Unpacking Higher Cancer Rates in Young Adults; Increasing Vaccine Uptake

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of Texas Tech Health El Paso, look at the top medical stories of the week.

This week’s topics include treating uncomplicated urinary tract infections (UTIs) in women, factors related to the rise in some cancers in younger people, a new agent for osteoarthritis of the knee, and increasing vaccine uptake.

Program notes:

0:35 Factors regarding vaccine uptake

1:35 Adolescents didn’t like human to human

2:35 Free vaccines helpful

3:00 Treating osteoarthritis of the knee

4:00 Dose response to reduce pain score

5:00 Does it elicit an immune response

5:35 Factors in increasing cancer rates in younger people

6:35 Things other than patient attributable factors

7:35 Unregulated growth with exposure

8:00 Treatment of uncomplicated UTIs in women

9:00 Symptoms plus dipstick

10:00 Short courses of antibiotics

11:01 Even single treatment disrupts

11:57 End

Transcript:

Elizabeth: What’s the best way to treat an uncomplicated UTI in a woman?

Rick: Factors associated with the rising incidence of cancer in younger adults.

Elizabeth: A new agent for treating osteoarthritis of the knee.

Rick: And interventions to increase vaccine uptake.

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech Health El Paso.

Elizabeth: Rick, I think it’s pretty timely right now to talk about vaccine uptake. So why don’t we turn first to The BMJ and take a look at that issue?

Rick: This regards vaccines just across the board. Those are in different age groups and we know that they’re effective. And overall, we know what their safety profile is. And the question is, how do you get vaccines in the right patient population at the right time? And how do you increase vaccine uptake?

What these investigators did was try to identify the effective components of interventions that would increase vaccine uptake and to explore the variations by different age groups and different populations. They did a systematic review of 237 studies, 570 intervention arms, and over 4.3 million participants. They basically categorized these into two things: delivery of the message and then content of the message.

In kids, there was evidence of beneficial effects for payment to cover costs if you could extend the opportunity to get vaccines on the nights or on weekends. For adolescents, they actually liked the delivery by community members alongside healthcare professionals. What they didn’t like was human-to-human interaction. They were more likely to enjoy vaccine uptake if it was non-human interactions. That’s usually social media. And for adults, they wanted human interaction, help with appointment scheduling. They wanted payment to cover costs and extended opportunities.

Elizabeth: What’s the role of parents with regard to children and adolescents when it comes to vaccine uptake?

Rick: That’s a great point because when you’re talking about vaccinating children, the children don’t make that decision; the parents do. When you’re talking about adolescents, suddenly you have to engage them as well because we’ve both raised adolescents. No matter what the parents want, the adolescents ultimately have some input into that. You’re right. It’s not just the patient who’s getting the vaccine. It’s the surrounding individuals that are involved in that decision-making process as well.

When you look at what persuaded individuals, it was oftentimes not the effectiveness of the vaccine or the safety, but how easy was it to get it and whether they could afford it or not. Paying for these vaccines or giving them freely contributed a lot to the uptake of the vaccines.

Elizabeth: I would have to opine that I think globally vaccines are just so good that they ought to be paid for by the state because the state is vested in the outcome.

Rick: You and I would agree upon that because the societal costs outweigh the small costs associated with the vaccine. Herd immunity effect is also important.

Elizabeth: Let’s move on to The Lancet. It’s the efficacy and safety of an agent called LEVI-04 in patients with confirmed osteoarthritis of the knee and this is a phase 2 trial of this agent. How does it work? It inhibits something that’s called neurotrophin-3, neurotrophin receptor fusion protein LEVI-04.

This is a randomized, placebo-controlled, double-blind, phase 2 trial that enrolled participants from Denmark, Hong Kong, Poland, Moldova, and the Czech Republic. They all had confirmed and painful knee osteoarthritis with radiographic evidence and a pain score greater than or equal to 4 out of 10. They were randomized into 4 different groups. They got a monthly intravenous placebo or LEVI-04 at 3 different dosages. They did that through week 16 with safety follow-up to week 30, and their primary endpoint was a change in the WOMAC pain score from randomization to week 17.

Sure enough, there was a dose response relative to this agent, and they were able to see that they were able to reduce the pain score significantly in all of the groups, starting with the lowest one. And the LEVI-04 administration had no increased incidence in serious adverse events or treatment-emergent adverse events.

Rick: This neurotrophin-3, this NT-3 you described, it’s a family of neurotrophins that regulate peripheral pain pathways. If something regulates the central pain pathway, it affects the brain. It can cause drowsiness, sleepiness, etc. So if we can somehow modify the peripheral pain pathway, that’s great.

Unfortunately, some of these agents also affect bones and cartilage formation adversely. This particular agent is an immunoglobulin that does not appear to adversely affect the bone or the cartilage in the joint. However, because it is an immunoglobulin, oftentimes we develop an immune response to it.

So this is a relatively short study. What we don’t know is if you give it over a long period of time, is it just as effective? How safe is it for the bone and the articular surfaces? And then does it elicit an immune response? The important thing is this is a new peripheral pain pathway and I think it holds promise in the future.

