Category Archives: Cell Medicine

A multiple myeloma expert helps newly diagnosed patients understand the standard of care for their disease.

Richter, an assistant professor of medicine at the Tisch Cancer Institute at the Ichan School of Medicine in Mt. Sinai Hospital located in New York City, noted that there are always exceptions to this rule, but the standard of care is to keep patients with multiple myeloma to continue therapy long term.

This standard of care, however, presents unique challenges and questions for newly diagnosed patients about to undergo treatment. In an interview during the 2019 CURE Educated Patient Summit on Multiple Myeloma in Charlotte, North Carolina, Richter had the chance to address the key aspects of a multiple myeloma diagnosis and how he addresses common questions from patients.

CURE: What does transplant eligible and transplant ineligible mean for patients?

Richter: The notion of transparent eligibility in the U.S. is not clearly defined. One of the people who trained me used to say, Do the patients have the tiger? relating back to Rocky, and essentially what this means is people who are younger tend to be more eligible. So, are you able to undergo the intensive nature of that procedure and chemotherapy?

If you're younger and healthier, you're generally transplant eligible. As you get older, with more medical problems, it becomes more of a risk. Everything in medicine from a Tylenol to a transplant has a risk and benefit. If you are 105 years old and had a heart attack last week, you're not going to be eligible. If you're 40 and otherwise healthy, you're eligible and everywhere in between is an evaluation of risks and benefits.

How would you describe the standard of care for patients with multiple myeloma?

In general, the standard of care is to attempt to get people onto three drugs. The three drugs usually mean a steroid, and then either an immunomodulatory drug, a proteasome inhibitor or a monoclonal antibody, and using those different combinations to come up with two or three-drug combinations, and actually in some cases four-drug combinations.

The general discussion of which one makes sense is we generally try to put some on a three-drug combination and the two most common ones now VRd (Velcade, Revlimid, and dexamethasone) is really a very big standard approach. There's some really wonderful, emerging data from the MAIA study, looking at taking Revlimid and dexamethasone and adding Darzalex (daratumumab) as a three-drug regimen for people who are not going on to transplant and some of that data looks amazing.

But for the most part, the precision that we use has to do not so much with the tumor but with the patient. Meaning for some diseases, the precision in the upfront setting is we look at a genetic marker and we target that. But for myeloma our upfront choice of therapy is saying, what are your comorbidities? What are your risks? For someone who has neuropathy, we may avoid Velcade. Someone has heart issues, we may avoid carfilzomib (Kyprolis) and if someone has difficult coming back and forth for long infusions, we may avoid Darzalex. So, most of the precision that we use is custom tailoring it not necessarily to the disease upfront, although that's part of it, but also to the patient.

What is the role of stem cell transplantation in treating patients with multiple myeloma?

The role of transplant is constantly evolving in myeloma. A generation ago, when we didn't have very good drugs, transplant was clearly the best thing to do because we didn't have good medicines. Transplant was the only way to get deep and durable remissions. Nowadays that we have such better therapies and even better ones along the way, it's being called into question about how much do we still need transplant. And it's a case by case basis, some people still clearly benefit from transplant.

It's an important discussion to have with your provider. But the risks have been well established for many years and we know how to manage them very well. Although there are risks for it, they're generally consolidated into a couple weeks to a couple of months, as opposed to being on long term treatment that can have ongoing risk of side effects. So, yes, they may be higher, but it's usually for a self-contained amount of time.

It's still a very important tool in our armamentarium to treat patients. Now, that being said, the majority of patients in the United States do not receive autologous transplant, so only about 30% and part of the reason has to do with the age of patients. The average age of a myeloma patient in the U.S. is 69, and many people in their 70s and 80s have other medical problems that make them not eligible for transplant.

There are some socioeconomic reasons, as well as referral patterns and access to care. I live in New York City, you can throw a rock and hit a transplant center, but there are parts of the country where the closest transplant center is hours and hours and hours away. And if you are older, sick or don't have easy transportation, it may be more difficult. So, many people do not receive transplant. However, many people nowadays may not even need it because our drugs have gotten so much better.

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Understanding the Key Aspects of a Multiple Myeloma Diagnosis - Curetoday.com

P. Todd Stukenberg, PhD, of UVAs Department of Biochemistry and Molecular Genetics and the UVA Cancer Center, works in his lab. Credit: Dan Addison | UVA

Scientists at the University of Virginia School of Medicine have discovered a strange new organelle inside our cells that helps to prevent cancer by ensuring that genetic material is sorted correctly as cells divide.

The researchers have connected problems with the organelle to a subset of breast cancer tumors that make lots of mistakes when segregating chromosomes. Excitingly, they found their analysis offered a new way for doctors to sort patient tumors as they choose therapies. They hope these insights will allow doctors to better personalize treatments to best benefit patients sparing up to 40 percent of patients with breast cancer, for example, a taxing treatment that wont be effective.

Some percentage of women get chemotherapy drugs for breast cancer that are not very effective. They are poisoned, in pain and their hair falls out, so if it isnt curing their disease, then thats tragic, said researcher P. Todd Stukenberg, PhD, of UVAs Department of Biochemistry and Molecular Genetics and the UVA Cancer Center. One of our goals is to develop new tests to determine whether a patient will respond to a chemotherapeutic treatment, so they can find an effective treatment right away.

The organelle Stukenberg and his team have discovered is essential but ephemeral. It forms only when needed to ensure chromosomes are sorted correctly and disappears when its work is done. Thats one reason scientists havent discovered it before now. Another reason is its mind-bending nature: Stukenberg likens it to a droplet of liquid that condenses within other liquid. That was the big wow moment, when I saw that on the microscope, he said.

These droplets act as mixing bowls, concentrating certain cellular ingredients to allow biochemical reactions to occur in a specific location. Whats exciting is that cells have this new organelle and certain things will be recruited into it and other things will be excluded, Stukenberg said. The cells enrich things inside the droplet and, all of a sudden, new biochemical reactions appear only in that location. Its amazing.

P. Todd Stukenberg, PhD, of UVAs Department of Biochemistry and Molecular Genetics and the UVA Cancer Center, discovered an unknown organelle in our cells that helps ensure genetic material is sorted correctly when cells divide. Credit: Dan Addison | UVA

Its tempting to think of the droplet like oil in water, but its really the opposite of that. Oil is hydrophobic it repels water. This new organelle, however, is more sophisticated. Its more of a gel, where cellular components can still go in and out but it contains binding sites that concentrate a small set of the cells contents, Stukenberg explained. Our data suggests this concentration of proteins is really important. I can get complex biochemical reactions to occur inside a droplet that Ive been failing to reconstitute in a test tube for years. This is the secret sauce Ive been missing.

While its been known for about eight years that cells make such droplets for other processes, but it was unknown that they make them on chromosomes during cell division. Stukenberg believes these droplets are very common and more important than previously realized. I think this is a general paradigm, he said. Cells are using these non-membranous organelles to regulate much of their work.

In addition to helping us understand mitosis how cells divide Stukenbergs new discovery also sheds light on cancer and how it occurs. The organelles main function is to fix mistakes in tiny microtubules that pull apart chromosomes when cells are dividing. That ensures each cell winds up with the correct genetic material. In cancer, though, this repair process is defective, which can drive cancer cells to get more aggressive.

He has also developed tests to measure the amount of chromosome mis-segregation in tumors, and he hopes that this might allow doctors to pick the proper treatment to give cancer patients. We have a way to identify the tumors where the cells are mis-segregating chromosomes at a higher rate, he said. My hope is to identify the patients where treatments such as paclitaxel are going to the most effective.

Having looked at breast cancer already, he next plans to examine the strange organelles role in colorectal cancer.

###

Stukenberg and his colleagues have described their discovery in the scientific journal Nature Cell Biology. The research team consisted of Prasad Trivedi, Francesco Palomba, Ewa Niedzialkowska, Michelle A. Digman, Enrico Gratton and Stukenberg.

