tbuckley/cabot-search huggingface dataset:
Prognostic biomarkers for primary Sjögren's syndrome-associated non-Hodgkin's lymphoma.
Authors: Kevin Sheng-Kai Ma, Angel Alfonso Velarde Lopez
Journal: Journal of Clinical Oncology (2021)

e19563 Background: Bidirectional relationship between non-Hodgkin’s lymphoma (NHL) and Sjögren’s syndrome (SS) has been recognized in large-scale cohort studies. We identified significant differentially expressed genes for SS-associated NHLs, and evaluated whether these genes could serve as a prognostic biomarker of diffuse large B-cell lymphoma (DLBCL). Methods: RNA-sequencing data from whole-transcriptome expression profiling were compared in a canonical pathway analysis using z-score and p-value visualization to identify significant differentially expressed genes and underlying cellular mechanisms for SS-associated NHLs including Burkitt lymphoma (BL), DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Collected biopsies included lymphoma biopsies for BL (n = 59), DLBCL (n = 88), FL (n = 65), MCL (n = 43), and MZL (n = 23), sorted B cells from healthy donors (n = 10), as well as parotid gland tissues for SS (n = 17). RNA-seq data with P values less than 0.05 or -log 10 (P) larger than 1.3 were considered significant, and positive z-scores indicated up-regulation while negative z-scores indicated down-regulation. After screening potential biomarkers through canonical pathway analysis, significant differentially expressed genes were subjected to survival analysis with genomic and clinical data of 420 DLBCL patients from The Cancer Genome Atlas (TCGA) using a log-rank test. Area under the ROC curve (AUC) was derived to validate the predictive ability of the survival model. Results: Among all genes involved in SS-associated NHLs, 16 genes were significantly differentially expressed in all types of NHLs. These genes included CXCL13, SEPP1, COL1A1, RGS13, IGFBP7, COL3A1, SPARCL1, GABBR1, SLC40A1, CXCL14, CXCL12, CXCL9, CCL19, VCAM1, C3, and CLU. The fold changes of the 16 genes for DLBCL were 465.67, 209.68, 436.94, 366.94, 189.59, 456.09, 195.37, 152.05, 90.29, 26.29, 215.18, 72.06, 51.09, 91.91, 74.70, and 20.88, respectively. Among all SS-associated pathways underlying NHL pathogenesis, the endocannabinoid system-driven cancer inhibition pathways were most significantly altered in SS-associated NHLs. The z-scores of the cancer inhibition pathway were -0.14 for BL (-log 10 (P) = 4.54), -1.298 for DLBCL (-log 10 (P) = 3.00), -0.33 for FL (-log 10 (P) = 4.67), -0.87 for MCL (-log 10 (P) = 3.77), and -2.61 for MZL (-log 10 (P) = 4.31). Survival analysis revealed that together the 16 genes may serve as a prognostic biomarker of DLBCL (hazard ratio = 3.57, 95% CI = 2.53–5.03), which was statistically significant (log rank test P &lt; 0.0001) and reliable (AUC = 0.897). Conclusions: Significant differentially expressed genes underlying the pathogenesis for SS-associated NHLs may be used as a biomarker for predicting the survival rate of DLBCL. Further studies are warranted to elucidate the functional association between these differentially expressed genes.
A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring HER2 amplification (JUPITER trial).
Authors: Ryo Kudo, Toshio Kubo, Yukiko Mori, Yohei Harada, Hidekazu Shirota, Hideyuki Hayashi, Masayuki Kano, Yasushi Shimizu, Eri Ishibashi, Hirotoshi Akita, Hisahiro Matsubara, Hiroshi Nishihara, Chikashi Ishioka, Naoko Sueoka-Aragane, Manabu Muto, Shinichi Toyooka, Ukihide Tateishi, Akihiro Hirakawa, Satoshi Miyake, Sadakatsu Ikeda
Journal: Journal of Clinical Oncology (2021)

TPS3141 Background: The human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. Despite its considerable therapeutic potential, the evidence is not yet mature enough for use as treatment in clinical practice. To address this unmet clinical need, we have designed an organ-agnostic basket trial, which covers a variety of solid cancers harboring HER2 amplification. Methods: JUPITER trial is a Japanese multicenter, single-arm, phase 2 basket study of combination therapy with trastuzumab and pertuzumab. Patients with solid cancers harboring HER2 amplification, who have progressed with standard treatment, or rare cancers for which there is no standard treatment, are eligible. Types of cancer include bile duct, urothelial, uterine, ovarian, and other solid cancers that HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. Target sample size is 38. All enrolled patients receive combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unacceptable toxicity, death, or withdrawal of informed consent. Response assessment using RECIST version 1.1 is performed at weeks 9 and 17, followed by every 12 weeks. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, duration of response, and safety. In total, 40 patients were enrolled by June 2020. Data fix is scheduled in September 2021. Trial registration: jRCT2031180150 Clinical trial information: jRCT2031180150.
