Stem cell sparing radiotherapy for head and neck cancer may avoid salivary gland damage

Public release date: 9-May-2012 [ | E-mail | Share ]

Contact: Emma Mason wordmason@mac.om European Society for Radiotherapy and Oncology (ESTRO)

Barcelona, Spain: Researchers believe they may have found a way to avoid damaging salivary glands during radiotherapy treatment for head and neck cancer a discovery that could improve the quality of life of 500,000 patients a year worldwide with the disease.

Presenting their findings to the 31st conference of the European Society for Radiotherapy and Oncology (ESTRO31) [1], the researchers said that they had discovered that the stem cells essential for regenerating the parotid gland (the largest pair of salivary glands) were located mainly in its major ducts, and that these could easily be avoided during radiotherapy or given a minimal radiation dose. "This would significantly reduce complications arising from radiotherapy for head and neck cancer," said Dr Peter van Luijk, a research associate at the University Medical Center Groningen, The Netherlands.

Around 40% of patients treated for head and neck cancer suffer from the distressing side-effects of dry mouth syndrome a condition that can occur when the parotid gland stops working properly after radiation damage. This causes problems with eating, sleeping, speech, tooth loss and oral hygiene, leading to diminished quality of life, social isolation and difficulty in continuing work. Attempts to treat dry mouth syndrome and its consequences can cost hundreds or even thousands of Euros per patient per year and are mostly insufficient.

Dr van Luijk said: "Parotid gland dysfunction after radiotherapy for head and neck cancer was, and still is, a major clinical problem. During radiotherapy, attempts to minimise the risk of this complication have been aimed at reducing the average dose to the salivary gland, on the assumption that it would not make a difference where in the gland the radiation dose was reduced. However, this does not seem logical according to the anatomy of the salivary gland and, in previous work, we discovered that reductions in the radiotherapy dose to some parts of the gland allowed the parotid gland to regenerate, whereas a dose to other parts did not. Therefore, we decided to investigate the reason for these regional differences. We hypothesised that our observations could be explained by a non-uniform distribution of stem cells necessary for the long-term maintenance of organ function and affected by irradiation."

Dr van Luijk and his colleagues investigated the location of stem cells and the effects of radiotherapy to particular regions of the gland first in mouse and rat models, and then in parotid and salivary gland tissue taken from patients (after informed consent) undergoing a neck dissection for head and neck cancer.

They found that in mouse, rat and human tissue, the stem cells were predominately located in the major ducts of the parotid gland. "We have found in previous work that these stem cells are capable of regenerating a parotid gland when they have been transplanted after irradiation," said Dr van Luijk.

Dissection of the rat parotid gland and culturing of the different parts of the gland in Petri dishes showed that a greater concentration of stem cells capable of regenerating the gland were located in the centre, where the largest ducts are located. The researchers then directed high-precision irradiation at this centre part in living rats and found that it resulted in excessive reduction of saliva production, in contrast to the minimal effects observed after irradiating other parts of the gland.

Dr van Luijk explained: "The position of the stem cells in rats corresponds to the cranio-ventral extension of the gland in humans, where the excretory duct leaves the gland on the ventral, or outward-facing side. So even though the glands have different shapes in rats and humans, the stem cells are in the exact same anatomical structure."

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Stem cell sparing radiotherapy for head and neck cancer may avoid salivary gland damage

Successful stem cell differentiation requires DNA compaction, study finds

ScienceDaily (May 11, 2012) New research findings show that embryonic stem cells unable to fully compact the DNA inside them cannot complete their primary task: differentiation into specific cell types that give rise to the various types of tissues and structures in the body.

Researchers from the Georgia Institute of Technology and Emory University found that chromatin compaction is required for proper embryonic stem cell differentiation to occur. Chromatin, which is composed of histone proteins and DNA, packages DNA into a smaller volume so that it fits inside a cell.

A study published on May 10, 2012 in the journal PLoS Genetics found that embryonic stem cells lacking several histone H1 subtypes and exhibiting reduced chromatin compaction suffered from impaired differentiation under multiple scenarios and demonstrated inefficiency in silencing genes that must be suppressed to induce differentiation.

"While researchers have observed that embryonic stem cells exhibit a relaxed, open chromatin structure and differentiated cells exhibit a compact chromatin structure, our study is the first to show that this compaction is not a mere consequence of the differentiation process but is instead a necessity for differentiation to proceed normally," said Yuhong Fan, an assistant professor in the Georgia Tech School of Biology.

