tbuckley/cabot-search huggingface dataset:
The genomic and transcriptomic characteristics of early recurrence patients in stage IA non-small cell lung cancer.
Authors: Shirong Zhang, Hong Jiang, Xueqin Chen, XiuLi Zhu, Jing Bai, Qiong Wu, Runlei Hu, Chenchen Zhu, Xuefeng Xia, Yanping Xun, Jing Zhang, Shenglin Ma
Journal: Journal of Clinical Oncology (2021)

e20547 Background: Lung cancer is the leading cause of cancer-related death worldwide. The mortality risk is still high in early stage because of the high relapse rates about 30–45% within 5 years after surgery. The main purpose of this study was to depict the genomic and transcriptomic characteristics in stage IA non-small cell lung cancer (NSCLC) patients and elucidate the recurrence risk factors for providing more postoperative intervention management and treatment. Methods: We prospectively enrolled 60 patients with stage IA NSCLC from 2012 to 2018 including 29 non-relapse patients and 31 early-relapse patients within 5 years. A total of 60 primary tumor specimens and 10 relapse tumor specimens were obtained. The paired adjacent non-tumor tissues for each patient were collected as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: The most frequently mutated genes in our cohort were EGFR (46.4%), TP53 (38.0%), TTN (35.2%) and USH2A (21.1%). Notably, USHA was enriched in relapse patients (32.3% vs 3.4%, p = 0.006). The median tumor mutation burden of the post-relapse group was 6.14/Mb, significantly higher than the pre-relapse group (Median: 2.63/Mb, p = 0.047) and the non-relapse group (1.91/Mb, p = 0.025). Among the early-relapse patients, copy number amplification at 2q31.1 was prevalent in the pre-relapse group (p &lt; 0.05). Two patterns of clonal evolution were identified during the recurrence, including autonomous clonal evolution and acquired clonal evolution. Compared with non-tumor tissues, differentially expressed genes in pre-relapse affected the metabolism-associated pathways. Furthermore, post-relapse samples down-regulated antigen processing and presentation signaling pathway compared to non-relapse group. Interestingly, lower plasma dendritic cell infiltration was detected in post-relapse (p = 0.0078), indicating the defect of antigen presentation in recurrence. Concentrating on the primary tumor specimens, samples from relapse patients showed higher infiltration of CD8+T cell (p = 0.019), Helper T cells (p = 0.0036) and Treg cells (p = 0.0071) than that from non-relapse patients. Conclusions: This study elucidated the recurrence risk molecular and immune microenvironment in stage IA NSCLC patients. Findings in our research may help find out the subset of patients with early stage at high risk for recurrence who have the urgent need for postoperative intervention and guide therapeutic strategies.
HGG-24. PRECLINICAL EFFICACY OF THE BRAIN PENETRANT CYCLIN-DEPENDENT KINASE INHIBITOR ZOTIRACICLIB IN PEDIATRIC DIFFUSE MIDLINE GLIOMAS
Authors: Timothy Mueller, Sridevi Yadavilli, Sandra Laternser, Chiara Cianciolo, Justyna Przystal, Erin Bonner, Matt C Biery, Nicholas A Vitanza, Michael Grotzer, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2021)

Abstract Children diagnosed with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have extremely poor outcomes with a median overall survival of 9–12 months from initial diagnosis. Standard-of-care is limited to focal radiation therapy, given the paucity of effective targeted therapies for DMG. To identify effective drugs for treatment of children diagnosed with DMG, we investigated the brain-penetrating multi cyclin-dependent kinase inhibitor Zotiraciclib (ZTR/TG02). ZTR has demonstrated encouraging response rates and a benign safety profile in phase 1 trials of adults with high-grade glioma. It is thought to achieve its anti-cancer activity mainly by transcription disruption, a previously described vulnerability of DMGs, by inhibiting multiple cyclin-dependent kinases 9 and 7 (CDK9, 7). We found that ZTR robustly reduces viability of different patient derived DMG cells in a dose-dependent manner, with a median IC50 of 201 nM across eight tested cell lines (range 11–1258 nM, 72 hrs). Consistently, we observed loss of RNA polymerase II phosphorylation after 24 hours of treatment, indicating effective CDK9 inhibition at low drug concentrations and after short incubation time. This effect was followed by depletion of short-lived proteins including MYC and the anti-apoptotic factor MCL-1. Putative biomarkers of response and resistance were identified in silico using DepMap data analysis. To assess the safety profile of ZTR, we exposed our zebrafish model to various drug concentrations and found the drug to be safe at IC50 molarity. Ongoing in vitro and in vivo studies evaluating the efficacy of ZTR in combination with promising combination therapies for more effective treatment of children with DMG are also underway.
HbA 1c と冠動脈硬化の重症度との関連-非糖尿病男性(HbA 1c ≦5.8%,FBS≦99mg/dl)における検討
Authors: Kasahara Hisashi, Endo Satoshi, Kinugasa Ryoji, Ozaki Shuichi, Otahara Akira
Journal: Circulation (2007)
Potential role of serum proteome in predicting immune-related adverse events from immune checkpoint inhibitors in non-small cell lung cancer.
Authors: Leeseul Kim, Young Kwang Chae, Chan Mi Jung, Emma Yu, Alice Daeun Lee, Yoonhee Choi, Hojung Jung, Inae Park
Journal: Journal of Clinical Oncology (2021)

