tbuckley/cabot-search huggingface dataset:
Association of gut microbiome with immune status and clinical response in solid tumor patients who received on anti-PD-1 therapies.
Authors: Shota Fukuoka, Motooka Daisuke, Yosuke Togashi, Eri Sugiyama, Hibiki Udagawa, Keisuke Kirita, Takahiro Kamada, Akihito Kawazoe, Koichi Goto, Toshihiko Doi, Kohei Shitara, Shota Nakamura, Hiroyoshi Nishikawa
Journal: Journal of Clinical Oncology (2018)

3011 Background: Significant advances have been made in cancer immunotherapy with immune check point blockade (ICB). Yet, most patients with various tumor types finally experienced disease progression after ICB. Therefore, to investigate predictive biomarker(s) and resistance mechanism(s) against ICB are of importance. While modulation of the gut microbiome reportedly augments anti-tumor immune responses induced by ICB in murine models, the association between gut microbiome and immune status in tumor microenvironment remains unclear. Here, we addressed this issue with a Japanese patient cohort harboring solid cancers (non-small cell lung cancer and gastric cancer) who received anti-PD-1 therapies. Methods: We performed Meta-sequencing analyses of bacterial 16S ribosomal DNA amplified from stools from 38 solid tumor (lung cancer, 14: gastric cancer, 24) patients. Tumor-infiltrating lymphocytes (TIL) were analyzed from 17 patients. Patients were classified as follows: Responder (R) with an objective response (complete or partial response, or stable disease lasting at least 6 months) and Non responder (NR) with disease progression or stable disease lasting less than 6 months) based on REICIST criteria. Results: We observed significant differences in the diversity and composition of gut microbiome in R (n = 7) versus NR (n = 31). No significant differences were observed in patient base-line characteristics between Rs and NRs including PD-L1 expression. Rs had a significantly higher alpha diversity compared with NR using Shannon's index (p = 0.0047). Progression-free survival was significantly longer in patients with high diversity than patients with lower diversity patients (median 93 vs. 28 days, p = 0.002). Particularly, Ruminococcaceae family in Clostridiales order was enriched in R with LEfSe analysis. Immune profiling revealed a statistically significant positive correlation between PD-1+CD8+T cell in TIL and abundance of Ruminococcaceae (r = 0.57, p = 0.020). Conclusions: The diversity of and composition of gut microbiome could predict the effect of ICB, suggesting that gut microbiome potentially augment therapeutic responses to ICB in patients with solid tumors.
A phase I study of BKM120, a novel oral selective phosphatidylinositol-3-kinase (PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer.
Authors: Gayathri Nagaraj, Cynthia X. Ma, Jingqin Luo, Matthew J. Ellis
Journal: Journal of Clinical Oncology (2012)

TPS664 Background: PI3K pathway activation plays a crucial role in mediating endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. We have shown previously that BKM120 in combination with fulvestrant induced synergistic apoptotic cell death in long-term estrogen deprived ER+ breast cancer (LTED) cell line models, supporting the clinical investigation of this combination in ER+ breast cancer. Methods: The study is composed of the dose escalation cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard 3+3 phase I design is employed to determine the maximum tolerated dose (MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER+ metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be enrolled at the MTD to further examine the toxicity profile and preliminary efficacy of this combination. Steady state concentrations of BKM120 will be analyzed. Postmenopausal women with ER+ MBC and measurable disease per RECIST are eligible. Pts who are currently taking fulvestrant without disease progression are eligible. There is no restriction on the number of prior lines of systemic therapy for metastatic disease in phase IA but &lt; 3 lines is required in phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level (DL) is DL1 (Table). Correlative studies include assessing PI3K pathway abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen, and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor biopsies collected at baseline and cycle 2 day 1 in consented patients. Enrollment to DL1 is complete and the study is currently enrolling pts to DL2. [Table: see text]
Update on the overall survival of patients with metastatic melanoma treated with immune checkpoint blockade following initial treatment with HD IL-2.
Authors: Michael K.K. Wong, Michael Morse, David F. McDermott, Joseph Clark, Howard Kaufman, Gregory A. Daniels, Janice P. Dutcher, Jessica C. Perritt, Hong Hua, Tharaknath Rao
Journal: Journal of Clinical Oncology (2016)

