tbuckley/cabot-search huggingface dataset:
A phase II trial testing interventions to shorten time to diagnosis and reduce abandonment of treatment of children with Burkitt lymphoma in Kenya.
Authors: Sandra Langat, Festus Njuguna, Saskia Mostert, Therese Lotodo, Nikol Kigen, Odwar Boaz, Gert Jan Kaspers, Ann Moormann, Gail Vance, Patrick J. Loehrer, Terry Vik
Journal: Journal of Clinical Oncology (2019)

10032 Background: Burkitt Lymphoma (BL) is a common pediatric cancer in sub-Saharan Africa. Despite advances in care, prognosis is poor. The BL treatment protocol at our center in Kenya used since 2010, had a one-year survival of 29% (Martijn et al. BMJ Paed Open 2017). We hypothesized that financial burdens and delays in start of therapy impact outcomes. Methods: Our trial tested interventions aimed to: 1) Shorten time from presentation to start of treatment to improve survival; and 2) Support families during therapy to reduce abandonment. Initial eligibility included clinical suspicion of BL in a child 0-13 years of age. Patients with confirmed diagnosis of a mature B-cell lymphoma received support to complete therapy. Children with prior treatment of cancer were excluded. The trial was approved by human protection boards in Kenya and Indiana and consent was obtained prior to study entry. We enrolled 96 children with possible BL. Study personnel expedited routing of tissue samples to laboratories. Touch preps or smears were stained with Giemsa and reviewed by pathologists. Fresh tissue from all sources was used for flow cytometry. Tissue from core needle or incisional biopsies was processed for routine and immunohistochemical staining. Of 96 patients, 43 had BL confirmed by pathologic studies and were treated with combination chemotherapy given over 25 weeks. We paid families for transport costs for care, called after missed appointments, and provided direct monetary support (~$200 USD) for the 200 days children were on treatment. Results: Facilitating the biopsy shortened, by 3 days, the median time from admission to initiation of therapy for BL, because families did not need to raise funds for testing. Monetary support reduced abandonment of treatment by patients. Only 2 of 43 (5%) patients abandoned therapy, compared to abandonment by 22 of a cohort of 63 (35%) patients treated previously (p &lt; 0.001). The combination of rapid diagnosis, early therapy, and financial support and communication with families improved event free survival of children with BL to 50% at 1 year (p = 0.045). Conclusions: Simple interventions to improve efficiency of diagnosis and reduce abandonment leads to improved outcomes for children with BL in Kenya.
HIV incidence, pregnancy, and implementation outcomes from the Sakh'umndeni safer conception project in South Africa: a prospective cohort study
Authors: Sheree R Schwartz, Jean Bassett, Lillian Mutunga, Nompumelelo Yende, Mutsa Mudavanhu, Rebecca Phofa, Ian Sanne, Annelies Van Rie
Journal: The Lancet HIV (2019)
Molecular differences between AFP-negative and AFP-positive hepatocellular carcinoma.
Authors: Wu yu Ling, Lifeng Li, Shifu Chen
Journal: Journal of Clinical Oncology (2019)

e15681 Background: Alpha-fetoprotein (AFP) is a major biomarker for diagnosis of hepatocellular carcinoma (HCC). Screening of molecular differences between AFP-negative and AFP-positive HCC can be helpful for its diagnosis. Methods: Genomic mutations, gene expressions and clinicopathological data of 270 HCC patients were collected from TCGA database. According to preoperative AFP level, patients were categorized into AFP - (0-20ng/mL, n = 112) and AFP + ( &gt; 20 ng/mL, n = 158) groups. We identified significantly mutated genes and differentially expressed genes (DEGs) between the two groups and analyzed their correlation with prognosis. Results: The 1-, 3-, and 5-year overall survival (OS) rates were 91.5%, 76.3%, and 67.9% in AFP - and 84.3%, 62.5%, and 34.2% in AFP + . The difference was statistically significant (p = 0.0053). To identify AFP-biased mutation genes, we focused on highly mutated genes in each group (≥5% mutation frequency). At FDR = 0.05, we identified 11 AFP-biased genes: CTNNB1, VWA5B2, HERC2, ZFYVE26, SPEN, MUC6, DST, WDR87, DNAH1, PTPN13, and FANCM. The most striking gene identified was CTNNB1, which is a WNT pathway oncogene. CTNNB1 was more frequently mutated in AFP - than in AFP + (35.8% vs. 17.0%, p = 0.00059). The OS for HCC was calculated on the basis of the mutation of each gene, which showed that MUC6 mutation was negatively associated with OS (p = 0.018), while other ten genes showed no obvious difference. With the mRNA expression data, a total of 949 DEGs were identified, consisting of 718 upregulated in AFP + , and 231 upregulated in AFP - . The enriched pathways of the DEGs included cell cycle, metabolism of xenobiotics by cytochrome P450 and chemical carcinogenesis. AVP, CCL20 and MUC6 genes were identified as hub genes in the PPI network. Conclusions: According to the results of this study, the AFP level is associated with patients’ OS rates, and AFP - patients tend to have higher CCTNB1 mutation rate. Our ongoing study will verify this result by enrolling new HCC patients.
The effect of <i>sukshma vyayama</i> joint loosening yoga on aromatase inhibitor-induced arthralgia (AI) in breast cancer patients: A feasibility study conducted on Facebook.
Authors: L. Leigh Leibel, Kashinath G. Metri, Rajendra Prasad, J. Gregory Mears
Journal: Journal of Clinical Oncology (2019)

