tbuckley/cabot-search huggingface dataset:
High prevalence of IBD-associated genetic variants in patients (pts) with immune checkpoint inhibitor (ICI) enteritis/colitis.
Authors: Shilpa Grover, Amitabh Srivastava, Sonia Friedman, Elizabeth Iannotti Buchbinder, F. Stephen Hodi, Osama E. Rahma
Journal: Journal of Clinical Oncology (2019)

2582 Background: Colitis is a frequent toxicity of ICI therapy but there is paucity of data on risk factors. Specific serological markers and genetic polymorphisms have been associated with inflammatory bowel disease (IBD) (ulcerative colitis, Crohn’s disease). However, the prevalence of these markers in pts with ICI colitis is unknown. We performed a pilot study to determine the prevalence of IBD-associated genetic and serologic biomarkers in pts with ICI colitis. Methods: Cancer pts with histologically confirmed ICI enteritis/colitis and no history of IBD underwent commercial IBD panel testing. The panel included 4 genetic markers ( ATG16L1, NXK2–3, ECM1, STAT3), 8 serological markers (anti-A4-Fla2, anti-A4-FlaX, anti-CBir1, anti-OmpC, ASCAIgA, ASCA-IgG, pANCA, ANCA), and 5 inflammatory markers (vascular endothelial growth factor [VEGF], intracellular adhesion molecule 1[ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], C-reactive protein, serum amyloid A [SAA]). Clinical testing on serum samples was performed by Prometheus Laboratories (San Diego, CA). Results: Of 15 cancer pts with biopsy confirmed ICI colitis, 10 (67%) were homozygous for 1 or more of 4 genetic markers. The remaining 5 pts were all heterozygous for two or more of the genetic markers. One or more serologic markers associated with IBD were elevated in 7/15 (47%) pts. Serum reactivity was noted for ASCA-IgA (1/15, 7%), ASCA-IgG (1/15, 7%), anti-OmpC (3/15, 20%), anti-CBR IgG (2/15, 13%), anti-A4-FlaX (1/15, 7%), and ANCA (2/15, 13%). One or more inflammatory markers were elevated in 13/15 (88%) pts. Elevations in VEGF, VCAM-1, ICAM-1, and SAA were noted in 2 (13%), 8 (53%), 8 (53%), and 11 (73%) pts, respectively. Only 6 (40%) pts had elevations in CRP levels despite the presence of active inflammation on biopsy. The IBD panel was reported as being consistent with Crohn’s disease in 2 pts, ulcerative colitis in 1 pt and inconclusive for type but consistent with IBD in 1 pt. Conclusions: In this pilot study, all patients with ICI colitis, were either homozygous or heterozygous for two or more high risk IBD alleles. If validated, such testing may prospectively identify pts at risk for developing ICI colitis.
TiFFANY study: A multicenter phase II basket-type clinical trial to evaluate efficacy and safety of pan-FGFR inhibitor TAS-120 for advanced solid malignancies with <i>FGFR</i> alterations identified by circulating tumor DNA.
Authors: Tomoko Jogo, Yoshiaki Nakamura, Yoshito Komatsu, Ken Kato, Eiji Shinozaki, Hideaki Bando, Takeshi Kato, Tomohiro Nishina, Taito Esaki, Satoshi Fujii, Mitsuko Suzuki, Nozomu Fuse, Akihiro Sato, Shogo Nomura, Martina Lefterova, Justin Odegaard, Hiromichi Ebi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2019)

TPS3156 Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations ( FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.
Positron Emission Tomography/Computed Tomography for Diagnosis of Prosthetic Valve Endocarditis
Authors: Wilco Tanis, Asbjørn Scholtens, Jesse Habets, Renee B.A. van den Brink, Lex A. van Herwerden, Steven A.J. Chamuleau, Ricardo P.J. Budde
Journal: Journal of the American College of Cardiology (2013)
Supramolecular Assemblies of Peptides or Nucleopeptides for Gene Delivery
Authors: Huaimin Wang, Zhaoqianqi Feng, Bing Xu
Journal: Theranostics (2019)

