Posted on

Roundtable Discussion: Adverse Events and Treatment Breaks for Hedgehog Pathway Inhibition in BCC

Roundtable Discussion: Adverse Events and Treatment Breaks for Hedgehog Pathway Inhibition in BCC

During a Targeted Oncology case-based event, Jason Luke, MD, and Laura K. Ferris, MD, PhD, discussed treatment for a patient with basal cell carcinoma.

LUKE: This is an unresectable case, so let’s reflect on how we think about unresectable BCC. The NCCN guidelines considerations for BCC stratification [help] determine the options in terms of how to manage patients.1

The low- and high-risk categories can be dictated by factors such as the location and size, so truncal lesions that are small are lower risk. If the border is well defined, that’s a good thing, relatively speaking. If it’s a primary lesion, that’s better than a recurrent lesion. If it’s not associated with immunosuppression, a site of prior radiation, or perineural involvement, those are all important features that predict better outcomes. The subtype, in terms of nodular or superficial, is in a lower-risk category.

Contrast that with the [high-risk group], where lesions on the extremities or on the trunk that are greater than 2 cm, or lesions located on the cheeks, forehead, scalp, neck, and tibia, or head, neck, hands—basically not the trunk— are higher risk. That often [speaks] to the ability to resect these lesions. If the borders are poorly defined, or it’s a recurrent lesion, that’s not good. If there’s associated immunosuppression, prior radiation, or perineural involvement, those are bad features as well. Then the subtype with an aggressive growth pattern is something that is not great, that we don’t want to see.

Dr Ferris, as you think about stratifying a case like this, are there any in particular of these factors that would sway you more than any others? I think our case is a little generic in this regard, but when you think about these things, which of these are the most impressive to you?

FERRIS: For this lesion, [I think about] the size and the location close to important anatomic structures—thinking about getting the appropriate margin on that, or clearing that, knowing that you’re right up against the nasal ala, and thinking about the closeness to the lower [eyelid] as well.

When we look at these, we’re thinking not just how do I get that tumor cleared, but how do I reconstruct that? Where am I going to get tissue, to bring that in? Those are all important features. And then the subtype, superficial basal cells, nodular basal cells tend to be a bit less aggressive and a little easier to clear. But some of those subtypes, like morpheaform or an atypical basal cell, can be harder to clear, too.

LUKE: Yes. When you think about the potential to do a Mohs procedure on the face vs a resection, which might take off part of the nose, how do you think about those kinds of considerations? What’s the point where dermatologic management might need to transition to a full surgical approach?

FERRIS: I would [definitely] clear this with Mohs surgery. This is the classic case where the borders are poorly defined. You want to have complete margin assessment. I think, sometimes, Mohs surgery is seen as “less surgery,” but we think of it as surgery that lets you evaluate every single margin.

If you just do a typical elliptical excision, and bread loaf through that tissue, the pathologist sees about 2% of the actual margin, so there are going to be big areas that aren’t evaluated. With Mohs, because of the way the tissue is processed, you can see the deep and peripheral margins. So for clearing it, [I would use] Mohs. If you’re going to plan to surgically clear, this is where multidisciplinary care comes in, with thinking about reconstruction. Oftentimes, these kinds of reconstructions can be done by most surgeons; however, if this was taking up half the scalp, you would want to think about a different closure reconstruction option.

LUKE: We talked about surgical approaches here and we’re describing this as unresectable, but we want to consider that in the context of a multidisciplinary team, because that determination is often quite complicated. Diagnosing someone as unresectable is a big deal because that sets them down a certain trajectory in terms of eventual outcome.

FERRIS: Patients with unresectable, locally advanced BCC oftentimes have other medical comorbidities. They might be significantly older. While sometimes very aggressive surgery might be an option for them if you only looked at the tumor, when you look at the patient, that patient may not be able to tolerate it. They may be on anticoagulants and have a lot of other issues that would make it hard.

In terms of unmet needs, we were excited when the HHIs came out because it was finally a systemic option for these patients. However, they’re not easy for all patients to tolerate. So I think an unmet need is having something for those patients who try an HHI and say, “I can’t tolerate this.”

When we have very young patients, we tend to think, Is this going to be a good option? What do we do here? This person is young; we’re committing them to long-term therapy with something that is going to have some adverse events [AEs].

