Eye movement affected in former childhood cancer patients

Nowadays, the lives of the majority of all children with cancer can be spared. However, the cure for the disease comes with a price: some of the survivors will suffer long-term injury from the treatment. A study from Lund University in Sweden now shows that commonly used chemo toxins impair the eyesight in childhood cancer survivors in a way that indicates an impact on the central nervous system.

It was not the former patients’ visual acuity that had been damaged; rather their eye motor skills – the eyes’ ability to follow moving objects.”We observed that most of these patients were not able to move their eyes smoothly and steadily, but jerkily and fitfully. Eye movement like that makes it harder to focus on moving objects in traffic, for instance. It can also cause headaches and dizziness“, says reader Per-Anders Fransson at Otorhinolaryngology in Lund.

The study included 23 childhood cancer survivors, at the current age of 20 to 30, and compared them to 25 healthy people of the same age. Only a few in the first group experienced no visual disorders, headaches and dizziness. The degree of the problem appeared to be related to the degree of which the eye motor skills had been affected, which suggests damage to the central nervous system from the chemotherapy.

It has been previously known that cisplatin, methotrexate, and ifosfamide – the types of chemo which the subjects of the study had been treated with – can penetrate the so-called blood-brain barrier, and thereby damage the nervous system. What has not been known, however, is whether the eye motor skills could be affected, and the consequences of that.An average of 15 years had passed since the patients underwent cancer treatment. The study could not determine whether any of them had experienced side-effects which by now had worn off, but it’s clear that the majority of them are still suffering the effects of their treatment. Age, at the time of treatment, appears to play an important role: those who were youngest at the time of treatment were the most affected.

A child’s brain has not completely developed, which makes it more susceptible to the influence of foreign substances“, says Thomas Wiebe, consultant in paediatric oncology.

He argues that for the time being, despite the risks, we must continue to use the medicines in question – after all, curing the cancer and saving lives is most important. However, the Lund University study reinforces the importance of coming up with new and better treatments. In the future, the new knowledge, and the diagnostic method described in the study will enable oncologists to pay closer attention to any side-effects, in which case it may be possible to reduce the dosage or change medications.

Thomas Wiebe also finds that Swedish healthcare needs to focus more on the growing group of childhood cancer survivors. Only a third of them are completely free from side-effects, while the rest experience anything from mild to severe effects from their treatment.

Today, childhood cancer patients are monitored in paediatric clinics until they turn 18, but after that there is insufficient follow-up. We have introduced a ‘delayed effect clinic’ here in Lund, but it lacks sufficient resources, and the rest of the country has even less resources!“, he says.

Because the survivors of childhood cancer may experience problems not only with their balance and vision, but also with for instance cardiovascular diseases, fertility, growth and cognition, they presumably turn to various forms of care in search of help. If there was a good system for diagnosis and follow-up, they could receive the support they need right away.

When it comes to balance and visual disturbances, there is an exercise programme that can significantly minimise problems. Simply being diagnosed is also valuable so you don’t have to wonder why you are experiencing things such as dizziness and fainting“, says Professor of Otorhinolaryngology Måns Magnusson.

Einarsson et al. Oculomotor deficits after chemotherapy in childhood. PLoS ONE. 2016; 11(1): e0147703. doi:10.1371/journal.pone.0147703 [Article]

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Chemoradiation may increase survival for a subset of elderly head and neck cancer patients

The addition of chemotherapy (CT) to radiation therapy (RT) improves survival rates among a subset of elderly head and neck cancer patients, specifically those ages 71 to 79 with low comorbidity scores and advanced disease stage, according to University of Colorado Cancer Center research presented at the 2016 Multidisciplinary Head and Neck Cancer Symposium. While previous research has demonstrated the efficacy of combining CT with RT to improve survival for HNSCC patients, this improvement had not been shown in patients older than 70 years.

Elderly patients have been underrepresented in prospective clinical trials that have defined standards of care for head and neck cancer,” said Sana Karam, MD, PhD, CU Cancer Center investigator, assistant professor of radiation oncology at the University of Colorado School of Medicine, and senior author on the study. “Our study drew on nationwide data to assess more comprehensively how combined therapy impacts this population.”