e23129 Background: AI therapy causes joint pain in up to half of women, and up to 20% become non-compliant with treatment due to pain and discomfort. This pilot study investigated the efficacy of sukshma vyayama in improving AI-induced joint pain and evaluated the feasibility of delivering the intervention on Facebook. Methods: Breast cancer patients undergoing treatment with AI's with self-reported arthralgia were recruited via an IRB-approved announcement posted in two closed breast cancer support groups on Facebook to participate in a yoga study delivered on Facebook. Participants completed BPI, DASH, PRAI and WOMAC questionnaires before and after the study. Intervention consisted of 12 joint loosening exercises performed in a chair, once daily for 12 minutes, Monday-Friday for 4 weeks. Asynchronous video demonstrations were available in a secret Facebook group and viewing confirmed by typing "done" (time-stamped) in comments. Results: 200 women responded. 38 met the inclusion criteria/consent, 26 completed the online consent, interventions and pre/post questionnaires. Paired simple t tests results showed significant (P &lt; 0.05) improvement in all the pain measures and quality of life parameters after yoga intervention compared to baseline. Conclusions: This study provides the first evidence that it is feasible to teach sukshma vyayama to patients on Facebook and that the intervention significantly improves AI-induced arthralgia. Teaching yoga via social media may provide better access to this therapeutic modality to patients at all points in the cancer care continuum globally. [Table: see text]
miR-200c in extracellular vesicles as a circulating biomarker of EGFR-TKI response and a mediator of EGFR-TKI sensitivity in heterogeneous NSCLC.
Authors: Chienchung Lin, Wu-Chou Su
Journal: Journal of Clinical Oncology (2019)

e20547 Background: Through intercellular transfer of EV(extracellular vesicles) miRNA, tumor cells can confer drug resistance to each other and contribute to tumor heterogeneity. However, the mechanisms why EGFR-TKI can be effective in heterogeneous NSCLC with low abundances of EGFR mutations remain unknown. The aim of the study is to investigate the significance of EV miRNA in mediating the efficacy of EGFR-TKI in heterogeneous NSCLC and serving as the biomarker of response to EGFR-TKI. Methods: We first evaluate if EVs from EGFR mutant cell (PC9) can affect EGFR-TKI sensitivity of EGFR wild type cell (CL1-5, H1299) in vitro co-culture system and i n vivo. We then identified the differential miRNA panel by comparing EVs from PC9 to those from CL1-5. Finally, we verified if the expressions level of these miRNA are different in blood EVs from patient with good response compared to those with poor response to EGFR-TKI. Results: We first verified that CL1-5 can take up labelled EVs from PC9 under time-lapse microscope and EGFR mutant DNA can be detected in recipient EGFR wild-type cell using digital PCR. We found EVs from PC9 enhanced gefitinib sensitivity of CL1-5. And co-culturing PC9 with CL1-5 enhanced CL1-5 gefitinib sensitivity which was reversed by adding GW4789, the inhibitor of exosome secretion. In subcutaneous CL1-5 animal model, in comparison to treating with gefitinib or PC9 EVs alone, only the combination treatment with gefitinib and PC9 EVs delayed cancer growth. Using small RNA sequencing, we identified a unique miRNA profile allowing discriminating EV from PC9 cells to those from CL1-5; MiRNA 200 family including 200a, 200b, 200c and mir429 were up-regulated significantly in PC9 EV. From Aug 2015 to Sep 2017, sixteen patients with good response (PFS &gt; 12M) or poor response (PFS &lt; 6M) to EGFR-TKI were enrolled and blood were collected for EV miRNA isolation. Ten of these blood samples were qualified for miRNA analysis and mir200a and 200c were found up-regulated in good responder to EGFR-TKI. The transfection of mir200c in CL1-5 cells not only inhibited the oncogenic pathway contributing to EGFR-TKI resistance including Stat3, Akt, EMT and BIM pathway but also enhanced gefitinib sensitivity of CL1-5 cells. Conclusions: Our data suggested mir200c from blood EV serve as a biomarker of response to EGFR-TKI and mir200c may mediate EGFR-TKI sensitivity in heterogenous EGFR mutant NSCLC.
Is immunotherapy toxicity associated with improved overall survival among older adults with advanced cancer?
Authors: Andrew Johns, Madison Grogan, Rebecca Hoyd, John F.P Bridges, Lai Wei, Sandipkumar Patel, Mingjia Li, Marium Husain, Kari Lynn Kendra, Gregory Alan Otterson, Jarred Thomas Burkart, Ashley Elizabeth Rosko, Barbara L. Andersen, David Paul Carbone, Dwight Hall Owen, Daniel Spakowicz, Carolyn J Presley
Journal: Journal of Clinical Oncology (2019)