Fan and Todd McDevitt, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, led the study with assistance from Georgia Tech graduate students Yunzhe Zhang and Kaixiang Cao, research technician Marissa Cooke, and postdoctoral fellow Shiraj Panjwani.

The work was supported by the National Institutes of Health's National Institute of General Medical Sciences (NIGMS), the National Science Foundation, a Georgia Cancer Coalition Distinguished Scholar Award, and a Johnson & Johnson/Georgia Tech Healthcare Innovation Award.

To investigate the impact of linker histones and chromatin folding on stem cell differentiation, the researchers used embryonic stem cells that lacked three subtypes of linker histone H1 -- H1c, H1d and H1e -- which is the structural protein that facilitates the folding of chromatin into a higher-order structure. They found that the expression levels of these H1 subtypes increased during embryonic stem cell differentiation, and embryonic stem cells lacking these H1s resisted spontaneous differentiation for a prolonged time, showed impairment during embryoid body differentiation and were unsuccessful in forming a high-quality network of neural cells.

"This study has uncovered a new, regulatory function for histone H1, a protein known mostly for its role as a structural component of chromosomes," said Anthony Carter, who oversees epigenetics grants at NIGMS. "By showing that H1 plays a part in controlling genes that direct embryonic stem cell differentiation, the study expands our understanding of H1's function and offers valuable new insights into the cellular processes that induce stem cells to change into specific cell types."

During spontaneous differentiation, the majority of the H1 triple-knockout embryonic stem cells studied by the researchers retained a tightly packed colony structure typical of undifferentiated cells and expressed high levels of Oct4 for a prolonged time. Oct4 is a pluripotency gene that maintains an embryonic stem cell's ability to self-renew and must be suppressed to induce differentiation.

"H1 depletion impaired the suppression of the Oct4 and Nanog pluripotency genes, suggesting a novel mechanistic link by which H1 and chromatin compaction may mediate pluripotent stem cell differentiation by contributing to the epigenetic silencing of pluripotency genes," explained Fan. "While a significant reduction in H1 levels does not interfere with embryonic stem cell self-renewal, it appears to impair differentiation."

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Stem cell shield may protect body from chemotherapy side effects

A new study suggests stem cells may be able to act as a shield to protect the body from the harmful side effects of chemotherapy, the BBC News reported.

As chemotherapy drugs attempt to kill cancer drugs, they can also affect the bone marrow and other healthy tissues.

In a new study, however, researchers from the Fred Hutchinson Cancer Research Center in Seattle were able to use genetically modified stem cells to protect the bone marrow.

The bone marrow is very susceptible to chemotherapy, and in response to the treatment, produces less blood cells. This leaves the body more prone to infection and fatigue.

Stem cell shielding appeared to stave off some of these negative side effects. Researchers took bone marrow from patients with brain cancer and isolated the stem cells. They infected the cells with a virus which carried a gene to protect the cells against a chemotherapy drug, and then re-implanted the cells into the patients.

"We found that patients were able to tolerate the chemotherapy better, and without negative side effects, after transplantation of the gene-modified stem cells than patients in previous studies who received the same type of chemotherapy without a transplant of gene-modified stem cells, Professor Hans-Peter Kiem told the BBC News.

All three patients lived longer than the average survival time of 12 months. One patient was still alive 34 months after treatment, according to the BBC.

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NY medical schools chart progress with stem cells

ALBANY, N.Y. (AP) -- Almost halfway through a $600 million state program supporting stem cell research, eight medical schools around New York are reporting progress on projects such as replicating liver cells and eradicating leukemia cells.

A new report from Associated Medical Schools of New York updates work at the institutions where hundreds of researchers are starting to unravel causes and potential treatments for conditions ranging from autism to heart disease and cancer. Stem cells are self-renewing and have the ability to develop into other types of cells.

The Mount Sinai School of Medicine reported finding a method to transform human skin cells into stem cells and turned differentiated human stem cells into heart cells. Those findings are expected to result in better understanding of how heart disease develops and allow initial testing of new treatments on stem cells before they are used on human subjects.

Dr. Ihor Lemischka, director of the Black Family Stem Cell Institute at Mount Sinai, said recreating heart cells in a dish from a patient with LEOPARD Syndrome, a disease caused by a genetic mutation, has opened ongoing avenues for researching the disease and screening potential drugs.

"It was a major achievement," Lemischka said. The initial work was reported in June 2010 in the journal Nature.

