Sickle Cell Disease and Genetics: Understanding the Cause and… – Sickle Cell Disease News

By Somatic Stem Cells

This content is sponsored by bluebird bio, Inc. (bbb) and is intended for US patient/caregiver audiences 18 years of age and older only. Any other present or future content posted by a contributor, not expressly designated as bluebird bio, Inc.sponsored content, is not associated with bbb.

As a progressive, unpredictable disease, sickle cell is a genetic condition that affects everyone differently, which can make it difficult to understand. Simply learning more about how the body works can help explain the cause of sickle cell. And with a better understanding of how this disease works and how genetics are involved, you can make informed decisions with your doctor about how to navigate treatment.

As the name implies, sickle cell disease involves your cells. Each person has trillions of cells in their body, all working together to perform functions that keep us alive. Within each cell is DNA, the molecule that contains the genetic information for our cells, including genes. Genes provide the instructions for your cells. They help make the proteins that keep us healthy by powering muscles, attacking invading bacteria, or delivering oxygen throughout the body. Since each cell in your body relies on thousands of proteins to work properly in order for the cells to function correctly, your genes are the blueprint, or instruction manual, for your body. When theres a mutation (or change) in a gene, the instructions can cause a cell or protein to not function properly and potentially cause diseasesuch as sickle cell.

Check out the video to learn more about how genes and proteins impact the symptoms and complications of sickle cell.

There are many different types of cells, but with sickle cell disease its the red blood cells, the most common type of cell in your blood, that are affected. These cells are responsible for delivering oxygen throughout the body, which fuels your organs by giving them the energy they need to function. The protein within these cells that performs this function is called hemoglobin, which is made up of beta-globin proteins and alpha-globin proteins. In order for normal adult hemoglobin (HbA) to work properly, there must be a balance of functioning beta-globin and alpha-globin. The HBB gene provides the instructions for these proteins within hemoglobin, and a mutation in that specific gene affects the instructions, causing your body to produce an abnormal form of beta-globin, such as hemoglobin sickle (HbS), which results in a person having sickle cell disease or carrying the sickle cell trait.

Since sickle cell disease affects everyone differently, its important to develop a comprehensive care plan that works for you and your healthcare team. This plan should aim to monitor symptoms, address chronic complications, and manage your overall health. Its also important to build a healthcare team that includes specialists from different areas who can make your care plan work for you. This team should include your primary care doctor but can also include a hematologist (who specializes in diseases of the blood), a genetic counselor (who can help with family planning), and a community health worker (who may be able to assist you with education and day-to-day monitoring by working with local hospitals), among others.

Pain, fatigue, and other unpredictable symptoms of sickle cell can affect many different aspects of your life. The daily tasks of family life, work, and/or school, as well as future plans, can all be impacted by symptoms and complications, whether theyre sudden (acute) or ongoing (chronic). Knowing how to manage these symptoms and complications can help you or your loved ones better navigate sickle cell care.

Progress continues to be made in the treatment of sickle cell disease, but current options mainly help relieve symptoms and require lifelong use. These treatment options include oral medications and infusions, blood transfusions, and, for a limited number of patients, a hematopoietic stem cell transplant (which can lead to a cure; however, they are mostly limited to people who are under the age of 18 and have a matched-related donor available).

There are also developing therapies now being explored to address unmet needs in the management and treatment of sickle cell. One therapy approach being researched is gene therapy,* which is designed to treat sickle cell at the genetic level with the goal of changing the course of the disease.

Taking the time to educate yourself on the genetics of sickle cell is an important step in managing sickle celland remember, youre not alone. Beyond your loved ones and care team, there is an entire sickle cell community, including advocacy organizations, who are here to help. For more information, visit SparkSickleCellChange.com, a website developed by bluebird bio, to stay proactive in sickle cell care and planning for the future.

*Gene therapies for sickle cell are investigational and not FDA approved. Safety and efficacy have not been established.

bluebird bio is a trademark of bluebird bio, Inc.

2023 bluebird bio, Inc. All rights reserved. SCD-US-00280 08/23

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Sickle Cell Disease and Genetics: Understanding the Cause and... - Sickle Cell Disease News

FDA Approves Nirogacestat for Patients With Desmoid Tumors – Targeted Oncology

By Somatic Stem Cells

The FDA has granted approval to nirogacestat for the treatment of adult patients with desmoid tumors.1

Findings from the phase 3 DeFi trial support this approval as in the study, nirogacestat reduced the risk of disease progression or death by 71% compared with placebo among patients with desmoid tumors (HR, 0.29; 95% CI, 0.15-0.55; P < .001).2

This study is the first positive study for a gamma secretase inhibitor in any indication, and it's the largest and the most rigorous and robust clinical trial ever done in desmoid tumor, said Bernd Kasper, MD, PhD, professor, Mannheim University Medical Center, in an interview with Targeted Oncology. Nirogacestat demonstrated rapid, sustained and statistically significant improvements in all primary and secondary endpoints with a manageable safety profile. So it is definitely a candidate for register for registration in this indication. And it will probably be the standard of care for decimo to most in need of systemic therapy.

Among those given nirogacestat (n = 70), the Kaplan-Meier-estimated median PFS was not estimated and patients treated with placebo (n = 72) had a median PFS of 15.1 months (95% CI, 8.4-not estimable). The likelihood of being event-free at 1 year was higher among patients treated with nirogacestat vs placebo, at 85% (95% CI, 73%-92%) and 53% (95% CI, 40%-64%), respectively.

Additionally, event-free survival rates at 2 years were 76% (95% CI, 61%-87%) with nirogacestat and 44% (95% CI, 32%-56%) with placebo, respectively. The confirmed ORR was 41% with nirogacestat vs 8% with placebo (P < .001), and the complete response rates were 7% and 0%, respectively.

The median time to confirm first response was 5.6 months and 11.1 for the investigative vs control arm, respectively, and the median best percent change in target tumor size was -27.1% (range, -100 to 37) vs 2.3% (range, -100 to 47).

Any-grade adverse events (AEs) were observed in 100% of patients in the nirogacestat arm compared with 96% in the placebo arm, with grade 3 or greater AEs observed in 55% vs 17% of patients in the nirogacestat vs placebo arms, respectively.

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FDA Approves Nirogacestat for Patients With Desmoid Tumors - Targeted Oncology

Gene-editing therapy by Vertex and CRISPR poised for FDA approval – The Boston Globe

By Somatic Stem Cells

Its kind of surreal, said Tornyenu, 22, who grew up in Bethlehem, Pa., and participated in a clinical trial at Childrens Hospital of Philadelphia. Im, like, wait, I dont have sickle cell anymore.

