Category: 8. Health

Heart disease still holds the top spot for causes of death in the U.S., but cancer isn’t far behind, with each condition claiming the lives of over 600,000 Americans every year. And while researchers are more certain about how to prevent heart disease through lifestyle changes, cancer remains a bit more elusive. 

Scientists are continually searching for ways to prevent cancer and increase survival rates for those with the disease. Researchers from China analyzed data from a long-running U.S. survey called the National Health and Nutrition Examination Survey (NHANES) collected between 2001 and 2018. They wanted to know what association, if any, exists between a ketogenic diet and cancer. They published their findings in Nutrition and Cancer—let’s break down what they found.

How Was This Study Conducted?

For this analysis, almost 44,000 participants from the NHANES met the researchers’ criteria. The participants were fairly evenly split between genders, but did skew slightly more female. Participants were at least 20 years of age. 

All the data were self-reported, including history of cancer, dietary information and demographics. To determine if a participant had a history of cancer, they answered yes or no to the question, “Have you ever been told by a doctor or other health professional that you had cancer or a malignancy of any kind?” 

Dietary intake was calculated using the average of two 24-hour dietary recalls, which researchers used to calculate each participant’s dietary ketogenic ratio (DKR). The DKR is a calculation that indicates the likelihood of someone entering ketosis based on their macronutrient ratio. Ketosis occurs when carbohydrates, the body’s preferred source of energy, are not available. In this case, the body turns to fat as an energy source, and then the liver converts fat into ketone bodies, which can also be used as an energy source. Based on their DKRs, participants were placed into one of four quartiles, with Q4 having the highest DKRs and Q1 having the lowest. 

Demographics that would be adjusted for during statistical analyses included age, sex, ethnicity, income and education levels, marital status, BMI, smoking status and medical history. 

What Did This Study Find?

Researchers found that as DKR increased, so did the risk of cancer. But not just one or two types of cancer—all cancers. In other words, they found a significant association between the keto diet and the risk of developing cancer.

While these study authors note that there are likely some short-term benefits of a keto diet, the long-term risks may outweigh the benefits. Why keto may raise cancer risk needs to be explored further, but researchers provide a few possible explanations. First, they note that ketones have been implicated in increasing oxidative stress, causing cellular damage, which increases the risk of developing cancer. They also point out that while cancer cells typically prefer to use glucose as an energy source, research suggests that some cancer cells can utilize ketones as an alternative energy source to survive and proliferate. 

In addition to these findings, these researchers also found that as the degree of ketosis increased, there was a notable decline in the antioxidant properties of vitamins A, C, and E, as well as trace elements such as manganese, zinc, and selenium. This aligns with numerous studies that have consistently shown deficiencies in antioxidant vitamins and trace elements can substantially increase the risk of all cancers.

One significant limitation of this study is that participants’ ketosis levels were not directly measured with bloodwork. Also, information was all self-reported, which leaves room for error and bias. This includes cancer diagnoses, which might have been more accurate had they used participants’ medical records. 

How Does This Apply to Real Life?

While a ketogenic diet does have some legitimate medical uses—like reducing seizures in children with epilepsy—beyond that, it’s mainly used to lose weight. The problem is following it long-term—let’s face it, one can only eat so much cheese and bacon. And while all foods can fit into a healthy eating pattern, it’s important to eat a variety of foods to ensure your body gets the nutrients it needs. Though this study can’t say that a keto diet causes cancer, based on this data, there appears to be a strong connection between the two, and more research should be done. 

Since we know there’s also a correlation between chronic inflammation and cancer, eating an anti-inflammatory diet may help reduce cancer risk. An anti-inflammatory diet focuses on fruits, vegetables, whole grains and healthy fats. 

Besides eating a varied, balanced diet and maintaining a healthy weight, the American Cancer Society recommends engaging in regular physical activity, managing your stressors, getting plenty of quality sleep, avoiding or limiting alcohol and not smoking to help lower your cancer risk.

Our Expert Take

This study suggests a connection between the ketogenic diet and cancer risk. While keto may help you lose weight, the risks may outweigh the benefits. If you feel better reducing carbs, there are healthier and more moderate ways to do so that don’t go to keto extremes. To get started, choose from our low-carb, high-protein dinners that come together in just 30 minutes or our high-protein, low-carb breakfasts to help you lose weight. If cancer prevention is top of mind, taking a holistic approach may not only help prevent cancer but also other diseases, including heart disease and diabetes. Include plenty of fruits, vegetables, whole grains, legumes, nuts, seeds, lean proteins and healthy fats in your diet. In addition, move your body often, deal with what’s stressing you out, get enough quality sleep and spend time with loved ones.

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, significant attention was drawn to the evolving role of immunotherapy in cutaneous squamous cell carcinoma (CSCC), a nonmelanoma skin cancer affecting a growing number of patients. Among the headline studies was MK-3475-630/​KEYNOTE-630 trial (NCT03833167), a phase 3 trial evaluating the efficacy of adjuvant pembrolizumab (Keytruda) following surgery and radiation in patients with high-risk CSCC.^1,2

The trial’s primary end point was event-free survival (EFS), defined as the time to recurrence or death. KEYNOTE-630 did not meet this primary end point at its first interim analysis. However, a notable reduction in recurrence was observed, including a 2-year recurrence rate in the placebo group of 28% vs 14% in the pembrolizumab group. Additionally, there were 22 deaths with pembrolizumab vs 9 deaths with placebo.