e21218 Background: Early recognition of immune-related adverse events (irAEs) of immune checkpoint inhibitors(ICI) is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We previously have reported that a serum-based proteomics test, Primary Immune Response (PIR) demonstrated a trend that PIR-sensitive patients are more likely to tolerate ICI treatment longer without developing irAEs in non-small cell lung cancer (NSCLC) patients. The VeriStrat test is another serum-based proteomic assay, which was reported to be predictive of survival outcomes for all treatment regimens and lines of therapy including ICI in NSCLC. We explored the associations between the VeriStrat test and developing irAEs in NSCLC patients treated with ICI. Methods: Data of 70 consented NSCLC patients treated with any regimens and lines of therapy including ICI were collected. Samples were grouped into either VeriStrat ‘Good’(VS-G) or VeriStrat ‘Poor’(VS-P). We analyzed the durations from the immunotherapy initiation to each episode of irAE and each irAE above grade 2 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among the 70 patients, 18 patients (25%) experienced one or more irAEs. There was no significant difference in ‘Time to first irAE’ between VS-G and VS-P (p = 0.72, HR = 0.82, 95% CI = 0.29-2.32). Among 48 VS-G patients, 12(25%) had one or more irAE and 5(10%)had irAE graded over 2. Among 22 VS-P patients, 6(27%) had one or more irAE and 2(9%) had irAE graded over 2. There was no significant difference between VS-G and VS-P groups in the development of irAE and irAE graded over 2. Conclusions: There was no statistically significant association between the VeriStrat test and the development of irAEs. Further studies are warranted to investigate proper serum based proteomic assay to predict the development of irAE.
OMIC-07. FEASIBILITY AND UTILITY OF EPIGENOMIC PROFILING FOR CHILDHOOD CNS TUMORS IN HONG KONG
Authors: Anthony P.Y. Liu, Ronnie S L Ho, Kay K W Li, Shing Chan, Dennis T L Ku, Eric Fu, Chung-Wing Luk, Jeffrey P W Yau, Siu-Cheung Ling, Brian H Y Chung, Wanling Yang, Amanda Kan, Matthew M K Shing, Ho-Keung Ng, Godfrey C F Chan
Journal: Neuro-Oncology (2021)

Abstract Genome-wide DNA methylation profiling has emerged as an important diagnostic tool that complements histopathology for CNS tumors in children and adults. Literature describing its application in Asian countries is nonetheless limited. Herein, we report the feasibility and utility of adopting such platform for children diagnosed with CNS tumors in Hong Kong. A multi-institutional cohort (n=94, 97% of Chinese ethnicity) with CNS embryonal or high grade neuroepithelial tumors (HGNET) diagnosed in Hong Kong from 1996–2020 was assembled based on tissue availability. DNA was extracted from FFPE tumor material (median 301ng, range 13-1000ng), bisulfite converted and profiled with the Infinium Methylation EPIC BeadChip kit. Raw data were analyzed on the German Cancer Research Center MNP 2.0 classifier and through unsupervised dimensionality-reduction analysis (t-SNE) referencing a published CNS tumor reference dataset (GSE90496). The radio-histologic diagnosis included medulloblastoma (n=65), ATRT (n=9), pineal parenchymal tumors (n=7), ETMR (n=5), CNS-PNET (n=4) and other embryonal tumors/HGNETs (n=4). Methylation class could be assigned based on results from MNP 2.0 (calibrated score ≥ 0.9) in 62 patients (66%, including 2 clustering with control) and t-SNE in 22 (23%), while no-match was encountered in 10 (11%). Methylation-based analysis allowed confirmation of diagnosis and assignment of molecular subgroup in 64 patients (68%), confirmation of histologic diagnosis alone in 5 (5%) and resulted in revision/reassignment of diagnosis in 13 (14%). Among medulloblastoma samples that were assigned molecular tumor classes (n=57), 8 clustered with WNT-activated medulloblastoma, 13 with SHH-activated medulloblastoma, 10 with Group 3 medulloblastoma, 21 with Group 4 medulloblastoma, and 5 with non-medulloblastoma entities (high-grade gliomas=3, ETMR=1, ATRT=1). In conclusion, epigenomic profiling allowed refinement of disease classification for pediatric CNS tumors. Availability of such methodology in Asia sets the stage for international collaborations in molecularly-driven trials.
The efficacy and safety of toripalimab combined with definitive chemoradiotherapy for patients with locally advanced esophageal squamous cell carcinoma.
Authors: Mian Xi, Yujia Zhu, Qiao-Qiao Li, Lei Zhao, Yadi Yang, Yonghong Hu, Mengzhong Liu
Journal: Journal of Clinical Oncology (2021)

