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Month: October 2019

Hormone therapy has a bigger impact than chemotherapy on women’s quality of life

Posted on by Graziella Cara

Cellules cancéreuses. Expression de la protéine PML en rouge et du gène ZNF703 en vert dans des cellules de la lignée de cancer du sein MCF7. ©Inserm/Ginestier, Christophe

Analysis of the CANTO cohort published in the journal Annals of Oncology will upset received wisdom on the effects that hormone therapy and chemotherapy have on the quality of life in women with breast cancer. Contrary to the commonly held view, 2 years after diagnosis, hormone therapy, a highly effective breast cancer treatment worsens quality of life to a greater extent and for a longer time, especially in menopausal patients. The deleterious effects of chemotherapy are more transient. Given that current international guidelines recommend the prescription of hormone therapy for 5 to 10 years, it is important to offer treatment to women who develop severe symptoms due to hormone antagonist medication and to identify those who might benefit from less prolonged or intensive treatment strategies.   

This work was directed by Dr Inès Vaz-Luis, specialist breast cancer oncologist and researcher at Gustave Roussy in the lab “Predictive Biomarkers and Novel Therapeutic Strategies in Oncology” (Inserm/Université Paris-Sud/Gustave Roussy).  

“This analysis of the CANTO cohort shows for the first time that anti-hormonal treatments do not have lesser effects than chemotherapy on women’s quality of life. Quite the contrary, as the diminution in quality of life which is noted at diagnosis is still present two years later, whereas the impact of chemotherapy is more temporary,” explained Dr Vaz-Luis.

In this study, researchers measured quality of life in 4,262 patients with localised breast cancer (stage I to III) at the time of diagnosis and at one and two years thereafter. Primary treatment for these patients was surgical and, for some of them, administration of chemotherapy and/or radiotherapy. About 75-80% of them then took hormone therapy for at least 5 years. Quality of life was measured using a tool which assesses general quality of life in patients with all types of cancer (EORTC QLQ-C30) combined with a tool more specifically designed for use in breast cancer (QLQ-BR23).

For the population studied as a whole there was an overall deterioration in the quality of life at two years from diagnosis. This deterioration was greater in patients who had received hormone therapy, especially after the menopause. By contrast, chemotherapy had a bigger effect on quality of life in non-menopausal patients, especially in terms of worsening of cognitive functions.  

“It is important in the future that we are able to predict which women are going to develop severe symptoms with anti-hormonal treatment so that we can support them,” added Dr Vaz-Luis. While it has been shown that hormone therapy provides a real benefit in reducing the relapse rate of hormone-dependent cancers[1] which represent 75% of all breast cancers, the deterioration in quality of life may also have a negative effect on patient adherence to treatment. It is, therefore, important to offer them symptomatic treatment, in particular for menopausal symptoms, musculoskeletal pain, depression, severe fatigue and cognitive dysfunction; and to combine this with supportive measures such as physical exercise and cognitive behaviour therapy.

“It will also be important in the future to differentiate prior to treatment patients who are at high risk of relapse from those at lower risk in order to tailor hormone treatment. This may be done to avoid escalation of anti-hormonal treatment in certain patients,” concluded Dr Vaz-Luis, emphasising that “hormone therapy is extremely effective in treating breast cancer, resulting in a reduction by approximately 50% in the risk of relapse, and that the finding of adverse effects does not in any way put into question the excellent risk/benefit ratio of this treatment.”

The CANTO cohort (CANcer TOxicities) comprises 12,000 women with breast cancer treated in 26 French centres. It is sponsored by Unicancer and directed by Professor Fabrice André, specialist breast cancer oncologist at Gustave Roussy, Inserm research director and responsible of the lab “Predictive Biomarkers and Novel Therapeutic Strategies in Oncology” (Inserm/Université Paris-Sud/Gustave Roussy). Its objective is to describe adverse effects associated with treatment, to identify the populations at risk of developing them and to adjust therapy accordingly, so as to afford a better quality of life following cancer.

Watch the video on YouTube :

This research was supported by the French National Research Agency (ANR), the Susan G. Komen Association, the Foundation for Cancer Research (ARC), Odyssea and the Gustave Roussy Foundation.