Reference: The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex by Prasad Trivedi, Francesco Palomba, Ewa Niedzialkowska, Michelle A. Digman, Enrico Gratton and P. Todd Stukenberg, 3 September 2019, Nature Cell Biology.DOI: 10.1038/s41556-019-0376-4

The research was supported by the National Institutes of Health, grants R01GM124042, R24OD023697 and P41-GM103540; and the National Science Foundation, grant MCB-1615701.

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Strange New Organelle That Helps Prevent Cancer Discovered in Our Cells - SciTechDaily

IN the summer of 2019, a mother in Nashville, Tennessee in the United States, with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old said.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so that doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as a molecular scissors.

The genetically-edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary, but theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease beta thalassemia.

She had previously needed 16 blood transfusions per year. Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible.

It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the co-founder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Gene cures

Crispr was the latest breakthrough in a year of great strides in gene therapy, a medical adventure that started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not, such as making normal red blood cells in Grays case or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he said. It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the US National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said US NIHs associate director for science policy Carrie Wolinetz.

These therapies are exorbitantly expensive, however, costing up to US$2 million (RM8.18 million) meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to Massachusetts Institute of Technology (MIT) researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

In this Oct 10, 2018, photo, He speaks during an interview at his laboratory in Shenzhen, China. The scientist was recently sentenced to three years in prison for practicing medicine illegally and fined 3 million yuan (RM1.76 million). AP

Bioterrorism potential

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

In 2018 in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA (deoxyribonucleic acid) of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV (human immunodeficiency virus), even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, he added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species, e.g. malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist -- weve been talking about bioterrorism for years, she said. Nothing has ever happened. AFP Relaxnews

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Gene editing breakthroughs that cured genetic diseases in 2019 - The Star Online

For all of the wondrous potential of immunotherapies, there have been some notable obstacles in the early goings. Engineering immune cells to attack cancerous tumors can lead to solid results shortly after administering a dose, but for many patients the effects wear off once rapidly mutating tumor cells acquire new defense mechanisms.

Cellectis (NASDAQ:CLLS) thinks it may have a partial solution. In mid-November, the gene editing company published the results from a proof of concept study for its "smart" immunotherapy approach. Is the technique the future of cellular medicine?

Image source: Getty Images.

Today, cellular oncology therapies genetically engineer immune cells to bolster their safety and efficacy as a cancer treatment. There are T cells, natural killer (NK) cells, tumor infiltrating lymphocytes (TILs), and others. They're often engineered with chimeric antigen receptors (CARs) or T cell receptors (TCRs), which allow them to home in on and suppress specific genes in cancer cells.

While current-generation CAR T cells or CAR NK cells are capable of mounting formidable attacks on tumors at first, treatment responses aren't durable for all patients. That's because cancer cells mutate to rely on different proliferation genes, or secrete new molecules into the tumor microenvironment that neutralize immune cells. Meanwhile, overstimulating the immune system can reduce the potency of immune cells and lead to devastating side effects, such as cytokine release syndrome.

That prompted Cellectis to design "smart" CAR T cells capable of adapting to changes in the tumor microenvironment. In a proof of concept study, the company utilized synthetic biology concepts to rewire genetic circuits in three different genes of the initial T cells.

One edit made the immunotherapy more potent, but in a controlled manner to reduce off-target toxicity. The other two edits imbued CAR T cells with the ability to secrete inflammatory proteins inside the tumor microenvironment in proportion to the concentration of cancer cells.

In other words, the smart CAR T cells only asked for help from the rest of the immune system when it was needed most, which increased the anti-tumor activity of treatment and made native immune cells less likely to become neutralized. That should reduce the likelihood of triggering cytokine release syndrome, the most common (and potentially fatal) side effect of cellular medicines, which is caused by high concentrations of immune cells.

The study was conducted in mice, which means the safety and efficacy observations can't be extrapolated into humans. But that wasn't the point. The proof of concept demonstrates that the basic idea of engineering tightly controlled genetic circuits into immunotherapies is feasible. It could even allow multiple genetic circuits of the same drug candidate to be tested against one another in parallel, hastening drug development and lowering costs. Is it the inevitable future of cellular medicine?

Image source: Getty Images.

Gene editing tools are required to engineer immune cells. In fact, immunotherapies are the lowest hanging fruit for gene editing technology platforms today. It's simply easier to engineer immune cells in the lab (ex vivo) than it is to engineer specific cell types in the complex environment of the human body (in vivo).

That explains why nearly every leading gene editing company has immunotherapy programs in its pipeline. Coincidentally, all of the leading drug candidates in the industry pipeline are off-the-shelf CAR T cells engineered to treat CD19 malignancies such as non-Hodgkin's lymphoma (NHL) and B-acute lymphoblastic leukemia (B-ALL), regardless of the gene editing approach used. The smart CAR T cells designed by Cellectis targeted CD22 malignancies, but the approach could be adapted to CD19 antigen.

Developer(s)

Drug Candidate

Gene Editing Approach

Development Status

Cellectis and Servier

UCART19

TALEN

Phase 2

Precision BioSciences (NASDAQ:DTIL)

PCAR0191

ARCUS gene editing

Phase 1/2

CRISPR Therapeutics (NASDAQ:CRSP)

CTX110

CRISPR-Cas9

Phase 1/2

Sangamo Therapeutics (NASDAQ:SGMO) and Gilead Sciences (NASDAQ:GILD)

KITE-037

Zinc finger nuclease

Preclinical

Data source: Company websites.

Will these companies eventually turn to "smart" immunotherapies with regulated genetic circuits? It does seem inevitable, especially if the approach can reduce or eliminate cytokine release syndrome and enable more durable responses.

For example, Cellectis reported that all seven patients taking part in the phase 1 trial of UCART19 suffered from at least grade 1 cytokine release syndrome, which caused complications that led to the death of one patient. Five of the seven patients achieved molecular remission, but one relapsed (and remained alive) and one died. To be fair, all patients taking part in the trial had advanced, heavily pretreated B-ALL.

Precision BioSciences has encountered similar obstacles in an ongoing phase 1/2 trial of PBCAR0191. The company's lead drug candidate was administered to nine patients with NHL or B-ALL. Three cases of cytokine release syndrome were reported, but all were manageable. Seven responded to treatment, including two that achieved a complete response, but three eventually relapsed.

CRISPR Therapeutics recently began dosing patients with CTX110 in a phase 1/2 trial that will eventually enroll up to 95 individuals, but initial results won't be available until 2020. Sangamo Therapeutics and Kite Pharma, a subsidiary of Gilead Sciences, are plowing ahead with zinc fingers,but are still in preclinical development.

Investors seem pleased with most of these gene editing stocksright now. After all, despite the obstacles, current-generation cellular medicines are delivering impressive results in patient populations with relatively few options. But upcoming data readouts could easily differentiate the pack. That could increase the need to invest in augmented capabilities, such as smart immunotherapies.

There's plenty of untapped potential in cellular medicine. Today, companies are developing drug candidates with engineered CARs and TCRs designed to test hypotheses about the function of immunotherapies. As approaches find success, measured in safer and more durable responses, the next layer of complexity will be added in an effort to find even more successful therapies. And the cycle will continue.

Therefore, it seems inevitable that the field of cellular medicine will turn to smart immunotherapies with more complex genetic edits, much like the field quickly embraced the need for engineered immune cells and off-the-shelf manufacturing processes. That said, the immediate focus for Cellectis and its peers is building a stable foundation -- and those efforts have only just begun.

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Did Cellectis Just Provide a Glimpse of the Future of Cellular Medicine? - The Motley Fool

Patients with multiple myeloma have a lot to look forward to in the treatment space thanks to precision medicine, but one treatment option alone will not cure the disease.

At the 2019 CURE Educated PatientSummit on Myeloma in Charlotte, North Carolina, Rodriguez, director of the myeloma and plasma cell disorder program at Wake Forest University, had the chance to speak to numerous patients with multiple myeloma on the current treatment landscape of the disease and precision medicines role in it.

