bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utility of next generation sequencing (NGS) in advanced malignancies in a community hospital in an underserved area: A game changer?
Authors: Desai Krishna , Iqbal Sabah , Baralo Bohdan , Pereira Kristal , Jain Akhil , Deshpande Sohiel , Renzu Mahvish , Mehta Vidhi , Rather Manzoor , Thirumaran Rajesh 
Published: June 2023

e15037 Background: Next Generation Sequencing (NGS) is a revolutionary test used in advanced malignancies to study specific mutations, define tumor burdens, & design personalized treatment plans based on the target mutations. With this study, our aim is to highlight the role of NGS, especially in a community hospital & emphasize on its implementation as a standard of care in advanced metastatic cancers. Methods: We retrospectively reviewed the charts of 51 patients after IRB approval, aged > 18 years with no specific demographic restrictions, with advanced malignancies who had NGS at Mercy Catholic Medical Center, PA. Results: Of 51 patients, 25 were males & 26 were females, 44 patients had positive results on NGS. 100 types of mutations were identified & 338 mutations in total were found. Lung cancer had highest mutations (41.17%-21/51), followed by colon (25.49% - 13/51), breast, ovarian & endometrium (13.72% 7/51), & the rest comprised of GI malignancies & prostate cancers. Of 100 mutations, 32% (32/100) had actionable targets & received NGS directed chemoimmunotherapy, 22% (22/100) mutations had experimental chemo-immunotherapeutic drugs, & 49% (49/100) had no specific NGS directed therapy actionable/target mutation. The most common (1,2,3) & some rare mutations (4,5 and 6) with directed immunotherapy noted on NGS are listed in Table 1. Conclusions: As per our study, 86.27% of the sample size showed positive results on NGS. 32% of these mutations had NGS directed chemoimmunotherapy against these target mutations. In contrary to standard treatment regimens, a personalized treatment plan was developed for these patients, thereby curbing further progression & improving survival in patients with advanced cancer. For example, a patient with stage IV colon cancer who was progressing on the standard treatment with FOLFOX (Folinic acid, flurouracil and oxaliplatin), was started on Ivosedenib, after undergoing NGS and showed marked improvement clinically and radiologically. 29 out of 43 guidelines for various malignancies established by National Comprehensive Cancer Network highlight the significance of NGS. With this study, our goal is to emphasize on the utility of NGS in patients with advanced cancer & the need for it to be incorporated as the standard of care, in small & mid-tier community hospitals, which would need a devised plan for its implementation. [Table: see text]
Comprehensive multi-omic testing from a single laboratory to provide information in ovarian cancer.
Authors: Mancini-Dinardo Debora , Lenz Lauren , Comeaux Matthew , Hatcher Shanell , Gutin Alexander , Thomsen Anne , Wroblewski Ashley , Eich Alexzandra , Moll Tyson , Poyser Lynette , Slavin Thomas Paul , Timms Kirsten ,   Precise Treatment Steering Committee
Published: June 2023

e15045 Background: Molecular profiling of ovarian tumors allows for personalized disease treatment but often requires testing from multiple laboratories. This study highlights results from a molecular testing pathway that reports on germline and tumor mutations, microsatellite instability (MSI), tumor mutation burden (TMB), and homologous recombination deficiency (HRD) to guide optimal treatment selection. Methods: Samples from a consecutive prospective cohort of ovarian cancer patients were collected and tested with an HRD companion diagnostic (CDx) test (FDA-approved) that assesses genomic instability score (GIS) via a 3-biomarker signature and tumor mutation screening using a 523-gene DNA and a 55-gene RNA panel to identify clinically actionable test results using Association for Molecular Pathology (AMP) tiering. Some patients also received germline analysis via a 48-gene panel or a BRCA1/2 CDx. Clinical data (tumor stage and grade, histological subtype) were compared using logistic regression models. GIS distributions were compared using Kolmogorov-Smirnov tests. Results: To date, results from 389 eligible patients have been analyzed. Table 1 shows the primary results of molecular testing. Tumor subtype analyses revealed that high-grade serous subtype was tested most frequently (66.1%). Some less-represented subtypes (e.g., carcinoscarcoma, mucinous) appeared to have GIS distributions like high-grade serous, while others generally have low GIS. GIS distributions were significantly different in high-grade (vs moderate and vs low-grade) and stage I (vs the similar stages II-IV) tumors. Tier 1A/B mutations were observed in 16.7% of tumors; 36.9% of those were non- BRCA pathogenic variants/mutations. Distributions of histological subtype and grade were significantly different between t BRCA+ and non- BRCA samples with other Tier 1A/B mutations. Mutations were observed in 9.0% of germline tests; tumor mutation testing identified all germline variants except for a PMS2 multi-exonic deletion. Conclusions: Multi-omic testing found ~30% of ovarian cancer patients received a clinically actionable test result (HRD was the most common) and ~90% of results conferred eligibility for clinical trials. Incorporation of germline testing and RNA analysis identified unique actionable findings. A single source for comprehensive testing combined with a single integrated report facilitates rapid testing, test interpretation, and treatment choice. [Table: see text]
Landscape of FGFR2/3 alterations in genitourinary cancer.