EFIOM-EKAHA: I’ve used vismodegib [Erivedge] before, and it’s not the easiest thing to tolerate. The taste issues and all the other toxicities are pretty prominent and tough [Table2]. My questions would be, for that patient for whom either the surgeon or the patient is [wary] of chopping off [the lesion]: What is the best option? How do we select it? Is there a preferred sequence, HHI vs PD-1–directed therapy? We all use immunotherapy in several tumor types and we’re [aware] of managing it but, again, drugs like this are not the easiest to tolerate.

LUKE: Absolutely. Anyone else have experience or want to give their opinion about how you might sequence things?

BEED: I’ve used an HHI in an older woman who came in and she had an unresectable tumor in the corner of her eye, in the inner canthus. She had put a Band-Aid over that, and she came in for something else. We treated her with [an HHI for the tumor] and she could tolerate it for maybe 6 months, then I’d take her off, put her back on, take her off. I have not changed it because it’s worked for her, and she’s now in her 90s. I would certainly use the other HHI as well. The other one is intravenous…and sometimes people can’t afford the [oral medication]. So that’s always a consideration, too.

LUKE: I think in clinical practice that relevance of intravenous vs oral is a big deal.

MALHOTRA: I had a patient at the VA [Veterans Health Administration] who I tried on cemiplimab [Libtayo] immunotherapy. There was a big lesion on his face, close to his eye, and he had stable disease for a long time.

MISBAH: I was almost able to use it, but I didn’t have the opportunity to use an HHI.

AKBAR: I have used an HHI in the past and the biggest trouble I had with that particular patient was bad muscle spasms, despite using the muscle relaxants. That was the reason we ended up discontinuing.

LUKE: You are raising important points on this. In terms of the pros and cons here—I think on a high level, is that the tolerability, generally speaking, of HHIs gets pretty tough after 3 months. I’m even surprised to hear that the 1 patient made it 6 months because most patients by about 3 months are having a tough time.

There are a lot of ongoing trials now, trying to look at pulsatile dosing, shortening the duration, taking breaks, and options like that. But it’s very interesting to think about when to use immunotherapy because if you determine that the patient would not tolerate an HHI, you can go to immunotherapy. The question is: When is that? Is that right away? Is that after you’ve tried it for a while? I think there is an intentional flexibility there that comes down to your clinical decision-making. But it is important to emphasize that Hedgehog inhibition can be quite powerful, in terms of controlling these lesions, and figuring out how to use it the best you can is an important consideration.

CHOWDHARY: I haven’t used vismodegib or sonidegib [Odomzo]. I see a lot of solid tumors, such as lung cancer; a lot of our patients with skin cancers go to the main campus. But I wanted to know, how do you differentiate between using one or the other? If I ever have a patient [in whom] I’m going to go for an HHI, how are you making the decision between vismodegib vs sonidegib?

LUKE: There are no head-to-head data so it’s going to be something about your familiarity, and probably your formulary considerations, in terms of which drug you can get more easily for a patient. I don’t think that there’s clear evidence that one is a lot better than the other. Whichever one you have familiarity with, or can get at a reasonable cost, is probably the way to go, in terms of choosing the in-class agents.

LUKE: Dr Beed, you mentioned your patient with whom you did 6-month treatment intervals on that therapy, and that sounded like that was dictated by the tolerability. Would you have preferred to continuously dose, or do you think that that model of treatment breaks would be something that’s broadly applicable?

BEED: I think it worked well for her. She lost weight, didn’t have any sense of smell and taste, was weak, and had alopecia; we’d stop it and then she’d be all good. Then when it started growing, I’d start it [again]. This has happened about 4 or 5 times now. I’d certainly change her [treatment], but she’s much older, and I thought to put her on intravenous therapy would be a bit much. But she’s amenable to starting something. What do you do when this stops working?

LUKE: That’s the hard question. In the context of other tumor types, and with targeted therapy, my experience is that I often find a utility in treating until what appears to be best response, and then assessing tolerability at that moment. That can, for some patients, be a month of therapy, or 3 months; it depends. But I have a lower threshold for discontinuing if the patient is having a good treatment effect. Whereas, with some other targeted therapies, a resistance doesn’t arise quite so quickly to HHIs. It’s a therapy that we can commonly go back to. So I try not to drag the patient through the painful toxicity, and try to get to that response, and then try to take a break.

What is your experience in terms of intermittent dosing? Were you able to take breaks, or did you notice resistance?

EFIOM-EKAHA: My patient was metastatic so we kept going and, unfortunately, quality of life wasn’t that great.

