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‘We’re All Exposed’: How Microplastic Is Affecting Our Health and … – The Epoch Times

Expert says mounting microplastic pollution is turning Earth into a giant chemistry experiment

Our world is getting polluted with plastics on a planetary scale. We cant see much of it, but were starting to feel it. And its getting worse.

The plastic bottle tossed by the roadside and the endless trash heaps in third-world countries are just the beginning. As the trash ages, it breaks down into smaller and smaller pieces, until it cant be seen with the naked eye anymore. At that point, however, the problems have barely begun.

These tiny pieces of plastic, called microplastics, have permeated everything, scientists have found in recent years. They can be as large as 5 millimeters and as small as 100 micronsabout as thin as a human hairor even smaller, at which point theyre sometimes referred to as nanoplastics.

Microplastics have been found in the most remote corners of the world.

It doesnt matter where we look. We find microplastics. In the environment, it could be the bottom of the Marianna Trench, it could be the top of Mount Everest and everywhere in between, said Sherri Sam Mason, associate professor at Penn State Behrend and expert on microplastic pollution.

As a consequence of it being everywhere in the environment, its everywhere within living organisms.

Microplastics have been found in the animals we eat, in the water we drink, and in the air we breathe. Its in our blood and in our organ tissues, even the deepest tissue of our lungs.

We have a tendency to have this illusion that our skin separates us from the environment, but it is an illusion, Mason said.

Children, nowadays, are being born with microplastic already in their bodies.

Plastic particles have been found on both sides of the placental boundary, meaning its seeping from the mothers body into the unborn child.

The repercussions of such pollution are largely unknown. Getting definitive answers has proven immensely difficult. What research has been done, however, indicates the effects are negative.

With regard to the human health impacts of it, perhaps unsurprisingly, none of them are good, Mason said.

There are many ways to address the issue, but its not clear whether a definitive solution is practically achievable. The pollution can be greatly reduced by ditching single-use plastic packaging and reforming the fashion industry. That still leaves a massive amount of plastic entering the environment, not to mention the substantial pollution there already is.

So far, research has largely focused on gauging the scale of the issue. It wasnt until 2018, for example, that a paper was published at least somewhat accurately estimating how much plastic is floating in the Great Pacific Garbage Patchthe largest of several massive accumulations of plastic trash in the oceans. Even then, the estimate ranged from 45,000 to 129,000 tonnes.

Worldwide, some 7 billion tonnes of plastic trash are estimated to be in the environment, in landfills, oceans, dumps as well as just strewn around. That amount is expected to grow to 12 billion by 2050.

Research has already found that small pieces of plastic are a problem for fish and birds who mistake them for food. The plastic sits in their stomachs, making them feel full even though they may be malnourished. That in turn affects their growth and ability to procreate.

What the more microscopic plastic particles may do to the bodies of animalsor humans for that matteris mostly unknown and may to a large degree remain so.

One of the problems is isolating the effect of plastics from all the other factors messing with human health.

Some of the impacts are not acute. If you have a liver pack-full of nanoplastics or its in your placenta, how do you correlate that to harm? said Marcus Eriksen, co-founder and researcher at 5 Gyres, an environmental group that aims to reduce plastic pollution.

He cautioned that in many cases, were not going to get clear-cut evidence because of the complexity of trying to establish a cause-effect relationship.

One of the most established ways to discover the health effects of a substance is through placebo-controlled clinical trialspreferably long-term. But thats particularly difficult in this case. Microplastics are so pervasive there may be nobody left to form a control group.

Were all exposed. Whos not? Eriksen commented.

Heath impacts can be studied to some extent through animal experiments. Its also possible to use artificial human tissue grown from stem cells.

Its expensive and time-consuming, he said.

Its easier to look at the effects of chemicals added to the plastics, such as flame retardants in solid plastics or water repellents in fabrics.

We know more about the chemicals than we do the plastics, the material itself, Mason acknowledged, adding that there are more than 10,000 chemicals that are used in the manufacturing of plastics, and many of these we already know have human health impacts.

Moreover, microplastic can act as a temporary sponge, absorbing chemicals from the environment and releasing them later inside an organism, said Lisa Erdle, director of Science & Innovation at 5 Gyres.

Some of the chemicals added to plastics can cause cancer or harm fertility, according to Mason.

As for the plastics themselves, some studies suggest they may worsen Alzheimers disease and disrupt cell function, according to Mason and Erdle.

Theres starting to be a connection being made between this material and certain neurological diseases, Mason said.

Another factor complicating the research is the immense variability of plastics.

At their core, plastics are made of large hydrocarbon molecules that can be assembled into a virtually infinite number of shapes and variations, giving them different physical and chemical properties. The complexity of discerning their health effects one by one and in various combinations is then also nearly infinite.

Moreover, new kinds of plastics are developed all the time. Current science has no way to determine in advance all the long-term health effects of each type of plastic after it breaks down into microplastics and spreads throughout the environment.

We have turned our planet into a giant chemistry experiment, Mason said.

Were doing an experiment on ourselves and our children and our childrens children.

She pointed to hubris as the cause of our throwing caution in the wind as we think that were smarter than we are.

Maybe it will take 10 years, maybe it will take 50 years, but its going to come back to bite us, she said.

Eriksen acknowledged that the jury is still out on the long-term effects of plastic pollution. But he argued its time to pause and rethink how we do things.

The abundance of novel chemicals in society, in our environment, and the lack of understanding of how they affect these living systems and their interaction effects, it makes me want to employ the precautionary principle, he said, though he acknowledged data on the issue is still lacking.

Does the research show that the impacts should cause public fear? Not quite there yet. Because the research, it takes a long time, he said.

But my gut says, Do no harm. Im always for prevention of a problem if you see it happening. Why wait until the problem is much bigger than it already is to then say, Oh, its a big problem?

Even though the plastic pollution problem may be impossible to solve completely, there are ways to mitigate it. About half of all plastic pollution is estimated to come from single-use packaging. Much of it has non-plastic alternatives.

There are also companies working on alternative materials that naturally break down.

Were seeing a lot of investment, [venture capital] money, going to some of the new biomaterial companies. Its pretty inspiring, Eriksen said.

A material called PHA, for example, is made of a chemical that microbes use in their cellular wall to store energy.

We can extract that and make what looks and feels like plastic. It has a long shelf life, it can be translucent, it can be made in different colors, it can be made into rigid plastics or flexible plastics. And in the environment, it begins to break down very quickly, he said.

Theres also a company thats developing a material that works as plastic cling wrap, but is made of seaweed and breaks down after discarding.

Those materials are still more expensive than plastics though.

They have the challenges that any startup might have, Eriksen said, hoping that as the production scales up, the price will drop.

Industries that use plastics for single-use packaging may be willing to pay a bit more in exchange for the positive PR a more nature-friendly material could bring, he suggested, referring to his conversations with corporate executives in the industry.

Theyll shift if the science is good, the packaging works for them, and gives them a good story to tell.

Recycling could work in theory, but in practice remains inefficientnew plastic ends up being cheaper.

You have to get it back from the consumer, then you have to repolymerize it, repelletize it, and distribute that to your costumers, Eriksen said. Those are real expenses and thats not as efficient as the system of extracting raw materials and making virgin resin.

Producers that are willing to use alternative or recycled materials are those in the high-end market able to absorb the costs, he said.

The only way to give recycling an economic chance, he opined, would be to force producers to buy recycled material by government fiat.

Another problem is that a lot of plastics cant be recycled, such as the thin plastic film used for packaging, which is expected to greatly increase in production in the coming years.

