tbuckley/cabot-search huggingface dataset:
THU0528 DISCONTINUATION OF COLCHICINE THERAPY IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER
Authors: Yonatan Butbul, Rawan Sliman, Shafe Fahoum, Yackov Berkun
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Clinical phenotype of FMF exists in some carriers of MEFV mutation. These patients tend to have a mild disease. Prolonged colchicine free remission was reported in a small group of FMF patients. <h3>Objectives</h3> To describe and characterize a group of children with FMF in whom colchicine was discontinued. <h3>Methods</h3> The study cohort consisted of all children with FMF followed at 2 referral centers in Israel in whom colchicine was discontinued following prolonged attack free period. Clinical presentation, mutations in MEFV gene and disease outcome of patients who successfully ceased colchicine therapy were compared with patients with relapse of FMF attacks. We performed a retrospective study in two referral centers in Israel of 43 patients with FMF with 1 or non-mutated MEFV allele who ceased colchicine therapy following prolonged attack free period. The phenotype of the patients was investigated in detail, and the MEFV mutations, laboratory findings, clinical picture and outcome of 30 (70%) patients that successfully ceased colchicine therapy were compared to 13 (30%) patients who failed. <h3>Results</h3> 47 patients (55% males), mean age 6±3.2 years at the diagnosis, were enrolled in the study, of them 4 patients were excluded due to poor follow up. Fever (93%), abdominal pain (79%), arthralgia (19%) and arthritis (12%) were the most common symptom at attack. The average period free of attacks before enrolment was 11.3±9.2 months. The average follow-up after ceasing colchicine was 5.1± 2.9 years. Thirteen patients (30.2%) had an attack during follow up with most common symptoms of fever (92%) and abdominal pain (77%) and colchicine therapy was restarted within 10.1 months (1.1-36.4months). There were no differences between the groups of patients that were able to stop colchicine and the group that needed to renew therapy in demographic, genetic and most clinical parameters, including the age (13.4±3.9 vs 11.9±3.7p-0.26), level of SAA at enrolment (4±3.6 vs 3.3±2.4p-0.7) and time of last attack prior to enrolment (12.6±9.6 vs 8.6±8.2 months p-0.08). Myalgia and arthritis were more common among children that required to renew therapy compared to the group that didn't (31% vs 6.7% p-0.058 and 31% vs 3% p-0.024 respectively). <h3>Conclusion</h3> Cessation of colchicine therapy following prolonged remission in selected group of patients who are not homozygous for MEFV mutation could be considered. Patients with arthritis or arthralgia are more likely to have an attack after ceasing colchicine therapy. <h3>References</h3> [1] Discontinuing colchicine in symptomatic carriers for MEFV (Mediterranean FeVer) variants. [2] Sönmez HE, Batu ED, Bilginer Y, Özen S. [3] Clin Rheumatol. 2017 Feb;36(2):421-425. d <h3>Disclosure of Interests</h3> None declared
A phase II, single-arm study of apatinib and oral etoposide in pretreated metastatic HER2-negative breast cancer.
Authors: Nanlin Hu, Peng Yuan
Journal: Journal of Clinical Oncology (2019)

1076 Background: There is no standard treatment strategy for patients with locally advanced or metastatic breast cancer suffering progression after one prior chemotherapy with metastasis setting. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Etoposide is a highly active chemo-drug in the treatment of advanced breast cancer, both as a single agent or in combination regimens, and is well tolerated, with a low incidence of severe toxicity. This study is performed to assessed the efficacy and safety of apatinib and oral etoposide in patients with HER2 negative locally advanced or metastatic breast cancer for whom at least one lines of prior chemotherapy had failed. Methods: This open-label, single arm study enrolled patients with HER2-negative breast cancer, pretreated with anthracycline, taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients. Apatinib was administered 425/500mg daily according to patients ECOG(Eastern Cooperative Oncology Group) status, oral etoposide was administered 50mg/m 2 for first 10 days in a 21-days cycle. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. The treatment duration is until disease progression or intolerability of apatinib or oral etoposide. Results: 20 eligible patients were enrolled in this, open-label, single arm study and received apatinib and oral etoposide with a median age of 54 years old(range 36 to 66 years). Median follow-up time was 11months. 20 patients were eligible for efficacy analysis. Median PFS was 5.6 months (95% confidence interval (CI), 4.01 m – 8.42 m). ORR was 20% (4/20). DCR was 70% (14/20). Median OS was 11.2 months (95% CI, 9.6 m – 14.95 m). The most common grade 3/4 treatment-related AEs were hypertension (30%), and proteinuria (5%), nausea (5%). 35%(7/20) patients had dose reduction because of adverse events, after that all adverse events can return to less than 2 grade. Conclusions: Apatinib with oral etoposide exhibited objective efficacy in pretreated, metastatic HER2-negative breast cancer with manageable toxicity. Prospective studies enrolling more patients are needed. Clinical trial information: NCT03535961.
