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in category oncology

646 results found. For more information, click each entry to expand.

581: Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple Negative Breast Cancer
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Posted 26 Oct 2021

Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple Negative Breast Cancer
137 downloads medRxiv oncology

Prashant Dogra, Javier Ruiz Ramirez, Joseph D. Butner, Maria J. Pelaez, Caroline Chung, Anupama Hooda-Nehra, Renata Pasqualini, Wadih Arap, Vittorio Cristini, George A Calin, Bulent Ozpolat, Zhihui Wang

The downregulation of miRNA-22 in triple negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs for TNBC, providing a basis for rational therapeutic combinations for improved response.

582: The clinical feature of triple-negative breast cancer in Beijing, China
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Posted 05 Aug 2021

The clinical feature of triple-negative breast cancer in Beijing, China
135 downloads medRxiv oncology

Hui Zhao, Yueqing Feng, Junzheng Yang

Objective: To collect and analyze the clinical feature of triple-negative breast cancer (TNBC) in Beijing, to provide the information for the local oncologist to make sound treatment plans. Methods: The clinical data of 280 breast cancer patients with TNBC admitted to the oncology hospital of China Academy of Medical Sciences were collected and divided into (recurrence and metastasis) group and non-(recurrence and metastasis) group. Breast cancer patients with TNBC were classified according to age distribution, family history of breast cancer, pathological type, histological grade, clinical stage, tumor thrombus, tumor size and lymph node metastasis. and 15 BRCA1 gene SNP loci were also measured by a high throughput Mass ARRAY time-of-flight mass spectrometry biochip system and compared the expression of 15 BRCA1 gene SNP loci between (recurrence and metastasis) group and non-(recurrence and metastasis) group. {chi}2 test was used to analyze the difference between two groups, and P<0.05 considered statistically significant. Results: A total of 280 breast cancer patients with TNBC were enrolled in this study, median age 45 years old. There were 117 cases breast cancer patients with TNBC in (recurrence and metastasis) group, accounting for 41.79% in total breast cancer patients with TNBC and 163 cases breast cancer patients with TNBC in non-(recurrence and metastasis) group, accounting for 58.21% in total breast cancer patients with TNBC; There was no significant difference in age distribution, family history of breast cancer, pathological type and histological grade between non-(recurrence and metastasis) group and (recurrence and metastasis) group (P>0.05); but there were significant differences in clinical stage, vascular tumor thrombus, tumor size and lymph node metastasis between two groups (P<0.05); and then we compared the expression of 15 BRCA1 gene SNP loci in (recurrence and metastasis) group and non-(recurrence and metastasis) group, found that BRCA1gene rs 12516 CC loci (38.8% VS 44.4%), BRCA1gene rs 12516 TT loci (15.6% VS 10.4%), BRCA1 gene rs 16940 CC loci (15.1% VS 10.4%), BRCA1 gene rs 16940 TT loci (39.0% VS 44.8%), BRCA1 gene rs 16941 AA loci (38.1% VS 44%), BRCA1 gene rs 16941 GG loci (15.0% VS 10.3%), BRCA1 gene rs16942 AA loci (39.0% VS 44.8%), BRCA1 gene rs16942 GG loci (15.1% VS 10.4%), BRCA1gene rs799906 CC loci (15.9% VS 10.4%), BRCA1gene rs799906 TT loci (38.7% VS 44.8%), BRCA1gene rs799917 CC loci (38.7% VS 44.4%), BRCA1gene rs799917 TT loci (15.7% VS 10.4%), BRCA1gene rs1060915 CC loci (15.5% VS 10.4%), BRCA1gene rs1060915 TT loci (39.1%VS 44.8%), BRCA1gene rs1799966 AA loci (37.7% VS 44.4%), BRCA1gene rs1799966 GG loci (15.1% VS 10.4%), BRCA1 Gene rs2070833 AA loci (3.1% VS 7.0%), BRCA1 Gene rs2070833 CC loci (56.3% VS 51.3%), BRCA1gene rs3737559 GG loci(78.5% VS 84.5%), BRCA1gene rs3737559 GA loci(19.0% VS 14.6%), BRCA1gene rs8176199 AA loci (60.5% VS 64.6%), BRCA1gene rs8176318 GG loci (38.4% VS 43.4%), BRCA1gene rs8176318 TT loci (15.1% VS 10.6%), BRCA1gene rs8176323 CC loci (38.6% VS 43.9%), BRCA1gene rs8176323 GG loci (15.2% VS10.5%), BRCA1gene rs11655505 AA loci (14.9% VS 10.4%), BRCA1gene rs11655505 GG loci (39.1% VS 44.8%) had a difference at the accident rate between recurrence and metastasis group and non-(recurrence and metastasis) group, but the frequencies of genotypes in the (recurrence and metastasis) group and non-(recurrence and metastasis) group were similar, there was no statistical significant correlation between the SNP genotype of the BRCA1 gene and the recurrence and metastasis risk of TNBC (P>0.05). Conclusions: There were higher recurrence and metastasis (41.79%) in total 280 cases breast cancer patients with TNBC in Beijing area; breast cancer patients with TNBC in Beijing area had a unique clinical feature no matter at clinical stage, vascular tumor thrombus, tumor size and lymph node metastasis or the expression of 15 BRCA1 gene SNP loci, those data may provide some information for clinical staff for TBNC treatment.