Even materials that can be recycled may end up in the landfill if the manufacturer combines them with unrecyclable substances in the same product.

If you take plastics and you line it with metal or paper or use adhesives or have different kinds of polymers in one product, it makes recycling mechanically very difficult, in some cases economically impossiblenot worth it, Eriksen said.

Youve got to set up for success. And thats been an endless fight for decades.

One of the supposed success stories of recycling is turning plastic PET bottles into synthetic fleece fabric.

In Eriksens view, however, thats a marketing scheme rather than a long-term solution.

Synthetic textile, and fleece in particular, stands as the No. 2 plastic pollutant behind single-use packaging. Synthetic threads are the most pervasive microplastic pollutant in human lungs, according to Erdle, who specializes in research in this area.

The fibers shed directly from synthetic fabrics like clothing, carpets, and upholstery. They also shed into wastewater when the fabric is washed.

A single load of laundry can release up to eight million fibers, Erdle said.

Wastewater treatment plants are able to filter out the threads, but some end up in the sludge called biosolids, which is then used as a fertilizer. The fibers are thus dumped into soil from which they are then picked up by wind or surface water and travel large distances in air currents. Just like other plastics, they break down into smaller and smaller pieces over time.

We dont really know how long theyll last in the environment just because all the studies to date that have tested them show little to no degradation, she said.

A partial solution is installing filters in washing machines that can capture most of the escaping lint.

It would also help to use less synthetic fabric, or at least switch to ones that shed less.

There are lots of brands that are working on developing textiles that shed fewer microfibers, or if they do shed fibers, they are less toxic, less persistent, and are ultimately causing less harm, Erdle said.

A major help would be to step back from the current fast fashion culture that produces a never-ending stream of fleeting trends followed by an avalanche of low-quality garments destined to be discarded.

One movie star wears a hat and suddenly there are a gazillion low-quality hats on the market and people buy them. And in a few months, theyre not in fashion anymore, Eriksen commented, noting that trashed clothing has become a major source of pollution.

Many plastics can be easily burned, but that comes with its own suite of problems, Mason said.

Its very dirty.

Burning plastics, particularly those that contain PVC, releases large amounts of toxic chemicals, many of which are highly poisonous and carcinogenic. The fumes can be filtered, but some amount of the chemicals still get through.

You cant engineer these things to perfection. And many of these chemicals are known to have human health impacts at parts-per-trillion levels, she said. Thats like a single drop in an Olympic-size swimming pool.

Mason sees only one true solution: use less plasticsubstantially less.

Both Mason and Eriksen support new government regulations that would ban single-use plastic packaging, for example.

The trouble is, much of the plastic packaging and much of the synthetic fabric is made overseas, in countries like Indonesia, Philippines, Thailand, Vietnam, and China. Even if they were forced to stop exporting such products to the United States, they still produce massive amounts of plastic pollution themselves.

The United States mismanages less than 3 percent of its plastic waste, according to estimates made in a 2020 paper, while China mismanages 25 percent, Thailand and Indonesia over 60 percent, and the Philippines and India over 70 percent.

And that doesnt even begin to address the billions of tons of plastic trash already in the environment that is steadily breaking down into microplastic trash.

Mason and Eriksen place some hope in the United Nations treaty on plastic pollution currently in the works. It was endorsed by 175 countries in a resolution last year (pdf).

But the resolution still emphasizes things like recycling and ocean cleanups, neither of which amount to a solution, Eriksen said.

The solution isnt going to be more cleanups. Were not going to recycle our way out of this problem. Its going to take smart policy that applies to everyone and levels the playing field.

The resolution, however, suggests that it wont apply to everyone equally.

It acknowledges that the effective implementation of some legal obligations under the instrument is dependent on the availability of capacity building and technical and adequate financial assistance and provides for flexibility that some provisions could allow countries discretion in implementation of their commitments taking into account the national circumstances.

Beyond the treaty, Mason and Eriksen suggested the West should still do what it can on its own, but if that doesnt make enough of a dent, there doesnt appear to be a definitive solution, save a miracle.

I do agree that currently it looks dark, that currently, at best, our present efforts are only working to slow the pace and not reverse the tide, which is what we need, Mason said via email.

I do certainly have my times of feeling like it is all hopeless, but cannot stay in that space because well I have a daughter and someday I may have grandchildren, and so I have to keep fighting. History does tell us that all is hopeless until it is not. At some point, and hopefully at a point in which it is not too late, we will have no choice but to change.

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'We're All Exposed': How Microplastic Is Affecting Our Health and ... - The Epoch Times

Best Pet Insurance That Covers Hip Dysplasia – MarketWatch

In this article: About Hip Dysplasia | Top Pet Insurance Companies | Is Pet Insurance Worth It? | Waiting Periods | Is Hip Dysplasia a Preexisting Condition? | FAQs | Methodology

Hip dysplasia is a painful malformation of the hip joint that can affect your pets mobility and quality of life. It can happen to cats and dogs at any age, but older, large-breed dogs such as German shepherds and golden retrievers are most susceptible.

Because hip dysplasia is an expensive chronic condition, many pet insurance companies place exclusions and waiting periods on related expenses. These are the best pet insurance providers for hip dysplasia to ensure your pet receives coverage.

Most pet insurance companies cover hip dysplasia, but only under certain conditions. Most importantly, there must not be any signs or symptoms before your policys effective date or during the waiting period.

Many providers have a special waiting period for orthopedic conditions, including hip dysplasia, typically six to 12 months. Additionally, theres often a bilateral condition exclusion, which means that if your pet shows symptoms in one hip before or during the waiting period, dysplasia in the other hip isnt covered either.

Based on our rigorous research, these are the top pet insurance companies for hip dysplasia.

Spot earns our top spot because it has one of the shortest waiting periods for hip dysplasia: only 14 days, the same as any other illness. The company also has more customizable coverage than competitors, including annual limit options between $2,500 and unlimited.

+ Short hip dysplasia waiting period

+ Option for unlimited annual coverage

+ No upper age limits

Relatively long accident waiting period

Doesnt pay the vet directly

Spot covers hip dysplasia under its accident-and-illness plan. You can add one of its wellness plans for preventive care.

To learn more: Spot Pet Insurance review

Get your quote: Fill out Spots online quote form

Trupanions waiting period for hip dysplasia is also relatively low at 30 days. Theres no upper age limit or bilateral exclusions, which is rare. Trupanion further stands out for its flexible deductible, allowing pet owners to choose a rate between $0 and $1,000. Its deductibles are per condition, not annual, and are paid for the lifetime of your pet once reached.

+ 30-day waiting period for hip dysplasia

+ Pays directly for vet visits, rather than reimbursing you later

+ Unlimited coverage cap

30-day waiting period for illness coverage

No add-on for preventive care

Trupanion covers hip dysplasia under its standard accident-and-illness plan. You can add its Recovery and Complementary Care package to get coverage for healing treatments such as acupuncture, chiropractic adjustments, hydrotherapy and rehabilitative therapy.

To learn more: Trupanion review

Embrace covers hereditary conditions such as hip dysplasia with no per-incident coverage caps. Although theres a six-month waiting period for orthopedic conditions, this can be reduced to as little as 14 days if you fill out a form and take your pet for an orthopedic exam. Embrace also offers multiple discounts and a Healthy Pet Deductible benefit that credits pet owners $50 toward their co-payment each year they dont file a claim.