The life-changing drug, developed by Boston-based Vertex and its Swiss partner CRISPR Therapeutics, is expected to be approved by the Food and Drug Administration by Friday for people with severe cases of the disease. Called Casgevy, it would usher in a new era not only for those with sickle cell but also for medicine: The drug would be the first gene-editing therapy authorized by US regulators, and uses a tool called CRISPR.

The likely approval Casgevy was cleared by British regulators last month raises both the promise of cures for diseases as well as the ethical concerns that come with the power to manipulate the building blocks of human life. With an expected price tag in the seven figures, it also touches on issues of equity in medicine.

Sickle cell primarily afflicts people of African descent. Research on the disease languished for decades, which many experts blame on structural racism, particularly in funding.

For Tornyenu, Casgevy has meant an end to the searing pain crises that caused her to miss a week of classes every month as a high school senior. After getting the treatment, she took the spring semester off from Cornell to recover from the debilitating effects of chemotherapy that made room in her blood marrow for gene-edited cells.

But now she no longer dreads the arrival of cold weather, which would often induce excruciating pain in her hips and legs. A senior at Cornell, she has a job lined up as a consultant at PricewaterhouseCoopers in Boston after graduation.

Im very hopeful [Casgevy] will be approved, she said, because I dont know what I would have done otherwise.

The gene-editing method that became known as CRISPR was first reported in a landmark 2012 paper by American biochemist Jennifer Doudna of the University of California, Berkeley, and French microbiologist Emmanuelle Charpentier of the Max Planck Institute for Infection Biology. They would share the 2020 Nobel Prize in chemistry for their work on the tool.

Sickle cell was an obvious choice for scientists to tackle with CRISPR. It was the first human disorder understood on a molecular level, its underpinnings explained in a landmark 1949 paper written by the future two-time Nobel laureate Linus Pauling. Yet progress against the disease was slow for decades afterward.

Sickle cell affects hemoglobin, the oxygen-carrying protein in red blood cells. It causes the round, flexible blood cells to deform into a sickle shape and stick to vessel walls. That deprives tissues of oxygen, causing crushing pain that can often only be relieved with opioids and blood transfusions.

Sickle cell can also lead to strokes, damage organs, and cause early death. A 2019 study in JAMA Network Open estimated the life expectancy of adults with sickle cell in the US is 54 years, about 20 years shorter than the general population.

In a clinical trial, Casgevy demonstrated remarkable results. The medicine completely relieved 29 of 30 sickle cell patients of debilitating episodes of pain for at least one year among trial participants who were followed for at least 18 months, according to Vertex. The patients received a one-time intravenous infusion of edited stem cells that flipped a genetic switch to restore their blood cells ability to carry oxygen throughout their bodies.

This is what a potential cure looks like, said Dr. Stephan Grupp, chief of the Cellular Therapy and Transplant Section at Childrens Hospital of Philadelphia. He was the principal investigator at the trial site where Tornyenu got Casgevy and was paid by Vertex to help organize the study at locations across the US.

About 100,000 Americans, most of them Black or Hispanic, are believed to have sickle cell. The Vertex-CRISPR treatment was geared for those with severe and repeated pain crises, roughly 20,000 people in the US. As of 2021, almost 8 million people around the world live with sickle cell, according to the Institute for Health Metrics and Evaluation at the University of Washington in Seattle.

The FDA has approved four medicines for the disorder, but none has been remotely as effective as Casgevy, which is expected to cost more than $1 million for a one-time infusion in the US, according to experts. (No price has been announced in the United Kingdom.) Sickle cell can be cured with a bone-marrow transplant, but few patients have compatible donors.

Patients are already inquiring about Casgevy, said Dr. Sharl Azar, a hematologist at Massachusetts General Hospital and medical director of its Comprehensive Sickle Cell Disease Treatment Center. He said he is eager to see whether the FDA clears it, how broad the approval would be, and whether Medicare and Medicaid would cover it.

Theres a lot of unknowns that were looking forward to working out in the coming months, he said. But I think everyone, from patients to providers, recognizes that this is a big deal.

Rahman Oladigbolu, a 52-year-old Harvard-educated filmmaker in Brockton, is among local patients interested in Casgevy. He has had six joints his hips, shoulders, and knees surgically replaced since 2000 because of damage from sickle cell. He walks with a cane at times, often gets lightheaded, and takes opioids to relieve persistent pain.

When Oladigbolu was growing up in Nigeria, his grandmother would take him to traditional medicine men and medicine women who prescribed herbs and potions, some of which they rubbed into his aching limbs after cutting him with a razor blade. He moved to the US when he was 28 and currently takes a sickle cell drug called crizanlizumab, which reduces his pain but doesnt eliminate it.

Pursuing a cure has been like a side job all my life, said Oladigbolu, who receives treatment at Boston Medical Center.

CRISPR-based treatments will likely be approved for other disorders in the coming years, experts say, although its hard to predict for what and when. Researchers, including scientists at multiple biotech companies and hospitals in Massachusetts, are studying the potential of gene editing for a variety of diseases, from ALS to forms of cancer.

There will be other gene-editing therapies, certainly, but each disease is different, said Dr. Stuart Orkin, a researcher at Dana-Farber Cancer Institute and Boston Childrens Hospital who in 2008 helped identify the gene that Casgevy snips to treat sickle cell. For some diseases, its not clear what to edit. People will argue about whats the right target. Each one is a special case.

Gene editing has also raised ethical concerns. In 2018, a Chinese scientist, He Jiankui, was widely condemned when he announced that he used CRISPR to edit DNA in human embryos to try to make them immune to HIV. The experiment sparked fears that He had opened the door to creating so-called designer babies children whose genetic makeup is altered to produce desired traits.

Dr. George Q. Daley, dean of Harvard Medical School, was among those who said Hes experiment raised the specter of a Brave New World of eugenics. Casgevy, he said recently, is completely different. The modifications it makes to DNA only helps sickle cell patients and cannot be passed on to their children.

Daleys bigger worry concerns access to Casgevy. While wealthy countries like the US have hospitals and doctors capable of preparing patients for the treatment and administering it, he said, millions of people with sickle cell in sub-Saharan Africa dont have those options.

This is a triumph of modern biomedicine, he said. The major ethical concerns now are issues of cost and equitable distribution.

Casgevy isnt the only gene-based medicine on the horizon for sickle cell. The Somerville biotech Bluebird Bio hopes the FDA approves a so-called gene therapy, lovo-cel, by Dec. 20. It also proved remarkably effective in clinical trials.

Unlike Casgevy, which cuts a gene, lovo-cel adds a modified gene into a patients DNA to enable blood cells to deliver oxygen. The FDA has approved at least eight gene therapies for mostly rare diseases since 2017.