583: The role of KPNA2 mutations in breast cancer prognosis: A survey of publicly available databases
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Posted 14 Nov 2021

The role of KPNA2 mutations in breast cancer prognosis: A survey of publicly available databases
132 downloads medRxiv oncology

Layla Alnoumas, Lisa van den driest, Alison Lannigan, Caroline H. Johnson, Nicholas JW Rattray, Zahra Rattray

Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions. We report a survey of several publicly available databases probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing information available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival. Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents. In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer.

584: RELATIONSHIP BETWEEN HELMINTHASIS AND GASTRIC CANCER: A SYSTEMATIC REVIEW
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Posted 10 Aug 2021

RELATIONSHIP BETWEEN HELMINTHASIS AND GASTRIC CANCER: A SYSTEMATIC REVIEW
132 downloads medRxiv oncology

David Fabian Ramirez

Introduction: helminths are parasitic worms able to produce diverse clinical manifestations in humans, mainly in the gut. Gastric cancer its a high incidence entity in Colombia, being the highland regions where its incidence is the highest in comparison with the lower incidence coastal region. From the above it is intended to determine the relationship between helminthiasis and the development of gastric cancer. Methodology: A systematic review was performed in four databases for studies evaluating the relationship between helminthiasis and the development of gastric cancer. Results: We included 16 articles from 929 records, with 11 articles reporting a positive relationship and 5 articles with negative relationship. Conclusions: Parasitic infections of the gastrointestinal tract by helminths promote TH-2 type immune responses and decrease TH-1 type that are involved in the progression of precancerous lesions associated with Helicobacter pylori infection. Keywords: Gastric cancer, Helminthiases, inflammation.

585: Prostate-specific membrane antigen is a biomarker for residual disease following neoadjuvant intense androgen deprivation therapy in prostate cancer
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Posted 29 Oct 2021

Prostate-specific membrane antigen is a biomarker for residual disease following neoadjuvant intense androgen deprivation therapy in prostate cancer
131 downloads medRxiv oncology

John R. Bright, Rosina T. Lis, Anson T. Ku, Nicholas T. Terrigino, Shana Y. Trostel, Nicole V. Carrabba, Stephanie A. Harmon, Baris Turkbey, Scott Wilkinson, Adam G. Sowalsky

Neoadjuvant intense androgen deprivation therapy can exert a wide range of histologic responses, which in turn are reflected in the final prostatectomy specimen. Accurate identification and measurement of residual tumor volumes are critical for tracking and stratifying patient outcomes. The goal of this current study was to evaluate the ability of antibodies against prostate-specific membrane antigen (PSMA) to detect residual tumor in a cohort of 35 patients treated with androgen deprivation therapy plus enzalutamide for six months prior to radical prostatectomy. Residual carcinoma was detected in 31 patients, and PSMA reacted positively with tumor in all cases. PSMA staining was 95.5% sensitive for tumor, with approximately 81.6% of benign regions showing no reactivity. By contrast, PSMA positively reacted with 72.2% of benign regions in a control cohort of 37 untreated cases, resulting in 27.8% specificity for tumor. PSMA further identified highly dedifferentiated prostate carcinomas including tumors with evidence of neuroendocrine differentiation. We propose that anti-PSMA immunostaining be a standardized marker for identifying residual cancer in the setting of neoadjuvant intense androgen deprivation therapy.

586: Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer
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Posted 02 Nov 2021

Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer
129 downloads medRxiv oncology

Jiaren Zhang, Bob Zimmermann, Giuseppe Galletti, Susan Halabi, Ada Gjyrezi, Qian Yang, Santosh Gupta, Akanksha Verma, Andrea Sboner, Monika Anand, Daniel J. George, Simon G. Gregory, Seunghee Hong, Virginia Pascual, Clio P. Mavragani, Emmanuel S. Antonarakis, David M. Nanus, Scott T. Tagawa, Olivier Elemento, Andrew J Armstrong, Paraskevi Giannakakou

Androgen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Here we performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of a prospective clinical trial of men with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). CTC RNA-sequencing identified that RB loss and enhanced E2F signaling along with BRCA loss transcriptional networks were associated with intrinsic ARSi resistance, while an inflammatory response signature was significantly associated with acquired resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of T and NK cells. Importantly, CTC gene signatures had a significant positive association with circulating immune macroenvironment (CIME) signatures. Taken together, these data demonstrate that liquid biopsy transcriptomics can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization in patients with mCRPC.

