bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overinterpretation and misreporting of prognostic factor and biomarker studies in medical oncology.
Authors: Kempf Emmanuelle , de Beyer Jennifer , Porcher Raphael , Nguyen Long , Moons Karel , Altman Douglas , Reitsma Johannes , Hopewell Sally , Sauerbrei Willi , Collins Gary 
Published: September 2018

e14023 Background: To generate empirical evidence, classify and estimate the frequency of distorted presentation and overinterpretation of results in prognostic factor (PF) studies in oncology. Methods: We selected 17 oncology journals with an impact factor of 7 or more. PubMed was searched to identify primary clinical studies evaluating one or more PFs published in 2015. Each article was independently evaluated by 2 reviewers using a data extraction form that was extensively pilot-tested. We classified aspects of overinterpretation as misleading reporting, interpretation and extrapolation. Results: Our search identified 10 844 articles, 98 met eligibility criteria. The PF was assessed prospectively in 8 of 56 observational studies, and in 16 of 42 clinical trials. The median number of PFs per study was 2 (Q1-Q3, 1-5). Overall survival was used as the outcome in 77 studies. The median number of statistical analyses reported with regards to the PF effect assessment was 42.5 per study (Q1-Q3, 15.5-86.5). Thirty-three reports reported using 2 or more different multivariable models to assess the PF effect and 21 did not adjust. Misleading reporting included selective and incomplete reporting of the PF effect (n = 26 and n = 8, respectively). The conclusions focused solely on significant results in 80 reports, and in those where there was at least one NS result, 80% of studies focused their conclusions solely on the significant results. Misleading interpretation included not reporting the PF effect within a multivariable model (n = 23 and n = 54 in full-texts and abstracts, respectively). One out of 5 conclusions used linguistic spin with strong statements in both full-text and abstract. Linguistic spin of NS results was found in 28 Results sections in the full-text and in 18 abstract conclusions. The conclusions were inconsistent with the study findings in one out of five articles (both in the full-text and abstract). Discrepancies between the conclusions presented in the full-text and in the abstract were found in 18 reports. Conclusions: Our study provides insight into the level of reporting and overinterpretation of findings that were frequently inconsistent with the results in oncology journals with high impact factors.
Breast cancer patients' willingness to travel to participate in a clinical trial.
Authors: Zdenkowski Nicholas , Lynam James F. , Wall Laura , Brown Scott , Wells Kathryn , Sproule Victoria 
Published: September 2018

e14031 Background: The option of clinical trial participation is an important component of high quality care for oncology patients. Despite a recognised need for generalizable research results to guide future practice, and the desire of current oncology patients to participate in trials, only 2-5% of oncology patients in developed nations enroll in a clinical trial. We aimed to determine the willingness of patients to travel, change location and/or clinician to participate in a clinical trial. Methods: Members of a national breast cancer consumer organization were invited by email to respond to an online cross-sectional survey. Questions included demographics, remoteness of residence, prior involvement in clinical trials and location of usual care. This was followed by a Discrete Choice Experiment (DCE) comprising an introduction and 10 hypothetical scenarios to test the effect of variation in travel time, clinician, treating centre, travel cost and type of trial. Results: Between July and August 2016, 288 responses were received, mean age 58. 86% had early stage disease, 51% were currently receiving treatment, 21% had prior clinical trial involvement. Ninety percent were willing to participate in a clinical trial in at least one scenario. Factors that decreased the likelihood of interest in clinical trial participation were increasing travel time, change in oncologist and out of pocket expenses. Type of trial (randomised placebo controlled; randomised open label; single arm) did not influence the decision. If the oncologist remained the same and there were no costs, respondents were willing to travel a mean extra 127 minutes, however if the oncologist changed and there were additional costs, they were willing to travel a mean of 30 minutes. If the oncologist changed and there was no cost, they were willing to travel a mean of 82 minutes. Conclusions: This group of respondents with a past history of breast cancer expressed interest in clinical trial participation, however willingness to travel in the most likely scenario (change oncologist and pay no additional cost) was 82 minutes. To facilitate optimal access to clinical trials, clinicians should consider referral within and between institutions.
A bioequivalence study of proposed bevacizumab biosimilar, MYL-1402O (A) vs EU-Avastin (B) and US-Avastin (C).
Authors: Socinski Mark A. , Hummel Matthew , Bosje Tjerk , Shaw Andrew , Liu Mark Shiyao , Baczkowski Mark , Barve Abhijit , Kothekar Mudgal , Pennella Eduardo J. 
Published: September 2018

