tbuckley/cabot-search huggingface dataset:
Effect of gastrointestinal microbiome and its diversity on the expression of tumor-infiltrating lymphocytes in breast cancer.
Authors: Jiajie Shi, Cuizhi Geng
Journal: Journal of Clinical Oncology (2019)

e14187 Background: The diversity of gastrointestinal microbiome is closely related to human health. In the present study, we compared gastrointestinal microbiome and tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) patients. Methods: A total of 80 BC patients were divided into three groups based on the expression of TILs as follows: high expression of TILs (TIL-H), medium expression of TILs (TIL-M) and low expression of TILs (TIL-L). DNA of gastrointestinal microbiome was determined by Illumina sequencing and taxonomy of 16S rRNA genes. Kruskal-Wallis test and UniFrac analysis of β-diversity were applied to assess the relationship between patients’ clinical characteristics and diversity of gastrointestinal microbiome. Results: The β-diversity distribution was statistically significant (weighted UniFrac P &lt; 0.01, unweighted UniFac P &lt; 0.01) when comparing between the TIL-L and TIL-H groups or among the three groups (TIL-H vs. TIL-M vs. TIL-L). At the genus level, higher abundances of Mycobacterium, Rhodococcus, Catenibacterium, Bulleidia, Anaerofilum, Sneathia, Devosia and TG5 but lower abundances of Methanosphaera and Anaerobiospirillum ( P &lt; 0.05) were identified in the TIL-L group compared with the TIL-H group . At the species level, the species of stercoris, barnesiae, coprophilus, flavefaciens and C21_c20 displayed a higher abundance in the TIL-L group, while producta and komagatae exhibited a greater abundance in the TIL-H group ( P &lt; 0.05). Conclusions: Collectively, the diversity of gastrointestinal microbiome was related to the expression of TILs in BC patients.
Effect of free amino acids mix with medium triglycerides and Withania somnifera on cancer cachexia.
Authors: Kalyan R Gaddam, Shawn C. Shambaugh, David E. Kanamori, Pradip K. Rustagi, Richard Kim-Thean Ng, Susana Bell, Ajay Desai, Giridhar R. Gorla, Alan D. Cartmell, Rishi Patel
Journal: Journal of Clinical Oncology (2019)

e23140 Background: Cancer cachexia is a multifactorial syndrome involving systemic inflammation, negative protein and energy balance, and involuntary loss of lean muscle mass. It not only adversely affects quality of life but also leads to poor responses to chemotherapy and reduced survival rates. Conventional nutritional support has not been successful in cancer cachexia and most commercially available formulas have shown little to no effect on cancer cachexia. This study assessed nutritional benefits of E2 Energy, an amino acid (AA) supplement powder enriched with branched-chain AAs, medium-chain triglycerides, and Withania somnifera, on body weight, lean muscle mass, and cancer-related piper fatigue score. Methods: This prospective, open-label preliminary feasibility study was conducted in patients receiving active treatment for cancer (e.g. chemotherapy, radiation, targeted therapy, or hormone therapy) with documented evidence of significant weight loss. Patients were evaluated at baseline and at the end of treatment (12 weeks) for lean muscle mass as measured by bioimpedance analysis, body weight, C-reactive protein (CRP), serum albumin, fatigue as measured by Piper Fatigue Scale (PFS), and proinflammatory cytokines (IL-1, IL-2, IL-6, and TNF-α). Being a pilot study, enrollment was restricted to approximately 30 patients with focus on descriptive statistics rather than formal tests of hypotheses. Results: We analyzed data of 15 patients who completed at least 6 weeks of treatment. Treatment with AA powder increased lean muscle mass in 12 (80%) patients. Similarly, PFS scores improved in 14 (93.33%) patients. Overall, in 6 patients (40%), body weight either remained stable or increased from baseline values. Six patients presented abnormal cytokine levels at baseline; however, their results at follow-up were unavailable, thus making interpretation inconclusive. Conclusions: Treatment with AA powder supplement may prevent loss in lean muscle mass, reduce fatigue, and curtail weightloss. However, these results must be substantiated in large well-designed (randomized) studies.
Efficacy and safety of pembrolizumab in patients with advanced adrenocortical carcinoma.
Authors: Nitya Prabhakar Raj, Youyun Zheng, Virginia Kelly, Seth Katz, Joanne F Chou, Richard K. G. Do, Marinela Capanu, Dmitriy Zamarin, Charlotte Eielson Ariyan, Brian R. Untch, Eileen Mary O'Reilly, Anuradha Gopalan, Michael F. Berger, Kelly Olino, Neil Howard Segal, Diane Lauren Reidy
Journal: Journal of Clinical Oncology (2019)

