Développement et pré-test d’un plan de soins de suivi pour des femmes atteintes du cancer de l’endomètre avec traitements adjuvants lors de la transition de la fin du traitement actif vers la survie au cancer

La fin du traitement actif et le début de la phase de survie correspondent à une période de transition qui présente de nombreux défis pour la personne survivante au cancer, les soignants et le système de santé. La phase de survie au cancer est une phase distincte mais négligée du continuum de soins. Pour faciliter la transition de la fin du traitement actif vers la survie et optimiser la coordination des soins de suivi, la mise en place d’un plan de soins de suivi (PSS) est proposée. Le but de cette recherche est de développer, de mettre en place et d’évaluer si un plan de soins de suivi (PSS) permet de répondre aux besoins globaux, de diminuer la détresse émotionnelle et de favoriser les comportements d’autogestion de santé de femmes atteintes du cancer de l’endomètre (FACE) lors de la transition de la fin du traitement actif vers la survie au cancer. Elle comprend deux phases distinctes. La première phase visait d’abord le développement d’un plan de soins de suivi (PSS) pour des femmes atteintes du cancer de l’endomètre avec traitements adjuvants. La sélection du contenu du PSS a été faite à partir de la recension des écrits et des données recueillies lors d’entrevues individuelles avec 19 FACE, 24 professionnels de la santé travaillant avec cette clientèle et quatre gestionnaires de proximité en oncologie. Cette première phase avait également pour but la validation du contenu du PSS auprès de dix professionnels de la santé impliqués dans l’étude. La seconde phase consistait à évaluer la faisabilité, l’acceptabilité du PSS et à en pré-tester l’utilité à répondre aux besoins globaux, à diminuer la détresse émotionnelle (peur de la récidive) et à favoriser l’autogestion de santé auprès d’un groupe de 18 femmes atteintes du cancer de l’endomètre avec traitements adjuvants à la fin du traitement actif vers la survie. Sur le plan de la faisabilité, les résultats suggèrent que la mise en place du PSS comporte des défis en termes de temps, de ressources et de coordination pour l’infirmière pivot en oncologie (IPO). Concernant l’acceptabilité du PSS, les FACE le perçoivent comme un outil d’information utile qui favorise la communication avec le médecin de famille ou d’autres professionnels de la santé. Les IPO soutiennent sa valeur ajoutée à la fin du traitement et soulignent que la discussion du contenu du PSS fait ressortir des éléments de surveillance et de suivi essentiels à prendre en compte pour la phase de survie et permet de mettre l’emphase sur l’autogestion de sa santé. Pour les médecins de famille, le PSS est un outil d’information pour les survivantes qui favorise la réassurance, la communication et la continuité des soins entre professionnels de la santé. Enfin, pour ce qui est de l’utilité du PSS à répondre aux besoins globaux, les résultats suggèrent que l’ensemble des besoins sont plus satisfaits trois mois après la fin des traitements pour le groupe ayant reçu un PSS. Bien que la peur de récidive du cancer (PRC) s’améliore au suivi de trois mois pour le groupe exposé au PSS, 55% des FACE conservent un score cliniquement significatif de 13 à la sous-échelle de sévérité de peur de récidive à la fin du traitement et 42% au suivi de trois mois. Les comportements d’autogestion de santé s’améliorent entre la fin du traitement et le suivi de trois mois pour le groupe exposé un PSS. Considérant ces résultats, la démarche soutient la pertinence de mettre en place un PSS à la fin du traitement actif pour les FACE pour répondre à des besoins d’information, favoriser la communication et la continuité des soins avec les professionnels de la santé et les comportements d’autogestion de santé dans la phase de survie. Cependant, des contraintes de temps, de ressources et de coordination doivent être prises en compte pour sa mise en place dans le milieu clinique. Mots-clés : Transition, fin du traitement actif, besoins, survie au cancer, plan de soins de suivi.

