“The dollar store expanding is the fastest-growing retail format, and we also have seen a lot of family, independently owned grocery stores going out of business,” Lopez said.

“So we try to link the two and to find not just a statistical correlation, but also we find that indeed when the dollar store comes to the neighborhood these stores tend to go out of business as well.”

The low-priced dollar store — primarily Dollar General, Family Dollar and its subsidiary, Dollar Tree — “is the most successful type of format that is proliferating all across the United States, especially in rural areas and food deserts, which are the more underserved areas,” Lopez said.

According to the study, published in Applied Economic Perspectives and Policy, there were 35,000 dollar stores in the United States in 2019 and they were “among the few food retailers” that grew in revenue after the Great Recession of 2008-10, outperforming big box discounters and retail clubs.

Between 2000 and 2019, dollar stores opening in a neighborhood resulted in a 5.7% drop in independent grocery store sales, a 3.7% decrease in employment and a 2.3% increase in the likelihood of the grocery stores closing, according to the research.

The effects are three times more likely in rural than urban areas, the study found.

The dollar stores tend not to offer fresh produce and meats, with foodstuffs being limited to canned and boxed goods.

“In general they provide an unhealthier food assortment … and less services,” Lopez said. “They don’t have bakery, butchers, they don’t have a lot of these.”

Dollar General disputes the characterization as offering only unhealthful items and notes customers depend on the business with goods they need and can obtain nearby, as well as providing local jobs.

Lopez said the dollar stores’ business model is “low prices, low cost, low quality. … But a lot of the food that they sell is not healthy. It’s processed foods that they can store. Keeping fresh food and vegetables costs money.”

Dollar stores are not necessarily a negative, if there was not a grocery store in the area before, Lopez said.

“Public health advocates, they’re against dollar stores, but a lot of people that visit the dollar store, they prefer to have a dollar store than not to have anything at all in some areas. … But in general … we find if they are driving some of the local businesses out, then that is the negative trend.”

There is also a potential that a dollar store may be “rupturing the connection to local communities and mom and pop stores, so that trend is negative,” Lopez said. “So it’s a mixed blessing, I will say.”

Caitlin Caspi is director of food security initiatives at the UConn Rudd Center for Food Policy and Health and has researched small and non-traditional food retailers.

“Historically speaking, basically, most dollar stores don’t offer any fresh fruits and vegetables and canned fruits and vegetables are the only options for produce,” she said, though she said it appears this has changed some in recent years.

“When we’re comparing dollar stores to other small and non-traditional retailers that sell food — so that includes independent corner stores, gas marts or pharmacy chains — even among that class of stores, dollar stores were really offering the fewest healthy options of any small or non-traditional food retailer,” she said.

The issue is that dollar stores don’t have the infrastructure for refrigeration, sourcing and supply for fresh foods, Caspi said, so they can’t offer those foods at a volume to be profitable.

“That’s going to have consequences for people’s diet quality, because we know that fresh fruits and vegetables is a cornerstone of a healthy diet and recommended in all of the U.S. dietary guidelines,” Caspi said. “It seems like for a long time, historically, they didn’t have the mechanism in place to be sourcing and supplying these foods at their stores.”

Most food sold at dollar stores is “energy dense and nutrient poor,” Caspi said, such as sugar-sweetened beverages and candy. She said the median amount spent on food at such stores is $2.89, with the food containing 1,200 calories, “and more than half of that energy was from added sugar. So this doesn’t paint a picture of a retailer that’s providing a staple.”

While the daily caloric intake is generally 2,000 a day for women and 2,500 for men, Caspi said the statistic is “reflecting the fact that this isn’t maybe where people are doing major grocery shopping. … So these are food retailers, but what is being purchased is not the cornerstone of a healthy meal or diet,” she said.

‘Affordable access to goods’

A Dollar General spokeswoman issued a statement via email:

“With approximately 75 percent of Americans within five miles of a DG store, thousands of our customers rely on us for convenient and affordable access to everyday household essentials. We also believe our mission of Serving Others and our intense customer focus differentiate Dollar General from other seemingly similar retailers,” she said.

“In a wide variety of communities across the country, our neighborhood general stores operate alongside local grocers and business owners to collectively meet customers’ needs. While we are not a grocery store, every Dollar General store offers components of a nutritious meal including canned and frozen vegetables, canned fruits, proteins, grains, dairy, and more,” she said. “Additionally, we’ve worked with a registered dietitian and nutritionist to create Better For You recipes to help our customers create healthier meals from products sourced primarily from our stores.”

“We believe each new store represents positive economic impact through the increased affordable access to goods; new jobs and career growth opportunities; the ability for nonprofits, schools and libraries to apply for DGLF grants and the generation of local tax revenue that can be reinvested into the community.”

Family Dollar also was asked to comment for this story.

“There’s a tremendous amount of darkness in the world today. There’s a tremendous amount of suffering in the world today. There’s a tremendous amount of injustice and terror in the world today,” said Rabbi Yitzchok Adler of Beth David synagogue in West Hartford.

While the war and suffering is front and center, Connecticut rabbis also said Hanukkah is a time to seek unity, inspiration and joy.

“And the timeliness of this holiday with current events is profound. For it gives everybody who practices the holiday and observes its traditions an opportunity to light a candle and spread the light,” Adler said.

“Light represents hope. Light represents knowledge. Light is a symbol of optimism and confidence.”

Hanukkah, the Festival of Lights, celebrates the miracle of the lamp oil lasting eight days when the Maccabees defeated the Seleucids and rededicated the Second Temple in the second century B.C.E. 

Adler focused on miracles, but not on miracles sent by God.

“One of the messages my congregation will be hearing from me this coming weekend is that there are many different ways of categorizing miracles,” he said. “The most celebrated on calendars are those miracles that we believe are trickle down, meaning they came from heaven intending to impact the quality of the human experience.”

Such miracles performed by God include freeing the Jews from slavery in Egypt.

“There are other miracles which I will contend … are trickle up,” Adler said. “We make miracles happen when we recognize the strength that comes in numbers, that comes in solidarity, that comes through unity, when large numbers of people come together for common cause, and that cause is reflective of what is believed to be the will of God, the best interest of humankind.” 

Now is a time when the world needs more “trickle-up” miracles, Adler said.

“The prophet Isaiah foretold a day when farm tools would replace weapons and feeding humankind will replace killing human beings,” he said.

“And if it happens, it will be trickle up. And it’ll be based on the choices that people make,” he said.

“The entire theme of Hanukkah is not just the general concept of freedom but really the idea of overcoming darkness,” said Rabbi Yosef Wolvovitz of the Chabad Jewish Center in Glastonbury.

“What it really is about is searching within to find our own energy … our own essence and our own spirit, and to reignite it,” he said. “So if ever there was a time that we have to be strong in our identity, and allow our souls to shine bright, I think it’s now.”

Wolvovitz said he was thinking about the Israeli-Hamas war, but not only about that.