e21039 Background: High-dose interleukin-2 (HD IL-2) and immune checkpoint inhibitors can provide survival benefit in patients with metastatic melanoma (mM). The clinical impact of using these therapies in sequence remains unknown. Herein, we report on the outcomes of sequencing ipilimumab and/or anti-PD-1/PD-L1 therapy after treatment with HD IL-2 using a national IL-2 patient registry, PROCLAIMSM (www.proclaimregistry.com, NCT01415167). Methods: Patients were prospectively enrolled into the registry as of 2011 and must have received at least one dose of HD IL-2 for this analysis. Those that received immune checkpoint inhibitors prior to HD IL-2 were excluded. Statistics and survival analysis were performed on datasets as of December 2, 2015. Results: The mOS for all mm patients (n = 273) was 19.4 months, with a median follow-up of 23.1 months. Three groups were further analyzed according to treatment after HD IL-2; no immune checkpoint blockade following HD IL-2 (no ICB, n = 137), HD IL-2 followed by ipilimumab alone (IL-2 then IPI, n = 82), and HD IL-2 followed by anti-PD-1/PD-L1 inhibitors with or without ipilimumab (IL-2 then aPD-1±IPI, n = 54). This latter group, IL-2 then aPD-1±IPI, could have received ipilimumab before or after anti-PD-1/PD-L1. Patients with no ICB, IL-2 then IPI, and IL-2 then aPD-1±IPI achieved a mOS of 14.1, 15.8, and 28.2 months, respectively (P= .96 IL-2 then IPI vs. no ICB; P= .002 IL-2 then aPD-1±IPI vs. no ICB). The estimated 12-month survival rates were 56%, 64%, and 96%, respectively. No HD IL-2 treatment-related deaths were reported. Conclusions: There was no difference in mOS between patients treated with ipilimumab post HD IL-2 compared to patients with no ICB following HD IL-2. Patients treated with anti-PD-1/PDL-1±IPI showed increased mOS compared to those treated with HD IL-2 alone. These data further support the concept of investigating IL-2 therapy in combination or sequence with newly developed immune checkpoint inhibitors. Clinical trial information: NCT01415167.
Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction
Authors: Yingxue Qi, Wenchun Chen, Xinyu Liang, Ke Xu, Xiangyu Gu, Fengying Wu, Xuemei Fan, Shengxiang Ren, Junling Liu, Jun Zhang, Renhao Li, Jianwen Liu, Xin Liang
Journal: Journal of Hematology & Oncology (2018)

Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy. We established a series of screening models and obtained rat anti-mouse GPIbα monoclonal antibodies (mAb) 1D12 and 2B4 that demonstrated potential value in suppressing cancer metastasis. To validate our findings, we further obtained mouse anti-human GPIbα monoclonal antibody YQ3 through the same approach. 1D12 and 2B4 affected the von Willebrand factor (vWF)-GPIbα interaction via binding to GPIbα aa 41-50 and aa 277-290 respectively, which markedly inhibited the interaction among platelets, tumor cells, and endothelial cells in vitro, and reduced the mean number of surface nodules in the experimental and spontaneous metastasis models in vivo. As expected, YQ3 inhibited lung cancer adhesion and demonstrated similar value in metastasis. More importantly, for all three mAbs in our study, none of their Fabs induced thrombocytopenia. Our results therefore supported the hypothesis that GPIbα contributes to tumor metastasis and suggested potential value of using anti-GPIbα mAb to suppress cancer metastasis.
P01.108 Use of complementary and alternative medicine in glioma patients
Authors: C Hertler, U Roelcke, K Conen, F Huber, T Weiss, S Hofer, O Heese, M Westphal, P Roth, M Weller, G Eisele
Journal: Neuro-Oncology (2018)

