bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of subcutaneous multipeptide active antigen-specific immunotherapy at lymph nodes and tumor sites on clinical outcomes in progressive tumors.
Authors: Marquez-Manriquez Juan Pablo , Lucero-Diaz Pedro Alejandro , Matute-Briseno Jose Antonio , Camacho-Hernandez Alejandro , Gallardo-Rincon Dolores 
Published: May 2019

2636 Background: The tumor and lymph nodes (LN) microenvironment clinically speaking are mainly unexplored and there are limited clinical studies of immunotherapeutic approaches manipulating those in progressive cancer patients. The tumor and LN microenvironment offers an opportunity to treat locally with multi-peptide immunotherapy in challenging clinical situations where we can have still a potential safe and effective therapeutic approach using the concept treat locally treat systemically. Methods: N = 11 patients were enrolled after the local IRB ethic committee approved the pilot clinical study number CICS/SS/0035. Previous identified targets such as FAP, b-2-microglobulin, Fascin, RCAS1/EBAG9, Bcl-2, survivin, Sox2, Ape-1, Valosin containing-protein (VCP) and EGFR were analyzed by IHC, Th1 and CD8 long-peptides were predicted, immune assays using PBMCs including tumor microenvironment were performed to detect Granzyme B by ELISPOT, naturally processed epitopes by T-cell expansion and cytokines. Patients were treated subcutaneously (S.C.) eight times in the axillary and inguinal LN area one week apart. Afterwards we treated S.C. as well but now in the areas with tumor activity according with the CT or PET every week 10 times. Initial DTH and at the end of the treatment was performed. Pathological, clinical and immunological correlations were made using multivariate analysis. Results: Despite progressive disease 100% of the patients responded to the treatment. 80% had CR and 20% pseudo-progression and then CR. 100% of the patients increased the levels of Granzyme B against Bcl-2 (p = 0.001), VCP (p = 0.0001), Ape-1 (p = 0.005) and RCAS1 (P = 0.0001) and this correlated with the scans post-treatment. The patients showed more CD8 infiltration in the DTH test at the tumor site (p = 0.002) than in the non-tumor site (p = 0.01). The number of metastatic lesions in lungs (p = 0.004) and hepatic tissue (p = 0.001) disappeared and correlated with increased levels of IL-12 production in vivo. Conclusions: Treating immunologically the LN and the microenvironment of the areas with tumor activity is a feasible and safe approach to limit systemic toxicity and improve the clinical outcomes in patients with progressive cancer including bone sarcoma, epithelial ovarian cancer, PDAC, pediatric sarcomas and TNBC.
Immunogenicity and tolerability of personalized mRNA vaccine mRNA-4650 encoding defined neoantigens expressed by the autologous cancer.
Authors: Cafri Gal , Gartner Jared J. , Hopson Kristen , Meehan Robert S. , Zaks Tal Z. , Robbins Paul , Rosenberg Steven A. 
Published: May 2019

2643 Background: Therapeutic vaccination against cancer has proven very challenging with little clinical benefit. Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer testis antigens, and over-expressed antigens. However, negative selection in the thymus against these normal non-mutated antigens severely limits the ability to generate high avidity anti-cancer T-cells. The importance of neoantigens to each patient’s unique cancer as targets for immunotherapy has been extensively studied, by our group and others. It is now clear that neoantigen-specific T-cells are present in most cancers and these neoantigens derived from somatic mutations offer a specific and highly immunogenic target for personalized vaccination. We developed a process to identify immunogenic T-cell epitopes derived from tumor-specific mutations using tumor-infiltrating lymphocytes. Methods: We combined, for the first time, validated defined neoantigens, predicted neoepitopes and mutations in driver genes into a single mRNA concatemer (mRNA-4650) to vaccinate patients with metastatic common epithelial cancers. We are conducting a phase I/II trial in patients with metastatic melanoma, gastrointestinal, or genitourinary cancers with at least one lesion that is resectable. Patients must have an ECOG status of ≤1 with adequate organ and bone marrow function. Patients are vaccinated intramuscularly at two-week intervals for four cycles, and dosing may be repeated for a second course of vaccination. Key primary endpoints are safety, tolerability and the development of T-cell reactivity as well as objective response rate. Results: mRNA-4650 is safe at all dose levels studied to date with no reported DLTs or drug related SAEs. Neoantigen specific CD8 and CD4 T cells responses against neoepitopes included in the vaccine have been observed and no tumor regressions were seen. Conclusions: Our data show that such a personalized mRNA vaccination is feasible and can elicit neoantigen specific T cell responses. Combination of vaccines with checkpoint inhibitors or adoptive T cell therapy can open the possibility to develop effective immunotherapies for patients with the common epithelial cancers. Clinical trial information: NCT03480152.
Phase I study of CC-90010 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL).
Authors: Moreno Victor , Braña Irene , Sepulveda Sanchez Juan Manuel Manuel , Villar Maria Vieito , Hernandez-Guerrero Tatiana , Doger Bernard , Saavedra Omar , Ferrero Olga , Sarmiento Rafael , Arias Marina , De Alvaro Juan , DiMartino Jorge F. , Zuraek Marlene , Sánchez Pérez Tania , Filvaroff Ellen , Aronchik Ida , Lamba Manisha , Hanna Bishoy , Nikolova Zariana G. 
Published: May 2019