+ Orthopedic Exam and Waiver reduces the waiting period for hip dysplasia

+ Diminishing deductible for each year without a claim

+ Two-day waiting period for accident coverage

Low coverage limit for preventive care

$25 enrollment fee

Embrace covers hip dysplasia in its standard accident-and-illness plan. You can get wellness coverage by opting for its wellness add-on.

To learn more: Embrace Pet Insurance review

Get your quote: Fill out Embraces online quote form

Formerly PetPlan, Fetch by Dodo covers hip dysplasia after a six-month waiting period. It doesnt limit payouts by condition or lifetime, which will prove valuable for something like total hip replacement surgery. It also offers robust holistic care such as acupuncture, homeotherapy and stem-cell therapy.

+ No per-condition coverage cap

+ Covers alternative therapies

+ Healthy Pet Credit offers discounts for years without filing claims

No routine care coverage

Long average claim processing period

Fetch covers hip dysplasia under its standard accident-and-illness plan. It doesnt offer add-ons for preventive care.

To learn more: Fetch Pet Insurance review

Get your quote: Fill out Fetchs online quote form

Youll need to enroll your pet by age 6 to qualify for hip dysplasia coverage from Healthy Paws. The companys selling point is its unlimited annual and lifetime coverage caps. These ensure you wont have to worry about going over your maximum limit when treating a condition like hip dysplasia, which sometimes requires costly surgery.

+ Most claims processed within two days

+ No coverage caps

+ Covers some alternative treatments

12-month waiting period for hip dysplasia

Other age-based exclusions

Healthy Paws covers hip dysplasia in its standard accident-and-illness plan. It doesnt offer add-ons for preventive care.

To learn more: Healthy Paws Pet Insurance review

Get your quote: Fill out Healthy Paws online quote form

ASPCA pet insurance is a seasoned provider with more than 15 years of experience. Though the company is a little unclear about its coverage policy for hip dysplasia, the condition doesnt appear to be subject to any exclusions apart from a 14-day waiting period.

+ Short waiting period for hip dysplasia

+ Covers alternative therapy, end-of-life expenses and some prescription food

+ Option to add wellness care

Unlimited coverage not available by online quote

Coverage may vary by state

ASPCA covers hip dysplasia in its accident-and-illness plan. It also offers two wellness add-ons with different coverage levels and annual limits.

To learn more: ASPCA Pet Insurance review

Pets Best insures pets of all ages, but it stands out for its coverage of older pets. Unlike competitors, it has no age limit and allows you to enroll your pet anytime. It offers excellent hip dysplasia coverage starting after 14 days and covers wheelchairs prescribed by a vet, which some pets will need when suffering from the condition.

+ Hip dysplasia waiting period is only 14 days

+ Coverage for wheelchairs and prosthetics

+ Vet Direct Pay available in some areas

Illness coverage not available to some pets with severe chronic conditions

Exclusions for parasites and alternative therapies

Pets Best covers hip dysplasia in its accident-and-illness plan. It also offers two wellness add-ons for preventive care.

Pet insurance for hip dysplasia is only worth it if you enroll your pet before it shows signs of the condition. Otherwise, hip dysplasia will be considered a preexisting condition, and you wont be reimbursed for related costs. Enrolling your pet while its still healthy could save you thousands of dollars since hip dysplasia treatments are generally expensive. Most treatments require surgical procedures such as triple pelvic osteotomy and femoral head osteotomy, which can cost $6,000 or more.

Theres always a waiting period for hip dysplasia, as there is for all illnesses and conditions. Many pet insurance policies have much longer waiting periods for hip dysplasia and cruciate ligament problems than other illnesses and conditions.

Preexisting conditions are never covered by pet insurance. If the condition shows up during the waiting period on your policy, its considered preexisting.

If your pet is already showing signs of hip dysplasia, you wont receive coverage for the condition. However, pet insurance will still cover expenses for accidents or unrelated illnesses. So if your pet is still young and healthy but prone to hip dysplasia, its worth buying pet insurance now to know it will be covered later. You could save thousands of dollars.

Frequently Asked Questions About Hip Dysplasia

Our review of pet insurance companies is based on in-depth industry research that includes reading hundreds of customer reviews, simulating the quote and purchasing process, speaking to representatives on the phone to assess the customer service experience and surveying 1,000 dog and cat owners nationwide to determine the most important elements of pet insurance coverage. We have scored each provider on a 100-point scale based on those elements.

Here are more details about each factor and how theyre weighted:

We use our rating system to compare and contrast each company against key factors to help us determine the best pet insurance companies in the industry. Additionally, we keep our research up to date and revisit our reviews on a regular basis.

Dana Getz is a seasoned editor with nearly a decade of experience writing and editing content. She has a background in journalism and worked as a fact-checker for prestigious magazines such as New York and Chicago. She holds a journalism and marketing degree from Northwestern University and has worked across numerous categories within the home services space.

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Best Pet Insurance That Covers Hip Dysplasia - MarketWatch

Derelict Leigh-on-Sea Post Office to be transformed into new gym – Essex Live

A derelict post office building in a seaside town in Essex is being transformed into a new gym. The former Post Office on Rectory Grove in Leigh-on-Sea closed down around six years ago and is now being turned into an Anytime Fitness gym.

The new gym will be run by Zoe Georgiou and her husband Tony. Speaking to EssexLive, Zoe said she was brought up in Leigh and feels passionately about bringing wellbeing and a healthy lifestyle to the area.

She said: "I know the area well and I know the building well and I remember the post office and so we thought it was perfect for us." She added: "We definitely want to restore the building. We definitely feel that it is vert much a hub of Leigh on Sea and we want to bring that back to life again, for the community.

Read more: The upmarket seaside town that's full of family-run, independent businesses

"And I think the community could benefit massively from a gym where people can come and meet, improve their health and their lifestyle." The building is also located right in the heart of the town, making it accessible for everyone.

Zoe said: "The key thing is that we want to operate our gym on the basis of bringing the community together. And that includes partnering with local businesses in the community to bring our members membership benefits and other benefits."

Due to the size of the building, instead of focusing on classes for members, the new gym will be offering group training with personal trainer-qualified team members as part of memberships. It'll deliver a more personalised experience, Zoe said, being able to see and engage with the instructors more easily and to get more personal training in that time as well.

The Anytime Fitness gym on Rectory Grove in Leigh-on-Sea will be opening in the second half of this year.

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Derelict Leigh-on-Sea Post Office to be transformed into new gym - Essex Live

Tisa-cel Reinfusion Shows Potential as HSCT Bridging Therapy in … – OncLive

Second infusion with tisagenlecleucel (tisa-cel; Kymriah) after prior tisa-cel infusion produced short durations of minimal residual disease (MRD)negative responses in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL), according to findings from a retrospective analysis, which were presented at the 2023 Transplantation & Cellular Therapy Meetings.

In total, 18 patients reinfused because of B-cell aplasia loss while in remission from first tisa-cel infusion (n = 24) had MRD negativity and 6 had detectable disease 28 days after reinfusion. In those reinfused for disease treatment (n = 17), 6 had MRD negativity and 11 had detectable disease at day 28.

For the majority of patients, our data indicate that if second infusion is used, a plan for definitive therapy, such as stem cell transplant, should be made early, as response and remissions were not durable, said Christa Krupski, DO, MPH, of the University of Cincinnati in Ohio, in a presentation of the data.