587: Molecular typing of breast cancer in Northern Henan Province
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Posted 30 Jul 2021

Molecular typing of breast cancer in Northern Henan Province
127 downloads medRxiv oncology

Hui Zhao, Haibin Ma, Bangze Chen, Yahui Li, Junzheng yang

Objective: Investigating and analyzing the clinical features of breast cancer patients in Northern Henan Province, measuring expression of biomarkers (ER, PR, HER2 and Ki-67) and classified the molecular typing of breast cancer patients, to understand the molecular typing distribution and correlation between biomarkers of breast cancer patients in North Henan Province, which may provide the information for the local oncologist to make sound treatment plans. Methods: We collected the clinical data of breast cancer patients in Xinxiang Central Hospital from 2016 to 2021, those data was classified by gender and pathological types of breast cancer patients; and we also measured and analyzed the expression of breast cancer related biomarkers (ER, PR, HER2 and Ki-67) by immunohistochemistry, and based on expression of these biomarkers, the molecular typing of breast cancer were also classified. Results: 3210 cases breast cancer patients were collected in this study; there were 3205 female patients and 5 male patients, accounting for 99.84% and 0.16% in total breast cancer patients, respectively. Classification according to pathological conditions of breast cancer patients, there were 2761 cases patients with invasive ductal carcinoma, accounting for 86.01% in total breast cancer patients, and then mucinous adenocarcinoma (109/3210, 3.40%), lobular carcinoma (106/3210, 3.30%), ductal carcinoma in situ (75/3210, 2.34%), papillary carcinoma (61/3210, 1.90%), intraductal carcinoma (40/3210, 1.25%), myeloid carcinoma (27/3210, 0.84%); There were also including some rare breast cancer types including cribriform carcinoma (6/3210, 0.19%), lymph node metastasis (7/3210, 0.22%), occult breast carcinoma (5/3210, 0.14%), invasive carcinoma (5/3210, 0.14%), squamous cell carcinoma (3/3210, 0.09%), fibroadenoma (3/3210, 0.09%), pleomorphic carcinoma (2/3210, 0.06%). Classification according to molecular typing of breast cancer, the number of breast cancer patients with Luminal A type [ER(+)/PR(+) HER2(-)Ki67<14%] were 207 cases, accounting for 6.45% in total breast cancer patients, the number of breast cancer patients with Luminal B type I [ER(+)/PR(+) HER2(-)] were 243 cases, accounting for 7.57% in total breast cancer patients, the number of breast cancer patients with Luminal B type II [(ER(+)/PR(+)HER2(+) any Ki67] was 254 cases, accounting for 7.91% in total breast cancer patients, and the number of Triple-negative breast cancer (TNBC) were 390 cases, accounting for 12.15% in total breast cancer patients. The average expression rate of Ki-67 in ER (+) and/or PR (+) breast cancer patients was 20.39+27.33%, while the average expression rate of Ki-67 in ER(-)/PR(-) breast cancer patients was 36.35%+30.14%, and the difference between two patients was significant (p=0.0021); the average expression rate of Ki-67 in HER2 positive breast cancer patients was 23.01%+21.96%, the average expression rate of Ki-67 in HER2 negative breast cancer patients was 29.44%+24.16%, and there was no significant difference between the two groups (P=0.2589). The main treatment methods of breast cancer patients in Northern Henan Province were antitumor drugs and chemotherapy, the results showed that 87.29% patients were treated by chemotherapy; and high frequency anti-tumor drugs used for breast cancer treatment were Epirubicin (1527/3210, 47.57%)Cyclophosphamide (1172/3210, 36.51%)Paclitaxel (1141/321035.55%), Tamoxifen (912/3210, 28.41%). Conclusions: The main pathological type of breast cancer are invasive ductal carcinoma, and the main treatment methods of breast cancer patients in Northern Henan Province were antitumor drugs and chemotherapy. In the four kinds of molecular typing of breast cancer, the incidence rate of TNBC is highest compared with Luminal B type II[(ER(+)/PR(+)HER2(+) any Ki67], Luminal B type I [ER(+)/PR(+)HER2(-)] and Luminal A type [ER(+)/PR(+) HER2(-) Ki67<14%]; these results may provide some suggestions for the local oncologist.