“We have obviously an external enemy that is causing us to be deeply united, and to be deeply committed,” he said. “But I think, especially in America but I would say in all free countries of the world, we also have the ability to self-inspire, to take the message of Hanukkah inside out, not just outside in.

“When I say there could not be a better time for Hanukkah than this, I’m referring more to the idea of us looking at the tradition, looking at the story, looking at our own identity, and trying to fortify that, not only because of external forces but also because of an internal inspiration.”

For Rabbi Michael Pincus of Congregation Beth Israel in West Hartford, the holiday means more because of the war.

“It’s still a joyful time,” he said. “And I will say the story of Hanukkah in some ways resonates more with me this year because it’s a story about how a few were able to overcome against all odds and survive. And it’s inspiring.”

Despite the suffering, Pincus said he looks at the positives.

“In terms of the war, in terms of all the hardships, all the suffering — the miracles that have come out of the darkness of the war, of people who survived and who had the courage to stand up,” he said.

“Among a lot of the sad stories of the war there have been some remarkable stories of people going above and beyond and saving lives. Modern-day Maccabees,” he said.

“We’re still worried about what’s going to happen next, and so it’s hard,” Pincus said. “But on the flip side, it’s also a time of joy and time with family and full blessings and such.”

Rabbi Alan Lefkowitz of Temple Beth Torah in Wethersfield focused on how “the Jewish people have always been known for bringing light to darkness … especially this time of year as the sun sets so much earlier.”

With a war being fought, “where there’s a lot of darkness for the Jewish people, we want to always remember that we can create light, not only for ourselves but creating light for others as well,” he said.

“But we also remember that there are other people suffering in the world as well, that we want to also make sure that we’ve (been able) to bring light to them,” Lefkowitz said.

In West Hartford, the annual “Chanukah Fire on Ice celebration” will be held Sunday, Dec. 10 starting at 3 p.m. During the fourth night of the Chanukah festival a “super-sized” ice sculpture menorah will be lit, according to Chabad of Greater Hartford. The event is free but registration is required at https://www.chabadhartford.com/. In a time of a rise in antisemitism, the event is intended to demonstrate pride, solidarity and unity, according to Rabbi Shaya Gopin, of Chabad.

Ed Stannard can be reached at estannard@courant.com. 

The New York Times recently reported that, according to the U.S. Census Bureau, more Americans say they have problems with memory, making decisions and other cognitive issues than at any time in the last 15 years.

It’s as common as other long COVID symptoms and continues to appear in adults in their 30s and 40s and has been reported to keep people out of work.

“If you can take the example of an engineer who works with computers and has to process the information and write down the data and do all kinds of mental calculations and make decisions, they cannot do that because they cannot process the information,” said Dr. Naheed Van de Walle, a rehabilitation physician with Hartford HealthCare. 

“I had a patient who had to give up the practice of law because of these brain fog symptoms,” she said. “And I have patients who are physicians who obviously have a lot of problems if they have brain fog. So it affects everyone basically, even if you’re not working.” 

Related: UConn study to test cognition training games to improve Covid-related ‘brain fog’

Van de Walle said she has not seen the issue as much in older people.

“I don’t see that. I see younger people, mostly between I would say 30s to 60s, and some patients are in their 20s,” she said. “And I don’t see that high an incidence in older people. So I think that’s something that we have to revisit and look at it, because it’s not really true that it’s always older people in their 80s.”

Brain fog, which is a loss of cognitive ability, “is very debilitating,” Van de Walle said.

It includes “memory deficits, word-finding problems, processing information. Short-term memory is the most devastating and I see that in my patients who are 30-something. It’s not all the people. These are very productive people. They’re working, and they are completely devastated by this symptom,” she said.

Van de Walle said scientists believe the cause of brain fog may be a loss of serotonin caused by the coronavirus, including a decrease of the precursor of serotonin in the gut. The loss of serotonin leads to impaired communication between the brain and the vagus nerve, which controls bodily functions such as digestion, heart rate and the immune system, she said.

This can lead to reduced function in the brain, mainly the hippocampus, she said.

Van de Walle said people with brain fog often find that their complaints aren’t taken seriously.

“One thing they will say is, thank you so much for listening to us and acknowledging our symptoms, because we’ve been dismissed so many times by so many different providers that they feel so invalidated. They don’t feel validated at all. And these symptoms are real,” she said.

She said brain fog can occur with other diseases as well, including fibromyalgia, depression, chronic fatigue syndrome and general cognitive decline.

Dr. Lindsay McAlpine, who runs Yale Neurology’s NeuroCOVID-19 Clinic, said brain fog can be associated with chronic fatigue syndrome or postural orthostatic tachycardia syndrome, knowns as POTS, which causes an increased heart rate after getting up from a sitting or lying position.

Patients with those issues make up a good portion of those McAlpine sees in her clinic, she said.

“I’ve seen a lot of very high-functioning people, busy moms who used to do 10 things at once, who now … can’t do that, have to prioritize,” McAlpine said.

Others will say, “I had this conversation with my wife yesterday and she gets so frustrated with me. I just totally don’t remember the conversation at all today,” she said. “The severity really ranges very widely, interestingly. Some people, most people are able to work through it and they just have to adapt and they’re frustrated.”

Others had to change jobs or retire, she said.

While brain fog can’t be cured, and can last from 12 weeks to as long as six months or even years, Van de Walle does teach her patients how to manage it.

First, she sends them to a speech pathologist.

“Speech pathologists are very well trained to do cognitive screening,” she said. “So if it’s mild brain fog symptoms, I will send them to a speech pathologist to see what are the deficiencies. They can do specific tests. These are standardized tests to see where the problem is and then give them recommendations, remedial techniques.”

She also tells her patients not to multitask.

“You’re going to cause more confusion and more problems and will not be able to complete any task,” she said. “So always do one thing at a time.”

She also advises people to pace themselves.

“Give themselves extra time, take breaks, computer breaks, and not to try to finish everything in one stretch, which is sometimes hard for younger patients to do who are very enthusiastic and work very hard, but they have to remind themselves to take breaks, so they can come back, let the brain rest a little bit and then go back to what they’re doing,” she said.

Hydration is important, as is avoiding physical fatigue, Van de Walle said.

McAlpine said she makes sure she’s not missing some other cause because “long COVID to me is the diagnosis of exclusion.” 

“And then, one of the main things I focus on is sleep. So what we’re finding is that individuals with long COVID are much more sensitive to sleep loss and sleep deprivation and sleep interruption.”

Anyone with sleep issues is given a sleep study. Exercise is also recommended for patients who are able to do it because it improves brain health. 

“And then making sure we’re not missing other things like … migraine disorders,” McAlpine said. “Migraines have an effect on function, making sure we’re treating new mood disorders after COVID or mood issues, because anxiety and depression has a huge effect on cognitive function.”

It’s a holistic approach, she said, which also includes medications such as guanfacine and N-acetyl cysteine “and patients respond well to that.” 

Ed Stannard can be reached at estannard@courant.com. 

According to June Everett of Colorado, campaign director for the clubs, the Satan Club was requested by a parent from Lebanon Elementary School as an alternative to the Good News Club that meets there. It’s sponsored by the Satanic Temple, an atheist group.