Authors: Che Xiangyu , Liu Huanhuan , Qin Jiayue , Cao Shanbo 
Published: June 2023

e15047 Background: FGFR2/3 is frequently activated by mutation or overexpression, and it is a validated therapeutic target in several cancers. However, the molecular profile of FGFR2/3 in genitourinary cancer is still lacking. In this study, we assessed FGFR2/3 alterations for better understanding therapeutic implications in genitourinary cancer. Methods: Patients diagnosed with genitourinary cancer were enrolled in the study. Tumors and plasma samples of participants were sequencing for next-generation sequencing from Chinese cohort and TCGA database. Results: A total of 3858 patients were enrolled with 1640 renal cell cancer (RCC), 1300 prostate cancer (PC), and 918 urothelial cancer (UC), containing 2482 tumor tissues and 1376 baseline plasma samples were collected. A total of 14.6% patients (563/3858) harbored at least one FGFR2/3 alterations . 24.1% (221/918) UC carried the most FGFR2/3 alterations , including somatic mutation (18.2%), CNV (5.7%), and fusion (2.1%). Furthermore, the altered FGFRs targets are mainly S249C (6.5%), Y373C (2.5%), FGFR3-TACC3 fusion (1.6%). R248C (1.2%), and G370C (0.5%) in UC. FGFR2/3 alterations were found in 14.0% (182/1300) PC, including somatic mutation (8.2%), CNV (5.8%), and fusion (0.4%). However, only 2 patients were found to have altered FGFRs targets including R248C mutation and FGFR3-TACC3 fusion (n = 1 each). Regarding of RCC, only 9.8% (160/1640) patients had FGFR3 alterations , including somatic mutation (5.8%), CNV (5.0%), and fusion (0.5%). Furthermore, the altered FGFRs targets are mainly R248C, S249C, Y373C (n = 4 each). Moreover, patients with FGFR2/3 alterations harbored a significantly higher TMB than those in patients without FGFR2/3 alterations (Mean: 13.3 vs 9.4; p < 0.001). There was a significant difference in TMB among different cancers with FGFR2/3 alterations , with UC being the highest and PC the lowest (Mean: 17.0 vs 13.0 vs 10.2; p < 0.001). Conclusions: FGFR2/3 alterations are frequently altered in genitourinary cancer, especially UC. Comprehensive genomic profiling of FGFR2/3 alterations highlights the clinical and therapeutic implication.
Utilize protein markers and genomic features for minimal residual disease detection in hepatocellular carcinoma.
