Honorary and ghost authorship in reports of randomised clinical trials in oncology

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Francisco Emilio Vera-Badillo, Marc Napoleone, Monika K. Krzyzanowska, Shabbir M.H. Alibhai, An-Wen Chan, Alberto Ocana, Arnoud J. Templeton, Bostjan Seruga, Eitan Amir, Ian F. Tannock
BackgroundThe International Committee of Medical Journal Editors (ICMJE) has developed guidelines for responsible and accountable authorship. Few studies have assessed the frequency and nature of ghost and honorary authorship in publications of oncology trials.Materials and methodsReports of randomised clinical trials evaluating systemic cancer therapy published from July 2010 to December 2012 in six high-impact journals were identified systematically. Ghost authorship was determined to be present in any scenario where investigators or statisticians listed in the protocol were not included as authors and not acknowledged in the report of the trial. The list of contributions for authors of published articles was recorded, and we defined an article as having an honorary author if any author did not meet all three criteria established by ICMJE in 1985.ResultsTwo hundred publications were identified. For 61 articles, protocols with listed investigators were available, and 40 (66%) of these articles met our definition of ghost authorship. Medical writers were involved in 89 articles (45%), and assistance was acknowledged only in sponsored trials. Contributions of each author were provided in 195 articles, and 63 (33%) articles met our definition for honorary authorship. Funding source was not a predictor for either honorary or ghost authorship. Journal impact factor was positively associated with honorary authorship (odds ratio = 1.03; 95% confidence interval = 1.004–1.065; P = 0.03), but not with ghost authorship.ConclusionGhost and honorary authorship are prevalent in articles describing trials for systemic therapy of cancer. Guidelines should be enforced to improve transparency and accountability.



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Long-term oncological safety of minimally invasive surgery in high-risk endometrial cancer

Publication date: September 2016
Source:European Journal of Cancer, Volume 65
Author(s): Martin Koskas, Marta Jozwiak, Marie Fournier, Ignace Vergote, Hans Trum, Christianne Lok, Frédéric Amant
BackgroundSeveral studies showed that women with low-risk endometrial cancers staged by minimally invasive surgery (MIS) experience fewer postoperative complications compared to those staged by laparotomy with similar disease-free survival (DFS) and overall survival (OS). However, high-risk patients were poorly represented. In this study, we compared DFS and OS in high-risk endometrial cancer patients who underwent surgical staging via MIS versus laparotomy.MethodsUsing a multicentric database, we compared DFS and OS between 114 patients with high-risk histology who underwent surgical staging via MIS and 114 patients who underwent laparotomy. Patients were matched for age, tumour type, FIGO stage and management criteria.ResultsAmong the 114 patients who underwent MIS, 93 underwent laparoscopy and 21 robotic surgery. Groups were comparable for stage, body mass index, histology and adjuvant therapies. However, patients in the MIS group underwent paraaortic lymphadenectomy less frequently (13% versus 29%; p = 0.01), had less lymph nodes removed (19.0 versus 28.6; p < 0.01) and had lower mean tumour size (30 versus 40 mm; p < 0.01). With a median follow-up time of 49 months, DFS and OS were not significantly different between the surgical cohorts. In multivariable analysis, both higher stage (hazard ratio [HR] = 2.2) and histology (HR = 4.9) were associated with DFS in contrast to surgical procedure (HR = 0.9).ConclusionsBeyond the benefit of MIS on immediate surgical outcome, our results show that fear for a poor long-term outcome should not be the reason to refrain from MIS in patients with high-risk endometrial cancer.



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Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma

Publication date: September 2016
Source:European Journal of Cancer, Volume 65
Author(s): Michael C. Kirchberger, Axel Hauschild, Gerold Schuler, Lucie Heinzerling
With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single-agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment-related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity.



