Immune system marker may improve bone marrow transplant outcomes

St. Jude Children’s Research Hospital investigators prove that an immune marker predicts transplant success and improves selection of bone marrow donors.

The risk of death following bone marrow transplantation can be reduced about 60 percent using a new technique to identify bone marrow donors who make the most potent cancer-fighting immune cells, according to research from St. Jude Children’s Research Hospital. The findings appear in the September 16 online issue of the Journal of Clinical Oncology.

The research builds on an earlier St. Jude discovery that specialized immune cells called natural killer (NK) cells dispatched cancer cells more efficiently when the NK cells carried a particular version of a KIR protein on their surface. KIR is short for killer-cell immunoglobulin-like receptor. KIR proteins regulate NK cells.

For this study, researchers reviewed the outcomes of the 313 bone marrow transplants performed at St. Jude during the decade ending in January 2010. Investigators found that patients were far more likely to have survived the transplant and far less likely to have their disease progress if their new bone marrow came from donors whose NK cells included the same version of the protein, rather than the alternative form.

A test developed at St. Jude Children’s Research Hospital is linked to a 60 percent reduced risk of death following bone marrow transplantation and a 62 percent reduced risk of disease progression.
Credit: Joshua Stokes, St. Jude Children’s Research Hospital

“This approach should dramatically improve the outcome for patients undergoing bone marrow transplantation, regardless of their age or underlying condition,” said Wing Leung, M.D., Ph.D., the paper’s corresponding author and chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “NK cells also play an important role in autoimmune disorders, chronic infections and other conditions, so these results will likely have an impact beyond cancer.”

Transplant patients benefited regardless of their disease, previous treatment, completeness of the genetic match or other donor characteristics, including whether the donor was a relative, Leung said. Screening for the NK cell variation uses blood collected for the current donor screening process and will not slow donor selection.

NK cells account for less than 15 percent of white blood cells, but play a major role in defending against cancer and viral infections. This research focused on a protein named KIR2DL1, which belongs to the KIR family of proteins. The KIR2DL1 protein is found on NK cells of nearly all healthy individuals.

Proteins are made up of long chains of amino acids. Due to natural genetic variation, there are 25 versions of KIR2DL1, each with a slightly different amino acid sequence.

In an earlier study, Leung and his colleagues discovered that NK cells with one of the KIR2DL1 variations killed cancer cells growing in the laboratory more efficiently than NK cells with a different version of the protein. The potent NK cells featured the amino acid arginine at position 245 of KIR2DL1 rather than the amino acid cysteine in that spot. That discovery led to this study, which offers the first proof that the amino acid difference impacts patient outcomes.

The new screening approach developed by St. Jude involves identifying donors who make the most potent version of specialized immune cells called natural killer (NK) cells. Illustrated is an NK cell destroying a cancer cell.
Credit: Joshua Stokes, St. Jude Children’s Research Hospital

Researchers checked the outcomes of all bone marrow transplants performed at St. Jude during the 10-year period. They found that donor bone marrow with two copies of the gene for the arginine 245 version of KIR2DL1 was associated with a 60 percent decreased risk of death following transplantation and a 62 percent reduced risk of disease progression compared to transplants with donor bone marrow that carried instructions for making just the cysteine version. The transplants involved patients battling both acute lymphoblastic and acute myeloid leukemia as well as other conditions.

St. Jude has patented and licensed a test to identify potential donors with the preferred amino acid. The goal is to make the screening test widely available to other transplant centers as soon as possible, officials said.

Bari et al., (2013). Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncology., EPub Ahead of Print, doi: 10.1200/JCO.2012.47.4007 [Abstract]


Unfounded fear prompts young breast cancer patients to remove healthy breasts

Despite evidence that contralateral prophylactic mastectomy (CPM) does not improve survival rates, an increasing number of young women with breast cancer elect to remove their healthy breast to avoid recurrence and improve survival.

Researchers surveyed 123 women aged 40 or younger without known bilateral breast cancer who reported having bilateral mastectomy. The purpose of the survey was to better understand how women approach the decision to have CPM. The survey included questions about the women’s health history, reason for choosing CPM, and knowledge and perceptions about breast cancer.

Most of the women (n = 97) had stage I or stage II breast cancer and 60 percent of tumors were estrogen receptor-positive. Almost all (98 percent) of the women surveyed indicated that desires to decrease their risk for contralateral breast cancer (CBC) prompted their decision to remove the healthy breast. Although 94 percent of the women surveyed said they chose bilateral mastectomy to increase survival, only 18 percent reported thinking that CPM improved survival rates.

