tbuckley/cabot-search huggingface dataset:
The vaginal microbiome and preterm birth
Authors: Jennifer M. Fettweis, Myrna G. Serrano, J. Paul Brooks, David J. Edwards, Philippe H. Girerd, Hardik I. Parikh, Bernice Huang, Tom J. Arodz, Laahirie Edupuganti, Abigail L. Glascock, Jie Xu, Nicole R. Jimenez, Stephany C. Vivadelli, Stephen S. Fong, Nihar U. Sheth, Sophonie Jean, Vladimir Lee, Yahya A. Bokhari, Ana M. Lara, Shreni D. Mistry, Robert A. Duckworth, Steven P. Bradley, Vishal N. Koparde, X. Valentine Orenda, Sarah H. Milton, Sarah K. Rozycki, Andrey V. Matveyev, Michelle L. Wright, Snehalata V. Huzurbazar, Eugenie M. Jackson, Ekaterina Smirnova, Jonas Korlach, Yu-Chih Tsai, Molly R. Dickinson, Jamie L. Brooks, Jennifer I. Drake, Donald O. Chaffin, Amber L. Sexton, Michael G. Gravett, Craig E. Rubens, N. Romesh Wijesooriya, Karen D. Hendricks-Muñoz, Kimberly K. Jefferson, Jerome F. Strauss, Gregory A. Buck
Journal: Nature Medicine (2019)

Abstract The incidence of preterm birth exceeds 10% worldwide. There are significant disparities in the frequency of preterm birth among populations within countries, and women of African ancestry disproportionately bear the burden of risk in the United States. In the present study, we report a community resource that includes ‘omics’ data from approximately 12,000 samples as part of the integrative Human Microbiome Project. Longitudinal analyses of 16S ribosomal RNA, metagenomic, metatranscriptomic and cytokine profiles from 45 preterm and 90 term birth controls identified harbingers of preterm birth in this cohort of women predominantly of African ancestry. Women who delivered preterm exhibited significantly lower vaginal levels of Lactobacillus crispatus and higher levels of BVAB1, Sneathia amnii , TM7-H1, a group of Prevotella species and nine additional taxa. The first representative genomes of BVAB1 and TM7-H1 are described. Preterm-birth-associated taxa were correlated with proinflammatory cytokines in vaginal fluid. These findings highlight new opportunities for assessment of the risk of preterm birth.
Tumor pathological and immunological changes in HER2+ metastatic breast cancer (MBC) following trastuzumab combined with expanded and activated autologous natural killer (NK) cell infusion.
Authors: Kritika Yadav, Noriko Shimasaki, Samuel Guan Wei Ow, Andrea Li Ann Wong, Joline Si Jing Lim, Priscillia Koe, Liang Piu Koh, Lip Kun Tan, Boon C. Goh, Dario Campana, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2019)

e12511 Background: A central mechanism for the anti-tumor activity of Trastuzumab, a HER2 monoclonal antibody, against HER2+ tumors is induction of antibody dependent cell cytotoxicity (ADCC) mediated by NK cells. We are conducting a first-in-human trial of Trastuzumab followed by infusion of expanded, activated autologous NK cells in refractory HER2+ MBC (ClinicalTrials.gov: NCT02030561) to test the hypothesis that NK cell infusions will augment Trastuzumab-mediated ADCC and increase immune cell infiltration in tumor. Pre- and post-infusion tumor biopsies were obtained in a subset of patients to determine degree of NK cell infiltration in tumor and histopathological and immunological effects after infusion. Methods: HER2+ MBC patients underwent apheresis to harvest NK cells for ex vivo expansion and activation. NK cells (10 7 /kg), expressing high levels of the antibody receptor CD16, were infused 24 hours post-Trastuzumab. Histology analysis and immunohistochemistry with CD56, CD3, CD20 and cleaved caspase-3 to identify NK, T, B, and apoptotic cells respectively, was performed in pre- and post-infusion biopsies. Studies of CD4 and CD8 to further classify T cell infiltrates, and CD16 to assess NK cell functionality are underway. Results: Analysis of 7 paired tumor biopsies collected before and 7-14 days after NK cell infusion showed absolute increase in lymphocyte infiltration (mean cell count/5 HPF: 204 vs 265 in pre- vs post- biopsy, p = 0.109). Most infiltrating lymphocytes were CD3+ T cells (74.28±12.72% vs 80 ±10% in pre vs post) and CD56+ NK cell number in the immune infiltrate were increased post infusion (mean cell count/5 HPF: 4.57±3.46 vs 20.57±13.83 in pre vs post; p = 0.009). Increased tumor apoptosis was observed post NK cell infusion (mean apoptotic cell count/5 HPF: 3.14±2.48 vs 5.86±6.72 in pre vs post, p = 0.27). Conclusions: Histopathology analysis of tumors from HER2+ MBC patients demonstrated significant increase in NK and T cells in tumor following Trastuzumab and NK cell infusion, suggesting that this combination might also augment recruitment of T lymphocytes into tumor, further enhancing anti-tumor activity. Clinical trial information: NCT02030561.