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Time trends in the incidence of oesophageal cancer in Asia: Variations across populations and histological types

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Shao-Hua Xie, Jesper Lagergren
ObjectiveWe aimed to assess temporal trends in incidence rates of oesophageal cancer in Asian countries.Materials and methodsUsing data from the Cancer Incidence in Five Continents series, we examined the temporal trends in incidence rates of oesophageal cancer by population and histological type in seven Asian countries in 1988–2007. Age-period-cohort analyses estimated the overall annual percentage changes (net drifts) and their 95% confidence intervals (CIs) in incidence rates.ResultsThe age-standardised incidence rate of oesophageal cancer declined in most Asian populations, but remained relatively unchanged in Japan and Israel. The rate of oesophageal squamous cell carcinoma decreased in Hong Kong, Singapore and Israel, but was stable in Japan. The net drifts were statistically significant in men in Hong Kong (−3.4%, 95% CI: −6.1%, −0.7%) and in women in Singapore (−10.1%, 95% CI: −14.4%, −5.5%). The age-standardised incidence rates of oesophageal adenocarcinoma were below 2 and 0.5 per 100 000 in men and women, respectively, across all periods in the all registers containing valid data on histological type. The age-standardised incidence rate of oesophageal adenocarcinoma slightly increased in Japan, Singapore, and Israel, although the net drift was statistically significant only in Israeli men (4.9%, 95% CI: 0.8%, 9.1%).ConclusionThe overall incidence rates of oesophageal cancer declined in most Asian countries, which is due to a decrease in oesophageal squamous cell carcinoma incidence. However, attention needs to be paid to a probable beginning of an increasing incidence of oesophageal adenocarcinoma in Asia.



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Inflammatory biomarkers, aspirin, and risk of colorectal cancer: Findings from the physicians’ health study

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Chul Kim, Xuehong Zhang, Andrew T. Chan, Howard D. Sesso, Nader Rifai, Meir J. Stampfer, Jing Ma
BackgroundChronic inflammation has been implicated in colorectal carcinogenesis. However, the associations between plasma inflammatory markers and risk of colorectal cancer have been inconsistent.MethodsIn a nested case-control study in the Physicians' Health Study, we prospectively investigated the associations of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor receptor 2 (TNFR-2) with risk of colorectal cancer, and whether aspirin modified these associations among 268 colorectal cancer patients and 446 age- and smoking-matched controls.ResultsIn multivariate-adjusted models, plasma levels of CRP, IL-6 and TNFR-2 were not significantly associated with risk of colorectal cancer, although a positive trend was observed for TNFR-2 (RRhighestvs.lowestquartile=1.55; 95% CI=0.95-2.54; Ptrend=0.05). We observed a statistically significant association between elevated TNFR-2 levels and colorectal cancer risk in the placebo arm (RRhighestvs.lowesttertile=1.77; 95% CI=1.02-3.06; Ptrend=0.02), but not in the aspirin arm (Ptrend=0.72). However, the interaction between TNFR-2 and aspirin was not statistically significant (Pinteraction=0.34).ConclusionPlasma inflammatory markers were not significantly associated with colorectal cancer risk among men, though there was a statistically non-significant positive trend between TNFR-2 and colorectal cancer risk. More studies are required to understand the relationship between the role of TNFα pathway, aspirin, and colorectal cancer risk.



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Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer

Abstract

Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine.

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Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer

Abstract

Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine.

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Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer

Abstract

Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine.

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Rituximab to treat gemcitabine-induced hemolytic–uremic syndrome (HUS) in pancreatic adenocarcinoma: a case series and literature review

Abstract

Purpose

Hemolytic–uremic syndrome (HUS) is a rare side effect of gemcitabine, which is reported as having a high morbidity and mortality despite interventions with standard HUS therapies including plasmapheresis. The purpose of this report was to describe the successful treatment of gemcitabine-induced HUS (G-HUS) with rituximab. It also aims to summarize the literature regarding the morbidity and mortality of G-HUS in pancreatic adenocarcinoma depending on the treatment given, ultimately providing some guidance for beneficial therapies.

Methods

This is a retrospective report of three patients with pancreatic adenocarcinoma who developed G-HUS and were treated with a combination of therapies including rituximab.

Results

All three patients received a combination of therapies to treat their HUS. One patient appeared to have some benefit with plasmapheresis. Resolution occurred following one course of rituximab for all three patients. This resolution has been long lasting with a minimum of eighteen month's follow-up. Similarly, in our literature review a variety of therapies were utilized, but immune therapies appear to reverse HUS if other therapies are failing.

Conclusion

Rituximab can be an effective therapy for reversal of hemolysis and stabilization of renal function in G-HUS when other therapies fail.

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