FERRIS: When it was our only drug, taking breaks—people have studied different sequences of 8 weeks; go 6 months, 8 weeks on, 8 weeks off vs 8 weeks off, 12 weeks on. In reality, the protocols probably get tailored to what the patient is able to tolerate. I think that those breaks give patients the ability to stick with it a little bit longer.

As we have more options, I’m curious: Do you end up ever cycling back and forth—having somebody on an HHI, going to cemiplimab, and going back? Or would you see it as a break or a transition? “We’ve really maxed this out; now let’s move on to cemiplimab.”

LUKE: It all depends on the patient in front of us. I think that would be very reasonable. I haven’t personally done that yet, but I probably haven’t had the chance to. That emphasizes this question of when does intolerance come in? Because if you can transition over without having to document progression, this question of can you go back to it is a good one later on if you’re not getting the response.

I probably wouldn’t give anti–PD-1 more than once. But in terms of targeted therapy, I would definitely be willing to go back to the well multiple times. If there’s been a reasonable period of time, you can often get a second response. So I think that’s an important consideration also, that with these patients, owing to comorbidities and advanced age, we try to keep things on the rails over time. It’s not exactly the same thing as your 40-year-old patient who is looking for a “cure.”

FERRIS: There are some data for using L-carnitine supplementation for the myalgias. Do you ever end up trying that? There’s evidence for some of the things we use in dermatology for hair loss. It seems like, in general, what people don’t tolerate is the muscle cramping more than anything. Just curious if you feel like things like L-carnitine supplementation help or even get you that extra few months to see that response before you would want to transition them.

LUKE: Yes, it’s a good point. I haven’t seen it make a big difference, but I think it’s probably anecdotal experience. But what you raise is an important consideration, which is if you’re starting patients on HHI, get the patient set up with palliative care and with your nutritional support at your cancer center. That can go a long way toward allowing them to stay on drug for longer periods of time.

Some other [factors] we think of, as it’s targeted therapy, is it’s going to be well tolerated. This is not exactly that, and the more help you can get for the patient early on—especially if they’re someone who may not have the level of capacity that they might have had when they were younger.

Depending on their family involvement, these kinds of things can make a big difference in terms of maintaining area under the curve on exposure for patients. In other words, can they keep taking the drug? All of those are important considerations, emphasizing the multidisciplinary care of the patient.

LUKE: One other note that can help with some of these patients with the muscle pains is the use of amlodipine.

How long did it take once you stopped the HHI to see some of the symptoms improve?

BEED: About a month to 6 weeks. She would say, “Christmas is coming; I want to feel good,” so we’d stop it. We’d do it around her holidays and vacations, what she felt was important.

LUKE: Yes, that’s an insightful comment. When we’re giving these palliative therapies—because in reality that’s what we’re talking about here—taking into account the patient’s real life, and what’s going to be meaningful to them, can be a very important thing.

My experience is similar. When patients get sick enough that they want to stop these drugs, it’s usually about 3 to 4 weeks that it takes before the symptoms start to get better. It’s probably going to be dependent, to some extent, on how robust your patient is in the first place. It sounds like your 90-year-old patient was quite the go-getter. It’s probably pretty variable, in terms of what their motivation is, in terms of trying to stay on the medicine. We emphasized [counseling the patients who are receiving HHIs]. Trying to get them set up with nutritional support and palliative care, to make sure that they’ll get all the resources that they might be able to have, in order to help manage through the AEs that they are experiencing, is an important aspect to all of this.

The other thing that I’m going to note, in this context— the obvious outlier here is that many patients with BCC are going to be those associated with solid organ transplant or some other form of immunosuppression. In those scenarios, this question about immunotherapy becomes much more nuanced. There is no evidence from the clinical trial that you could give immunotherapy in that setting. In reality, there’s probably a reason they’re on immunosuppression.

So if you give them anti–PD-1 therapy, you’re probably running a pretty big risk that you’re going to do something bad. That’s another consideration here, and why it’s important to understand how to use HHIs, because anti–PD-1 therapy is not this panacea for all patients. Unfortunately, in skin cancer especially, you’re in a tough spot when thinking about that.

LUKE: In our patient, what would we do next? What are the triggers for thinking about switching over from an HHI to anti–PD-1 therapy? We’ve alluded to a lot of them. Even those who haven’t used these drugs, how would you think about this?