Importantly, there were no grade 5 toxicities, indicating that the deaths were not directly attributed to treatment. The cause remains unclear but may relate to trial timing, COVID-19 complications, or other unknown factors.

In an interview with Targeted Oncology, Shlomo Koyfman, MD, a radiation oncologist at Cleveland Clinic, provided a comprehensive overview of the trial, its results, and its implications for future standards of care.

Targeted Oncology: Can you summarize this trial, the design, and the high-risk patient population that it focused on?

Shlomo Koyfman, MD: Most cutaneous squamous cell cancer skin cancers are super curable with just surgery, but there’s a small amount, maybe 10% of them, that have a higher risk of developing bad outcomes, either a recurrence or death. The highest risk population is those patients with very advanced disease, big T4 tumors, nodal disease, or a multiply recurrent T2 or T3 tumor with a lot of perineural invasion, or it is large, or it is deep, or things like that.

This trial, the KEYNOTE-630 trial, included all high-risk patients, all very high-risk patients with either big T4 disease, big nodal disease with multiple nodes or extraneural extension, or patients with T3 tumors with multiple risk factors. Essentially the standard of care for those patients is surgery and postoperative radiation. What this trial did was randomize patients after they completed surgery and postop[erative radiotherapy], randomized them to adjuvant pembrolizumab vs placebo, and that was done for 9 cycles, and the goal was to reduce recurrence and cancer related death and to improve the event-free survival.

What were the key efficacy outcomes, and how significant was the benefit with adjuvant pembrolizumab?

The study did not meet its primary end point. The primary end point was an approval of event-free survival with particular confidence intervals and statistical significance. The study did not meet that end point, unfortunately. However, when you look at the actual data, the recurrence rate was considerably lowered. The overall recurrence rate for patients in 2 years went from 28% for the placebo arm down to about 14% for the pembrolizumab arm. It reduced recurrence by 50%.

However, patients in the pembrolizumab arm had an increased risk of death, an increased episode of death. There were more deaths in the patients in the immunotherapy arm, which was unexpected. Now, what is weird about it is there were no grade 5 toxicities in the study, which means there were no actual deaths related to pembrolizumab. There was an increased number of deaths in the pembrolizumab arm. We do not know why that is, but because there were more deaths, the primary end point, which was event-free survival, included any recurrence or death as an end point. Even though the recurrences were much better and much lower, 50% lower with the immunotherapy, the death rate was higher. There were 22 deaths in the pembrolizumab arm, vs only 9 deaths in that arm. That essentially made it so that the trial did not meet its end point of improvement, event-free survival, and the trial was actually closed.

How do these results compare with previous standards of care or observation following surgery or radiation in this population?

If you look at the recurrence rates, it compares very favorably, and the curves separate with a statistically significant difference. It didn’t meet the prespecified P value. But certainly, the recurrences have improved. However, overall, the event-free survival was not improved, and therefore it was overall a negative trial. Still, patients in the pembrolizumab arm, at least from a recurrence standpoint, did better.

It is important to note that at the same ASCO session, presented at the same oral presentation, there will be presented the C-POST data. The C-POST was a similar trial with similar eligibility criteria designed by Regeneron using cemiplimab [Libtayo], and it was similarly structured—after surgery and radiation, adjuvant cemiplimab vs placebo. That trial was positive. There was a substantial reduction in events. The event-free survival was improved, and that did meet statistical significance.

Looking at these 2 trials, the cemiplimab C-POST trial being positive, and the KEYNOTE-630 trial not meeting its primary event free survival end point but significantly reducing recurrence, I believe that adjuvant immunotherapy compares favorably to the standard surgery and radiation, and, hopefully, there will be an FDA approval for cemiplimab in this disease.

Looking at both of those trials, are there any remaining questions about longer-term benefit or patient selection?

There are some unanswered questions. First of all, in the KEYNOTE-630 trial, why were there those unexplained deaths in the pembrolizumab? We don’t know. The trial did occur during [the] COVID [pandemic], and that complicated things. It was an international trial during COVID, which was complex. Similarly, in the KEYNOTE-630 trial, you were able to go on trial within 16 weeks of radiation, and that’s a long time—4 months between radiation and starting immunotherapy. If you look at the placebo arm, patients who did enroll, there were quite a number of people who actually recurred within the first few months. There are people that rapidly recur, and there were quite a number of people that, when we screened them, within that first 4 month period, they did not meet eligibility because they had already recurred. One of the challenges and the criticisms of the KEYNOTE-630 trial is that it was too long—4 months was too long a window to allow people to get the adjuvant immunotherapy. It is possible that if you are trying to give adjuvant immunotherapy to these patients, getting it in within the first couple of months is important. That is one unanswered question.

The other is, will this translate to an ultimate overall survival benefit? As of yet, there’s no overall survival benefit in the KEYNOTE-630 trial. I do not know about the C-POST trial—we have to see. It may translate to an overall survival benefit. However, in the KEYNOTE-630 trial, there was a crossover arm, so a large number of patients in the placebo arm who recurred ended up getting PD-1 therapy—mostly pembrolizumab, some cemiplimab—and of course, many of them had terrific responses. That is why the overall survival may not show, because a lot of these patients ended up getting immunotherapy anyway, because it is such an effective therapy. Overall, I do believe that certainly the aggregate of these 2 trials is that it is an effective therapy, it dramatically reduces recurrence, and in the right patient population, where we are not worried about excessive morbidity, I think my hope is that it is ingrained in our future standards of care.