Phase II trial of surufatinib plus toripalimab for disease progression after first-line chemotherapy with platinum and fluoropyrimidine in advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Lin Shen, Ming Lu, Zhendong Chen, Feng Ye, Yanqiao Zhang, Zhiping Li, Xing Zhang, Fei Yin, Wei Chen, Wang Sheng, Yue Ma, Yaqin Zhao, Desheng Weng, Xiaolei Yin, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Weiguo Su
Journal: Journal of Clinical Oncology (2021)

e16040 Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFRs, FGFR and CSF-1R, simultaneous targeting of angiogenesis through VEGFRs/FGFR1 and modulating tumor immune microenvironment through CSF-1R may be a uniquely potent strategy to enhance antitumor activity. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Encouraging efficacy of surufatinib plus toripalimab treating patients with advanced solid tumors was reported at 2020 AACR. This is an ongoing, multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of surufatinib in combination with toripalimab in various solid tumors. Here we report the results of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Patients with histologically confirmed gastric or GEJ adenocarcinoma who have failed first-line of systemic chemotherapy were enrolled. Surufatinib 250 mg once a day (QD) will be orally administrated and toripalimab 240 mg will be intravenously administered every 3 weeks. Primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: As of Dec 31, 2020, a total of 21 gastric or GEJ adenocarcinoma patients were enrolled. The median age was 58 years old, and 81% of the patients were male. Median duration of treatment was 3 months (surufatinib, 3 months; toripalimab, 3 months). Among 15 patients with at least one post-baseline efficacy evaluation, 2 patients achieved confirmed partial response (PR), with 3 additional unconfirmed PR. And there were 6 in stable disease (SD), 3 in progressive disease (PD) and one not evaluable per RECIST v1.1. There were 5 in PR, 7 in SD and 2 in PD per irRECIST, respectively. The confirmed and unconfirmed ORR were 13.3% (95% CI: 1.7%-40.5%) and 33.3% (95% CI: 11.8%-61.6%), respectively. The disease control rate (DCR) was 73.3% (95% CI: 44.9%-92.2%) per RECIST v1.1. Median PFS was 3.71 months (95% CI: 1.41-unknown). 14.3% (3/21) of patients had treatment-related adverse events (TRAEs) of ≥ Grade 3. The most common TRAEs of ≥ Grade 3 were herpes zoster (4.8%), lymphopenia (4.8%), lymphocyte count decreased (4.8%), white blood cell count decreased (4.8%), liver injury (4.8%) and anaemia (4.8%). 4.8% (1/21) of patients had serious TRAEs. One patient died due to unknown reasons. Conclusions: Surufatinib plus toripalimab appeared to show encouraging activity in advanced gastric or GEJ adenocarcinoma with manageable safety profile. Such combination could be a promising strategy for advanced gastric or GEJ adenocarcinoma in the future. Clinical trial information: NCT04169672.
Association between Medicaid expansion under the Affordable Care Act and survival among newly diagnosed cancer patients.