6580 Background: There is growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response. There is a paucity of evidence examining the relationship between toxicity and overall survival (OS) in older adults. Methods: We performed a single institution retrospective cohort study of adults who received IO for advanced cancer from 2011-2017. Baseline clinical characteristics were abstracted from the electronic health record. Immune-related toxicities were graded by physicians based on Common Terminology for Adverse Events criteria, v4.0. Bivariate analysis with chi-squared statistics was used to describe baseline characteristics of patients ≥70 years (y) vs. &lt;70y. Survival outcomes were estimated by the Kaplan-Meier method (time zero = start of first-line IO) and compared using the log-rank test. The association of age and ≥ grade 3 toxicity with OS was tested with a Cox proportional hazards model. Results: Among 676 patients treated with IO, 238 (35.4%) were ≥70y. There was no difference in baseline characteristics of each age group except cancer type (P&lt;0.01). The incidence of ≥ grade 3 toxicity did not differ by age (&lt;70y: 14.5% vs. ≥70y: 13.5%, P=0.71). Median OS was significantly longer for adults &lt;70y (16.4 vs. 13.2 months, P&lt;0.01) or those with ≥ grade 3 toxicity (18.3 vs. 14.7 months, P&lt;0.01). When stratified by age and toxicity, patients &lt;70y with ≥ grade 3 toxicity had longer OS vs. those without ≥ grade 3 toxicity (P&lt;0.01). However, there was no OS difference among adults ≥70y with vs. without ≥ grade 3 toxicity (P=0.78). Adjusted hazard ratios with an interaction term are below. Conclusions: Though the incidence of ≥ grade 3 toxicity did not significantly differ by age, there was no significant OS advantage for older adults with ≥ grade 3 toxicity as compared to younger adults. Caution should be used in considering a toxicity-survival relationship in older adults.[Table: see text]
Final report of a phase I/II study of veliparib (Vel) in combination with 5-FU and oxaliplatin (FOLFOX) in patients (pts) with metastatic pancreatic cancer (mPDAC).
Authors: Michael J. Pishvaian, Hongkun Wang, Sarah Parenti, Aiwu Ruth He, Jimmy J. Hwang, Lisa Ley, Holly Difebo, Brandon George Smaglo, Sunnie S. Kim, Benjamin Adam Weinberg, Louis M. Weiner, John Marshall, Jonathan Robert Brody
Journal: Journal of Clinical Oncology (2019)