La place de la chimiothérapie dans le traitement du cancer broncho pulmonaire

Single agent chemotherapy of advanced lung cancer is still unsatisfactory. The most encouraging results have been obtained with high dose intermittent treatment with cyclophosphamide, methotrexate or adriamycin. Combination chemotherapy is probably more efficacious than single agent chemotherapy, especially in oat cell carcinoma. The best treatment schedules give a response rate of approximately 80%. The value of adjuvant chemotherapy is not yet established, but new controlled clinical trials are indicated considering the poor results achieved by surgery and radiotherapy.

Le blocage androgénique intermittent versus continu dans le traitement du cancer de la prostate

L’administration du blocage androgénique de façon intermittente pourrait offrir plusieurs avantages dans le traitement du cancer de la prostate. Toutefois, ce mode d’administration demeure controversé. Nous avons donc effectué une revue systématique et méta-analyse d’essais cliniques randomisés afin de comparer l’efficacité et la tolérabilité du blocage androgénique intermittent versus continu. Une analyse de non-infériorité a été effectuée pour la survie avec un seuil préétabli de 1,15 pour la borne supérieure de l’intervalle de confiance (IC). Au total, 15 études étaient éligibles. Le blocage androgénique intermittent était non inférieur au blocage androgénique continu avec un hazard ratio de 1,02 (IC à 95%: 0,93-1,11). Il y avait peu de différence entre les deux groupes pour la qualité de vie globale. Toutefois, plusieurs études ont rapporté une meilleure fonction physique et sexuelle avec le traitement intermittent. Le blocage androgénique intermittent est une alternative thérapeutique acceptable dans le cancer de la prostate.

Vitamine D et prévention du cancer colorectal associé à la colite ulcéreuse : modèles murins

Les patients atteints de maladies inflammatoires de l'intestin (MII) ont un risque accru de développer un cancer colorectal dû aux lésions épithéliales secondaires à l’inflammation chronique. La vitamine D (vD) régule NOD2, gène impliqué dans la réponse inflammatoire et dans la susceptibilité aux MII, et induit son expression dans les monocytes et dans l’épithélium intestinal. Dans ce projet, nous avons d’abord induit le cancer colorectal associé à la colite ulcéreuse (CAC) en administrant un traitement combiné d’azoxyméthane (AOM) et de dextran de sulfate de sodium (DSS) aux souris C57BL/6J. Par la suite, nous avons étudié l'effet d’une carence en vD3 sur le développement du CAC et évalué la capacité préventive d’une supplémentation en vD3 sur la tumorigenèse, et vérifié si cet effet est médié par NOD2, en utilisant les souris Nod2-/-. Les C57BL/6J et les Nod2-/-, ayant reçu une diète déficiente en vD3, étaient moins résistantes au CAC par rapport aux souris supplémentées. Le pourcentage de perte de poids, l’indice d’activation de la maladie (DAI), le taux de mortalité et le poids relatif du côlon (mg/cm) chez les souris déficientes en vD3 étaient plus élevés en comparaison avec celles supplémentées en vD3. Une augmentation du score d'inflammation et de la multiplicité tumorale corrélait avec une expression accentuée de l’Il6 dans les colonocytes des souris déficientes en vD3. La vD3 régulait l’expression génétique de Cyp24, Vdr et de gènes pro-inflammatoires chez les C57BL/6, comme chez les Nod2-/-. En conclusion, la supplémentation en vD3 peut prévenir le développement du CAC indépendamment de NOD2.

Vitamine D et prévention du cancer colorectal associé à la colite ulcéreuse : modèles murins

