Snus use, smoking and survival among prostate cancer patients

Abstract

Smoking is associated with prostate cancer mortality. The Scandinavian smokeless tobacco product snus is a source of nicotine but not the combustion products of smoke, and has not been studied with respect to prostate cancer survival. The study is nested among 9,582 men with incident prostate cancer within a prospective cohort of 336,381 Swedish construction workers. Information on tobacco use was collected at study entry between 1971 and 1992, and categorized into (1) never users of any tobacco, (2) exclusive snus: ever users of snus only, (3) exclusive smokers: ever smokers (cigarette, cigar, and/or pipe) only, and (4) ever users of both snus and smoking. Hazard ratios for prostate cancer-specific and total mortality for smoking and snus use based on Cox proportional hazards models adjusted for age, calendar period at diagnosis, and body mass index at baseline. During 36 years of follow-up, 4,758 patients died – 2,489 due to prostate cancer. Compared to never users of tobacco, exclusive smokers were at increased risk of prostate cancer mortality (HR 1.15, 95% CI: 1.05-1.27) and total mortality (HR 1.17, 95% CI: 1.09-1.26). Exclusive snus users also had increased risks for prostate cancer mortality (HR 1.24, 95% CI: 1.03-1.49) and total mortality (HR 1.19, 95% CI: 1.04-1.37). Among men diagnosed with non-metastatic disease, the HR for prostate cancer death among exclusive snus users was 3.17 (95% CI: 1.66-6.06). The study is limited by a single assessment of tobacco use prior to diagnosis. Snus use was associated with increased risks of prostate cancer and total mortality among prostate cancer patients. This suggests that tobacco-related components such as nicotine or tobacco-specific carcinogens may promote cancer progression independent of tobacco's combustion products. This article is protected by copyright. All rights reserved.

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Cancers, Vol. 8, Pages 82: Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials

The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2), there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO) for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef) reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling.

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The up-regulation of PD-L1 promotes the resistant response in non-small cell lung cancer patients with neo-adjuvant chemotherapy

Abstract

To assess the significance of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) and its association with cisplatin-based neo-adjuvant chemotherapy (NAC) response. We investigated that PD-L1 was increased in chemo-resistant tumors compared with chemo-sensitive tumors according to RNA-Seq analysis, which was confirmed in the same cohort using IHC. In a cohort of 92 patients with NAC, the positive staining of PD-L1 was correlated with the TNM stage, lower sensitive-response rates and shorter overall survival rates. In another 30 paired tumor specimens pre- and post-chemotherapy, the patients with high PD-L1 expression of post-chemotherapy had a worse outcome and higher stable disease rate. CD8⁺ tumor infiltrating lymphocytes (TILs) was found to be related to chemosensitive response and better prognosis and negative PD-L1 expression. Furthermore, in two PDX models and cell lines A549 and PC-9, cisplatin up-regulated PD-L1 expression, and the enhancement of PD-L1 in cancer cell lines was in a drug dose dependent manner. Moreover, the depletion of PD-L1 significantly reduced the cisplatin resistance. When PI3K/AKT signaling was inhibited by corresponding inhibitors, PD-L1 expression was down-regulated and apoptosis was up-regulated in the cisplatin treated cancer cells. These results suggest that the up-regulation of PD-L1 promotes the resistant response in lung cancer cells that might be through activation of PI3K/AKT pathway and suppression of TILs. The high expression of PD-L1 after NAC could be the indication of therapeutic resistance and poor prognosis of NSCLC patients.

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FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib

Summary

Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non–small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.