588: Surgical Resection, Radiotherapy, And Percutaneous Thermal Ablation for Treatment of Stage 1 Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis
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Posted 22 Sep 2021

Surgical Resection, Radiotherapy, And Percutaneous Thermal Ablation for Treatment of Stage 1 Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis
127 downloads medRxiv oncology

Arun Chockalingam, Brandon Koo, John T Moon, Menelaos Konstantinidis, Andrew Tran, Sahar Nourouzpour, Emily Lawson, Kathleen Fox, Peiman Habibollahi, Bruno Odisio, Mohammed Loya, Ali Bassir, Nariman Nezami

Introduction: Non-small cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Currently surgical resection of the affected lung parenchyma is the gold standard of treatment. However, as patients are becoming medically more complex and presenting with more advanced disease, minimally invasive image guided percutaneous ablations are gaining popularity. Therefore, comparison of surgical, ablative, and second-line external beam therapies will help clinicians, as management of NSCLC changes. We will conduct a meta-analysis, reviewing literature investigating these therapies in adult patients diagnosed with Stage I NSCLC (tumor ranging from 0-5 cm, with no hilar nor mediastinal nodal involvement, confirmed either through cytology or histology regardless of type). Methods and Analysis: We will search electronic databases from their inception to January 2021 to identify randomized controlled trials (RCTs), cluster-RCTs, and cohort studies comparing the survival and clinical outcomes between any two interventions (lobectomy, wedge resection, radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation and consolidated radiation therapies (EBRT, SBRT and 3D-CRT). The primary outcomes will include: cancer-specific survival (CSS), lung disease free survival, locoregional recurrence, death, toxicity, and non-target organ injury. In addition to the electronic databases, we will search for published and unpublished studies in trial registries and will review the references of included studies for possible inclusion in this review. Risk of bias will be assess using tools developed by the Cochrane collaboration. Two reviewers will independently assess the eligibility of studies and conduct the corresponding risk-of-bias assessments. For each outcome, given a sufficient number of studies, we will conduct a network meta-analysis. Finally, we will use the Confidence in Network meta-analysis (CINeMA) tool to assess the quality of the evidence for each of the primary outcomes. Ethics and Dissemination: We aim to share our findings through high-impact peer review. As interventional techniques become more popular, it will be important for all providers in multi-disciplinary teams focused on care of these patients to receive continuing medical education on related to these interventions. Data synthesized in this study will be made available to readers.

589: Development of an accessible gene expression bioinformatics pipeline to study driver mutations of colorectal cancer
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Posted 15 Nov 2021

Development of an accessible gene expression bioinformatics pipeline to study driver mutations of colorectal cancer
126 downloads medRxiv oncology

Lisa van den driest, Caroline H. Johnson, Nicholas JW Rattray, Zahra Rattray

Colorectal cancer (CRC) is a global cause of cancer-related mortality driven by genetic and environmental factors which influence therapeutic outcomes. The emergence of next-generation sequencing technologies enables the rapid and extensive collection and curation of genetic data for each cancer type into clinical gene expression biobanks. In this study we used a combination of bioinformatics tools to investigate the expression patterns and prognostic significance of two genes, adenomatous polyposis coli (APC) and B-Raf proto-oncogene (BRAF), that are commonly dysregulated in colon cancer. Subsequently, we investigated the pathways and biomolecular effectors implicated in APC and BRAF function. Our results show mutation types, frequency, anatomical location and differential expression patterns for APC and BRAF between colorectal tumour and matched healthy tissue. The prognostic values of APC and BRAF was investigated as a function of expression level in CRC and other cancer types. In the era of precision medicine and with significant advancements in biobanking and data curation, there is significant scope to use existing clinical datasets for evaluating the role of mutational drivers in carcinogenesis. This offers the potential for studying combinations of less well-known genes and the discovery of novel biomarkers or studying the association between various effector proteins and pathways.

590: Derivation of anthropometric-based equations to predict lean body mass composition of cancer patients
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Posted 07 Jul 2021

Derivation of anthropometric-based equations to predict lean body mass composition of cancer patients
123 downloads medRxiv oncology

Autumn B Carey, Ashley S Felix, Jared D Huling, James B Odei, Christopher C. Coss, Xia Ning, Macarius M Donneyong