Single center, open and prospective evaluation of genomic sequencing on cerebro-spinal fluid, brain metastatic lesions and plasma from patients in non-small cell lung cancer with brain metastasis.
Authors: Chunhua Ma, Chuoji Huang, Zhi Li, Rong Jiang, Juncheng Zhang
Journal: Journal of Clinical Oncology (2019)

e13578 Background: Leptomeningeal metastases are observed in 9.4% non–small Cell Lung Cancer (NSCLC) patients with EGFR mutations. Depending on patient specific gene mutations, tumor cells may also have different proliferative activity, leading to differential metastatic potential. However, the clinical significance of observed gene mutation differences between CSF, plasma, primary pulmonary tumor and metastatic brain tumor samples remains unclear and should be further explored. Methods: From Apr. 2018 to Jan. 2019, plasma and CSF paired samples were drawn from consented NSCLC patients with diagnosed brain metastasis. Of these 21, brain lesion samples were obtained from 5 patients. All the samples were tested by next-generation sequencing. Patients were treated based on the detection results. Results: For this cohort, the detection rate of EGFR mutations in CSF cfDNA versus plasma cfDNA/CTC was 57.1% and 23.8% respectively (p &lt; 0.05). For patients who had not received tyrosine kinase inhibitor (TKI) therapy, the CSF cfDNA EGFR mutation results were consistent with results for plasma, brain lesion and primary tumor samples. Conversely, for patients who had received TKI therapy, EGFR mutations detected in CSF were consistent with those from brain samples, but different from those observed in plasma or primary tumor samples. A high response rate (ORR, 70%; DCR, 90%) was observed in patients with EGFR positive detected in CSF after treatment with second orthird-generation TKI. Among the EGFR mutations detected in CSF, the EGFR uncommon mutation frequency was 58.3%(7/12), including G7I9A/L861Q/L703P/R776H/G575R/T790M 85.7% (6/7) of these occurred in LM patients. One patient who progressed from BM to LM had an uncommon mutation in the CSF sample. Among these five patients with EGFR G719A or L861Q positive and T790M negative, 4 patients had PR and 1 patient had SD after the second-generation TKI therapy. Conclusions: Differences in EGFR gene mutations were observed between CSF, plasma, primary pulmonary lesion and brain tissue samples in NSCLC patients with diagnosed brain metastasis after TKI therapy. The reasons for this discrepancy remain to be understood. Nevertheless, CSF may be a useful prognostic tool for patient monitoring and metastasis risk evaluation. The detection of uncommon EGFR mutations may increase the risk of LM in NSCLC patients. Clinical trial information: ChiCTR1800017499.
Hepatocellular carcinoma with tumor thrombus in portal vein branch: Transarterial chemoembolization combined with Iodine125 brachytherapy versus transarterial chemoembolization combined with sorafenib.