Elizabeth: I definitely agree. I find it very interesting that the authors described this as a supplement. They also noted that they had a rapid reduction in this daily pain score. It was within 3 days of the first administration. And, of course, it would be optimal to get something that was oral versus something that required IV administration.

Rick: Three days, significant reduction in pain that’s sustained over a period of time. At least the initial results sound good. Now they need to be confirmed and see if we can expand those.

Elizabeth: On to your next one.

Rick: Trying to identify what’s causing cancer in young individuals. There has been an increase in the diagnosis of colorectal cancer. Is it because we have an increasing incidence of the risk factors — and we know what some of those risk factors are — or are there additional risk factors that we haven’t identified that may be responsible? I’m going to highlight two studies, one in The BMJ and the other in Nature Medicine.

Let’s highlight the first. They looked at temporal trends and behavioral risk factors for cancers that have a rising incidence in younger adults. They identified cancer sites — 22 different sites in women and 21 in men — that have had an increasing incidence in adults aged 20 to 49. And then they look at trends in things like smoking, alcohol, diet, body mass index, and physical activity because those are all known to be risk factors.

What they discovered was the incidence of cancers is increasing in young adults and older adults, but except for obesity, all these other trends are going down. That means there must be things other than patient-attributable factors responsible for this, or obesity accounts for a bigger risk factor than we assumed otherwise. So we can’t explain it all by a rise of these other patient-attributable factors.

The follow-up to that article is one in Nature Medicine that looked at epigenetic footprints. These risk factors cause differences not in the genes, but in DNA methylation — that’s epigenetic changes. Rather than looking at each of these individual changes, we can get an epigenetic map and see if that’s changing at all in individuals that have early-onset colon cancer compared to late-onset.

And what they discovered is there was epigenetic risk factors, but they’ve also identified a new risk factor, that is exposure to an herbicide called picloram. This herbicide didn’t become available until about 1964. And the way it acts upon plants, it causes abnormal stimulation and maturation of tissues, which triggers growth discontinuation, root deterioration, and eventually plant death. It causes the same thing as cancer — that is, unregulated growth. So this is a very early finding. We need to confirm this because in animals it looked like picloram was fairly safe, although it’s not been studied extensively in humans.

Elizabeth: I don’t think there’s any question that there’s an environmental factor that’s at work in explaining this rise. It’d be really great if we’re able to get our arms around what that might be. No doubt we’re going to be looking for more smoking guns.

Let’s finally, then, turn back to The Lancet. And this is a very practical study that’s taking a look at the treatment of uncomplicated UTIs in women. This, of course, is an extremely common problem and the authors remind us that 50% of women will have an experience with a UTI in their lifetime.

Looking at the guidelines, there are three agents that are frequently recommended — nitrofurantoin, fosfomycin, pivmecillinam — for this condition. What this study wanted to do was look at a direct comparison between these, which the authors state has not been done before. They were looking at a single dose of fosfomycin compared with two doses of that and short-course regimens of the other two agents in women with UTIs. They enrolled women 18 years and older with one UTI-specific symptom and a positive urine dipstick test for either nitrites or leukocyte esterase. And they were randomly assigned to one of those four treatment arms. They had 768 patients. Their median age was 48 years.

The single dose of fosfomycin had the lowest proportion of clinical resolution. Only 59% of the participants had resolution with that single treatment, while nitrofurantoin had the highest, 74% of the patients experienced resolution. The other two regimens sort of fell in between those.

What these authors conclude is that this single dose-fosfomycin, which is something that has been advocated previously, really ought to be scrutinized more closely. I thought that was a rather soft land on a point that I would have landed a lot harder on. And it sure looks like the nitrofurantoin is probably the best thing. However, that was associated with slightly more side effects.

Rick: Short courses of antibiotics — fosfomycin is a single day. The nitrofurantoin, you have to take it three times a day for 5 days. And the pivmecillinam, you take it three times a day for 3 days. So it was hopeful that the fosfomycin, the single dose, would be just as effective. It’s not. It looks like the two-dose is fairly effective, that is on two successive days. But the statistics, there weren’t enough patients to actually prove that.

When they looked at these women that had a single symptom, and they started treating with antibiotics. Just before they started, they tried to culture the bacteria out of the urine, and they were only successful in doing that about 55% of the time. And the other 45% either it was contaminated by normal flora or they just couldn’t grow anything at all. And those individuals, it’s not clear that antibiotics really is necessary at all.

So the authors not only highlighted what the best treatment is, but they also say, “Gosh, should we be reexamining who we’re giving these antibiotics to? Because the single symptom, and that dipstick isn’t very sensitive and isn’t very specific for bacterial UTIs.”

Elizabeth: I think that, that absolutely deserves scrutiny, especially if we go back to the gut flora, all this emerging data on even single treatments with antibiotics disrupt that flora quite a lot. And that disruption is persistent. So if you don’t need them at all, maybe that’s something we really need to figure out how to identify.

Rick: Yeah. Well, unfortunately, the current recommendation is, just based upon symptoms, women get treated. Getting a culture delays things for 2 or 3 days. And so I can understand the simplicity. But if we’re over-treating individuals and we’re concerned about antibiotic resistance and also concerned about changing the microbiome, we may need to reconsider who we’re treating.

Elizabeth: More research needed.

On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.

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