tbuckley/cabot-search huggingface dataset:
RARE-20. A RARE CASE OF A PRIMARY CENTRAL NERVOUS SYSTEM NEUROENDOCRINE CARCINOMA AND SUCCESSFULL THERAPY IN A FIVE-YEAR-OLD CHILD
Authors: Natalia Stepien, Christine Haberler, Maria-Theresa Schmook, Johannes Gojo, Amedeo A Azizi, Thomas Czech, Irene Slavc, Andreas Peyrl
Journal: Neuro-Oncology (2021)

Abstract Neuroendocrine tumors (NETs) are rare neoplasms predominantly arising in the GI-tract or the lungs of adults. To date, only ten cases of primary CNS NETs have been reported with just three of them describing a neuroendocrine carcinoma (NEC) in patients aged 34–77 years and none occurring in a child. We report on a previously healthy 5-year-old boy, who presented with headaches, nausea and vomiting and was diagnosed with a left cerebellar solid mass with a cystic component, radiologically suggestive of a pilocytic astrocytoma. After gross-total resection, histological analysis revealed an epithelial tumor growing in a nest-like pattern with a very high mitotic frequency, staining positive for CK8, CK18 and CK19. Chromogranin A and synaptophysin expression indicated a neuroendocrine differentiation. Molecular analysis of the tumor tissue revealed a KRAS- splice-site mutation (c451-3C&amp;gt;T). After extensive search for an extracranial primary, including Ga-68 DOTANOC-PET-CT, the diagnosis of a primary CNS NEC was made, and proton irradiation was performed. However, the patient developed an in-field recurrence just five weeks after the end of radiotherapy. The tumor was re-resected en-bloc, showing vital tumor tissue, demonstrating its aggressiveness. Chemotherapy consisting of etoposide, cisplatin and ifosfamide was initiated. After two cycles chemotherapy was continued with etoposide and carboplatin for another four cycles. The patient remains disease free one year after the end of relapse-treatment, supporting the beneficial effect of platinum- and etoposide-based chemotherapy for this tumor entity. Physical exam revealed a sagittal synostosis with a mild dolichocephaly. Interestingly, the KRAS-mutation was discovered to be a maternal germline mutation, previously described as likely benign. However, alterations of the RAS/MAPK pathway have been described in NECs and in craniosynostosis cases. It remains to be elucidated whether the KRAS-mutation is merely a variant of uncertain significance or might have been implicated in the development of this exceptional tumor.
An investigation into the impact of next generation sequencing on the use of targeted treatments in glioblastoma.
Authors: Jordan John, Rimas Vincas Lukas, Priya Kumthekar
Journal: Journal of Clinical Oncology (2021)

2035 Background: Next-generation sequencing (NGS) provides clinicians immense amounts of information about a patient’s cancer. NGS allows the detection of a wide range of gene alterations undetectable by older techniques. This has the promise to help guide clinicians in their decision-making as genetic alterations can be both prognostic and predictive. NGS may reveal new treatment options for patients with glioblastoma. The goal of this project was to evaluate how often NGS results influence the use of targeted treatment agents in glioblastoma. This study did not investigate the impact of NGS on reclassification of cancers, prognosis, or treatment decisions outside of the use of targeted therapy. Methods: We conducted a retrospective chart review to see if adult glioblastoma patients received treatments for potentially actionable gene alterations and for fusion variants because of NGS. Here we looked at alterations labeled as actionable from the Tempus company’s NGS results. We collected diagnosis and treatment information from the Electronic Medical Record and from the Electronic Data Warehouse. We examined if patients after receiving NGS would receive targeted treatment, as that likely indicated these treatments were given due to NGS indication. We excluded cytotoxic chemotherapy agents and bevacizumab as these therapies are utilized regardless of a targeted gene indication. This analysis excluded treatments received in clinical trials in which enrollment was independent of NGS. This analysis looked at the proportion of patients with actionable alterations that were treated with targeted agents. Results: 261 glioblastoma patients were found on NGS to have mutations which were potentially actionable. Thirty-three of these patients (12.6%) received a respective targeted therapy, and the other 228 patients (87.4%) did not receive an NGS guided targeted therapy. 97 patients had EGFR copy number gains or EGFR gain of function mutations of which 21 were treated with depatuxizumab mafodotin, and one additional patient who was treated with ABBV 321. Of the NGS treatment guided therapies, depatuxizumab mafodotin was the most used targeted agent in our sample set. Additionally, there were 30 patients with fusion variants and 11 of them were FGFR3-TACC3 fusions. Of these 11, 4 received targeted regimens (36.4%) with either TAS-120, pemigatinib, erdafitinib, or erdafitinib with ponatinib. The other fusion variants were not acted upon. Conclusions: These preliminary results suggest that NGS data currently does not frequently impact treatment decisions for glioblastoma. Although this study is limited by being a single institution study, future efforts include expanding this analysis to multiple institutions. With improvements in therapeutics as well as with wider availability of NGS testing, sequencing data may impact a larger percentage of glioblastoma patients.
Prevalence of fertility discussions between young adult colorectal cancer survivors and their providers.
Authors: Julia Stal, Serena Yi, Sally Cohen-Cutler, Phuong Gallagher, Afsaneh Barzi, Joel Milam, David R. Freyer, Heinz-Josef Lenz, Kimberly Ann Miller
Journal: Journal of Clinical Oncology (2021)