Authors: Jingjun Huang, Wensou Huang, Mingyue Cai, Yongjian Guo, Jingwen Zhou, Kangshun Zhu
Journal: Journal of Clinical Oncology (2019)

e15646 Background: Patients with hepatocellular carcinoma (HCC) accompanied with portal vein tumor thrombus (PVTT) have a poor prognosis. Although transarterial chemoembolization (TACE) plus sorafenib (TACE-S) could lead to an improved survival than TACE alone in HCC patients with first- or second-branch PVTT (branch PVTT), the survival was very limited. We compared the safety and efficacy of TACE plus Iodine125 brachytherapy (TACE-I) with TACE-S in patients with unresectable HCC and branch PVTT. Methods: The medical records of consecutive patients with HCC and branch PVTT who underwent TACE-I (TACE-I group) or TACE-S (TACE-S group) from January 2015 to December 2017 were retrospectively evaluated. Iodine125 seeds were implanted into the PVTT under CT guidance 3-5 days after the initial TACE. The matched peripheral dose of Iodine125 brachytherapy was set to be 120-140 Gy. Sorafenib was administered 400 mg twice daily. Outcomes of patients who underwent TACE-I, including adverse events, treatment responses, time to progression (TTP), and overall survival (OS), were compared with those of patients who underwent TACE-S. Results: One hundred and twenty patients were included in the analysis; 62 patients underwent TACE-I and 58 underwent TACE-S. The overall incidence of adverse events was significantly lower in TACE-I group than in TACE-S group (58.1% vs. 93.1%, P &lt; .001), and incidence of grade 3 or higher adverse events also was significantly lower in TACE-I group than in TACE-S group (3.2% vs. 27.6%, P &lt; .001). PVTT OR rates at 12 weeks (58.1% vs. 13.8%, P &lt; .001) and at 24 weeks after the treatment (68.9 % vs. 10.9%, P &lt; .001) in TACE-I group were higher than those in TACE-S group. TACE-I led to significantly longer TTP (median, 11.2 months vs. 6.2 months, P &lt; .001) and OS (median, 20.9 months vs. 14.0 months, P &lt; .001) than TACE-S. In uni- and multivariable analyses, TACE-I treatment, PVTT extent, tumor size ≥10 cm, PVTT OR at 12 weeks, and intrahepatic tumor OR at 12 weeks were independent prognostic factors for OS. Conclusions: TACE-I had less side effects and may improve OS than TACE-S for HCC patients with branch PVTT.
Improving risk assessment of obesity-associated breast cancer.
Authors: Neil M. Iyengar, Ayca Gucalp, Xi K. Zhou, Hanhan Wang, Dilip D. Giri, Samantha Williams, Domenick J. Falcone, Lisle Winston, Jonathan Landa, Laurie J. Kirstein, Monica Morrow, Andrew J. Dannenberg
Journal: Journal of Clinical Oncology (2019)

1544 Background: Elevated body mass index (BMI) is associated with increased risk of estrogen receptor (ER)-positive postmenopausal breast cancer. The risk is also elevated in women with a normal BMI but excess body fat. These risks may be driven by breast white adipose tissue inflammation (WATi), which is associated with elevated aromatase levels and systemic metabolic dysfunction (e.g. hyperinsulinemia). We hypothesized that body fat assessment is superior to BMI for detecting the pathophysiology that promotes obesity-related breast cancer, particularly among normal BMI women. Methods: Non-tumorous breast tissue was collected from women undergoing mastectomy for breast cancer treatment or prevention. Breast WATi was detected by the presence of crown-like structures in the breast, which are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. Body composition was measured prior to mastectomy via dual energy X-ray absorptiometry. Exercise behavior was also assessed prior to surgery using the Godin Leisure Time Exercise Questionnaire. Associations among categorical variables were examined using Χ 2 or Fisher’s exact test. Relationships between continuous variables were examined using the Spearman correlation. Results: From April 5, 2016 to August 31, 2018, 100 patients were enrolled; median age 49 (range 29 to 82) years. Breast WATi was present in 56/100 (56%) women and was associated with elevated BMI and body fat levels, breast adipocyte hypertrophy, postmenopausal status, metabolic syndrome and decreased physical activity (P &lt; 0.05). Among 39 women with normal BMI, breast WATi was present in 14 (36%) and was associated with elevated body fat levels, breast adipocyte hypertrophy, dyslipidemia, and decreased physical activity (P &lt; 0.05). There was no statistically significant association between BMI and breast WATi in the normal BMI group. Menopausal status and total fat mass had greater sensitivity and specificity for the detection of breast WATi compared to a BMI-based model (AUC 0.843 vs. 0.779, respectively). Conclusions: Measurement of body fat is superior to BMI for predicting breast inflammation, which has been shown to promote obesity-related breast cancer.