Treatment options are limited for children and young adults with B-ALL who do not respond to or relapse after first CAR T-cell infusion. Previously, a retrospective analysis investigated the efficacy of CAR T-cell therapy reinfusion in children and young adults with B-ALL who participated in 1 of 3 phase 1 clinical trials (NCT01593696, NCT02315612, and NCT03448393) between July 2012 and January 2021. This analysis revealed that 38.9% (n = 7) of patients who received reinfusion because of persistent or relapsed antigen-positive disease following their first infusion responded to reinfusion, 5 of whom achieved MRD negativity.2

Krupski presented findings from a retrospective review of tisa-cel reinfusion in pediatric B-ALL that included patients from 13 Pediatric Real World CAR Consortium sites who all received 2 tisa-cel infusions. Patients received second infusions from the time of tisa-cel commercialization, with a data cutoff of November 2021.1

The primary end point of this study was day 28 complete remission rate after tisa-cel reinfusion. Secondary end points included B-cell aplasia reestablishment rates, as well as overall survival (OS) and event-free survival (EFS) after reinfusion. Exploratory analyses evaluated tisa-cel reinfusionassociated toxicities and the feasibility of tisa-cel reinfusion as an effective bridge to hematopoietic stem cell transplantation (HSCT).

This study included 42 patients initially diagnosed with B-ALL. Patients had a median age of 8 years (range, 0-25) at diagnosis and a median age of 12.5 years (range, 0-26) at their first tisa-cel infusion.

This population was heavily pretreated, as 33% (n = 14) of patients had experienced 2 prior relapses and 24% (n = 10) of patients had experienced 3 or more prior relapses. Additionally, 43% (n = 18), 9% (n = 4), and 19% (n = 8) had received 3, 4, and 5 or more therapies prior to their second tisa-cel infusion, respectively. In total, 83% (n = 35) of patients had not received prior HSCT. All 17% (n = 7) of patients who did undergo prior HSCT did so prior to their second tisa-cel infusion. Reinfusions occurred at a median of 173 days (range, 52-521) after first infusion.

In total, 81% (n = 34) of patients received the standard lymphodepleting chemotherapy regimen fludarabine and cyclophosphamide. Additionally, most patients received the same tisa-cel dose for both infusions, at 69% (n = 29) vs 19% (n = 8), 7% (n = 3), and 5% (n = 2) who received second doses that were higher, lower, or unknown relative to their first doses, respectively.

Overall, 41% and 57% of patients received second reinfusion for detectable disease or loss of B-cell aplasia while in ongoing remission, respectively. In addition, 1 patient received reinfusion because they did not respond to their first tisa-cel infusion; the investigators excluded this patient from subsequent analyses.

In all evaluable patients (n = 41), the 1-year OS rate after reinfusion was 84%. The 1-year EFS rate was 41%, with events including relapse and death.

Patients reinfused for B-cell aplasia loss while in remission were analyzed to determine whether reinfusion led to B-cell aplasia reestablishment and remission maintenance. At day 28, of the 18 patients in this subgroup with MRD negativity, 6 had reestablished B-cell aplasia. The median duration of B-cell aplasia in these patients was 67 days, and all lost B-cell aplasia by 3 months. Four of these patients relapsed and required multiple lines of salvage therapy, including transplant. Reinfusion for loss of B-cell aplasia while in remission may be of more benefit in initial response vs reinfusion during active disease, Krupski noted.

Of the 12 patients reinfused for B-cell aplasia loss who achieved MRD negativity at day 28 but did not reestablish B-cell aplasia, 6 received consolidation with HSCT, and 4 maintained remissions without additional therapy. Three of these 12 patients relapsed, including 1 who relapsed post-HSCT. Of these 12 patients, 1 each died of disease and HSCT complications. Overall, second reinfusion was definitive therapy for 5 of the 24 patients reinfused while in remission.

Of the 6 patients reinfused while in remission who did not achieve MRD negativity and instead had disease progression at day 28, 3 died, 2 from disease and 1 from HSCT complications.

Patients reinfused for disease treatment were analyzed to determine the role of reinfusion in reestablishing remission. Of these 17 patients, 6 achieved MRD negativity at day 28, of whom 5 relapsed. Four of those patients had early relapse at a median of 115 days and required multiple lines of salvage therapy, and 1 patient relapsed after consolidative HSCT. Of the 6 patients in this group who achieved MRD negativity, 1 died of HSCT complications.

A total of 65% (n = 11) of patients reinfused for disease had detectable disease at day 28. After additional salvage attempts, 7 of these patients died, 5 from disease and 1 each from HSCT complications and infection.

The investigators also evaluated the role of tisa-cel as a bridge to transplant. In total, 71% (n = 29) of all studied patients underwent HSCT at any time after reinfusion. Of these patients, 52% (n = 15) were reinfused for disease, 9 of whom were alive at the last follow-up, and 48% (n = 14) were reinfused for B-cell aplasia loss, 11 of whom were alive at the last follow-up. These patients were transplanted for various indications, including consolidative transplant or transplant after relapse.

Of the 24 patients across both reinfusion indication groups who achieved reinfusion-induced MRD-negative remission, 9 received early HSCT, at a median of 64 days (range, 49-99) post-reinfusion. Of these patients, 2 relapsed post-transplant, and 2 died of transplant-related complications. At a median of 474 days (range, 385-686) post-reinfusion, 5 of the 9 patients were alive in remission and did not require additional therapy.

In addition, 15 patients in MRD-negative remission did not undergo HSCT, 10 of whom experienced early relapse at a median of 138 days (range, 79-641) post-reinfusion. This group highlights a missed opportunity where patients could have gone to transplant in a window of remission, Krupski said. At a median of 849 days (range, 284-1270) post-reinfusion, 5 of the 15 patients in MRD-negative remission were alive and did not require additional therapy.

Regarding reinfusion-associated toxicities, 24% of patients experienced any-grade cytokine release syndrome (CRS), and 2% of patients had grade 3 or higher CRS. Additionally, 7% of patients had any-grade neurotoxicity, and 2% of patients experienced grade 3 neurotoxicity. No reinfusion-related deaths occurred.

Tisa-cel reinfusion is well tolerated. It may be a good option for some patients, such as those who cannot tolerate transplant or who have limited other therapeutic options, Krupski concluded. Based on these data, we recommend tisa-cel reinfusion be used as a bridge to transplant in patients who are eligible.

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Tisa-cel Reinfusion Shows Potential as HSCT Bridging Therapy in ... - OncLive

Vedolizumab Plus Standard Prophylaxis Reduces Rate of Lower GI … – OncLive

The addition of vedolizumab (Entyvio) added to standard prophylaxis following unrelated allogeneic hematopoietic stem cell transplantation (HSCT) was superior to placebo at preventing lower gastrointestinal (GI) acute graft-vs-host disease (aGVHD), according to findings from the global, phase 3 GRAPHITE study (NCT03657160) presented data at the 2023 Transplantation & Cellular Therapy Meetings.1

Vedolizumab was more effective than placebo for the prevention of lower GI GVHD after unrelated allogeneic transplant when added to a standard calcineurin inhibitorbased GVHD platform, said Yi-Bin Chen, MD, director of the Hematopoietic Cell Transplant & Cell Therapy Program and the Allen B. Rogers Jr and Cara J. Rogers Endowed Chair at Massachusetts General Hospital.

Its safety profile was comparable to placebo with no new safety signals identified, given as part of GVHD prophylaxis, he added. This is the first positive phase 3 study for this specific prevention of lower GI GVHD.