Les patients atteints de maladies inflammatoires de l'intestin (MII) ont un risque accru de développer un cancer colorectal dû aux lésions épithéliales secondaires à l’inflammation chronique. La vitamine D (vD) régule NOD2, gène impliqué dans la réponse inflammatoire et dans la susceptibilité aux MII, et induit son expression dans les monocytes et dans l’épithélium intestinal. Dans ce projet, nous avons d’abord induit le cancer colorectal associé à la colite ulcéreuse (CAC) en administrant un traitement combiné d’azoxyméthane (AOM) et de dextran de sulfate de sodium (DSS) aux souris C57BL/6J. Par la suite, nous avons étudié l'effet d’une carence en vD3 sur le développement du CAC et évalué la capacité préventive d’une supplémentation en vD3 sur la tumorigenèse, et vérifié si cet effet est médié par NOD2, en utilisant les souris Nod2-/-. Les C57BL/6J et les Nod2-/-, ayant reçu une diète déficiente en vD3, étaient moins résistantes au CAC par rapport aux souris supplémentées. Le pourcentage de perte de poids, l’indice d’activation de la maladie (DAI), le taux de mortalité et le poids relatif du côlon (mg/cm) chez les souris déficientes en vD3 étaient plus élevés en comparaison avec celles supplémentées en vD3. Une augmentation du score d'inflammation et de la multiplicité tumorale corrélait avec une expression accentuée de l’Il6 dans les colonocytes des souris déficientes en vD3. La vD3 régulait l’expression génétique de Cyp24, Vdr et de gènes pro-inflammatoires chez les C57BL/6, comme chez les Nod2-/-. En conclusion, la supplémentation en vD3 peut prévenir le développement du CAC indépendamment de NOD2.

CD151 is associated with prostate cancer cell invasion and lymphangiogenesis in vivo

CD151, a member of the tetraspanin family, is associated with regulation of migration of normal and tumour cells via cell surface microdomain formation. CD151 was found in our laboratory to have a prognostic value in prostate cancer and is a promoter of prostate cancer migration and invasion. These roles involve association with integrins on both cell-cell and cell-stroma levels. Furthermore, CD151 plays a role in endothelial cell motility. CD151 expression was examined in three commonly used prostate cancer cell lines. We investigated CD151 expression, angiogenesis (microvessel density; MVD) and lymphangiogenesis (lymphatic vessel density; LVD) in an orthotopic xenograft model of prostate cancer in matched tumours from primary and secondary sites. CD151 was found to be heterogeneously expressed across different prostate cancer cell lines and the levels of CD151 expression were significantly higher in the highly tumorigenic, androgen-insensitive cells PC-3 and DU-145 compared to the androgen-sensitive cell line LNCaP (P<0.05). The majority of in vivo xenografts developed pelvic lymph node metastases. Importantly, primary tumours that developed metastasis had significantly higher CD151 expression and MVD compared to those which did not develop metastasis (P<0.05). We identified, for the first time, that CD151 expression is associated with LVD in prostate cancer. These findings underscore the potential role of CD151 and angiogenesis in the metastatic potential of prostate cancer. CD151 has a prognostic value in this mouse model of prostate cancer and may play a role in lymphangiogenesis. CD151 is likely an important regulator of cancer cell communication with the surrounding microenvironment.

Integrated analysis of epigenomic and genomic changes by DNA methylation dependent mechanisms provides potential novel biomarkers for prostate cancer

Epigenetic silencing mediated by CpG methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with tumor progression may identify potential prognostic markers for prostate cancer (PCa). We treated two PCa cell lines, 22Rv1 and DU-145 with the demethylating agent 5-Aza 2’–deoxycitidine (DAC) and global methylation status was analyzed by performing methylation-sensitive restriction enzyme based differential methylation hybridization strategy followed by genome-wide CpG methylation array profiling. In addition, we examined gene expression changes using a custom microarray. Gene Set Enrichment Analysis (GSEA) identified the most significantly dysregulated pathways. In addition, we assessed methylation status of candidate genes that showed reduced CpG methylation and increased gene expression after DAC treatment, in Gleason score (GS) 8 vs. GS6 patients using three independent cohorts of patients; the publically available The Cancer Genome Atlas (TCGA) dataset, and two separate patient cohorts. Our analysis, by integrating methylation and gene expression in PCa cell lines, combined with patient tumor data, identified novel potential biomarkers for PCa patients. These markers may help elucidate the pathogenesis of PCa and represent potential prognostic markers for PCa patients.