e14034 Background: MYL-1402O is a proposed bevacizumab biosimilar. The similarity of MYL-1402O to Avastin has been demonstrated in physicochemical analyses, and nonclinical studies. Methods: This single-center, randomized, double blind, three-arm, parallel-group, study was conducted in healthy adult male volunteers. The primary objective of this study was to establish PK similarity of A to B and C, and B to C. Subjects were randomized to receive either A, B or C 1 mg/kg over 90 minutes as an intravenous infusion. Dose was selected based on the lower dose in the linear range of PK and acceptable safety in healthy volunteers. Bioequivalence was to be concluded if the 90% CIs of the ratios (A/B, A/C and B/C) of LS means of the natural log transformed AUC0-inf were within 80% to 125%. AUC0-t, Cmax, tmax, kel and t½ were assessed as secondary PK parameters. Results: A total of 111 subjects (37/treatment) were enrolled and 110 [37 (A), 36 (B), 37(C)] were included in the analysis. Bioequivalence was demonstrated between A and B, A and C and between B and C. LS mean ratios were close to 1, and 90% CIs were within 0.80 to 1.25 for all of the comparisons. The secondary PK parameters were also comparable with the 90% CIs for ratios of AUC0-t and Cmax within 80%-125%. A total of 313 TEAEs were reported, 116 by 33 (89%) subjects who received A, 99 by 29 (78%) subjects who received B and 98 by 28 (76%) subjects who received C. Most TEAEs were consistent with the clinical data of bevacizumab (Avastin). No serious or unexpected TEAEs were reported. TEAEs were grade 1 or grade 2 in severity. The anti-drug antibodies are being evaluated (pending results). Conclusions: These results confirm bioequivalence of Myl-1402O vs. EU-Avastin and US-Avastin. All treatments were well tolerated and no significant safety issues emerged. Clinical trial information: NCT02469987 Clinical trial information: NCT02469987.
A phase Ia/Ib trial of the DNA-dependent protein kinase inhibitor (DNA-PKi) M3814 in combination with radiotherapy in patients with advanced solid tumors.
Authors: Van Triest Baukelien , Damstrup Lars , Falkenius Johan , Budach Volker , Troost Esther , Samuels Michael , Goddemeier Thomas , Geertsen Poul F. 
Published: September 2018

e14048 Background: DNA-PK, with its protein subunits, Ku70 and Ku80, regulates one of the major pathways responsible for repair of double-strand breaks in DNA that are induced by radiotherapy (RT) and some chemotherapeutic agents (CT). Therefore, the combined strategy of RT with a DNA-PKi is promising. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT and chemo-RT (CRT). Methods: Patients (pts) with tumors or metastasis in the head and neck region or thorax in need of palliative RT (10 x 3 Gy) are eligible for the dose escalation part Ia, with a starting dose of 100 mg once daily. Dose escalation decisions are aided by the Bayesian logistic regression model with overdose control. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: As of January 2017, 7 pts had been enrolled into the part Ia dose escalation arm and treated with 100 mg daily. The most frequent adverse events (AEs) were fatigue, constipation, decreased appetite, dry mouth, dysphagia, headache, oral pain, radiation skin injury, and mucositis in more than 1 pt (20%). No pts discontinued due to AE. Two episodes of grade 3 mucositis lasting > 7 days were reported; one of these was classified as a DLT, and both pts recovered without sequelae. Two of 7 pts enrolled had local tumor control at +300 days. PK analysis demonstrated high exposure variability. Conclusions: M3814 at the 100 mg daily dose was tolerable as palliative treatment and dose escalation is currently at 200 mg. In part Ib of the study, two separate dose escalation arms will enroll pts with either head and neck squamous cell carcinoma (SCCHN; US only) or non-small cell lung cancer (EU and US) to receive CRT 2 Gy x 30-35 over 6-7 weeks with curative intent; the SCCHN cohort is now open for enrollment. For these two cohorts, the DLT window will be 12 weeks. Clinical trial information: NCT02516813.
A first in human study using photodynamic therapy with Redaporfin in advanced head and neck cancer.
Authors: Oliveira Julio , Monteiro Eurico , Santos Juliana , Silva Jose Dinis , Almeida Luis , Santos Lúcio Lara 
Published: September 2018