4015 Background: 17 – 25% of mPDACs harbor DNA damage response (DDR) mutations, the presence of which can be predictive of a response to platinum and PARP inhibitor-based therapy. The PARP inhibitor, Vel is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. Methods: We initiated a Phase I/II trial of Vel + FOLFOX in pts with mPDAC. Pts received standard mFOLFOX6 except without the 5FU bolus, Q2 weeks. For the Phase I portion, a 3+3 dose escalation of Vel identified a recommended Phase II dose of 200mg orally BID, days 1-7, Q2 weeks. For the Phase II portion, we enrolled two cohorts: 1) Untreated pts; 2) Previously treated pts. Also, for Phase II, pts were pre-selected if they had either a pathogenic germline or somatic DDR mutation (e.g. BRCA1/2, PALB2, ATM), and/or a family history suggestive of a breast or ovarian cancer syndrome (labelled FH+). Objective response rate (ORR) was the primary objective of the Phase II cohorts; key secondary endpoints were median progression-free survival (PFS) and overall survival (OS). Results: Between 01-2011 and 12-2018, 64 pts received treatment, 31 in Phase I, and 15 untreated and 18 previously treated in Phase II. The combination was well tolerated, with the main Grade 3/4 AEs being myelosuppression (16%) and nausea/vomiting (6%). Of the 64 pts, 55% were male; median age was 64; 95% had an ECOG PS of 1; 78% were platinum-naïve; 69% were FH+; and 27% had a known DDR mutation. 57 pts were evaluable for response, and the ORR, PFS, and OS for the different pt subgroups are detailed below. The Phase II cohorts achieved the primary endpoint of an ORR ≥ 25%. Most notably, plat-naïve, FH+, and DDR mutation+ pts had an ORR of 58%. Conclusions: The combination of Vel + FOLFOX is safe, well tolerated, and shows promising efficacy particularly in plat-naïve pts who are FH+ and/or harbor DDR mutations. A randomized trial to assess the contribution of Vel to the regimen is warranted. Clinical trial information: NCT01489865. [Table: see text]
Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge
Authors: Michael K. Lo, Friederike Feldmann, Joy M. Gary, Robert Jordan, Roy Bannister, Jacqueline Cronin, Nishi R. Patel, John D. Klena, Stuart T. Nichol, Tomas Cihlar, Sherif R. Zaki, Heinz Feldmann, Christina F. Spiropoulou, Emmie de Wit
Journal: Science Translational Medicine (2019)

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.
A phase I study of [<sup>225</sup>Ac]-FPI-1434 radioimmunotherapy in patients with IGF-1R expressing solid tumors.
Authors: Rosalyn A. Juergens, Katherine A. Zukotynski, Daniel Juneau, Lily Krnezich, Ryan Simms, John Forbes, Eric S. Burak, John Valliant, Lauren Stafford, Thomas Armor, Istvan Molnar, Fred Saad
Journal: Journal of Clinical Oncology (2019)

TPS3152 Background: Type I insulin-like growth factor receptor (IGF-1R) is a transmembrane protein which is overexpressed in solid tumors including non–small cell lung, prostate, and breast cancers. [ 225 Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody that binds to the external domain of IGF-1R, a proprietary bifunctional chelate, and an alpha-emitting radionuclide actinium-225 (Ac-225), which binds to the external domain of IGF-1R. Internalization of the conjugate and decay of Ac-225 causes tumor cell death primarily through double stranded DNA breaks. The indium-111 analog, [ 111 In]-FPI-1547, with the identical antibody and bifunctional chelate is used for patient selection, in-vivo imaging, and quantification of IGF-1R targets prior to therapy. Based on anti-tumor activity of [ 225 Ac]-FPI-1434 in preclinical models, favorable toxicology studies in cynomolgus monkeys, and prior human experience with the unconjugated antibody, the first in human clinical evaluation was initiated. Methods: This open-label multi-center phase I study (NCT03746431) follows a modified 3+3 dose-escalation design to characterize the safety profile, determine a maximum tolerated dose (MTD), evaluate dose-limiting toxicities (DLT), describe pharmacokinetics, derive radiation dose estimates to normal organs, and evaluate the objective response rate of [ 225 Ac]-FPI-1434 therapy in patients with IGF-1R expressing solid tumors. Eligibility requirements for therapy include: presence of at least one measurable lesion as determined by sufficient tumor uptake using SPECT/CT of an imaging analog [ 111 In]-FPI-1547; radiation dose estimates of the planned therapeutic activity within prespecified limits; and adequate bone marrow reserves, hepatic, and renal function. Dose cohorts begin with 10 kBq [ 225 Ac]-FPI-1434 per kilogram (kg) patient weight and successively increase to 20, 40, 80, and 120 kBq/kg as a single intravenous injection per patient followed by an 8-week DLT evaluation period. This trial is currently enrolling patients. Clinical trial information: NCT03746431.
A phase 3 (COSMIC-311), randomized, double-blind, placebo-controlled study of cabozantinib in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy.
Authors: Marcia S. Brose, Bruce Robinson, Candy Bermingham, Soham Puvvada, Anne E. Borgman, Monika K. Krzyzanowska, Jaume Capdevila, Steven I. Sherman
Journal: Journal of Clinical Oncology (2019)