Everett said it’s the first Satan Club in Connecticut.

“This particular parent was aware of the Good News Club and did not feel comfortable sending her children to the Good News Club and was more closely aligned with our seven tenets and our beliefs,” she said.

“So she reached out and asked if we can start an After School Satan Club at her kid’s elementary school, and so we went through the process and we lined up our volunteers to help with the club. And of course, the school district understands constitutional law and the First Amendment, so they approved us without any issues.”

There’s nothing evil about the club, Everett said.

“We identify with the statement that is in John Milton’s ‘Paradise Lost,’ where Satan stands up to the adversary and is essentially the ultimate rebel standing up for the rights of the other angels and the other people,” she said.

“I always have to explain to the Christians that you don’t have a monopoly on Satan,” Everett said. “We understand that he is a triggering evil, terrible being in your biblical world. But in our world, we look to him differently. And we consider him the embodiment of standing up to radical authority.”

Satan represents the freedom of equal access for minorities and the marginalized, including LGBTQ people, “because a lot of those people have been kicked out of their church or abandoned by family,” Everett said.

The club “focuses on science, critical thinking, creative arts, and good works for the community,” according to its website. “While engaged in all of these activities, we want clubgoers to have a good time.”

Everett said the Satan Clubs only go where there are religious clubs operating.

“What we do is we wait for the Good News Club to return and then we can return, but we don’t want to be the only religious club operating on campus,” she said. “So we have to wait for basically their permission slips or their fliers to start coming out before we take action.”

Both the Bible-based Good News Clubs and the Satan Clubs are allowed in the schools because of a Supreme Court ruling, and the Lebanon superintendent has followed that ruling.

Superintendent Andrew Gonzalez issued a statement saying, “The Lebanon Public Schools … must allow community organizations to access school facilities, without regard to the religious, political, or philosophical ideas they express, as long as such organizations comply with the viewpoint-neutral criteria set forth in the (school board’s) policy. 

“Not everyone will agree with, or attend meetings of, every group that is approved to use school facilities,” the superintendent continued.

“However, prohibiting particular organizations from accessing our school buildings based on the perspectives they offer or express could violate our obligations under the First Amendment and other applicable law and would not align with our commitment to non-discrimination, equal protection, and respect for diverse viewpoints.” 

Everett said the Satanic Temple has a cybersecurity team that monitors the many threats that come in whenever they start a Satan Club, and there have been a number stemming from the Lebanon club, but none have ever been carried out.

“It gets interesting because the school’s first inclination is to shut us down after they receive a threat like that,” she said. “But what we learned when we won our case with a federal Trump-appointed judge in Pennsylvania this past year was that the First Amendment doesn’t cave to violence or threats.”

“They hate the fact that we teach the Bible to children in public schools,” he said. “They cannot remove us legally because we won a United States Supreme Court ruling in June 2001 that we have the right to be in public schools. … We cannot be discriminated against because of our viewpoint. And so they come at us in a variety of ways, creatively trying to shut us down. This is their latest strategy.”

That strategy has worked a couple of times, when a school district closed down all outside groups, which it has a right to do.

Esteves said the Satanic Temple has been operating the Satan Clubs since 2016, with little success.

“Their strategy has proven to fail, but they still continue to pursue the schools where we have Good News Clubs,” he said. “They’ve had very few clubs, they don’t get a lot of kids, they don’t last very long.”

Esteves said the Good News Clubs teach a better lesson to children. “They reject authority, right? And they kind of admire Satan as this supreme rebellious guy that rebelled against the authority, because he rebelled against God, is basically the point they’re trying to make,” he said. 

“We believe in authority,” he said. “We believe that God is the originator of authority and God establishes authority. For example, God gives mom and dad authority to raise their children and children need to be taught to honor authority. Honor the teacher in school, honor the parent, honor the police officer.” 

Ed Stannard can be reached at estannard@courant.com. 

Now a consortium, including Yale University, underwritten by Facebook founder Mark Zuckerberg and his wife, Priscilla Chan, is focused on programming those cells to more efficiently prevent disease.

It’s the country’s third BioHub, following San Francisco and Chicago, and it will combine the scientific resources of Yale, Columbia and Rockefeller universities, financed by the Chan Zuckerberg Initiative.

“It sounds a bit science fiction when you first hear about it, but at the same time it’s also very grounded in solid science,” said John Tsang, Yale’s lead on the project and director of the Yale Center for Systems and Engineering Immunology.

“Immune cells are unique in that they go around your body, they are circulating, they go into tissues, they can detect issues in your tissues, for example, without us knowing,” Tsang said.

That includes cancer cells, he said.

“Typically we believe that our immune system is taking care of those for us already so they typically don’t grow out,” he said. “But the process of how that works, it’s not really well understood. We know that the immune cells are doing some of that, and the immune cells are also going around and sensing other things.”

The challenge for the scientists in the BioHub, which eventually will be a brick-and-mortar center in Manhattan, is how to use the immune cells “as a programming device,” Tsang said.

Andrea Califano, chairman of the Systems Biology Department at Columbia, leader of the New York BioHub, called the engineered immune cell a “cellular endoscope.”

“It will actually be not invasive at all,” he said. “It will be one of your own cells that has been changed a little bit to go to a particular organ and to detect whether there’s, for instance, a tumor that would be very easy to treat, if it were detected early but will be actually be very difficult or even impossible to treat if it’s caught later.”

Examples are pancreatic cancer and glioblastoma, which “are on the top hit list of what kills human beings.”

The plan is to “program the cells in a way that (they) can now go into your liver go in through a gut, and then they can be sensors of those issues and report back to us on what’s going on, and also potentially the cells can actually do something in those tissues as well … specifically to our liking,” Tsang said.

“We get tumors basically a million times a day,” Califano said. “The immune system just wipes them out before they’re harmful, but how do they wipe them out? Because when cancers have mutations those mutations are not recognizing it as a cell that is part of your body so the tumor detects that and kills the cancer cell.”

But cancer cells also recruit nearby immune cells, which prevent other immune cells from attacking the tumor “so the tumor is very good at emitting signals that will recruit cells or reprogram cells that are now becoming immunosuppressive, he said. “They no longer allow the immune system to think the cancer is a bad thing, basically hiding behind a cape of invisibility.”

The BioHub team’s job is to program immune cells to recognize the signals sent out by the protective cells.

Some immune cells prefer to go into certain organs better than others, so Tsang wants to decode what he calls “cell trafficking.”

“And then once we understand that, then we can use that knowledge to engineer the cells,” he said. “For example, let them express certain types of genes that will then go into specific locations.”

Immune cells could also be used to insert DNA into specific places into the genome, using CRISPR technology, which edits genes, that would guide immune cells into specific locations.

“And they can then sense the kind of events we want them to sense,” Tsang said. “They could be sensing for example, specific signals in the early tumor, and then that signal gets into the cell, which would then guide the cell to do other things.”