What are the broader takeaways here about the evolving role of immunotherapy in nonmelanoma skin cancers?

There is a lot of excitement about neoadjuvant therapy for skin cancer. A very exciting trial done with cemiplimab showed exciting results with neoadjuvant [therapy]. In 79 patients, there was a 50% pathologic complete response rate. A confirmatory, large phase 3 trial is currently underway and open—it’s the NRG Oncology HN014 trial led by Neil Gross, MD, FACS. It is an exciting trial. We will be opening it along with many other centers in the US and Australia, and that will look at neoadjuvant immunotherapy vs the standard surgery-first approach. We are all optimistic that that will potentially lead to benefit and a new standard of care for patients who do get neoadjuvant immunotherapy.

I think the role of adjuvant immunotherapy is totally up in question, but for patients who get surgery first and adjuvant radiation, my hope is that—looking at the C-POST trial and the KEYNOTE-630 trial—that adjuvant immunotherapy for surgery-first patients becomes embedded in our future standards of care.

REFERENCES:

1. Koyfman SA, Lee JH, Mortier L, et al. Phase 3 randomized trial (KEYNOTE-630) of adjuvant pembrolizumab (pembro) versus placebo (pbo) for high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) following surgery and radiation (RT). J Clin Oncol. 2025;43(suppl 17):6000. doi:10.1200/JCO.2025.43.16_suppl.6000

2. Adjuvant Libtayo® (cemiplimab) significantly improves disease-free survival (DFS) after surgery in high-risk cutaneous squamous cell carcinoma (CSCC) in phase 3 trial. News release. Regeneron Pharmaceuticals, Inc. January 13, 2025. Accessed July 14, 2025. https://tinyurl.com/46b9f65k

Antimicrobial resistance is an issue that affects many different parts of medicine. It also has led to patient deaths, with more projected around the world in coming years. Jason G. Newland, MD, MEd, is division chief of infectious diseases for Nationwide Children’s Hospital in Columbus, Ohio. Here he opens discussion to explain the scope and scale of the problem.

This transcript has been edited for length and clarity.

Medical Economics: Can you discuss the current state of medicine and research regarding antimicrobial resistance, and how would you describe the scope and scale of the problem?

Jason G. Newland, MD, MEd: Antimicrobial resistance is an important, we’ll say concept or thing that is impacting all of us, whether you might know it or not. So what we mean by this is that we have a lot of pathogens, like bacteria, one might have heard of staphaureus or MRSA, as well as even viruses like influenza and even parasites, maybe people have heard of malaria. And all of these, those specifically, all have kind of medicines or antibiotics for bacteria or antivirals for influenza or antimalarials, for parasites, for the malaria, and those medicines can treat them, and they have made people healthy for a century, and that’s really important. But what we have seen in the use of them is that we develop — those pathogens are living organisms that can change, and they evolve. And in that evolution, they’re like, look, something’s trying to kill me. I change so that they don’t kill me. And that is where we are, that antimicrobial resistance impact. And what we have seen in the United States, and that in 2019 report from the CDC, that 35,000 Americans die annually, again, die annually from an antimicrobial resistant infection, which are predominantly bacteria in origin. We know that worldwide data suggests that by 2050 we’ll have annually, so every year, we’ll have 11 million deaths worldwide due to antimicrobial resistance, and that’s at a more global scale, with more pathogens. So to say we’re not in a state that scares us in medicine would be an understatement.

Nearly 800,000 doses of mpox vaccine pledged to African countries working to stamp out devastating outbreaks are headed for the waste bin because they weren’t shipped in time, according to reporting by Politico.

The nearly 800,000 doses were part of a donation promised under the Biden administration, which was meant to deliver more than 1 million doses. Overall, the US, the European Union, and Japan pledged to collectively provide 5 million doses to nearly a dozen African countries. The US has only sent 91,000 doses so far, and only 220,000 currently still have enough shelf life to make it. The rest are expiring within six months, making them ineligible for shipping.

“For a vaccine to be shipped to a country, we need a minimum of six months before expiration to ensure that the vaccine can arrive in good condition and also allow the country to implement the vaccination,” Yap Boum, an Africa CDC deputy incident manager, told Politico.

Politico linked the vaccines’ lack of timely shipment to the Trump administration’s brutal cuts to foreign aid programs as well as the annihilation of the US Agency for International Development (USAID), which administered those aid programs.

COVID-19 vaccine boosters for adult patients with cancer helped to keep these patients from being hospitalized or admitted to intensive care units due to severe COVID-19 infections, according to the results of a retrospective cohort study published in JAMA Oncology. 

“Cancer patients are a vulnerable population,” said senior study author Jane Figueiredo, PhD, Director of Community Health and Population Research at Cedars-Sinai Medical Center in Los Angeles, California. “Their immune systems can be weakened by their disease and the treatments they receive, which is why major health organizations recommend that these patients be vaccinated against COVID-19. Our study supports these recommendations. We used real-world data across four major health systems in the United States to show that these booster vaccines reduce the risk of hospitalization and severe illness.”