Authors: Tu Shichun , Li Shiyong , Ren Qingqi , Zhong Guolin , Li Yunfei , Feng Yumin , Zhang Yixia , Chang Yinyin , Long Guanghui , Zhu Dandan , Geng Shuaipeng , Mao Mao 
Published: June 2023

e15054 Background: Several studies have shown the clinical value of using circulating tumor DNA (ctDNA) for minimal residual disease (MRD) detection, which is more sensitive than traditional imaging methods. However, most MRD detection technologies focus on identifying mutations and require cancer tissue samples. These methods often have limitations, such as high cost, inaccessible cancer tissue, or inability to overcome tumor heterogeneity. SeekInCure is a cost-effective multi-dimensional MRD test that does not require cancer tissue analysis. The purpose of this prospective study was to evaluate the potential broad clinical utility of SeekInCure for detecting MRD in patients with hepatocellular carcinoma (HCC). Methods: 34 HCC patients undergoing radical surgery were prospectively enrolled in this study from Peking University Shenzhen Hospital. Peripheral blood samples of 8 mL were collected before and after surgery and analyzed using the SeekInCure assay, which integrates the protein tumor marker (AFP) and cancer genomic hallmarks: copy number aberrations and fragment size from ctDNA. Patients with positive results for AFP and/or ctDNA in the preoperative/postoperative samples were defined as MRD-positive (MRD+), while negative results were defined as MRD-negative (MRD-). Results: Of the 34 patients, 73.5% (25/34) were in early stages (stages I/II: 61.8%/11.8%), and 61.8% (21/34) received adjuvant therapies. The median follow-up was 279.5 days, ranging from 90 to 1,253 days. 82% (28/34) of the patients had MRD+ results in the preoperative samples, which showed remarkable sensitivity in a cohort with more than 70% of early-stage patients. Our previous findings were confirmed, with preoperative MRD+ patients having worse survival than MRD- patients1. After radical surgery, 26.5% (9/34) were MRD+. MRD+ patients had worse survival than MRD- patients, with a median overall survival (OS) time of 298 days for MRD+ patients, while the OS time for MRD- patients was not reached (P < 0.01). 6 patients with MRD- in both pre- and post-operative samples had a very favorable outcome (100% OS). Conversely, 9 patients with both positive results had the worst outcome. We also found that MRD- patients receiving adjuvant therapies did not have a survival benefit compared to those without adjuvant therapies, but MRD+ patients receiving adjuvant therapies had better OS than those without adjuvant therapies (P = 0.026). Conclusions: This study confirms the excellent performance of our SeekInCure assay, which does not require cancer tissue analysis, in detecting MRD and the prognostic value of MRD in HCC patients. Adjuvant has no influence on survival, especially in MRD- patients, which indicates that amost one-third of HCC patients do not need additional adjuvant therapy.
MATRIX plasma-in-plasma contrived samples assessment and detection of MRD using the Personalis NeXT Personal assay.
Authors: Labrousse Paul 
Published: June 2023

e15056 Background: Detection of circulating tumor DNA (ctDNA) has been shown to correlate with clinical outcome of oncology patients. Molecular residual disease (MRD) profiling by ctDNA is being rapidly deployed. Current tumor-informed MRD tests assess a relatively small number of personalised variants, placing limits on their detection sensitivity and ultimately leading to false-negative results due to insufficient assay limit of detection (LOD). Here we report a performance evaluation of the Personalis NeXT Personal tumor-informed MRD assay, using a novel design for contrived samples that are highly commutable to clinical samples, enabling robust assessment of these emerging MRD assays. Methods: Our novel samples were built from commercially acquired matched tumor and plasma samples, across different indications. The cancer plasma was diluted into a background of healthy donor plasma to create the 72 plasma-in-plasma samples in each study (total of 144). Personalis performed WGS on the matched solid tumor and normal samples from each patient. ~1800 somatic variants were selected for each patient. A personalized panel was designed and used to enrich for the selected targets in the individual plasma samples. An aggregated positive variant score was evaluated to determine the presence of ctDNA in each plasma sample. Results: MATRIX 1 panels averaged 1863 variants (range: 1818 to 1888) selected for MRD tracking. With 152 clinically relevant variants and additional assay components, an average of 2206 variants were assessed per patient. MATRIX 2 panels averaged 1836 variants (range: 1819 to 1867) selected for MRD tracking. With 2130 clinically relevant variants they averaged 4094 variants assessed per patient. In the MATRIX 1 study, tumor signal was detected in all analyzed samples, including 9 samples at 0.002% tumor plasma dilution, with an assay sensitivity of 100%. The MATRIX 2 study showed tumor signal detected in 14 of 16 samples at 0.001% tumor plasma dilution. The 2 false negatives were reported at the 0.001% tumor plasma dilution. Thus, the assay sensitivity was 87.5% at the lowest dilution (0.001%) and 96.8% overall. Conclusions: The MATRIX plasma-in-plasma approach is a robust option for assessing the sensitivity of MRD assays to low levels of ctDNA. This approach addresses all parts of an MRD assay for both the plasma and tumor/normal tissues, and is the closest thing to real clinical samples while allowing direct interrogation of sensitivity. Additionally, it allows assessment of any genomic or epigenomic biological feature. The Personalis NeXT Personal assay shows ultra-high sensitivity with reproducible data down to the 1-3 PPM range, and expansion of the personalized panel fixed clinical content allows tracking of more driver and resistance mutations with no impact to the MRD sensitivity.