Using non-covalent interactions between nucleic acids (DNA, siRNA, miRNA, and mRNA) with peptides or nucleopeptides is a promising strategy to construct supramolecular assemblies for gene delivery and therapy.Comparing to conventional strategies for gene delivery, the assemblies of peptides or nucleopeptides provide several unique advantages: i) reversible interactions between the assemblies and the nucleic acids; ii) minimal immunogenicity; iii) biocompatibility.This field has advanced considerably in recent years so that it is worth summarizing the recent progresses and future challenges.In this review, we introduce the development of assemblies of peptides or nucleopeptides for applications in gene delivery and related fields.After introducing the promises of gene therapy and the current strategies for the delivery, we discuss the unique advantage of using peptide assemblies for gene delivery.Then we describe several representative strategies for gene delivery by the assemblies of peptides or nucleopeptides.Finally, we discuss the key factors for designing such assemblies for gene delivery, and speculate future directions and challenges in the field, particularly the rational design and the spatiotemporally controlled release in live cells.
CD205, a target antigen for a novel ADC: Evaluation of antigen expression on TNBC, pancreatic adenocarcinoma and bladder urothelial carcinoma.
Authors: Simona Massa, Paola Collini, Rosalin Dolores Spagnuolo, Alessia Bertolotti, Giovanna Garzone, Giancarlo Pruneri, Maria Luisa Carcangiu, Angelo Kaplan, Christian Rohlff, Serena Buontempo, Mariagiuseppa Matera, Vanessa Bussolo, Giuseppe Merlino, Monica Binaschi, Cristina Rossi, Giulia Tonini, Valentina Fedi, Cecilia Simonelli, Angela Capriati, Andrea Ugo Pellacani
Journal: Journal of Clinical Oncology (2019)

e14726 Background: CD205 is a type I transmembrane surface protein belonging to the mannose receptor family with propensity for antigen uptake/internalization. CD205 is expressed in different cancer histotypes and seems to have a role in migration and invasion. For these features CD205 is an ideal candidate to be exploited as an ADC target. MEN1309/OBT076 (herein as MEN1309) is a humanized IgG1 antibody against CD205, conjugated through a cleavable linker to DM4. It has shown impressive anti-tumor activity when tested in high/low CD205 expressing xenografts for solid tumours and NHL. MEN1309 is under assessment in Phase I trials in EU (NCT03403725) and as OBT076 in USA. Methods: A retrospective evaluation of CD205 expression in 103 triple negative breast carcinomas (TNBC), 50 pancreatic adenocarcinomas (PAC) and 100 bladder urothelial carcinomas (UC) was performed at INT in Milan, Italy. Immunohistochemistry was performed on one FFPE representative sample per case, using a commercial anti-CD205 antibody. A semiquantitative score was applied to measure CD205 expression. Absence of staining tumor cells was scored as negative. Positivity was scored based on the percentages of neoplastic cells (NCs), with intensity of cytoplasmic staining ranging from 1 (weak) to 3 (strong). Membrane staining in NCs, immunoreactivity of the intratumoral/peritumoral inflammatory component and of normal tissue were scored as absent or present. Results: TNBC: 85% were positive, 70% in &gt; 5% of NCs; 14% showed 2+/3+ staining intensity in &gt; 50% of NCs. 57% of cases showed a membrane positivity. PAC: 100% were positive in &gt; 5% of NCs; 50% showed 2+/3+ staining intensity in &gt; 50% of NCs. 98% of cases showed a membrane positivity. UC: 67% were positive, 60% in &gt; 5% of NCs; 10% showed 2+/3+ staining intensity in &gt; 50% of NCs. 29% of cases showed a membrane positivity. Inflammatory component and normal tissue were positive in almost all cases. Conclusions: CD205 is heterogeneously expressed in the majority of TNBC and UC and in all PAC cases. The results of this study support the clinical investigation of MEN1309 in these tumor types.
SurVaxM with standard therapy in newly diagnosed glioblastoma: Phase II trial update.
Authors: Manmeet Singh Ahluwalia, David A. Reardon, Ajay P Abad, William T. Curry, Eric T. Wong, Ahmed Belal, Jingxin Qiu, Kathleen Mogensen, Cathy Schilero, Alan Hutson, Danielle Casucci, Laszlo Mechtler, Erik J Uhlmann, Michael J Ciesielski, Robert Fenstermaker
Journal: Journal of Clinical Oncology (2019)

