The relationship of study and authorship characteristics on trial sponsorship and self-reported conflicts of interest among neuro-oncology clinical trials

Abstract

Propose

To examine the association between trial sponsorship sources, self-reported conflicts of interest (COI), and study and author characteristics in central nervous system (CNS) oncology clinical trials (CT).

Methods

MEDLINE search was performed for original CT on "Central Nervous System Neoplasms"[Mesh]. The investigators assessed for relationships between funding source (industry, academic or cooperative, none, not described), COI (presented, none, or not reported), CT, and author characteristics.

Results

From 2010 to 2015, 319 CT were considered eligible. The majority of the studies involved primary gliomas (55.2%) and were Phase II CT (59.2%). Drug therapy was investigated in 83.0% of the CT. The remaining studies investigated surgery or radiotherapy. A minority of papers were published in journals with impact factor (IF) higher than > 10 (16%) or in regions other than North America and Europe (20.4%). Overall, 83.1% of studies disclosed funding sources: 32.6% from industry alone, 33.9% from an academic or cooperative group, and 10.7% from a mixed funding model. COI data was reported by 85.9% of trials, of which 56.2% reported no COI and 43.8% reported a related COI. Significant predictors for sponsorship (industry and/or academia) on univariate analysis were study design, type of intervention, journal impact factor, study conclusion, transparency of COI and presence of COI. On multivariate analysis, type of intervention, (P < 0.001), journal impact factor (IF) (P = 0.003), presence of COI (P < 0.001) and study conclusion (P = 0.003) remained significant predictors of sponsorship. For predicting COI, significant variables on univariate analysis were disease type, type of intervention, journal IF, funding source, and intervention arm being related to sponsor. On multivariate analysis, disease type (P = 0.003), journal IF (P < 0.001), type of intervention (P = 0.001), and funding source (P = 0.008) remained significant.

Conclusions

The majority of CNS CT reported some external funding sources and non-related COI. We identified that drug trials, higher IF, presence of COI, and a neutral or negative study conclusion are associated with external funding. Likewise drug trials, higher IF, and glioma trials are associated with presence of COI.

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Cancers, Vol. 10, Pages 179: Allogeneic Hematopoietic Cell Transplantation for Older Adults with Acute Myeloid Leukemia

Cancers, Vol. 10, Pages 179: Allogeneic Hematopoietic Cell Transplantation for Older Adults with Acute Myeloid Leukemia

Cancers doi: 10.3390/cancers10060179

Authors: Jodi J. Lipof Kah Poh Loh Kristen O'Dwyer Jane L. Liesveld

Acute myeloid leukemia (AML) is a disease that affects adults aged 65 years and above, and survival in this population is poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for these patients but is underutilized due to frequent comorbidities and perceived higher risk of treatment-related mortality and non-relapse mortality. Increasing data supports the utility of allo-HCT in fit older patients after intensive chemotherapy resulting in improvement of outcomes. With the development of reduced intensity and non-myeloablative conditioning regimens that are associated with lower rates of treatment-related toxicity and mortality, this has allowed more older patients with AML to receive allo-HCT. In this review, we provide some guidance on appropriate selection of older patients as transplant candidates, benefits and risks associated with allo-HCT, conditioning regimen choice, and stem cell transplant sources as they relate to the conduct of stem cell transplantation in older patients.

https://ift.tt/2LVeuOV

Cancers, Vol. 10, Pages 178: p53 and the Viral Connection: Back into the Future ‡

Cancers, Vol. 10, Pages 178: p53 and the Viral Connection: Back into the Future ‡

Cancers doi: 10.3390/cancers10060178

Authors: Ronit Aloni-Grinstein Meital Charni-Natan Hilla Solomon Varda Rotter

The discovery of the tumor suppressor p53, through its interactions with proteins of tumor-promoting viruses, paved the way to the understanding of p53 roles in tumor virology. Over the years, accumulating data suggest that WTp53 is involved in the viral life cycle of non-tumor-promoting viruses as well. These include the influenza virus, smallpox and vaccinia viruses, the Zika virus, West Nile virus, Japanese encephalitis virus, Human Immunodeficiency Virus Type 1, Human herpes simplex virus-1, and more. Viruses have learned to manipulate WTp53 through different strategies to improve their replication and spreading in a stage-specific, bidirectional way. While some viruses require active WTp53 for efficient viral replication, others require reduction/inhibition of WTp53 activity. A better understanding of WTp53 functionality in viral life may offer new future clinical approaches, based on WTp53 manipulation, for viral infections.

