tbuckley/cabot-search huggingface dataset:
Diagnostic signatures for lung cancer by gut microbiome and urine metabolomics profiling.
Authors: Bo Qiu, Yu Xi, Ying Li, XinQiang Xie, FangJie Liu, Lei Wu, TingTing Liang, Longyan Li, Ying Feng, JinYu Guo, DaQuan Wang, Yu Zeng, Lingshuang Yang, Jumei Zhang, Juan Wang, Moutong Chen, Liang Xue, Yu Ding, QingPing Wu, Hui Liu
Journal: Journal of Clinical Oncology (2021)

e20514 Background: To develop the diagnostic signatures for lung cancer (LC) by gut microbiome and urine metabolomics profiling with multi-omics approach. Methods: We surveyed 145 Fecal Samples and 120 Urine Samples in a cohort containing 109 LC patients and 50 healthy individuals. The total cohort had been separated into testing set and validation set. The testing set comprised 47 patients and 20 healthy individuals (8 first-degree relatives and 12 non-relatives), while the validation set had 48 patients and 30 healthy individuals (14 first-degree relatives and 16 non-relatives). The urine research set comprised 100 patients and 18 first-degree relatives as healthy individuals. Gut microbiota was analyzed through the 16S ribosomal RNA (rRNA) gene sequencing and shotgun metagenomics. Urine untargeted metabolomics was analyzed by liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Results: LC patients had a significant shift of intestinal microbiota composition and functional genes distribution compared with healthy individuals. Diagnostic model had been achieved by combining gut microbiome and urine metabolomics profiling, the area under curve (AUC) of the testing set was 0.9997. The model performed reasonably well in the validation set with the AUC of 0.9769. We also found a significant decrease of Prevotella in LA-NSCLC patients and it was negatively correlated with multiple functions in KEGG level 2 in healthy individuals. Conclusions: The current study employs a multi-omics approach, analyses the fecal microbiome and urine metabolites from LC patients and healthy individuals/relatives using a standardized pipeline, and identified disease-associated microbiome shifts across datasets using statistical analysis. We inferred a microbiome-metabolite catalog and its molecular pathway and functional link to host targets, which could be further utilized to aid lung cancer diagnosis and treatment decision.
Very low seroprevalence of sars-cov-2 among health care personnel (HCP) in a French northern comprehensive cancer center at the end of first national containment.
Authors: Philippe Doutrelant, Nicolas Penel, Charlotte Renaudat, Cassandre Von Platen, Marie Paule Lebitasy, Pauline Smis-Papillon, Bruno Hoen, Eric Lartigau, Yves-Marie Robin
Journal: Journal of Clinical Oncology (2021)

e13604 Background: To limit SARS-Co-2 transmission in general population, French government had set up a first National containment from March 16, 2020 to June 2, 2020. Furthermore, General Direction of our hospital have implemented and organized physical distancing (telework, teleconsultation, virtual multi-disciplinary board), mask wearing, use of alcoholic ... to limit interpersonal contacts. To assess the impact of this policy, we have carried out a seroprevalence study and identified risk factors for SARS-Co-2 prevalence among HCP in May/June 2020. Methods: This is part of CORSER Study (“Etude séro-épidémiologique du virus SARS-CoV-2 en France d’une Cohorte CORSER-2d de personnels d’établissements de santé »), registered with ClinicalTrials.gov (NCT04325646). Two serological tests were applied in this cohort: S-Flow assay and Luciferase-linked immune-sorbent assay (LuLisa-N test). Results: Between 04 May to 26 June 2020, 392 Osar Lambret Cancer Center employees were included in the present study (about 40% of all staff). The most common jobs were: 92 nurses (23.4%), 80 radiology/radiotherapy manipulators (20.4%), 51 physicians (13.0%), 33 medical interns (8.4%) and 47 administrative staff members (11.9%). There were 98 men (25.0%) and 294 women (75.0%). The mean age was 38.7 (+/- 11.4). There were 7 seropositive cases; the seroprevalence was 1.8% (95%-CI: 0.7-3.6). Among the 7 positive cases, 5 were symptomatic (71.4%). In univariate analysis, factors associated with SARS-Co-2 seroprevalence: symptoms suggesting viral infection within 2 months (OR=5.33), dysgueusia (OR=37.00), anosmia (OR=66.29) and HCP exposed to COVID-19 patient outside work (OR=6.69). Gender, tobacco consumption, O blood group, HCP versus administrative staff, HCP working in different services, HCP providing care to suspected COVID-19 patients, HCP providing high-risk cares were not found to be associated with seropositivity. Of note, we have noticed that BMI≥ 24 kg/m² was associated with seroprevalence (OR=15.45), without biological rational. Conclusions: Our study suggests that strict implementation of protective measures was associated with low SARS-Cov-2 prevalence at the end of first National Containment, including among HCP treating COVID-19+ patients. HCPs seroprevalence seemed lower than seroprevalence of the general population at the same period (4-5%). Clinical trial information: NCT04325646.
Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer.
Authors: Judith Michels, François Ghiringhelli, Jean-Sebastien Frenel, Caroline Brard, Benoit You, Anne Floquet, Lauriane Eberst, Rastilav Bahleda, Catherine Genestie, Corinne Balleyguier, Sophie Broutin, Patricia Pautier, Emeline Colomba, Fanny Pommeret, Christophe Massard, Aurelien Marabelle, Alexandra Leary
Journal: Journal of Clinical Oncology (2021)