Diagnostic utility of next generation sequencing for somatic variants in cancer: A seven year cumulative cohort.
Authors: Boga Ibrahim , Sonmezler Ozge , Rencuzogullari Cagla , Mujde Cem , Tug Bozdogan Sevcan , Bisgin Atil 
Published: June 2023

e15060 Background: Next generation sequencing (NGS) makes it possible to identify the specific molecular biomarkers to define patient eligibility for targeted therapies via multigene panels. Since then, even though the interpretation of data is complex and not all tumors have genomic alterations within actionable genes, using somatic sequencing for cancer patients becomes a daily routine in clinical oncology. Thus, here we present the data derived from our experience in NGS testing of different cancer patients and biological samples over the course of 7 years in our genetic diagnosis center. Methods: The cohort was consisted of total 5511 cases. While 2590 (46.99%) of them were formalin fixed paraffin embedded (FFPE) tissues, 2906 (52.73%) were liquid biopsies and 15 (0.27%) were other types of biological samples. Total of 15 different cancers were classified (Table 1) and were sequenced using 3 different multigene NGS panels (additional Table 1, BRCAs’ testing for breast/ovarian cancer is not included). NGS was performed via GeneReader NGS System (Qiagen, Germany). Bioinformatics analyzes and variant classification were performed using QCI-Analyze and QCI-Interpret interfaces. Results: As a result, the cases of 93.36% (n = 5145) among all samples were successfully sequenced. The lung cancer group was the most frequent with 47.96% (n = 2643 patients), followed by 491 (%8.9) colorectal 288 (5.23%) and breast cancer patients respectively, while 781 cases (14.17%) grouped as other including many rare cancers. Overall positivity rate was 42.57% (n = 2346) and 366 samples (6.64%) were not sufficient enough to be sequenced. The distribution of positivity rates in relation to cancer type and biological samples used were listed in Table 1. Classification and diagnosis of all tested cases, specimens and Tier 1-2 variants included in this cohort are available on the Additional Table 2. Conclusions: This report is a comprehensive review of the aggregate data across the entire cohort of cancer patients referred to a genetics diagnosis center. While our findings highlight the importance of NGS testing in the somatic setting for cancer patients, also these data stress the importance of diagnosis, biological sample types tested and test results. [Table: see text]
Expanding the spectrum of neoplasms harboring EWSR1:CREM fusion as detected by a real-world clinical genomics platform.
Authors: Campoverde Leticia , Evans Mark Gordon , Elliott Andrew , Camacho Felipe , Adler Jeremy , Oberley Matthew James , Sledge George W. , Rosenberg Andrew E. , Trent Jonathan C. 