The third technology is called writing, “how do you write information within the cells like it’s like writing to a tape?” he said.

The team is a long way off from being able to have immune cells perform these tasks, Tsang said. There are challenges in both basic science and engineering to be met.

Chan Zuckerberg has committed $250 million over 10 years to the project.

“I think it’s scientifically very exciting; it’s challenging,” Tsang said. “But of course, you need to get the right teams and getting all the people together and I think that’s part of the excitement but it’s also part of the challenge.”

Tsang said he’s also excited about getting together with colleagues from Columbia and Rockefeller. “I think a new spark would come out even beyond what you envision in terms of these specific goals,” he said.

“You get a bunch of people together and with this being the glue and the catalyst for getting the folks together, I think we’re going to advance both on the front that we can see now but also there will be unexpected new things I think that would come up,” he said. 

“The collaborative nature of this effort is really remarkable because this is something that, when I was originally exposed to the idea I thought it was science fiction, and there was no way we’re going to be able to do it,” Califano said.

“And then when we started to go around the three institutions, we saw that all the individual pieces were actually there. And so this is something that cannot be done by any institution in isolation, and I think that’s what makes it truly remarkable,” he said. 

Ed Stannard can be reached at estannard@courant.com. 

It could help humans at some point, but Mamula, a professor of rheumatology at the Yale School of Medicine, is happy to be saving the lives of dogs.

“Mark is all for the dogs. That’s his main goal,” said Rick Kneisel of Wilmington, Ohio, whose golden retriever Ranger was given an additional 3½ years of life after Mamula’s treatment shrank Ranger’s osteosarcoma tumor to nothing.

Mamula now has a patent and has launched a company, TheraJan LLC, with rented lab space in New Haven, financed by dog-loving investors, that he hopes soon will enable every veterinarian to be able to administer his “therapeutic vaccine” to dogs with osteosarcoma and other cancers. He’s awaiting licensing from the U.S. Department of Agriculture, he hopes in about six months.

There are fewer than 350 veterinary oncologists in the United States, Mamula said.

“It’s difficult to get your dog with cancer into a specialist that knows dog cancers perfectly,” he said. “So most people obviously take their dogs to their local vets. … The local vet, if they’re skilled, can potentially provide chemotherapies or other therapies, and they could also provide our therapy.” 

Mamula’s lab at Yale has studied immune system diseases like lupus and type 1 diabetes for 30 years, he said.

“I’m actually an immunologist by training and so-called immunotherapies have really changed the landscape of cancer care in humans, certainly in the last probably four or five years,” Mamula said. 

“Our interest in dog cancers arose a bit by serendipity,” he said. A dog lover, whose yellow Labrador retriever, Savannah, had died of cancer, Mamula met a veterinary oncologist at a party and started talking about using dogs as a model for immunotherapies, rather than mice.

“Dogs, just like humans, get spontaneous cancers. They arise naturally,” he said. “They get virtually all of the same cancers that humans do, such as breast cancer. They get melanoma, colon cancer, osteosarcoma, lung cancer, pancreatic cancer, all of these things, and they almost all have identical growth and mutations that human cancers have.”

Also, treatment of canine cancers is similar to human cancers: CT scans, radiation, chemotherapy and surgery.

Mamula suggested to the veterinary oncologist that they start a clinical trial, which they did, in Norwalk. That site now is closed, but there are now 11 sites across the country and in Canada. The closest to Connecticut is in Manassas, Va.

Information on the trials can be found at therajan.com or the Canine Cancer Alliance, www.ccralliance.org. The vaccine is provided for free. Other costs, such as imaging, must be borne by the dog owner.

“We published the early results of those studies, and they’re compelling,” Mamula said. “And just by way of background, generically to emphasize the importance of studying and treating dog cancers, there are about 65 million households in the country that have a dog or more than one dog. There are about 90 million dogs in the United States alone.”

Mamula said about one in four of those dogs will get cancer.

“If your dog happens to live to 10 years old, then about one in two dogs will get cancer,” he said. “So you can appreciate the numbers out there. Of course, people are very connected to their dogs, as we are.”

Mamula now has two golden retrievers, Tripp, 11, and Sherman, 3.

While he calls it a vaccine, Mamula’s therapy does not prevent cancers. It does reduce the tumor, however, and is successful at more than twice the rate of standard treatments, he said. 

In dogs with osteosarcoma, a bone cancer, “about 70% of them will not survive 12 months,” Mamula said. “So that means there are 30% or so of these cancers in dogs that will survive 12 months, 30, 35%. We’ve increased that survival outcome to about 60, 65%.”

Kneisel said Ranger began limping when he was 7 years old and he had to amputate a leg. “I was reluctant to do that. I did not want to have amputation, didn’t want a tripod dog,” he said. “But it got to the point where it had to be done and so he had an amputation.”

After four rounds of chemo, it was found the cancer had spread to Ranger’s lungs and he was given six months to live. Then he found one of Mamula’s clinical trials at Ohio State University.

“My vet was willing to give the vaccine to Ranger … and he got those in November 2019. … So I took him back to Ohio State to have X rays done right before Christmas. … And when they took the X-rays, they told me that, well, the tumor had become stagnant, that it was not growing anymore, that it had stopped growing.”

Two months later, with more X-rays, Kneisel was told, “the tumor was completely gone, that it had been resolved. And you know, it’s a miracle.” Ranger lived another 3½ years and died in January.

Mike Rossa of Bayville, N.J., had a similar experience with his Carolina shepherd, Codi, who also had a leg amputated and underwent chemo.

A few months later, however, “another X-ray showed he had a golf ball-sized tumor in his lung. It had metastasized from his bone to his lung,” he said. At the time, the trial was being held in Norwalk, so Rossa brought Codi to Connecticut. 

“And then I noticed eight months later, I know it sounds strange, but I noticed, you’re still alive,” Rossa said. “And I was kind of like, it’s odd, you know, by now osteosarcoma should have killed him.

“So we took him back up to Connecticut and they did an X-ray and the tumor was gone,” he said. “It was amazing. Even the vet that was in the trial couldn’t believe it when he saw the X-ray. He says, it’s gone. So he lived another 3½ years and then he died, unfortunately, from another cancer.” 

Rossa now runs a Facebook page, where people tell their stories about their experiences with canine cancer and Mamula’s therapy.

During the treatment, the dogs get two injections, three weeks apart. “It triggers an immune response, antibodies in particular, that hopefully seek out and bind to proteins on the tumor, on the surface of the tumor, and start to kill it or inhibit growth,” Mamula said. “And either of those things are good.”

Mari Maeda began the nonprofit Canine Cancer Alliance after her three golden retrievers got cancer. The alliance is now helping support Mamula’s work.

“Osteosarcoma is a death sentence,” she said. “With surgery and chemo you could get about 12 months, maybe. If you’re lucky, maybe longer. But cancer does spread. It’s just like human osteosarcoma. It’s deadly. But with his vaccine, some dogs are living longer and some dogs with metastasis also became ‘cured.’ Cancer went away, which is really unheard of.”