Authors: Xuesong Han, Jingxuan Zhao, Robin Robin Yabroff, Christopher J. Johnson, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2021)

1502 Background: Medicaid expansion under the Affordable Care Act (ACA) is associated with increased insurance coverage and early stage at diagnosis among patients with cancer. Whether these gains translate to improved survival is largely unknown, however. This study examines changes in one-year survival rates among persons newly diagnosed with cancer following the ACA Medicaid expansion. Methods: Patients aged 18-62 years from 41 population-based state cancer registries diagnosed pre-(2010-2012) and post-(2014-2016) ACA Medicaid expansion were followed through October 1, 2013 and December 31, 2016, respectively. Difference-in-differences (DD) analysis was conducted to estimate changes in one-year overall and cause-specific survival rates associated with Medicaid expansion, adjusting for age group, sex, race/ethnicity, area-level poverty, urban/rural status and region. Stratified analysis was conducted by cancer type, sex and area-level poverty. Results: A total of 2,537,818 patients diagnosed with cancer were included from Medicaid expansion (N = 1,492,729) and non-expansion (N = 1,045,089) states. During follow-up, 291,854 patients died including 246,660 deaths from cancer. The one-year overall survival rate (%) increased from 88.1 pre-ACA to 89.1 post-ACA in Medicaid expansion states and from 85.6 to 86.4 in non-expansion states for both sexes combined, resulting in a net increase of 0.4 (95%CI = 0.3-0.6) in expansion states after adjusting for sociodemographic factors. By cancer site and for both sexes combined, the increase in adjusted one-year overall survival in expansion states versus non-expansion states was greater for cancers of lung (DD = 1.6; 95%CI = 0.8-2.5), pancreas (DD = 2.2; 95%CI = 0.5-3.9) and liver (DD = 3.4; 95%CI = 1.7-5.1); as were the increases for cervix (DD = 1.3; 95%CI = 0.1-2.5), melanoma (DD = 0.4;95%CI = 0.04-0.9), non-Hodgkin lymphoma (DD = 1.2; 95%CI = 0.1-2.2) and esophagus (DD = 7.1; 95%CI = 0.5-13.7) among women. The improvement in one-year overall survival was larger among patients residing in the poorest areas (DD = 0.7; 95%CI = 0.3-1.1) compared to those in the richest areas (DD = 0.2; 95%CI = -0.2 to 0.5), leading to a narrowing survival disparity by area-level poverty. Patterns in one-year cause-specific survival were similar. Conclusions: Medicaid expansion was associated with greater increase in one-year overall survival rates, largely driven by the improvements in survival for cancer types with poor prognosis, suggesting improved access to timely and effective treatments. Furthermore, the increase was largest in poorest areas, highlighting the promising role of Medicaid expansion in reducing health disparities. Future studies should monitor changes in longer-term health outcomes following the ACA.
Corrigendum to ‘Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries’ [Bioactive Mater. 6 (3) (2021) 638–654]
Authors: Lihua Luo, Yan He, Ling Jin, Yanni Zhang, Fernando P. Guastaldi, Abdullkhaleg A. Albashari, Fengting Hu, Xiaoyan Wang, Lei Wang, Jian Xiao, Lingli Li, Jianming Wang, Akon Higuchi, Qingsong Ye
Journal: Bioactive Materials (2021)
Surgery versus radiation therapy outcomes in patients with clinical stage 0 non-small cell lung cancer.
Authors: Swapna Narayana, Attila J. Kovacs, Andrew J. Borgert, Matthew McGee, Susan M. Frankki, David E. Marinier
Journal: Journal of Clinical Oncology (2021)

e20537 Background: There are currently no clear national guidelines for management of in-situ (stage 0) non-small cell lung cancer (NSCLC). With no prospective clinical trial data, treatment strategies include both surgical resection and definitive radiation therapy (RT). We aimed to investigate survival outcomes in patients with stage 0 NSCLC who underwent surgery or RT. We also aimed to identify any differences in the treatments that the two groups received with respect to rural versus urban setting and racial variation. Methods: The 2016 National Cancer Data Base was reviewed from 2006-2015 for patients registered with a pathological diagnosis of Stage 0 NSCLC, based on the AJCC 7th edition classification for lung cancer. Patients with a prior history of malignancy, secondary malignancy other than lung, and contraindications to surgery were excluded. Univariate comparison and multivariate logistic regression modeling were utilized to identify factors associated with receipt of surgery. Patients were stratified into two groups, surgical resection and RT. Kaplan-Meier estimators and Cox proportional-hazards regression were used to compare overall survival(OS). Propensity score matching was performed using relevant demographic and clinical factors associated with receipt of surgery. All analysis was completed in SAS version 9.4 and p-values less than 0.05 were considered significant. Results: A total of 156 patients were identified with Stage 0 NSCLC who received surgery (n = 104) or RT (n = 52). Surgery was defined as lobectomy or less. Histologic subtypes were squamous cell carcinoma (54%), adenocarcinoma (45%), and bronchioloalveolar carcinoma (1%). Median age was 65 years for the surgical resection cohort and 70 years for the RT cohort. From diagnosis, median time to surgery was 21 days for the surgical resection cohort and 47 days to start of radiation for RT cohort. We did not identify any major differences with respect to rural versus urban setting or racial differences within the surgery and RT cohorts. Patients who underwent surgical resection had a superior 5 year overall survival 65% (CI, 43.49-80.56) when compared to patients who underwent RT 37% (CI, 10.63-65.05), hazard rate 0.403, p = 0.0009, 95% CI. 0.236 – 0.689). Conclusions: Our findings show a significant improved survival with surgical resection compared to RT in patients diagnosed with Stage 0 NSCLC.