Background Lean body mass (LBM) composition of cancer patients is a predictor of chemotherapy-related adverse events and overall cancer survival. However, clinicians lack validated algorithms that can be applied to measure the LBM of cancer patients to facilitate accurate chemotherapy dosing. Our goal was to develop LBM predictive equations using routinely measured anthropometric measures among cancer patients. Methods We leveraged the 1999-2006 National Health and Nutrition Examination Survey (NHANES) data cycles containing information on self-reported cancer diagnosis, LBM measures based on dual-energy x-ray absorptiometry (DXA) and several anthropometric and demographic factors. We restricted our analysis to participants who had been diagnosed with cancer at the time of surveys. The data was randomly split to 75%:25% to train and test predictive models. Least absolute shrinkage and selection operator (LASSO) models were used to predict LBM based on anthropometric and demographic factors, overall and separately among sex and sex-by-race/ethnic subgroups. LBM measured directly with DXA served as the gold standard for assessing the predictive abilities (correlations [R2] and the Root Mean Square Error [RMSE]) of the derived LBM-algorithms. We further compared the correlations between both DXA-based LBM and predicted LBM and urine creatinine levels, a known biomarker of muscle mass. Results We identified 1,777 cancer patients with a median age of 71 (interquartile range [IQR]: 60-80) years. The most parsimonious model comprised of height and weight, which accurately predicted LBM overall (R2=0.86, RMSE =2.26). The predictive abilities of these models varied across sex-by-race/ethnic groups. The magnitude of correlations between derived LBM-algorithm and urine creatinine levels were larger compared to those measured between DXA-based LBM and urine creatinine levels (R2=0.30 vs. R2=0.17) Conclusions We successfully developed a simple sex-specific and sex-by-race/ethnicity-specific models to accurately predict the LBM of cancer patients by using only height and weight. The simplicity and high accuracy of these models make them inexpensive alternatives to measuring the LBM of cancer patients. Data on the LBM of cancer patients could help guide optimal chemotherapy dose selection among cancer patients.

591: Hairpin structure facilitates high-fidelity DNA amplification reactions in both qPCR and high-throughput sequencing
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Posted 14 Nov 2021

Hairpin structure facilitates high-fidelity DNA amplification reactions in both qPCR and high-throughput sequencing
121 downloads medRxiv oncology

Kerou Zhang, Alessandro Pinto, Peng Dai, Michael Wang, Lauren Yuxuan Cheng, Ping Song, Luis Rodriguez, Cailin Weller, David Yu Zhang

Effective polymerase chain reactions (PCR) are important in bio-laboratories. It is essential to detect rare DNA-sequence variants for early cancer diagnosis or for drug-resistance mutations identification. Some of the common detection quantitative PCR (qPCR) methods are restricted in the limit of detection (LoD) because of the high polymerase misincorporation rate in Taq DNA polymerases. High-fidelity (HiFi) DNA polymerases have a 50- to 250-fold higher fidelity. Yet, there are currently no proper designs for multiplexed HiFi qPCR reactions. Moreover, the popularity of targeting highly multiplex DNA sequences requires minimizing PCR side products, as the potential of dimerization grows quadratically as the plexes of primers increases. Efforts tried before were either an add-on step, or technology-specific, or requiring high-level computing skills. There lacks an easy-to-apply and cost-effective method for dimerization reduction. Here, we presented the Occlusion System, composed of a 5'-overhanged primer and a probe with a short-stem hairpin. We demonstrated that it allowed multiplexing high-fidelity qPCR reaction, it was also compatible with the current variant-enrichment method to improve the LoD by 10-fold. Further, we found that the Occlusion System reduced the dimerization up to 10-fold in highly multiplexed PCR. Thus, the Occlusion System satisfactorily improved both qPCR sensitivity and PCR efficiency.

592: Diagnostic surveillance of high-grade gliomas: towards automated change detection using radiology report classification
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Posted 27 Sep 2021

Diagnostic surveillance of high-grade gliomas: towards automated change detection using radiology report classification
121 downloads medRxiv oncology

Tommaso Di Noto, Chirine Atat, Eduardo Gamito Teiga, Monika Hegi, Andreas Hottinger, Meritxell Bach Cuadra, Patric Hagmann, Jonas Richiardi

Natural Language Processing (NLP) on electronic health records (EHRs) can be used to monitor the evolution of pathologies over time to facilitate diagnosis and improve decision-making. In this study, we designed an NLP pipeline to classify Magnetic Resonance Imaging (MRI) radiology reports of patients with high-grade gliomas. Specifically, we aimed to distinguish reports indicating changes in tumors between one examination and the follow-up examination (treatment response/tumor progression versus stability). A total of 164 patients with 361 associated reports were retrieved from routine imaging, and reports were labeled by one radiologist. First, we assessed which embedding is more suitable when working with limited data, in French, from a specific domain. To do so, we compared a classic embedding techniques, TF-IDF, to a neural embedding technique, Doc2Vec, after hyperparameter optimization for both. A random forest classifier was used to classify the reports into stable (unchanged tumor) or unstable (changed tumor). Second, we applied the post-hoc LIME explainability tool to understand the decisions taken by the model. Overall, classification results obtained in repeated 5-fold cross-validation with TF-IDF reached around 89% AUC and were significantly better than those achieved with Doc2Vec (Wilcoxon signed-rank test, P = 0.009). The explainability toolkit run on TF-IDF revealed some interesting patterns: first, words indicating change such as "progression" were rightfully frequent for reports classified as unstable; similarly, words indicating no change such as "no" were frequent for reports classified as stable. Lastly, the toolkit discovered misleading words such as "T2" which are clearly not directly relevant for the task. All the code used for this study is made available.