The empire of cancer: Gene patents and cancer voices

In his book, The Emperor of All Maladies, Siddhartha Mukherjee writes a history of cancer — "It is a chronicle of an ancient disease — once a clandestine, 'whispered-about' illness — that has metamorphosed into a lethal shape-shifting entity imbued with such penetrating metaphorical, medical, scientific, and political potency that cancer is often described as the defining plague of our generation." Increasingly, an important theme in the history of cancer is the role of law, particularly in the field of intellectual property law. It is striking that a number of contemporary policy debates over intellectual property and public health have concerned cancer research, diagnosis, and treatment. In the area of access to essential medicines, there has been much debate over Novartis’ patent application in respect of Glivec, a treatment for leukaemia. India’s Supreme Court held that the Swiss company’s patent application violated a safeguard provision in India’s patent law designed to stop evergreening. In the field of tobacco control, the Australian Government introduced plain packaging for tobacco products in order to address the health burdens associated with the tobacco epidemic. This regime was successfully defended in the High Court of Australia. In the area of intellectual property and biotechnology, there have been significant disputes over the Utah biotechnology company Myriad Genetics and its patents in respect of genetic testing for BRCA1 and BRCA2, which are related to breast cancer and ovarian cancer. The Federal Court of Australia handed down a decision on the validity of Myriad Genetics’ patent in respect of genetic testing for BRCA1 in February 2013. The Supreme Court of the United States heard a challenge to the validity of Myriad Genetics’ patents in this area in April 2013, and handed down a judgment in July 2013. Such disputes have involved tensions between intellectual property rights, and public health. This article focuses upon one of these important test cases involving intellectual property, public health, and cancer research. In June 2010, Cancer Voices Australia and Yvonne D’Arcy brought an action in the Federal Court of Australia against the validity of a BRCA1 patent — held by Myriad Genetics Inc, the Centre de Recherche du Chul, the Cancer Institute of Japan and Genetic Technologies Limited. Yvonne D’Arcy — a Brisbane woman who has had treatment for breast cancer — maintained: "I believe that what they are doing is morally and ethically corrupt and that big companies should not control any parts of the human body." She observed: "For my daughter, I've had her have [sic] mammograms, etc, because of me but I would still like her to be able to have the test to see if the mutation gene is in there from me." The applicants made the following arguments: "Genes and the information represented by human gene sequences are products of nature universally present in each individual, and the information content of a human gene sequence is fixed. Genetic variations or mutations are products of nature. The isolation of the BRCA1 gene mutation from the human body constitutes no more than a medical or scientific discovery of a naturally occurring phenomenon and does not give rise to a patentable invention." The applicants also argued that "the alleged invention is not a patentable invention in that, so far as claimed in claims 1–3, it is not a manner of manufacture within the meaning of s 6 of the Statute of Monopolies". The applicants suggested that "the alleged invention is a mere discovery". Moreover, the applicants contended that "the alleged invention of each of claims 1-3 is not a patentable invention because they are claims for biological processes for the generation of human beings". The applicants, though, later dropped the argument that the patent claims related to biological processes for the generation of human beings. In February 2013, Nicholas J of the Federal Court of Australia considered the case brought by Cancer Voices Australia and Yvonne D’Arcy against Myriad Genetics. The judge presented the issues in the case, as follows: "The issue that arises in this case is of considerable importance. It relates to the patentability of genes, or gene sequences, and the practice of 'gene patenting'. Briefly stated, the issue to be decided is whether under the Patents Act 1990 (Cth) a valid patent may be granted for a claim that covers naturally occurring nucleic acid — either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) — that has been 'isolated'". In this context, the word "isolated" implies that naturally occurring nucleic acid found in the cells of the human body, whether it be DNA or RNA, has been removed from the cellular environment in which it naturally exists and separated from other cellular components also found there. The genes found in the human body are made of nucleic acid. The particular gene with which the patent in suit is concerned (BRCA1) is a human breast and ovarian cancer disposing gene. Various mutations that may be present in this gene have been linked to various forms of cancer including breast cancer and ovarian cancer.' The judge held in this particular case that Myriad Genetics’ patent claims were a "manner of manufacture" under s 6 of the Statute of Monopolies and s 18(1)(a) of the Patents Act 1990 (Cth). The matter is currently under appeal in the Full Court of the Federal Court of Australia. This article interprets the dispute over Myriad Genetics in light of the scholarly work of Nobel Laureate Professor Joseph Stiglitz on inequality. Such work has significant explanatory power in the context of intellectual property and biotechnology. First, Stiglitz has contended that "societal inequality was a result not just of the laws of economics, but also of how we shape the economy — through politics, including through almost every aspect of our legal system". Stiglitz is concerned that "our intellectual property regime … contributes needlessly to the gravest form of inequality." He maintains: "The right to life should not be contingent on the ability to pay." Second, Stiglitz worries that "some of the most iniquitous aspects of inequality creation within our economic system are a result of 'rent-seeking': profits, and inequality, generated by manipulating social or political conditions to get a larger share of the economic pie, rather than increasing the size of that pie". He observes that "the most iniquitous aspect of this wealth appropriation arises when the wealth that goes to the top comes at the expense of the bottom." Third, Stiglitz comments: "When the legal regime governing intellectual property rights is designed poorly, it facilitates rent-seeking" and "the result is that there is actually less innovation and more inequality." He is concerned that intellectual property regimes "create monopoly rents that impede access to health both create inequality and hamper growth more generally." Finally, Stiglitz has recommended: "Government-financed research, foundations, and the prize system … are alternatives, with major advantages, and without the inequality-increasing disadvantages of the current intellectual property rights system.’" This article provides a critical analysis of the Australian litigation and debate surrounding Myriad Genetics’ patents in respect of genetic testing for BRCA1. First, it considers the ruling of Nicholas J in the Federal Court of Australia that Myriad Genetics’ patent was a manner of manufacture as it related to an artificially created state of affairs, and not mere products of nature. Second, it examines the policy debate over gene patents in Australia, and its relevance to the litigation involving Myriad Genetics. Third, it examines comparative law, and contrasts the ruling by Nicholas J in the Federal Court of Australia with developments in the United States, Canada, and the European Union. Fourth, this piece considers the reaction to the decision of Nicholas at first instance in Australia. Fifth, the article assesses the prospects of an appeal to the Full Federal Court of Australia over the Myriad Genetics’ patents. Finally, this article observes that, whatever happens in respect of litigation against Myriad Genetics, there remains controversy over Genetic Technologies Limited. The Melbourne firm has been aggressively licensing and enforcing its related patents on non-coding DNA and genomic mapping.