https://ift.tt/2xLHO7E

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study

Abstract

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register (www.clinicaltrialsregister.eu, 2008-001430-27)

https://ift.tt/2JrTJMh

Non-canonical WNT6/WNT10A signal factor expression in EBV+ post-transplant smooth muscle tumors

Abstract

Post-transplant smooth muscle tumors (PTSMTs) are rare mesenchymal neoplasms which occur after solid organ or haematopoietic stem cell transplantation. PTSMT typically consist of Epstein–Barr-virus (EBV)+ smooth muscle-like cells and show an intermediate malignancy. Their main occurrences are visceral organs, especially the liver, but intracranial appearances are described and associated with a poor prognosis. EBV drives the growth of PTSMT; however, the underlying molecular mechanisms still remain unclear. Gene expression analysis of a set of morphologically similar tumors (leiomyomas, leiomyosarcomas, angioleiomyomas and endothelial haemangiomas) from patients without immunosuppression or EBV-association was performed. Our findings indicate that PTSMT's growth is driven by two factors of the wingless-type protein family: WNT6 and WNT10A. We are first to report that in PTSMTs, a non-canonical activation of WNT, independent of beta-catenin, drives tumor cell proliferation via MTOR/AKT1, MYC and Cyclin D2.

https://ift.tt/2JmCE6q

HER2 positive rates are enriched amongst colorectal cancer brain metastases: a study amongst 1920 consecutive patients

https://ift.tt/2LVpjAo

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation

Abstract

Background

Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients.

Patients and methods

Key inclusion criteria were: centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval (IFI) >3 months. TEMIRI (TMZ 150mg/sqm on days 1-5 plus irinotecan 100mg/sqm on days1,15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary endpoint was overall response rate (ORR). Exploratory translational analyses included MGMT immunoistochemistry (IHC) and methylBEAMing (MB).

Results

Between December 2014 and June 2017, 25 patients were enrolled. The primary endpoint was met, since 6 patients achieved a partial response (ORR 24%, 95% CI, 11%-43%). At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only 4 (16%) patients had ≥ grade 3 adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; HR = 0.29, 95%CI, 0.02-0.41; p = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy.

Conclusions

TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

https://ift.tt/2Je30V1

Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft tissue sarcomas

Abstract

Background

Prediction of metastatic outcome in sarcomas is challenging for clinical management since they are aggressive and carry a high metastatic risk. A 67-gene expression signature, the Complexity INdex in SARComas (CINSARC), has been identified as a better prognostic factor than the reference pathological grade. Since it cannot be applied easily in standard laboratory practice, we assessed its prognostic value using nanoString on formalin-fixed, paraffin-embedded (FFPE) blocks to evaluate its potential in clinical routine practice and guided therapeutic management.

Methods

A code set consisting of 67 probes derived from the 67 genes of the CINSARC signature was built and named NanoCind®. To compare the performance of RNA-seq and nanoString (NanoCind®), we used expressions of various sarcomas (n=124, frozen samples) using both techniques and compared predictive values based on CINSARC risk groups and clinical annotations. We also used nanoString on FFPE blocks (n=67) and matching frozen and FFPE samples (n=45) to compare their level of agreement. Metastasis-free survival and agreement values in classification groups were evaluated.

Results

CINSARC strongly predicted metastatic outcome using nanoString on frozen samples (HR = 2.9, 95% CI 1.23-6.82) with similar risk-group classifications (86%). While more than 50% of FFPE blocks were not analyzable by RNA-seq owing to poor RNA quality, all samples were analyzable with nanoString. When similar (risk-group) classifications were measured with frozen tumors (RNA-seq) compared to FFPE blocks (84% agreement), the CINSARC signature was still a predictive factor of metastatic outcome with nanoString on FFPE samples (HR = 4.43, 95% CI 1.25-15.72).

Conclusion

CINSARC is a material-independent prognostic signature for metastatic outcome in sarcomas and outperforms histological grade. Unlike RNA-seq, nanoString is not influenced by the poor quality of RNA extracted from FFPE blocks. The CINSARC signature can potentially be used in combination with nanoString (NanoCind^®) in routine clinical practice on FFPE blocks to predict metastatic outcome.

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Accelerated subcutaneous nodulosis in patients with rheumatoid arthritis treated with tocilizumab: a case series

Tocilizumab is a monoclonal antibody directed against the interleukin-6 receptor, which is approved for the treatment of moderate-to-severe rheumatoid arthritis. Authors have found that it prevents lung and su...