Study Methods and Key Findings

The investigators reviewed data from patients with cancer who were treated with chemotherapy or immunotherapy between 2022 and 2023 at one of four included health-care systems. Of the 72,831 included patients, 69% received a monovalent COVID-19 booster by January 1, 2022, and 38% of 88,417 patients with cancer received a booster during the bivalent period. 

The hospitalization rate due to COVID-19 was 30.5 per 1,000 person-years among patients who received a booster compared with 41.9 for those who received the primary booster alone. The adjusted vaccine effectiveness was calculated as 29.2% (95% confidence interval [CI] = 19.9%–37.3%) and the number of patients needed to vaccinate to prevent one COVID-19 hospitalization was 166 (95% CI = 130–244).

Calculated effectiveness for preventing diagnosed COVID-19 was 8.5% (95% CI = 3.7%–13.0%) and 35.6% (95% CI = 20.0%–48.3%) for preventing COVID-19–related intensive care unit admission.  

“The reduction in hospitalizations was significant, and the number of patients we needed to treat to see a benefit to the boosters is quite low,” said Dr. Figueiredo, who is also Program Leader of Cancer Prevention and Control at Cedars-Sinai. “This shows a great benefit to our cancer patients and should encourage patients to discuss vaccination with their health-care providers.”

During the bivalent period, the COVID-19 hospitalization rate among patients who received a booster was 13.4 per 1,000 person-years compared with 21.7 per 1,000 person-years for those who did not receive a booster. The adjusted vaccine effectiveness was calculated as 29.9% (95% CI = 19.4%–39.1%) and the number needed to vaccinate to prevent one COVID-19 hospitalization was 451 (95% CI = 345–697). To prevent COVID-19–related intensive care unit admission, the adjusted vaccine effectiveness was 30.1% (95% CI = 7.7%–47.0%). 

The study authors highlighted that uptake of vaccine boosters was low overall for patients with cancer. “Whether this is due to patient concerns about safety or provider uncertainty about whether to administer a vaccine during treatment is not clear,” Dr. Figueiredo said. “What is clear is that we need to advocate strongly for vulnerable groups, including cancer patients, to receive these vaccines.”

“This is the largest study to date of COVID-19 booster effectiveness in cancer patients, a high-risk population of critical importance,” stated Robert Figlin, MD, Interim Director of Cedars-Sinai Cancer. “It adds substantially to our understanding of the effectiveness of COVID-19 vaccines, and we will undertake additional studies as vaccine formulations change and new variants emerge so that we can make recommendations that best protect the health of our patients.”

Disclosure: For full disclosures of the study authors, visit jamanetwork.com. 

Introduction

Primary sclerosing cholangitis (PSC) is an idiopathic, progressive cholestatic liver disease, associated with inflammatory bowel disease (IBD).¹ Despite conservative treatment, the disease usually progresses, and ultimately, a liver transplantation (LT) is the only curative solution for more than 50% of patients.² Nevertheless, recurrence of PSC (rPSC) in liver graft is reported in 17–25% of patients, which significantly worsens outcomes after liver transplantation,³ and the pathogenesis of recurrent disease is still not entirely understood.

The gold standard for assessing PSC severity, progression, and complications is serum concentrations of liver enzymes, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin, in combination with magnetic resonance cholangiopancreatography (MRCP) and histology.¹

Nevertheless, there are several lines of evidence that the gut–liver axis, altered immune function, intestinal barrier dysfunction, and microbial dysbiosis have a significant impact on the pathogenesis of PSC.¹ The different microbiota composition in patients with PSC compared with controls was reported.^4,5 In regard to rPSC, active colonic inflammation has been identified as one of the risk factors for rPSC,⁶ as it contributes to the impairment of intestinal barrier function and promotes translocation of bacterial endotoxins, metabolites, and other bacterial products via the portal vein into the liver,⁷ increasing inflammation and fibrogenesis. Several studies have proven an association of serologic markers of intestinal barrier dysfunction with worse outcomes of PSC,^8,9 but no studies are reporting intestinal permeability markers in the post-transplant population.

Our study focused on three serologic markers (zonulin, Reg3a, and iFABP) that are considered good markers of impaired intestinal barrier function, each reflecting different aspects of gut epithelial integrity and permeability. The regenerating family member 3 alfa (Reg3a) is a multifunctional protein with antimicrobial and antiapoptotic function, primarily secreted by Paneth cells in the intestine and in the pancreas.¹⁰ Circulating levels of REG3α increase in response to gut epithelial damage and correlate with disease severity in inflammatory gut conditions such as ulcerative colitis. REG3α can translocate into the blood through increased intestinal permeability, making it a soluble marker of gut epithelial integrity and damage.¹¹ The intestinal fatty acid binding protein (iFABP) is found in enterocytes, and contributes to fatty acid transport and metabolism.¹² Elevated serum iFABP levels reflect early epithelial injury and correlate with increased intestinal permeability determined by functional measures of permeability (eg, lactulose/mannitol ratio).^13,14 Zonulin is the only known physiological regulator of intercellular tight junctions and has been shown to correlate with intestinal permeability as well as intestinal inflammation in IBD and could thus be used as a measurement of impaired gut barrier function.^15,16 Fecal calprotectin is a neutrophil-derived protein that indicates the migration of neutrophils to the intestinal mucosa, which occurs during intestinal inflammation. It helps differentiate inflammatory bowel disease from non-inflammatory conditions like irritable bowel syndrome.