This year, Rodriguez also participated in the Multiple Myeloma Research Foundations Moving Mountains for Multiple Myeloma program when he took a 10-day journey through the South American region of Patagonia with other multiple myeloma survivors and specialists. This journey allowed Rodriguez to have intimate contact with patients who have multiple myeloma and talk with them about the future of treatment for the disease.

In an interview with CURE, Rodriguez explained the role of precision medicine in the treatment of patients with multiple myeloma and how he addresses common questions about it from patients.

CURE: How has precision medicine changed the landscape of treatment for patients with multiple myeloma?

Rodriguez: Precision medicine has changed the way we treat myeloma in many ways, and that not only means that we are finding new therapy that can target specific areas of the cancer cells, (allowing us) to have more effective therapy with less side effects, but it also means that we can actually tailor therapy to an individual patient.

It's not just that we're developing new drugs that are homing in on the cancer cells, but it also is that we're taking some time to individualize the care based on each patient's needs, each patient's requirements, and the cancer that each patient has. We do know that multiple myeloma is not a one-stop, everybody-has-the-same-type disease; everybody has different variants, and within a person, there's different subgroups of myeloma cells that needs to be targeted in a different way.

What are some of the questions about precision medicine that patients might have for you, and how do you address them?

One of the questions that normally arises whenever precision medicine, or personalized medicine, or targeted therapy all of these words are used interchangeably in clinic (comes up) is: Will a new treatment that targets a specific mutation cure my disease, if I have that mutation? And that's a very valid question, because you would think that if we've designed a therapy that can target a particular mutation that your cancer has, that we would eradicate the cancer.

Yet, the reality is, I don't think that targeting one particular mutation is going to be the solution to our problems. Myeloma is composed of many subgroups of myeloma cells within one patient.

So, combining precision medicine with a therapy that we already have and targeted immunotherapy that might give us a broader aspect of how we can target the cancer and have better control of it. Hopefully, by combining different targeted therapies with standard therapy, we might be able to eradicate the cancer. But the precision medicine or a single agent on its own is probably not going to be the solution for it.

What are some of the unique challenges from the use of precision medicine to treat patients with multiple myeloma?

One of the challenges of precision medicine in myeloma in particular is that myeloma tends to evolve as time goes by, and it's developing new mutations. And these new mutations can cause resistance to therapy. Even if we're using precision medicine that can target a particular mutation, if that cancer cell continues to evolve and mutate, maybe that particular mutation, or that target, might change as well, and then the therapy stops working.

That's a big challenge that we still have with precision medicine, that we need to figure out how we can factor that in whenever we're treating patients. So, resistance to therapy, despite (the use) of precision medicine, is something that we can potentially see.

What is the difference between DNA and RNA testing for patients with multiple myeloma?

The difference between DNA and RNA when it comes to cancer is a little bit different. We're using genes now to understand how cancer behaves. That's given us a lot of information about how we can potentially treat myeloma and how it normally behaves. A lot of doctors might say, Oh, I'm checking your DNA, or I'm checking your RNA to see what information we can get from it.

The main difference is, DNA is all the genes that we have in our body, and all the genes that are going to be in a cell and particular in a cancer cell. RNA are the genes that are actually used and expressed in those cancer cells. So not all the DNA is used. It's just the RNA portion that's going to be telling us what sections of the DNA are actually active and which ones are not.

Can you discuss some of the highlights from your keynote lecture at the 2019 CURE Educated Patient Summit on Multiple Myeloma?

The focus of the talk was on a few factors. One is that we've realized that treating myeloma patients it's not the same if I treat somebody here or if I treat somebody in a different state or in a different country. Humans are not all the same. We all are very unique. We all have very different characteristics and features, medical problems, social issues, environmental differences and walks of life. We cannot use one same treatment for all of us, because it's not going to be effective for all of us.

So, tailoring it for our different characteristics is one part of precision medicine. And then the other factor in my talk was the cancer itself. Myeloma is not just one cell type, where all the people who have myeloma are going to have the same characteristics. It's very variable, and within patients, there's variability, and there are different clones of myeloma cells in that same patient, and then each patient is very different in terms of how their myeloma is.

We've learned so much about cancer, and myeloma in particular, that we've now been able to identify different subgroups of myeloma cells within a patient, or between patients, that we can target and be more specific in how we treat. So, the goal of the talk was to let everybody see that whenever we are treating myeloma, we have to individualize the care to that particular patient.

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Precision Medicine Paves the Way for Exciting Treatment Combinations for Patients with Multiple Myeloma - Curetoday.com

For biotech, 2019 ended like the penultimate episode of a prestige TV show. We got answers to some weighty questions, but mostly, the year left a breadcrumb trail to some major reveals.

The IPO window stayed open, helping scores of companies go public. Futuristic therapies proved their worth in clinical trials, pointing to a new era in medicine. And the markets ended the year on a high, buoyed by a Food and Drug Administration that seems ever more flexible when it comes to approving new drugs.

Now, with 2020, well get the more important answers. Sure, theres a lot of public biotech companies now, but what if thats a bad thing? Yes, cell and gene therapies look transformational, but what if they never make any money? And since when is everyone so confident they understand whats going on inside the FDA?

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Here are three trends to watch in biotech in 2020, a year that looks to be laden with opportunities and stumbling blocks for the drug industry.

While every biotech startup is undoubtedly special in the eyes of the venture capitalists quoted in its press releases, 2020 could be a year marked by fatigue for the outside public.

More than 140 biotech companies have gone public since 2017, according to the analysts at Evercore ISI, and now theres upward of 500 of them trading on the Nasdaq. Keeping tabs on them all is essentially impossible, and its become fairly commonplace for biotech types to see the name of a given company for the first time by reading about its implosion.

Thats arguably a good problem to have in societal terms. More biotech companies means more efforts to treat human disease. But it could be problematic for the herd. Drug development remains an expensive proposition, and the majority of the biotech companies that went public in the past three years have negligible or nonexistent revenue. That means theyre going to have to go back to the market with follow-on offerings, and they may not like what they find.

According to Cowens biotech thermometer, a regular update on Wall Street sentiment, investors are increasingly selective when it comes to equity offerings, spooked by slumping IPO returns and a glut of supply. If that trend continues into 2020, some of those 500-plus biotech companies might need to look for other means of keeping the doors open, including mergers that thin the flock.

Much of the conversation around cell and gene therapies has focused on how much they cost, and understandably so. Two million dollars is, objectively, a lot of dollars. But the anxiety in biotech circles is a bit different: Is anyone going to make money on these things?

Take, for instance, CAR-T cancer therapy. For some patients, a single dose erases any trace of aggressive, otherwise untreatable cancer. For every patient, a single dose costs about $400,000. That sounds like a lot, but churning out a genetically engineered immune cell is hardly akin to widget manufacture. CAR-T companies dont disclose their underlying costs, but these therapies are understood to be low-margin products.

Theyre also considered commercial disappointments. The first two approved CAR-Ts, Kymriah and Yescarta, have underperformed analyst expectations to date. And that has stoked concern that a coming wave of gene therapies could face similar commercial difficulties.

Like CAR-T, gene therapy is costly to make, can be administered only at certain sites, and has made headlines for its six- or seven-figure list prices. Biotech companies and their investors have staked billions of dollars on the idea that such one-time treatments can become lucrative products. If that assumption is incorrect and the industry cant figure out how to make money in therapy, there could be a painful knock-on effect for biotech.

Handily, theres a one-company test case to follow in 2020. Novartis (NVS) sells a CAR-T in the form of Kymriah and a gene therapy called Zolgensma. Furthermore, thanks to a recent $9.7 billion acquisition, it will likely soon sell an RNAi treatment for high cholesterol. Each endeavor is a bet that futuristic science can turn into money-making medicines. By the end of the year, well have a decent idea of whether its a wise one.

Remember 2015, when the FDA would approve or reject a drug, and people would form an opinion and move on? That all changed the following year when the agency approved eteplirsen, now called Exondys 51, which is a treatment for Duchenne muscular dystrophy from a company called Sarepta Therapeutics (SRPT).