3518 Background: Clinical guidelines indicate that oncologists should discuss potential treatment-induced infertility with patients with reproductive potential. Due to tumor location and use of multimodal therapies, young adults with colorectal cancer (CRC) are at heightened risk for treatment-related infertility. Methods: An online, cross-sectional survey was administered in collaboration with a national patient advocacy organization for young adult CRC survivors (currently under age 50). Survivors were asked to indicate if a doctor had ever talked to them about potential problems with their ability to have children after treatment and if they banked eggs/embryos (females) or sperm (males) prior to their cancer therapy. Those who reported that they did not preserve fertility were asked to indicate why ( not sure; I chose not to; I did not know this was an option; I wanted to, but could not afford it; and I wanted to, but my treatment would not allow it). Results: A total of 234 colon (N=86) or rectal (N=148) cancer survivors were included in the study (male [61.9%] and White [77.9%; table]). Most respondents were diagnosed with stage 2 cancer (55.8% colon, 61.6% rectal). Over half of male and female survivors reported that their doctor did not talk to them about problems with their ability to have children after treatment, and 75% did not bank eggs/embryos or sperm prior to their cancer therapy. Of those, over 20% endorsed ‘I wanted to, but could not afford it’ and over 20% endorsed ‘I did not know this was an option’. Conclusions: Most CRC survivors in this study reported never having a fertility discussion with their provider, suggesting that survivors are not receiving, or cannot recall, comprehensive and guideline-concordant cancer care. In addition, one-fifth were not aware of preservation options, suggesting potential healthcare and/or provider-level barriers to appropriate fertility counseling. Fertility preservation cost is another barrier to the appropriate delivery of care. Providers must ensure that patients receive timely fertility discussions covering options to preserve fertility to mitigate this late effect of cancer treatment to ensure optimal quality of life for CRC patients with reproductive potential.[Table: see text]
Application of the Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma
Authors: Yun Xu, Ying Yao, Weiqin Yao, Song Jin, Lingzhi Yan, Jingjing Shang, Chengcheng Fu, Depei Wu
Journal: Blood (2017)
Characterizing unplanned resource utilization associated with cancer-related diarrhea.
Authors: Lee S. Schwartzberg, Eric Roeland, Pablo C. Okhuysen, Ruthwik Anupindi, M Hull, Jason Yeaw, Lucille Sun, Iris M. Tam, Gina Franklin, Pravin Chaturvedi
Journal: Journal of Clinical Oncology (2021)