The presented study aimed to investigate the association between impaired intestinal permeability and the pathophysiology of rPSC in patients following liver transplantation. To achieve this, we compared serological markers of intestinal permeability in post-LT PSC patients with those in a suitable control group consisting of patients who underwent transplantation for alcoholic liver disease (ALD).

Methods

Patients

The patients who underwent orthotopic liver transplantation (LT) for PSC at the Institute for Clinical and Experimental Medicine in Prague between 1995 and 2021 were included in the study. Exclusion criteria for PSC patients were history of colectomy or other intestinal surgery, active malignancy, active alcohol abuse, BMI >35, pregnancy, or lactation. The control group consisted of patients who underwent LT for ALD with or without hepatocellular carcinoma (HCC). The exclusion criteria for the control group were BMI >35, age >65, active alcohol abuse, active malignancy, pregnancy or lactation, history of HBV or HCV infection, or detectable viremia at the time of sampling, history of colectomy or IBD.

Study Design

We have performed a cross-sectional single-center study. PSC patients were divided based on the presence of rPSC. Demographic data, including age, sex, IBD status, rPSC status, type of immunosuppression, IBD treatment, and retransplantation history, were collected. Based on current guidelines, all PSC patients underwent coloscopy with biopsies. The endoscopic Mayo score (eMayo) was evaluated, and all the biopsies were evaluated for Nancy histological index (NHI). Control group patients underwent coloscopy with no biopsies. Therefore, the Mayo and Nancy indices, as well as fecal calprotectin, were not evaluated in this group. Blood and stool samples were collected and stored at −80°C until analysis. rPSC was diagnosed based on the Mayo criteria proposed by Graziadei et al,¹⁷ and patients have undergone MRCP to evaluate their rPSC status. The authors are accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted following the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics committee of the Institute for Clinical and Experimental Medicine and Thomayer University Hospital, Prague, Czech Republic (n. 31869/20, 10.6.2020). Written informed consent was obtained from each study participant. All organs were donated voluntarily with written informed consent and were conducted in accordance with the Declaration of Istanbul.

Biochemical Analyses

Serum concentrations of intestinal permeability markers were assessed using commercially available kits (Human I-FABP ELISA Kit, MyBiosource, USA; IDK Zonulin Serum ELISA, Immunodiagnostik ^®, Germany; Human Reg3a ELISA, ThermoFisher Scientific, USA), following the manufacturer’s instructions.

Statistics

Associations between serological markers and PSC incidence were determined with a multivariable binary logistic regression model. The data was divided into a train/test dataset to evaluate the accuracy of the multivariate models from their confusion matrix. Baseline characteristics between PSC and control were compared using Wilcoxon rank test. The statistical analyses were performed using R software packages (version 4.2.2) and in-house scripts. Power analysis was performed based on the formula described in Hsieh et al.¹⁸

Results and Discussion

Characteristics of the Group

The clinical characteristics of the study participants are listed in Table 1. A total of 182 liver transplant recipients were enrolled in the study, 113 patients for PSC and 69 patients for ALD with or without HCC. rPSC was diagnosed in 23% of patients (n = 26) and PSC-IBD in 89% of patients (n = 100) in the PSC group. Most of the IBD patients were diagnosed with ulcerative colitis (UC, n = 97) while only three suffered from Crohn’s disease. At the time of sample collection, the majority of the UC patients were in endoscopic remission (eMayo 0, n = 45) or had mild disease activity (eMayo 1, n = 30), fewer had moderate (eMayo 2, n = 11) and severe disease activity (eMayo 3, n = 1). In CD patients, one patient had endoscopic remission, one patient had mild, and one severe disease activity (Table 1). The median age was lower in both PSC groups, reflecting the earlier onset of this disease compared to the manifestation of alcohol cirrhosis. The gender distribution was approximately 1:2 (F/M) in all groups, reflecting the male predominance in PSC. Nine patients in the rPSC group and one patient in the control group had undergone liver retransplantation. We did not observe any elevation of the markers of hepatocellular injury (ALT, AST) in any groups. In contrast, the markers of cholestasis (ALP, GGT, bilirubin) were significantly higher in both PSC groups than in controls. The former two parameters also distinguished between the non-rPSC and rPSC groups. The standard immunosuppression regimen was tacrolimus-based. However, there were some exceptions as displayed in Table 1.

Table 1 Cohort Characteristics. The Values are Given as Median (1st, 3rd Quartile) When Appropriate. For Continuous Variables, the Statistical Significance of the Median Difference Was Calculated by the Kruskal–Wallis Test, and if Significant, Pairwise Post-Hoc Mann–Whitney U-Test Was Performed. For Categorical Variables, the Fisher Exact Test Was Used

Serological Markers of Intestinal Permeability and Inflammation as Predictors of PSC and rPSC

As mentioned in the introduction, all three molecules (Reg3a, iFABP, zonulin) are being investigated as potential markers of intestinal permeability, but they may reflect different aspects of intestinal barrier dysfunction. Therefore, their combined use may provide more comprehensive information. We built a multivariable binary logistic regression models for the prediction of PSC diagnosis independent of recurrence (IP_Model_1), for the prediction of non-rPSC (IP_Model_2), and for the prediction of rPSC (IP_Model_3) using all three permeability markers as predictors. We further included BMI and age as covariates, as the relationship between these variables and intestinal permeability markers has been described.^19,20 The intestinal inflammatory marker calprotectin, a known risk factor for PSC,⁶ was only included among the predictors in Model 3, as it was unavailable in the controls. Model significance was assessed using a log-likelihood test, comparing the full model to a null model that included only the covariates, and the Akaike Information Criterion (AIC). The results of the models are shown in Table 2.