Both Casgevy and lovo-cel are expected to be breathtakingly expensive. That has renewed questions about whether the health care system can afford such cutting-edge medicines.

Still, the Institute for Clinical and Economic Review, or ICER, an independent Boston-based drug-pricing watchdog, estimates that either drug could cost nearly $2 million and be worth it, given the cumulative costs of treating sickle cell over a lifetime and the benefits the new approaches would bring to patients and families.

Casgevy, which was called exa-cel in clinical trials, works by editing a patients bone marrow stem cells to make high levels of fetal hemoglobin the healthy, oxygen-carrying form of hemoglobin produced during fetal development that is replaced by adult hemoglobin soon after birth.

Unlike adult hemoglobin, fetal hemoglobin resists forming a crescent shape in sickle cell patients, and scientists have long searched for a way to restart it. The researchers behind Casgevy solved the problem by editing a gene called BCL11A, which regulates fetal hemoglobin.

The treatment involves multiple steps over several months. Patients must donate stem cells to be modified at a laboratory. Then donors have to undergo a grueling regimen of chemotherapy to make room in their bone marrow for the genetically altered cells. Finally, the patients get the cells back through a single infusion.

Dr. David Altshuler, Vertexs chief scientific officer, acknowledged that the gene-editing treatment is extremely complex and resource intensive. He said Vertex is researching the possibility of developing a pill that could do what Casgevy does without gene editing. (Vertexs business partner for Casgevy, CRISPR Therapeutics, is based in Zug, Switzerland, but has most of its workforce in Boston.)

FDA officials have raised concerns about the possibility that Casgevy could inadvertently change patients DNA beyond the targeted disease so-called off-target editing. Dr. Daniel E. Bauer, a staff physician at Dana-Farber Cancer Institute and Boston Childrens Hospital, told an FDA advisory panel on Oct. 31 that Casgevy contains hundreds of millions of edited cells and one could undoubtedly go off target and cause leukemia. But he described the risk as modest given the benefits of the treatment.

Altshuler said recently that there is no evidence to date of off-target editing, but it is important to be humble and to continue to follow patients. Vertex and CRISPR have pledged to follow trial participants for 15 years to make sure they stay healthy.

Tornyenu, the Cornell student, says she considers Casgevy a miracle and would celebrate Dec. 8 every year if the FDA approves the drug that day.

For lack of a better term, she said, its a big FU to sickle cell.

Jonathan Saltzman can be reached at jonathan.saltzman@globe.com.

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Gene-editing therapy by Vertex and CRISPR poised for FDA approval - The Boston Globe

Major Breakthrough: UofM Research Team 3D Prints Heart Valves – Mirage News

By Somatic Stem Cells

Credit: CHU Sainte-Justine

In a breakthrough in pediatric cardiac science, Canadian researchers have successfully produced a bio-ink that could someday be used to print functional, durable heart valves, offering hope for improving the prognosis of children with heart defects.

The discovery of a way to 3D print functional heart valves was made at the CHU Sainte-Justine Research Centre by Universit de Montral assistant medical professor Houman Savoji and his PhD student Arman Jafari.

The results of their research are published in the journal Advanced Functional Materials.

Tissue engineering can be used to create living tissues and organs by combining biomaterials with cells. Unlike mechanical heart valves, engineered biomimetic valves could develop and grow with the recipients. Such tissues and organs could someday be manufactured with a 3D printer, with the right bio-ink such as that developed by Savoji and his colleagues.

Houman Savoji and Arman Jafari

Credit: CHU Sainte-Justine

"My team has shown that an ink composed of polyvinyl alcohol, gelatin and k-carrageenan can be used to print heart valves that open and close correctly and has in-vitro and in-vivo biocompatibility and anti-thrombogenic properties," he explained. "They function well in a physiological environment like that of the human body, in both adult and children's sizes."

This compound also provides a structure (called a "scaffold") in which stem cells can potentially grow until they are replaced by a fully living tissue. Better still, in laboratory tests the valves generated fewer adverse effects than the mechanical or animal valves currently used in patients.

"These results suggest that our valves may be associated with a lower risk of complications than those currently used in transplants," said Jafari. "And since these are biomimetic artificial tissues, they can potentially grow with a transplanted child, limiting the need for repeat surgery."

Over the next few years, the scientists plan to pursue their research through in vivo trials, with the ultimate goal of seeing this technology one day be made available for use in a real-life, surgical setting.

Credit: CHU Sainte-Justine

Credit: CHU Sainte-Justine

Credit: CHU Sainte-Justine

"Formulation and evaluation of PVA/gelatin/carrageenan inks for 3D printing and development of tissue-engineered heart valves," by Aman Jafari et al, was published Oct. 10, 2023 in Advanced Functional Material. Funding was provided by the Fonds de recherche du Qubec - Sant, the Natural Sciences and Engineering Research Council of Canada, the TransMedTech Institute, the CHU Sainte-Justine Research Centre and Universit de Montral. The Savoji lab also benefits from equipment funded by CHU Sainte-Justine Foundation. Arman Jafari also received a doctoral scholarship from the FRQS and a bursary of excellence from Universit de Montral's Faculty of Medicine.

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Science Talk – I survived cancer as a child and now I’m working to … – The Institute of Cancer Research

By Somatic Stem Cells

Image: Andrew Wicks in the lab at The Institute of Cancer Research. Credit: Andrew Wicks.

I still remember getting my diagnosis, even though it was all a bit of a whirlwind. Within a couple of days, Id gone from having a cough to having cancer. These things come at you fast!

At 12, I was very active and loved sports. That summer, I spent most of my time playing football or rugby, or doing athletics at school. I developed a persistent cough, but because I seemed so well otherwise, my family and I didnt think much of it. When the antibiotics the doctors had given me didnt work and I was sent to the local hospital for a chest X-ray, we assumed an infection was to blame.

Instead, the X-ray revealed a visible tumour the size of an orange in the lymph nodes around my lungs. Suspecting lymphoma, the doctors put me in an ambulance and sent me to Great Ormond Street Hospital, a childrens hospital in London. There, I had a bone marrow biopsy, which showed that I actually had acute lymphoblastic leukaemia (ALL).

ALL is a type of blood cancer that results from the bone marrow making too many immature white blood cells called lymphocytes. Many of the initial symptoms, including fatigue, frequent infections, and a fever, are nonspecific, but its important to start treatment immediately. Without treatment, the disease progresses very quickly and is fatal.

I didnt really digest the news at first. I was too numb, too shocked to be scared. I just went into autopilot and tried to adapt to the situation as it rapidly changed. However, I vividly remember my parents being scared and upset. They were devastated by my diagnosis.