3015 Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth and oncogenesis. CC-90010 is an oral, potent and reversible BET inhibitor that showed promising activity in lymphoma and solid tumor cell lines and reduced tumor growth in xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Three schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine safety, maximum-tolerated dose and/or recommended phase II dose (RP2D). Secondary objectives were the identification of early activity signals, pharmacokinetics and pharmacodynamics (PD). Results: As of 10 Dec 2018, 69 pts were enrolled, 67 with solid tumors and 2 with R/R NHL. Data shown are from all pts (N = 69). The median age was 57 y (range, 21–80), 38 (55%) were male, and the median number of prior systemic anticancer regimens was 3 (range, 1–9). The RP2Ds were dose cohorts 3A and 4B. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17 pts (25%), most commonly (≥2 pts) thrombocytopenia (7%), platelet count decreased (4%), fatigue (3%), and increased alanine aminotransferase (3%). No deaths from toxicity occurred. Two pts (endometrial carcinoma and astrocytoma) had a partial response (PR); 1 occurred after the data cutoff. Seven pts had prolonged stable disease (SD) > 9 mo. Exposures and PD marker regulation increased with dose in each dosing schedule; terminal half-life was ~ 73 h. Conclusions: Most of the TRAEs observed were mild or moderate in severity, reversible, and manageable by dose adjustments and/or supportive care. Promising ongoing anticancer activity with prolonged SD and PRs were observed. The preliminary clinical data provide the rationale for dose expansion of CC-90010 in pts with selected advanced malignancies. Clinical trial information: NCT03220347. [Table: see text]
Risk of QTc interval prolongation among cancer patients treated with tyrosine kinase inhibitors.
Authors: Abu Rmilah Anan Abdelmoti , Lin Grace , Herrmann Joerg 
Published: May 2019

3033 Background: QTc interval prolongation can lead to life-threatening complications such as torsade de pointes (TdP), ventricular tachycardia (VT), and sudden cardiac death (SCD). It can occur with various tyrosine kinase inhibitors (TKIs) but comparative analyses on the incidence and complication rates are scarce. We thus conducted a comprehensive analysis of TKI use and QTc prolongation in clinical practice. Methods: We retrospectively reviewed the electronic medical records of all cancer patients who were treated with TKI between 01/2005 and 12/2018 at our institution. QTc prolongation was defined as a QTc ≥ 450 ms or 460 ms among male or female patients, respectively. For each type of TKIs, we determined the administration rate and incidence of QTc interval prolongation. We also studied the frequency of QTc prolongation ≥ 500 ms, rate of increase of the QTc interval by ≥ 60 ms, and the development of complications (VT, TdP and SCD). Results: In the present study, we analyzed the data of 685 cancer patients (431 male and 254 female), including 299 patients with RCC, 188 with chronic leukemia, 55 with acute leukemia, 65 with thyroid cancer, 48 with lung cancer and 39 with GIST. These patients received 902 TKI administrations and QTc prolongation was reported in 1/3 of these (289 administrations). The highest frequency was seen with imatinib, nilotinib and dasatinib (30, 40 and 50%). Among cases of QTc prolongation, a QTc interval ≥ 500 ms was documented in 53 (18.3%) and QTc progression ≥ 60 ms in 72 (25%). Complications were found in 14 cases (5%) including VT in 9, TdP in 2 and SCD in 3 administrations. Conclusions: The current findings suggest that TKI therapy leads to QTc prolongation in 1/3 of patients on average and most commonly with the Bcr-Abl TKIs, imatinib, nilotinib and dasatinib. While SCD is rare (1%) it can still evolve and in 5% of all QTc prolongations with TKIs are potentially life-threatening. These data support recommendations for serial ECGs in cancer patients undergoing TKI therapy. [Table: see text]
A prospective study tracking longitudinal changes in genome-wide cell-free DNA (cfDNA) methylation to identify early nonresponders to cancer treatment.
Authors: Davis Andrew A. , Iams Wade Thomas , Chan David , Oh Michael S , Lentz Robert William , Srivas Rohith , Lambert Nicole , Robertson Alex , Peterman Neil , Shah Abhik , Wilson Timothy , Close Jason , George Peter , Wood Haleigh , Tezcan Ayse , Yalamanchili Ram , Nesmith Ken , Spinosa John C , Tezcan Haluk , Chae Young Kwang 
Published: May 2019