The results of 3000 Fit: A prospective study led at Saint Joseph University of Beirut.
Authors: Ronaldo Elkaddoum, Roland Eid, Fady Haddad, Myrna Germanos, Cybel Mehawej, Hampig Raphael Kourie, Joseph Gergi Kattan
Journal: Journal of Clinical Oncology (2019)

e15141 Background: In terms of frequency, colorectal cancer (CRC) is the 3rd cancer in Lebanon with 1093 incidences registered in 2015. To this date not a single screening campaign has been organized in the country. Fecal immunochemical test (FIT) is an advised screening technique. We found it useful to organize a screening campaign using FIT to determine the prevalence of CRC in a population of 3000 healthy Lebanese allowing the extraction of useful data. Methods: 3000 tubes were distributed to Lebanese adults (45-80 years old) at average risk of developing CRC, followed by explanations. FIT analysis was done at the medical genetics unit (UGM) of Saint-Joseph University and patients with positive FIT were asked to undergo further investigations. Results: Out of the 3000 distributed tests, 705 were returned (23.5%) with 459 fully analyzable. The age median was 56 (45-80). Sex ratio F/M 2.3. Out of the 459 patients, 278 (60.5%) showed 0ng/ml, 137 (29.8%) showed 1-79ng/ml, 3 (0.6%) showed 80-99ng/ml (intermediate risk values), 33 (7.1%) showed 100-800ng/ml considered as a positive value and finally 8 (1.7%) showed over range values. Among the 44 positive patients we contacted 41. Out of the 8 (18%) colonoscopies results received: 5 showed hemorrhoids leading to false positive, 1 ulcerative ileitis, 1 tubular adenomas and 1 carcinoma. Conclusions: While it was hard for us to quantify people for whom a free FIT was proposed, the low restitution rate among those who took the test shows the necessity of national screening and sensitization campaigns.
Quantitative MHC II protein expression levels in tumor epithelium to predict response to the PD1 inhibitor pembrolizumab in the I-SPY 2 Trial.
Authors: Julia Dianne Wulfkuhle, Christina Yau, Denise M. Wolf, Rosa Isela Gallagher, Lamorna Brown Swigart, Gillian L. Hirst, Michael Campbell, Rita Nanda, Minetta C. Liu, Lajos Pusztai, Laura Esserman, Donald A. Berry, Laura van 't Veer, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2019)

2631 Background: Response to immune checkpoint inhibitors has been associated with immune activation and mutational load within a tumor. Previous results in other tumors have implicated MHC II protein tumor cell expression as a response predictor to immune checkpoint inhibitors. In the I-SPY 2 TRIAL, the anti-PD1 therapeutic antibody pembrolizumab (P) was available to HER2-negative subtypes and graduated in both the HR+/HER2- and TNBC signatures. Pre-specified biomarker analysis was performed to test tumor MHC II expression as a predictor of response to P in the I-SPY 2 TRIAL based on its central role in tumor antigen presentation. Methods: 156 patients (P: 67, controls: 89) had RPPA and pCR data. RPPA-based quantitative data for pan-MHC II protein isotypes HLA-DR/DP/DQ/DX and HLA-DR protein isotype was obtained from LCM-enriched tumor epithelium, and protein levels were assessed for association with pCR in the P and control arms separately using the Wilcoxon Rank Sum test (p &lt; 0.05). Analysis was also performed in the HR+ and HR- subgroups. Markers were analyzed individually; p-values are descriptive and were not corrected for multiple comparisons. Results: Across all P- treated patients, the HLA class II molecules –DR and -DR/DP/DQ/DX had a positive association with response to P (p = 0.014 and p = 0.001). Expression of HLA-DR/DP/DQ/DX also had a positive association with response to P in HR+ tumors. Neither of these associations were seen in the control arm samples. Conclusions: The observation of elevation of MHC II protein expression in HER2- responding patients treated with P suggests that activation of antigen peptide exchange facilitated by these molecules in T and B cells may enhance response to P treatment.