4112 Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333.
TERT Promoter Mutation Spatial Heterogeneity in a Metastatic Follicular Thyroid Carcinoma: Implications for Clinical Work-Up
Authors: Adam Stenman, Martin Hysek, Kenbugul Jatta, Robert Bränström, Eva Darai-Ramqvist, Johan O. Paulsson, Na Wang, Catharina Larsson, Jan Zedenius, Carl Christofer Juhlin
Journal: Endocrine Pathology (2019)

Follicular thyroid carcinoma (FTC) is not routinely diagnosed by a preoperative fine needle aspiration biopsy (FNAB), and the final diagnosis relies on histopathological criteria visible upon microscopic examination of the excised tumor. Several markers have been proposed as helpful in the identification of follicular thyroid tumors with malignant potential and worse prognosis, of which the specific point mutations C250T and C228T in the Telomerase Reverse Transcriptase (TERT) promoter region seem to be particularly promising. We describe a patient presenting with a large pelvic mass, in which a core needle biopsy was consistent with follicular-patterned thyroid tissue positive for a Q61R NRAS mutation and the C228T TERT promoter mutation. Upon clinical investigation, a 60-mm lesion was detected in the right thyroid lobe. The ensuing FNAB was consistent with a follicular thyroid tumor, Bethesda IV, positive for the same NRAS mutation and both the C228T and C250T TERT promoter mutations. A total thyroidectomy was performed, and a widely invasive FTC was diagnosed. Tumor tissue samples from various parts of the primary lesion were investigated for TERT promoter mutations, displaying C228T in three samples and C250T in one. Interestingly, the C228T mutations showed a coupling to areas with high Ki-67 proliferation indexes. Our data indicate that TERT promoter mutations can exhibit spatial heterogeneity in FTCs, with implications for clinical management as well as providing insights into the molecular biology underlying the tumoral etiology.
Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome
Authors: Claudia M. B. Carvalho, Zeynep Coban-Akdemir, Hadia Hijazi, Bo Yuan, Matthew Pendleton, Eoghan Harrington, John Beaulaurier, Sissel Juul, Daniel J. Turner, Rupa S. Kanchi, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, Pawel Stankiewicz, John W. Belmont, Chad A. Shaw, Sau Wai Cheung, Neil A. Hanchard, V. Reid Sutton, Patricia I. Bader, James R. Lupski
Journal: Genome Medicine (2019)

Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.
Host transcriptomic signatures associated with dysbiosis in a preclinical model of lung cancer.
Authors: Mariam El-Ashmawy, Benjamin Wu, Jun-Chieh Tsay, Brendan Franca, Luisanny Perez, Sheik Mohammad Imran Sulaiman, William Rom, Kwok-Kin Wong, Leopoldo Segal
Journal: Journal of Clinical Oncology (2019)