Use of DNA methylation to distinguish gallbladder carcinoma.
Authors: Xiaoqing Jiang, Bin Li, Zhiquan Qiu, Yong Yu, Zhishuai Li, Jingjing Zheng, Chenyang Wang, Fujun Qiu, Shuai Fang, Bingsi Li, Zhihong Zhang
Journal: Journal of Clinical Oncology (2019)

e15605 Background: Gallbladder cancer (GBC), an uncommon malignancy with a high mortality rate, is often diagnosed late due to lack of early symptoms and the relative hidden nature of the gallbladder. Despite the advancements in imaging technologies, there is no reliable screening test for GBC. The role of aberrant DNA methylation in the process of tumorigenesis both at individual genes and a genome-wide scale has been well elucidated. It occurs very early in cancer development, thus capable of serving as a screening marker. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were derived using a Bayesian hierarchical model-DSS with an adjusted p-value &lt; 0.05. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. This panel contains 12,196 GBC relevant CpG sites. We performed targeted bisulfite sequencing on 23 GBC patients (6 stage II-III, 17 stage IV) and 13 patients with non-malignant gallbladder diseases (cholecystitis and gallstones). Of the 23 GBC patients, we obtained adjacent normal tissue from 7 of them. Basic clinical features such as age, gender, of patients with GBC and patients with non-malignant gallbladder diseases were comparable. Results: Among the 12,196 GBC relevant CpG sites, 10,216 sites were statistically significantly hypermethylated and 275 sites were statistically significantly hypomethylated comparing to patients with non-malignant gallbladder disease as well as adjacent normal gallbladder tissues. Subsequently, we used the derived differentially methylated CpG sites to construct a linear regression model, achieving an area under curve of 99%. Collectively, the methylation levels were comparable between tissues with non-malignant disease and adjacent normal. Interestingly, when considering the 275 hypomethylated markers alone, we observed that the methylation level of adjacent normal tissues is significantly higher than tissues with non-malignant disease. Conclusions: Collectively, our panel can effectively distinguish GBC samples from non-cancerous samples, demonstrating the potential of DNA methylation in GBC screening. Furthermore, hypomethylation markers can be used to distinguish non-malignant disease from the healthy.
Integrating liquid biopsy with advanced imaging analysis to improve the prediction of response to immunotherapy in patients with NSCLC.
Authors: Marzia Del Re, Lorenzo Fontanelli, Alessandra Romano, Giulia Pasquini, Nicole Gri, Eleonora Rofi, Caterina Vivaldi, Stefania Crucitta, Lorenzo Belluomini, Antonio Frassoldati, Iacopo Petrini, Alfredo Falcone, Camillo Porta, Enrico Vasile, Emanuele Neri, Romano Danesi
Journal: Journal of Clinical Oncology (2019)

e14054 Background: Immunotherapy has revolutionized the treatment of NSCLC. However, response rate is variable, with a substantial failure rate. Thus, the identification of predictive biomarkers of response to immunotherapy is an area of great interest. Methods: Patients with locally advanced or metastatic NSCLC treated with nivolumab or pembrolizumab were enrolled. Disease response was defined following RECIST criteria (v. 1.1). Four ml of plasma were collected for the analysis of exosomal mRNA levels of PD-L1 (e-PD-L1) and IFN-γ (e-IFN-γ) at baseline and at the time of first radiological assessment. Exosome isolation and mRNA extraction was obtained by the exoRNeasy kit (Qiagen, Valencia, CA). e-PD-L1 and e-IFN-γ were evaluated by the QX100 ddPCR (Bio-Rad, Hercules, CA) and expressed as allele frequency (%). Chest computed tomography (CT) scan at baseline was used for the radiomic analysis. Tumor segmentation was performed on DICOM-formed images taken from the picture archiving, and the regions of interest were delineated manually and analyzed using the QUIBIM SL software. Survival was calculated stratifying patients based on e-PD-L1 and e-IFN-γ median values. Results: Nivolumab was given to 17 patients as 2nd line and to 8 subjects as further line of treatment, while 13 patients received 1st line pembrolizumab. Median PFS was 11 vs 16.2 months (mos) in patients with baseline e-PD-L1 of &lt; 0.3% vs ≥0.3%, respectively (p = 0.16). e-PD-L1 significantly increased in disease progression (PD) vs partial response (PR) and disease stabilization (SD) (p = 0.01) after 2 mos of treatment. In patients with e-IFN-γ ≥4.1% vs &lt; 4.1% at baseline, median PFS was 5.6 mos vs not reached, respectively (p = 0.003). The multiparametric radiomic analysis identified the Cluster Prominence Value (CPV, p = 0.012) and the Cluster Shade Value (CSV, p = 0.034) as significantly correlated with treatment outcome. Moreover, the D2d parameter and e-IFN-γ were inversely correlated (p &lt; 0,0001). CPV and D2d reflect the intra-tumor architecture, including necrosis, cell proliferation, and angiogenesis. Conclusions: Liquid biopsy data correlate with radiomic parameters and predict response to immunotherapy.