In patients assigned to vedolizumab, the rate of intestinal aGVHD-free survival by 180 days following allogeneic HSCT, the primary end point, was 85.52% (95% CI, 79.17%-90.05%) vs 70.85% (95% CI, 61.63%-77.22%) for those assigned to placebo (HR, 0.45; 95% CI, 0.27-0.73; P < .001). Sixteen (9.7%) patients died in the placebo arm vs 12 (7.1%) in the experimental arm. Fourteen (8.5%) patients in the placebo arm developed stage 2 to 4 intestinal aGVHD compared with 4 (2.4%) for vedolizumab.

In the sensitivity analysis, which excluded clinical stage 0 lower GI GVHD events, 13.7% of patients in the experimental arm had GI aGVHD by day 180 following allogeneic HSCT, compared with 27.3% in the placebo arm (HR, 0.44; 95% CI, 0.27-0.73; P = .001).

Despite progress in prophylaxis and treatment, approximately 40% to 70% of patients who undergo allogenic HSCT will develop grade 2 to 4 aGVHD. Investigators have found mixed results in small studies assessing vedolizumab, a gut-selective anti- integrin antibody that inhibits migration of Gl-homing T lymphocytes across the gut endothelium, as a preventative for aGVHD. The agent is currently approved to treat ulcerative colitis and Crohns disease.2

Investigators conducted this global investigation from February 2019 through May 2022 at 94 centers in North and South America, Europe, Asia, and Australia. Investigators hoped to enroll 558 patients, but the study closed after enrolling 343 patients because the COVID-19 pandemic hampered recruitment. A total of 169 patients were randomly assigned to placebo and 165 were included in the safety and efficacy populations. In the vedolizumab arm, 169 patients were evaluated for safety and 168 for efficacy.

Patients aged 12 years or older undergoing a first allogeneic HSCT for treatment of hematological malignancies from unrelated donors were eligible. Unrelated donors were human leukocyte antigen (HLA)matched (8/8) or 7/8 matched (a single mismatch at HLA-A, -B and -C, and HLA-DRB1) were allowed. All patients received a standard GVHD prophylaxis regimen consisting of a combination of a calcineurin inhibitor plus methotrexate or mycophenolate mofetil.

All patients were assigned to standard of care prophylaxis on day 13, day 41, day 69, day 97, day 125, and day 153 after allogeneic HSCT plus placebo (n = 169) or intravenous 300 mg vedolizumab on day 1 before allogeneic HSCT (n = 174).

In the placebo group, the median age was 55.0 years (range, 16-74), 64.2% of patients were male, and the most common primary disease was acute myeloid leukemia (AML; 43.6%). More than half (52.4%) of patients had an ECOG performance status of 1, 39.6% had an ECOG performance status of 0, and 7.9% had a score of 2.

Stem cells came from the peripheral blood in 86.6% of patients, and 90.9% were 8/8 matched for HLA compatibility. Eighty-four percent of patients were in complete remission 1.

In the experimental group, the median age was 53.0 years (range, 19-74), 61.3% of patients were male, and the most common primary disease was AML (43.5%). More than half (53.0%) of patients had an ECOG performance status of 1, 38.1% had an ECOG performance status of 0, and 8.3% had a score of 2.

Stem cells came from the peripheral blood in 83.9% of patients and 90.5% were 8/8 matched for HLA compatibility. More than two-thirds of patients (71.4%) patients were in complete remission 1.

Chen noted that vedolizumab induced superior results for the primary end point, irrespective of conditioning, prophylaxis, calcineurin inhibitor, or HLA match.

Vedolizumab outperformed placebo across key secondary end points including intestinal aGVHD-free and relapse-free survival events (20.8% for vedolizumab vs 33.9% for placebo; HR, 0.56; 95% CI, 0.37-0.86; P =.0043), grade C-D aGVHD-free survival events (20.8% vs 31.5%; HR, 0.59; 95% CI, 0.39-0.91; P =.0204), non-relapse mortality events (6.0% vs 11.5%; HR, 0.48; 95% CI, 0.22-1.04; P = .0668), overall survival events (10.1% vs 15.2%; HR, 0.63; 95% CI, 0.34-1.17; P = .1458), and grade B-D aGVHD survival events (33.3% vs 46.7%; HR, 0.64; 95% CI, 0.46-0.91; P .0105). Intestinal aGVHD-free and relapse free survival events excluding clinical grade 0 patients also favored vedolizumab (20.2% vs 32.7%; HR, 0.56; 95% CI, 0.36-0.86; P = .0062).

All patients in both groups experienced any-grade adverse effects (AEs). Grade 3 or higher AEs were 89.1% in the placebo group and 92.3% in the experimental arm. Drug-related grade 3 or higher AEs occurred in 11.5% and 10.7% of patients in the vedolizumab and placebo arms, respectively. AEs leading to discontinuation occurred in 30.9% of patients in the placebo arm and 26.0% in the experimental arm.

Serious AEs leading to discontinuation occurred in 23.0% of patients in the placebo arm and 23.1% in the experimental arm. Drug-related serious AEs occurred in 8.5% and 6.5% of patients, respectively. Twenty-seven (16.4%) patients in the placebo arm experienced AEs leading to death compared with 21 (12.4%) in the experimental arm.

Approximately two-thirds (67.3%) of the placebo arms experienced serious infections, 82.4% experienced hypersensitivity/injection site reactions, and 41.8% experienced liver injury. Those results were 74.0%, 79.3%, and 40.2% in the vedolizumab arm, respectively.

Chen said that vedolizumab should be evaluated with combination with post-transplant cyclophosphamide. He added that vedolizumab requires more evaluation to define its optimal role in treatment.

Some further analysis we'll need to do islook at maximum stage of GI GVHD to truly understand the impact of what we presented here and also perhaps the impact on chronic GVHD, as well, he said. With the changing landscape of GVHD prevention, as weve seen recently and even at this meeting, its unclear how to incorporate this and the other new agents into what is a rapidly changing landscape, which is interesting. It's also great for our field.

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Vedolizumab Plus Standard Prophylaxis Reduces Rate of Lower GI ... - OncLive

Novel Therapies Are Needed to Reduce Cost Burden With AlloHCT … – OncLive

Because of an economic burden on the healthcare system occurring through the per-patient cost of allogeneic hematopoietic cell transplant (alloHCT), novel treatments to replace transplant and prevent graft-vs-host disease (GVHD) are necessary to improve patient outcomes while controlling healthcare costs, according to an analysis presented during the 2023 Transplantation & Cellular Therapy Meetings.

Results showed that the curr ent average per-patient medical cost of alloHCT over a lifetime was estimated at $1,247,917, 53% of which was due to treatment for chronic GVHD (cGVHD); the discounted expected quality-adjusted life years (QALY) was 4.7. Based on the expected availability of new cGVHD agents, the future per-patient medical cost of alloHCT was estimated to be between $1,370,839 and $1,616,684 with 4.8 discounted expected QALYs.

In a projection analysis that evaluated the current and future estimated lifetime costs over a 10-year period, data showed that the annual number of alloHCTs was 8326, and 76% of those transplants were for patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS). The average allo-HCT growth, based on the past 5 years, was calculated at 0.34%, along with an average Medicare inflation rate of 2.53%.

The aggregate costs associated with allo-HCT are expected to increase and pose an increased burden on the healthcare system, lead study author Miguel-Angel Perales, MD, chief of the Adult Bone Marrow Service at Memorial Sloan Kettering Cancer Center, New York, New York, and coinvestigators, wrote in the poster presented at the meeting. Novel drugs have recently emerged. Clinical use and data on their utilization and impact are currently sparse.

The number of HCT procedures has increased annually, the investigators noted. Emerging agents have been designed to address and manage posttransplant complications, such as GVHD. However, such agents are not widely utilized and their impact on clinical practice is unclear.