Without relitigating the whole ordeal, its fair to say Sareptas case relied on scant, debatable evidence from a small trial. To some, the FDAs decision to approve eteplirsen anyway was a sign of forward-thinking regulation that put patients first. To others, it was a dereliction of duty that threatened to erode decades of pharmaceutical jurisprudence. And to a great many, it was reason to get on the internet and be churlish, conspiratorial, and even threatening.

On Twitter, the fight over eteplirsen has never really ended, just taken on different forms, like a biotech analog to Gamergate. Earlier this year, the debate over a heart drug made by Amarin (AMRN) quickly metastasized into eteplirsen redux, with name-calling, accusations of bad faith, and armchair psychoanalysis of FDA staff. There were smaller but similar fights over Axovant Sciences, Clovis Oncology (CLVS), and nearly every biotech company with a sizable short interest.

Its at least somewhat understandable why eteplirsen marked such a shift in biotech discourse. Where FDA past decisions seemed to come down from Mount Sinai with little in the way of transparency, the messy eteplirsen process made public internal infighting and clashing personalities at the agency. The FDAs top drug evaluator even considered Sareptas balance sheet while evaluating the drug, a departure from the agencys hands-off approach to the business of biopharma and evidence that approval decisions can be about more than benefits and risks.

Theres no evidence that the FDA was fundamentally changed by a single decision, as organizations that employ 17,000 people rarely are. But that peek behind the curtain was enough to give credence to seemingly any biotech bull case online. Where the FDA once appeared monolithic, now there were heroes and villains within, actors whose imagined biases could support any conspiracy theory. Formerly anonymous public servants became the topic of vicious debate among strangers with alphanumeric Twitter handles and pictures of dogs as online avatars. One even got called a cuck.

With all that as a backdrop, next year, Biogen (BIIB) is going to ask the FDA to approve aducanumab, a treatment for Alzheimers disease. The supporting data are confusing, drawn from a pair of terminated trials with divergent results. The agencys decision will have major implications for the drug industry, the health care system, and the more than 5 million Americans with Alzheimers.

And, on the fractious little planet that is biotech Twitter, aducanumab presents an opportunity to play out the eteplirsen debate on the grandest scale yet, with more kremlinology, more circular logic, and more vitriol. Be nice to one another out there.

Originally posted here:
3 trends in biotech to watch in 2020 - STAT

Head and neck injuries from cell phones have increased steadily over the last two decades according to a new study, peaking sharply when the iPhone debuted in 2007, and Boston doctors say its a common occurrence in their emergency departments.

We often see injuries in the ED related to cell phone use. When your phone grabs your attention, you are less aware of other things in your environment, and more likely to miss a step or not notice something in your path as you are walking, said Dr. Carrie Tibbles, Beth Israel Deaconess Medical Center emergency medicine attending physician.

And as we know, distraction while you are driving can lead to very serious consequences, said Tibbles.

A recent study published in the Journal of the American Medical Association shows 76,043 patients in the U.S. went to the emergency room with head and neck injuries related to cell phone use between January 1998 and December 2017. The information was collected from a national database.

Dr. Regan Bergmark, associate surgeon at Brigham and Womens Hospital said, Anecdotally, yes, this is a problem and you can see it driving around Boston anywhere you go so its not surprising that there would be injuries from cell phones.

The most common injuries were minor, such as cuts, bruises or scrapes, but 18% of patients had internal organ injuries.

The injuries resulted from a range of activities as common as texting and walking to cell phone battery explosion or using a phone while driving.

According to data from the Massachusetts Department of Transportation, there have been more than 46,000 distracted driving crashes in the state between 2014 and 2018. Of those crashes, 38% were caused by the use of an electronic device.

AAA spokeswoman Mary Maguire said, Smart phones are a potent distraction behind the wheel, and we see evidence of that every day on our roads: drivers who are looking at their phones, and not the road.

Most injuries logged in the study happened in people aged 13-29 years old, with a sharp increase in injuries happening in 2007, This period also coincides with the release of the first major successful smartphone in the US market, the iPhone, researchers wrote.

A new distracted driving bill, signed into law by Gov. Charlie Baker last month bans drivers from using handheld devices while driving. Warnings will be issued during the current grace until March 31, 2020, and violators thereafter will be subject to fines.

Original post:
Injuries from cell phones increasing nationwide - Boston Herald

Taysir Garadah,1,2 Fatema Mandeel,2 Ahmed Jaradat,1 Khalid Bin Thani1,2

1Medical Department, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain; 2Medical Department, Cardiac Unit, Salmanyia Medical Complex, Manama, Kingdom of Bahrain

Correspondence: Taysir GaradahMedical Department, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 26671, Manama, Kingdom of BahrainTel +973-17239681Fax +973-17230730Email garadaht@hotmail.com

Background: The impact of hydroxyurea (HU) medication as treatment of choice has not been evaluated in adult sickle cell anemia (SCA) patients in terms of the 6-min walk distance (6 MWD).Aim: The aim of the study was evaluating the effects of HU on the 6 MWD, serum brain natriuretic peptide (NT-pro BNP) level, and pulmonary hypertension (PH) measured by tricuspid regurgitation velocity (TRV).Methods: In this cross-sectional, prospective study, 110 patients with homozygous SCA were studied and compared with age- and gender-matched healthy controls. Every patient was investigated via pulsed and tissue Doppler echo evaluation, 6-min walk test (6 MWT), and blood level for the level of NT-pro-BNP hormone. Data were compared in patients with (n = 59; group 1, G1) and without (n = 51; group 2, G2) HU medication. Pearson correlation analysis was applied and clinical follow-up for the frequency of acute chest syndrome (ACS). Analysis of variance (ANOVA) multivariate statistical analysis was applied between groups.Results: In the study, 110 patients with SCA were studied and compared with 110 control patients. Patients in G1 compared with G2 had a longer 6 MWD (491 64.4 m vs 428.6 54.3 m, p < 0.005), higher HbF% (21 2.5% vs 8 1.8%, p < 0.005), and lower NT-pro-BNP level (314.1 27.5 pmol/L vs 407 18.9 pmol/L, p = 0.05). The mean TRV values were 2.8 0.5 m/s in G1 versus 3.4 0.4 m/s in G2, p < 0.005, and 1.5 0.7 m/s in the control group. The high probability of PH based on a TRV > 3.4 m/s was 10.1% in G1 versus 17.6% in G2 and 3.6% in the control. There were weak positive correlations between NT-pro-BNP and TRV (r = 0.264; p = 0.005) and HbF% and 6 MWD (r = 0.452; p = 0.001). After 12 months of follow-up, frequency of acute chest syndrome (ACS) was twice as high in G2, at 32 patients, versus 16 in G1.Conclusion: Patients with SCA on HU medication compared with no HU had significantly longer 6 MWD, lower level of NT-pro-BNP, higher HbF% level. After 1-year follow-up HU patients had less frequency of ACS. There were significant positive correlations between the level of NT-pro BNP level and TRV in m/s on echo.

Keywords: sickle cell anemia, 6-min walk test, hydroxyurea, NT-pro BNP, echocardiography, diastolic dysfunction, pulmonary hypertension

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

See the original post here:
The Effects of Hydroxyurea Therapy on the Six-Minute Walk Distance in | JBM - Dove Medical Press

This is a rush transcript. Copy may not be in its final form.

NERMEEN SHAIKH: Why has there been so little progress in the war on cancer? According to the director of the National Institutes of Health, Dr. Francis Collins, quote, Americans are living longer, healthier lives. Life expectancy for a baby born in the U.S. has risen from 47 years in 1900 to more than 78 years today. Among the advances that have helped to make this possible are a 70% decline in the U.S. death rate from cardiovascular disease over the past 50 years, and a drop of more than 1% annually in the cancer death rate over the past couple of decades. A drop of just over 1%? For the trillions of dollars that have been poured into cancer research, just over 1%? Today, we spend the hour with a renowned oncologist who says we should be treating the disease differently.