Patients suffering from brain tumors, as other cancer patients, may rely on additional support of complementary and alternative medicine (CAM) treatment during the course of disease. However, the assessment and documentation of CAM is not necessarily part of the clinical routine in oncological consultations. Moreover, CAM comprises different agents and treatments that may vary depending on the country the patient lives. Overall, there is a lack of information on type and motivation for CAM use in glioma patients in Switzerland. A multi-center cross-sectional survey analysis of CAM use in glioma patients was conducted in 3 specialized Neuro-Oncology Centers in Switzerland from 2012–2015. On the occasion of a regular consultation, a questionnaire including multiple choice questions as well as open response questions was provided to patients suffering from a glioma WHO II-IV. Overall, 208 patients completed the survey. Approximately half of the patients (n=101 patients, 49 %) reported the use of CAM during the course of the disease. Patients reported the wish to contribute actively to the cancer treatment as the most important motivation for CAM use. CAM user were most likely younger patients, usually using CAM without medical supervision and without necessarily being reimbursed by the insurance company. CAM use was distributed amongst WHO grades and both genders. In this multi-center survey analysis conducted in Switzerland, almost half of the glioma patients reported to have used CAM during the course of the disease. This demand should be addressed by the treating physicians. An accurate documentation and counseling could improve patient care, by avoiding potential interactions with the standard treatment and by incorporation of patients’ needs into therapy. Funded by the Swiss Brain Tumor Foundation
Emerging role of FAT1 gene in the regulation of oncogenic miRNA 221/222- 3p in glioma
Authors: N. Malik, P. Chattopadhyay, C. Sarkar, A. Suri, S. Sinha, K. Chosdol
Journal: Annals of Oncology (2018)

Background: FAT1 is a transmembrane protein helps in adhesion. FAT1 gene is localized at chromosome 4q35.2 encoding a 506KDa. The role of FAT1 in tumors is not fully characterized. Few reports suggest it behaves as a tumor suppressive and few reported it as an oncogenic. miRNAs are noncoding RNAs which bind to the 3'UTR of target mRNA and repress their expression. miR-221-3p/222-3p has been reported to have oncogenic role and targets tumor suppressors (e.g. CDKN1B, PTEN, PUMA etc.) in many cancers including GBM. Here, we have investigated the role of FAT1 gene in the regulation of miRNAs in glioblastoma. Methods: In-silico examination of miR targets was done by target prediction software miRDB, TargetScan, miRTarBase. FAT1 knockdown was done using specific siRNA and mRNA expression analysis was done for FAT1 and miR targets by using gene specific primers and miR-221/222-3p using LNA-primers (locked nucleic acid) in GBM cell lines (U87MG, U373MG, A172 and LN229). Expression and correlation analysis of FAT1 and miR-221-3p was done in GBM tumor samples (n = 30). Results: We have detected increased expression of FAT1 and miRNAs (miR221-3p/miR222-3p) in different GBM cell lines (U87MG, U373MG, A172 & LN229). On FAT1 knockdown, using FAT1 specific siRNA we observed significantly decreased expression of miR-221/222-3p. In-silico analysis identified CDKN1B, CREBZF, PUMA and PTEN as potential targets of miR-221/222-3p. Furthermore, FAT1 knocked-down cells showed significantly increased expression of PUMA in all studied glioma cell lines. In order to ratify our in-vitro observation and its clinical application, we have done expression and correlation study in GBM tumor samples. We detected significant positive spearman correlation between FAT1 and miR-221-3p (r = 0.5669, p ≤ 0.0011) and negative correlation of FAT1 with PUMA (r= -0.5378, p ≤ 0.0022). These results suggest that FAT1 expression positively regulates the expression of miR-221-3p leading to downregulation of miR targets in GBM cell lines as well as in GBM tumors. Conclusions: FAT1 plays an oncogenic role in glioma and miR-221/222-3p plays and important role. FAT1 may emerge as a target for therapeutic intervention. The exact mechanism involved in the oncogenesis by FAT1 is under study. Legal entity responsible for the study: DST. Funding: DST. Disclosure: All authors have declared no conflicts of interest.
Phase II trial of eribulin for recurrent or metastatic salivary gland cancers.
Authors: Keith D. Eaton, Bernardo H. L. Goulart, Rafael Santana-Davila, Laura Quan Man Chow, Rebecca L. Wood, Cristina P. Rodriguez, Christina S. Baik, Renato G. Martins
Journal: Journal of Clinical Oncology (2016)