Table 2 GLM Linear Models Based on Intestinal Permeability and Inflammation Markers

The increased probability of PSC occurrence estimated by IP_Model_1 was associated with higher Reg3a serum concentration (OR = 1.01, 95% CI: 1.00–1.02, p = 0.031), while a negative relationship was found for iFABP (OR = 0.998, 95% CI: 0.998–0.9997, p = 0.009), BMI (OR = 0.85, 95% CI: 0.77–0.93, p < 0.001) and age (OR = 0.96, 95% CI: 0.92–1.00, p = 0.035). The effect of serum levels of zonulin was not significant (OR = 0.97, 95% CI: 0.94–1.01, p = 0.123).

In the IP_Model_2, prediction of PSC without recurrence (non-rPSC), the probability of non-recurrence status was associated with lower Reg3a serum concentration (OR = 0.99, 95% CI: 0.99–1.00, p = 0.039), higher age (OR = 1.05, 95% CI: 1.00–1.09, p = 0.036), and higher BMI (OR = 1.15, 95% CI: 1.04–1.27, p = 0.005). All these conditions may reflect a more beneficial health status of non-rPSC subjects. BMI in this group fell within the normal range (median 24.8 kg m-2), while lower Reg3a concentration indicates less inflammatory status.

For IP_Model_3, in contrast to previous models, BMI, age, Reg3A, and iFABP were not significantly associated with rPSC, while both higher serum concentrations of zonulin (OR = 1.06, 95% CI: 1.00–1.14, p = 0.050) and calprotectin (OR = 1.001, 95% CI: 1.000–1.001, p = 0.033) increased the probability of PSC recurrence. In contrast to the non-rPSC subjects, where we found a significant correlation between BMI and serum zonulin (r = 0.23, p = 0.003), no relationship between these two variables was observed in the rPSC subgroup. The association between BMI and zonulin concentrations in serum was described in various pathological conditions, like obesity and obesity-related insulin resistance²⁰ or IBD.¹⁹ Therefore, the independence of BMI and zonulin as predictors in this model suggests that rPSC differs from the non-rPSC in terms of intestinal permeability parameters. As shown previously, LTx does not restore gut microbiota composition⁵ and PSC patients often retain gut dysbiosis, characterized by reduced microbial diversity and increased abundance of pathogenic bacteria, even in a recurrence-free state. The altered microbiota composition may prevent the full restoration of intestinal barrier function and contribute to intestinal inflammation.^21–23

Validated Serological Markers as Predictors of PSC and rPSC

Cholestasis, a typical pathophysiology related to PSC, is associated with elevated serum concentrations of ALP, GGT, and bilirubin. Therefore, we built three multivariable binary logistic regression models to explore the association of these markers with the diagnosis of PSC (ST_Models) (Table 3). ST_Model_1, predicting PSC diagnosis irrespective of recurrence, showed that higher ALP levels were associated with increased odds of PSC (OR = 1.47, 95% CI: 0.99–2.36), although this association was only marginally significant (p = 0.081). GGT levels were significantly inversely associated with PSC (OR = 0.79, 95% CI: 0.61–0.96, p = 0.038), and higher bilirubin was positively associated with PSC (OR = 1.05, 95% CI: 1.01–1.09, p = 0.014). Both lower BMI (OR = 0.87, 95% CI: 0.80–0.95, p = 0.001) and younger age (OR = 0.94, 95% CI: 0.91–0.97, p < 0.001) were significantly associated with PSC diagnosis.

Table 3 GLM Linear Models Based on Validated Serological PSC Markers

ST_Model_2, predicting of PSC without recurrence, revealed that GGT (OR = 1.47, 95% CI: 1.09–2.18, p = 0.033), BMI (OR = 1.10, 95% CI: 1.01–1.20, p = 0.032), and age (OR = 1.06, 95% CI: 1.02–1.10, p = 0.002) were significantly positively associated with non-rPSC diagnosis, whereas bilirubin was inversely associated (OR = 0.95, 95% CI: 0.91–0.99, p = 0.011). ALP was not significantly associated with non-rPSC (OR = 1.04, 95% CI: 0.59–1.85, p = 0.881).

In contrast, ST_Model_3, focused exclusively on rPSC patients, showed that ALP was strongly associated with rPSC (OR = 2.15, 95% CI: 1.04–4.69, p = 0.044), while GGT and bilirubin were not statistically significant. Lower BMI remained significantly associated with rPSC (OR = 0.86, 95% CI: 0.73–0.98, p = 0.040). Age was not associated with rPSC (OR = 1.00, 95% CI: 0.96–1.04, p = 0.956).