The authors queried the National Cancer Data Base (NCDB) for records of patients older than 70 years who were treated for non-metastatic oropharyngeal, laryngeal and hypopharyngeal cancers between 1998 and 2011. The NCDB is a jointly-sponsored project of the American College of Surgeons and the American Cancer Society that aggregates data from more than 1,500 facilities accredited by the Commission on Cancer. Sixty-eight percent of the patients received RT alone, and 32 percent received CRT.

​Compared with RT alone, CRT was associated with improved survival in patients age 79 and younger with advanced disease but without comorbid conditions. Collaborators included Dr. Arya Amini, first aurthor on the study, and Drs. Bernard Jones, Antonio Jimeno, Jessica McDermott, David Raben, Debashis Ghosh and Daniel Bowles as co-authors on the study.

Patients who did not see an OS benefit from CRT tended to be age 80 or older, had a comorbidity score of two or greater, presented with less advanced disease, or were treated with three-dimensional RT. Patients age 80 or older with multiple comorbidities trended toward worse OS with CRT, though the difference was only marginally significant.

Findings may aid clinicians in discussing treatment options with their elderly HNSCC patients. Moreover, results of this study could guide future prospective trials to confirm the benefit of multimodality treatment in elderly patients, not only for head and neck cancer but for other cancer sites, as well.

Because the toxicity of concurrent chemoradiation is greater than radiation alone for definitive HNSCC treatment, many clinicians have reservations about offering CRT for elderly head and neck cancer patients,” said Karam. “However, in the era of improved radiation techniques, improved systemic therapy and better supportive care, we find that CRT does, in fact, improve survival for a large segment of this population.

The abstract, “Does Age Matter? Survival Outcomes with the Addition of Concurrent Chemotherapy for Elderly Head and Neck Cancer Patients Undergoing Definitive Radiation Using the National Cancer Data Base,” will be presented in detail as a poster presentation at the 2016 Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, Arizona.

Multidisciplinary Head and Neck Cancer Symposium, 2016, Scottsdale, Arizona, USA.

Bone loss associated with leukemia therapy occurs sooner than previously thought

Investigators at Children’s Hospital Los Angeles have found that significant bone loss – a side effect of chemotherapy for acute lymphoblastic leukemia (ALL) – occurs during the first month of treatment, far earlier than previously assumed. Results of the study will be available online in advance of publication in the journal Bone.

ALL is the most common pediatric cancer. Forty years ago, only one in five children survived this disease. Today with the development of powerful chemotherapies, over 90 percent of patients can expect to be cured. Unfortunately, there are some significant side effects to these life-saving therapies, including loss of bone density resulting in an increased risk for bone fractures during and even after therapy. Previous studies to determine the changes to bone density during ALL therapy had focused on the cumulative effects of chemotherapy after months or even years of treatment.

In clinic, we would see patients with fractures and vertebral compression during the very first few weeks of treatment,” said Etan Orgel, MD, MS, first author on the study and an attending physician in the Survivorship & Supportive Care Program at the Children’s Center for Cancer and Blood Diseases at CHLA. “But we were unaware of any study that specifically examined bone before chemotherapy and immediately after the first 30 days of treatment – which would allow us to understand the impact of this early treatment phase.

In a prospective study in newly diagnosed patients 10 to 21 years of age, the investigators explored leukemia-related changes to bone at diagnosis, and then the subsequent effects of the first – or induction – phase of chemotherapy. Using quantitative computerized tomography (QCT) – a newer technique more accurate for use in growing bone – they determined that leukemia did not dramatically alter the properties of bone before chemotherapy (in comparison to similar age- and sex-matched control patients).

During the 30-day induction phase, however, bone mineral density of the lower spine decreased by more than 25 percent with significant thinning of the dense cortex occurring in the bones of the leg. To help clinicians relate to these findings, the team also measured bone mineral density using the older but more widely available technique of dual-energy x-ray absorptiometry (DXA) and found that it underestimated these changes as compared to QCT measurements.

Now that we know how soon bone toxicity occurs, we need to re-evaluate our approaches to managing these changes and focus research efforts on new ways to mitigate this common – yet significant – adverse effect,” said Steven Mittelman, MD, PhD, principal investigator at The Saban Research Institute of Children’s Hospital Los Angeles and senior author on the study.