Now they are working to help improve the immunotherapy.

“Quite a bit of funds that we’ve raised has been supporting his work,” Maeda said of Mamula. “We understand the limitations of his vaccine. But we also see that it’s very promising because it’s safe. It is effective for some of the dogs and it is potentially extremely affordable.”

The work definitely can extend to human cancers, Mamula said.

“Once it gets into human clinical trials, that’s probably where I will license, or Yale will license technology to others that are best equipped to do human clinical trials,” he said. “Yale has an active program for doing that, but that’s a bit outside of my expertise. I’d obviously be involved with that.”

Mamula is content with working on canine cancers, though.

“As far as hands-on work, the canine work is not only needed by the community or by pet owners in general, but also just an interest of mine,” he said. 

He said he gets emails from people who may have lost a spouse and how their dog has cancer and they are asking for help.

“Or I get emails from those same people that say, My dog’s doing great and it’s now a year or two later and the vet said they were going to survive maybe two months or six months, and now it’s two or three years later and you know, gosh, thanks,” he said.

“So that’s what allows me to sleep at night and that’s what’s fun, honestly, about the project,” he said.

Ed Stannard can be reached at estannard@courant.com. 

That’s why genetic sequencing is so important.

Now The Jackson Laboratory in Farmington is able to sequence the entire genome, an advance that will roughly double the number of rare diseases that can be positively diagnosed. It’s the only whole-genome sequencing test offered in Connecticut.

Until next-generation genome sequencing became available about 10 years ago, there was no way for many rare disorders to be accurately diagnosed, according to Melissa Kelly, clinical laboratory director at the Jackson lab.

Previously, Sanger sequencing, developed in 1977, was too slow to be useful.

“There’s been studies on this actually, how many missed diagnoses patients will have prior to getting their actual diagnosis from a genome, and it’s something like seven,” Kelly said.

“It’s crazy how many times these patients get told the wrong thing, or get told nothing,” she said. “No one can tell them an answer at all. And that’s the problem with current clinical care is the genome isn’t the first step and so these patients are going through test after test after test and being told different things and not really getting the right answer, and that takes a toll on the patients and on their family.”

There are as many as 7,000 rare diseases, according to the National Organization for Rare Disorders. A rare disease is one carried by no more than one in 200,000 Americans, and includes Duchenne muscular dystrophy, hemophilia, cystic fibrosis and Hodgkin’s disease, according to the organization’s database.

Not all rare diseases are genetic, but many are, Kelly said. Sometimes sequencing is called for because of “unusual facial characteristics,” she said.

“It might be that their nose is a little misshapen or their forehead’s really tall,” she said. “Ears are rotated funny or something. So it’s just the facial features that are ‘normal.’”

The issues one patient has could resemble more than one disease, so until you know the genetic mutations, “you don’t really know, can you do anything about it. It’s just sort of a guessing game,” she said. One example is Niemann-Pick disease.

Before the whole-genome sequencing was developed, the best that next-generation sequencing could do was to sequence the exome, or the proteins in the gene, which, while it contains most of the information, is about 1.5% of the genome.

That yielded a positive diagnosis about 25% of the time. “The rest of them are left on what we call the diagnostic odyssey,” Kelly said. So they’re getting test after test after test, but never getting a diagnosis. And those are the perfect candidates for whole-genome sequencing,” which can get an answer at least 40% of the time.

“There have been some reports where there are situations where they’re looking at a particular cohort where they have gotten higher, but I would say across the general rare disease scope, I wouldn’t say higher than 40 or 50%,” Kelly said.

“It seems crazy because, if we’re sequencing the entire genome, why aren’t we capturing 100%, right? So that’s another area that’s still being explored,” she said.

“One of the issues is, there are factors in the environment that can affect genes,” known as epigenetics, she said. “That’s a whole area of study that’s going on now. And I’d love to bring on clinical tests that can target more of the epigenetic and other factors to diagnose additional patients as well.”

The bottom line is to help families “who have been searching for oftentimes years to find the answers,” Kelly said. “Even when those answers mean it’s not treatable, and they really can’t do anything about it, to have the answer is just invaluable to them. That’s what this is for. We want to get patients the answer.”

The Jackson lab’s research into rare diseases goes further at the Rare Disease Translational Center in Bar Harbor, Maine.

“What we do is we take that genetic information, and we engineer that mutation into a mouse model,” said Cat Lutz, vice president of the center. “And that creates essentially a patient avatar. We have mouse models for cystic fibrosis. We have mouse models for Duchenne muscular dystrophy. We have mouse models for Huntington’s and ALS and Friedrich’s ataxia.”

This way, the genetic mutations can be studied “to understand genetic pathways,” she said. “We can look at disease course. … We can find so much about what that patient is experiencing just by looking at the avatar of the mouse. And then, most importantly, we can take therapeutics, like gene therapy … FDA-approved drugs, and we can test them in the mouse and see if there’s a benefit that might be had in the patient.”

The center has helped develop three FDA-approved drugs for spinal muscular atrophy, which causes death among young children.

“If you don’t treat an SMA baby in the first few weeks of their disease, they’re not necessarily going to have the benefit of the therapy,” Lutz said. “If a therapy’s given early, patients can lead almost a normal life. If it’s given too late, it can have very little effect or no effect at all, and patients can be wheelchair-bound or succumb to the disease perhaps a little bit later.”

‘The diagnostic odysseys’

One problem with genetic sequencing is the expense. Next-generation sequencing of just the exome can cost up to $4,000, according to Dr. Ed Neilan, chief medical and scientific officer of NORD, and the full genome sequence will cost much more than that.

A spokeswoman for The Jackson Laboratory issued a statement about pricing, saying, “While we do not comment on specific customer pricing since it can vary with testing volume and turnaround time requirements, as a nonprofit biomedical research institution, our focus is and always has been on improving human health. JAX endeavored to make this crucial testing available as cost-effectively as possible knowing the financial responsibility will, in many cases, be patient-based.”

Lutz believes every baby should have its genome sequenced in order to avoid the emotional pain and hardship families experience when they are faced with an unknown disease.

“I think it is economically possible,” she said. “You think about the cost of that sequencing compared to the cost of doctor’s visits, emergency room visits, and then the sustainability of the health care of a very sick child. I think it’s very worth it.”

Concerning the lack of insurance coverage, Lutz said, “I think that’s where we have some changes that we need to make in our health care system, quite frankly. I mean, we screen for other things, right? We screen for breast cancer. We screen for colon cancer. … We’ll even screen prenatally for cystic fibrosis and I don’t think it makes sense to have tests that are done one by one.”

She added, “Wouldn’t it be more economical to try to take a single drop of blood, do the whole genome sequencing and try to figure out if this child is going to have Batten’s disease or some other inborn error of metabolism and not spend the six years and the doctor’s visits and the diagnostic odysseys … I mean from a health care perspective.” 

Neilan cautioned not to set expectations too high with the whole-genome sequence test compared to the former test. “You get maybe 80% of the answer from looking at that 1.5% of the DNA, which is why it’s cheaper and more common right now to order a whole exome test,” he said.