The ACC melanoma pilot project: “Real-world” evaluation of an NGS platform for molecular characterization of melanoma in Italy.
Authors: Ivan Molineris, Lauretta Levati, Enrico Berrino, Stefania D'Atri, Chiara Menin, Gabriele Madonna, Jenny Bulgarelli, Paola Ghiorzo, Virginia Ferraresi, Tiziana Venesio, Licia Rivoltini, Monica Rodolfo, Luisa Lanfrancone, Luca Mazzarella, Alessandro Guida, Pier Giuseppe Pelicci, Ruggero De Maria, Paolo Antonio Ascierto, Enzo Medico, Giandomenico Russo
Journal: Journal of Clinical Oncology (2019)

e14600 Background: Alliance Against Cancer (ACC), the network of Italian Cancer Centers, is involved in designing targeted NGS panels to enable sequencing a significant number of therapeutically actionable genes from FFPE tissue samples at the cost of a routine molecular diagnostic test (RMT). In this retrospective study we used the ACC oncochip v.1 on a cohort of stage III-IV metastatic melanoma patients, with the aim of: a) validating the diagnostic use of this oncochip in comparison with RMTs for BRAF mutation detection; b) evaluating how many additional actionable gene mutations can be identified per patient; c) evaluating possible associations between mutational profiles and outcome. Methods: DNA was extracted from 120 FFPE samples from 9 Italian hospitals previously profiled for BRAF status with a RMT, and matching germline samples. 60% of the patients underwent immunotherapy and 40% targeted therapy, with an overall survival ranging from few days to several years. 10-20 ng of DNA were profiled with the amplicon-based ACC Oncochip v.1, that covers ~700 Kb, including the full coding sequence of 182 genes. Samples were sequenced in a Ion Torrent S5 instrument (ThermoFisher), and mutational profiles were generated with the Ion Reporter software. Results: Adequate coverage of the BRAF codon 600 hotspot was reached in 99% of the samples, and BRAF status was 95% concordant with previous RMTs. In 4/6 discordant cases, BRAF V600 mutations were only detected by NGS (with VAF below 10%); in the remaining two cases NGS did not confirm mutations detected by RMT, possibly due to tumor heterogeneity. In accordance with TCGA data, BRAF was mutated in 55% of patients, NRAS in 23% and NF1 in 13%, with almost complete mutual exclusivity; moreover 86% of triple negative patients showed mutations in other actionable genes. We also observed great variability in mutational load, ranging from ~3 to &gt; 500 somatic mutations per Mb; correlation between mutational profiles and clinical outcome is underway. Conclusions: The ACC Oncochip v.1 NGS panel is accurate and affordable, providing a comprehensive mutational profile for the cost of a RMT and allowing a precision medicine approach to melanoma diagnosis and identification of actionable mutations.
Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in bladder cancer (BC): Differences in recurrent, progressive, and metastatic disease.
