Laurentiis Michelino , Cavalcanti Ernesta , Di Francia Raffaele , Taibi Rosaria , Montopoli Monica , Botti Gerardo , Maurea Nicola 
Published: June 2021

e15065 Background: : Polydatin has anticancer and anti-inflammatory properties, however no studies investigated on its putative cardioprotective effects against anticancer therapies. Sunitinib, a recently-approved, multi-targeted tyrosine kinases inhibitor, prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. We investigated on the reduction of cytokines and growth factors of polydatin resulting in putative cardioprotective effects. Methods: Human fetal cardiomyocytes were untreated (control) or treated for 48 h with polydatin (50,100,200 and 400 µM) or sunitinib (5,10,25 and 50 µM) alone or combined to polydatin. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Exposure of adult cardiomyocytes to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly intracellular reactive oxygen species, lipid peroxidation and cytochrome c release from mitochondria leading to a reduction in cell death compared to cells exposed to sunitinib alone. Polydatin reduces expression of pro-inflammatory cytokines and growth factors involved in myocardial damages and down-regulates the signaling pathway of NLRP3 inflammasome and NF-κB, increasing cellular resistance to sunitinib-mediated damages. Conclusions: Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, has cardioprotective and anti-inflammatory properties, thus indicating one the mechanism(s) by which this metabolite of resveratrol might decrease sunitinib-mediated cardiotoxicity.
Integration of molecular cancer classification and next-generation sequencing to identify metastatic patients eligible for PARP inhibitors.
Authors: Hart Lowell L. , Treuner Kai , Ma Li , Wong Jenna , Schnabel Catherine A. , Reeves James Andrew 
Published: June 2021

e15080 Background: Olaparib, rucaparib, and niraparib are 3 poly-ADP-ribose polymerase inhibitors (PARPi) approved by the FDA for ovarian, breast, pancreatic, prostate, fallopian tube and peritoneal cancers with BRCA mutations. Several ongoing clinical trials aim to determine the efficacy of PARPi in various other cancer types, including specific cancer subtypes, such as clear cell renal cell carcinoma and cholangiocarcinoma either as monotherapy or combination therapy; however, eligibility for PARPi therapy requires the identification of the primary tumor type and confirmation of BRCA mutation. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for metastatic patients with unknown or uncertain diagnoses. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. In the current study, a database of metastatic cases that integrates tumor type with biomarker analysis was characterized to identify those eligible for PARPi treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tissue-guided multimodal biomarker testing by NGS, including tumor mutational burden (TMB) fluorescent in situ hybridization (FISH), and microsatellite instability (MSI), and immunohistochemistry (IHC) (NeoTYPE profiles, Neogenomics). For the current study, metastatic cancers classified as ovarian, breast, pancreatic, or prostate were identified in the database, followed by NGS analysis to detect mutations in BRCA1 or BRCA2. Results: The current analysis included 2151 CancerTYPE ID cases, from which 71 ovarian, 47 breast, 12 pancreatic and 15 prostate cancer cases were identified. Out of 46 cases of ovarian cancer with molecular biomarker results, NGS identified 7 (15.3%) cases with BRCA1 mutation and 4 (8.7%) cases with BRCA2 mutation. Additionally, 4 (10.5%) cases with BRCA1 mutation and 1 (2.6%) case with BRCA2 mutation out of 38 cases of breast cancer with BRCA results were detected. No cases of prostate cancer or pancreatic cancer with mutations in BRCA1 or BRCA2 were detected. Conclusions: These findings in metastatic patients demonstrate the clinical utility of tumor type identification combined with molecular biomarker profiling, leading to additional options for patients with advanced disease. Specifically, analysis of the MOSAIC database identified a subset of patients with metastatic cancers eligible for PARPi therapy based on tumor type and BRCA mutation status. As new and approved PARPi are evaluated for efficacy in additional tumor types, patients can be identified that may be eligible for these targeted cancer drugs.
The clinicopathological characteristics, gene mutation characteristics and survival analysis of carcinoma of unknown primary origin.
Authors: Cui Yanzhi , Jiang Da , Hou Ran , Zhang Xue , Song Wenya , Zhou Xinliang , Hu Zexian 
Published: June 2021