“I think though the world is sort of waiting for a whole-genome test to become cheap enough that you could order it for the same as an exome,” he said.

Ed Stannard can be reached at estannard@courant.com. 

A researcher at the Yale School of Medicine, however, has developed a way to find the seemingly invisible problem using artificial intelligence.

Dr. Rohan Khera, clinical director of the medical school’s Center for Health Informatics and Analytics, said a simple electrocardiogram can be analyzed using AI, which can detect what a basic reading of an ECG cannot.

Khera’s paper about his research appeared in the July 25 issue of the journal Circulation. The work is centered in the Cardiovascular Data Science Lab, where Khera is the principal investigator.

“Many people, up to one in 20, have structural heart disorder, so their heart function is down, but they don’t know that until they develop symptoms and go to the hospital … or (suffer) adverse effects of a certain sort that trigger health care needs,” Khera said.

The disorder is known as left ventricular systolic dysfunction, which reduces the ability of the heart to pump blood. It develops before symptoms appear and medical attention is required, Khera said. The problem can lead to more than an eightfold increase in heart failure and double the risk of premature death, according to Khera’s study.

There are “very inexpensive treatments” for the dysfunction, he said.

“However, we just don’t have a way to know who had this. The way to diagnose it is actually getting cardiac imaging, which is an ultrasound of the heart, or an MRI,” he said. “But those tests are not something you can do with everyone in the community, so this is not feasible.”

Using AI and deep learning, “which are very exciting domains in medicine, we developed a technology that actually uses ECG data,” Khera said.

ECGs, which register electrical activity in the heart, are routinely done during physical exams. They can now be taken on a wearable device such as an Apple Watch, Khera said. About 100 million ECGs are done in the United States each year, he said.

“We have now identified ways to find signatures of structural heart disorders from these very inexpensive and widely available tests,” Khera said. “And that’s the key observation and we are able to do that with accuracy in the 90 to 95% range.”

The Yale study has been repeated in California, Missouri and Texas, and validated in a Brazilian longitudinal study. “So (we’ve) kind of shown that our approach to identifying those with disease really works across the board,” he said.

“Before, when we were doing echocardiograms, when we were only relying on cardiac imaging, there was not infrastructure in place to do that at scale for the population,” Khera said. “But now with these technologies, you can actually get people without any expense or challenge … a diagnosis that is very treatable.”

ECGs, which measure a number of different electrical signals in the heart, are printed out on paper. “We can use the photos of those ECGs and we use computer vision algorithms,” Khera said.

“These are tools built to infer deep signatures of disease from photos. So we take photos of ECGs and identify areas within an ECG that may actually be suggestive of a diagnosis of low heart function. … It’s a hidden feature inside that photo of an ECG that none of us as clinicians can pick up on.”

While the ECG is used to measure the electrical signals, AI can pick up structural abnormalities in the heart by examining the photo.

“Screening for heart disorders with ECGs is likely going to become a more and more common thing as time goes on,” Khera said. “And it’s nice to see AI actually helping pick up things that humans cannot.”

Ed Stannard can be reached at estannard@courant.com.

While cancer drugs have been most publicized recently, experts in pharmacy say they often find themselves scrambling to find common generic medications such as antibiotics and fear having to resort to rationing.

They say only a national effort to bring generic drug manufacturing back from overseas, among other steps, will help relieve the problem, which mostly affects injectable drugs, including chemotherapy and cardiac medications.

“It is not just cancer, said Dr. Peter Yu, physician-in-chief of the Hartford HealthCare Cancer Institute in Hartford, Connecticut. “It’s pediatrics, it’s infectious diseases, it’s rheumatology.”

Yu said the American Society of Clinical Oncology looked into the problem when he was president in 2014-15. “In part what we learned is it wasn’t just oncology; it really is a health economics issue about how drugs are paid for and manufactured and distributed in the United States and the world,” he said.

“We are experiencing it ourselves across Hartford HealthCare,” Yu said. “We treat hundreds of patients a day with chemotherapy. We tried to keep a several weeks’ supply of our chemotherapy drugs on hand and we’ve been down to as low as a two-day supply, which makes us extremely nervous.”

Yu said health care systems rely on a few large distributors, “big names like Cardinal Health, American BioSource and McKesson, and they’re unable to tell us when they can deliver supplies. We call every day and they say, we’re not sure we can distribute your order.”

He said Hartford HealthCare has been able to shift supplies among its seven hospitals to avoid a total shortage, but “there’s very little margin for error here, or very limited.”

‘A spike in shortages’

“What we’re seeing now is a spike in shortages,” said Eric Arlia, vice president for pharmacy services at Hartford HealthCare.” We’ve gone through these waves on and off over the last five years. We seem to be going through another period where there’s going to be more than the typical number of drug shortages that we’re dealing with.”

Arlia said the business office and pharmacy buyers for the health care system are holding weekly meetings because of the seriousness of the issue.

“The team is tracking 46 drugs in short supply as of this week,” Arlia said last week. “Not all at the same level of criticality, but 46 of them that they’re talking about and talking about mitigation strategies, whether that be trying to buy it from a different company or looking at different dosage forms.”

Other options are looking at therapeutically equivalent medications and switching patients to another drug if necessary. But that isn’t always the best treatment, especially if a patient has been on one medication for a while.

The two main cancer chemotherapy drugs, cisplatin and carboplatin, have been among those in short supply, but Arlia said methylprednisolone, used to treat asthma, arthritis and allergies, is “our No. 1 shortage product at the moment.”

“It’s an anti-inflammatory — probably one of the biggest issues is people with breathing issues to help them breathe better, but it has other uses too,” Arlia said.

However, “the good news with that one is sometimes people can take oral if they’re able to and then there’s a couple other drugs … in the same therapeutic class with similar effects,” he said.

Manufacturing in China and India

According to a U.S. Department of Homeland Security report, drug shortages increased 30% between 2021 and 2022. There was a five-year high of 295 drug shortages at the end of 2022, according to the report.

A major concern is that 90% to 95% of the chemicals that make up acute-care injectable drugs, known as the active pharmaceutical ingredient, are manufactured in India and China, according to the report. The Food and Drug Administration does not have the same level of oversight of those countries, and officials worry about geopolitical threats disrupting supply.

“The drugs are being manufactured overseas and not just the drugs but also the active ingredients” and the inactive ingredients, said C. Michael White, chairman of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy.

“India makes most of the finished pharmaceutical products,” he said. “So that’s the actual tablet or the capsule. China makes a lot of the active ingredients.” And that won’t change anytime soon.

“One of the things that’s actually scary from a national security standpoint is that the United States doesn’t have any capacity to be able to have the fermenting plants that they would need to have to make penicillin and cephalosporin antibiotics,” White said. “They’ve all shut down and they’ve all moved overseas, and most of them are now in China.”

That could cause a major problem if China were to attack Taiwan, for example, he said. 