TPS6097 Background: Treatment options are limited for patients with RAI-refractory DTC that is resistant to VEGFR-targeted therapy. Cabozantinib inhibits receptor tyrosine kinases including VEGFR2, MET, AXL, and RET, which are implicated in the development of DTC, and has shown clinical activity in early-phase studies of patients with RAI-refractory DTC. This study evaluates the efficacy and safety of cabozantinib in patients with RAI-refractory DTC who have progressed during or after prior VEGFR-targeted therapy. Methods: This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT03690388). The co-primary endpoints are progression-free survival and objective response rate evaluated by blinded independent radiology committee (BIRC) per RECIST v 1.1. Additional endpoints include safety, overall survival, quality of life, and changes in relevant biomarker levels (eg, thyroglobulin). Approximately 300 patients will be randomized in a 2:1 ratio to receive either cabozantinib (60 mg QD orally) or placebo. Randomization is stratified by prior treatment with lenvatinib and age (≤ 65 yrs vs &gt; 65 yrs). Eligible patients must have a pathologic diagnosis of DTC and must have been previously treated with or deemed ineligible for treatment with iodine-131 for DTC. Patients must have received lenvatinib or sorafenib for DTC and progressed during or following treatment with a VEGFR inhibitor. Up to 2 prior VEGFR-targeting TKI agents are allowed. Patients randomized to placebo may be eligible for real time on-study crossover to cabozantinib based on BIRC confirmation of disease progression. Unblinded patients randomized to cabozantinib may continue on study treatment if there is clinical benefit per investigator. Key words: Radioiodine-refractory differentiated thyroid cancer, cabozantinib, VEGFR-targeted therapy, trial-in-progress. Clinical trial information: NCT03690388.
Connective tissue growth factor (CTGF) methylation status is associated with prognosis of patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy (RCHT): A multicenter study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Bouchra Tawk, Christian Schwager, Karim Zaoui, Jochen Hess, Annett Linge, Volker Budach, Martin Stuschke, Panagiotis Balermpas, Anca Grosu, Daniel Zips, Stephanie E. Combs, Mechthild Krause, Elias Kouchakji, Kenneth Lipson, Esther Herpel, Claus Belka, Michael Baumann, Christel Herold-Mende, Juergen Debus, Amir Abdollahi
Journal: Journal of Clinical Oncology (2019)

6050 Background: CTGF plays a central role in tissue remodeling and has emerged as an attractive novel therapeutic target. We sought to investigate the impact of CTGF methylation status (CTGF-M) in predicting outcome of HNSCC patients undergoing RCHT. Methods: CTGF-M was discovered by applying Illumina 450K/850K arrays to DNA extracted from FFPE material of patients homogeneously treated with surgery followed by adjuvant cisplatin-based RCHT in frame of the DKTK-ROG multicenter retrospective trial (n = 194, training cohort). Methylation probes correlating with overall survival (OS) and progression were identified using random forest. Validation was done in 4 cohorts including DKTK-ROG definitive RCHT (n = 110) and 3 RCHT cohorts from Heidelberg, Dresden and Munich (n = 222). CTGF-M and RNAseq data from The Cancer Genome Atlas (TCGA) (n = 206) were analyzed to identify differentially expressed genes (DEG) as a function of CTGF-M. Results: Increased methylation of 2 probes (mapping to CTGF 3’UTR and gene body) was associated with significantly improved OS in the training cohort (HR = 0.51, p = 0.044) and the validation cohort (HR = 0.67, p = 0.016), in multivariate cox regressions adjusting for HPV status, age, T and N stages, location and treatment (adjuvant vs definitive RCHT). In the TCGA, probes’ methylation was significantly inversely correlated with CTGF gene expression (r = -0.18 and -0.51, p &lt; 0.05). 1843 DEGs were found at FDR &lt; 0.05 as a function of CTGF-M. Pathways mapping to tissue remodeling were significantly enriched for among downregulated genes in CTGF hypermethylated tumors. Increased CTGF methylation was inversely correlated with the mesenchymal subtype mRNA gene signature (r = -0.21, p = 0.0026) and correlated with the atypical subtype (r = 0.32, p = 0.000002). Conclusions: Implementation of CTGF-M in routine diagnostic is feasible and correlates well with CTGF gene-expression levels and activation of tissue remodeling pathways. Therefore, CTGF-M might be instructive for stratifying HNSCC patients for CTGF targeting therapies. CTGF emerges as a promising prognostic marker independently of HPV status.