e16043 Background: Definitive chemoradiotherapy (CRT) is the standard treatment option for unresectable locally advanced esophageal cancer. However, the loco-regional and distant recurrences after definitive CRT were as high as 50%. Immunotherapy targeting the PD-1/PD-L1 axis has demonstrated antitumor activity in advanced esophageal cancer. With the potential benefit of combining PD-1 blockade to CRT, we performed a phase II trial to evaluate the efficacy and safety of the combination of toripalimab (an anti-PD-1 antibody) and definitive CRT in locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with previously untreated, unresectable, stage II–IVA ESCC were enrolled. Patients received concurrent radiotherapy (50.4 Gy in 28 fractions), chemotherapy (weekly paclitaxel 50 mg/m 2 and cisplatin 25 mg/m 2 for 5 cycles), and toripalimab (240 mg, every 3 weeks until 12 months or disease progression). The primary endpoint was clinical complete response (cCR) rate at 3 months after CRT according to PET-CT scan and esophagogastroduodenoscopy with biopsies. Second endpoints were overall survival (OS), progression-free survival (PFS), adverse events (AEs). Exploratory endpoints included PD-L1 expression, tumor mutational burden, and genetic biomarkers as potential efficacy predictors. Results: Between November 2019 and December 2020, 42 eligible patients (2 stage II, 19 stage III, and 21 stage IVA) were included. Of them, 39 completed CRT and 3 remained under treatment. Twenty-eight patients were included for efficacy analysis (median follow-up: 7.2 months) and 42 for safety analysis (median follow-up: 5.8 months). The cCR rate was 60.7% (17/28) and the median OS and PFS were not reached. Thirty-nine patients (92.9%) had AEs, 20 patients (47.6%) experienced grade ≥3 AEs, and 1 patient (2.4%) suffered grade 5 esophageal fistula. The most common grade ≥3 AEs were lymphopenia (45.2%), neutropenia (33.3%), and anemia (28.6%), respectively. Conclusions: The addition of toripalimab to definitive CRT for locally advanced ESCC demonstrated encouraging efficacy and acceptable toxicity. The exploratory endpoints including PD-L1 expression and genetic biomarkers analyses are ongoing. Clinical trial information: NCT04005170.
Efficacy and safety of toripalimab combination with SOX regimen as a first-line treatment in patients with unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer: Preliminary data from a single-armed, exploratory study.
Authors: Xiaolin Lin, Qing Xia, Ting Han, Meng Zhuo, Haiyan Yang, Xiaoxia Qiu, Liwei Wang, Xiuying Xiao
Journal: Journal of Clinical Oncology (2021)