“You can’t just build a manufacturing plant for pharmaceuticals,” White said. “It takes years in order to be able to construct it. And that’s one of the things I think we found with COVID, is that we’re always behind the eight ball because we didn’t have the capacity to be able to manufacture it here, so we were beholden to the normal supply chains, which were all being interrupted.” 

A contamination scandal

A major shortage occurred when Ranbaxy USA, based in India, was found to have contaminated drugs and was shut down.

“The FDA did not have any funding in order to be able to go overseas and do any of the inspections of those foreign manufacturing plants,” White said. The companies were put on the honor system, “where you would send them reports of the stuff that you were doing, but they would never visit you.”

After a whistleblower notified the FDA that Ranbaxy was falsifying reports, the FDA began scheduling inspections, but the foreign companies knew when inspectors were coming so that would take plants offline to bring them up to standards. That in itself causes shortages, White said.

Another issue is the age of equipment. “They were beating us on price because they were dealing with equipment that was much much older and then prone to breakdowns and whatnot, but because it was less expensive to be able to use that equipment they ended up dominating the market, putting other people out of business,” White said. “But then when the equipment breaks, then you have a drug shortage.”

However, the quality of foreign-made drugs is higher now than it had been, he said.

“The FDA is behind on inspecting them, and sometimes when they get to them, if they have violations, they can shut them down and then it just has a trickle effect,” Arlia said.

“Obviously, if companies either in the U.S. or in another part of the world can’t get the raw materials needed to make a medication, there’s going to be a shortage.”

Looming threat of rationing

Dr. Daniel Petrylak, an oncologist and professor of urology at the Yale Cancer Center in New Haven, Connecticut, said a notice went out two months ago about a shortage of cisplatin, also known as cisplatinum.

“Unfortunately, for tumors such as testes cancer, there are no alternatives,” Petrylak said. “Cisplatinum is the backbone of treatment for these patients. Same thing with bladder cancer for those patients that can receive cisplatinum.”

He said there was a clinical trial comparing cisplatin and carboplatin in testes cancer patients “because the concept was that (carboplatin) was a less toxic drug, but unfortunately it was found that there was a higher relapse rate in those patients who received carboplatinum versus those patients who received cisplatinum.”

If there is a shortage, decisions about who will get the drug are difficult to make, Petrylak said.

“I’m not trying to say that it’s any less important to treat somebody who is older but most of the testes patients are in their 20s and 30s, and they have long lives ahead of them,” he said. “And this is a pretty much curable disease in most patients. In fact, in a good-risk patient, 90% of those patients are cured.”

Older men have a higher relapse rate, which requires more treatment and could lead to side effects. “So there’s not only a quantity-of-life issue but a quality-of-life issue,” Petrylak said. “Those are important factors, but I view this as a national health emergency. No question.”

Lisa Holle, clinical professor of pharmacy practice at the UConn School of Pharmacy and an oncology pharmacist, also sees rationing as a possibility. 

A consideration is, “What is the reason they’re getting the chemotherapy?” she said. “Is it because we know we could cure this patient of their cancer and they can be free from their disease? … But in some instances, we can’t cure the cancer because it’s such an advanced stage of cancer and we’re giving the chemotherapy to try to keep the cancer at bay for as long as we can.”

In that ethical situation, “we might think about the patients who are curable versus those who are not,” Holle said. “And of course we do not ever want to be in that situation because we think it’s really important to also keep some of these cancers at bay, but those are sort of ethical dilemmas I think that one gets faced with when there’s a limited supply of a life-saving drug.”

Another alternative is for the FDA to allow importing of unapproved foreign drugs on an emergency basis, Holle said.

“Back in 2012, 2013, there was a drug that was in short supply, and the FDA allowed an emergency use of an internationally manufactured version of the drugs,” she said. “It required the FDA to be able to approve this drug temporarily so that we could import it into the United States and use it for patients because there was no alternative to that drug for that type of cancer.”

‘Inconsistent availability’

Dr. Pragna Kapadia, assistant professor in hematology and medical oncology at UConn Health, said the health care system has avoided shortages of cisplatin, docetaxel and carboplatin, three common chemotherapy drugs, so far.

“Fortunately, we have not had any issues that have directly impacted a patient, meaning we haven’t had to change a treatment course or substituted therapeutic drugs because of a shortage,” she said. 

“We previously had tried to keep a one-month supply of most of our medications on hand,” Kapadia said. “There are certain chemotherapy drugs as of late it’s just not available. So we have more of maybe a two- to three-week supply on hand and it’s just inconsistent availability.”

This causes pharmacists to have to be creative, she said. 

“So there may be certain vial sizes that are available and certain concentrations that are available, but then it’s up to us, our pharmacists, to compound the medication to make it what we need it to be, because it’s not available in the form that we need it to be,” she said.

She said UConn Health has not had to resort to rationing of drugs.

“I will say, I’ve been at UConn for five years, and there was a point where … they said, we have X number of doses of this drug and so be mindful of that as you talk to patients about starting them on a treatment regimen that includes that drug,” Kapadia said.

Doctors don’t want to alter a treatment plan because “that is only going to potentially be harmful to the patient, she said. 

UConn Health uses a group purchasing organization, Vizient, which helps mitigate shortages. Kapadia said that is more available to large health care systems, whereas smaller hospitals may not have access.

“You never want to be that patient who has to hear, I can’t treat you with what is felt to be our best standard of care because the drug isn’t available,” Kapadia said “You never want to have to have that conversation with a patient.”

She said she hasn’t had to do that recently, “but it’s something that we worry about, and I do think that smaller institutions who don’t have these large purchasing groups, or they don’t have a large volume that they’re purchasing, I think they are at a higher risk of not having enough drugs.”

Cardiovascular drug issues

In cardiovascular medicine, the biggest shortages are in lidocaine, adenosine and dofetilide, White said.

Lidocaine is an anesthetic that also treats arrhythmias. A shortage can lead to delayed procedures, White said.

A lack of adenosine, used for people in arrhythmia, “acutely causes a break so people will go back into a regular heart rhythm.” A lack of it can put patients at risk because the substitute, calcium channel blockers, stay in the system for several hours.

“The adenosine gives you the advantage that you can come in and you could break the person out of that arrhythmia, put them back into a regular heart rhythm,” White said. “And then you only have to do that intensive monitoring for a few minutes.”

If channel blockers must be used, “you may have more low blood pressure and you’ve got to monitor the patient and be concerned for a longer period of time,” he said. Adenosine is also used in stress tests.

Dofetilide is used daily to prevent atrial fibrillation. The problem with the substitute, sotalol, is that dofetilide must be out of the system before the new drug is used, putting the patient at risk for several days, White said. Both drugs require a three-day hospital stay when they are introduced.

“You can’t just on the same day take somebody off dofetilide and put them on sotalol,” White said. “You have to wait until all of the dofetilide is out of the body. And then you have to bring them into the hospital for another three days to put them on sotalol.”

When dofetilide is available again, doctors are faced with a conundrum. “Do you keep them on the sotalol, or do you take them off, give them several days without any antiarrhythmic therapy, and then have to put them back on the dofetilide?” White said.