Authors: Axel Hegele, Franziska Wahl, Peter Rexin, W Nimphius, Rainer Hofmann, Joerg Haenze
Journal: Journal of Clinical Oncology (2019)

e16001 Background: The significance of PD-L1/PD-1 expression in BC is still unclear. In the present study we evaluated the PD-L1/PD-1 expression in tumor tissue (TT) and immune cells (IC) in the primary BC tumor as well as in case of BC recurrence and/or metastasis to detect possible changes in PD-L1/PD-1 expression using immunohistochemstry. Methods: PD-L1/PD-1 expression was determined in histological specimens of 20 pat. with a recurrent non-muscle invasive BC (NMIBC – Cohort 1) as well as in 20 pat. with muscle-invasive BC (MIBC- Cohort 2) treated by radical cystectomy and appearance of metastases during follow up using commercial available assays (E1L3N, Cell Signaling/ Zytomed). Staining intensity was performed using the Cologne Score. PD-L1/PD-1 status was compared between primary tumor and metastatic/recurrent/progressive BC tissue and correlated with clinical data. Results: Cohort 1: In NMIBC (18m,2f) a recurrent tumor occurred after 25 mo (1-114). In the recurrent TT PD-L1 expression was higher compared to primary BC in 15%. In case of progression higher PD-L1 expression was detectable in 42.9%. IC showed higher PD-L1 expression in 50% of recurrent NMIBC and in 42% in case of progression. PD-1 expression on IC rose in 70% in recurrent and 71% in progressive NMIBC without correlation to time interval of appearance. Cohort 2: After curative cystectomy (17m,3f) metastases occurred after a median time of 20.5 mo (0-58). Comparing PD-L1 expression in cystectomy specimens and metastases we found differences in 52.9% (4x down/5x up). Expression of PD-L1 in primary BC tissue correlated significantly with the time to metastasis (p &lt; 0.05). Conclusions: In case of metastasis after cystectomy as well as in recurrent/progressive NMIBC we found distinct variations in PD-L1/PD-1 expression in TT and IC. In MIBC primary PD-L1 status correlates with the time to metastasis. Whether PD-L1/PD-1 status can be helpful for clinical decisions (i.e. adjuvant therapy, instillation therapy) or as prognosticator have to be subject of further study.
Effect of intensification of induction II chemotherapy and liberalization of stem cell donor source on outcome for children with high risk acute myeloid leukemia: A report from the Children’s Oncology Group.
Authors: Richard Aplenc, Lillian Sung, Jessica Anne Pollard, Lisa Brodersen, Michael Loken, Robert B Gerbing, Kelly D. Getz, Soheil Meshinchi, William G. Woods, E. Anders Kolb, Todd Allen Alonzo, Alan S. Gamis
Journal: Journal of Clinical Oncology (2019)

10002 Background: Patients with residual acute myeloid leukemia (AML) after induction fare poorly. The recently completed AAML1031 Phase III clinical trial intensified Induction II chemotherapy, altered the stem cell transplant (SCT) conditioning regimen, and liberalized SCT donor source criteria. We sought to test whether these practice changes improved clinical outcomes. Methods: Patients on AAML0531 and AAML1031, sequential Phase III trials for AML with shared high risk features of both &gt; 15% residual blasts by morphology and ≥ 0.1% minimal residual disease (MRD) by flow cytometry with uninformative cytogenetics or high risk cytogenetic features (-7 or -5/5q-) were included. Gemtuzmab exposed and patients with high allelic ratio FLT3 ITD were excluded. Patients were observed from the start of Induction II through last available follow up. Induction II chemotherapy (ADE or AraC/Mito) was the exposure of interest. Disease free and overall survival (DFS, OS) were the primary outcomes. Standard descriptive statistics were used to compare patient characteristics and secondary outcomes; Kaplan Meier analyses were used to evaluate DFS/OS. Results: A total of 47 patients from AAML0531 (ADE) and 95 patients from AAML1031 (AraC/Mito) were included and did not differ in baseline characteristics. Five year DFS ±2SE was 17.5 ± 11.4 for ADE and 23.9 ± 8.8 for AraC/Mito, p = 0.528. Five year OS was 38.1 ± 14.2 for ADE and 33.3 ± 10.7 for AraC/Mito, p = 0.364. End of Induction II disease response and MRD did not differ between ADE and AraC/Mito. Patients receiving ADE had a higher probability of neutrophil recovery (74% vs 53%, p = 0.019) and recovered neutrophils a median of 7 days more quickly (27 vs 34 days), p = &lt; 0.001. ADE patients also had fewer inpatient hospital days (28 days versus 32 days, p = 0.002). The percentage of patients receiving SCT did not differ, 34% vs 44%, p = 0.253 and post-SCT outcomes did not differ. Conclusions: The intensification of Induction II chemotherapy, change in SCT conditioning regimen, and liberalization of SCT donor source was not associated with improved clinical outcomes. Intensification of Induction II was associated with increased hematologic toxicity and length of stay. These data do not support the intensification of Induction II chemotherapy with AraC/Mitoxantrone. Clinical trial information: NCT01371981.
Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.
Authors: Wolfgang Wick, Tobias Kessler, Michael Platten, Christoph Meisner, Michael Bamberg, Ulrich Herrlinger, Caroline Happold, Sarah Weisang, Hanna Boelting, Joachim Steinbach, Guido Reifenberger, Felix Sahm, Andreas von Deimling, Antje Wick, Michael Weller
Journal: Journal of Clinical Oncology (2019)

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients &gt; 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p &lt; 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.
Phase I study of pembrolizumab in people with HIV and cancer.
Authors: Thomas S. Uldrick, Priscila Hermont Goncalves, Mohammad Maher Abdul Hay, Alisa J Claeys, Brinda Emu, Marc S. Ernstoff, Lawrence Fong, Judith C Kaiser, Holbrook Edwin Kohrt, Andreanne Lacroix, Steve Young Lee, Lisa Lundgren, Kathryn Anne Lurain, Christopher Parsons, Sharavi Peeramsetti, Ramya Ramaswami, Elad Sharon, Chia-Ching Jackie Wang, Robert Yarchoan, Martin A. Cheever
Journal: Journal of Clinical Oncology (2019)

2500 Background: People with HIV have been excluded from immuno-oncology (IO) studies. Anti- PD-1/PD-L1 therapies are approved for a growing number of cancers. We evaluated pembrolizumab (pembro) in people with HIV and cancer. Methods: CITN-12 is a multicenter phase 1 trial. Key eligibility: advanced cancer; ECOG ≤1; CD4 ≥100 cells/μL; ≥4 weeks antiretroviral therapy (ART), HIV viral load (VL) &lt; 200 copies/mL. Exclusion: uncontrolled HBV/HCV, autoimmune disease. Participants (pts) accrued into CD4 based cohorts (C): C1 100-199; C2 200-350; C3 &gt; 350 CD4 cells/μL. Pembro 200 mg IV administered Q3W for up to 35 doses. Adverse events (AE) evaluated by CTCAE. Immune related AE ≥ grade (Gr) 2 were events of clinical interest (irECI). Clinical benefit (tumor shrinkage or stable disease [SD] ≥24 weeks) was estimated. Data were locked for safety analysis and publication once C2 and C3 completed accrual and all pts completed ≥2 cycles. Accrual continued for 6 C1 pts and a new phase 1b Kaposi sarcoma (KS) cohort (C4). Results: 30 pts, characteristics: C1 (6), C2 and 3 (12 each), median (med) age 57 years (range 39-77), 28 men, 2 women, 60% White, 30% Black, 10% Hispanic. Med CD4 285 cells/μL (132 - 966). Cancers: KS (6), non-Hodgkin lymphoma (NHL) (5), non-AIDS defining (19) – most common: anal (6) and squamous cell skin (3). Prior radiation (19), med prior systemic therapies 2 (0-8). Safety observed over 183 cycles, med 5 (1-32). Treatment emergent AE ≥ possibly attributed to pembro mostly Gr 1-2, with 20% of pts having Gr 3. irECI: hypothyroidism (6), elevated AST/ALT (1), pneumonitis (3), rash (2), musculoskeletal (1).1 KS pt developed KSHV-associated multicentric Castleman disease (KSHV-MCD) and died of the AE. HIV was controlled and increasing CD4 counts were observed. Best response: complete (lung, 1), partial (NHL, 2), SD ≥24 weeks (KS, 2), SD &lt; 24 weeks (13), progressive disease (10), not evaluable (2). Conclusions: Pembro has acceptable safety in cancer pts with HIV on ART and &gt; 100 CD4 cells/µL, similar to patients without HIV. Anti-PD-1 may unmask KSHV-MCD and such KSHV-viremic patients should be excluded. Clinical benefit was noted in several tumor types. Anti-PD1 is appropriate for FDA-approved indications in this population. Patients with HIV meeting appropriate eligibility criteria should be included in IO studies. Clinical trial information: NCT02595866.