Estramustine and its Derivatives in Potentiating Radiotherapy of Prostate Cancer

The purpose of this study was to deepen our knowledge of the combined use of estramustine and radiotherapy in the treatment of prostate cancer. Prostate cancer is a common disease, with a high variability between subjects in its malignant potential. In many cases, the disease is an incidental finding with little or no clinical significance. In other cases, however, prostate cancer may be an aggressive malignant disease, which, if the initial treatment fails, lacks an effective cure and may lead to severe symptoms, metastasis, and death despite all treatment. In many cases, the methods of treatment available at the moment provide cure or significant regression of symptoms, but often at the cost of considerable side effects. Estramustine, a cytostatic drug used for treating advanced cancer of the prostate, has been shown to inhibit prostate cancer progression and also to increase the sensitivity of cancer cells to radiotherapy. The goals of this study were, first, to find out whether it is possible to use either estramustine or an antibody against estramustine binding protein as carrier molecules for bringing therapeutic radioisotopes into prostate cancer cells, and, secondly, to gain more understanding of the mechanisms behind the known radiosensitising effect of estramustine. Estramustine and estramustine binding protein antibody were labelled with iodine-125 to study the biodistribution of these substances in mice. In the first experiment, both of the substances accumulated in the prostate, but radioiodinated estramustine also showed affinity to the liver and the lungs. Since the radiolabelled antibody was found out to accumulate more selectively to the prostate, we studied its biodistribution in nude mice with DU-145 human prostate cancer implants. In this experiment, the prostate and the tumour accumulated more radioactivity than other organs, but we concluded that the difference in the dose of radiation compared to other organs was not sufficient for the radioiodinated antibody to be advocated as a carrier molecule for treating prostate cancer. Mice with similar DU-145 prostate cancer implants were then treated with estramustine and external beam irradiation, with and without neoadjuvant estramustine treatment. The tumours responded to the treatment as expected, showing the radiation potentiating effect of estramustine. In the third experiment, this effect was found without an increase in the amount of apoptosis in the tumour cells, despite previous suggestions to the contrary. In the fourth experiment, we gave a similar treatment to the mice with DU-145 tumours. A reduction in proliferation was found in the groups treated with radiotherapy, and an increased amount of tumour hypoxia and tumour necrosis in the group treated with both neoadjuvant estramustine and radiation. This finding is contradictory to the suggestion that the radiation sensitising effect of estramustine could be attributed to its angiogenic activity.