MISBAH: I haven’t used an HHI but I’ve used PD-L1 therapy in other cancers and I would feel comfortable switching, or if it was referred from the dermatologist, to start them on a PD-L1 therapy, taking into consideration those things. You’re right; the patients who get BCC are on immunosuppressives in the first place. But in the case that they could be eligible for a PD-L1 therapy, I feel comfortable using them in other cancers. I haven’t used them often in BCC. I would be OK using it in BCC as well.

LUKE: Dr Malhotra, how would you think about this? The label is fairly vague; it says, “or intolerant,” so what constitutes intolerance? You have a lot of experience at the VA. The people at the VA often have a lot of comorbidities. How might you think about trying to sequence things, or use them optimally?

MALHOTRA: I was trying to think what treatment I would give to my patient—he was an older man with multiple comorbidities. He was cachectic, had lost a lot of weight, had significant bone pains and joint pains, and wasn’t ambulating well at home.

We did not wish to significantly affect his quality of life, and that was the way we decided we were going to stay away from the HHIs. But I think if patients are losing weight, and it has significantly affected quality of life, then that would be a trigger for me to switch at that time if I had started him on an HHI.

LUKE: Dr Beed, you had mentioned before wanting to avoid intravenous treatment in an older patient; that can make sense. Any other thoughts about a slightly different patient where that would be less of a concern?

BEED: I’ve treated a patient with a PD-L1 inhibitor, too. We get surgeons who say, “We can’t do anything; take these patients.” It was fine; it worked well. Both of these [treatments] have worked great. [The lesion] was on his ear and the side of his face, but he was much older and had multiple comorbidities, and he went on to die of something else. I’ve used each of these a few times, and they seem to be very good.

I’m at a small hospital. We have 1 palliative care [unit], which is more like a hospice. So we have to do all this, and spend the time—my nurse practitioner and I—to get them through these AEs, go over everything, and get to know them. It’s a small town, so if I don’t know them, somebody knows them, or their grandmother knows them. You get to give very personalized medicine that way.

LUKE: I’m also quite comfortable giving anti–PD-1 therapy in the context of other cutaneous malignancies. I would be thinking about it from the perspective of disease control. If it’s a lesion that isn’t otherwise out of control, I might be leaning toward anti–PD-1 relatively earlier than later, because if it’s not urgent, you might get 1 of those patients who can go a very long time benefiting from that. However, if their lesion’s quite gnarly [in terms of] putting the anatomic structures in place, I’m probably going to try to treat at least until maximum treatment response, if the patient can tolerate that, and go as long as we can before we think about switching over.


1. NCCN. Clinical Practice Guidelines in Oncology. Basal cell skin cancer, version 2.2022. Accessed May 17, 2022.

2. Lacouture ME, Dréno B, Ascierto PA, et al. Characterization and management of Hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. Oncologist. 2016;21(10):1218-1229. doi:10.1634/theoncologist.2016-0186

Posted on

Meta-analysis: Testosterone treatment not linked to short-, medium-term CV events in men

Graphical depiction of data presented in article

Hudson reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

We were unable to process your request. Please try again later. If you continue to have this issue please contact

In men with hypogonadism, there was no evidence that testosterone treatments cause short-term or medium-term CV risks, according to a meta-analysis published in The Lancet Healthy Longevity.

There were not enough data to conclude anything about the relationship between testosterone treatments and long-term CV risks, according to the researchers.

Graphical depiction of data presented in article

Source: Adobe Stock

“Prescribing of testosterone for hypogonadism is increasing globally, but conflicting messages about its safety may have led to many patients not receiving the treatment,” Jemma Hudson, MSc, from the Health Services Research Unit at the University of Aberdeen, United Kingdom, said in a press release. “Ongoing studies should help to determine the longer-term safety of testosterone, but in the meantime, our results provide much-needed reassurance about its short- to medium-term safety. Our findings could have important implications for the treatment of men with hypogonadism worldwide.”

Hudson and colleagues conducted a meta-analysis of 35 studies of trials of testosterone vs. placebo for hypogonadism including 5,601 participants (mean age, 65 years). Of those studies, 17 comprising 3,431 participants with a mean follow-up of 9.5 months had individual participant data. The researchers performed a one-stage meta-analysis of the individual participant data and a two-stage meta-analysis integrating individual participant data with the studies that did not provide it.