e14056 Background: Photodynamic therapy (PDT) may be an appealing approach when head and neck cancer (HNC) patients (pts) develop locoregional standard treatment failure. Currently available systemic photosensitizers (PST) present several limitations, such as longstanding photosensitivity. Redaporfin is a new PST specifically designed to achieve improved efficacy and safety over existing options. Methods: This phase I/IIa clinical trial had the objective to determined Redaporfin tolerability, anti-tumor effect and pharmacokinetics (PK). “Dose-finding phase”: each patient was submitted to a single-ascending dose of Redaporfin, administered by iv infusion, lasting 10-20 minutes, in ≥ 21 days interval; drug was titrated up to a dose that, in combination with a laser light of 50 J/cm2 at 749±3 nm, was safe and caused tumor necrosis (“effective dose”) in a spot of 1.0 cm of diameter of tumor surface. “Final PDT session”: all accessible tumor was treated with the individual effective dose. Results: Thirteen pts (10 men, 3 women; median age 62 yrs; range 35-80) with advanced HNC in symptomatic treatment were submitted to Redaporfin doses: 0.05 mg/kg (n = 6), 0.1 mg/kg (n = 4), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 4), 0.75 mg/kg (n = 6) and 1.0 mg (n = 1). Treatment-related adverse events (TRAE): 2 pts had grade (G) 3 photosensitivity reaction (PR) after accidental exposure to intense sun-light (0.75 mg/Kg dose); G≤2 TRAEs in 7 pts (G2 infusion-related reactions in 2 pts and PR in 2 pts). Photodynamic effect was observed in all subjects at doses ≥ 0.5 mg/kg and was dose-dependent; 0.75 mg/kg dose caused necrosis in 1 cm diameter target spot deeper than 5 mm. The patient submitted to final PDT session achieved complete tumor necrosis of treated area. PK showed to be linear; drug was eliminated from the body in a relatively fast manner (half-life of 19 hrs following Redaporfin 0.75mg/Kg). Reported data allowed to conclude phase I part of the trial; next steps of clinical development were authorized. Conclusions: Redaporfin effective dose was established at 0.75 mg/Kg. PDT with Redaporfin revealed anti-tumor effect and was safe in patients with advanced HNC. Further research with this promising compound is ongoing. Clinical trial information: NCT02070432.
Phase Ib pharmacokinetics of non-hormonal SM88 in patients with non-metastatic recurrent prostate cancer.
Authors: Del Priore Giuseppe , Rothman John , Sokol Gerald H. , Hoffman Karen , Retter Avi S. , Hoffman Steve 
Published: September 2018

e14061 Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]
Hypomagnesemia and exposure to romidepsin: A Research on Adverse Drug events and Reports (RADAR) project.
Authors: Lee Dylan E. , Serrano Linda , Martinez-Escala Estela , Kaplan Jason B. , Pro Barbara , Guitart Joan , Temps William H. , West Dennis P. , Belknap Steven M. 
Published: September 2018

e14072 Background: Romidepsin (R) is indicated for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Hypomagnesemia (HM) is common in these patients and is also listed in the Full Prescribing Information (FPI) for R. Moreover, since cardiac arrhythmias are associated with HM, patients exposed to R may be at higher risk. This study assessed whether HM was causally related to R exposure and to what extent magnesium (M) supplementation was undertaken in those with HM. Methods: We searched a large, U.S. patient data repository to detect all patients (aged 20-94 years) exposed to R (10/2010-01/2017). For these patients, serum M, as well as M supplementation data, was collected. Baseline M was assessed at initial R exposure, and HM was defined as either, a decline in M to < 1.8 mg/dL after R exposure or, in those with baseline M < 1.8 mg/dL, a decline in M by ≥0.1 mg/dL after R exposure. For each patient with HM after R exposure, the validated Naranjo Adverse Drug Reaction Probability Scale (NADRPS) was used to determine the probability that HM was caused by R. Results: Of 51 R-exposed CTCL (or other lymphoma) patients, 25 (49.0%) had HM. Of these 25, NADRPS scores yielded: 1 doubtful, 16 possible, 8 probable and 0 definite. Additionally, 24 of 25 patients with HM had documentation for presence or absence of M supplementation: 9 (37.5%) had supplementation with M agents considered to be bioavailable, 12 (50%) received M agents considered to have low bioavailability, and 3 (12.5%) had no M supplementation. Conclusions: In this study population, 25 of 51 (49.0%) patients had HM after R exposure, which appears to nearly double the percentage of patients described in the FPI. Moreover, 8 of 25 (32%) patients with HM had causality attributed to R exposure. In addition, 15 of 24 (63%) patients with HM received M supplementation with agents considered to have low bioavailability or received no M supplementation. These findings support the need for ongoing monitoring of R-exposed patients with low M, as well as the importance of repleting M with agents considered to be adequately bioavailable. Also, given that HM appears to be more frequent in this study population compared to pre-marketing data in the FPI, further studies are warranted.
Combination of WEE1 and AURKA inhibition in HPV negative head and neck squamous cell carcinoma.
Authors: Parameswaran Janaki , Lee Jong Woo , Sandoval-Schaefer Teresa , Koo Jaseok P. , Burtness Barbara 
Published: September 2018