EGFR L858R mutation as a possible target for individual-independent immunotherapy in Chinese population.
Authors: Yu Chen, Shiguang Hao, Zeng-qing Guo, Jing Lin, Li-zhu Chen, Ling Chen, Jia-mi Yu, Gang Chen, Xiong-wei Zheng, Yuting Yi, Yan-Fang Guan, Xuefeng Xia, Xin Yi
Journal: Journal of Clinical Oncology (2019)

8538 Background: Neoantigens arise from tumor-specific mutations and potentially provoke immune responses. General vaccines targeting these peptides could be beneficial for patients suffering from common cancers, like lung cancer. Therefore, a retrospective analysis was performed on 799 non-small cell lung cancer (NSCLC) tissue samples previously profiled using our 1021-gene panel. Each sample was collected from a unique patient, from whom peripheral blood or normal tissue was also obtained as control. Methods: Sequencing data were generated and pre-analyzed according to our in-house procedures. HLA typing was done using OptiType v1.0 (required sequences were captured by 1021-gene panel) and neoantigens were predicted by netMHCpan v4.0 based on typed HLA alleles and curated non-frameshift somatic mutations with frequency &gt; 5%, which were called in pre-analysis. A neoantigen is considered mutant-specific if IC 50 mut is &lt; 500 nM and IC 50 wild is &gt; 500 nM, and especially, it is considered a strong-binder if IC 50 mut is &lt; 50 nM. Results: HLA typing returned 141 unique alleles, with the top 3 by carrier frequency being A*1101 (39%), C*0102 (33%) and A*2402 (28%). A further investigation into HLA alleles, mutations and neoantigens revealed two mutations on EGFR as candidates for off-the-shelf vaccine development: (1) L858R mutation (19%, 151 out of 799) and (2) E746_A750del mutation (13%, 106 out of 799). Among the four neoantigens derived from EGFR L858R mutation is HVKITDFGR, which can be recognized by A*3303 (IC 50 mut = 22.93 nM and IC 50 wild = 12,733.96 nM) and the combination is shared by 3% of the patients (23 out of 799), despite that A*3303 is not a very frequent allele in this population (16%, 127 out of 799). Two neoantigens were derived from EGFR E746_A750del mutation, including IPVAIKTSPK, which is mainly recognized by A*1101 (IC 50 mut = 158.16 nM and IC 50 wild = 31,132.66 nM). This combination is shared by 5% of the patients (41 out of 799). Conclusions: (1) EGFR L858R mutation and HLA-A*3303 could be a good target for individual-independent vaccine development. (2) HLA-A*1101 is the most frequent allele in this population. However, HLA-A*1101 and E746_A750del mutation is not so ideal for off-the-shelf vaccine development.
Risk of colonic adenoma in patients with non–colorectal cancers.