All-cause deaths were numerically lower in the testosterone group but were too few to determine statistical significance (0.4% vs. 0.8%; OR = 0.46; 95% CI, 0.17-1.24; P = .13), according to the researchers.

The rate of CV events was similar in both groups (testosterone, 7.5%; placebo, 7.2%; OR = 1.07; 95% CI, 0.81-1.42; P = .62), Hudson and colleagues wrote.

The most frequently occurring CV events were arrhythmia, CHD, HF and MI, all of which occurred at similar rates in both groups, according to the researchers.

There was no difference in CV risk by age (P for interaction = .17), baseline testosterone level (P for interaction = .69), smoking status (P for interaction = .35) and diabetes status (P for interaction = .025), the researchers wrote.

“An important strength of this [individual participant data] meta-analysis is its large size compared with individual testosterone trials, which have provided limited and situation-dependent information on cardiovascular safety,” Hudson and colleagues wrote. “This study has allowed us to more precisely estimate the incidence of cardiovascular events associated with testosterone treatment, which might be generalizable to patients worldwide.”


  • Little evidence testosterone treatment increases the risk of cardiovascular events, most in-depth analysis suggests. Published June 8, 2022. Accessed June 9, 2022.

Posted on

Analysis finds little proof that testosterone treatment increases the risk of cardiovascular events

Analysis finds little proof that testosterone treatment increases the risk of cardiovascular events

Testosterone replacement therapy appears safe in the short-to-medium term to treat a condition caused by deficiency of the male sex hormone, according to the most comprehensive analysis of the treatment to date, published in The Lancet Healthy Longevity journal.

The findings suggest that men given testosterone to treat hypogonadism are at no greater risk of heart attack, stroke, and other cardiovascular events in the short-to-medium term than men who do not receive testosterone treatment.

Testosterone replacement therapy is the standard treatment for hypogonadism, which can cause sexual dysfunction, weakening of bones and muscles, and reduced quality of life. Risk factors for the condition include aging (as testosterone levels decline with age), obesity (BMI of 30 kg/m2 or above), and diabetes.

Despite being widely used, the cardiovascular safety of testosterone treatment has until now remained unclear due to inconsistent findings. This is because most previous clinical studies have relied on aggregate data, rather than individual participant data and have not published details of individual adverse events.

Prescribing of testosterone for hypogonadism is increasing globally, but conflicting messages about its safety may have led to many patients not receiving the treatment. Ongoing studies should help to determine the longer-term safety of testosterone but, in the meantime, our results provide much-needed reassurance about its short-to-medium term safety. Our findings could have important implications for the treatment of men with hypogonadism worldwide.”

Jemma Hudson, Study Lead Author, University of Aberdeen

The authors conducted a systematic review identifying 35 eligible clinical trials published since 1992, of which 17 provided individual participant data. A blinded analysis by two independent clinicians enabled the classification of every cardiovascular event, allowing for a more robust analysis of the cardiovascular safety of testosterone treatment.

A meta-analysis using individual participant data from 17 studies and a further meta-analysis integrating these data with the aggregate data provided by the 18 trials that did not provide individual participant data were performed.

Among the 17 trials with individual patient data, 1,750 participants received testosterone and 1,681 were given a placebo. The average length of testosterone treatment was 9.5 months. The average age of participants was 65 years, and most were white and did not smoke. Participants’ average BMI was 30 kg/m2, which is considered obese.

A meta-analysis showed there were 120/1,601 (7.5%) cardiovascular events in the testosterone group and 110/1,519 (7.2%) in the placebo group across 13 trials that provided this information. Patient age, smoking or diabetes status did not affect cardiovascular risk. Similarly, there was no significant difference in mortality rate between the testosterone group (6/1,621 deaths, 0.4%) and the placebo group (12/1,537 deaths, 0.8%) across the 14 trials that provided individual patient data on mortality, but only limited data were available.

The researchers also found that testosterone significantly reduced serum total cholesterol, high-density lipoprotein (HDL), and triglycerides compared with placebo. However, there were no significant differences in serum low-density lipoprotein (LDL), blood pressure, glycaemic parameters, diabetes incidence, and prostate adverse outcomes between the testosterone and placebo groups.

The meta-analysis that integrated individual participant data with aggregate data showed similar results.

The authors acknowledge some limitations to their study. There was little available data evaluating the cardiovascular safety of testosterone treatment beyond 12 months, and the very small number of deaths recorded during testosterone trials hampered the authors’ ability to analyze why they occurred.