Almost all of the women surveyed overestimated the actual risk of CBC. While physicians were identified as the most important sources of information about breast cancer, only one-third of the women cited a desire to follow a physician’s recommendations as an extremely or very important factor in their decision.

The authors suggest that this survey underscores a need for better risk communication strategies that help patients make decisions based on evidence.

Rosenberg et al., (2013). Perceptions, Knowledge, and Satisfaction With Contralateral Prophylactic Mastectomy Among Young Women With Breast Cancer. A Cross-sectional Survey. Ann. Intern. Med.159: 373-381. doi:10.7326/0003-4819-159-6-201309170-00003 [Article]

Microencapsulation produces uniform drug release vehicle

Consistently uniform, easily manufactured microcapsules containing a brain cancer drug may simplify treatment and provide more tightly controlled therapy, according to Penn State researchers.

“Brain tumors are one of the world’s deadliest diseases,” said Mohammad Reza Abidian, assistant professor of bioengineering, chemical engineering and materials science and engineering. “Typically doctors resect the tumors, do radiation therapy and then chemotherapy.”

The majority of chemotherapy is done intravenously, but, because the drugs are very toxic and are not targeted, they have a lot of side effects. Another problem with intravenous drugs is that they go everywhere in the bloodstream and do not easily cross the blood brain barrier so little gets to the target tumors. To counteract this, high doses are necessary.

Perfect microspheres were produced using 4 percent by weight of the polymer.
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Current treatment already includes leaving wafers infused with the anti-tumor agent BCNU in the brain after surgery, but when the drugs in these wafers run out, repeating invasive placement is not generally recommended.“We are trying to develop a new method of drug delivery,” said Abidian. “Not intravenous delivery, but localized directly into the tumor site.”

“BCNU has a half life in the body of 15 minutes,” said Abidian. “The drug needs protection because of the short half life. Encapsulation inside biodegradable polymers can solve that problem.”

Encapsulation of BCNU in microspheres has been tried before, but the resulting product did not have uniform size and drug distribution or high drug-encapsulation efficiency. With uniform spheres, manufacturers can design the microcapsules to precisely control the time of drug release by altering polymer composition. The tiny spheres are also injectable through the skull, obviating the need for more surgery.

Microfibers were produced using 10 percent by weight solutions of the polymer.
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Abidian, working with Pouria Fattahi, graduate student in bioengineering and chemical engineering, and Ali Borhan, professor of chemical engineering, looked at using an electrojetting technique to encapsulate BCNU in poly(lactic-co-glycolic) acid, an FDA-approved biodegradable polymer. In electrojetting, a solution containing the polymer, drug and a solvent are rapidly ejected through a tiny nozzle with the system under a voltage as high as 20 kilovolts but with only microamperage. The solvent in the liquid quickly evaporates leaving behind anything from a perfect sphere to a fiber.

“Electrojetting is a low cost, versatile approach,” said Abidian. “We can produce drug-loaded micro/nano-spheres and fibers with same size, high drug-loading capacity and high drug-encapsulation efficiency.”

The researchers tested solutions of polymer from 1 percent by weight to 10 percent by weight and found that at 1 to 2 percent they obtained flattened microspheres, at 3 to 4 percent they had microspheres, at 4 to 6 percent they had microspheres and microfibers, at 7 to 8 percent they had beaded microfibers and above 8 percent they obtained only fibers. They report their results in the current issue of Advanced Materials.

This is a scanning electron micrograph of BCNU-loaded microspheres (black and white background) with 3D rendered images of brain cancers cells (yellow) and released BCNU (purple).
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The researchers also investigated the sphericality of the spheres.“Depending on the desired applications, all the shapes are useful except for the beaded fibers,” said Abidian. “While fibers are not good for drug delivery, they are good for tissue engineering applications.”

“We looked at how spherical they were and found they were perfect,” said Abidian. They have a height versus width ratio of 1.05 and they have size uniformity. A perfect sphere would have a ratio of 1.

The researchers also looked into how BCNU releases from the microcapsules. Using mathematics, the researchers established a drug diffusion coefficient for the encapsulation system. This helps in designing how much drug to include in each microcapsule and how long the microcapsules will deliver the required dosage.