6095 Background: Salivary gland cancers (SGC) are rare, biologically and histologically diverse malignancies with no standard of care therapy in the recurrent/metastatic setting. Eribulin is a microtubule inhibitor with established efficacy in previously treated breast cancer. The purpose of this study was to determine the anticancer activity of eribulin in advanced SGC. Methods: In a single center two-stage single arm phase II design, patients with progressive, recurrent and/or metastatic SCG of the head and neck or other sites, with documented disease progression within the past 6 months and not amenable to curative intent therapy were eligible. Any number of prior cytotoxic chemotherapies was allowed. Patients received eribulin 1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicities. Response was assessed by CT imaging every 6 weeks. The primary endpoint was overall response rate by RECIST 1.1. Secondary endpoints were duration of response (DOR), progression free survival (PFS), disease control rate (DCR), and grade > = 3 toxicities. Results: Between May 2012 and August 2015, 29 patients were enrolled. Median age was 63 (range 34-75); 20 (69%) were male. The most common histologies were adenoid cystic (n = 10) and adenocarcinoma (n = 5). Prior radiation was administered in 25 (86%). Number of prior cytotoxic therapies were: 0 (12, 41%), 1 (13, 45%), 3(3, 10%), 5 (1, 3%). Neutropenia was the most common toxicity (Grade 3 (9, 31%), Grade 4 (4, 14%)). Other grade 3 toxicities were: febrile neutropenia, increased QTc, fatigue and peripheral neuropathy in a single patient each. Median follow-up is 2 years, with 5 patients continuing on treatment. The median number of cycles administered was 4 (range 2-28). Response by RECIST criteria was observed in 3/29 (10%) with 2 PR and 1 CR , 20/29 (69%) patients demonstrated a decrement in tumor size at first assessment. Median PFS was 3 months, DCR was 26/29 (90%) and median DOR was 17.2 months. Conclusions: In this phase II trial of eribulin for advanced SGC, we observed response rates similar to those reported to other cytotoxic therapies and superior to those observed in trials of TKIs. Toxicities were similar to those observed in prior trials with eribulin. Clinical trial information: NCT01613768.
Genetic plasma cell signatures in high-risk smoldering myeloma versus multiple myeloma patients.
Authors: Sham Mailankody, Neha Korde, Mark J. Roschewski, Austin Christofferson, Martin Boateng, Yong Zhang, Elisabet Esteve Manasanch, Dickran Gano Kazandjian, Mary Kwok, Manisha Bhutani, Nishant Tageja, Adriana Zingone, Rene Costello, Laurence Lamy, Malin Hultcrantz, Elli Papaemmanuil, Maryalice Stetler-Stevenson, William Douglas Figg, Jonathan J Keats, Ola Landgren
Journal: Journal of Clinical Oncology (2016)

8003 Background: Smoldering myeloma (SMM) is an ill-defined clinical myeloma precursor state. Recently, treatment studies targeting high-risk SMM patients have been conducted, showing promising clinical outcomes. Limited information is available on the biology of SMM. Using samples from a prospective clinical trial based on carfilzomib, lenalidomide and dexamethasone (CRd) (Korde et al. JAMA Oncology 2015), we showed near complete response (CR) or better in 28 of 45 (62%) patients with newly diagnosed multiple myeloma (NDMM); in high-risk SMM patients we reported stringent CR in 12 of 12 (100%) and 11 of 12 were MRD negative. Here, we sequenced the patients on our clinical trial and provide novel insights on tumor cell biology. Methods: We performed whole exome sequencing (median 125x, range 105-184x) and RNA sequencing of plasma cells obtained from baseline bone marrow samples in 39 patients with NDMM and 12 patients with high-risk SMM. Results: Whole exome sequencing on the 39 patients with NDMM identified a total of 2273 non-synonymous variants (median 53, range 26-139). Amongst the 12 SMM patients, 692 non-synonymous variants were identified (median 44, range 26-124). Previously reported recurrently mutated genes in multiple myeloma patients (BRAF, DIS3, FAM46C, IDH1, INTS12, IRF4, KRAS, NRAS, PRDM1, TP53, TRAF3, CYLD, RB1, ACTG1, LTB, HIST1H1E and MAX) were observed in 16 of 39 (41%) NDMM patients. In the high-risk SMM cohort, we did not detect any non-synonymous mutations amongst these genes. Conclusions: Amongst patients with NDMM and high-risk SMM enrolled in a prospective clinical trial of treatment with CRd, we confirmed previously reported recurrent mutations in NDMM. While the number of non-synonymous variants was similar in the two groups, none of the high-risk SMM patients had mutations in these genes. Our novel results suggest that at least a proportion of high-risk SMM patients have different molecular profiles compared to NDMM patients, which could have implications for risk determination and initiation of therapy. Additional analysis including clonal heterogeneity and subclonal architecture will be presented at the meeting. Clinical trial information: NCT01402284 and NCT01572480.
Abstract 17096: Assessing the Prevalence of Atherogenic Dyslipidemia in EURIKA Patients
Authors: Julian P Halcox, Carine Roy, Karin M Henriksson
Journal: Circulation (2015)

