̽��ֱ�� of Cambridge - Leukaemia and Lymphoma Research

Should breast implants come with a health warning?

cjb250 — Wed, 18 Mar 2015 17:40:54 +0000

“Breast implants to carry cancer warning” read the headline of an article on the MailOnline website today. This follows the outcome of a study by the French National Cancer Institute, which reported that there was “clearly a link” between breast implants and anaplastic large cell lymphoma, a relatively rare form of cancer of the immune system that usually affects children and young adults independently of breast implants.

This is the not the first health scare to surround breast implants in France: remember the “exploding” Poly Implant Prosthese (PIP) breast implants widely reported in 2010, which led to the company that manufacture them being closed down?

So, should women who have received a breast implant be concerned and should they consider having them removed?

I run an active research group at the Department of Pathology, ̽��ֱ�� of Cambridge. Last year, I co-led an independent study, funded by Leukaemia and Lymphoma Research, looking at the risks to women with breast implants of developing implant-associated anaplastic large cell lymphoma (iALCL). Our study, which was published last year in the scientific journal Mutation Research Reviews, was part of the evidence considered by the French National Cancer Institute when preparing its report.

In our study, we found 71 cases of iALCL worldwide: this means it is an extremely rare occurrence – for every three million breast implant procedures, we estimated that between one and six women would develop iALCL.

̽��ֱ��French study, which considered cases of iALCL diagnosed in France since 2011, found that of approximately 400,000 women with breast implants in France, 18 had been diagnosed with iALCL. This rate is clearly significantly higher than that found by our study – the reason why is not clear, though it may be due in part to better screening. ̽��ֱ��French National Cancer Institute suggests that this increasing incidence confirms a strong link between breast implants and cancer – as a consequence, some newspaper reports have suggested that the French government may even consider a ban on this cosmetic procedure in France.

Whether such drastic action is required will depend on future monitoring of these patients; of the 49 cases reported in our study where information on the patients’ progress was available, there were only five reported deaths. While some patients received chemotherapy and radiotherapy, for many women their lymphoma was put into remission simply through removal of the breast implant and surrounding tissue. This suggests that it is the body’s abnormal immune response to the implant that is causing the cancer. Chemotherapy did not appear to significantly increase a patient’s chances of survival.

So far, the incidence of iALCL has not been associated with any specific form of breast implant and there have been no links with the PIP prostheses, even though the first woman reported to die from this lymphoma in France was a carrier of a PIP implant.

On Tuesday, the French Minister of Social Affairs, Health and Women’s Rights, Marisol Touraine, called a press conference at which she sought to calm fears about the risks. According to the Mail, she said: “We do not recommend that women carrying these implants have them removed.” Instead, it has recommended that women remain vigilant for symptoms of iALCL, which include swelling of the breast sometimes associated with pain and ulceration and a general impaired condition around the breast containing the implant. If any of these symptoms are recognised, they should consult their GP for advice.

There are many reasons why women choose to have a breast implant. It’s not all about vanity, a desire for larger breasts, as unfairly characterised by much of the media. It can be about corrective surgery following breast cancer removal, increasing one’s self-image and confidence or correcting uneven breasts, for example.

I would like to see the UK establish a cancer registry to record and follow-up on all cases of iALCL in the future. There are still many unanswered questions and only by getting to the bottom of this very rare disease will we be able to find alternative ways to treat it. It’s becoming clear that having implants is not itself without risk, but the associated cancer risk is still extremely small. In the meantime, we need a measured debate: alarmist headlines do not help, but only serve to cause unnecessary anxiety.

Newspaper reports suggest that France may be considering health warnings – or even an outright ban – on breast implants, following a cancer scare. Should women be concerned? Dr Suzanne Turner from the Department of Pathology, ̽��ֱ�� of Cambridge, looks at the truth behind the headlines.

It’s becoming clear that having breast implants is not itself without risk, but the associated cancer risk is still extremely small

Suzanne Turner

National Cancer Institute/Linda Bartlett

Breast implant

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Order matters: sequence of genetic mutations determines how cancer behaves

cjb250 — Wed, 11 Feb 2015 22:00:00 +0000

Most of the genetic mutations that cause cancer result from environmental ‘damage’ (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors as cells divide. In a study published today, researchers at the Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show for the first time that the order in which such mutations occur can have an impact on disease severity and response to therapy.

̽��ֱ��researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems.

Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke’s Hospital, part of the Cambridge ̽��ֱ�� Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2.

Dr David Kent, one of the study’s lead authors, says: “This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.”

Professor Tony Green, who led the study, adds: “This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer.”

Work in the Green Lab is supported in part by Leukaemia and Lymphoma Research and Cancer Research UK.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: “We are becoming more and more aware that a cancer’s genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. ̽��ֱ��discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. ̽��ֱ��technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general.”

Dr Áine McCarthy, Science Information Officer at Cancer Research UK, says: “ ̽��ֱ��methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs – this insight could help doctors personalise treatment to make it more effective for each patient.”

Reference
Ortmann, CA and Kent, DG et al. ̽��ֱ��Impact of Mutation Order on Myeloproliferative Neoplasms. NEJM; 11 Feb 2015

Additional funding came from the Kay Kendall Leukaemia Fund; the NIHR Cambridge Biomedical Research Centre; the Cambridge Experimental Cancer Medicine Centre; the Leukemia & Lymphoma Society of America; the Canadian Institutes of Health Research; and the Lady Tata Memorial Trust.

̽��ֱ��order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the ̽��ֱ�� of Cambridge, published today in the New England Journal of Medicine.

This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy

Tony Green

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Red blood cells (illustration)

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Computer model of blood development could speed up search for new leukaemia drugs

cjb250 — Mon, 09 Feb 2015 16:00:00 +0000

̽��ֱ��human body produces over 2.5 million new blood cells during every second of our adult lives, but how this process is controlled remains poorly understood. Around 30,000 new patients each year are diagnosed with cancers of the blood each year in the UK alone. These cancers, which include leukaemia, lymphoma and myeloma, occur when the production of new blood cells gets out of balance, for example if the body produces an overabundance of white blood cells.

Biomedical scientists from the Wellcome Trust-MRC Cambridge Stem Cell Institute and the Cambridge Institute for Medical Research collaborated for the past 2 years with computational biologists at Microsoft Research and Cambridge ̽��ֱ��’s Department of Biochemistry. This interdisciplinary team of researchers have developed a computer model to help gain a better understanding of the control mechanisms that keep blood production normal. ̽��ֱ��details are published today in the journal Nature Biotechnology.

“With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory, dramatically speeding up research into blood development and the genetic mutations that cause leukaemia,” says Professor Bertie Gottgens whose research team is based at the ̽��ֱ��’s Cambridge Institute for Medical Research.

Dr Jasmin Fisher from Microsoft Research and the Department of Biochemistry at the ̽��ֱ�� of Cambridge says: “This is yet another endorsement of how computer programs empower us to gain better understanding of remarkably complicated processes. What is ground-breaking about the current work is that we show how we can automate the process of building such programs based on raw experimental data. It provides us with a blueprint to develop computer models relevant to other human diseases including common cancers such as breast and colon cancer.”

To construct the computer model, PhD student Vicki Moignard from the Stem Cell Institute measured the activity of 48 genes in over 3,900 blood progenitor cells that give rise to all other types of blood cell: red and white blood cells, and platelets. These genes include TAL1 and RUNX1, both of which are essential for the development of blood stem cells, and hence to human life.

Computational biology PhD student Steven Woodhouse then used the resulting dataset to construct the computer model of blood cell development, using computational approaches originally developed at Microsoft Research for synthesis of computer code. Importantly, subsequent laboratory experiments validated the accuracy of this new computer model.

One way the computer model can be used is to simulate the activity of key genes implicated in blood cancers. For example, around one in five of all children who develop leukaemia has a faulty version of the gene RUNX1, as does a similar proportion of adults with acute myeloid leukaemia, one of the most deadly forms of leukaemia in adults. ̽��ֱ��computer model shows how RUNX1 interacts with other genes to control blood cell development: the gene produces a protein also known as Runx1, which in healthy patients activates a particular network of key genes; in patients with leukaemia, an altered form of the protein is thought to suppress this same network. If the researchers change the ‘rules’ in the network model, they can simulate the formation of abnormal leukaemia cells. By tweaking the leukaemia model until the behaviour of the network reverts back to normal, the researchers believe they can identify promising pathways to target with drugs.