Orgel et al. Early Injury to Cortical and Cancellous Bone from Induction Chemotherapy for Adolescents and Young Adults Treated for Acute Lymphoblastic Leukemia. Bone 2016; http://dx.doi.org/10.1016/j.bone.2016.01.027 [Abstract]

Harnessing the power of light to fight cancer

By controlling the actions of immune cells, they could be ‘instructed’ to kill cancerous tumor cells. Immunotherapy is one of the hottest emerging areas of cancer research. After all, using the body’s own cells to fight cancer can be more effective and less invasive than flooding the entire system with toxic chemicals.

Yubin Zhou, Ph.D., assistant professor at the Center for Translational Cancer Research at the Texas A&M Health Science Center Institute of Biosciences & Technology, is studying how to use light to control the immune system and induce it to fight cancer.

Although neuroscientists have been using light to stimulate neurons for years, this is the first time the technique, called optogenetics, has been used in the immune system,” Zhou said. In neuroscience, the process involves genetically engineering cells to produce proteins from light-sensitive microbes and results in nerve cells that will either send–or stop sending–nerve impulses when they are exposed to a particular color of light. “Neuroscientists have learned a lot about brain circuits using the technique,” Zhou said, “and now researchers in many other fields are giving it a try.”

Zhou and his collaborators have modified the technique for the immune system. It wasn’t easy: unlike nerve cells, immune cells don’t use tiny electrical impulses to communicate. Additionally, immune cells are located deep in the body and are constantly moving around, so getting the light to them can be difficult.

The development took some ingenuity and cooperation. “We collaborated with Dr. Gang Han at the University of Massachusetts Medical School who does bionanotechnology and photomedicine development,” Zhou said. “Together, we were able to combine state-of-the-art optogenetic approaches with cutting edge nanotechnology.” Called optogenetic immunomodulation, their method was featured in a recently published article in eLife.

This work was driven by talented scientists in the lab: graduate students Lian He and Peng Tan and postdoctoral research fellow Guolin Ma, Ph.D.,” Zhou said, “who fearlessly undertook this daunting project and overcame all the challenging obstacles to make this technique into reality.”

With this method, the researchers can control the action of immune cells and “instruct” them to kill cancerous tumor cells. They use a near-infrared laser beam, which can penetrate deep–in this context, deep means a centimeter or two–into the tissue, where a nanoparticle turns the near-infrared light into blue light, and that directs the activity of genetically engineered immune cells. “
” Zhou said.

The team genetically engineered immune cells so that a calcium gate-controlling protein became light sensitive. When they are exposed to the blue light emitted by the nanoparticle, their calcium ion gates open. When the light is turned off, the gates close. More light leads to a greater flow of calcium, so the researchers are able to finely tune the calcium-dependent actions of immune cells to fight against invading pathogens or tumor cells.

When an animal tumor model was injected with both the nanoparticle and the light-sensitive genetically engineered immune cells, the near-infrared laser beam caused calcium channels to open, which boosted an immune response to aid the killing of cancer cells. “The technique reduced tumor size and metastasis, so there are lots of applications,” Zhou said.

One advantage of this method is that it only activates a certain type of immune cell, the dendritic cell or T-cell, and only in one part of the body, near the draining lymph nodes or tumor, which helps cut down on the system-wide side effects often seen with chemotherapy. It’s also light-tunable, non-invasive and has great temporal resolution–in other words, it can be turned on when it is needed and turned off when it is not.

The implications of the research are far-reaching. “Other scientists will likely use the technique to help them study immune, heart and other types of cells that use calcium to perform their tasks,” Zhou said. “It’s quite a cool technology. With these tools, we can now not only answer fundamental questions of science that we never could before but also translate it into the clinic for disease intervention.”

In parallel, the Zhou lab has been applying this technique to establish a way to screen potential cancer drugs more effectively. “If successful,” Zhou said, “all these efforts would remarkably improve the current cancer immunotherapies by personalizing the treatment to exactly where and when it is needed, while reducing side effects.

He et al. Near-infrared photoactivatable control of Ca2+ signaling and optogenetic immunomodulation. eLife 2015;4:e10024 [Article]