AMY GOODMAN: In her new book, The First Cell: And the Human Costs of Pursuing Cancer to the Last, our guest for the hour, Dr. Azra Raza, notes we spend $150 billion each year treating cancer, yet a patient with cancer is as likely to die of it today with a few exceptions as one was 50 years ago. She argues experiments and the funding for eradicating cancer look at the disease when its in its later stages, when the cancer has grown and spread. Instead, she says, the focus should be on the very first stages, the first cell, as her book is titled. She says this type of treatment would be more effective, cheaper and less toxic.

NERMEEN SHAIKH: Dr. Raza criticizes what she calls the, quote, protocol of surgery, chemotherapy and radiation the slash-poison-burn approach to treating cancer, which she says has remained largely unchanged for decades. She calls for a transformation in the orientation of cancer research, writing, quote, Little has happened in the past fifty years, and little will happen in another fifty if we insist on the same old, same old.The only way to deal with the cancer problem is to shift our focus away from exclusively developing treatments for end-stage disease and concentrate on diagnosing cancer at its inception and developing the science to prevent its further expansion. From chasing after the last cell to identifying the footprints of the first, Dr. Raza writes.

AMY GOODMAN: Well, for more, Dr. Azra Raza joins us to speak in her own words. Oncologist and professor of medicine at Columbia University, shes also the director of the MDS Center. MDS is myelodysplastic syndromes, a form of bone marrow cancer. In her book, she notes, again, that we spend $150 billion each year treating cancer, yet a patient with cancer is as likely to die of it today than one 50 years ago it is an astounding fact with a few exceptions.

Dr. Azra Raza, welcome back to Democracy Now! Its great to have you with us. How can this be? How can it be, the lack of progress that has been made in this last half-century?

DR. AZRA RAZA: Thank you for having me again, Amy. Im delighted to be here.

Since 1903, it has been well appreciated, actually, that its not cancer that kills; its the delay in treatment that kills. So, forever we have been making attempts to try and diagnose this disease early. In the last three decades, we have seen a 26% decline in cancer mortality, which is about 1% a year, as you pointed out. But thats not happened because we have developed some grand, new treatment strategy. It has happened because of two main things. One is the anti-smoking campaign, so the incidence started going down. And second is because we started using screening measures to diagnose cancers earlier and earlier.

This approach of preventive medicine, where you catch the disease early and intercept early, is what caused the drop in cardiovascular disease by 70%, because, there, the cardiologists were smarter than oncologists. They realized that if they allow a myocardial infarction, or a heart attack, to damage the heart muscle, then the only treatment would be a heart transplant, which is so draconian and so terrible. They started to diagnose not only earlier and earlier, but try and prevent the appearance by using anti-cholesterol drugs, for example. Thats a very clear case of early detection, but then even prevention of the disease. And 70% decline in mortality. Why arent we doing the same in cancer?

NERMEEN SHAIKH: So what is the answer to that?

DR. AZRA RAZA: Well, the answer is that we have been trying to do it. And the screening measures that were put in place, like mammography, colonoscopy, PSA testing, Pap smears, theyre the ones that caused the decline by 26% mainly, in addition to anti-smoking campaigns. But those measures were put in 50 years ago. Imagine, in this day and age of technology, we are still putting a tube into someones gut and looking to find cancer. That is primitive. Thats paleolithic for today.

AMY GOODMAN: And the alternative is?

DR. AZRA RAZA: The alternative is that we have milked these technologies as much as we could . They have yielded the 26% decline in mortality. Theyre not going anywhere else. We need to invest in developing technology based on current imaging, scanning devices, detection of biomarkers, for example, from blood, sweat, tears, saliva, urine, stool samples, and find the earliest footprint of cancer and see how we can intervene. And this is a strategy that is not limited to just cancer, Amy. This is a strategy that is going to apply to every single chronic disease in the coming years.

AMY GOODMAN: So, what has prevented that from happening?

DR. AZRA RAZA: I wish there was a very neat kind of answer about this, but its something like this. You take a frog and put it in cold water and start heating it slowly; nothing is going to happen. On the other hand, you throw a frog into boiling water, it will jump out. But if you heat it slowly, the frog dies without jumping out, because it slowly gets used to it. This is an apocryphal story, by the way; scientifically, its incorrect. Just a warning. As a purist, I have to add that. But the analogy is true, that things have happened so slowly that we keep getting desensitized to the next step. One thing is that there is so much hyperbole around cancer treatment. If a few months of survival are added by a drug, it is welcomed as a game changer. Let me

AMY GOODMAN: At the end of life.

DR. AZRA RAZA: Yes, exactly. Let me give you just a few statistics. I want to be very clear that using the slash-poison-burn approach, we are curing 68% of cancers that are diagnosed today. We are curing them. Thirty-two percent that present with advanced disease, their outcome is the same exact outcome that it was 50 years ago. The 68% we are curing, why are we still using these Stone Age treatments? You know how terrible it is to get chemotherapy and radiation therapy.

AMY GOODMAN: Explain how it works.

NERMEEN SHAIKH: Explain what yeah, yeah. What happens?

DR. AZRA RAZA: The first rule of medicine is first, do no harm. In fact, when a patient is diagnosed with cancer, its a silent killer. Thats the problem. It can reach stage IV disease without producing symptoms. So, somebody comes to us I recently saw a 42-year-old young man who has just finished a game of tennis and come to see me, and suddenly, because he was exhausted and feeling so tired, and now I diagnosing him acute myeloid leukemia. I look at this toned and tanned young man, and the first thought that comes to me is about what we are going to do to him with the chemotherapy we are going to give him.

It is unconscionable that in 2019 I am still going to give this young man the same combination of two drugs that we popularly known as 7+3, that I was giving in 1977, when I arrived in this country. I feel ashamed of myself, having to repeat the same side effects, that you are going to lose all your hair, throw your guts out, and your counts are going to tank. Your blood counts will go down to essentially zero for weeks on end, where you are going to be susceptible to all kinds of terrible infections. You will be in the hospital suffering with shivering night sweats and fevers and all kinds of aches and pains and constitutional symptoms. And then there is a chance that a percentage of those patients will improve. So, this is what we do with just chemotherapy alone.

AMY GOODMAN: Were going to break and then come back to this discussion and also hear about your personal story with your own husband, also a renowned cancer doctor, who died of the very disease that he was studying, and hear the stories of your patients. Were talking to the renowned cancer doctor, the oncologist, the professor of medicine at Columbia University, Dr. Azra Raza. She has a new book. It is called The First Cell: And the Human Costs of Pursuing Cancer to the Last. Stay with us.

[break]

AMY GOODMAN: Nocturnes, Op. 27, No. 2, in D-flat major, _lento sostenuto _, performed by Abbey Simon. Abbey Simon passed away December 18th at the age of 99. This is Democracy Now!, democracynow.org, The War and Peace Report. Im Amy Goodman, with Nermeen Shaikh, as we spend the hour with Dr. Azra Raza, a renowned oncologist, professor of medicine at Columbia University, where shes also the director of the MDS Center a form of bone marrow cancer her new book, just out, titled The First Cell: And the Human Costs of Pursuing Cancer to the Last.

NERMEEN SHAIKH: So, Azra Apa, Dr. Raza, we were talking earlier, in the first part of the program, about the slash-poison-burn approach to treating cancer, which youve been very critical of, which involves surgery, chemotherapy and radiation. You say that this has been responsible for curing 68% of cancers. So a couple of questions: Would it have been possible, even though this is counterfactual, to cure such a high number of cancers using alternative methods? And, two, what kinds of advances have been made in how chemotherapy is administered and how the effects of that, of changes in the way that its administered, have had on patients?