2016 Background: SVN53-67/M57-KLH (SurVaxM) is a novel cancer vaccine designed to stimulate an immune response targeting the tumor-specific antigen survivin. A multi-center, single-arm phase 2 clinical trial of SurVaxM in survivin-positive newly diagnosed glioblastoma (nGBM, NCT02455557) is now fully enrolled and data updated. Methods: Patients (n = 63) with nGBM were enrolled at 5 US cancer centers and followed for safety, 6-month progression-free survival (PFS6), 12-month overall survival (OS12) and immunologic response. All patients underwent craniotomy with near-total resection ( &lt; 1 cm 3 residual contrast enhancement), TMZ chemoradiation, adjuvant TMZ and SurVaxM. Patients received 4 doses of SurVaxM (500 mcg) in Montanide with sargramostim (100 mcg) biweekly, followed by maintenance SurVaxM with adjuvants every 12 weeks until tumor progression. Immunogenicity of SurVaxM was assessed by detection of survivin-specific antibody (IgG) and CD8+ T-cell levels. Results: Median age was 60 yrs (range, 20-82), 53% methylated MGMT, 46% unmethylated MGMT (1 N/A) and 60% were male. Survivin expression ranged from 1-40% (median 12%) by immunohistochemistry. Median time to first immunization was 3.0 mo (1.9-4.0 mo) from diagnosis. There have been no RLT or grade ≥ 3 SAE attributable to SurVaxM. The most common AE was grade 1-2 injection site reactions. OS12 was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Median OS has not yet been reached. SurVaxM produced an increase in survivin-specific IgG titre from pre-vaccine baseline to ≥ 1:10,000 in 67% of pts and ≥ 1:100,000 in 27%. CD8+ T cell responses were observed. Anti-survivin IgG and OS were correlated. Conclusions: SurVaxM immunotherapy generated encouraging efficacy and immunogenicity in nGBM and has minimal toxicity. A randomized, prospective trial of SurVaxM in nGBM is planned. Clinical trial information: NCT024455557.
Novel staging system using carbohydrate antigen (CA) 19-9 in extrahepatic cholangiocarcinoma (ECCC) and its implications on overall survival (OS).
Authors: Sri Harsha Tella, Siddhartha Yadav, Anuhya Kommalapati, Amit Mahipal
Journal: Journal of Clinical Oncology (2019)

4091 Background: Optimal management of ECCA patients with elevated CA19-9 remains undefined. We hypothesized CA 19-9 elevation as a marker of aggressive biology in ECCA and that inclusion of CA 19-9 in the staging may improve OS discrimination. Methods: Patients with ECCA with CA 19-9 levels reported to the National Cancer Database (years 2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Based on the current knowledge, we considered 37 U/ml as our cut off. Kaplan Meier method was used to compare OS between the groups. The net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model. Results: A total of 2100 patients met the inclusion criteria: 601 (32%) and 1436 (68%) had normal and elevated CA19-9 levels, respectively. Rates of chemo (p=0.16) and radiation therapy (p=0.07) were similar between groups, but patients with elevated CA19-9 were less likely to undergo resection. Resected patients with CA19-9 elevation had higher 30-day mortality (p=0.02) and lower median OS (p&lt;0.01). Patients with elevated CA 19-9 levels had decreased stage-specific survival in all stages (p&lt;0.01). On adjusted analysis, CA19-9 elevation independently predicted poor OS (HR: 1.67 [1.42-1.97]) with impact resembling nodal metastasis, positive resection margin, lymphovascular invasion, and non-receipt of surgery or chemotherapy (p&lt;0.01). CA 19-9 included proposed staging system (Table) had a better OS discrimination over AJCC 7th edition. The new staging system had a concordance of 60% as opposed to 58% for the AJCC staging, leading to an improvement of 2% (p&lt;0.01). NRI of 46% (95% CI: 39-57) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC staging. Conclusions: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the newly proposed staging system markedly improved OS discrimination.[Table: see text]
Multiple genetic alterations to predict the clinical outcome for bevacizumab plus chemotherapy in advanced ovarian cancer: A retrospective study.
Authors: Nan Du, Jie Gao, Fang Li, Zihao Liu, Huoming Chen, Guoqing Liao, Jichang Meng, Hui Zhao, Mengli Huang, Qing Wang, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