593: Sparse canonical correlation to identify breast cancer related genes regulated by copy number aberrations
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Posted 02 Sep 2021

Sparse canonical correlation to identify breast cancer related genes regulated by copy number aberrations
121 downloads medRxiv oncology

Diptavo Dutta, Ananda Sen, Jaya Satagopan

Background: Copy number aberrations (CNA) have proved to be of clinical and therapeutic significance for many diseases including breast cancer, since they drive numerous key underlying biological processes, by regulating molecular phenotypes like gene expression and others. To comprehensively assess the effect of CNAs, it is not sufficient to only identify significant CNA-gene expression pairs, but also to identify the overall gene networks and regulatory structures that are influenced by CNAs, subsequently producing change in outcomes. Methods: In this article, we adopt a two-step analysis approach to identify CNA regulated genes whose expression levels affect breast cancer related outcomes: (1) we identify gene modules that are regulated by CNAs through sparse canonical correlation analysis (sCCA) which selects a set of closely located CNAs that regulates the expression levels of selected genes. (2) then, we use a using generalized linear model, to identify which genes within the gene modules are associated with breast cancer related outcomes. Results: Analyzing clinical and genomic data on 1904 breast cancer patients from the METABRIC study, we found 14 gene modules to be regulated by groups of proximally located CNA sites. The identification of gene modules was further validated using independent data on individuals in a study of breast invasive carcinoma from The Cancer Genome Atlas (TCGA). Association analysis on 7 different breast cancer related outcomes identified several novel and interpretable regulatory associations which highlights how CNA can impact key biological pathways and process in context of breast cancer. Through downstream analysis of two example outcomes: estrogen receptor status and overall survival, we show that the identified genes were enriched in relevant biological pathways and the key advantage of our method is that we additionally identify the CNA that regulate these genes. Due to the availability of multiple types of outcomes, we further meta-analyzed the results to identify genes that had potentially associations with multiple outcomes. Conclusions: Overall we present a generalizable analysis approach to identify genes associated to different outcomes that are regulated by sets of CNA and can further be used to combine results across various types of outcomes. The results show that our method can identify novel and interpretable associations, by providing mechanistic insights on how the effects of CNA are cascaded via gene expression to impact breast cancer and related outcomes.

594: Individual treatment effect estimation in the presence of unobserved confounding using proxies: a cohort study in stage III non-small cell lung cancer
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Posted 30 Oct 2021

Individual treatment effect estimation in the presence of unobserved confounding using proxies: a cohort study in stage III non-small cell lung cancer
119 downloads medRxiv oncology

Wouter A.C. van Amsterdam, Joost J.C. Verhoeff, Netanja I Harlianto, Gijs A Bartholomeus, Aahlad Manas Puli, Pim A de Jong, Tim Leiner, Anne S.R. van Lindert, Marinus J.C. Eijkemans, Rajesh Ranganath

Randomized Controlled Trials (RCT) are the gold standard for estimating treatment effects but some important situations in cancer care require treatment effect estimates from observational data. We developed "Proxy based individual treatment effect modeling in cancer" (PROTECT) to estimate treatment effects from observational data when there are unobserved confounders, but proxy measurements of these confounders exist. We identified an unobserved confounder in observational cancer research: overall fitness. Proxy measurements of overall fitness exist like performance score, but the fitness as observed by the treating physician is unavailable for research. PROTECT reconstructs the distribution of the unobserved confounder based on these proxy measurements to estimate the treatment effect. PROTECT was applied to an observational cohort of 504 stage III non-small cell lung cancer (NSCLC) patients, treated with concurrent chemoradiation or sequential chemoradiation. Whereas conventional confounding adjustment methods seemed to overestimate the treatment effect, PROTECT provided credible treatment effect estimates. RCT: randomized controlled trial; PROTECT: Proxy based individual treatment effect modeling in cancer; NSCLC: non-small cell lung cancer

595: Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study
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Posted 01 Nov 2021

Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study
119 downloads medRxiv oncology

Xinyi Shen, Yuping Cai, Lingeng Lu, Huang Huang, Hong Yan, Philip B. Paty, Engjel Muca, Nita Ahuja, Yawei Zhang, Caroline H. Johnson, Sajid A Khan