Luckily, because leukaemia is the most common type of cancer in children, and ALL is the most common type of leukaemia at this age, doctors know how to treat it.

Image: Andrew aged 12, before receiving the ALL diagnosis. Credit: Andrew Wicks.

I started on high-dose chemotherapy, which was very intense. It made me feel nauseated and fatigued, and it weakened my immune system. For a year, long hospital stays and my low immunity meant that I was unable to go to school or anywhere else really. Most of the time, I felt too poorly to leave the house anyway. But I missed seeing my friends, having a social life and playing sports. My mum stopped working so that she could stay at home with me and take care of me, and my dad took a lot of time out from work so that he could be at my hospital visits.

My trips out were mainly to the hospital, which I visited at least once a week. I underwent procedures such as bone marrow biopsies and lumbar punctures, and I received chemotherapy as an outpatient there. Now, as an adult, I can reflect on how tough the treatment was, but at the time, I tried to keep a positive mindset, focusing on taking each day at a time and getting through it. To me, each treatment or hospital visit meant that I was taking a step closer to the finish.

Once I moved onto maintenance therapy, I was able to return to school, and my mum went back to work. The side effects of the treatment were more manageable, and my life started to feel a bit closer to normal. I was able to see my friends again and to go into town. But then, in the third year of my treatment, my ALL relapsed. I felt very dispirited because treatment had been going so well, but my doctors still had hope.

I needed to try a new form of treatment, so they recommended that I undergo a stem cell transplant. I had to have high-dose chemotherapy and radiotherapy to deplete my immune system before the transplant. Then I had to take immunosuppressive drugs to prevent my immune system from rejecting the donor cells and to prevent the donor cells from attacking healthy cells in my body.

Again, I had to be really careful to protect myself from infection while my immunity was low. I ended up taking some of my GCSE exams while in hospital for treatment because I was stubbornly determined not to let it disrupt the normality that had seemed so close. But it felt like a step backwards.

Thats why, when I had finally the long-desired appointment in which they told me that I was done with treatment and would only need to see the team again for checkups, my first feeling was just incredible relief. Were here, I remember thinking. Weve made it! It was such a happy moment for my family. My parents, two brothers and sister had all gone through it too. My diagnosis and treatment were tough for everyone.

Image: Andrew receiving stem cells in the hospital. Credit: Andrew Wicks.

The support and care I received from hospital staff and my family were incredible, and I cant express enough how much that helped me.

With hindsight, I was probably quite an annoying patient! Seeing lots of other people with cancer and hearing about many different treatments meant that I always had lots of questions. What is this drug? I would ask. How does it work? I took part in clinical trials during my treatment and, even as a young patient, I was intrigued by how research leads to new treatments.

Three years after completing treatment, I chose to study biology as an undergraduate. Learning about cancer in detail the different types of the disease and how it develops and progresses furthered my interest, and I went on to complete a Masters degree focused on cancer drug resistance. Wanting to get some research experience and learn even more about cancer, I joined The Institute of Cancer Research, London, as a Scientific Officer (technician) in Professor Chris Lords labin the Division of Breast Cancer Research.

I learned a lot during this time from my colleagues, who are among the leaders in their field. I knew that, given the expertise and breadth of knowledge in the team, there would be nowhere better for me to learn and undertake my own independent research project.

I am now in the fourth year of my PhD here at The Institute of Cancer Research (ICR). Supervised by Professor Lord and Professor Andrew Tutt, Head of the Division of Breast Cancer Research and Director of the Breast Cancer Now Toby Robins Research Centre at theICR, I am working on a project investigating PARP inhibitors. In particular, I am studying how tumour cells react and change when exposed to these agents, and how these changes might confer drug resistance. The long-term aim is being able to prevent or treat this resistant disease.

This years ICR Christmas fundraising appeal features the story of Tommy Edwards, a seven-year-old who is currently responding well to treatment for ALL, the same type of cancer I had.

Tommys parents, Jo and Chris Edwards, have set up a charity called Prevent ALL, which is funding work by the highly-honoured Professor Sir Mel Greaves, Founding Director of the ICRs Centre for Evolution and Cancer. Professor Greaves research shows that leukaemia, including ALL, may be preventable, and his team is working towards developing simple and safe interventions to stop the disease from developing.

All of us at the ICR are incredibly grateful for the support we receive from our amazing family charity partners like Prevent ALL. Without them, a lot of the work we do would not be possible.

Cancer is hard for everyone, including family members. In my experience, its important, where possible, to have moments where the focus on the disease is temporarily put to the side and you are just a family, as you were before the diagnosis. I hope that Tommy and his family have the opportunity to do just that this Christmas.

We are world-leaders in the study of cancer in children, teenagers and young adults and have made huge strides over the past decade in understanding the causes and improving treatments. With your support, we can make the hope of safer, kinder and more effective treatments a reality for these children. Help cure more children with cancer, more kindly.

Make a monthly donation today

Image: Tommy Edwards. Credit:ICR/John Angerson.

We still have much to learn about childhood cancer, but it is clearly not the same as adult cancer. Ideally, we should be treating it accordingly. We need treatments that are targeted to children and more appropriate for their needs.

Although the priority is, rightly, to provide treatments that are as effective as possible, in an ideal world, they would be much kinder too.

While I feel exceedingly fortunate that my treatment was successful, the debilitating side effects cost me at least a year of my childhood. Kinder treatments could allow children to go to school, see their friends and generally have a life outside of their illness. I believe that improving the quality of life for children with cancer is nothing short of essential.

At the ICR, Ive seen with my own eyes the strong connection between work in the labs and the resulting benefits for patients. The translational aspect of the ICRs work means that it has a direct impact on people. I find it very motivating to work at an institution that is so well-placed to change clinical practice for the better.

Although I dont work in the field of paediatric cancer, when I think back to my childhood, it makes me feel really positive about my career choice. Knowing that my current research might go on to help others who find themselves facing a cancer diagnosis means that I look forward to Monday mornings.

Im hopeful that, one day, outcomes can be improved for everyone living with cancer, and Im proud to be contributing to this mission. The important thing is that we keep going.

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Science Talk - I survived cancer as a child and now I'm working to ... - The Institute of Cancer Research

How Kansas football coach Matt Lubick found strength in marathon running to battle cancer – The Athletic

By Stem Cell Doctors

In April 2022, college football coach Matt Lubick fulfilled a decade-long dream of running the Boston Marathon. He set an ambitious goal of finishing in under three hours, but headwinds slowed him during the race, and he finished in three hours, one minute.