DR. AZRA RAZA: Both very good questions. So, the first question you asked is what could have been really done. And what have we been aiming at doing? So, sure, we started by using these blunt approaches. Its literally like taking a baseball bat to hit a dog to get rid of its fleas. Thats how bad this kind of treatment is. But we had to do it because we had no alternatives. In the meantime, we invested billions of dollars in trying to study the biology of cancer, hoping that we will identify some intricate signaling pathway, some genetic defect, that is going to allow us to target it specifically. And this did happen in two diseases. In chronic myeloid leukemia, we developed a targeted therapy, because theres one gene had gone wrong, and one magic bullet could target it and cure the disease. Now we

AMY GOODMAN: And again, just to note, youre one of the worlds leading authorities on AML, this kind of cancer.

DR. AZRA RAZA: On this, Im talking about chronic myeloid leukemia. But yes, youre absolutely right: I am an expert in myeloid diseases. And CML, chronic myeloid leukemia, is something Ive treated for decades.

Now, this was a huge advancement that happened in the early 2000s, that we could now use a targeted therapy which is not chemotherapy, which only goes and attacks the abnormal cell which is expressing this protein. While it helped patients, its also put the field behind by 20, 30 years. Why? Because we felt that this now establishes a paradigm. Every cancer will be caused by one genetic defect, for which we just have to develop one drug. So, one gene, one targeted therapy. Everybody and their grandmother has been trying to find the one gene for pancreatic cancer, the one gene for acute myeloid leukemia. It turns out that, unfortunately, for all other cancers, most of them, really, there are too many genes that are mutated simultaneously. And so the targeted therapies weve developed, even for those multiple proteins or one protein that is dominant, it turns out it works for a little bit.

So, let me give you some statistics again. Ninety-five percent 95% of the new drugs that we are bringing, the experimental drugs we bring to the bedside, 95% of them fail. And to bring one of those drugs to the bedside is a billion dollars almost. So imagine how much we are losing. Five percent that succeed should have failed, in my opinion. Why? Because theyre only prolonging survival by a few months. So, for example, theres a drug that extends the life of a pancreatic cancer patient by 12 days, at the cost of $26,000 a year and not every pancreatic cancer patient, just a fraction. So think of the financial toxicity we are causing to these patients now. For very little prolongation and survival, we are financially ruining 42% of cancer patients diagnosed, newly diagnosed with cancer today, by year two. They lose every penny of their life savings.

AMY GOODMAN: Speaking of which, before we go on to the incredible stories you describe in The First Cell, your thoughts on Medicare for All? I have spent a lot of time accompanying family and friends, for example, at Sloan Kettering, who are dealing with cancer. The astounding devastation of peoples, aside from lives, financial destruction. Medicare for All, what would that mean for cancer patients?

DR. AZRA RAZA: Amy, while Im not an expert on these issues, I have common sense. And one thing I can say is that the current situation is completely untenable. We are on the verge of a collapse with the healthcare system. We cant continue it the way it is going. And, to me, the only solution seems to be but again, its not speaking as an expert is to have Medicare available for everybody. I think thats the only compassionate and humane solution.

NERMEEN SHAIKH: Well, Azra Apa, I want to ask you about another incident that you mention in the book, before going on to the longer case histories of patients in their own words as well as in the words of their family members. I mean, the cost of cancer treatment, as you say, in the U.S. is exorbitant, and many families have been driven to financial ruin. But what about in places where cancer treatment is so prohibitive that it entirely deprives patients of access? You talk about arriving in Karachi and meeting in Karachi, Pakistan, which is where youre from and talking to Zaineb, a cancer patient about whom you write, quote, How does one go in and talk to a thirty-five-year-old woman for whom dying from leukemia is only her second-biggest problem? Could you talk about that, access to cancer treatment and who the people are who are entirely deprived of any treatment at all?

DR. AZRA RAZA: This is a subject which is very close to my heart, Nermeen, because, obviously, I am from that part of the world. The entire world looks to America for leadership. What kind of leadership are we providing? A leadership where we are developing drugs or cellular therapies now that will cost over a million dollars per patient, for helping very few patients. These are rarified cases for whom this kind of treatment will work. As you said, what about the 20 million new cancer patients being diagnosed universally all around the world? We just dont have a compassionate solution for them. Why arent we thinking not just of those even in America, in the remote areas and many, many places where healthcare is becoming harder and harder to access just because hospitals are closing down from financial ruin themselves? Why arent we thinking of them? Why arent we thinking beyond American borders, for humanity as a whole?

And when you think about that solution, I mean, you dont have to be a genius. No, no, look, the only thing that works in cancer if you have someone who gets diagnosed with cancer, the first thing youll say is, Was it advanced, or was it caught early? No, early, so theres hope. We know that early detection helps, right? Why are we investing money in chasing down the last cell, in which with drugs which have a 95% failure rate today? Because the pre-clinical testing platforms we are using are so artificial, and thats why we are bringing up drugs that are not going to be successful.

Instead of doing that, why arent we simply improving on the techniques we know work? What worked? Early detection. How do you do early detection? Well, mammography, colonoscopy, Pap smear, etc., has been reached to their maximal limits. Lets develop the new technology so that from one drop of blood, you can put it on a little chip, which can be read by a cellphone, which costs $180 for 12 cancers to be diagnosed early. This is something that was just announced by a Japanese company. So these are things not that are a pie in the sky. These are things that are happening now. Except how fast will it happen to reach the rest of the world? It depends on the amount of resources we invest.

AMY GOODMAN: Were talking to Dr. Azra Raza. Her book is called The First Cell. She is a leading oncologist in the world. She is a Pakistani American, a Muslim, a woman. You talk about your own story in the book, the story of your husband, also a leading oncologist. Dr. Harvey Preisler died of lymphoma in 2002. You write, Cancer is what I had been treating for two decades, yet until I shared a bed with a cancer patient, I had no idea how unbearably painful a disease could be. Lets first turn to your daughter, to Sheherzad Raza Preisler, speaking at the memorial service for her father, your husband, about his cancer diagnosis and the effect his condition had on the family. The 15th Harvey Preisler Memorial Symposium was held in New York in 2017.

SHEHERZAD RAZA PREISLER: What a cruel twist of irony it was that as he was directing the Rush University Cancer Center in Chicago, he was cut down in the prime of his life by the very disease he had dedicated his life to cure. I was only 3 when he was diagnosed and 8 when he died. My parents took great pains to never mention the C-word in my earshot, and yet most of my memories of Dad are related, at least in part, to the presence of this nameless other in our lives. And even though I was too young to know what was going on at any tangible level, I had some sort of instinctual knowledge that something was terribly wrong. I could sense my mother struggle as she was navigating through stages of optimism, pain, dread, despondency and, eventually, hopelessness, as my dad underwent a seemingly endless stream of experimental treatments. These stages are what most cancer patients and their caregivers and families experience.

AMY GOODMAN: That was Sheherzad Raza Preisler, the daughter of our guest today, Dr. Azra Raza, oncologist, professor of medicine at Columbia University, talking about her dad, who died of one of the cancers that he specialized in. He was head, Dr. Harvey Preisler, of the Rush Cancer Institute in Chicago. Tell us, as you begin your book, what happened to your husband, what happened to Harvey.

DR. AZRA RAZA: First of all, Amy, when I started writing this book, I had no intention of putting Harvey into the book. I was writing about my other patients. But when I wrote about them in such detail and with such painful granularity, I felt it would be dishonest if I held back my own story. And so, at that point, I decided to add. And once I decided that, this story became like a red line running throughout the whole book, because then I couldnt escape, at every level, where Harvey came in.

Ill give you just one example. I mean, he was the head of the cancer center. He gets the very disease hes trying to cure. And now he dies, after a very, very exceedingly painful almost five-years battle. Sheherzad was 8 years old when he died. And a couple of weeks after he died, she developed a terrible cold and flu and was pretty sick for a few days and then started getting better. And one morning I was sitting in the living room reading, and she suddenly comes out crying inconsolably. I was sure that shes had a relapse and is much worse. But when I was able to calm her down, this is what she said, Amy. She said, Actually, I feel perfectly fine now. But I know what it feels like to be so sick and how good it is to get better. And my dad never got better. Which brought on a second fit of crying. So, an 8-year-old, at a visceral level, is able to experience the kind of anguish that cancer patients suffer.