e18625 Background: In clinical oncology practice, diarrhea is a very common and severe side effect of cancer treatments including from radiotherapy, chemotherapy, and targeted therapies. Cancer-related diarrhea (CRD) leads to increased healthcare resource consumption due to unscheduled outpatient visits, and , increased hospital stays requiring intensive supportive care measures. We evaluated CRD patients receiving chemotherapy, targeted therapy, or both, requiring emergency department (ED), physician office visits, hospitalizations, and length of stay (LOS) compared to a matched cohort of non-CRD patients. Methods: We performed a longitudinal study among adult patients ( &gt; 18 yrs) with CRD identified by diagnosis codes or pharmacy claims compared to matched non-CRD patients using claims data derived from the IQVIA PharMetrics Plus database. Index date was the first cancer claim date and patients were re-indexed based on their CRD claim. Each patient had a 6-month pre-index period, a minimum 3-month post-index period and had ≥12 months of continuous enrollment following the CRD index date. To adjust for selection bias and baseline differences, we matched CRD patients to non-CRD patients (1:1) by age, gender, geography and payer type. Patients were stratified by cancer therapy type (chemotherapy, targeted therapy or both treatments). We reported proportion of patients with hospitalizations, average length of stay (LOS), and ED visits. A generalized estimating equation model with log link and binomial distribution adjusted for type of cancer, therapy, and Charlson Comorbidity Index (CCI) was built to estimate the difference in occurrence of hospitalization between CRD and non-CRD cohorts. Results: We evaluated a total of 104,135 matched pairs of CRD and non-CRD adult patients with solid or hematologic cancer with 12-month continuous enrollment. The proportion of patients with ED visits (36.2% vs 18.9%, p &lt; 0.0001) and hospitalizations (29.6% vs 12.8%, p &lt; 0.0001) were significantly higher among CRD versus non-CRD cohort. When compared to non-CRD patients, CRD patients were more likely to be hospitalized (adjusted OR 2.28. 95% CI of 2.23-2.33). Mean CRD-specific office/hospital visits were significantly higher in the CRD cohort compared to the non-CRD cohort over the 12-month post-index period and patients had more CRD-specific visits to ED (7.5% vs 1.8%); physician’s offices (14.7% vs 3.8%); laboratory testing (11.6% vs 3.2%) and outpatient ancillary services (10.9% vs 2.6%) (all p &lt; 0.0001). Mean hospital LOS among patients with CRD was higher than non-CRD patients (6.6±8.9 vs 5.8±10.5 days, p &lt; 0.0001). Conclusions: Patients with CRD used significantly more resources, including outpatient services, ED visits, and hospitalizations. Effective prevention of CRD remains an unmet strategy to reduce the overall cost of cancer care.
Abstract 16005: Automated Aortic Analysis Using MRI and Deep Learning: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Vivek P Jani, Gisela Texido-Tura, Nadjia Kachenora, Kevin Bouaou, Alain De Cesare, Shelby Kutty, Colin Wu, David Bluemke, Joao A Lima, Bharath Ambale-Venkatesh
Journal: Circulation (2019)

Introduction: Direct measurement of central aortic stiffness by means of aortic distensibility has been shown to be an early marker of subclinical vascular alteration. However, current methods to m...
Multi-omics characterization of left-right colorectal cancer.
Authors: John Marshall, Takayuki Yoshino, Sun Young Rha, David N. Church, Anelisa Kruschewsky Coutinho, Carlos Alberto Sampaio-Filho, David James Gallagher, Jesús García-Foncillas, Silvia von der Heyde, Hartmut Juhl, Jonathan Woodsmith, David J. Kerr
Journal: Journal of Clinical Oncology (2021)