e16015 Background: Gastric cancer (GC) is one of the most common malignancies of the digestive system with a poor prognosis and limited treatment option. Currently immunotherapy is approved for the third-line treatment of GC, but there are limited data on first-line treatment. Therefore, this study will further explore the efficacy and safety of the domestic PD-1 antibody toripalimab combined with S-1 plus oxaliplatin (SOX) regimen as the first-line treatment of unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer. Methods: A prospective, single-armed, exploratory, investigated initiated trial explores the efficacy and safety of toripalimab combined with SOX regimen as first-line treatment of unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer. The primary objectives are objective response rate (ORR). Secondary objectives include disease control rate (DCR), DOR, PFS, and OS. The dosage regimen is: Toripalimab, 240mg D1; oxaliplatin, 130mg/m 2 , D1 ; S-1, 40mg/m 2 , bid oral D1-14 days, every 21 days as a cycle and plan 6 cycles of treatment. Tumor responses were assessed radiologically every two cycles. Major eligibility requirements include: unresectable advanced, recurrent or metastatic gastric/gastroesophageal junction cancer with diagnoses confirmed histologically or cytologically, age 18 and 80 years, first-line treatment, at least one measurable lesion according to RECIST 1.1, ECOG 0-1, adequate organ function and HER-2 negative. Results: So far, 17 of planned 20 patients have been enrolled. 14 patients completed 2 cycles of treatment, the ORR rate was 57% (8/14) and the disease control rate (DCR) was 93% (13/14). 10 patients completed 4 cycles of treatment, the ORR rate was 60% (6/10) and the disease control rate (DCR) was 90% (9/10). 7 patients completed 6 cycles of treatment, the ORR rate was 43% (3/7) and the disease control rate (DCR) was 57% (4/7). Common adverse reactions during treatment in 17 patients included rash 17.6% (3/17), diarrhea 41.2% (7/17), hypothyroidism 11.8% (2/17), elevated amylase 35.3% (6/17), decreased platelets 41.2% (7/17), mostly grade I-II. Conclusions: Toripalimab combination with SOX regimen as a first-line treatment demonstrated promising anti-tumor activity in unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer patients with a good ORR and controllable safety. Clinical trial information: NCT04202484.
Complete metabolic response in advanced non-small cell lung cancer patients with prolonged response to immune checkpoint inhibitor therapy.
Authors: Daniel Christian Christoph, Justin Ferdinandus, Martin Metzenmacher, Peter Kessler, Lale Umutlu, Clemens Aigner, Karl-Otto Kambartel, Viktor Grünwald, Wilfried Ernst Erich Eberhardt, Wolfgang Peter Fendler, Ken Herrmann, Martin Faehling
Journal: Journal of Clinical Oncology (2021)

9050 Background: Recently reported, extended follow-up data from KEYNOTE-024 or -010 indicates that non-small-cell lung cancer (NSCLC) patients can experience long-term benefit from immunotherapy irrespective of discontinuation (per protocol: 35 cycles ∼24 months) or type of response in computed tomography (CT). Similar results were observed in the pooled analysis of 5-year follow-up data from CheckMate-017 and -057. This raises the question, whether patients may safely discontinue immunotherapy after achieving durable response. However, recently published results from CheckMate-153 demonstrated inferior survival rates in patients ceasing immunotherapy after one year, therefore optimal treatment duration of immunotherapy in advanced NSCLC remains unknown. Protocols from published Phase-III trials implemented treatment for a period of approximately 24 months or until evidence of disease progression or unbearable toxicity. Therefore, the ideal duration of immunotherapy remains unclear, and finding markers of beneficial outcome is of great importance. Here, we determine the proportion of complete metabolic responses (CMR) in patients that have not progressed after 24 months of immunotherapy. Methods: This is a retrospective analysis of forty-five patients with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) imaging for assessment of residual metabolic activity after at least 24 months of immunotherapy. Lesion-uptake in FDG PET on or below background level (using mediastinum as reference) was considered as CMR. Time until best objective morphological response including disease stabilization was measured from start of immunotherapy until first stable CT-scan (i.e. no progression or further response compared to previous scan) using RECIST 1.1. Results: Out of 45 patients, 29 patients had a CMR (64%). CMR was observed more frequently in non-first line patients. Patients with CMR were younger (median 65.7 vs. 75.5, P = 0.03). Fourteen patients with CMR have discontinued therapy and have not progressed until time of analysis; however median follow-up was only 5.6 (range 0.8-17.0) months. Conclusions: After a minimum of 24 months of palliative immunotherapy for NSCLC, CMR occurred in almost two thirds of patients. Potentially, achievement of CMR might identify patients, for whom palliative immunotherapy may be safely discontinued.
Early cancer detection using low-coverage whole-genome sequencing of cell-free DNA fragments.
Authors: Shunli Yang, Pei Zhihua, Jianing Yu, Xiuyu Zhao, Yiqian Liu, Yaxi Zhang, Geng Chen, Weizhi Chen, Ji He
Journal: Journal of Clinical Oncology (2021)