Being a cancer widow, did it make me into a different kind of doctor? No. But my perceptions changed entirely. You know, Marcel Proust has said that real voyage does not lie in finding new landscapes, but in having new eyes. And so it became a voyage of discovery for me, in having new eyes.

AMY GOODMAN: And that issue of prevention, of catching early, what happened in your husbands case? Who I mean, he was head of a major cancer institute.

DR. AZRA RAZA: The same thing that happens to all other cancer patients: He was diagnosed way too late. And actually, the lymphoma didnt kill him. The treatment we gave killed him. The chemotherapy we gave destroyed his immune system, so that he died eventually of sepsis. He didnt die of the lymphoma.

Theres a family friend of ours who once told my younger brother he said, Abbas, if the sun rose suddenly from the west one day, the entire world will stop and stare at it. But there are some people who watch the sun rise from the east every day, and they wonder why. And he said, Those are the only kinds of people who can make a difference in the world.

And thats the kind of person Harvey was. He was an extremely thoughtful person with a great curiosity about life in general, but specifically scientific issues. Yet what I learned from taking care of him and sharing a bed with him as a cancer patient was a deeply humbling acceptance of his condition. Basically, his attitude was I am a man, and a man is responsible for himself, even though I know that this is not going anywhere.

AMY GOODMAN: You write at the beginning of your book, in your introduction, From Last to First, talking about that idea of the first cell, I have learned new things about what I thought I already knew: like the difference between illness and disease; between what it means to cure and to heal; between what it means to feel no pain and to feel well. Can you elaborate on this?

DR. AZRA RAZA: I mean, really, the whole concept of this is can be expressed better in poetry. So, if you dont mind, I will recite a short piece by Emily Dickinson:

I measure every Grief I meetWith analytic eyes I wonder if It feels like Mine Or has an Different size.

I wonder if They bore it long Or did it just begin I cannot find the Date of Mine Its been so long a pain

I wonder if it hurts to live And if They have to try And whether could They choose between They would not rather die.

NERMEEN SHAIKH: Well, I want to ask about another patient who you profile in the book, who is in fact subjected to a particularly brutal form of this slash, burn and poison. And thats Andrew Slootsky, who died in 2017 at the age of only 23. The book includes a testimonial from his mother, Alena, who criticizes the attitude of the oncologists who treated him, but says she would have wanted Andrew to undergo any treatment that might have extended his life. So, could you talk about Andrew was also one of the best friends of your daughter, Sheher. Could you talk about the treatment that he was subjected to? What happened? And also your decision one of the most remarkable things about this book is not just, of course, your expertise in cancer and cancer treatment, but also these stories that you weave into the narrative, of patients youve treated, of patients families who have witnessed their family members being treated in this way and ultimately dying. And this is Alena, Andrews mother, saying that she would have Andrew go through all of this treatment, even if it meant the slightest possibility of extending his life.

DR. AZRA RAZA: Yes. Nermeen, actually, Andrew is the impetus for me to write this book. In 2016, when he gets diagnosed with cancer, he has weakness in his arm. He goes to the emergency room. They do an MRI. They find an inoperable brain tumor, nine centimeters long. They couldnt remove it. From the day one, every oncologist that treated Andrew knew that his chance of survival is 0.00, beyond what is to be expected. No matter what we give him, he was going to die. We all knew it.

This boy, when he opened his eyes, coming out of anesthesia, he turned to his mother, and he said, Mom, dont worry. Just call Azra. Shes on the cutting edge. She will find the best treatment and cure for me. And Alena called me. This young man, whos been in and out of my house since hes 15 years old, because hes best friends with my daughter. I felt so ashamed of myself that there is nothing I can offer this poor boy, and the fact that we are failing the Andrews and the Zainebs and the Harveys and the Omars of this world so spectacularly, and instead of feeling embarrassed, we go around pumping our chest, claiming that we are curing 68% patients. Sixty-eight percent of what? again and again I ask.

And what we do to Andrew in the next 16 months, even though we knew his chance of survival is zero, is we give him chemotherapy, radiation therapy, surgery after surgery, more chemo, more radiation, more immune therapy. And he suffered the side effects of every one of them, without benefiting from anything.

But then, the converse is also a problem. Lets say we didnt treat him and let the brain tumor take over. That death from advanced cancer is just horrendous. So, basically, the treatment, what are the choices we offered Andrew at this point? Either you die of your cancer or die of the treatment, but you are going to die. And the question I ask myself is Why? Why was Andrew diagnosed when his cancer was nine centimeters long? We know that cancer is a silent killer. We know no age is immune to getting cancer. At 22, this boy got cancer.

AMY GOODMAN: And specifically in his case, how could it have been detected earlier? Talk about the tests that you think need to be developed, and are actually already there but somehow missed him?

DR. AZRA RAZA: So, Amy, I am calling for a complete paradigm shift. What Im saying is that even the screening measures that we are using annually, for example, doing a mammogram is too late for some people. What we need to do is consider the human body as a machine and continuously learn to monitor it for the detection of diseases, whether its Alzheimers or cancer or diabetes. We need to catch all of these diseases early and try to nip them in the bud. This is what Im asking for. So, what has to be done for that? Children get cancer. Not that many, but certainly they do. And again, we treat them with these draconian measures, and they end up with developmental issues, fertility issues, all kinds of problems. So, what Im asking for is we need to develop those markers that can identify cancer at its inception. It is doable. It is possible.

A lot of research is going on, in this country and elsewhere also, to find footprints of cancer, for example Ill give you a couple of examples. When cancer starts, it divides fast its cells divide faster than normal cells, which means it needs more nutrition, so it starts making new blood vessels. As soon as that happens, the area becomes hot because of new blood going into that one area. This hot area can be detected. People are developing bed sheets and mattresses where you can go to sleep and you are overnight youre being scanned for hot areas. Lets say a hot area is detected in my pancreas one day. It doesnt mean the next morning I should have an open abdominal surgery and eviscerated and removal of all my no, it means that now theres something abnormal which needs to be monitored. I am now considered someone at high risk, so I should be monitored for other biomarkers. These cells which are developing in my pancreas will be shedding their proteins into the bloodstream. If theyre not shedding, you know one thing we can do? We can yell at them. How do you yell at them? You use sound waves, literally, ultrasound, to hit them. And they start shivering, and they start shedding their proteins into the blood. And we get the blood and detect the biomarker.

AMY GOODMAN: Is there a cancer-industrial complex thats preventing this kind of research and development of the preventive and the early-detection approaches to cancer?

DR. AZRA RAZA: Absolutely not, Amy. In fact, my contention and my conceit is that if heres an industry that is investing in an enterprise that has a 95% chance of failure, but they keep investing billions of dollars, because if one of their drugs makes it, if it improves survival by 10 seconds more than two months

AMY GOODMAN: So youre saying there is a cancer-industrial complex that is

DR. AZRA RAZA: But theyre not preventing it.

AMY GOODMAN: Right.

DR. AZRA RAZA: They just dont know whats a better thing to do. So, what Im saying is, we just set a new goal, and we financially incentivize the goal, then all these people will turn around and come to the first cell instead of going after the last cell.

AMY GOODMAN: What about Vice President Bidens moonshot challenge around curing cancer?

DR. AZRA RAZA: I was one of the fortunate people to meet Vice President Biden in his across his dining room table for the cancer moonshot and had a very wonderful discussion with Vice President Biden. His heart is in the right place. And there is a certain fraction of that billion dollars, the money that he has allocated for cancer research, is definitely towards prevention and early detection of cancer. But its not enough. That kind of vision is what we really need. But we need Im not saying all current research should stop. Nobody should misquote or mishear me. I am saying we have correct patients. Of course we have to worry about them, and we have to keep developing better treatments and better understanding of biology. But I think at least half of the resources, and all the resources going into these failing clinical trials, these billions and billions of dollars, can be redirected for future patients to try and detect the disease early a solution which will be applicable universally.