When Lubick ran the Boston Marathon, he cared only about his finishing time. He looked at his watch every two steps, for all three hours and one minute of the race. Lubick constantly told himself, Breath. Relax. Breathe. Relax. You got this. Breath, Relax. Breathe. Relax. You got this. That marathon was both physically and mentally grueling, but for the long-time coach, the 26.2 miles he walked on October 19, 2023 was much more emotional and exhilarating.

Lubick was the only marathoner on that course, a 60-meter bridge and tunnel on the 11th floor of the Anschutz Center for Advanced Medicine in Aurora, Colo. It took him 13 hours, from 9 a.m. until 10 p.m., to walk 26.2 miles, and he did it hooked up to an IV unit. It was Day 1 of his chemotherapy for leukemia.

Lubick, diagnosed on Oct. 7, walked all 51,550 steps briskly, with that wobbly, six-wheeled IV unit feeding him chemotherapy and fluids. He ran through all of the sobering statistics about what individuals with cancer could die from, about the percentage of people who become casualties, but he focused on the hope his doctor gave him the day he was diagnosed. Thats why Lubick, whose work as a coach is rooted in percentages and numbers, was so moved by the people who told him to do something different: Dont listen to any of that!

At first he hadnt set out to walk the distance of a marathon. That idea popped into his head around mile 18: OK, I might as well do this. Those first eight hours were pretty easy, he thought. But then, it became something different. This wasnt about his finishing time. This was about proving something to himself and having faith in God.

This time, the chorus in his head was much different: Im not a friggin statistic! I am not a friggin statistic! I am not a friggin statistic! A statistic doesnt do this!

For much of those 13 hours, he prayed and talked to God. Lubick was grateful for the support of his nurses and doctors, who in addition to their encouragement also switched out the batteries to his monitor. Just be smart, they told him. If you need to sit down, sit down. He never needed to. He felt great, he said, for most of the marathon until the last two hours. Soreness set in. But thats about the time when his running buddies stepped up and talked him over the top.

Something else, though, was also motivating him.

Lubick is the 51-year-old son of Sonny Lubick, a legendary former Colorado State coach and one of the most beloved figures in coaching. His brother, Marc, is a cancer survivor and an assistant quarterbacks coach with the Buffalo Bills. Matt Lubick has coached in every conference in major college football, and hes coached everything from defensive backs to wideouts and special teams.

Hes been an offensive coordinator at Oregon and Nebraska, and at almost every program hes worked, Lubicks been regarded as the most dogged recruiter on staff. At Ole Miss, he found an undersized three-star recruit in Florida named Dexter McCluster, who blossomed into a Rebels great. One year at Arizona State, he almost signed all 25 recruits by himself. After he was let go at Nebraska in 2021, despite his Huskers offense ranked No. 16 in yards per play in the country, he landed a job at Kansas as a senior offensive analyst.

Coach Lance Leipold and offensive coordinator Andy Kotelnicki were impressed by Lubicks wrinkles in the option attack and creativity in the red zone. Lubick was always studying, picking up ideas from everywhere from the NFL to Division II Nebraska-Kearney. The year before Lubick was hired by Kansas, Kansas ranked No. 104 in the country in offense. In 2022, the Jayhawks shot up to No. 6.

A key reason for the dramatic change, according to Kansas coaches, was Lubick, who lives and watches the Jayhawks from 620 miles away. Leipold was fine with Lubick staying in Colorado, other than his offseason and training camp visits. He makes suggestions about everything from the passing game to upcoming opponents to Kotelnicki over Zooms that often last up to two hours.

He had always been a big film watcher, but in his role with Kansas, where he didnt have to attend practices or recruit, he was really freed up. Lubick would wake up by 4 a.m., be at his local Starbucks for 5 a.m. opening and order his black venti Pike Place, and then dive into all the film he could handle, often downing eight cups of coffee during his film study.

On Saturdays, hed go to his parents to watch his Jayhawks. Lubicks one hobby away from football projects, aside from the two days hed do rides for Meals on Wheels, was distance running.

Lance is really a great CEO and lets his coaches coach, Lubick told The Athletic. He said that selfless attitude is also epitomized by Leipolds longtime offensive coordinator Kotelnicki, who has the wherewithal to mesh the ideas seamlessly. It takes a huge non-ego to let me (have input in game planning) and hes still the one coaching it and let it fit his vision.Lances leadership skills are amazing, and his staff is second to none.

In summer 2022 when Lubick came back from Kansas, he felt off. His mother convinced him to go see a doctor. He had a freakishly low white blood count, he said. Just before the Jayhawks opener against Missouri State, on Aug. 22, doctors admitted him to the hospital for three days. Initially, doctors thought it was something viral. They tested him for West Nile. He was discharged and doctors advised him to stay away from people. He had no symptoms. He kept working for Kansas and kept running.

Then, on Oct. 5, he went in for a bone marrow test that revealed he had leukemia. Though the diagnosis sounded devastating, Lubick was not really fazed by it; he felt he was more prepared for it because of all the people hed talked to and heard their inspiring stories.

As a football coach, you always prepare for the worst, he said. Thats kind of my nature. I talked to three friends who had been through this, so it didnt really throw me for a loop. And I knew I still needed to do my red zone presentation for that week.

After Lubick was fired from Nebraska, he needed to do something, he said. Hed always kept a strict diet and workout routine; the running joke on almost every staff hed been on was that Lubick had lower body fat than players. After leaving Lincoln, he ramped up his distance running. Some of the people he was training with were competitive marathoners who noted that he had talent.

You can make Boston! they encouraged.

Lubick was surprised by the feedback, but decided he should pursue it. That encouragement, and getting fired, ended up being a blessing.

Physically, Im a little more prepared for this because of the marathon training, and psychologically too, because marathon training is not easy, he said. Its like three hours a day where youve got to run, and youve got to run when you dont feel good.

His devotion to running and his new role in Kansas even allowed him to visit a doctor in the first place.

I dont think I would go to the doctor if I was coaching, said Lubick. The only reason I went to the doctor in the first place is because I was so worried about my training. I didnt want to take two days off (from running), so I went to get medication, and thats when I got my first hospitalization.

If I was coaching full-time at a school theres no such thing as sick in football. You just go to work every day. In a weird way, looking back at it, it mightve saved my life.

Lubicks friends both inside and outside the football world have rallied to his side. Brian Armstrong, a former teammate of his from Western Montana who is now the offensive line coach at Fresno State, connected Lubick to a man hed coached with named Tom Purcell who left football and is now the CMO at Fred Hutchinson Cancer Research Center.

Hes been a blessing along the way to bounce things off, Lubick said.