In the analysis presented, investigators sought to estimate the total lifetime medical costs of an alloHCT patient, and the aggregate lifetime burden over the next decade for incident alloHCT patients while considering newly available therapies for chronic GVHD.

Investigators utilized a 100-day and long-term Semi-Markov Partitioned survival model with peer-reviewed evidence and data from the CIBMTR of US patients with AML, ALL, and MDS who had undergone alloHCT. The clinical inputs studied were overall survival (OS), GVHD-free relapse-free survival (GRFS), incidence of both acute GVHD (aGVHD) and cGVHD, relapse of primary disease, and infections. Economic inputs included alloHCT cost, aGVHD, cGVHD, relapse episode, infection hospitalization, maintenance treatment, and end-of-life costs.

The primary outcomes were total direct medical costs, total expected life years (LYs), and quality-adjusted QALYs. Investigators noted that all cost and outcomes were discounted at 3% annually.

Moreover, patient characteristics, estimated time spent in each health state, OS, and GRFS outcomes came from CIBMTR and published literature data.

Based on the data pulled, the age at transplant was 53 years and 58% were male. Fifty-one percent of patients had AML, 21% had ALL, and 28% had MDS. In related donors (32%), 8% were from bone marrow and 92% were from peripheral blood stem cell (PBSC); in unrelated donors, 9% and 91% were from bone marrow and PBSC, respectively.

Regarding costs, an alloHCT was $182,642, and the 100-day and annual costs of acute GVHD treatment were $79,197 and $158,938, respectively. For cGVHD treatment, the current cost was $220,202, with an estimated 25% future uptake in costs totaling $261,413 and an estimated 75% future uptake totaling $343,836. Relapse episodes had a cost of $206,003 and infection hospitalization at $53,214; the annual costs of maintenance sorafenib (Nexavar) and imatinib mesylate (Gleevec) were $277,765 and $184,861, respectively. End-of-life costs were $174,102.

Patient utilities were also calculated, posttransplant without GVHD (0.86) and with GVHD (current, 0.69; future, 0.76), and relapsed/progressed AML (0.53), ALL (0.74), and MDS (0.60); a disutility was infection (-0.23).

The projection analysis was run to account for a likely increased growth of allogeneic transplants in the projected years 1 through 10. Here, an average annual growth rate was applied to the current number of alloHCT recipients; this was based on the mean alloHCT growth from the past 5 years. Based on this information, there is an estimated 6544 allogeneic recipients occurring in year 10 and a total of 64,461 alloHCTs over the 10-year span.

Volume and costs were also analyzed in the projection analysis. The cumulative total over the 10-year span was calculated at $92.6 billion. When including the future alloSCT costs with a 25% uptake, this total was $101.7 billion, which was a $9.1-billion net difference vs the current cost; this was $120.0 billion with a 75% uptake, which was a $27.4-billion net difference vs the current cumulative total.

The analysis suggests that the small gain in QALYs [0.1 QALY average per patient] as a result of new treatment approaches for active [chronic] GVHD would cost an additional $9 billion to $27 billion in the aggregate over 10 years, the authors noted.

Because 15-year OS and GRFS outcomes were used to inform the model consisted of a cohort of allo-HCT recipients from 2000 to 2005, the authors stated that the data may not fully be representative to outcomes observed in present dayespecially as cancer treatment and care continues to evolve and improve.

They added that the OS/GRFS outcomes were adjusted by utilizing data from 2016 to 2019 for the first 3 years, before using the observed trend from a 2000 to 2005 cohort. This permitted the inputs to be more representative of current treatment outcomes.

Further limitations the authors cited were that inputs were obtained from published claims analyses and mirror averages of multiple populations, which can introduce heterogeneity into the model. Finally, off-label maintenance therapy for patients with FLT3-ITDpositive AML and Philadelphia chromosomepositive ALL is not fully adopted in clinical practice, so not all patients in these subgroups may receive this treatment. Incorporating the costs of such treatment may result in an overestimation of the total lifetime costs of allo-HCT, the authors concluded.

Perales M-A, Devine SM, Garrison LP, et al. Estimating the current and future costs and health outcomes of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract 495

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Novel Therapies Are Needed to Reduce Cost Burden With AlloHCT ... - OncLive

Urgent warning to dog owners as new deadly Alabama Rot case confirmed in UK – The Mirror

Dog owners are being warned to 'remain vigilant' after a second fatal case of Alabama Rot in 2023 has been confirmed in Berkshire, tragically killing six-year-old Hungarian Vizsla Marnie

Pet owners are being warned to spot the signs of Alabama Rot after the deadly disease took the life of Marnie the six-year-old Hungarian Vizsla in Berkshire. Also known as cutaneous and renal glomerular vasculopathy (CRGV), Alabama Rot is an extremely rare disease which claims the lives of 90 percent of infected dogs.

The caution comes after a three-year-old Labrador sadly died last month, marking two deaths already in 2023. Marnie's owner, Sabina Richardson, wants to highlight the early symptoms of the canine disease, including sores on paws, to ensure other pet parents are fully aware of the warning signs of CRGV.

Sabina told the Mirror: "Marnie's first symptoms were sores on her paws which then began to spread onto her legs. She also stopped eating and started to vomit.

"We took her to local vets who gave her antibiotics but she couldn't keep the tablets down and continued to deteriorate.

"By this point, we were very concerned and visited another vets, who said they feared it was Alabama Rot.

"They gave Marnie an injection of antibiotics and took blood tests which confirmed her kidneys were failing.

"That was such a shock and it was really tough when we finally had to make the heart-breaking decision to put her to sleep."

The anguish was all the more acute as a dog belonging to Sabina's partner, a two-year-old whippet called Goose, had shown similar symptoms but, thankfully, survived.

Sabina added: "Goose had very similar sores that were oozing puss and had the same sort of treatment but he survived and is absolutely fine now.

"It's so hard to understand. We keep going over it all and trying to identify where they could have come in touch with such a rare disease.

"We have re-traced our walks and can't think of anywhere we went that was unusual.

"Everyone in the village tends to walk their dogs in the same spots so it's baffling how there haven't been more cases."

Anderson Moores Veterinary Specialists has been leading research since 2012 and confirmed the latest case, which is the second in the county in the past six weeks.

Josh Walker, from Anderson Moores, told the Mirror: "There were 11 cases recorded across the UK in 2022, so to report two deaths in Berkshire in a six-week period is unusual.

"However, I must emphasise this is a very rare disease and we're advising dog owners to remain calm but vigilant and seek advice from their vet if their dog develops unexplained skin lesions.

"Treatment largely revolves around management of the sudden onset kidney failure and is only successful in around 10 per cent of cases."

Josh advises pet owners to use the veterinary specialists' bespoke online map to see the exact location of confirmed cases in the UK.

Do you have a dog story to share? Email nia.dalton@reachplc.com.

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Urgent warning to dog owners as new deadly Alabama Rot case confirmed in UK - The Mirror

Roswell Park in the Spotlight at Tandem Meetings: Experts Share … – Roswell Park Comprehensive Cancer Center

Physicians speak on personalizing treatment for graft-versus-host disease, arming CAR T cells against macrophages

ORLANDO, FL Two experts from Roswell Park Comprehensive Cancer Center are delivering presentations this week at an international conference highlighting research aimed at extending and improving the lives of patients with blood-related cancers. Nataliya Buxbaum, MD, from the Department of Pediatric Oncology and Marco Davila, MD, PhD, Vice Chair for Cellular Therapies and Senior Vice President and Associate Director for Translational Research, were invited to highlight their work in podium talks at the 2023 Tandem Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR) this week in Orlando, Florida.