AMY GOODMAN: We have to break. Then were coming back to our guest, Dr. Azra Raza, oncologist, professor of medicine at Columbia University, where she directs the MDS Center, a form of bone marrow cancer. Her new book is out. Its called The First Cell: And the Human Costs of Pursuing Cancer to the Last. Stay with us.

[break]

AMY GOODMAN: New York by St. Vincent. The photos in the video were compiled by Kat Slootsky for her brother Andrew, one of the patients profiled in Dr. Azra Razas book, The First Cell: And the Human Costs of Pursuing Cancer to the Last. He died when he was 23 years old, of a particularly aggressive form of brain cancer. Im Amy Goodman, with Nermeen Shaikh. Were spending the hour with Dr. Azra Raza, the renowned oncologist, professor of medicine at Columbia University. Nermeen?

NERMEEN SHAIKH: So, Azra Apa, I want to ask you about one of the criticisms that your book has come under. In The New York Times, Dr. Henry Marsh praises the book but says youre too optimistic about the solutions you propose. Marsh writes, quote, Her diagnosis of the ills from which cancer treatment suffers strikes me as accurate, but her solutions seem infused with the same unrealistic optimism she identifies as the cause of so much suffering. This is Dr. Henry Marsh writing in The New York Times. Are you guilty of too much optimism?

DR. AZRA RAZA: No. Thats the short answer. But, Nermeen, you know, I started my career in oncology basically in 1977. I was 24 years old, fresh out of med school. I had come here. I started working at Roswell Park Cancer Institute, because I was going to cure cancer very quickly, I thought. And within seven, eight years, it was very clear to me, the disease that I had invested all my energies in, acute myeloid leukemia, that in my lifetime this disease will not be cured. It is so complicated.

So, at that point, I turned my attention toward studying an earlier form of the disease, because many of my patients who came with acute leukemia gave a history of having had some low blood counts and being anemic for a few months before it developed to leukemia. So I said to myself, Why not catch this disease earlier, the pre-leukemia phase, and intercept then and not let it become this end-stage monstrosity?

So I started collecting this is where being an immigrant helped me, Amy, because had I gone to school in this country, if I had started to study acute leukemia, my next step would have been to make a mouse model of this disease, which are very artificial and which just for drug development, at least. Theyre very good models for studying biology, but not for drug development. But because I was an immigrant, I simply started saying, Oh, I have to study cancer, so let me save these cells. And I started banking cells on my patients. Today I have a tissue repository which has 60,000 samples from thousands of cancer patients, followed longitudinally, well annotated, with all their clinical and pathologic data in the computerized forms. And this is a very precious resource, one of a kind. Not one single cell comes from another physician. I still do the bone marrows with my own hands, which Im going to do in the next hour, when I get to my clinic.

But the idea I had was that earlier detection will help. That was many years ago. Wheres my solution? So, the question you ask me and the criticism that Dr. Marsh is giving can be applied to me, yes, that 35 years ago I felt that detecting the disease early, pre-leukemia, would help me. It hasnt helped me, because pre-leukemia itself is a very malignant disease and can kill.

So then I realized that by using these samples of acute leukemia, working my way back to pre-leukemia, I can then ask the question: Why did some people get pre-leukemia, to begin with? Why did they get MDS? And once we can discover that, by using these tissue samples and the latest technology of proteomics, genomics, transcriptomics, metabolomics, panomics, we will find the same kind of thing you have, say, for breast cancer, the BRCA gene. Can we find something thats making people susceptible because of their inherited DNA?

AMY GOODMAN: What about targeted immunotherapy? People think that it has gone so far to help cancer patients. What is it? And what do you see are the prospects for it?

DR. AZRA RAZA: The answer to that is, first, you have to understand what is the cell therapy. So, there are many, many different forms of immune therapies, fourteen, fifteen different kinds. But the ones that are receiving all the attention are basically two types. Checkpoint inhibitors are drugs which cancer cells so, every cell expresses proteins that either say, Eat me, or Dont eat me. Cancer cells learn to express only proteins that say, Dont eat me. Dont eat me. Dont. So, this is how they deflect the immune system.

AMY GOODMAN: We have less than a minute.

DR. AZRA RAZA: And so, we tried drugs to do that. We succeeded. The response doesnt last. The other form of therapy is cell therapies that we use. Immune therapy using cells T cells, for example cannot distinguish between a normal cell and a cancer cell in the organ. All we can do is we can activate these T cells and say, Go kill the whole organ, and cancer will die with it. So the only cells we have succeeded in killing, or the only organ we have succeeded in killing, so far, is B cells, which are a kind of lymphoid cells in the body.

AMY GOODMAN: Ten seconds.

DR. AZRA RAZA: We kill them, and then we replace B cell function by giving immunoglobulins for the rest of their time. We cant do that for the liver. We cant kill the liver and expect to replace it. Thats why immune therapy using cells is not going to work.

AMY GOODMAN: Well, were going to have to leave it there, but people can pick up the book and take it from there. Dr. Azra Raza, oncologist, professor of medicine at Columbia University, heads up the MDS Center, a form of bone marrow cancer. Her new book, The First Cell: And the Human Costs of Pursuing Cancer to the Last. Im Amy Goodman, with Nermeen Shaikh.

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The First Cell: Dr. Azra Raza on Why the Slash-Poison-Burn Approach to Cancer Has Failed - Democracy Now!

Zhenhua Cui,1 Bingbing Han,2 Xianren Wang,1 Zhiwen Li,1 Jianxin Wang,1 Yanfeng Lv1

1Department of Colorectal & Anal Surgery, The Second Hospital of Shandong University, Jinan 250033, Peoples Republic of China; 2Microcirculation Laboratory, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Peoples Republic of China

Correspondence: Yanfeng LvDepartment of Colorectal & Anal Surgery, The Second Hospital of Shandong University, No. 247 BeiYuan Street, Jinan 250033, Peoples Republic of ChinaEmail ttdpilsxpsle11@163.com

Introduction: Long non-coding RNAs (lncRNAs) have obtained increasing attention due to their regulatory functions in many cancers. This work aimed to investigate the functional roles of lncRNA TTN-AS1 in colorectal cancer (CRC) and to explore the underlying mechanisms.Methods: The expression profiles of TTN-AS1 and miR-497 in CRC tissues and cell lines were determined by RT-qPCR analysis. MTT assay, transwell assay, western blot analysis, and xenograft tumors in nude mice were employed to analyze the effects of TTN-AS1 on the proliferation, migration, invasion, EMT, and in vivo tumorigenesis of CRC cells. Bioinformatics analysis and dual-luciferase reporter assay determined the direct binding relation betweenTTN-AS1 and miR-497 in CRC.Results: We observed a significant increase of TTN-AS1 expression level in CRC tissues and cell lines compared with normal counterparts. High expression of TTN-AS1 predicted a poor prognosis and was correlated with aggressive clinicopathological characteristics in CRC patients. Functionally, gain- and loss-of-function studies indicated that TTN-AS1 knockdown suppressed the proliferation, migration, invasion and epithelialmesenchymal transition of CRC cells in vitro, whereas TTN-AS1 overexpression showed the complete opposite effects. Mechanistically, we found that TTN-AS1 could directly interact with miR-497, and co-transfection with miR-497 mimics blocked the activation of PI3K/Akt/mTOR signaling, and reversed the effects of TTN-AS1 overexpression in CRC cells.Conclusion: To conclude, our findings provide novel insight into CRC tumorigenesis and indicate that TTN-AS1 may serve as a potential therapeutic target for CRC treatment.

Keywords: colorectal cancer, long non-coding RNA TTN-AS1, epithelial-mesenchymal transition, microRNA-497, PI3K/Akt/mTOR signaling

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Long Non-Coding RNA TTN-AS1 Promotes the Proliferation and Invasion of | OTT - Dove Medical Press