3542 Background: Right (R) vs left (L) sided colorectal cancers are clinically distinguishable based on prognosis and response to certain therapies, but as of yet, limited data have emerged to explain these differences. The science of molecular testing has evolved rapidly. Enabled by improved technologies and computing power, it is now feasible to obtain to systematic multi-omic datasets covering DNA, RNA, proteins, phospho-proteins and metabolomics on large numbers of patients. Multi-omic analysis can further define disease specific subgroups but pre-analytic quality of the tissues (ischemia time) and comparison to normal tissue controls is paramount to optimize results. Methods: Following informed consent, 450 colorectal cancer primary tumors and paired normal tissues were collected following an SOP to minimize ischemia time, and were analyzed using comprehensive genomics, transcriptomics, proteomics, phosphoproteomics, morphology and annual clinical information. Right (C18.0,2,3) and left (C18.6,7) CRC tumors, normal tissue were compared using machine learning tools to unravel the molecular mechanisms that underpin these clinically distinguishable phenotypes as well as correlating with known genomic metrics such MSI and KRAS mutation status. Results: Through leveraging the tumor and paired normal patient samples, systematic differences between left and right tumor samples were observed including specific molecular events associated with these anatomical differences. The detailed results will be presented at the meeting. Conclusions: Progress in precision medicine requires the inclusion of multi-omics which in turn requires changes to our current SOPs of tissue collection. The ability to define molecular distinctions such as between R and L colon cancer will permit the rapid discovery of clinically useful prognostic and predictive markers, dramatically adding to our fundamental understanding to colon cancer biology. Future work will focus on the discovery of novel targets and signatures, creating innovative tools that depict multi-omic results for clinicians.
Impact of stratifying levels of serum lactate dehydrogenase (LDH) at diagnosis on the overall survival (OS) in newly diagnosed multiple myeloma (NDMM).
Authors: Laura Evans, Shaji Kumar, David Dingli, Angela Dispenzieri, Martha Lacy, Ronald S. Go, Francis Buadi, Nelson Leung, Yi Lin, Suzanne R. Hayman, Stephen J. Russell, Eli Muchtar, Prashant Kapoor, Mustaqeem Ahmad Siddiqui, Rahma M. Warsame, Taxiarchis Kourelis, Robert A. Kyle, Morie A. Gertz, S. Vincent Rajkumar, Wilson I. Gonsalves
Journal: Journal of Clinical Oncology (2021)

e20016 Background: An elevated serum LDH level is an adverse prognostic factor in NDMM. However, this category includes quantitative serum LDH levels that range from just over the upper limit of normal (ULN) to levels that may be 2 or more-fold higher than the ULN. This binary classification of serum LDH level of “normal versus elevated” fails to discriminate between the different disease biology that exists among NDMM patients with elevated serum LDH levels. Thus, we attempted to further stratify NDMM patients by the level of their serum LDH and determine its impact on OS. Methods: The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester from 2003 - 2017 who were treated with novel agent induction therapy and had serum LDH levels measured at the time of diagnosis. The serum LDH levels were stratified into three levels: Normal (LDH &lt; 222 U/L), Elevated (LDH 223-444 U/L), and Very Elevated (LDH &gt;444 U/L or &gt;2x upper limit of normal). Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Results: The cohort consists of 1,196 NDMM patients with a median age of 65 (22 – 95). R-ISS classification and cytogenetic risk were available for 968 and 970 patients respectively. The median serum LDH level was (162 U/L (3- 1260)) and an elevated LDH was present in 199 patients (17%). The median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%) and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months and 23 months respectively (P &lt; 0.001). The impact of these different levels of LDH on OS by R-ISS stage and cytogenetic risk is shown in the Table. Conclusions: A very small subset of NDMM patients has very elevated LDH levels that confer an exceptionally poor OS irrespective of R-ISS stage and cytogenetic risk. Future studies elucidating their disease biology responsible for such poor OS outcomes are warranted.[Table: see text]
Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).
Authors: Shun Lu, Xiaorong Dong, Hong Jian, Jianhua Chen, Gongyan Chen, Yuping Sun, Yinghua Ji, Ziping Wang, Jianhua Shi, Junguo Lu, Shaoshui Chen, Guojun Zhang, Dongqing Lv, Chunling Liu, Juan Li, Xinmin Yu, Zhong Lin, Zhuang Yu, Zhehai Wang, Jiuwei Cui
Journal: Journal of Clinical Oncology (2021)