Abstract Background The interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study aims to examine the link between tumor metabolome and prognosis by sex for CRC patients. Methods Using untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N=95 females, N=102 males) after surgical colectomy for stage I-III CRC. Cox Proportional Hazards (PH) regression models were applied to estimate the associations between tumor metabolome and 5-year overall survival (OS) and 5-year recurrence-free survival (RFS), and their interactions with sex. Results Eleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS (Pinteraction < .05). The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, sex-specific differences were found in the associations between prognosis and metabolic pathways. Notably, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (hazard ratio [HR] = 6.39, 95% confidence interval [CI] = 1.78-22.91, P = .004) and RFS (HR = 4.36, 95% CI = 1.39-13.68, P = .01) for female patients only (Pinteraction, OS = .02, Pinteraction, RFS = .003). Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis. Conclusions Unique metabolite profiles indicated increased asparagine synthesis was associated with poorer prognosis for females only, providing insights into precision medicine for CRC treatment stratified by sex.

596: Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study in Southeast Scotland
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Posted 25 Jul 2021

Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study in Southeast Scotland
116 downloads medRxiv oncology

Michael TC Poon, Shivank Keni, Vineeth Vimalan, Chak Ip, Colin Smith, Sara Erridge, Christopher J Weir, Paul M Brennan

Background: MGMT methylation in glioblastoma predicts response to temozolomide but dichotomising methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival. Methods: We included consecutive glioblastoma patients diagnosed (April 2012-May 2020) at a neuro-oncology centre. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumours were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, post-operative Karnofsky performance score, extent of resection, temozolomide regimen and radiotherapy. Findings: There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%) and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46-0.79, p=0.005) and low (HR 0.67, 95%CI 0.50-0.89, p<0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation p=0.097; high methylation p=0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms p<0.001). Interpretation: Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.

597: Common genetic alterations of SPOP-MATH domain in prostate cancer tissues and association with pathological tumor characteristic.
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Posted 14 Sep 2021

Common genetic alterations of SPOP-MATH domain in prostate cancer tissues and association with pathological tumor characteristic.
115 downloads medRxiv oncology

Berjas Abumsimir, Mohammed Mrabti, Abdelilah Laraqui, Imane Saif, Meryame Lamsisi, Youssef Ennaji, Ahmed Ameur, Saad Ibnsouda Koraishi, Moulay Mustapha Ennaji

SPOP gene has a critical role in prostate cancer development and found high mutated in the prostate tumor through various populations. MATH domain represents an important site for SPOP-DNA linkage and other sensitive gene-gene interactions. To investigate the genetic alterations of the MATH domain of SPOP gene in prostate cancer biopsies and correlation with clinical and pathological parameters; DNA samples from 50 prostate cancer tissues were genotyped and confirmed by Sanger sequencing. The frequency and distribution of high frequent mutations were determined and correlated with the patients tumor characteristics. Among 50 samples 34 (68%) were carrying one or more common mutations. Novel frame shift deletion mutation: c.255delA (p.Leu86Phefs) was detected in eight patients (16%), in addition to five novel missense mutations with moderate frequency (6%) namely: c.209G>C (p.Arg70Pro), c.215A>C (p.Asn72Thr), c.334G>A (p.Glu112Lys), c.373T>C (p.Phe125Leu), and c.388G>A (p.Asp130Asn), All missense mutations located in MATH domain. The effects of novel mutations described in the MATH domain are uncertain. No significant differences between carriers and noncarriers of common mutations detected regarding Gleason score, prostate-specific antigen concentration PSA, and tumor stage [p > 0.05]. Clinical significance of mutations detected on prostate tumors progression can be investigated in future analysis. Our findings revealed novel SPOP alterations in prostate cancer tissues probably associated with cancer development.

598: Multi-omics Data Analyses Construct Tumor Microenvironment and Identify the Immune-Related Prognosis Signatures in Colorectal Cancer
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Posted 30 Aug 2021

Multi-omics Data Analyses Construct Tumor Microenvironment and Identify the Immune-Related Prognosis Signatures in Colorectal Cancer
115 downloads medRxiv oncology

Shuai Zhang, Jiali Lv, Bingbing Fan, Zhe Fan, Chunxia Li, Bingbing Gu, Wenhao Yu, Tao Zhang