3107 Background: Enrichment of the lower airway microbiota with oral commensals has been associated with transcriptomic changes affecting several inflammatory pathways associated with non-small cell lung cancer (NSCLC) development and progression. Using a mouse model of NSCLC, we evaluated the effects of lower airway dysbiosis on tumor progression and host transcriptomics. Methods: Preclinical model of lung cancer was constructed by introducing luminescence-tagged Kras mutated cells into C57/B6 mice, causing lung cancer to develop. Lower airway dysbiosis was induced by weekly intratracheal challenge with either PBS or Veillonella parvula in wild type and lung cancer mice. Experiments were repeated twice to evaluate for survival as well as lower airway host response using flow cytometry and RNA sequencing (HiSeq). Sequence data was processed using a validated mouse gene expression signature matrix with cibersort from https://cibersort.stanford.edu and DESeq using FDR correction. Results: In wild type mice, lower airway dysbiosis with Veillonella did not affect the survival, weight gain or airway lumen diameter. Among lung cancer mice, dysbiosis led to increased mortality, weight loss, and tumor burden. Multiple transcriptomic signatures were identified among the dysbiosis groups (both in WT and lung cancer mice). Unsupervised hierarchical clustering of immune cell profiles using cibersort on whole transcriptome showed near perfect separation between the four experimental conditions. Amongst the most differentially enriched immune cell subsets, we identified that lung dysbiosis upregulates genes annotated to Th1 and Th2 cells (p &lt; 0.01, q &lt; 0.2). Using flow cytometry, we identified that PD-1, IL-17, and ROR-gamma are differentially expressed in CD4+ cells in dysbiosis conditions, and these patterns are consistent in whole RNA transcriptome. Conclusions: Transcriptomic signatures reveal immune profiles associated with dysbiosis, an experimental condition associated with worse outcomes in lung cancer. This investigation provides novel insights into how disruption of the lower airway microbiome may contribute to the pathogenesis of NSCLC.
Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility
Authors: Ali Afrasiabi, Grant P. Parnell, Nicole Fewings, Stephen D. Schibeci, Monica A. Basuki, Ramya Chandramohan, Yuan Zhou, Bruce Taylor, David A. Brown, Sanjay Swaminathan, Fiona C. McKay, Graeme J. Stewart, David R. Booth
Journal: Genome Medicine (2019)

Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. We have investigated transcriptomes of B cells and EBV-infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection and with expression levels associated with the MS risk genotype (LCLeQTLs). The association of LCLeQTL genomic burden with EBV phenotypes in vitro and in vivo was examined. The risk genotype effect on LCL proliferation with CD40 stimulation was assessed. These LCLeQTL MS risk SNP:gene pairs (47 identified) were over-represented in genes dysregulated between B and LCLs (p < 1.53 × 10−4), and as target loci of the EBV transcription factor EBNA2 (p < 3.17 × 10−16). Overall genetic burden of LCLeQTLs was associated with some EBV phenotypes but not others. Stimulation of the CD40 pathway by CD40L reduced LCL proliferation (p < 0.001), dependent on CD40 and TRAF3 MS risk genotypes. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2, with expression of each correlated with EBNA2 expression dependent on genotype. These data indicate targeting EBV may be of therapeutic benefit in MS.
Clinical utility of SERUM extracelullar domain of HER2 receptor (ECD) in HER2-positive breast cancer.
Authors: Ariadna Gasol Cudós, Serafin Morales Murillo, Joel Veas Rodriguez, Carles Canosa Morales, Jordi Melé Olivé, Antonia Salud
Journal: Journal of Clinical Oncology (2019)