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value &lt;0.0001). DoR was also significantly prolonged with Au. Median OS has not been reached. Efficacy and relevant safety results are summarized in Table. Despite a significantly longer duration of treatment (median 463 vs 254 days), Au was associated with a lower incidence of rash, diarrhea, AST/ALT increase, and treatment related serious adverse events (SAEs) (4.2% vs 11.2%). Au was associated with more frequent events of CPK increased, platelet count decreased, and neutrophil count decreased, which were predominantly low grade. Conclusions: Au significantly prolonged PFS and DoR compared to G as first-line therapy in pts with advanced NSCLC with EGFRm. Au demonstrated a favorable safety profile, especially regarding toxicities mediated by wild-type EGFR. These results establish Au as a promising option for advanced NSCLC with EGFRm. Clinical trial information: NCT03849768. [Table: see text]
Histone citrullination: a new target for tumors
Authors: Dongwei Zhu, Yue Zhang, Shengjun Wang
Journal: Molecular Cancer (2021)

As the main protein components of chromatin, histones play central roles in gene regulation as spools of winding DNA. Histones are subject to various modifications, including phosphorylation, acetylation, glycosylation, methylation, ubiquitination and citrullination, which affect gene transcription. Histone citrullination, a posttranscriptional modification catalyzed by peptidyl arginine deiminase (PAD) enzymes, is involved in human carcinogenesis. In this study, we highlighted the functions of histone citrullination in physiological regulation and tumors. Additionally, because histone citrullination involves forming neutrophil extracellular traps (NETs), the relationship between NETs and tumors was illustrated. Finally, the clinical application of histone citrullination and PAD inhibitors was discussed.
An ultrasensitive method for noninvasive pan-cancer early detection based on targeted methylation sequencing of cell-free DNA.
Authors: Tiancheng Han, Yuanyuan Hong, Pei Zhihua, Song Xiaofeng, Jianing Yu, Geng Chen, Weizhi Chen, Ji He
Journal: Journal of Clinical Oncology (2021)

10544 Background: Screening the biomarkers from the cell-free DNA (cfDNA) of peripheral blood is a non-invasive and promising method for cancer diagnosis. Among diverse types of biomarkers, epigenetic biomarkers have been reported to be one of the most promising ones. Epigenetic modifications are widespread on the human genome and generally have strong signals due to the similar methylation patterns shared by adjacent CpG sites. Although some epigenetic diagnostic methods have been developed based on cfDNAs, few of them could be applied to pan-cancer and their sensitivities are barely satisfactory for early cancer detection. Methods: Targeted methylation sequencing was performed using our in-house-designed panel targeting regions with abundant cancer-specific methylation CpGs. The cfDNA samples from 80 healthy individuals and 549 cancer patients of 14 cancer types were separately sequenced. The dataset was randomly split into one discovery dataset and one validation dataset. Moreover, cfDNA samples from four cancer patients were diluted with the healthy cfDNAs to generate 12 in vitro simulated samples with low circulating tumor DNA (ctDNA) fraction. Additionally, DNAs extracted from 130 unmatched tumor formalin fixation and paraffin embedding (FFPE) samples of 10 cancer types were sequenced to screen the diagnostic biomarkers. Adjacent CpG sites were first merged into methylation-correlated blocks (MCB) according to their correlations of methylation levels in tumor DNAs. The MCBs with higher methylation levels in tumor DNAs than that of healthy cfDNAs (from the discovery dataset) were defined as our hypermethylation biomarkers. For each cfDNA sample, a hypermethylation score (HM-score) was computed to measure the overall methylation level difference of selected biomarkers. The performance of our method was evaluated with the real-world dataset, while the limit of detection was estimated using the simulated low-ctDNA samples. Results: Our model based on 37 hypermethylation MCB biomarkers achieved an area under the curve (AUC) of 0.89 and 0.86 in the real-world pan-cancer discovery and validation cfDNA datasets, respectively. Furthermore, the overall specificity and sensitivity are 100% and 76.19% in the discovery dataset, and 96.67% and 72.86% in the validation dataset. In the validation dataset, 28/40 (70%) of early-stage colorectal cancer patients and 10/20 (50%) of non-small-cell lung cancer patients were successfully diagnosed. Additionally, all the simulated samples with theoretical ctDNA factions over 0.5% were predicted as diseased, demonstrating the ability of our method to detect tumor signals at early stages. Conclusions: Our cfDNA-based epigenetic method outperforms currently available methods in various cancer types, and is promising to be applied to early-stage cancer detection and samples with low ctDNA fractions.