Landscape of <i>KRAS<sup>G12C</sup></i>, associated genomic alterations, and interrelation with immuno-oncology (IO) biomarkers.
Authors: Mohamed E. Salem, Sherif El-Refai, Wei Sha, Axel Grothey, Alberto Puccini, Thomas J. George, Jimmy J. Hwang, Laura W. Musselwhite, David King, Kunal C. Kadakia, Derek Raghavan, Eric Van Cutsem, Josep Tabernero, Jeanne Tie
Journal: Journal of Clinical Oncology (2021)

3127 Background: Sotorasib has shown promising activity in cancer patients (pts) specifically harboring the KRAS G12C mutation. Response rates vary significantly by tumor type, suggesting KRAS G12C pathogenesis may be cancer-type-dependent. Methods: We retrospectively analyzed de-identified records of 79,004 pts with various cancer types that underwent Tempus xT and xF next generation sequencing assays. Fisher’s exact test was used to analyze the association between cancer subtypes and KRAS variants. Logistic regression was used to study co-mutations between KRAS G12C and other oncogenes, as well as the association between KRAS variants and IO biomarkers. False discovery rate-adjusted P-value (FDR P) was used for multiple testing. Results: In total, 13,578 (17.4%) tumors harbored KRAS mutations, of which 1,632 were G12C; 750 KRAS wild-type (WT) tumors gained KRAS mutation on follow-up testing, with 79 harboring G12C. The most frequent KRAS variants across all cancers were G12D, G12V, G12C, and G13D (see Table). The distribution of KRAS variants significantly varied by cancer type, with G12C and G12D being the most prevalent in non-small cell lung (NSCLC) and colorectal (CRC) cancers, respectively. G12C was most prevalent in NSCLC (9%), appendiceal cancer (3.9%), CRC (3.2%), tumors of unknown origin (1.6%), and pancreatic cancer (1.3%). Compared to non-G12C, G12C was more frequently identified in females (56% vs. 51%, FDR P = 0.0005), smokers/prior smokers (85% vs. 56%, FDR P &lt; 0.0001), and pts &gt; 60 years of age (73% vs. 63%, FDR P = 0.0006). While no G12C tumors exhibited BRAF V600E co-mutations, BRAF non-V600E co-mutations were seen in 3.1% of pts. Significant differences were observed in genomic alterations co-occurring with G12C compared to non-G12C (e.g., STK11 (20.6% vs 6%), KEAP1 (15.4% vs 4.6%), SMAD4 (7.2% vs 19%), and PDGFRA (5.8% vs 3%); FDR P &lt; 0.0001). However, G12C and oncogene co-mutations were not significantly different between NSCLC and CRC, except for KEAP1 (FDR_ P = 0.04). Compared to non-G12C and WT, G12C tumors were associated with TMB-High and PD-L1 over expression but were less likely to have MSI-H status (FDR P &lt; 0.0001; Table). Conclusions: Our data suggest that KRAS variants significantly differ by cancer type. Tumors harboring KRAS G12C were significantly associated with high TMB and PD-L1 overexpression. KRAS G12C mutation appeared to be associated with smoking status. These results may guide future therapeutic strategies.[Table: see text]
Concurrent BRAFV600E and BRCA mutations in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Prevalence and case series of mCRC (pts) with prolonged overall survival (OS).