e12086 Background: Although ECD expression was validated as tumor marker years ago, it is not used in daily clinical practice even if a prognostic value was demonstrated in some trials. Methods: In our single institution, during January 2013-2019, ECD was analyzed in a series of HER2 positive breast cancer patients; 71 in early or locally-advanced and 45 in metastatic setting. Results: In the metastatic cohort, median ECD expression was of 28 ng/ml (6,5-350), thus 10 (22%) patients had lower levels than threshold of 15ng/ml. No correlation was found between ECD expression and other clinicopathological variables. No association was found with overall survival however in patients with metastases at diagnosis higher ECD expression was correlated with a short overall survival (25 vs 54 months). Higher levels of ECD decreased according to good response to treatment. Median ECD expression was of 12ng/ml (3,6-97) in non-metastatic setting, however only 11 (15%) patients had elevated levels ( &gt; 15ng/ml). Estrogen receptor and ki67 expression were not correlated with ECD levels. Median ECD expression in tumors &gt; 5cm was 21,87 ng/ml versus 12ng/ml in smaller tumors (p = 0,006); in nodal involvement median ECD was 16,77 ng/ml versus 12,05 without affectation (p = 0,09). Patients with ECD higher than 10 ng/ml had a 55% pathologic complete response (pCR) versus 25% if less than 10ng/ml (OR 3.68, p = 0.027). Interestingly, none of tumors &gt; 5cm and ECD &lt; 10ng/ml achieved a pCR. Conclusions: Higher levels of ECD were observed in the metastatic setting and their decreased levels during treatment was correlated with response. In early and locally-advanced setting higher levels were found in larger tumors; and also these tumors had better response than lower levels of ECD. ECD could be used as a monitoring tool in the metastatic scenario and as a predictive factor of response in the neoadjuvant setting, specifically in tumors &gt; 5cm.
Combined effect of radiotherapy and anthracyclines on risk of breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Lene H. S. Veiga, Rochelle E. Curtis, Lindsay M. Morton, Diana Withrow, Rebecca M. Howell, Susan A Smith, Rita Weathers, Kevin C. Oeffinger, Chaya S. Moskowitz, Tara O. Henderson, Michael A. Arnold, Todd M. Gibson, Wendy Leisenring, Joseph Philip Neglia, Lucie Marie Turcotte, John Whitton, Leslie L. Robison, Peter Inskip, Gregory T. Armstrong, Amy Berrington de González
Journal: Journal of Clinical Oncology (2019)

10053 Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m 2 ). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p &lt; 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend &lt; 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- &lt; 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.
Immune profiling of tumor-infiltrating T cells using mass cytometry.
Authors: David Roumanes, Evan Newell, Michael Fehlings
Journal: Journal of Clinical Oncology (2019)

2607 Background: Immunotherapy recent successes have opened new avenues for the treatment of cancer and the presence of tumor-specific CD8+ T cells in tumor-bearing individuals offer a promising therapeutic target. However, the detection and profiling of such T cells are challenging due to the need to detect rare antigen-specific T cell subpopulations in patient samples that are limited in size thus making it difficult to exploit these parameters for predictive signatures of clinical response. Moreover, the identification and analysis of neoantigen-specific CD8 + T-cells in tumor-bearing individuals is challenging due to the small pool of such cells. Methods: In order to identify therapy-relevant tumor antigens and to facilitate a concurrent in-depth characterization of cells directed towards these targets, immunoSCAPE leverages the high-dimensional immune profiling capabilities of cytometry by time of flight (CyTOF) combined with a unique technology allowing the identification rare antigen-specific T-cell subsets. Results: We applied this technology to patient tumor-infiltrating lymphocytes from human cancer samples and tumor-derived neoantigens recognized by T-cells were identified and characterized. Interestingly, the majority of patient-derived tumor infiltrates consisted of tumor-unrelated T-cells characterized by a diverse phenotype. Strikingly, the expression of CD39 was absent from these bystander cells, suggesting that CD39 could be a useful biomarker for the identification of putative tumor-reactive T cells. Conclusions: Simultaneous immune profiling revealed that tumor-unrelated, bystander CD8 + T-cells are phenotypically different in human tumor infiltrates and identified CD39 as a putative marker of neoantigen-specific T-cells. By providing insights into the nature, frequency and phenotype of antigen-specific T-cells, immunoSCAPE’s unique target discovery and high-dimensional immune profiling platform is a valuable tool for the development of novel diagnostic and therapeutic strategies in immunotherapy.