e22510 Background: Recent advances in circulating cell-free DNA (cfDNA) of plasma have shown that tumor diagnosis based on tumor-specific genetic and epigenetic changes (e.g., somatic mutations, copy number variations, and DNA methylation) is a promising non-invasive method. However, the number of tumor-specific genomic variants identified by whole-genome sequencing (WGS) in early cancer patients is very limited. Moreover, the mutations generated by clonal hematopoiesis in cfDNA can further confound the detection of cancer-specific mutations. It has been shown that ctDNA and cfDNA fragments have differences in length distribution. Compared with a limited number of genomic mutations, cfDNA fragment size index (FSI) is more abundant and easier to be detected. Methods: We designed a novel method for fragment detection of plasma cfDNA based on low-coverage WGS. The fragment length differences between healthy individuals and tumor patients were systematically analyzed. The training dataset includes 50 healthy individuals and 354 patients from eight different cancers. After the data preprocessing, we calculated the weight of fragmental bins and built a model for distinguishing healthy individuals from cancer patients. An independent dataset involving 22 healthy controls and 340 cancer patients was used to validate the model. The performance of our method was measured by the area under the curve (AUC) using the one-versus-all approach. Results: In our analysis, a total of 504 markers were selected from the dataset for model construction. Our model performed well for all cancer types on both training (AUC = 0.804) and validation (AUC = 0.837) datasets. Conclusions: The good performance of our model in large-scale plasma samples demonstrates the potential clinical application of cfDNA fragment analysis in early cancer detection based on low-coverage WGS.
Localized osteosarcoma analysis of very poor responders subgroup (Huvos I).
Authors: Alessandra Longhi, Antonio Carella, Valquiria Broll, Emanuela Palmerini, Marilena Cesari, Anna Paioli, Rossella Hakim, Marco Gambarotti, Alberto Righi
Journal: Journal of Clinical Oncology (2021)

e22010 Background: Osteosarcoma is a malignant primitive bone tumor whose prognosis is not changed since 4 decades, after the introduction of neoadjuvant chemotherapy with Methotrexate, Cisplatin, Doxorubicine and Ifosfamide. Histologic response to preoperative chemotherapy is a significant prognostic factor. Huvos I (necrosis ≤ 50%) has worst prognosis . Previous studies reported a 3 years EFS of this Huvos I patients around 25% (Tsuda Y,2020). In order to evaluate if survival has changed in recent years in this unfavourable prognostic group we evaluated the outcome of osteosarcoma patients with Huvos I. Methods: from our Pathology archieves we retrieved all cases of localized osteosarcoma treated at Rizzoli with neoadjuvant chemotherapy who reported an histologic necrosis below or equal to 50% (Huvos I grade) after preoperative chemotherapy MAP (Ethical C. Approval 917/2020/Oss/IOR). Results: from 2003 to 2019 we had 70 cases of localized osteosarcoma with Huvos I necrosis after neoadjuvant chemotherapy ( MAP in 66 and MAPI in 4) evaluable. Median age 21,5 (3-70); M:F = 44:26. 10/70 had axial localization vs extremity(60), subhistotype distribution:46 osteoblastic,11 chondroblastic, 7 fibroblastic, 5 teleangectatic, one not classified. In 24 cases PgP was available(14 PgP positive). With a median follow up of 86.7 ms (IQR 41-136) 43/70 had already relapsed. The median EFS was 25 ms (95% CI 15-42) and the 3 yrs EFS was 40.6% (95% CI 29-52). The 3 yrs overall survival was 80% (95%CI 68-88) and median OS was not reached. Axial tumor site was associated with significant inferior EFS (P = .004). Conclusions: these data confirm the poor prognosis of patients with necrosis ≤50% and the need of new drugs to improve their survival in this sub-group.
Cardiac Magnetic Resonance in Cardio-Oncology
Authors: Rupal O’Quinn, Victor A. Ferrari, Ryan Daly, Greg Hundley, Lauren A. Baldassarre, Yuchi Han, Ana Barac, Anita Arnold
Journal: JACC CardioOncology (2021)

Diagnosis of acute and late cardiotoxicity from cancer therapeutics has become increasingly important as the scope of cardio-oncology increases exponentially, both in terms of the number of people affected and the types of therapies it encompasses. Cardiac magnetic resonance (CMR) is a tool that can offer unparalleled diagnostic information compared with other imaging modalities, but its utilization is often delayed, at the expense of patient care, due to the need for insurance pre-authorization. This paper highlights situations in which CMR is preferred as the diagnostic modality and provides examples of diagnoses more likely to be approved by insurance companies. It also provides specific cardio-oncology diagnoses or questions to help the clinical cardio-oncologist navigate the pre-authorization process.