 

[1] [1] J Clin Oncol. 2019 Feb 10;37(5):423-438 : https://doi.org/10.1200/JCO.18.01160https://doi.org/10.1200/JCO.18.01160

Atopic dermatitis: how allergens get on our nerves

Posted on by Léa Surugue

Mast cells and sensory neurons cluster in “bunches” under the skin. ©Nicolas Gaudenzio

Atopic dermatitis, or eczema, primarily affects infants and children, and manifests itself in hypersensitivity to allergens in the environment. A skin disease characterized by flare-ups, it is often treated with topical anti-inflammatories. A new study led by Inserm researcher Nicolas Gaudenzio, from the Epithelial Differentiation and Rheumatoid Autoimmunity Unit (UDEAR – Inserm / UT3 Paul Sabatier), in collaboration with his colleagues at Stanford University (United States) shows that immune cells and sensory neurons interact in the skin to form units that can detect allergens and trigger inflammation. A discovery that provides an insight into how atopic dermatitis works, and points the way to new therapeutic possibilities. Their findings have now been published in the journal Nature Immunology.

Dry skin, pain, and itching… Atopic dermatitis affects the everyday lives of nearly 20% of children, and up to 5% of adults. The condition can have a significant impact on the quality of life of these patients.

Several studies have shown that genetic factors are involved in the development of this chronic inflammatory skin disease, and suggest that they result in impairment of the skin barrier. This enables the allergens present in the environment, from pollen to dust mites, to penetrate the dermis and stimulate the immune system, which reacts abnormally to this “threat” by triggering eczema.

However, the mechanisms of hypersensitivity to allergens and immune system hyperactivity in patients with atopic dermatitis are not yet fully understood. Led by Inserm researcher Nicolas Gaudenzio, the young “IMMCEPTION” group studies the way in which the immune system interacts with sensory neurons to regulate inflammatory processes in atopic dermatitis.

In particular, the researchers have taken a lead from existing clinical data which show that patients with this disease have numerous neuropeptides in their blood: chemical messengers that carry nerve messages, and whose level is correlated to disease severity. Identification of these neuropeptides in the blood indicates activation of the sensory neurons. These patients also have a number of enzymes in the blood indicating the presence of mast cells. Mast cells are immune cells present in the skin that play an essential role in modulating inflammatory and allergic processes.

Based on these observations, Gaudenzio and his team decided to focus on the interaction between sensory neurons and mast cells, and have now published their findings in the scientific journal Nature Immunology.

The researchers studied animal models of atopic dermatitis. Under the skin of mice showing signs of inflammatory reactions, they observed mast cells and sensory neurons clustering together in “sensory neuroimmune units” not dissimilar in form to a bunch of grapes. “The mast cells and neurons cling together in the dermis. We don’t yet understand the molecular interactions that bind them together, but we have quantified the distances between them, which are tiny,” highlights Gaudenzio.

The researchers then showed that when the mice were exposed to dust mites, these “sensory neuroimmune units” were able to detect the presence of these allergens, triggering allergic inflammation.

In the longer term, this discovery could have practical therapeutic implications.  “Until now, patients could be treated with biological treatments (biological therapy), but these obviously treat the disease further down the line, after flare-ups have occurred. We believe we have put our finger on a trigger mechanism and now want to continue our research to identify new molecules that could block interactions between mast cells and sensory neurons, and thus have a beneficial therapeutic effect for patients,” explains the researcher.

To do so, the group will first need to characterize the molecular interactions within these units in more detail, and analyze the role they play in modulating the immune system.

“One of the questions we are now going to try and answer is what these mast cell-sensory neuron units are for. They must represent a defense mechanism for the body, since they are also found in healthy individuals. But it could be that they don’t work properly in people who have atopic dermatitis—that’s what we’re trying to understand,” concludes Gaudenzio.

This study was funded by the European Research Council (ERC).