e14105 Background: Aurora Kinase A (AURKA) is overexpressed in HNSCC, and correlates with poor prognosis. It has been identified as a potential therapeutic target, yet the response rate for the AURKA inhibitor MLN8237 is only 9% in treatment refractory HNSCC. We hypothesized that although AURKA inhibitors lead to defective spindle assembly, they may also reduce mitotic entry, undermining cytotoxic effect. We predicted that adding a WEE1 inhibitor to an AURKA inhibitor would mitigate this effect and enhance cell death Methods: Cell viability assays were performed on FaDu ( p53 mut.), Detroit562 ( p53 mut.), and UNC7 ( p53 WT) HPV negative HNSCC cell lines treated with AZD1775 (AZD), MLN8237 (MLN), and combination of AZD+MLN. Oncosphere formation assays were used to confirm findings of cell death, and western blot analysis and confocal microscopy were used to investigate mechanism of synergy. The above drugs were also given at varying doses via oral gavage to FaDu xenografted nude mice. Results: There was clear synergy of AZD and MLN in-vitro. Combination Indices were determined by the Chou-Talalay method: FaDu 0.4, Detroit562 0.5, and UNC7 0.6 (synergy = < 0.8). Oncopshere assays showed inability of AZD+MLN treated cells to re-differentiate. FaDu cells treated with MLN had increased p-CDK1 and reduced phospho-histone H3 (pHH3), suggesting reduced mitotic entry. AZD+MLN treated cells had reduced p-CDK1 and increased pHH3, similar to AZD treated cells; they also had spindle disarray with poor chromatin organization on confocal microscopy indicating mitotic catastrophe. In mice, the combination of AZD+MLN inhibited tumor growth, with no apparent toxicity. Mice treated with either drug alone had tumor volumes over 1000mm3 and were sacrificed at day 21; those treated with AZD 90mg/kg and MLN 30mg/kg had tumors volumes around 300mm3 on day 28. Conclusions: AZD and MLN synergistically enhance cell death in HNSCC cell lines and significantly inhibit tumor growth in mouse xenograft models. The ability of AZD to overcome intrinsic resistance to MLN may underlie mechanism of synergy. We recommend further investigation of AURKA and WEE1 inhibition in other cancers with high AURKA expression, and in patients with HNSCC.
Immunomodulatory effects of tyrosine kinase inhibitors (TKIs) in renal cell carcinoma (RCC) patients.
Authors: Nuti Marianna , Zizzari Ilaria , Napoletano Chiara , Botticelli Andrea , Calabro Fabio , Gelibter Alain , Rughetti Aurelia , Ugolini Alessio , Ruscito Ilary , Mazzuca Federica , Rahimi Hassan , Onesti Concetta Elisa , Cortesi Enrico , Marchetti Paolo 
Published: September 2018

e14506 Background: RCC is considered a highly immunogenic tumor responding to anti-angiogenetic TKI and immunotherapy. A better understanding of the functions of immune cells in RCC, the immune-modulatory effects of TKIs treatment as well as defining patients most likely to benefit to the different therapies will be crucial to optimize combined or sequential immunotherapeutic approaches in RCC patients. Methods: Monocyte derived Dendritic Cells (DCs) from 10 healthy donors were differentiated in presence of Pazopanib and Sunitinib used at plasmatic equivalent concentration (Sigma-Aldricht). At the end of the culture, DCs were characterized for marker expression, endocytosis, signal transduction and microvesicle release. Similarly, DCs derived from RCC patients were analyzed together with circulating T cells before and during TKI treatments. Results: Pazopanib and Sunitinib differently affect DC differentiation. Pazopanib, but not Sunitinib, strongly improves DC performance as antigen-presenting cells, promoting the upregulation of the maturation markers HLA-DR (+1,5 fold increase compared to Sunitinib-treated DCs), CD40 (+3 fold increase) and CCR7 (+2 fold increase) a decrease in phagocytosis and the inhibition of pERK1/2 signaling. 99% of Sunitinib-DCs expressed PD-L1 vs 80% Pazopanib-DCs , with a higher expression of the receptor as indicated by mean fluoresce intensity (MFI fold increase of +2,1). Similar results were obtained analyzing shedded microvesicles. Results were confirmed in DCs differentiated from RCC patients during Pazopanib treatment (before and at 30 and 60 days) and suggest a reverse of the tumor induced immunosuppression. Moreover, only Pazopanib treatment appears to induce in these patients a defined circulating CD4+ T cell population highly expressing CD137 molecule (%CD4+CD137+: T0:0,3; T30: 4,7; T60:29,4). Conclusions: TKIs can affect immunity in RCC patients. In particular, Pazopanib appears to function as a potent activator of DCs in vitro and in vivo associated with the neo-activation of a CD137+ T cell population. These results can guide for designing novel protocols to combine TKIs with immunoregulatory receptors targeting in RCC.