Les facteurs de transcription du groupe PEA3: Régulateurs transcriptionnels dans le processus de cancérisation

Erm, Er81, and Pea3 are the three members of the PEA3 group which belong to the Ets transcription factors family. These proteins regulate transcription of multiple target genes, such as those encoding several matrix metalloproteinases (MMP), which are enzymes degrading the extracellular matrix during cancer metastasis. In fact, PEA3-group genes are often overexpressed in different types of human cancers that also over-express these MMP and display a disseminating phenotype. In experimental models, regulation of PEA3 group member expression has been shown to influence the metastatic process, thus suggesting that these factors play a key role in metastasis. © John Libbey Eurotext.

Role of Nitric Oxide-Signalling in Hypoxia-Induced Immune Escape in Cancer

A key step in malignant progression is the acquired ability of tumour cells to escape immune-mediated lysis. A potential mechanism by which tumour cells avoid immune destruction involves the shedding of MHC Class I Chain-Related Protein A (MICA), a Natural Killer (NK) cell-activating ligand, from the tumour cell membrane. Hypoxia has been shown to cause increased MICA shedding; however, this hypoxia-induced effect can be attenuated by pharmacological activation of the cyclic guanosine monophosphate (cGMP)-dependent nitric oxide (NO)-signalling pathway in cancer cells. The primary objective of the present study was to determine whether treatment of tumour-bearing nude mice with the NO-mimetic glyceryl trinitrate (GTN) attenuates in vivo tumour growth and if so, whether this effect is dependent on the presence of an intact NK cell compartment. Results indicated that continuous transdermal administration of GTN (1.8 µg/h) can significantly attenuate the growth of transplanted human DU-145 prostate tumours but that this effect of GTN is lost in mice whose NK-cells have been depleted. Tumours and serum from the mice in this study were analysed to determine whether GTN treatment had any effect on the expression levels of proteins integral to the proposed MICA shedding mechanism; however, the results of these studies were inconclusive. As phosphodiesterase (PDE) inhibition represents a potential method to enhance NO-signalling, experiments were performed to determine whether treatment with the PDE5/6 inhibitor zaprinast could also attenuate hypoxia-induced MICA shedding and decrease in vivo growth of DU-145 tumours. Results demonstrated that treatment with zaprinast (10 mg/kg) significantly attenuates MICA shedding in DU-145 cancer cells and significantly decreases in vivo tumour growth. Taken together, the results of these experiments indicate that GTN attenuates tumour growth by sensitising tumour cells to innate immunity, likely by increasing membrane-associated tumour cell MICA levels through the reactivation of NO-signalling, and that zaprinast decreases tumour growth likely through a similar mechanism. These findings are important because they indicate that agents capable of reactivating NO-signalling, such as NO-mimetics and PDE inhibitors, can potentially be used as immunosensitisers in the treatment and/or prevention of cancer.