The shared research facility at Mount Sinai supports the work at 80 different labs, Lemischka said.

The Empire State Stem Cell Program was intended to fund projects in early stages, including those that initially have been unable to get federal or private funding. Grants have also been used for capital projects like renovating labs and establishing new stem cell centers.

The Albert Einstein College of Medicine reported replicating liver cells that could help reduce the need for liver transplants using live donors and cadavers.

Dr. Allen Spiegel said 12 new researchers have been hired with state funding at the Bronx school, which also lists anemia, brain disorders, heart disease and obesity among its stem cell research subjects.

"It offers tremendous potential for understanding the causes of and developing better treatments for diseases like cancer, type 1 diabetes and Parkinson's," he said.

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NY medical schools chart progress with stem cells

Neuralstem Updates ALS Stem Cell Trial Progress

ROCKVILLE, Md., May 8, 2012 /PRNewswire/ --Neuralstem, Inc. (CUR) announced that the Federal Drug Administration (FDA) has approved the return of three patients from earlier cohorts in its ongoing Phase I safety trial to treat amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) with its spinal cord stem cells (HSSC's). These patients will be permitted to return to the trial for second treatments as the next cohort of patients, provided they meet inclusion requirements at the scheduled time. They will be the first to receive stem cell transplantation along the length of the spinal cord.

(Logo: http://photos.prnewswire.com/prnh/20061221/DCTH007LOGO )

The first twelve patients in the trial, which is taking place at Emory University Hospital in Atlanta, Georgia, received stem cell transplants in the lumbar (lower back) region of the spinal cord only. Thelast cohort of three, completed in April, received transplants in the cervical (upper back) region of the spinal cord, where stem cell transplantation could help support breathing, a key function that is lost as ALS progresses. The next cohort of three patients is designed to receive 10 HSSC injections in the lumbar region and 5 in the cervical, for a total of 15 injections along the length of the spinal cord. In the case of the returning patients, who have already received 10 lumbar injections, they will receive five cervical injections. These patients are between 15-17 months out from their first dosing and appear to have tolerated the first procedure well.

Additionally, Neuralstem has submitted a trial amendment to the FDA to increase both the number of patients treated as well as the dose in future cohorts. The amendment would also expand the trial to include certain efficacy endpoints. The trial was initially designed as a safety trial to treat 18 patients.

"The return of these patients to the trial for second treatments is a continuing validation of the trial's safety. Typically, Phase I trials do not bring study subjects back, as that could increase their exposure to potentially harmful treatments," said Karl Johe, PhD, Neuralstem Chairman and Chief Scientific Officer. "Treating these patients who have already received injections in one part of their spine allows us to both increase the overall dosage for each patient as well as transplant them in regions of the spine where they have not been treated," Dr. Johe continued. "Thisnext cohort of patients will be the first in the world to receive stem cell transplants in both cervical and lumbar regions of their spinal cord. With cervical injections of the lumbar patients, for example, we could also potentially support their breathing function, which is vital for preserving quality of life."

"Patients 10-12, who might return to the trial, were among those studied in a paper examining the first safety data from the trial, published online in STEM CELLS last month," said Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System. "As the paper showed, we believe that the cells and the route of administration are safe. It is a further validation of the safety profile to be able to bring patients back for additional dosing several months past the period which was reported on in the journal." Dr. Feldman is also principal investigator (PI) of the ALS trial and an unpaid Neuralstem consultant.

The FDA-approved amendment to the protocol requires approval of the Emory Institutional Review Board before it can be implemented.

About the Study

The ongoing Phase I study is designed to assess the safety of Neuralstem's spinal cord stem cells (HSSC's) and transplantation technique in up to 18 patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease).

The first twelve patients were all transplanted in the lumbar (lower back) region of the spine. Of these, the initial six (Cohort A) were all non-ambulatory with permanent paralysis. The first patient was treated on January 20, 2010. Successive surgeries have followed at the rate of one every one-to-two months. The first three patients (Cohort A1) were each treated with five unilateral HSSC injections in L2-L4 lumbar segments, while the next three patients (Cohort A2) received ten bilateral injections (5 on each side) in the same region. The next six patients (Cohort B and C) were all ambulatory. Of these, the first three (Cohort B) received five unilateral injections in the L2-L4 region. The last three patients (Cohort C) in this study group received ten bilateral injections in the same region.

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Neuralstem Updates ALS Stem Cell Trial Progress