Introduction: Atherogenic dyslipidemia (AD), a condition identified by high triglyceride (TG) and/or low high-density lipoprotein cholesterol (HDL-C) levels, is associated with worse cardiovascular disease (CVD) outcomes. Methods: We used data from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, NCT00882336) to analyze the prevalence of AD according to patients’ CVD risk levels, determined using AHA/ACC (risk of atherosclerotic cardiovascular disease [ASCVD]; Table 1) and European (systematic coronary risk evaluation-HDL [SCORE-HDL]; Table 2) criteria. Patients in EURIKA were free from CVD but had at least one CVD risk factor (N=7641). AD was defined as TG ≥200 mg/dL and/or HDL-C &lt;40 mg/dL in men and &lt;50 mg/dL in women. Results: A large proportion of patients from EURIKA have high TG and/or low HDL-C levels characteristic of AD (Tables). Using AHA/ACC criteria to assess patients not receiving statin treatment and at high risk for CVD (type 2 diabetes [T2DM]; ASCVD risk ≥7.5%), the proportions with high TG, low HDL-C or both were 28.9%, 31.7% and 16.3%, respectively; for patients at low risk (without T2DM; ASCVD risk &lt;7.5%), the respective proportions were 11.6%, 17.9% and 4.9%. Similarly, a higher proportion of patients defined as being at high risk by European criteria (T2DM, or SCORE-HDL ≥5%) had signs of AD than those at low risk (without T2DM, or SCORE-HDL &lt;5%). Prevalence of AD was greater in patients with T2DM, but similar in those receiving statins and those who were not. Conclusions: Many patients at high risk of CVD also have signs of AD and may benefit from more intensive preventive measures.
Adult osteosarcoma experience in a cancer center in Mexico.
Authors: Jackeline Grace Lara Campos, Jose Luis Gonzalez Vela, Abrham Josafath Hernández, Aaron Saenz, David Hernández Barajas
Journal: Journal of Clinical Oncology (2018)

e23504 Background: Osteosarcomas are the most common tumors of bone, being more common in young people. There is scant evidence from prospective clinical trials in adult populations. We report our clinical experience in this particular group. Methods: Retrospective analysis of the Hospital records in the past 11 years, with statiscal analysis and conclusions from comparision with literature review. Results: There were 24 patients (pt) with osteosarcoma, representing 35% of bone sarcomas in our institution in the past 11 years. Median age was 30 years (range 18-67 years). Histology was conventional osteosarcoma in 66.6%, osteoblastic 12.5%, condroblastic 12.5%, telengientasic 4.1% and undifferentiated in 4.1%. Clinical stage was found to be stage II 13%%, III 25%, IV 62%. Metastases were 100% lung, 4.1% bone. The most frequent anatomic location was distal femur in 58%, humerus in 16.6%, pelvis 8.3%, jaw 8.3% and scapula in 4.1%. Limb-sparing surgery was only feasible in one of eight pt after neoadjuvant treatment. Radical amputation was performed in 87.5% of the pt with localized disease and in 60% of those with metastatic disease. Chemotherapy consisted in sistemic AP (Adriamicyn and cisplatin). All the pt with localized disease received neoadyuvant therapy (8 pt). Three of eight pt who received preoperative chemotherapy are alive and without evidence of relapse; they all had more than 90% necrosis in the pathologic specimen. The remaining five died, having a relapse free survival (RFS) of 6.4 months. The five pt who died received suboptimal therapy due to socioeconomic limitations. The two patients with osteosarcoma of the jaw are long term survivors at 132 and 72 months. In the metastatic setting AP was administered as the first line in 46.6%, High dose metotrexate + AP (HdMtxAP) in 26.6%, IE (etoposide and ifosfamide) 20% and one pt did not receive chemotherapy. Overall survival was 16.8 months in this group. Conclusions: Many of the pt were diagnosed with advanced disease. Our experience confirms that pt with localized disease can be cured if they attain more than 90% necrosis with chemotherapy. Jaw localization conferes good prognosis. In our population the availability of adequate chemotherapy in time is crucial to obtain cure in pt with adult osteosarcoma.