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Irradiation normofractionnée des cancers du sein. Indications et bénéfices

Publication date: Available online 31 August 2016
Source:Cancer/Radiothérapie
Author(s): A. Fourquet, S.-L. Krhili, F. Campana, A. Chilles, Y.-M. Kirova
L'irradiation normofractionnée du sein après une chirurgie conservatrice est la référence de pratique. Elle consiste à délivrer une dose de 50Gy en 25 fractions de 2Gy dans le point de référence, et dans certains cas, une dose additionnelle de 16Gy en 8 fractions de 2Gy dans le lit tumoral. Plusieurs essais thérapeutiques et des méta-analyses, dans les cancers infiltrants comme dans les cancers intracanalaires, ont évalué les résultats et la toxicité à long terme de cette irradiation. Les taux de récidive intrammaire à 10ans sont en moyenne de 6 %, avec une toxicité cardiaque, pulmonaire et des tissus mous (fibrose) qui reste très limitée avec les techniques modernes. L'identification des facteurs de risque à long terme peut contribuer à définir de nouveaux schémas de fractionnement adaptés à la biologie tumorale. Les nouveaux schémas d'irradiation doivent être évalués rigoureusement sur le long terme dans le cadre d'essais thérapeutique, pour qu'ils puissent constituer de nouveaux standards.Whole-breast normofractionated irradiation following breast-conserving surgery is the reference treatment. It delivers a dose of 50Gy in 25 fractions of 2Gy to the reference point, and, in some patients, an additional dose of 16Gy in 8 fractions of 2Gy in the tumor bed. Long-term results and toxicity of this irradiation scheme was prospectively evaluated in several randomised trials and meta-analyses, in invasive cancers as well as in ductal carcinoma in situ. The average 10-year rate of in breast recurrences was 6 % in these trials, with limited cardiac and pulmonary toxicity and limited rate of severe fibrosis. Identification of risk factors of recurrences may help to design new irradiation schemes adapted to tumor biology. The new irradiation schemes must be rigorously evaluated in the long-term in the frame of prospective clinical trials, in order to validate them as new standards of treatment.



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Synchronisation respiratoire et radiothérapie mammaire

Publication date: Available online 31 August 2016
Source:Cancer/Radiothérapie
Author(s): A. Mège, A. Ziouèche-Mottet, V. Bodez, R. Garcia, A. Arnaud, G. de Rauglaudre, N. Pourel, B. Chauvet
La radiothérapie adjuvante des cancers du sein améliore les taux de contrôle locorégional et de survie globale, mais le bénéfice des techniques d'irradiation de haute précision, comme la modulation d'intensité, peut être compromis par les mouvements respiratoires. Ces mouvements pendant les fractions peuvent entraîner un sous- ou un surdosage des volumes cibles, ou à exposer les organes à risque de proximité. Cet article résume les mouvements respiratoires, leurs effets sur l'imagerie, la dosimétrie et la délivrance de dose lors de la radiothérapie des cancers du sein. Nous proposons une mise au point sur les méthodes de synchronisation respiratoires disponibles en radiothérapie mammaire, pour minimiser l'impact des mouvements respiratoires et épargner les organes de proximité, comme le cœur et les poumons.Adjuvant radiation therapy following breast cancer surgery continues to improve locoregional control and overall survival. But the success of highly targeted-conformal radiotherapy such as intensity-modulated techniques, can be compromised by respiratory motion. The intrafraction motion can potentially result in significant under- or overdose, and also expose organs at risk. This article summarizes the respiratory motion and its effects on imaging, dose calculation and dose delivery by radiotherapy for breast cancer. We will review the methods of respiratory synchronization available for breast radiotherapy to minimize the respiratory impact and to spare organs such as heart and lung.



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Superior Therapeutic Index in Lymphoma Therapy: CD30+ CD34+ Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-cell Attack

Superior Therapeutic Index in Lymphoma Therapy: CD30+ CD34+ Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-cell Attack

Molecular Therapy 24, 1423 (August 2016). doi:10.1038/mt.2016.82

Authors: Andreas A Hombach, André Görgens, Markus Chmielewski, Florian Murke, Janine Kimpel, Bernd Giebel & Hinrich Abken

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