Siri Lindley, a professional triathlete who overcame leukemia, has become a great resource, telling Lubick what to expect and why fostering a positive attitude is so vital. To Lubick, that has meant finding purpose and meaning within a different type of adversity.

I can control my attitude, my exercise and my food, he said. Im really trying to emphasize that, trying to build those things up. Walking gives me energy and it helps me think. I used to always run. They say not to push it. Its been very therapeutic to exercise for a whole bunch of reasons.

For someone who has never been married and whose adult life has revolved so much around football, this fall has made Lubick very reflective.

I have spent so much time thinking, whats the purpose of this? Lubick said.

A week into his chemotherapy, Lubick did feel a tinge of guilt because he wasnt able to help the Jayhawks prepare for Oklahoma State. But he was able to jump back into his routine for Iowa State. Lubick has done the majority of his chemotherapy as an outpatient.

Its therapy for me, he said. The KU staff calls and sends texts every day. I couldnt ask for a better support system.

And hes had a similar impact on others at Kansas.

Its been so good in so many ways for us with Matt, Leipold said. He and Andy developed a really good relationship early. Matt is so extremely thorough and thought-provoking. Sometimes hes been here and stayed with me and my wife or stayed with Andy. Hes been great for us.

This fall after he visited during camp, hed said he wasnt feeling well, but didnt know what it was. Once he found out, hes been in constant contact with our video coordinator. He talked about having two screens up in the hospital. When I saw that he walked that marathon on his first day, I thought that was frickin amazing. I think its refreshing for him to on the zooms with the staff thoughout all this and I think its made us all in this building even more appreciated for what we have seeing how quickly it can all be turned upside down.

Lubick will get a stem cell transplant on Dec. 8. That, his doctors told him, means his body is responding well to the chemo. He feels fortunate that he has the best doctors in the world, and hes been training for the stem cell transplant much like he did the Boston Marathon. He tries to bike 10 miles a day. Sometimes he walks 8 or 10 miles. Hes also been intentional in trying to gain back weight that hes lost. His recovery from the transplant is expected to take three months, where he wont be able to drive or go to a grocery store, so hell rely on his parents.

When Kansas beat No. 6 Oklahoma for the Jayhawks first home win against a top-10 opponent in 39 years, Lubick watched it from his house in Colorado, while trying to get his red zone presentation ready for the upcoming Iowa State game during the commercial breaks. He cant stay up all night like he used to. I have to be smarter and plan ahead now, he said.

He is aware things are about to get a lot harder with his treatments. When he met with the stem cell doctor, Lubick was reeling.

A big part of it was him explaining just how serious this really is and about all the things that can go wrong, said Lubick, but at the same time, I felt grateful that he was so compassionate and that I have someone who is one of the best in the field to oversee the transplant.

The stem cell is gonna be where the rubber meets the road and thats where you get the most sick. Its like Mike Tyson said, everyone has a plan till you get punched in the mouth. When everything hits the fan and I start getting really sick from the chemo, thatll be where I hopefully can give a testimonial to help others.

He has always considered himself religious and spiritual, but since being diagnosed with leukemia, he looks at things much clearer.

Ive always been looking for purpose and meaning in my life, Lubick said. I always felt coaching was that for me. I can see it changing. The things I used to think were so important and I got stressed out about arent that important really. No one wants to get this, but I can feel it refining my character. Its teaching me more about empathy, forgiveness and patience. I feel like that stuff is changing in me for the better.

This has brought me closer to my parents and my family. Its brought me closer to God. Its teaching me to be more patient and be more reliant on my faith. God is putting people in my life to help me through this. I know that. I can feel the prayers and the people supporting me. We would tell our players this you either get better or you get bitter. Well, I feel pretty darn fortunate. Every day is a gift. I took that for granted. I took relationships for granted. I dont any more.

(Top photo of Matt Lubick (left) with Mark Helfrich (right) while coaching at the University of Oregon in 2016: Brian Murphy / Icon Sportswire via Getty)

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How Kansas football coach Matt Lubick found strength in marathon running to battle cancer - The Athletic

ASK THE DOCTORS: STEM CELL TREATMENT FOR TYPE 1 … – MDJOnline.com

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ASK THE DOCTORS: STEM CELL TREATMENT FOR TYPE 1 ... - MDJOnline.com

Judge credits family, community, fitness and prayer with his rebound … – The Winchester Star

By Stem Cell Doctors

WOODSTOCK Kevin and Kathy Black are grateful for many things this Thanksgiving. Like many families throughout the Valley, theyll gather for fellowship and a meal that might taste a little sweeter after the challenges of the last few years.

Nearly one year ago, Kevin a judge in the 26th Circuit Court who presides in Shenandoah, Warren, Frederick, Clarke, Page, and Rockingham counties and the City of Winchester received a stem cell transplant for treatment of leukemia.

The Woodstock couple, married for 42 years, said they are thankful for family and community support and advances in medicine, adding that they believe Kevins physical fitness and positive attitude were vital in seeing them through the ordeal.

After an unusual fainting spell in the summer of 2020, Kevin, who is notoriously physician-averse, went to get checked out.

Im a guy who never wants to go to the doctor, never wants to have anything done to me. At that time, nobody would see you, Kevin recalled, referencing the practice of telehealth that was common at that stage of the COVID pandemic.

An initial bone marrow biopsy confirmed that Kevin had Chronic Lymphocytic Leukemia (CLL), a type of cancer of the blood and bone marrow that typically progresses more slowly than other types of leukemia.

Kathy, who has served as the Shenandoah County Commissioner of the Revenue for 24 years, recalled doctors telling them, But dont worry, thats the best leukemia to have.

Kathy took a deep dive into understanding what was happening with her husband.

I didnt want to know any of that, said Kevin, aJuvenile and Domestic Relations Court judge for four years before his current appointment and a Woodstock lawyer for 31 years before that.

She started asking questions about a different type of blood cancer.

In August, Kathy was talking about multiple myeloma and the doc had me have a PET scan and she pretty much said, Nope, youre good. You just have CLL. But then she had me go do another bone marrow biopsy in April and then the phone call was the one you dont ever want to hear, Kevin said, adding that he was referred to a multiple myeloma specialist. Of course, I knew that was bad.

Along with CLL, Kevin was diagnosed with multiple myeloma, a cancer that forms in a type of white blood cell called a plasma cell. In multiple myeloma, cancerous plasma cells build up in bone marrow.

From the first bone marrow biopsy to the second, it had exploded. It was moving really fast. Its just lucky that we caught it so early. Its probably an act of God that he got sick originally, Kathy said.

Added Kevin, Oh yeah. I'd never have gone to the doctor. I dont know what would have convinced me. Its really weird when you think how much Ive avoided doctors and healthcare and all that its just fortuitous that the events played the way they did. A lot of people find out they have multiple myeloma theyll be walking along and a leg will break. They say your bones turn into like Swiss cheese.