Background: The tumor immune microenvironment (TIME) plays a key role in occurrence, progression and prognosis of colorectal cancer (CRC). However, the genetic and epigenetic alterations and potential mechanisms in the TIME of CRC are still unclear. Methods: We investigated the immune-related differences in three types of genetic or epigenetic alterations (gene expression, somatic mutation, and DNA methylation) and considered the potential roles that these alterations have in the immune response and the immune-related biological processes by analyzing the multi-omics data from The Cancer Genome Atlas (TCGA) portal. Additionally, a four-step method based on LASSO regression and Cox regression was used to construct the prognostic prediction model. Cross validation was performed to validate the model. Results: A total of 1,745 differentially expressed genes, 178 differentially mutated genes and 1,961 differentially methylation probes were identified between the high-immunity group and the low-immunity group. We retained 15 genetic and epigenetic variables after using LASSO regression and Cox regression. For the prognostic predictions on the TCGA profiles, the performance of the model with 1-year, 3-year, and 5-year areas under the curve (AUCs) equal to 0.861, 0.797, and 0.875. Finally, the overall risk score model was constructed based on genetic, epigenetic, demographic and clinical characteristics, which comprised 18 variables and achieved a high degree of accuracy on the 1-year (AUC = 0.865), 3-year (AUC = 0.839), and 5-year (AUC = 0.914) survival predictions. Kaplan-Meier survival analysis demonstrated that the overall survival of the high-risk group was significantly poorer compared with the low-risk group. Prognostic nomogram, calibration plot and cross validation showed excellent predictive performance. Conclusions: Our study provides a new clue to explore the TIME of CRC patients in genetic and epigenetic aspects. Meanwhile, the prognostic model also has clinical prognostic value and may provide new indicators for the treatment of CRC patients.

599: Frequent Quantitation of Circulating Tumor Cells Predictive of Real-Time Therapy Response
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Posted 04 Jan 2022

Frequent Quantitation of Circulating Tumor Cells Predictive of Real-Time Therapy Response
114 downloads medRxiv oncology

Christine M Lim, Junli Shi, Jess Vo, Wai Min Phyo, Min Hu, Min Chin Tan, Augustine Tee, Yoon Sim Yap, Wenlong Nei, Daniel Chan, Seng Weng Wong, Meusia Neo, Norhidayah Binte Mohammad Mazian, Jackie Y Ying, Min-Han Tan, Kaicheng Liang, Jamie Mong

Precision medicine is playing an increasingly important role in cancer management and treatment. Specifically in the field of oncology, circulating tumor cells (CTCs) hold significant promise in enabling non-invasive prognostication and near real-time monitoring to individualize treatments. In this study, we present strong associations between CTC subtype counts with treatment response and tumor staging in lung, nasopharyngeal and breast cancers. Longitudinal analysis of CTC count changes over short-time windows further reveals the ability to predict treatment response close to real-time. Our findings demonstrate the suitability of CTCs as a definitive blood-based metric for continuous treatment monitoring. Robust processing of high-throughput image data, explainable classification of CTC subtypes and accurate quantification were achieved using an in-house image analysis system CTC-Quant, which showed excellent agreement with expert opinion upon extensive validation.

600: Prediction of radiation-induced hypothyroidism using radiomic data analysis does not show superiority over standard normal tissue complication models
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Posted 26 Sep 2021

Prediction of radiation-induced hypothyroidism using radiomic data analysis does not show superiority over standard normal tissue complication models
113 downloads medRxiv oncology

Urszula Smyczynska, Szymon Grabia, Zuzanna Nowicka, Anna Papis-Ubych, Robert Bibik, Tomasz Latusek, Tomasz Rutkowski, Jacek Fijuth, Wojciech Fendler, Bartlomiej Tomasik

State-of-art normal tissue complication probability (NTCP) models do not take into account more complex individual anatomical variations, which can be objectively quantitated and compared in radiomic analysis. The goal of this project was development of radiomic NTCP model for radiation-induced hypothyroidism (RIHT) using imaging biomarkers (radiomics). We gathered CT images and clinical data from 98 patients, who underwent intensity-modulated radiation therapy (IMRT) for head and neck cancers with a planned total dose of 70.0 Gy (33-35 fractions). During the 28-month (median) follow-up 27 patients (28%) developed RIHT. For each patient, we extracted 1316 radiomic features from original and transformed images using manually contoured thyroid masks. Creating models based on clinical, radiomic features or a combination thereof, we considered 3 variants of data preprocessing. Based on their performance metrics (sensitivity, specificity), we picked best models for each variant ((0.8, 0.96), (0.9, 0.93), (0.9, 0.89) variant-wise) and compared them with external NTCP models ((0.82, 0.88), (0.82, 0.88), (0.76, 0.91)). Our models reach accuracy comparable with or better than previously presented non-radiomic NTCP models. The benefit of our approach is obtaining the RIHT predictions before treatment planning to adjust IMRT plan to avoid the thyroid region in most susceptible patients.

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