e17037 Background: Bevacizumab(BV) plus chemotherapy is widely used in patients with advanced ovarian cancer(OC). However, there was not predict biomakers to determined the use of BV-based treatment in OC currently.Therefore, exploring the predict biomarkers for BV is imperative. Methods: Tumor issues of advanced OC treated with BV plus chemotherapy were used for next generation sequencing (NGS) with a 150-gene targeted panel. The correlation between Progression-Free Survival (PFS) and genes or clinicopathology features was analyzed by Kaplan-Meier or Cox regression. For multivariate Cox regression, all factors with a p-value &lt; 0.05 in univariate Cox regression were included. The potential predictive genes would be analyzed with VEGF-related signatures by using 374 OC mRNA data from The Cancer Genome Atlas (TCGA).Statistical analysis was performed using GraphPad Prism and SPSS. Results: 62 Chinese advanced OC patients treated with BV-base therapy were enrolled in this study from May 2015 to March 2018.The median PFS of these patients was 5.7 months , while ORR and DCR rate was 14.5% and 96.8%, repecitively.Patients with EGFR or HER2 alterations had poorer PFS compared with wild-type (EGFR,4.2 months vs. 7.4 months,p = 0.019;HER2,3.8 months vs. 7.3 months, p = 0.045), while MYC amplification patients got better PFS than MYC wild-type patients(17.4 months vs. 6.0 months,p = 0.049). However, in multivariate Cox regression anlysis, EGFR and HER2 were significantly correlated with PFS(P &lt; 0.001 and p = 0.016,respectively),and MYC amplification seemed to have a positive trend(p = 0.052).Moreover,patients with HER2 alterations has a poorer OS(p = 0.008).The VEGF-related signatures analysis results indicated EGFR variants may upregulated VEGFA expression to induced resistant of BV,while downregulation of HIF was significantly correlated with MYC amplification,which was beneficial to efficacy of BV.HER2 alterations has not correlated with VEGF pathways,suggesting HER2 was a poor prognosis of OC instead of an negative predictor of BV. Conclusions: NGS is an effective method to reveal the potential predictor for BV plus chemotherapy in advanced ovarian cancer, and the patients with EGFR or HER2 alterations should consider alternative regimens such as anti-EGFR or anti-HER2 target therapy instead of BV-based regimens.
Accuracy of primary laparoscopic staging in patients with early ovarian malignancies: A retrospective multicenter study.
Authors: Julia Caroline Radosa, Pauline Mertke, Christoph Georg Radosa, Sara Brucker, Florin Andrei Taran, Stefan Kommoss, Uwe Ulrich, Andreas Hackethal, Martin Deeken, Marc P Radosa, Ingolf Juhasz-BÃ¶ss, Erich-Franz Solomayer
Journal: Journal of Clinical Oncology (2019)

e17052 Background: Early ovarian malignancies (eOM) are often diagnosed incidentally in the course of diagnostic minimal invasive surgery or laparoscopy for preoperative suspected benign indications. To what extent initial minimal-invasive staging matches final FIGO stage following definite surgery is controversially discussed and current literature on this question is sparse. The aim of this study was to assess accuracy of laparoscopic staging of eOM with regard to final FIGO stage. Methods: We retrospectively identified all patients treated for eOM between 01/2000 and 10/2018. Participating sites were Gynecologic comprehensive cancer centers with great expertise in minimal invasive surgery. Inclusion criteria were no preoperative suspicion of advanced malignancy, initial staging laparoscopy, completion of surgical treatment via laparotomy and complete follow-up data. Clinical data and outcomes were abstracted from the medical record. Rate of upstaging and distinct causes were assessed and initial and definite FIGO stage and 3-year disease free (DFS) and overall survival (OS) were compared with regard to the incidence of upstaging. Results: 107 patients with eOM were included in the final analysis. In 72 (67 %) patients primary laparoscopic staging was concordant with final staging. 35 (33 %) cases were upstaged after the second operation. Regarding the cause for upstaging 4 (11 %) were upstaged because of infiltration of the contralateral ovarian capsule, 16 (46 %) because of peritoneal infiltrates and in 15 (43 %) patients an iatrogenic rupture of the ovarian tumor occurred during laparotomy. 21 (60 %) cases were upstaged within FIGO stage I and 14 (40 %) cases from stage I to II. Comparison of 3-year DFS and OS showed no differences regarding upstaging. Conclusions: In this population of patients with eOM, staging laparoscopy performed by specialized laparoscopic oncologic surgeons showed a sufficient accuracy with no case of upstaging to advanced FIGO stages. Regarding oncologic safety laparoscopic staging showed no impact on 3-year DFS and OS.
Risk stratification in earl- stage luminal breast cancer patients treated with and without RT.
Authors: Charlotta Wadsten, Pat W. Whitworth, Rakesh Patel, Jess Savala, Fredrik Warnberg, Troy Bremer
Journal: Journal of Clinical Oncology (2019)