An avid fitness enthusiast, Kevin lifts weights a couple of times a week and runs about 30 miles each week. He said that he had been feeling great despite his diagnosis.

The day I took my first chemo pill, the night before I had just run up the mountain. When I go by myself I go really hard, he said, adding that he told Kathy that he felt like a million bucks." I said, I cannot believe I have cancer and I cannot believe that Im going to start taking this poison and God knows whats going to happen to me.' It was weird because I felt that good.

After seeking opinions from several oncologists and cancer specialists, Kevin reluctantly came to terms with the fact that hed had to go through a stem cell transplant.

They kill your bone marrow with chemo. I didnt like the sound of that. Before they do all that, they harvest your stem cells, Kevin said. Understand, the idea of somebody sticking me with a needle for my whole life was the most repulsive thing. Ive been stuck by hundreds of needles in the last two years, but anything that sounded like that was just something that I didnt want to do.

Kevin stayed as active as possible before the procedure, continuing his runs up a steep mountainside until his stem cells were harvested in late September 2022. After a couple of mishaps a dog bite and a battle with respiratory syncytial virus (RSV) the transplant finally happened Dec. 1, Kathy said.

A former ultrarunner, Kevin said the transplant was difficult on many levels from the procedure itself which left him humbled at the weakness in his body to the forced 100-day isolation required to protect his rebuilding immune system but grateful for advances in medicine.

Think about what theyve done. Its kind of amazing to think that 20 years ago they didn't have that. The doc told me in Winchester, except for the chemo theyve discovered in the last 20 years, which is way better than what they had, and the stem cell thing, I probably wouldnt be here now, Kevin said.

In the challenges of the process, the couple said they were well supported by their community.

Im grateful for all the support, mostly from Kathy, but also from everybody around me. That would be the number one thing I learned from all of this you really need to have someone there who is capable of processing and advocating for you, Kevin said, adding that the couples three sons and their wives were especially supportive.

Kevin added, My colleagues, they filled in the gaps for what I couldnt do and just all the people who prayed. You realize you need that support. I dont know if you take it for granted, but you just dont realize the support you have around you until you get in that situation.

The Blacks, who connected with another local couple who were going through the stem cell transplant process, said they are happy to talk with others about their experiences.

It was nice to have this other couple that we could talk to and I could talk to his wife about her job as the caregiver. It helped us so we would hope that if either of us could help someone, wed be happy to, Kathy said, adding that her staff stepped up to cover for her and keep things running smoothly at the county office and friends were there to lend an ear or a shoulder or provide a meal.

Set to retire from her post at the end of the year, Kathy added, Im thankful that Kevin is such a strong person because I don't know how to live without him. Our kids were very helpful. Even right now. Our second son is coming home from Asheville for the week. He was supposed to come yesterday, but hed had the flu and they wanted to make sure that his wife didnt have it before they came. The thoughtfulness and caring that everyone has shown were blessed to live in a community like this where people are more than willing to help you.

Kevin said that he was especially grateful for his longtime friend, Roy Marshall, who emphasized the importance of staying positive.

We had some talks and thats where I got his wisdom about how so many people were so gloomy [during cancer treatment]. I made my mind up that I didnt want to be that person, Kevin said, adding that Roy helped introduce him to ultrarunning, a sport he enjoyed for several years in his 40s.

Noting that hed always been interested in staying healthy, Kevin said that he met Roy when he returned to the area after law school.

My whole lifestyle all along lent itself to somebody who could weather all this stuff, he said. Theres no cure. Someday, most likely, thisll come back and Ill have battle two. Hopefully, going out and running and staying in shape will help me go through the next battle. The sermon I would preach to people is you need to get yourself in as good a shape as you can because when round two comes, you want to have something to fight it with.

That being said, Kevin added, Im not doing what Im doing to get ready for round two. Thats a collateral benefit. Im just trying to live my life.

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Judge credits family, community, fitness and prayer with his rebound ... - The Winchester Star

Crew Studies Biology and Works in Dragon as Station Turns 25 – NASA Blogs

By Stem Cell Doctors

The space station is pictured from the SpaceX Crew Dragon Endeavour during its departure and flyaround on Nov. 8, 2021.

Space biology and Dragon work were the top duties at the beginning of the week for the Expedition 70 crew. The International Space Station also turned 25 years old today with its first module having orbited Earth since 1998.

Eye scans were on the biomedical research schedule for four astronauts on Monday afternoon. Commander Andreas Mogensen kicked off the exams activating the Ultrasound 2 device then setting up communications gear allowing doctors on the ground to remotely monitor the activities. Mogensen from ESA (European Space Agency) then took turns with flight engineers Loral OHara, Jasmin Moghbeli, and Satoshi Furukawa in the Columbus laboratory module participating in the regularly scheduled eye exams.

Mogensen partnered with Moghbeli from NASA at the end of the day and practiced SpaceX Dragon Endurance undocking and landing procedures on the crew spacecrafts computers. Mogensen earlier unpacked medical supply kits from Endurance and stowed them inside the orbital outpost. OHara from NASA and Furukawa from JAXA (Japan Aerospace Exploration Agency) worked inside Endurance as well configuring orbital plumbing gear in the vehicle that has been docked to the station since Aug. 27.

OHara later worked on a space botany study to promote STEM (Science, Technology, Engineering, and Math) education among tribal members. Five varieties of seeds provided by the Choctaw Nation of Oklahoma are exposed to microgravity for several months then returned to Earth and planted next to the same seeds left on Earth for comparison. Furukawa turned off a microscope in the Kibo laboratory module and removed samples for a study that was observing how cells sense gravity or the lack gravity. He then stayed in Kibo setting up research hardware and connecting an incubator for an upcoming experiment to observe stem cell growth that may support regenerative medicine technology.

In the Roscosmos segment of the space station, veteran cosmonaut Oleg Kononenko spent the day inside the Nauka science module checking its airlock, ventilation, and docking systems. Flight Engineer Nikolai Chub attached sensors to himself monitoring his cardiac activity then cleaned air ducts inside the Nauka and Poisk modules. Flight Engineer Konstantin Borisov wore a sensor-packed cap that recorded his responses while practicing futuristic planetary and robotic piloting techniques on a computer.

On Nov. 20, the International Space Station passes 25 years since the first module launched into orbit. The Zarya module lifted off in November 1998 from the Baikonur Cosmodrome in Kazakhstan and would shortly be joined by the Unity module less than a month later. Through this global endeavor, 273 people from 21 countries now have visited the unique microgravity laboratory that has hosted more than 3,000 research and educational investigations from people in 108 countries and areas.