Professor Gottgens adds: “Because the computer simulations are very fast, we can quickly screen through lots of possibilities to pick the most promising ones as pathways for drug development. ̽��ֱ��cost of developing a new drug is enormous, and much of this cost comes from new candidate drugs failing late in the drug development process. Our model could significantly reduce the risk of failure, with the potential to make drug discovery faster and cheaper.”

̽��ֱ��research was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, Leukaemia and Lymphoma Research, the Leukemia and Lymphoma Society, Microsoft Research and the Wellcome Trust.

Dr Matt Kaiser, Head of Research at UK blood cancer charity Leukaemia & Lymphoma Research, which has funded Professor Gottgens’ team for over a decade, said: “For some leukaemias, the majority of patients still ultimately die from their disease. Even for blood cancers for which the long-term survival chances are fairly good, such as childhood leukaemia, the treatment can be really gruelling. By harnessing the power of cutting-edge computer technology, this research will dramatically speed up the search for more effective and kinder treatments that target these cancers at their roots.”

Reference
Moignard, V et al. Decoding the regulatory network of early blood development from single-cell gene expression measurements. Nature Biotech; 9 Feb 2015.

̽��ֱ��first comprehensive computer model to simulate the development of blood cells could help in the development of new treatments for leukaemia and lymphoma, say researchers at the ̽��ֱ�� of Cambridge and Microsoft Research.

With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory

Bertie Gottgens

E. M. Unit, Royal Free Hospital

SEM image of normal red blood cells, computer-coloured red

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Researchers discover new test for chronic blood cancers

sj387 — Tue, 10 Dec 2013 15:27:54 +0000

A simple blood test will soon be able to catch the vast majority of a group of chronic blood cancers, a new study reveals. Although around 60 per cent of cases can be identified with the current blood test, scientists did not know what caused the other cases and therefore could not test for it. Cambridge researchers have now identified a new cancer gene which accounts for the other 40 per cent of these chronic blood cancers. ̽��ֱ��research was published today, 10 December, in the New England Journal of Medicine.

Professor Tony Green, from the ̽��ֱ�� of Cambridge’s Cambridge Institute for Medical Research and Department of Haematology, who led the research said: “Diagnosing these chronic blood cancers is currently difficult and requires multiple tests, some of which are invasive and painful. Now, most patients with a suspected blood cancer will be able to be given a diagnosis after a simple blood test.”

This group of chronic blood cancers – which affect an estimated 30,000 people annually in the UK – cause the over-production of red blood cells and platelets. These changes result in an increased incidence of blood clots which can be devastating when strokes or heart attacks occur. Although many patients can live for years with few or no symptoms, in some patients the disorders can become more aggressive with time and may even develop into acute leukaemia.

In 2005 scientists identified the JAK2 gene, mutationt in which are associated with around 60 per cent of blood cell disorders. Based on these findings a blood test was developed which transformed the way these blood disorders are diagnosed. Unfortunately, because the gene was only found in a little over half of people with chronic blood cancers, individuals who tested negative for the JAK2 gene would then have to undergo a battery of protracted, invasive testing to determine if they indeed had one of these disorders.

In the new study, led by the ̽��ֱ�� of Cambridge and the Wellcome Trust Sanger Institute and supported by Leukaemia & Lymphoma Research together with the Kay Kendall Leukaemia Fund, scientists identified a new gene, CALR, which is altered in the other 40 per cent of blood disorders. For the research, the scientists sequenced the DNA of patients with chronic blood disorders. By analysing the DNA sequence, they were able to identify CALR as a new cancer gene which, when mutated, results in chronic blood cancers. Additionally, they found that patients with the CALR mutation – unlike those with the JAK2 mutation – had higher platelet counts and lower haemoglobin levels.

Peter Campbell from the Sanger Institute, who co-led the research, said: “There is now a sense of completeness with these disorders – the vast majority of our patients can now have a definitive genetic diagnosis made. In the next year or two, we will see these genetic technologies increasingly used in the diagnosis of all cancers, especially blood cancers.”

Dr Jyoti Nangalia co-first author of the study from the ̽��ֱ�� of Cambridge said: “Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments – just as the discovery of JAK2 did. ̽��ֱ��CALR gene is involved in a cell function – aiding with the folding of proteins made by the cell - which has not implicated in these disorders before, so our research raises as many questions as it answers.”

A new test for blood cancers will catch many more cases than the present test that identifies only 60 per cent.

Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments

Dr Jyoti Nangalia

Nephron

Micrograph of a plasmacytoma, a hematological malignancy

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