568 Background: The goal was to develop and validate a biologic signature for 10-year ipsilateral invasive breast event (IBE) risk in luminal Stage 1 breast cancer (BC) patients treated surgically and either with or without radiation therapy (RT). Methods: This cohort was from Uppsala University and Västerås Hospitals diagnosed with Stage 1 BC and treated surgically between 1987 and 2004. Treatment was neither randomized nor strictly rules based, including adjuvant RT, Hormone Therapy (HT), and Chemotherapy (CT). Biomarkers (HER2, PR, Ki67, COX2, p16/INK4A, FOXA1 and SIAH2) were assessed on tissue microarrays in PreludeDx’s CLIA lab by board-certified pathologists. Risk groups were calculated using biomarkers and clinical factors age and size. A multivariate Cox proportional hazards analysis was used to determine hazard ratio for biologic signature. 10-year IBE risk was assessed using Kaplan-Meier survival analysis. Results: There were 423 luminal cases with biomarker data having 54 IBEs, and a median follow-up of 11.8 years. There were 372 patients treated with BCS and 51 with Mastectomy, and 325 received RT, 169 received HT, and 47 received CT. In a multivariate analysis, the biologic signature (HR = 1.6, p = 0.019) and RT (HR = 0.51, p = 0.027) were associated with IBE risk adjusting for other treatments (HT and CT) and Luminal A status (p = 0.37). For patients over 50 yrs of age with luminal A disease and treated without CT (n = 205), an elevated biologic signature identified a subset of patients with a 15% (+/- 14%) 10-year IBE risk without RT (n = 38) compared to a 4% (+/-6%) IBE risk with RT (n = 72), while patients with a low biologic signature had a 10-year IBE risk of 4% (+/- 4%) without RT (n = 26) and 3% (+/-5%) IBE risk with RT (n = 69). Conclusions: With further prospective validation, the biologic signature identified herein may provide a tool enabling improved management for women diagnosed with early luminal BC.
Enhancing access to genetic cancer risk assessment (GCRA) in Monterrey, Mexico: The beginning of a prevention program.
Authors: Dione Aguilar y Méndez, Jeffrey N. Weitzel, Kathleen Reilly Blazer, Danielle Castillo, Josef Herzog, Juan Carlos A. Marrufo, Marisol García-García, Fernanda Mesa-Chavez, Melina Miaja, Servando Cardona-Huerta, Cynthia Villarreal-Garza
Journal: Journal of Clinical Oncology (2019)

e13150 Background: In limited-resource countries like Mexico, GCRA is not routinely provided due to elevated costs, lack of public coverage for testing and prophylactic surgeries, and limited GCRA expertise or awareness among providers and patients. Thus, GCRA services in Mexico are 20 years behind higher income countries, resulting in suboptimal care and limited opportunity for prevention. The Breast Cancer Center TecSalud established formal GCRA services for underserved patients by recruiting a cancer geneticist who provides care at no added expense to patients, building academic collaborations for training and research with City of Hope, and enabling free genetic testing through the Clinical Cancer Genomics Community Research Network, supported in part by the Breast Cancer Research Foundation. Aim: To report the uptake of the GCRA program by patients and relatives at TecSalud from January 2016 - December 2018. Methods: Eligibility includes Mexican women who meet hereditary breast cancer testing criteria and family members of mutation carriers. Risk reduction procedures are covered by Seguro Popular and/or the NGO Fundación Santos y de la Garza Evia. Results: GCRA was offered to 255 patients and 74 at risk relatives, with an increasing reach (proportion of those eligible who access the program). A significant growth of cascade testing and access to risk reduction surgery over time are noted. Conclusions: A growing number of referrals and GCRA visits shows improving reach, possibly due to engagement of the multidisciplinary team and increased patient awareness. The expansion of cascade testing and performance of risk-appropriate surgeries reflects a maturing prevention program. Key determinants of our progress are collaborations that provided us with crucial mentorship, access to genetic assays, as well as the increasing involvement of local leaders, administrators and benefactors for the establishment of vital clinical and research capacity. Multilevel efforts should continue to enhance the delivery of standard of medical care for the most vulnerable and underserved high-risk patients and families. [Table: see text]