e15098 Background: Analyze the characteristics of CUPS clinicopathology and gene mutation spectrum, and discuss CUPS drug treatment strategies. Methods: A retrospective analysis of the data of 30 patients with metastatic cancer of CUP admitted to our department from April 2015 to April 2020. Including clinicopathological characteristics, treatment process and methods, gene molecular information, follow-up survival period. The follow-up was until February 1, 2021 or the patient died. Results: The pathological types of these cases were adenocarcinoma (14/30,46.7%), squamous cell carcinoma (5/30, 16.7%), neuroendocrine carcinoma (3/30,10%), small cell carcinoma (2/30,6.7%), sarcomatoid carcinoma (2/30,6.7%), large cell carcinoma (1/30,3.3%), lymphoepithelial carcinoma (1/30,3.3%), and poorly differentiated carcinoma (2/30,6.7%) . The most predilection site was lymph nodes, accounting for 70%. Primary lesions were not found in 23 cases in the course of diagnosis and treatment. They were head and neck in 1 case, lung in 1 case, mammary gland in 1 case, digestive tract in 3 cases and thymus in 1 case. 23 patients received chemotherapy alone or combined with antiangiogenic therapy, 2 patients received molecular targeted agents, 1 patient received ICI combined with antiangiogenic therapy, and the remaining 4 patients died without antitumor therapy or gave up treatment. The survival time of 26 patients was between 1 to 143 months, and the median survival time was 8.6 months. The 1-year, 2-year, 3-year and 5-year OS rate were 40%, 20%, 6.7% and 3.3%, respectively. Mean survival time was significantly longer among patients without visceral metastasis vs. with visceral metastasis (15.6m vs. 7.3m, P = 0.023). OS rate were 70% vs. 25%, 30% vs. 15%, 20% vs. 0% and 10% vs. 0%, respectively. The median survival time were 18.3m (with targeted therapy), 8.8m (without targeted therapy), 23.2m (with primary lesion), 8.4m (without primary lesion), The 1-year, 2-year, 3-year and 5-year OS were 53.3% vs. 26.7%, 40% vs. 0%, 23.3% vs. 0% and 6.7% vs. 0% for patients with targeted therapy vs. without targeted therapy, respectively. The 1-year, 2-year, 3-year and 5-year OS were 85.7% vs. 261%, 42.9% vs. 13%, 28.6% vs. 0% and 14.3% vs. 0% for patients with primary lesion vs. without primary lesion, respectively. 20 patients were interrogated genes using NGS of ctDNA. 80% of patients exhibited ctDNA alterations; TP53-associated genes were most commonly altered (13/20,65%) followed by genes involved in the MAPK pathway (20%), PI3K signaling (10%) and the cell cycle machinery (5%). The genomic profiles help guide treatment in 4 cases. Conclusions: CUPS has a poor prognosis. The pathological type is mostly adenocarcinoma, and lymph node metastasis is the first diagnosis. Chemotherapy is still the main treatment method. Molecular detection is helpful for individualized treatment.
Dihydropyrimidine dehydrogenase deficiency in patients treated with 5FU or capecitabine based regimens: A single center experience from South India.
Authors: Pavithran Keechilat , Ariyannur Prasanth , Jayamohanan Hridya , Philip Arun , Jose Wesley Mannirathil , Soman Sumi 
Published: June 2021

e15517 Background: DPYD deficiency is present in 3-5% of patients. The risk of treatment-related death in DPYD mutation carriers who receive fluoropyrimidine chemotherapy has been estimated at 3-10%. There is growing data in support of widespread screening for DPYD deficiency prior to fluoropyrimidine chemotherapy. The purpose of our study was to identify the prevalence of DPYD deficiency among patients receiving 5-fluorouracil (5FU) or capecitabine based combination chemotherapy, and to analyse the toxicity profile among the DPYD deficient group. Methods: The study involved patients who have received 5FU and capecitabine based chemotherapy for the treatment for gastrointestinal, breast and head and neck cancers between 2019-2020. Four DPYD variants were checked using real-time PCR based Genotyping assay. Three common DPYD variants recommended by the CPIC guidelines (IVS14+1 G>A (*2A), c.1679T>G (*13), c.2846A>T) and a common variant in Asian population (c.496A>G), based on previous studies, was included in our analysis. These variants were assessed prior to the initiation of the chemotherapy and dose was modified based on the activity score and the toxicity profile was assessed. Descriptive statistics was performed using SPSS version 20. Results: 375 patients were included in this analysis. The median age of the cohort was 61years (21-84 years). 51.3% were males and 49.7% females. Among the 375 patients, 47 patients had DPYD mutation (12.5%). The median age of the DPYD mutated patients were 68 years; 29 (61.7%) males and 18 (38.2%) females. 32 (68.8%) had deleterious mutation in DPYD variant c.496A>G (rs2297595) and 15 (31.9%) showed mutation IVS14+1 G>A (rs3918290). 35 out 47 patients had grade II-III toxicity even after dose reduction during the first cycle of chemotherapy. The commonly seen adverse events were hand and foot syndrome in 18 (38.3%), mucositis in 7 (14.9%), diarrrhoea in 15 (31.9%) and neutropenia in 25 (31.9%) patients. Four patients had febrile neutropenia. One patient experience myocardial infarction. There was no mortality. Chi square analysis showed DPYD mutation had significant association with presence of severe adverse reaction (74.5%, p-value. 0.002). Conclusions: Prevalence of DPYD mutation in our patients was 12.5%. They experienced more toxicities while receiving 5-FU/Capecitabine even after dose modification. c.496A>G (rs2297595) was the most common variant seen in our patients. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using pharmacogenetic methods may help identify those patients who are at risk for adverse effects, allowing a more individualized approach to their chemotherapy management. c.496A>G (rs2297595) variant should also be in included routinely in DPYD screening among South Asian population.
Genomic profiles of BRAF inhibitor resistance mechanisms in metastatic colorectal cancer.
Authors: Xu Ting , Wang Xicheng , Changsong Qi , Wang Zhenghang , Li Jian , Shen Lin , Wang Jia , Lin Xuan , Zhang Lu , Lin Jing , Li Xi 
Published: June 2021

e15527 Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.