3042 Background: Methylation is an epigenetic modification linked to cancer pathogenesis. The aim was to determine if changes in cfDNA methylation patterns before and after initiation of treatment could predict non-response to treatment prior to routine imaging and clinical follow-up. Methods: We prospectively collected clinical data and blood from 28 patients with metastatic malignancies (13 lung, 11 breast, 4 other). Blood was drawn prior to start of a new treatment, after first cycle (median 30 days), and/or second cycle (median 57 days). We performed whole-genome (WG) bisulfite sequencing (median depth 18X) on plasma cfDNA to determine methylation levels. By tracking how methylation levels deviate from unaffected individuals, from baseline to subsequent timepoints, we classified patients as either progressors (greater deviance) or non-progressors. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1. Study endpoints were agreement with first FUI and progression-free survival (PFS) by cfDNA classification. Results: The cohort consisted of 68% females and the median age was 70. Main treatment regimens were chemo- (N = 12), immuno- (6), endocrine (5), or targeted-therapy (5). PFS was significantly shorter (log-rank p = 8 x 10-7) in patients classified as progressors by cfDNA (N = 8; median: 62 days) compared to non-progressors (N = 20, median: 263 days). For patients classified as progressors, the cfDNA assay preceded imaging and clinical evaluation by a median of 34 days. 7 out of 8 patients classified as cfDNA progressors were later confirmed to progress at first follow-up evaluation (88% positive predictive value). The one patient who was classified as progressor based on cfDNA was stable based on FUI (day 93 of treatment) but was later confirmed as progression on day 128 by FUI. For the remaining patients, 18 of 20 did not progress (90% negative predictive value). Thus, sensitivity for the assay for identifying progression was 78% and specificity was 95%. Conclusions: Our results show that WG cfDNA methylation change is a novel signature with potential to identify patients whose treatment regimen is ineffective prior to imaging.
Circulating bacterial DNA as a tool towards noninvasive biomarkers for colorectal adenocarcinoma and adenoma.
Authors: Ding Ke-Feng , Xiao Qian , Kong Xiangxing , Hu Yeting , Lu Wei , Wang Ao , Liu Kaihua , Bao Hua , Yuan Ying , Chen Jiaqi , Wang Da , Wang Xiaonan , Wu Xue , Shao Yang 
Published: May 2019