5522 Background: There is a medical unmet need for effective treatments in platinum resistant ovarian cancer patients. We assessed the safety and efficacy of a combination of pembrolizumab with bevacizumab and pegylated liposomal doxorubicin (PLD). Methods: This is an open-label phase 1b trial in patients ECOG 0 or 1 with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The safety of the dual combinations of pembrolizumab with bevacizumab or with PLD were previously evaluated in 6 patients respectively. In the absence of dose limiting toxicities (DLT) the triple combination was evaluated at a maximum tolerated dose (MTD)-1 for PLD in 3 patients and in the absence of DLT at MTD. The sample size was calculated according to the modified toxicity probability interval design. The primary evaluation criteria was the safety, the secondary endpoint was the outcome. Pharmacokinetics of the flat dose of bevacizumab will be evaluated. Results: 22 patients were enrolled from September 2019 until June 2020 in six French centers. 3 initial patients have been treated at 20mg/m 2 of PLD (MTD-1) and 19 patients were treated at the dose of 30mg/m 2 of PLD (MTD) combined with 200mg of pembrolizumab until progression, unacceptable toxicity, or withdrawal of consent and 400mg of bevacizumab for a total of six cycles. The patients’ characteristics are reported in the table. No DLT occurred. Grade 3 palmar-plantar erythrodysesthesia were reported in 4 patients. The recommended phase II dose of PLD was 30mg/m 2 in combination with pembrolizumab and bevacizumab. For patients treated at MTD, the overall response rate was 32% (6 partial responses) with 74% of clinical benefit with a durable response in 10 patients (53%). Median number of cycles was 7.5 (2 to not reached). Two patients are still on treatment. Correlative studies are ongoing. Conclusions: The combination was well tolerated and demonstrated clinical benefit in 74% platinum resistant ovarian cancer patients with durable response (&gt;6 months) in 53% of patients. Clinical trial information: NCT03596281. [Table: see text]
Identification and prognostic impact of <i>PBRM1</i> mutations in biliary tract cancers: Results of a comprehensive molecular profiling study.
Authors: Kai Zimmer, Florian Kocher, Gerold Untergasser, Alberto Puccini, Joanne Xiu, Dominik Wolf, Gilbert Spizzo, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, John Marshall, Michael J. Hall, Wolfgang Michael Korn, Chadi Nabhan, Francesca Battaglin, Heinz-Josef Lenz, Wafik S. El-Deiry, Arno Amann, David Hsiehchen, Andreas Seeber
Journal: Journal of Clinical Oncology (2021)

4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p &lt; 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p &lt; 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p &lt; 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p &lt; 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p &lt; 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p &lt; 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.
FAT4 mutation serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma.
Authors: Jifa Zhang, Dongsheng Chen, Qin Zhang, Qianqian Duan, Qidong Yang, Si Li, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2021)

e21553 Background: FAT4 functions as a tumor suppressor, and previous findings have demonstrated that FAT4 can inhibit the epithelial-to-mesenchymal transition (EMT) and the proliferation of gastric cancer cells. FAT4 is involved in the maintenance of PCP and inhibition of cell proliferation. FAT4 mRNA is repressed in breast cancer and lung cancer due to promoter hypermethylation. FAT4 gene is recurrently mutated in several types. Previous work suggested that FAT4 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of function in melanoma is needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the FAT4 mutation in 3547 tumor tissue or plasma ctDNA samples (including 122 melanoma) from different patients, and the public database of TACG was also compared. Data from Miao-249 study (n = 151, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of FAT4 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 8.11 % (288 in 3547). Meanwhile, the frequency of FAT4 mutation in TCGA cohort was 10.08 % (1105 in 10953). In melanoma datebase, the frequency of FAT4 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 5.73 % (7 in 122). Meanwhile, the frequency of FAT4 mutation in melanoma in TCGA cohort was 38.2 % (169 in 422) We further analyzed Kaplan-Meier curves from Miao-249 study (n = 151, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In Miao-249 melanoma cohort, mutation of FAT4 was associated with higher TMB (P = 0.032) and higher mutation count (P = 0.003) in melanoma. FAT4 mutation was associated with prolonged overall survival (OS) compared with FAT4 wt in melanoma (P = 0.0478). Conclusions: In our study, the frequency of FAT4 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. FAT4 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating TMB and mutation count.
An investigation on biomarkers of hyperprogressive disease after PD-1/PDL-1 therapies in Chinese non-small cell lung cancer patients.
Authors: Qingchun Song, Lei Han, Yulong Mao, Tanxiao Huang
Journal: Journal of Clinical Oncology (2021)