Learn more about station activities by following thespace station blog,@space_stationand@ISS_Researchon X, as well as theISS FacebookandISS Instagramaccounts.

Get weekly video highlights at:https://roundupreads.jsc.nasa.gov/videoupdate/

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Crew Studies Biology and Works in Dragon as Station Turns 25 - NASA Blogs

Wall thickness analysis method for judging the degree of lower … – Nature.com

By Stem Cell Doctors

Patients

The institutional review board of our hospital approved this study (Number 20150129). All patients provided written informed consent. From April 2014 to October 2019, patients with complete follow-up data who underwent internal fixation surgery for lower extremity fractures at our hospital were recruited. The follow-up data included X-ray and CT data 9months after surgery. Two senior orthopedic doctors and an imaging physician judged the degree of fracture healing in the patients according to the patients X-ray, CT and clinical data. According to the above criteria, the status was judged as bone healing, poor bone healing and bone nonunion. If the diagnosis was inconsistent among the three doctors, the same result provided by two of the doctors was taken, and if the results of the three doctors were not the same, the case was excluded. A total of 79 patients were included in the study. A total of 112 CT scans were performed, 49 of the scans were judged to show bone healing (group A), 37 were judged to show poor bone healing (group B), and 26 were judged to show nonunion (group C). There were 21 females in group A, with an average age of 46.712.4years and a follow-up time of 18.73.4months. There were 12 cases of femoral fracture, 37 cases of tibial fracture, 15 cases of intramedullary nail fixation, and 34 cases of plate screw fixation in group A. There were 15 females in group B, with an average age of 51.214.5years and an average follow-up time of 14.73.8months. There were 9 cases of femoral fracture, 28 cases of tibial fracture, 24 cases of plate fixation, and 13 cases of intramedullary nail fixation in group B. There were 15 females in group C, with an average age of 49.213.5years and an average follow-up time of 15.74.4months. There were 8 cases of femoral fracture, 18 cases of tibial fracture, 17 cases of plate fixation, and 9 cases of intramedullary nail fixation in group C (Table1). The fractures of the samples were diaphyseal and metaphyseal, not intra-articular fractures.

Hardware: GE 64-row spiral CT machine (Light Speed spiral CT, GE, USA). Dell high-performance computer (CPU: E3-1225 V2 3.20GHz, memory: 16GB, graphics card: NVIDIA Quadro K4200, operating system: Windows 10, 64-bit).

Software: Mimics Research 20.0, 3-matic Research 12.0 (Materialise, Belgium), provided by Sandi Tribe (Shanghai) Technology Co., Ltd.

The lower limbs of the patients were placed in parallel with the toes up, and a full-length scan was performed. The CT scan interval was 0.625mm, and the matrix size was 512512 pixels. The scan voltage was 140kV, the exposure was 100 mAs, and the screw pitch was 0.625mm (GE 64-slice spiral CT machine with automatic tube current control system with the same scan parameters on both sides). The obtained general DICOM 3.0 standard format data were stored.

Mimics 20.0 software was used to directly read the CT images in DICOM 3.0 format. Three-dimensional geometric models were established under the same threshold conditions for the affected side with internal fixation, the affected side without internal fixation and the unaffected side, and the average CT data of the models were recorded.

The three sets of data from the models of the healthy side, the affected side with internal fixation, and the affected side without internal fixation were imported into 3-matic Research 12.0. An adaptive triangle mesh was applied, and the side length was set to 1mm to optimize the details of the model. The detailed characteristics of the model were retained, and the maximum wall thickness threshold was set to 10,000mm during wall thickness analysis.

To interpret the weak areas of the cortical bone in terms of the wall thickness and the transformation in terms of the relationship between the density and stiffness of the material, the median wall thickness of the unaffected limb and the affected limb with and without internal fixation was measured. The analysis was performed as follows: in the Analyze tab, the Create Wall Thickness Analysis button was clicked, and then Cortical As Entity was selected. The threshold was set to 10,000.0mm. A histogram with the wall thickness distribution was displayed, and a series of colors was visualized on the Cortical 3D object, with green representing thinner structures and red corresponding to thicker areas.

We performed three-dimensional reconstruction of the CT data of the healthy and affected segments under the same conditions, resulting in wall thickness graphs corresponding to the basic phase and the target phase, respectively. Three-dimensional reconstruction of the CT data of the affected limb with simulated removal of the internal fixation was performed, yielding a wall thickness graph corresponding to the simulated phase (Fig.1).

Three phases of wall thickness analysis: the basic phase (A), the target phase (B), and the simulated phase (C).

The ratio of the median wall thickness and the average CT value in the simulated phase to the corresponding values in the basic phase was calculated to obtain the ratios R2 and R4: R2=median wall thickness of the simulated phase/median wall thickness of the basic phase; R4=average CT value of the simulated phase/average CT value of the basic phase. The product of the average CT value and the median wall thickness was defined as the healing index (HI), and R5=simulated phase HI/basic phase HI.

The fracture healing state was evaluated through imaging and clinical examinations at 9months after surgery. The bone healing of patients was observed for half a year after removal of the internal fixation to monitor for refracture. In the case that nonunion continued to be observed, bone grafting and internal fixation were performed again. Patients with poor bone healing were further observed. If there were no signs of healing, bone grafting was performed.

The criteria for bone healing were as follows: X-ray images showed blurring of the fracture line and a continuous callus passing through the fracture line11; additionally, upon the release of external fixation, the patient does not have any tenderness at the fracture site, can walk with weight, and has no longitudinal pain in the fractured limb on percussion12.

The criteria for bone nonunion were as follows: Nonunion was defined by pain and abnormal activity at the fracture site, persistent light-transmitting bands on X-ray examination, and no progress in the formation of the callus at 12weeks after treatment13.

Poor bone healing was defined as a healing state between that of bone healing and bone nonunion.

Measurement data are expressed as the meanstandard deviation or median, and Pearson or Spearman correlation analysis was performed. One-way ANOVA was conducted to analyze differences between multiple groups. Receiver operating characteristic (ROC) curve analysis was performed for the diagnostic analysis, and the critical point of diagnosis was analyzed by the maximum Youden index method. P<0.05 was set as statistically significant, and all data analyses were performed by SPSS (version 20.0; IBM Corp., Armonk, NY, USA).

Informed consent was obtained from all the patients and the study was approved by Biomedical Ethics Committee of Anhui Medical University (reference number 20150129). The study has been performed in accordance with the ethical standards of the Declaration of Helsinki in 1964.

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Wall thickness analysis method for judging the degree of lower ... - Nature.com