However, the longer-term safety of testosterone treatment is currently being investigated in another clinical trial. While the meta-analysis of aggregate data showed similar results to the one involving individual patient data only, it cannot be ruled out with certainty that a high number of unreported cardiovascular events in the trials that did not provide individual participant data could alter the current conclusions.


Journal reference:

Hudson, J., et al. (2022) Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. The Lancet Healthy Longevity.

Posted on

Study Identifies 24 Adverse Events Associated with Secukinumab Treatment

Study Identifies 24 Adverse Events Associated with Secukinumab Treatment

A new systematic review of secukinumab-induced adverse events of special interest (AESI) in patients with moderate to severe plaque psoriasis found that the most common AESI were inflammatory bowel disease, eczematous drug eruption, drug-associated vasculitis, and drug-induced lupus erythematosus.

Despite most AESI being deemed mild to moderately severe in nature, these types of events have been increasingly reported in real-world practice.

Additionally, the adverse effect profile of the treatment has not been fully described in previous research, and many of the adverse effects such as lupus erythematosus had not been identified in clinical trials despite gradually being reported in more case reports and case series.

As such, an investigative team led by Jingyao Liang, PhD, Institute of Dermatology at Guangzhou Medical University, China, perfomed a systematic review intended to establish a secukinumab-induced AESI profile and management strategies.

The literature search was performed in PubMed databases from the earliest cases of secukinumab use to August 2021 for the treatment of any type of clinical condition.

Search terms such as secukinumab or secukinumab-induced, adverse effects, side effects, and adverse events were used to find relevant studies, at which point investigators extracted data regarding study type, demographics, treatment history and dosage, disease type, onset of AESI, and management and outcomes of AESI.

Overall, the search resulted in 1426 potentially relevant articles, 55 of which were included in the review. Among these studies were 2 clinical studies, 2 reviews, 50 case reports, and 1 case series, all of which were published between 2016 and 2021.

Investigators noted that more thab 1077 adult patients 18-74 years old experienced AESi after being treated with secukinumab for a myriad of conditions including psoriatic disease and spondyloarthritis (SpA).

The onset of the AESI ranged from 2 days to 96 weeks, and a total of 24 AESI were identified, including adiposity, alopecia areata, bullous eruption, scleroderma, and the AESI previously listed.

The most commonly reported AESI was IBD with over 1000 cases, followed by eczematous drug eruptions at 30 cases and drug-associated vasculitis at 8 cases.

As mentioned, most of the events were mild to moderate in severity, and patients typically experienced full recovery following discontinuation. Notably, some patients continued secukinumab treatment due to significant disease regression, with AESI being stabilized and/or well-controlled by other treatments.

With this study, investigators suggested that clinicians “should be aware that secukinumab may cause various AESI and follow-up patients for exacerbation of symptoms or new onset of AESI during treatment”.

The study, “Review of secukinumab-induced adverse events of special interest and its potential pathogenesis,” was published online in Dermatologic Therapy.

Posted on

Common Adverse Events with Single-Agent or Combination Therapy

Common Adverse Events with Single-Agent or Combination Therapy

Metastatic Renal Cell Carcinoma: Safety and Efficacy of Available Treatment Options and Considerations for Patient Management – Episode 18

Mehmet Asim Bilen, MD, provides an overview of commonly observed adverse events in patients with metastatic RCC receiving single-agent or combination therapy.

Posted on

World events, time change and anger piling on pandemic pressures

World events, time change and anger piling on pandemic pressures

Chuck Norris

Chuck Norris

Don’t care much for the constant mid-March ritual of moving our clocks ahead one hour? According to Beth Ann Malow, a professor of neurology and pediatrics at Vanderbilt University, 63% of Americans would like to see it eliminated.

The thing is, daylight saving time represents much more than a disruption to daily routines. Given the stresses heaped upon us in our world of uncertainties, it could be the proverbial straw that broke the camel’s back.

“Beyond simple inconvenience,” writes Malow on, “Researchers are discovering that ‘springing ahead’ each March is connected with serious negative health effects.”

“In a 2020 commentary for the journal JAMA Neurology, my co-authors and I reviewed the evidence linking the annual transition to daylight saving time to increased strokes, heart attacks and teen sleep deprivation,” she says.