e21173 Background: Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, are becoming standard of care for lung cancer treatment. However, low response rates to ICI antibodies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. Considering HPD for patients means shorter survival times and worse prognoses, valid biomarkers are in urgent demand to predict the occurrence of HPD and the efficacy of ICI. Here, we explored the genomic biomarkers of HPD in Chinese non-small cell lung cancer (NSCLC) patients. Methods: 749 NSCLC patients with both genomic information and PD-L1 expression data were screened from HapLab database. HaploX 605-gene panel sequencing, covering 1.31 MB genome, was performed to analyze the genomic data of patients. PDL-1 expression was detected by immunochemistry. Results: 15 genes related to HPD were detected altered in NSCLC patients. Collectively, 511 out of 749 patients (68.22%) had at least one alteration of HPD related genes. The frequent alterations were EGFR mutation (46.86%), ALK fusion (7.49%), MDM2 amplification (6.54%), KEAP1 mutation (5.34%), STK11 mutation (4.27%), FGF3/4 amplification (4.14%), DNMT3A mutation (2.14%) and MDM4 amplification (2.00%). While in EGFR wild-type and ALK-negative patients, the top 5 frequent alterations were KEAP1 mutation (8.96%), FGF3/4 amplification (7.00%), STK11 mutation (6.16%), PTEN mutation (5.32%) and MDM2 amplification (4.20%). Notably, EGFR mutation (49.27%, 68/138), ALK fusion (9.42%, 13/138) and MDM2 amplification (4.35%, 6/138) were also observed in PDL-1 positive (TPS≥1%) patients. Conclusions: It is urgent to identify specific biomarkers that could predict HPD and to develop eﬀective methods to prevent HPD. Our study investigated the genomic alterations associated with HPD in Chinese NSCLC patients.
Updated results of European Organization for Research and Treatment of Cancer (EORTC) phase 2 trial 1202 cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma.
Authors: Roberta Sanfilippo, Richard L Hayward, Jammbe Musoro, Charlotte Benson, Michael Gordon Leahy, Antonella Brunello, Jean-Yves Blay, Neeltje Steeghs, Ingrid Desar, Nasim Ali, Alice Hervieu, Khin Thway, Sandrine Marreaud, Saskia Litiere, Bernd Kasper
Journal: Journal of Clinical Oncology (2021)

11518 Background: Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. The most effective agents include doxorubicin, ifosfamide, trabectedin and eribulin, but, in general, objective response rates (ORR) and progression free survival (PFS) are modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. The clinical cut-off date for the primary analysis was performed on August 31, 2020. Data base lock was performed on February 2, 2021. Eligible patients with metastatic or inoperable locally advanced DD LPS, after a centralized pathological review, were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Currently, a centralized radiological assessment is ongoing. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. One patient was still on treatment at the clinical cut-off date. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. PFS at 12 weeks was 55% (conditional 1-sided 95% CI 40.8-100), achieving the primary study endpoint. The median FU was 21.6 months, median PFS was 6 months and median OS 21 months. RR was 8% with one CR and two PR. Twenty-three(60.5%) pts had a SD. Disease control (PR+SD) was achieved in 26 patients (68%). The most common cabazitaxel -related grade &gt;3 adverse events in all 40 registered patients were Neutrophil count decreased (50%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 21/38 pts (55%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and looks interesting if compared to the other available options and experimental drugs recently reported in this patient population. Clinical trial information: NCT01913652.
Comparison of Surgical Resection and Systemic Treatment for Hepatocellular Carcinoma with Vascular Invasion: National Cancer Database Analysis
Authors: Rajalakshmi Govalan, Marie Lauzon, Michael Luu, Joseph C. Ahn, Kambiz Kosari, Tsuyoshi Todo, Irene K. Kim, Mazen Noureddin, Alexander Kuo, Ayoub S. Walid, Vinay Sundaram, Shelly C. Lu, Lewis R. Roberts, Amit G. Singal, Julie K. Heimbach, Vatche G. Agopian, Nicholas Nissen, Ju Dong Yang
Journal: Liver Cancer (2021)