3045 Background: The gut microbiota is closely associated with the progression of colorectal neoplasia. While most metagenomics studies utilized fecal samples, circulating bacteria DNA in colorectal adenocarcinoma (ADC) or adenoma (ADM) patients remain unexplored. This study aimed to characterize microbiota DNA in plasma samples and build a machine-learning model for ADC and ADM early detection. Methods: In this proof-of-concept study, we performed whole genome sequencing (~30X) of plasma samples from 25 ADC patients, 10 ADM patients, and 22 healthy controls (HC). Significant biomarkers were identified in the discovery cohort (12 ADC and 11 HC) and built into a random-forest model which was tested in the validation cohort (13 ADC and 11 HC). These biomarkers were further examined in ADM and tested for abundance difference with ADC and HP. Results: In the discovery cohort, 111 species had increased relative abundance in ADC compared to HC and 165 species had decreased relative abundance. Alteration in several species such as Flavobacterium and Ruminococcus torques were consistent with previously published results in faecal and gut microbiome samples. The random forest-recursive feature elimination model selected 28 significant species from the discovery cohort (mean AUC = 0.98, repeated 2-fold cross-validation) and yielded an AUC of 1 in the validation cohort. Interestingly, most biomarker species in ADM patients, with abundance intermediate between ADC and HC, were distinguished from HC. To further test the clinical utility of this model, sequencing data were randomly down-sampled to 1X and the model performance remained robust (AUC = 1) at distinguishing ADC and ADM from HC. Conclusions: This study is the first effort to characterize circulating bacteria DNA in patients with ADC and ADM. Our findings revealed significant difference in relative abundance of several bacterial species between ADC, ADM and HC. A predictive model constructed with selected microbial features accurately distinguished ADC and ADM from HC. Circulating bacteria biomarkers represent potential non-invasive tools for early diagnosis of colorectal neoplasia.
First-in-human phase I and pharmacological study of TAS-119, a selective Aurora A (AurA) kinase inhibitor, in patients (pts) with advanced solid tumors.
Authors: Robbrecht Debbie , Eskens Ferry , Calvo Emiliano , He Xiaomin , Hirai Hiroshi , Soni Nital , Cook Natalie , Dowlati Afshin , Fasolo Angelica , Moreno Victor , De Bono Johann S. 
Published: May 2019

3063 Background: AurA is a serine threonine kinase regulating cell division and cell cycle progression and has a role in carcinogenesis. This clinical trial investigated safety, pharmacokinetics and -dynamics and antitumor activity of the selective oral AurA kinase inhibitor TAS-119. Methods: Pts with advanced solid tumors were enrolled into 6 dose escalation cohorts (70-300 mg BID 4 days on/3 days off; every 3 out of 4 weeks; or the same schedule in a continuous weekly schedule). In the expansion phase (intermittent schedule), pts with small-cell lung cancer (SCLC), breast cancer, or MYC-amplified/B-catenin mutated (MT) tumors were enrolled, and pts with other solid tumors in a basket cohort. Results: Overall, 34 pts were enrolled to the escalation (median age 67 years; 45.3% > 2 prior therapies); DLT was observed in 5 (16.1%) of 31 DLT evaluable pts; 1/10 at 150 mg, 1/6 at 200 mg, 1/5 at 250 mg, and 2/2 at 300 mg BID (fatigue, nausea, dry eyes, corneal epithelial microcysts). The maximum tolerated dose (MTD) was 250 mg BID and recommended Phase 2 dose (RP2D) was 200 mg BID. The most frequent treatment-emergent adverse events were diarrhea (28.3%), eye disorders (27%), fatigue (22.9%), and decreased appetite (14.8%). Grade 3 ocular toxicity were corneal epithelial microcysts in 1 pt (300 mg cohort) and punctate keratitis (expansion breast cancer cohort) in 1 pt. Toxicity grade ≥ 3 in ≥ 10% of pts were diarrhea (escalation part only), and increased lipase. Plasma exposure was dose-proportional and accumulation ratio was low. Pharmacodynamic data demonstrated target inhibition. Overall, 40 pts were enrolled to multiple expansions (10 SCLC, 9 breast cancer, 13 MYC-amp/B-cat MT tumors, 8 other; median age 60 years; 72.5% > 2 prior therapies). Median delivered relative dose intensity was 89.1% (47.9% - 100%). Stable disease was reported in 37.8% of patients but no complete or partial responses. Conclusions: TAS-119 demonstrated favorable safety and tolerability. Low-grade eye toxicity was a dose-dependent toxicity. Preliminary anti-tumor activity of monotherapy TAS-119 is limited. A Phase 1 trial combining TAS-119 with paclitaxel was conducted in parallel. Clinical trial information: NCT02448589.
An artificial intelligence approach to variant calling of ALK resistance mutations.
Authors: Lennerz Jochen K , Chin Emily , Rooney Marguerite , Zomnir Michael , Dominguez Meneses Enrique , Lipkin Lev , Iafrate A. John , Le Long P. , Shaw Alice Tsang 
Published: May 2019