Published: June 2023

e15061 Background: Malignancies with various well-defined phenotypes and prognoses have been shown to possess gene fusions between Ewing Sarcoma Breakpoint Region 1 ( EWSR1) and one of the CREB family genes, specifically CREB1 and ATF1. However, less is known about neoplasms that harbor EWSR1:CREM rearrangements, which are thought to result in constitutive activation of CREM and subsequent dysregulation of oncogenes, such as BCL-2 family genes, EGFR1, and cyclins. EWSR1:CREM fusion has been identified in rare cases of angiomatoid fibrous histiocytoma, clear cell sarcoma, hyalinizing clear cell carcinoma of the head and neck, and intracranial myxoid mesenchymal tumor. Our study represents the largest to date and seeks to expand and further define the diversity of tumor subtypes that possess EWSR1:CREM fusions. Methods: Detection of EWSR1:CREM rearrangements by whole transcriptome sequencing was performed for > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ). Histological review of the identified tumors was performed by two board-certified pathologists (MGE, AER). Treatment and outcome information were collected, where available. Results: An EWSR1:CREM fusion was detected in 18 cases, which included one intracranial myxoid mesenchymal tumor, one mesothelioma, four hyalinizing clear cell carcinomas of the head and neck, two clear cell sarcomas, two small round and spindle cell sarcomas, and eight histologically malignant tumors having an epithelioid morphology. While the latter were in keeping with a disease entity recently reported in the medical literature (epithelioid neoplasm with predilection for mesothelial-lined cavities), several of these cases demonstrated unexpected neuroendocrine differentiation and were found at unusual sites, including the kidney, uterus, and cervical spine. Moreover, three cases had the features of squamous cell carcinoma. Surgical resection was performed in all patients, and pazopanib was utilized in two round and spindle cell sarcoma cases. This medication was shown radiographically to produce a partial response at 19 months and stable disease at 26 months, respectively, in heavily pretreated patients. Conclusions: By detecting an EWSR1:CREM rearrangement, molecular testing may aid in the diagnosis of a variety of rare tumor types, including a poorly understood malignant epithelioid neoplasm that arises in a variety of anatomic sites including mesothelial-lined cavities. Tumors harboring this fusion may ultimately be susceptible to treatment with tyrosine kinase inhibitor targeted therapy.
Comprehensive clinical tumor RNA sequencing for children with cancer.
Authors: Vaske Olena Morozova , van den Bout Anouk , McCabe Molly , Echandia-Monroe Kathryn , Beale Holly , Kephart Ellen T. , Learned Katrina , Draper Jolene , Lyle Geoff , Bjork Isabel , Devine Patrick 
Published: June 2023

e15067 Background: Cancer is the number one cause of death by disease for children in the United States. The underlying cause for most childhood cancers is unknown and unlike most adult cancers, childhood cancers harbor fewer coding mutations compared to adult cancers and are often driven by epigenetic deregulation. The functional impact of both genetic and epigenetic abnormalities can be detected from the analysis of tumor RNA. While tumor RNA profiling has entered several clinical trials, it is not utilized comprehensively and there is limited availability of clinical-grade RNA-Seq assays. We have published preliminary evidence of the utility of using research tumor RNA information in the pediatric oncology clinic. The next step is to develop an RNA-Seq assay that identifies gene fusions, expressed mutations, and important gene expression abnormalities in pediatric tumors. Methods: To validate our RNA-Seq assay pipeline, we have started with fusion detection and compared our results with a CLIA-validated DNA-based assay. We used RNA-Seq data generated from three fusion-positive cell lines to define the minimum of Mapped, Exonic, Non-Duplicate (MEND) reads necessary to accurately identify known fusions. Results: We found that the fusion, which has moderate expression (above 3 log2(TPM+1)), was consistently detectable in subsets containing at least 1 million MEND reads (Table). We next evaluated the precision of this finding. The fusion was detected in each of 21 additional subsets of 2 million MEND reads with replacement, but in only 71% of 21 subsets of 1 million MEND reads. In RNA-Seq data generated from tumor samples preserved with FFPE, we compared our RNA-based fusion findings with structural variants detected with the DNA-based gene panel test UCSF 500. Seven positive results were concordant, and one negative result was concordant. Two negative findings were positive by UCSF 500. Evaluation of these discordant results is ongoing, but the expression data indicates that the RNA result for one, a TMPRSS-ERG fusion, is accurate. To incorporate gene expression into our assay, we assessed the precision of gene expression measurements. In a preliminary dataset of three technical replicates, we found that the 95% confidence interval of expression values greater than 3 log2(TPM+1) is 4.5% of the measured value. Comprehensive clinical validation of our protocol will involve additional previously-characterized cancer samples. Conclusions: In summary, these data establish and validate key analytical parameters necessary for successful implementation of RNA-Seq analysis in the pediatric oncology clinic and advance our ultimate goal of bringing the most innovative molecular diagnostic methods to every child with cancer. [Table: see text]