Authors: Timothy Lewis Cannon, Jamie Randall, Ethan Sokol, Sonja Alexander, Raymond Couric Wadlow, Daniel Barnett, Danny Rayes, John F. Deeken, Halla Nimeiri, Kimberly McGregor
Journal: Journal of Clinical Oncology (2021)

3561 Background: BRAF V600E+, MSS mCRC patients comprise up to 10% of advanced CRC. They have a poor prognosis with median survivals typically &lt;1 year. Despite use of multi-agent first-line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board database, we identified 3 consecutive mCRC pts with MSS/ BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had prolonged overall survival. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. Methods: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes ( BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis were BRAF V600E co-mutated with BRCA1 and BRCA2, separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation are described along with 3 consecutive cases of CRC patients, identified through the Inova Schar Cancer Institute (ISCI) molecular tumor board (MTB) registry, whom had prolonged OS. Results: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% having co-mutations of BRAF V600E and BRCA1/2. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of these occurred in MSS BRAF V600E. BRCA1 co-mutated was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p &lt;0.001 ). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, one confirmed germline and 2 somatic in origin, and had average gLOH of 21.4% with overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. Conclusions: Co-existence of BRAF V600E/ BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. Larger prospective clinical validation trials in this subset is warranted.[Table: see text]
Stem-like markers in the circulating tumor cells assessment in ovarian cancer.
Authors: Snezhanna Gening, Tatyana Abakumova, Inna Antoneeva, Tatyana Gening
Journal: Journal of Clinical Oncology (2021)

e17542 Background: Circulating tumor cells (CTCs) are a potential source of dissemination and relapse in ovarian cancer (OC). Stem cell properties can provide a survival advantage for CTCs. The clinical significance of stem-like CTCs in OC remains to be studied. We aimed to assess the quantities of the stem, epithelial, mesenchymal CTCs and their relationships with the clinical parameters in the OC. Methods: Peripheral blood samples (7.5 ml) were obtained from patients with primary epithelial OC before treatment. CTCs were isolated by flow cytometry (Cytoflex S (Beckman Coulter, USA)) using antibodies to CD45 (BioLegend, USA); CD44 (BioLegend, USA), CD133 (Miltenyi biotec, Germany), ALDH (Stemcell, Canada) to detect the stem markers; EpCAM (BioLegend, USA), cytokeratins 8, 18 (Abcam plc., UK), vimentin (BioLegend, USA) for epithelial and mesenchymal markers. Blood samples from patients with benign ovarian tumors served as a control. Informed voluntary consent was obtained from all the women. Statistical processing included Mann-Whitney U-test, linear regression, Cox proportional hazards model for progression-free survival (PFS) (Statistica 13.0 (TIBCO, USA)). Results: The study included 30 patients, median age 64 (34-76) years. 15 patients had a FIGO stage IV, 12 - stage III, 1 – stage II and 1 – stage I. The content of CTCs populations is presented in the table. The CTCs counts did not differ depending on age, platelet count, and stage 3 or 4. The amount of CD45-CK+Vim- was higher in the presence of ascites (p = 0.035). We found a regression relationship between the serum CA-125 and the number of CD45-CD44+CD133+ (R 2 = 0.220, p = 0.016); the leukocyte count in blood and CD45-CD44+ALDHhigh (R 2 = 0.234, p = 0.017); the number of CD45-Vim+ and CD45-CD44+CD133+ALDH+ (R 2 = 0.305, p = 0.014); CD45-CK-Vim+ and CD45-EpCAM+CK+ (R 2 = 0.717, p &lt; 0.001). The Cox regression model for PFS included the number of CD45-CD44+CD133+ALDH+ (HR 1.51 95% CI 1.01-2.24 p = 0.043) and the cytoreductive surgery performance (HR 0.09 95% CI 0.01-0.89 p = 0.039) during the first line of treatment. Conclusions: Various populations of circulating tumor cells coexist in ovarian cancer patients. The use of a combination of stem markers in the CTCs detection can increase their prognostic value in OC. This work was supported by the RFBR grant No. 19-315-90011.[Table: see text]
The role of regulated necrosis in endocrine diseases
Authors: Wulf Tonnus, Alexia Belavgeni, Felix Beuschlein, Graeme Eisenhofer, Martin Fassnacht, Matthias Kroiss, Nils P. Krone, Martin Reincke, Stefan R. Bornstein, Andreas Linkermann
Journal: Nature Reviews Endocrinology (2021)