No one keeps reserves

To Arlia, “the other big issue is that nobody keeps any reserve supplies in the supply chain anymore.”

Companies used to keep inventory reserves, but economics has eliminated that, he said.

“What happens now is, if there’s even a relatively minor disruption, it just hits everybody very fast, because there’s just very little reserves in the system.” He said there are programs where “if you’ll commit to buying a certain product, they’ll guarantee that they’ll hold 90 or 120 days’ supply in a warehouse for you. And we did that with a few drugs.”

Arlia said he would “happily commit to buying one brand of a generic, commit to it for a year or a couple of years at a certain price if I know they’re going to hold stock for me. … Because ultimately, I think you end up spending more money when you have a shortage and you’re changing things around. And of course, it’s bad for patient care.”

For Arlia, the lack of reserves is a critical issue. “I think there just needs to be more of a national focused effort on this,” he said.

“As a country, to me it’s a vulnerability that we don’t have reserve supply of critical pharmaceuticals. And nobody’s going to do it out of the goodness of their heart. Somebody needs to be incentivized, really, to hold more supply than they need to for their general business.”

“You may have everything that you need, but then you don’t have the vial or you don’t have the ampule, or you don’t have one of the really important ingredients but you have all the others,” disrupting the manufacturing process, White said.

Kapadia sees another cause. “If you look across the board at the different medications that have been affected, I think some of it is still a ripple effect from COVID, workforce issues and supply chain issues,” she said. “Even though we feel that the pandemic is behind us, those things I think are still playing a role.”

The problem with generics

The low prices of generics have their own issues, according to Yu. As long as a manufacturer has a patent, the price may be high.

“When that patent drops, you get the entry of generic manufacturers that can now produce that drug … but the price begins to drop, and it drops pretty quickly,” Yu said. “So within a year’s time, the price may fall by 97% or more. So it fairly rapidly reaches a level where that generic manufacturer is no longer so interested in making that drug. … Manufacturers may shift to another generic drug where they have a higher margin.” 

White said manufacturers’ move to overseas added to the problem.

Generic drug manufacturing “shifted overseas with the understanding that prices would continue to go down, which they have for generic drugs,” he said. “And that created a lot of pressure on the system so that only the ones that have the cheapest price were the ones that we’re going to be getting a majority of the sale.”

Insurance companies reimburse based on the lowest-priced drug, so there is little incentive to spend money to increase automation or maintain equipment, White said. And companies have consolidated so there may be just two making one drug.

White said of the shortages that “at most points, it’s a severe inconvenience. … Periodically it becomes dangerous when some of the drugs that are in shortage are more vital-type drugs, like the cancer drugs.

“But we have this extreme vulnerability and the extreme vulnerability could really be devastating to the United States if all of the manufacturing was taken away,” he said.

UConn working on problem

White said one faculty member is working on “a new manufacturing-type process that is much, much more efficient and doesn’t use a lot of worker time in order to be able to set up and be able to create.”

“The U.S. had allocated money. I think there’s like a billion dollars or whatever into research specifically on bringing manufacturing back to the United States. … And UConn is is part of a consortium of major universities in the country, called NIfTI (Neuroimaging Informatics Technology Initiative) that have been working on ways to be able to support bringing manufacturing back to the United States and be able to do it in an efficient manner.” 

Yu said Congress passed a law requiring manufacturers to notify the FDA if they anticipate a drug shortage within six months.

“Often they don’t know six months in advance if there’s going to be a problem,” Yu said. “And just notifying people that there’s a problem doesn’t solve the problem. It’s not a very satisfying answer.

“I think we need Congress to put sharper focus on this,” Yu said. “I think we need to think about this as a consumer protection issue as well as a public health issue.”

Yu called the health care system “very fragmented and nonsensical in many ways. We have some parts of the health system that are highly regulated, and then some parts like drug manufacturing and production that have a lot less regulation behind pricing and distribution.”

Ed Stannard can be reached at estannard@courant.com.

It’s another step in using the body’s immune system to fight diseases, using a person’s own mRNA to target cancer.

The randomized Phase 2 study compares personalized mRNA vaccines given along with Keytruda, an immunotherapy drug with the generic name pembrolizumab, vs. giving Keytruda alone.

“Keytruda was established as part of standard of care for stage three melanoma patients … after surgery to help minimize recurrence risk for individuals with high-risk disease,” according to Dr. Thuy Tran, the principal investigator.

Moderna proposed the study combining Keytruda with the mRNA vaccine “to try to improve upon those odds to further decrease recurrence,” she said. Of 157 participants, 107 received both drugs and 50 received only Keytruda.

“What they found, which was presented earlier this year, was that the combinations of the vaccine with Keytruda further decreased recurrence risk by about 44% compared to just Keytruda alone,” she said. 

The clinical trial, known as Keynote-942, began before the COVID pandemic hit, and the research was the basis for Moderna’s COVID-19 vaccine, the first mRNA vaccine to be used in patients, according to  Dr. Harriet Kluger, co-investigator in the study.

“The original messenger RNA vaccine was this one developed by Moderna to fight cancer,” Kluger said. “The Moderna vaccine that we’re using in this trial is a personalized vaccine. … And based on this experience, Moderna was then able to generate next-generation vaccines for COVID as well, when the new strains came out.”

Moderna is collaborating with Merck Research Laboratories in the study, which the companies say will expand to Phase 3 trials this year. It takes about six weeks to make each vaccine, during which time the patient is given Keytruda, Kluger said.

“Pharmaceutical collaborators have been trying to create vaccines against melanoma for a long time,” Kluger said. “What’s different this time is that it’s personalized. … We’re using a different mechanism of attack by hijacking the body’s own immune cells to present these mutations as foreign.”

The vaccines use mRNA to tell the body to trigger an immune response that targets the cancer cell. Each person’s vaccine is created from the individual’s tumor.

The researchers were able to target 34 antigens, or protein markers, on the tumor cells because melanoma mutates readily. That makes it easier to create a vaccine that will target the tumor and trigger the immune response, Kluger said.

“Essentially, they took the patient’s tumor that was already resected from their surgery,” Tran said. “They sequence that using next-generation sequencing technology to identify at most 34 different unique antigens, which are unique properties on the patient’s tumor cells that will help them recognize the cancer cells as being foreign.”

Further research is being done to determine whether fewer antigens can be targeted when developing each person’s vaccine.

“Some of the ongoing studies are trying to decipher what is the minimum number of potential new antigens that would elicit a good immunologic response,” Tran said. “That is not well defined, but the idea is, the more antigen markers you have, the more opportunities for the immune system to identify it.”

Moderna and Merck say they plan to expand research into additional cancers.

“It’s still early in the development of this approach, but if it succeeds, it’s a completely new paradigm for a number of different kinds of cancers, where one harvests a patient’s own immune system but in a very personalized way,” Kluger said.

More data from Keynote-942 will be presented at the annual meeting of the American Society or Clinical Oncology in Chicago in June.

Ed Stannard can be reached at estannard@courant.com.