A separate post on co-authored by Deepa Burman, co-director of the Pediatric Sleep Evaluation Center at UPMC Children’s Hospital of Pittsburgh, and Hiren Muzumdar, director of the Pediatric Sleep Evaluation Center, notes that sleep deprivation can result in increases of workplace injuries and automobile accidents. One individual’s sleep deprivation can affect an entire family.

People are also reading…

“You may notice more frequent meltdowns, irritability and loss of attention and focus,” they say.

I wonder, could uncontrolled anger be far behind?

Now, watching a devastating war unfold on social media is also hammering away at our collective mental health. We’re all being heightened by graphic and disturbing images that fill our feeds, writes Time magazine reporter Jamie Ducharme.

“Tracking up-to-the-minute developments can come at a cost. … Footage and photos from Ukraine flooding social media and misinformation spreading rampantly (has) implications for public health,” she reports.

It has long been the responsibility of traditional media outlets for editors to decide which content is too graphic to show, or to label disturbing images with warnings. As pointed out by Roxane Cohen Silver, a professor of psychological science at the University of California, Irvine, today anyone “can take pictures and videos and immediately distribute that (on social media) without warning, potentially without thinking about it.”

Jason Steinhauer, founder of the History Communication Institute, says, “Russia has been waging a social media and misinformation war for the past 10 to 12 years.” This has only gotten worse since its invasion of Ukraine.

We should not be surprised at all that studies now suggest that news coverage of the pandemic has contributed to our mental distress. “Adding yet another difficult topic to the mix can worsen those feelings,” Cohen Silver says.

Yet the war is hardly the only attack on our senses. At a time when we are most vulnerable, the Federal Trade Commission reports that predatory fraudsters bilked consumers of an estimated $5.8 billion last year. According to the agency, it represents a 70% increase over 2020. “Almost 2.8 million people filed a fraud complaint, an annual record” and “the highest number on record dating back to 2001,” reports the FTC. “Imposter scams were most prevalent, but investment scams cost the typical victim the most money.”

“Those figures also don’t include reports of identity theft and other categories,” the report points out. “More than 1.4 million Americans also reported being a victim of identity theft in 2021; another 1.5 million filed complaints related to ‘other’ categories (including credit reporting companies failing to investigate disputed information, or debt collectors falsely representing the amount or status of debt).”

The mounting stresses placed upon us are now posing a threat to not just our mental and financial health but our physical well-being.

According to a working paper from researchers at the Naval Postgraduate School and the University of Pennsylvania, “In 2020, the risk of outdoor street crimes initially rose by more than 40% and was consistently between 10-15% higher than it had been in 2019 through the remainder of the year.” Researchers also believe that the finding “points to the potential for other crimes to surge the way homicides have as cities reopen and people return to the streets,” says the report.

Adds Megan McArdle commenting on the report in an op-ed for the Washington Post, “community trust in the police might have plummeted, possibly making people more likely to settle scores on their own. Or police might have reacted to public anger by pulling back from active policing, creating more opportunities for crime.”

Hans Steiner is a professor emeritus of Stanford’s Department of Psychiatry and Behavioral Sciences who has logged decades of work studying anger and aggression. In an interview posted on the Stanford University website, he says he believes that “the coronavirus pandemic, with its extreme disruption of normal daily life and uncertainty for the future, compounded by several other crises (economic distress, racial tension, social inequities, political and ideological conflicts) puts us all to the test: we find ourselves immersed in a pool of negative emotions: fear, sadness, contempt, and yes, anger. What do we do with this forceful emotion?”

“Anger signals that we are being threatened, injured, deprived, robbed of rewards and expectancies,” Steiner says. It should be “one of our adaptive tools to deal with the most difficult circumstances. Sometimes it becomes an obstacle to our struggles, especially when it derails into aggression and even violence.”

Anger problems are now spilling over into record accounts of hate crimes. It seems that today’s circumstances, with anger management and rule of law seemingly at an all-time low, have caused many individuals to become ticking time bombs. Reports CBS News, “the total number of hate crimes nationwide has increased every year but one since 2014, according to FBI data, which includes statistics through 2020.”

Steiner says that “maladaptive anger and aggression has the following characteristics: 1. It arises without any trigger, seemingly out of the blue; 2. it is disproportionate to its trigger in its frequency, intensity, duration and strength; 3. it does not subside after the offending person has apologized; 4. it occurs in a social context which does not sanction anger and aggression.”

Who among us has not seen or maybe even experienced some, maybe all, of these behavior characteristics?