Authors: Hamzah Abu-Sbeih, Faisal Ali, Wei Qiao, Phillip Lum, Mehnaz Shafi, Robert Bresalier, Ernest Hawk, Raju S. Gottumukkala, Yinghong Wang
Journal: Journal of Clinical Oncology (2019)

e13070 Background: In the last two decades, the incidence of colorectal cancer (CRC) has decreased dramatically after the implementation of CRC screening in the United States. Several risk factors for colonic adenoma (CA), the main precursor for CRC, have been found. Whether personal history of non-colorectal cancer (NCRC) is a risk factor for CA has not been studied. Here, we assess the risk of CA in patients with NCRCs. Methods: We conducted a retrospective study of cancer patients who underwent colonoscopy after cancer diagnosis between 2009 and 2018. We included patients without history of NCRC as a control group. Multivariate logistic regression was used to assess independent risk factors for CA (Table 1). Results: Total of 9408 patients with NCRC were included; CA was detected in 4503 (48%). Histology revealed tubulovillous features in 611 (14%) patients and villous in 51 (1%). High grade dysplasia was detected in 1,317 (29%) patients and adenocarcinoma in 388 (9%). The rate of adenocarcinoma was the highest in patients with multiple myeloma (14%). Adenoma detection rate (ADR) was 30% in patients younger than 40 years ( n= 1621), 32% in patients between 40 and 50 years ( n= 812), 47% in patients between 50 and 60 years ( n= 2892), and 55% in patients older than 60 years ( n= 4493). Multivariate analysis revealed an increased risk of CA with old age, male sex, family history of CRC, and high body mass index ( P&lt; 0.05). The median time from NCRC diagnosis to CA detection was 3 years (IQR 1-8). Conclusions: ADR in patients with a personal history of NCRC is higher than the ADR of patients without NCRC. CRC screening should be performed after the diagnosis of NCRC is made, even if it was before the standard threshold of CRC screening age of 50 years.[Table: see text]
Kinase Networks Regulate Metabolism: I'D(H1) Never Have Guessed!
Authors: Sarah Horton, Brian J.P. Huntly
Journal: Cancer Discovery (2019)

Abstract Summary: Mutations in isoforms of isocitrate dehydrogenase (IDH) enzymes are described in multiple cancers and both mutant and wild-type IDH are important for the generation and maintenance of tumors, but how their activity is regulated is poorly understood. An article in this issue of Cancer Discovery identifies a novel posttranslational mechanism of IDH1 regulation involving phosphorylation of specific tyrosine residues by a network of kinases that alter the specificity of substrate and cofactor binding, dimer formation, and ultimately enzyme activity. See related article by Chen et al., p. 756.
Detection of KRAS mutations in colon adenocarcinoma by droplet digital PCR.
Authors: Yaroslav S. Enin, Oleg I. Kit, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Dmitry A. Kharagezov, Anton G. Milakin, Vyacheslav A. Sustretov, Andrey Dashkov, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e15080 Background: The screening of mutations in the KRAS gene is a traditional marker of the effectiveness of targeted therapy for colorectal cancer. Mutations in the 12 codon of the second exon of the KRAS gene are present in 40% of colorectal tumors, and monitoring of the mutational status together with the level of mutant DNA is of particular clinical interest. However, the sensitivity level of the traditionally used real-time polymerase chain reaction (RT-PCR) method is insufficient in some cases. Recently, Droplet Digital PCR (DD-PCR) has been considered as an alternative method, which is more sensitive. The purpose of this study was to compare the methods of detection of somatic mutations in the second exon of the KRAS gene using DD-PCR versus RT-PCR. Methods: This study included 134 patients with colon adenocarcinoma. The presence or absence of activating mutations in the second exon of the KRAS gene in samples of FFPE blocks was detected by RT-PCR using the “Real-time-PCR-KRAS-7M reagent kit” (Biolink, Russia) and Digital Droplet PCR using the “KRAS Screening Multiplex kit” (Bio-Rad, USA). Results: For all 134 samples, selected for the study, the WT status of the KRAS gene was identified by the RT-PCR method. According to the results of DD-PCR for 131 samples (96.2%), a positive amplification response of mutant DNA with more than 200 events was obtained. The number of amplicons varied from 312 to 117917 per sample, the median was 2940 copies. According to recent trials, a clinically significant level of mutational events must exceed 5% of the total number of amplicons in a sample. In our study, 12.9% of cases (17 patients) met this criterion. Conclusions: The DD-PCR method demonstrated a much higher analytical sensitivity for the detection of SNP mutations in comparison with RT-PCR that may be of critical importance in the therapeutic decision.