Comparison of Predictive Models Based on Validated Serological Markers and Intestinal Permeability Measures

Based on AIC or Log Likelihood criteria of model validity, the performance of each of the three models is comparable when using validated serum markers (ALP, GGT, bilirubin) or intestinal permeability measures (zonulin, Reg3a, iFABP), though the outcomes obtained when using intestinal permeability measures were lower. The best performance was reached for the prediction of PSC per se (ST_Model_1 AIC = 203, IP_Model_1 AIC = 182), followed by models predicting non-rPSC (ST_Model_2 AIC = 183, IP_Model_2 AIC = 167). rPSC prediction was less precise for both datasets (ST_Model_3 AIC = 108, IP_Model_3 AIC = 92).

Limitations of the Study

We are aware of the fact that the observed effects are rather subtle. The size of the cohort, especially the rPSC group, was rather small, which is the limitation given by the rare nature of the disease and the rate of the recurrence.

Conclusion

Our data suggest different intestinal permeability marker signatures associated with uncomplicated and recurrent PSC. These data could serve as a basis for testing on a larger independent validation cohort and, if confirmed, could contribute to the explanation of the mechanisms underlying the PSC pathophysiology as well as post transplantation recurrence of this disease.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

Supported by the Ministry of Health of the Czech Republic in cooperation with the Czech Health Research Council under project No. NU21J-06-00027 and NU22-06-00269. All rights reserved. Supported by Ministry of Health, Czech Republic – conceptual development of research organization (“Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“).

Disclosure

All authors declare no conflicts of interest in this work.

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Chronic lymphocytic leukaemia (CLL) is the most common adult blood cancer in the western world, and it predominantly affects older adults. Most people are diagnosed after the age of 70, but increasing numbers of younger people, some under 60, are also being affected.

CLL starts when a type of immune cell called a B cell – normally responsible for producing antibodies – becomes cancerous. This not only stops it from working properly, but also weakens the rest of the immune system.

For many people, CLL begins as a slow-moving, low-grade disease that doesn’t need immediate treatment. These patients are placed on “active monitoring,” where they’re regularly checked for signs of progression. Others, especially those with more aggressive forms of the disease, will need immediate and targeted treatment to destroy the cancer cells.

But regardless of the stage, CLL involves a prolonged and often unpredictable course. It’s associated with a higher risk of infections, secondary cancers and a heavy symptom burden that can affect quality of life for years.

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People on active monitoring often find themselves in a kind of medical limbo: well enough not to need treatment, but not well enough to feel secure. Fatigue, anxiety, social isolation and fear of infection are common. For those receiving treatment, side effects including nausea, bleeding, diarrhoea and extreme tiredness can make everyday life even more challenging.

Because CLL weakens the body’s ability to fight infection, many people begin avoiding places where germs might spread: busy shops, family gatherings, even the gym. But while this instinct is understandable, it can come at a cost. Over time, isolation and inactivity can chip away at physical fitness, reduce resilience and make it harder to recover from illness or cope with stress.

The role of exercise

Exercise is good for everyone but for people living with CLL, it can be life-changing. Our research shows that physical activity is strongly linked to fewer symptoms and a better quality of life. Fatigue, the most common and often most debilitating symptom, was significantly lower in people who stayed active. Many also reported reduced pain and a greater sense of physical wellbeing.

Cancer-related fatigue isn’t just feeling a bit tired. It’s a deep, persistent exhaustion that doesn’t improve with sleep or rest. The exact biological reasons behind it aren’t fully understood, but one thing is clear: regular movement helps. People who are more active tend to feel better – and live better.

The good news is that even gentle activity can make a difference. Low-intensity activities are safe for almost everyone and come with meaningful health benefits. Walking, yoga, swimming – anything that gets you moving – can help ease symptoms. In fact, research shows that just 12 weeks of regular exercise can reduce fatigue and improve day-to-day wellbeing.

People with additional health concerns, such as heart disease, diabetes or bone conditions, should take extra care. It’s always a good idea to speak to a doctor or physiotherapist before starting a new routine. The PAR-Q+ (physical activity readiness questionnaire) is a helpful tool to assess whether it’s safe to begin exercising.

Once cleared, the goal is to work up to the recommended activity levels: 150–300 minutes of moderate activity a week (like brisk walking or cycling) or 75–150 minutes of vigorous activity (like jogging or swimming), along with two sessions of muscle-strengthening activities per week. Start slowly and build gradually.

Because people with CLL are immunocompromised, it’s important to reduce infection risks while staying active. That might mean exercising outdoors, avoiding crowds, wearing a mask, or choosing quieter times at the gym. But, as long as precautions are taken, the benefits of movement far outweigh the risks.

Benefits of keeping active

In one of our pilot studies, people with CLL who had not yet started treatment showed smaller increases in tumour cell counts after 12 weeks of exercise. Their immune systems also appeared more robust, with stronger responses to abnormal cells. This research is still in its early stages, but it’s encouraging to see that exercise doesn’t appear to accelerate disease progression – and might even help to slow it.

The biggest improvements were seen in people who started off with the worst symptoms or poorest physical condition. In other words, those with the most to gain, gained the most. Older adults, in particular, seemed to benefit from even modest activity.

People receiving treatment were generally less active and reported lower quality of life than those who weren’t but their symptom levels were similar. That suggests physical activity might offer especially meaningful benefits for people going through treatment.

Exercise is already a well-established part of care for people with solid tumours such as breast or bowel cancer.

What’s different about CLL is that many people don’t receive treatment for years – yet still experience symptoms and lower quality of life. Our study shows that physical activity matters just as much for this group. Whether someone is on active monitoring or undergoing treatment, staying active can help ease symptoms, boost energy and improve daily life.