“In such conflicts we need to remind ourselves that diatribes, lies and accusations will not move us forward; compassion, empathy and the reminder that we are all in this horrible situation together (needs to) inspire us,” Steiner advises.

Write to Chuck Norris at with questions about health and fitness.

Posted on

Female Patients More Likely Than Males to Experience Severe Adverse Events During Cancer Treatment, Study Finds

Female Patients More Likely Than Males to Experience Severe Adverse Events During Cancer Treatment, Study Finds

Women are known to experience more adverse events with chemotherapy, but a recent study found an increased risk across therapy types, especially immunotherapy.

Women receiving chemotherapy are likely to have more adverse events (AEs) than men undergoing the treatment, but very little research has assessed the differences between men and women’s experiences with immunotherapy or targeted therapy. A recent study explored the role of patient sex in symptomatic and objective AEs with cytotoxic, immune, and targeted therapies for cancer.

The study, published in the Journal of Clinical Oncology, used SWOG Cancer Research Network phase 2 and 3 clinical trial data from trials between 1980 and 2019. Sex-specific cancers were excluded from the analysis.

In total, 13 symptomatic AEs and 14 objective and measurable AEs were analyzed. Symptomatic AEs included those in the Patient-Reported Outcome Common Terminology Criteria for Adverse Events given past evidence that clinician reports may under-report symptomatic AEs. Objective AEs were laboratory-based or measurable and were also categorized as either hematologic or nonhematologic.

Overall, 23,296 patients including 8838 women (37.9%) from 202 trials were included in the study. Of the patients included, 17,417 received chemotherapy, 2319 received immunotherapy, and 3560 received targeted therapy. Collectively, patients experienced 274,688 AEs, with 15,051 (64.6%) experiencing AEs of grade 3 or higher. Chemotherapy was especially prevalent in trials between 1989 and 1999. Immunotherapy and targeted therapies were more common from 2010 to 2019.

“It has been understood that women have more toxicity from chemotherapy than men, but almost no research has aimed to understand whether that pattern held for novel treatments like immunotherapy or targeted therapies,” study author Joseph Unger, PhD, associate professor, biostatistician, and health sciences researcher at Fred Hutchinson Cancer Center, said in a statement. “We found similar large differences, especially for immune treatments.”

While 64.6% of all patients experienced 1 or more severe AE, women had a 34% greater risk of severe toxicity than men (odds ratio [OR], 1.34; 95% CI, 1.27 to 1.42; P < .001). Women were at an increased risk across treatment types, especially immunotherapy (OR, 1.49; 95% CI, 1.24 to 1.78; P < .001).

Women were at a 33.3% greater risk of experiencing symptomatic AEs (OR, 1.33; 95% CI, 1.26 to 1.41; P < .001) compared with men (27.9%). They also had an increased risk of hematologic AEs compared with men (45.2% vs. 39.1%) and objective nonhematologic AEs (30.9% vs 29.0%). Women treated with immunotherapy were at an especially higher risk of severe symptomatic and hematologic AEs than men who received immunotherapy (33.7% vs 25.4%). Severe objective, nonhematologic AEs occurred at similar rates in men and women across treatment types.

These findings suggest that, in addition to the typical patient and tumor characteristics considered in cancer treatment decisions, patient sex may be a key factor in maximizing treatment efficacy while limiting toxicity. This is especially relevant with immunotherapy, during which women were at the greatest risk for severe AEs in this study.

The authors presented several possible explanations for the sex-related differences in AEs. They could be related to body size differences and relative dosing, differences in medication adherence for oral therapies, bias in the interpretation and reporting of AEs, or different reporting habits in men and women. However, the authors noted that objective hematologic AEs were also more common in women in these trials.

One study limitation is the population, which is limited to clinical trials and therefore likely includes younger, healthier patients than the general patient population, study authors said. The study also only included the worst toxicity grade in each category, so there was no observation of toxicity patterns over time.

Despite limitations, these findings suggest that sex could be an important factor in individualizing cancer treatment and maximizing efficacy.

“If confirmed, our findings suggest that underlying mechanisms may result in generalized worse toxicity outcomes for women, with or without corresponding survival improvements or detriments,” the authors wrote. “Therefore, more awareness of symptom differences or reporting differences in women versus men is needed.”


Unger JM, Vaidya R, Albain KS, et al. Sex differences in risk of severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in cancer clinical trials. J Clin Oncol. Published online February 4, 2022. doi:10.1200/JCO.21.02377