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Complexity, Variation, and the Ever-moving Cheese

No abstract available

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Hepatocellular Carcinoma Tumor Dose Response following 90Y-radioembolization with glass microspheres using 90Y-SPECT/CT based Voxel Dosimetry

Publication date: Available online 2 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): S.Cheenu Kappadath, Justin Mikell, Anjali Balagopal, Veera Baladandayuthapani, Ahmed Kaseb, Armeen Mahvash
PurposeTo investigate hepatocellular carcinoma (HCC) tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative ⁹⁰Y-SPECT/CT after ⁹⁰Y-radioembilization with glass-microspheres. We also investigated the relationship between normal liver D and toxicities.Methods⁹⁰Y-radioembolization activity distributions for 34 patients were based on quantitative ⁹⁰Y-bremsstrahlung SPECT/CT. D maps were generated using a local-deposition algorithm. Contrast-enhanced CTs or MRIs of the liver were registered to ⁹⁰Y-SPECT/CT and all tumor larger than 2.5 cm diameter (53 tumors) were segmented. Tumor mean D and BED (Dmean and BEDmean) and dose volume coverage from 0-100% in 10% steps (D0-D100 and BED0-BED100) were extracted. Tumor response was evaluated on follow-up using WHO, RECIST, and mRECIST. Differences in dose metrics for responders and non-responders were assessed using Mann-Whitney U test. Univariate logistic regression model was used to determine tumor dose metrics that correlated with tumor response. Correlations between tumor size, tumor Dmean, and tumor dose heterogeneity (defined as the coefficient of variation) were assessed.ResultsThe objective response rates were 14/53, 15/53, and 30/53 for WHO, RECIST, and mRECIST criteria, respectively. WHO and RECIST response statuses did not correlate with D or BED. D and BED between mRECIST responders and non-responders were significantly different for Dmean, D20-D80, BEDmean, and BED0-BED80. Threshold doses (and the 95% confidence interval) for 50% probability of mRECIST response (D50%) were 160 Gy (123-196 Gy) for Dmean and 214 Gy (146-280 Gy) for BEDmean. Tumor dose heterogeneity significantly correlated with tumor volume. No statistically significant association between Dmean to normal liver and complications related to bilirubin, albumin, or ascites was observed.ConclusionsHCC tumor dose-response curves following ⁹⁰Y-radioembolization with glass-microspheres showed Dmean of 160 Gy and BEDmean of 214 Gy for D50% with PPV of ∼70% and NPV of ∼62%. No complications were observed in our patient cohort for normal liver Dmean less than 44 Gy.



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Automated instead of manual treatment planning? A plan comparison based on dose-volume statistics and clinical preference

Publication date: Available online 2 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Barbara Vanderstraeten, Bruno Goddeeris, Katrien Vandecasteele, Marc van Eijkeren, Carlos De Wagter, Yolande Lievens
Purpose/ObjectiveAutomated planning aims to speed up treatment planning and improve plan quality. We compared manual to automated planning for lung stereotactic body radiation therapy (SBRT) based on dose-volume histogram (DVH) statistics and clinical preference.Methods and MaterialsManual (MP) and automated (AP) intensity-modulated radiation therapy (IMRT) plans were generated for 56 patients using in-house developed software and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients and the impact of AP on the total treatment cost was estimated. For the remaining 46 patients each plan was checked against our clinical objectives and a pairwise DVH comparison was performed. Three experienced radiation oncologists (ROs) evaluated each plan and indicated their preference.ResultsAP reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. 3 AP / 0 MP failed our clinical objectives, while 13 AP / 9 MP showed a minor deviation. AP significantly reduced D2% for the spinal cord, esophagus, heart, aorta and main stem bronchus (p<0.05), while preserving target coverage. The ROs found over 75% of the AP clinically acceptable without any further fine tuning.ConclusionsAP may help to create satisfactory treatment plans fast and effectively. As the critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet.

Teaser

Automated planning aims to improve the efficiency of the treatment planning process as well as the final plan quality. We compared automated plans to manual plans for 56 patients based on clinical objectives, DVH metrics and a blind clinical assessment by three experienced radiation oncologists. We observed a statistically significant reduction in OAR dose while maintaining PTV coverage for the automated plans. Clinically, however, the automated plans were not always preferred over their manual counterparts.


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