Small studies from outside of the USA suggest excellent outcomes after surgical resection for hepatocellular carcinoma (HCC) with vascular invasion. The study aims to (1) compare overall survival after surgical resection and systemic therapy among patients with HCC and vascular invasion and (2) determine factors associated with receipt of surgical resection in a US population.HCC patients with AJCC clinical TNM stage 7th T3BN0M0 diagnosed between 2010 and 2017 from the National Cancer Database were analyzed. Cox and logistic regression analyses identified factors associated with overall survival and receipt of surgical resection.Of 11,259 patients with T3BN0M0 HCC, 325 (2.9%) and 4,268 (37.9%) received surgical resection and systemic therapy, respectively. In multivariable analysis, surgical resection was associated with improved survival compared to systemic therapy (adjusted hazard ratio: 0.496, 95% confidence interval: 0.426-0.578) with a median survival of 21.4 and 8.1 months, respectively. Superiority of surgical resection was observed in noncirrhotic and cirrhotic subgroups and propensity score matching and inverse probability of treatment weighting adjusted analysis. Asians were more likely to receive surgical resection, whereas Charlson comorbidity ≥3, elevated alpha-fetoprotein, smaller tumor size, care in a community cancer program, and the South or West region were associated with a lower likelihood of surgical resection.HCC patients with vascular invasion may benefit from surgical resection compared to systemic therapies. Demographic and clinical features of HCC patients and region and type of treating facility were associated with surgical resection versus systemic treatment.
Abstract 12978: A Deep Learning Based Model for Risk Stratification of Sudden Cardiac Death in Hypertrophic Cardiomyopathy
Authors: Ahmed S Fahmy, Ethan J Rowin, Warren J Manning, Martin S Maron, Reza Nezafat
Journal: Circulation (2019)

Introduction: hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death (SCD). Treatment planning requires identifying patients at high risk of SCD. We sought to develop a novel ...
ASTRO suitability criteria assessment in early-stage breast cancer patients treated with intraoperative radiation therapy (IORT) plus 21 gene recurrence score (RS) assay result guided adjuvant medical therapy.
Authors: Barbara Stewart Schwartzberg, Kathryn T. Howell, Joyce A Moore, Devchand Paul
Journal: Journal of Clinical Oncology (2021)

e12598 Background: A patient subset consented in an institutional review board-approved single institution clinical trial designed to determine the efficacy and outcome of single fraction IORT received adjuvant medical therapy recommendations based on their RS results. Patients were categorized according to American Society for Radiation Oncology (ASTRO) suitability criteria for accelerated partial breast irradiation. Comparison was made between ASTRO suitability criteria, RS and post-IORT outcomes. Methods: Outcome of pts completing single fraction (20Gy) IORT per protocol using disposable balloon electronic brachytherapy and RS assessment were reviewed. Data collection included demographics, pathology, RS, medical therapy, local (LR) and axillary (AR) recurrences, and survival. Results: From Nov 2011 – Jan 2016, 115 pts (aged 43 – 84, mean 63 years) completed both IORT per protocol and RS assessment. Pts with estrogen receptor positive invasive carcinomas (range 0.2 – 2.4 cm, median size 0.9 cm) and RS results were categorized by ASTRO suitability criteria, LR and AR, as shown in Table 1. The recurrence rate at mean follow-up of 6.8 years was 3.5%. There were 3 LR (RS 0, 17, 18) and 1 AR (RS 19). There has been no breast cancer related death. Adjuvant endocrine therapy was recommended to all pts. Twenty-three (20%) patients received chemotherapy, including 12 (71%) pts in the high RS (RS &gt;25) groups. Chemotherapy was not given to any pt with a RS &lt;18. One LR (RS 0, ASTRO Suitable, age 65, 1.5 cm) declined endocrine therapy. Ten (19%) pts with RS of 11 – 25 received chemotherapy. One LR (RS 17, ASTRO suitable, age 64, 1.5 cm) and 1 axillary recurrence (RS 19, ASTRO Suitable, age 66, 1.3 cm), neither receiving chemotherapy, were compliant with endocrine therapy. One LR (RS 18, ASTRO Suitable, age 51, 0.6 cm) was treated with cyclophosphamide and docetaxel. Seven (78%) pts with RS of 26 - 30 and 5 (63%) pts with RS &gt;30 received chemotherapy, with no recurrences in these groups. Conclusions: One hundred fifteen pts treated with single fraction IORT per protocol and RS guided adjuvant medical therapy at a single institution were found to have a 3.5% recurrence rate at mean follow-up of 6.8 years. ASTRO suitability criteria and high RS results (RS &gt; 25) did not correlate with recurrence. The success of IORT observed in this trial as local therapy for early-stage breast cancer patients was independent of genomic factors or patient suitability criteria. Recurrence rates were comparable to those reported in IORT peer-reviewed published data and treatments using breast conserving surgery plus whole breast radiation therapy. [Table: see text]