A biology-based approach to GvHD

Dr. Buxbaum, a member of the Chronic GvHD National Institutes of Health (NIH) Consensus Project Biology Task Force, described recent advances in understanding the biology of chronic graft-versus-host disease (GvHD) a potentially fatal condition that affects between 25% and 75% of patients who undergo allogeneic hematopoietic cell transplant. She also discussed her research on the immunometabolism of GvHD that may lead to new imaging approaches and therapy for this condition.

If its successful, the strategy may:

We are still uncovering the complex biological underpinnings of GvHD, Dr. Buxbaum observes. For four decades we treated all patients with the same systemic treatment corticosteroids. Not only do many patients not respond, but those who do respond end up being on them a long time, and they have many side effects.

She notes that preclinical work has opened insights into the biological pathways involved in GvHD and has led to the development of targeted therapies for this transplant barrier. At the same time, the work of the NIH Consensus Project Biology Task Force has better defined the disease, laying the groundwork for the FDA to approve three drugs for chronic GvHD and one to prevent acute GvHD in the last five years alone. Thats groundbreaking, she says.

However, while blood-based biomarkers are being developed for GvHD, it is still challenging to pinpoint the exact areas of the body where GvHD is developing based on blood sampling alone. Because there currently is no diagnostic imaging for detecting GvHD, a minimum of 28 days must elapse after the start of treatment before a biopsy can determine whether or not the disease has responded to treatment and a biopsy is challenging to do in somebody whos sick, Dr. Buxbaum notes. If the initial treatment hasnt worked, a different drug is started and more time is needed before re-evaluation for response.

Locating areas of high glucose metabolism is key to detecting the presence of cancer. This is currently accomplished with a positron emission tomography (PET) scan after having the patient ingest a radioactive sugar molecule. PET is then able to map where glucose is being absorbed by cancer cells. But high sugar metabolism can also indicate the presence of GvHD: When you first start getting GvHD, the immune system fires up the T cells, and they start using a lot of sugar, explains Dr. Buxbaum.

She and her team see great potential in performing metabolic imaging with magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce images and, unlike PET, does not require radioactive sugar molecules. Within the next six to 12 months, Dr. Buxbaum and her colleagues hope to run a pilot study to gauge the effectiveness of locating GvHD with metabolic MRI, using a sugar molecule labeled with deuterium, a nonradioactive form of hydrogen.

Targeting this metabolic pattern of high glycolysis is something we should do therapeutically, says Dr. Buxbaum. Were studying it in preclinical models right now and having some success. She says previous work with preclinical models has shown that GvHD can be detected this way in the liver and gut, and we think the same can happen in a human being. We then use a drug that inhibits the processing of sugar to ameliorate GvHD.

Allogeneic stem cell transplants are especially challenging. Each time its a unique mismatch between the host and donor, if theyre unrelated, says Dr. Buxbaum. Its a unique situation every time, so it requires personalized therapy.

Dr. Buxbaums talk, Biology of GvHD, was presented Wednesday, Feb. 15, from 11-11:30 a.m. EST.

Identifying the cause of poor outcomes in CAR T-cell therapy for B-cell malignancies

Dr. Davila will discuss his teams efforts to determine why some patients with B-cell malignancies do not respond well to CAR T-cell therapy targeting CD19, a surface protein expressed by most B cells. What accounts for poor outcomes in those patients?

Using patient samples, the investigators identified gene signatures and cell signatures showing that the lymphoid tissue in those patients contained high numbers of myeloid cells, which originate in the bone marrow and can develop into various types of adult blood cells, including macrophages, which are capable of killing tumor cells and other cells. They then developed assays of CD19-targeted CAR T cells, tumors and macrophages, and cultured them together and discovered that certain types of macrophages were capable of killing CAR T cells.

While macrophages might kill up to 90% of the CAR T cells, the remaining 10% that survive proliferate and persist, says Dr. Davila, which means it would be possible for the surviving CAR T cells to continue attacking the cancer cells. But how well would they function? We compared them to other CD19-targeted T cells that had never been exposed to macrophages, and they performed worse, he explains. They didnt kill as well, they didnt secrete as much cytokine which can stimulate the immune system and they didnt proliferate as well.

Further investigation using preclinical models revealed the specific metabolic pathways that Dr. Davila and his colleagues believe are key to how macrophages trigger this dysfunction in CD19-targeted CAR T cells. Our goal now, he says, is to retrain the CAR T cells to be more resistant to this metabolic dysfunction. We hope this will result in better outcomes for patients.

Dr. Davila will present Mechanisms of Resistance to CD19-Targeted CAR T Cells: Lessons from Mice and Patients, Friday, Feb. 17, from 3-3:30 p.m. EST, World Center Marriott, Cypress 3.

###

Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancers grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at http://www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.

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Roswell Park in the Spotlight at Tandem Meetings: Experts Share ... - Roswell Park Comprehensive Cancer Center

Is it still worth pursuing the repurposing of metformin as a cancer … – Nature.com

Prasad V, Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Intern Med. 2017;177:156975.

Article PubMed PubMed Central Google Scholar

DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:2033.

Article PubMed Google Scholar

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:60714.

Article CAS PubMed PubMed Central Google Scholar

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig. 2001;108:116774.

Article CAS PubMed PubMed Central Google Scholar

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:13045.

Article PubMed PubMed Central Google Scholar

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife. 2014;3:e02242.

Article PubMed PubMed Central Google Scholar

Fendt SM, Bell EL, Keibler MA, Davidson SM, Wirth GJ, Fiske B, et al. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 2013;73:442938.

Article CAS PubMed PubMed Central Google Scholar

Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67:674552.

Article CAS PubMed Google Scholar

Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:35160.

Article CAS PubMed Google Scholar

Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:21426.

Article CAS PubMed PubMed Central Google Scholar

Blandino G, Valerio M, Cioce M, Mori F, Casadei L, Pulito C, et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012;3:865.

Article PubMed Google Scholar

Lochhead PA, Salt IP, Walker KS, Hardie DG, Sutherland C. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes. 2000;49:896903.

Article CAS PubMed Google Scholar

Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab. 2003;88:132332.

Article CAS PubMed Google Scholar

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:25660.

Article CAS PubMed PubMed Central Google Scholar

Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499503.

Article CAS PubMed PubMed Central Google Scholar

Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020;16:27683.

Article CAS PubMed PubMed Central Google Scholar

Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, et al. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab. 2018;28:679688.e674.

Article CAS PubMed PubMed Central Google Scholar

Lord SR, Collins JM, Cheng WC, Haider S, Wigfield S, Gaude E, et al. Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin. Br J Cancer. 2020;122:25865.

Article CAS PubMed Google Scholar

Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, et al. Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA.32 randomized clinical trial. J Am Med Assoc. 2022;327:196373.

Article CAS Google Scholar

Goodwin PJ, Dowling RJO, Ennis M, Chen BE, Parulekar WR, Shepherd LE, et al. Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial. NPJ Breast Cancer. 2021;7:74.

Article CAS PubMed PubMed Central Google Scholar

Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19:674150.

Article CAS PubMed Google Scholar

Tsakiridis T, Pond GR, Wright J, Ellis PM, Ahmed N, Abdulkarim B, et al. Metformin in combination with chemoradiotherapy in locally advanced non-small cell lung cancer: the OCOG-ALMERA randomized clinical trial. JAMA Oncol. 2021;7:133341.