3079 Background: ALK tyrosine kinase inhibitors (TKIs) are effective in treating advanced anaplastic lymphoma kinase (ALK) fusion-positive non-small-cell lung cancers (NSCLC), and specific ALK variants are associated with the development of resistance to specific TKIs. Humans struggle to harness the full potential of the highly complex next-generation sequencing bioinformatics pipeline output. As a consequence, the decision to report a variant remains difficult, and we considered the discrete nature of the data and the binary decision (report vs. not-report) as an ideal setting to apply an artificial intelligence (AI) approach for variant reporting. Methods: We assessed diagnostic performance of an AI model in calling ALK-resistance mutations in n = 50 consecutive ALK fusion positive patients who relapsed on TKI-therapy and underwent repeat biopsy at MGH. The random forest model was derived from independent datasets (training and validation) capturing the reporting decision on > 36,000 variants with ~500 features per variant resulting in a matrix of > 18 million data points. The model output is a contiguous prediction score from 0 (not report) to 1 (report) and a visual drill-down functionality allows exploration of the underlying features that contributed to the decision. Results: Examination of n = 76 tests from n = 50 patients with a total of n = 130 reported variants (and = 115 not reported variants) included a total of n = 31 ALK point mutations: p.1156(n = 2), p.1171(n = 8), p.1174(n = 2), p.1180(n = 2), p.1196(n = 1), p.1198(n = 1), p.1202(n = 8), p.1203(n = 1), p.1204(n = 1), p.1206(n = 1), p.1269(n = 4). Setting a screening threshold of the model at > 10% for reporting showed only one false-negative (p.Ile1171Asn) variant and 96.7% sensitivity. The average model score for ALK variants was 0.664 (range: 0.08–0.98; median 0.8) and did not show significant differences from other reported variants (0.636; 0–1; 0.7; t-test 0.66). The model would have called n = 18 of the non-reported control variants (average 0.07; range < 0.001–0.64; P < 0.0001) and was 84% specific. Review of the drill-down function identified prior call frequency, allelic ratio, and predicted transcript consequences as common model features. Importantly, the model is currently agnostic to the medical literature and does not take clinical parameters (e.g. TKI type) into account, which may further improve performance. Conclusions: Applying artificial intelligence to large discrete datasets is one approach to help identify clinically relevant variants in the setting of ALK resistance in ALK-fusion positive NSCLC.
Determining clinical relevance of genomic heterogeneity in an ethnically diverse cohort of newly diagnosed patients with breast cancer.
Authors: Rajagopal Padma Sheila , Beaubier Nike , Hattori Masaya , Sveen Lise , Khramtsova Galina , Abboushi Taylor , Barber Mathew , Liu Fang , Yoshimatsu Toshio , Zheng Yonglan , White Kevin , Huo Dezheng , Olopade Olufunmilayo I. 
Published: May 2019

3084 Background: The trajectory from early breast cancer to distant metastasis has not been precisely characterized. We are building an ethnically diverse, longitudinal cohort of prospectively ascertained breast cancer patients with integrated genomic, transcriptomic, epidemiological and clinical data, with the goal of identifying biomarkers that can improve on clinical predictors. Methods: Our goal is 500 histologically confirmed invasive cases with a minimum follow-up of 5 years. To date, Tempus Labs, Inc. has completed xT assays (595-gene panel DNA-seq and full-transcriptome RNA-seq) on 127 cases with matched tumor-normal samples. Clinical information was obtained from electronic health records and our cancer registry. Results: Median age of diagnosis was 51, with 47% African-Americans. 73% had stage 2 or 3 disease (2 patients were stage 4). 24.4% had TNBC; 30% had HER2+ and 62.2% HR+ status. Somatic alterations were identified in 560 genes with most common mutations in TP53 (56%), MCL1 (35%), PIK3CA (30%) and ERBB2 (17%). Somatic mutations in BRCA1 (10%) and BRCA2 (5%) were associated with increased tumor mutation burden (TMB). 2 patients were MSI high; 6 were equivocal. After a median follow-up of 6.5 years, 46 patients died and 38 had recurrent disease. With adjustment for clinical factors, TMB showed a slight nonsignificant negative association with recurrence-free survival (HR: 0.97, 95% CI: 0.91-1.00, p = 0.31). TP53 was associated with recurrence-free survival (HR: 1.76, 95% CI 0.94-3.29; p = 0.08) as was MSI (HR: 0.24, 95% CI: 0.06-1.06, p = 0.06). Conclusions: These data support the importance of integrating tumor sequencing in a diverse cohort with full clinical annotation to assess the diversity of actionable genomic alterations at the time of primary diagnosis to develop interventions for prevention of metastases.