The researchers note that BCNU is not the only drug that can be encapsulated in polymer beads for drug delivery. Other drugs can be used but would have their own diffusion coefficients and half lifes.

Fattahi et al., (2013). Microencapsulation: Microencapsulation of chemotherapeutics into monodisperse and tunable biodegradable polymers via electrified liquid jets: Control of size, shape, and drug release.Adv. Mater., 25: 4529 [Abstract]

When things are at their worst, Christianity is intensely enacted

A new University of Copenhagen PhD thesis has taken a look at faith as practised in the daily lives of Danish cancer survivors. The thesis shows that Christian beliefs play a significant role in the lives of people suffering from cancer, and that their faith is often displayed in ways that challenge common perceptions of what Christianity is.

“My results show that people’s individual Christian faith becomes present during times of personal crisis. Faith and hope manifest themselves very intensely, but it is rare that they show in the classical forms we normally associate with Christianity. Rather than a single and static set of beliefs, everyday Christianity constantly unfolds in multiple ways and in relation to others,” says Christine Tind Johannessen-Henry, a PhD fellow at the University of Copenhagen’s Department of Theology.

Connections between faith and cancer

Christine Tind Johannessen-Henry carried out her research in collaboration with the Danish Cancer Society Research Center, as part of a cross-disciplinary project involving theology and health sciences. The research involved a questionnaire study of 1,043 people who have survived cancer; 20 of these survivors were also involved in an interview study with participant observation.

“The results of the study show that the deeper the crisis people find themselves in, the higher the level of validation of their various forms of faith and beliefs in God, while they also experience a greater will to live and more vibrant sense of being. The diverse forms of beliefs and hopes are enacted tightly interwoven with situations of confusion, anxiety and joy, all of which emerge as individual pass through diagnosis, chemotherapy, surgery and sequelae. These types of situations manifest in the bodies of the survivors, and continue to affect the individual for long periods of time,” says Christine Tind Johannessen-Henry.

Faith is belief in action

The research, Johannessen-Henry says, found that those participating in the study perform their faith in multiple ways. Denmark is often characterised as a very secular society, which builds on Christian values. The study results show that participants believe in Christian doctrine such as ‘God’ (59%), ‘A loving God’ (55%), ‘A forgiving God’ (49%), ‘Christ’ (51%) and ‘life after death’, in the sense that “the impact someone has had on the lives of others will continue to live on in their hearts after they die” (87%). People’s individual faith, however, shows through more than just utterances which can be determined by “yes” and “no”, but shows through the survivors’ different practices.

“Faith is how we ‘enact’ our beliefs – what we do when we find ourselves in any given situation and must deal with it. One example is when a cancer survivor gives a gift to a relative with the intention that will keep them related after the survivor passes away. Another is when we tell our children that God, angels or deceased family members will take care of them – or even speak to those who we believe will watch over our loved ones – we are, in effect, creating, sharing, giving and receiving faith as a part of a congregation. The images and metaphors we use and use to cope with difficult situations elucidate that Christianity always unfolds in relations and through the life situation of the believer. In this sense Christianity constantly develops, moves and renews and new spaces of faith is created” Johannessen-Henry says.

The relation between dogmatic and everyday Christianity

In her PhD thesis, Johannessen-Henry emphasises the difference between Christianity that is dogmatically practice in theology and Church rituals, and Christianity that people live in their daily lives. These different  “Christianities” repeatedly connect and link together, however. The project’s research shows that an individual’s faith constantly moves between ideas from Christian tradition and all sorts of non-Christian elements. According to Johannessen-Henry, these network of faith practises offer an understanding of how a doctrine such as “resurrection” is enacted in everyday life.

“Even though people suffering from cancer hold beliefs that might not be specifically Christian – for example ‘rebirth’ in other and very different versions – the mosaic of the Danish participants faith does incorporate pieces of Christianity – ‘God as loving father’, ‘omnipotence’, ‘sacrifice’, ‘crucifixion’, ‘guiding stars’, ‘angels’ – that it is impossible to claim that it isn’t Christian either. The different elements are so tightly woven together that it is impossible to distil perceptions of a ‘real’ Christianity from the ‘manyfolded’ and diverse Christianity,” Johannessen-Henry says.

Christine Tind Johannessen-Henry defended her dissertation, “The Polydoxy of Everyday Christianity. An Empirical-Theological Study of Faith in the Context of Cancer”, Friday 23 August 2013.