Article PubMed PubMed Central Google Scholar

Skinner H, Hu C, Tsakiridis T, Santana-Davila R, Lu B, Erasmus JJ, et al. Addition of metformin to concurrent chemoradiation in patients with locally advanced non-small cell lung cancer: the NRG-LU001 phase 2 randomized clinical trial. JAMA Oncol. 2021;7:132432.

Article PubMed Google Scholar

Alghandour R, Ebrahim MA, Elshal AM, Ghobrial F, Elzaafarany M, MA EL. Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED). Urol Oncol. 2021;39:831.e810.

Article Google Scholar

Arrieta O, Barron F, Padilla MS, Aviles-Salas A, Ramirez-Tirado LA, Arguelles Jimenez MJ, et al. Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5:e192553.

Article PubMed PubMed Central Google Scholar

El-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clin Exp Metastasis. 2016;33:33957.

Article CAS PubMed Google Scholar

Marrone KA, Zhou X, Forde PM, Purtell M, Brahmer JR, Hann CL, et al. A randomized phase II study of metformin plus paclitaxel/carboplatin/bevacizumab in patients with chemotherapy-naive advanced or metastatic nonsquamous non-small cell lung cancer. Oncologist. 2018;23:85965.

Article CAS PubMed PubMed Central Google Scholar

Yee D, Isaacs C, Wolf DM, Yau C, Haluska P, Giridhar KV, et al. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer. NPJ Breast Cancer. 2021;7:131.

Article CAS PubMed PubMed Central Google Scholar

Gulati S, Desai J, Palackdharry SM, Morris JC, Zhu Z, Jandarov R, et al. Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer. Cancer. 2020;126:35462.

Article CAS PubMed Google Scholar

Trucco M, Barredo JC, Goldberg J, Leclerc GM, Hale GA, Gill J, et al. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin. Pediatr Blood Cancer. 2018;65:e27224.

Article PubMed Google Scholar

Khawaja MR, Nick AM, Madhusudanannair V, Fu S, Hong D, McQuinn LM, et al. Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. Cancer Chemother Pharm. 2016;77:9737.

Article CAS Google Scholar

Ashton TM, Fokas E, Kunz-Schughart LA, Folkes LK, Anbalagan S, Huether M, et al. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun. 2016;7:12308.

Article CAS PubMed PubMed Central Google Scholar

Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, et al. Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer. Clin Cancer Res. 2021;27:245969.

Article CAS PubMed PubMed Central Google Scholar

Lissanu Deribe Y, Sun Y, Terranova C, Khan F, Martinez-Ledesma J, Gay J, et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat Med. 2018;24:104757.

Article CAS PubMed Google Scholar

Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 2014;508:10812.

Article CAS PubMed PubMed Central Google Scholar

Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2013;49:24150.

Article CAS PubMed Google Scholar

Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:36776.

Article CAS PubMed Google Scholar

Tosic I, Frank DA. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications. Neoplasia. 2021;23:116778.

Article CAS PubMed PubMed Central Google Scholar

Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80:593543.

Article PubMed PubMed Central Google Scholar

Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018;24:191929.

Article CAS PubMed PubMed Central Google Scholar

Broadfield LA, Saigal A, Szamosi JC, Hammill JA, Bezverbnaya K, Wang D, et al. Metformin-induced reductions in tumor growth involves modulation of the gut microbiome. Mol Metab. 2022;61:101498.

Article CAS PubMed PubMed Central Google Scholar

Han K, Fyles A, Shek T, Croke J, Dhani N, DSouza D, et al. A phase II randomized trial of chemoradiation with or without metformin in locally advanced cervical cancer. Clin Cancer Res. 2022;28:526371.

Article CAS PubMed Google Scholar

Fu Z, Mowday AM, Smaill JB, Hermans IF, Patterson AV. Tumour hypoxia-mediated immunosuppression: mechanisms and therapeutic approaches to improve cancer immunotherapy. Cells. 2021;10:1006.

Article CAS PubMed PubMed Central Google Scholar

Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res. 2017;5:916.

Article CAS PubMed Google Scholar

Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell. 2018;71:60620.e607.

Article CAS PubMed PubMed Central Google Scholar

Zhang Z, Li F, Tian Y, Cao L, Gao Q, Zhang C, et al. Metformin enhances the antitumor activity of CD8(+) T lymphocytes via the AMPK-miR-107-Eomes-PD-1 pathway. J Immunol. 2020;204:257588.

Article CAS PubMed Google Scholar

Li L, Wang L, Li J, Fan Z, Yang L, Zhang Z, et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 2018;78:177991.

Article CAS PubMed PubMed Central Google Scholar

Chiang CF, Chao TT, Su YF, Hsu CC, Chien CY, Chiu KC, et al. Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-kappaB signaling. Oncotarget. 2017;8:2070618.

Article PubMed PubMed Central Google Scholar

Wang JC, Sun X, Ma Q, Fu GF, Cong LL, Zhang H, et al. Metformins antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J Cell Mol Med. 2018;22:382536.

Article CAS PubMed PubMed Central Google Scholar

Davis SR, Robinson PJ, Jane F, White S, Brown KA, Piessens S, et al. The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial. Clin Endocrinol. 2018;89:60512.

Article CAS Google Scholar

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Is it still worth pursuing the repurposing of metformin as a cancer ... - Nature.com

Dr. Nieto on High-Dose Chemotherapy and ASCT in R/R Multiple … – OncLive

Yago L. Nieto, MD, PhD, professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses findings from a phase 2 trial investigating panobinostat (Farydak), gemcitabine, busulfan, and melphalan plus autologous stem cell transplant (ASCT) in patients with high-risk or relapsed/refractory multiple myeloma.

This trial enrolled 80 patients to 1 of 2 cohorts. The first cohort consisted of patients who were receiving a first transplant for relapsed/refractory disease or as frontline consolidation for disease with high-risk cytogenetics, Nieto says. The second cohort consisted of patients who were receiving a second transplant after progressing on a previous transplant, Nieto explains.

This trial showed that the combination of panobinostat, gemcitabine, busulfan, and melphalan plus ASCT was safe, with manageable toxicities, Nieto notes. This regimen was also associated with high overall response rates and complete response rates, at 67% and 40%, respectively, in cohort 1 and 93% and 64%, respectively, in cohort 2, Nieto emphasizes. Additionally, minimal residual disease (MRD) negativity rates improved after transplant in both cohorts, and MRD negativity conversion was associated with better outcomes, Nieto says. The MRD negativity rate increased from 8.5% to 23% after transplant in cohort 1 and from 34% to 55% in cohort 2.

The second part of this trial was a comparison between both cohorts of the study and a concurrent control cohort consisting of patients who were eligible for the trial but instead received off-trial transplant with either busulfan and melphalan or melphalan alone, Nieto explains. A matched pair analysis showed progression-free survival (PFS) superiority with the study regimen vs the control arm in patients receiving a first transplant, Nieto says. Conversely, the matched pair analysis of patients receiving a second transplant showed no significant difference in PFS between the study regimen and control arm, Nieto notes.

Based on these findings, the investigators concluded that panobinostat, gemcitabine, busulfan, and melphalan plus ASCT is more effective than standard-of-care transplant with busulfan and melphalan or melphalan alone in patients receiving a first transplant for relapsed/refractory or high-risk multiple myeloma, Nieto concludes.

Editors Note:Dr. Nieto has received research funding from Novartis, Secura Bio, AstraZeneca, and Affimed.

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Dr. Nieto on High-Dose Chemotherapy and ASCT in R/R Multiple ... - OncLive

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