Nobel prize 2019

Posted on by Priscille Rivière

Only available in french

Dysentery: Shigella, bacteria with adaptation to respiration

Posted on by Lea Roy

Imagerie montrant la déplétion de l'oxygène au sein de la muqueuse intestinale par Shigella (vert), induisant une hypoxie (rouge) au sein des foyers infectieux inflammatoires (neutrophiles: marqués à l'aide du Myelotracker, bleu).

Déplétion de l’oxygène au sein de la muqueuse intestinale par Shigella (vert), induisant une hypoxie (rouge) au sein des foyers infectieux inflammatoires (neutrophiles: marqués à l’aide du Myelotracker, bleu). ©Benoit Marteyn/ Inserm/ Institut Pasteur

Bacillary dysentery caused by the intestinal bacteria Shigella is a major health problem in tropical regions and developing countries. Complications from this infection lead to several hundred thousand deaths a year, primarily among infants. Researchers from Inserm and the Institut Pasteur have studied the mechanisms of Shigella virulence. They found that these bacteria are not only able to consume the oxygen in colonic tissue in order to grow and create foci of infection, but can also adapt their mode of respiration so that they can continue to grow once the oxygen in these foci has been used up. These findings, published in Nature Microbiology, open up new prospects for the development of antibiotics and vaccines to combat this group of bacteria, which is on the WHO list of 12 priority pathogens.

Shigella is a group of pathogenic enterobacteria (bacteria found in the digestive tract) that cause bacillary dysentery, which is also known as shigellosis. They are transmitted via the fecal-oral route, for example through food or water contaminated with fecal matter, and are thus primarily endemic in tropical regions, particularly in developing countries where a lack of hygiene and healthcare infrastructure favor outbreaks of disease. After ingestion, Shigella bacteria invade the cells of the intestinal wall and then the colonic mucosa, causing major inflammation combined with severe tissue damage. This causes symptoms such as abdominal pain, vomiting, diarrhea containing blood or mucus, and fever.

With no commercialized vaccine (the infection is currently treated with antibiotics), shigellosis remains a major public health problem, and results in 700,000 deaths per year around the world—primarily among children under the age of 5—from acute complications.

The emergence of new multi-drug resistant strains of Shigella has prompted inclusion of the bacteria on the WHO list of 12 “priority pathogens” for which new treatments (vaccines or antibiotics) are urgently needed.

With this in mind, a team led by Inserm researcher Benoit Marteyn within Unit 1202, “Molecular Microbial Pathogenesis” (Institut Pasteur/Inserm), sought to better understand the mechanism used by Shigella to infect tissue by modulating the levels of oxygen present. To do this, the researchers used innovative image analysis methods developed by the Imagopole at the Institut Pasteur, which allowed them to study each cell individually (single-cell analysis) and monitor variation in the levels of oxygen O2 in intestinal tissues around isolated bacteria and in foci of infection, where bacteria are numerous.

The research group also found that foci of Shigella infection had abnormally low levels of oxygen (hypoxia). The denser the population of bacteria, the greater the consumption of O2. Hypoxia was not, however, seen around isolated bacteria away from the foci of infection.

Shigella bacteria are “facultative anaerobes,” which means that while they favor aerobic respiration (which uses O2 as fuel), if oxygen is lacking they can also switch to “anaerobic” respiration, which does not require O2. This characteristic enables them to continue to grow in hypoxic, or even anoxic (O2-depleted) foci after they have consumed all the oxygen in the tissues.

The researchers have thus shown that aerobic respiration of Shigella and their capacity to modulate the oxygenation of infected tissues enables the formation of hypoxic foci of infection within the intestinal mucosa, which constitutes the first stage in their colonization strategy, with over 99% of the bacterial population growing in these areas. When these foci are depleted of oxygen, the adaptability of the bacteria to O2-poor environments gives them a crucial advantage that explains their virulence and that of other facultative anaerobic enterobacteria.

“These findings are very important in relation to the search for new antibiotics and candidate vaccines to combat Shigella infection. Their mechanisms of action will need to be confirmed in hypoxic or even anoxic conditions, to reflect the pathophysiological conditions in which Shigella primarily grow within the colonic mucosa,” concludes Benoit Marteyn.

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