It’s a powerful reminder that even small steps can make a big difference and that living well with CLL isn’t just about waiting for treatment. It’s about reclaiming strength, mobility and agency, one movement at a time.

Alliance researchers and partners, including Embrapa, Brazil’s largest agricultural research organization, launched a rapid response plan to slow the spread and mitigate potentially devastating consequences for food security and livelihoods.

In 2023, cassava farmers in remote French Guiana watched in shock as their crops withered. They pulled dilapidated stems from the ground. Instead of unearthing massive root bunches, which are cornerstones of diets across South America, they found nothing larger than carrots. Researchers identified the problem as cassava witches’ broom disease, provoked by a little-understood fungus, after analyzing results from a 2024 expedition to French Guiana. It was the first report of the disease in the Americas.

Around the same time, cassava witches’ broom disease was also observed in neighboring Brazil. In 2025, the first two confirmed reports in Latin America’s largest country, in March and May, were at least 1,000 km apart.

Scientists at the Alliance of Bioversity International and CIAT (The Alliance) and the Brazilian Agricultural Research Organization (Embrapa) launched a rapid-response plan in June 2025 to mitigate the spread of disease to formalize collaboration efforts that began early in the year. The immediate concern is to slow or contain the spread of witches’ broom and avoid a continental food-security disaster.

“We are facing an emergency,” said Paulo Melo, a researcher at Embrapa’s International Relations Office, during a strategizing meeting at the Alliance’s Americas headquarters in Colombia.

“Cassava is an everyday food in Brazil. If producers, particularly many women and Indigenous communities, don’t have cassava roots, they won’t have anything to eat or anything to make money from.”

Northeastern Brazil is one of the world’s largest consumers of cassava. Brazil, by far, is Latin America’s largest cassava producer. CWBD, as cassava witches’ broom disease is known for its English initials, has plant infection rates as high as 90% in Southeast Asia, where the Alliance first identified the fungal pathogen as the cause of the disease in 2023. Early reports point to staggeringly high cassava mortality in Brazil and French Guiana.

Cassava is a critical source of calories, carbohydrates, vitamins and micronutrients. Easy to grow under even the harshest conditions, its roots and the flour developed from them play an outsized role in diets. Cassava is central to the food security of about 800 million people globally, particularly smallholder farmers. Many African countries consume more cassava per capita than even Brazil. So far, CWBD has not been reported in Africa.

CWBD’s spread in Brazil is additionally concerning because the Amazon is cassava’s center of origin, meaning it was first domesticated there and is home to the plant’s greatest natural biodiversity, including at least 98 wild relatives. Because the disease is new to South America, scientists believe there is little natural resistance to it.

While a separate line of research is needed, CWBD likely jumped from a yet unknown host in Southeast Asia to cacao, avocado and cassava, raising the concern that it could jump back from cassava to cacao in South America, which is also cacao’s center of origin. Alliance researchers expect to understand cacao’s susceptibility to the fungus that causes witches’ broom, Ceratobasidium theobromae.

Science for prevention

With CWBD flying across South America, the race is on to understand the extent of the threat. The Alliance-Embrapa collaboration has several immediate actions aimed at containing witches’ broom. Ultimately, researchers hope to find a way to treat CWBD, or understand the natural resistance that some cassava varieties have to the pathogen and transfer those characteristics into new breeding lines.

There is currently no treatment for CWBD. The only way to eradicate it is by collecting all infected plants in an area and burning them. But because some infected plant stems remain viable for planting – ones that don’t show outward signs of infection – transmission is believed to be strongly linked to trade in cassava stakes, which are the primary material for cassava propagation.

“Embrapa’s main concern now is stopping witches’ broom so it does not put the lives and livelihoods of millions of people at risk,” said Jane Simoni, at Embrapa’s International Relations Office.

“This work is about South-South collaboration and fighting hunger and poverty. This problem is aimed directly at the most vulnerable people in very poor regions of Latin America.”

Immediate priorities are to map the distribution and severity of CWBD in northeastern Brazil. For this, scientists will need to implement a standardized set of molecular tools first developed for Southeast Asia, that can be used for in-field detection of C. theobromae. Alliance researchers aim to deploy this technology in the region and provide Embrapa’s large network of experts with detection tools.

Scientists also want to map cassava diversity and urgently collect wild cassava relatives and cassava landraces – the varieties farmers have selected and cultivated over generations. But the key is for researchers to get to the plants before they are infected.

Brazil maintains large collections of both cassava varieties and wild relatives. But Embrapa’s Melo said new collection expeditions should be launched soon. Part of the Alliance-Embrapa collaboration would include bringing new material to the Alliance’s gene bank in Colombia, Future Seeds, which has almost 6,000 cassava accessions (plant samples) from 28 countries, including 1,557 from Brazil.

The accessions must be kept alive and replicated in vitro, a delicate task. Plant samples must be quickly transported to suitable facilities to ensure they stay alive.

Future Seeds researchers distribute several new varieties of cassava every year but breeding new varieties is time-consuming. Past analyses by the Alliance identified sources of resistance to brown streak disease in cassava, a major threat in Africa. Brown streak disease research is part of ongoing Alliance research.

“It’s hard to understate the importance of the cassava germplasm collections,” said Jonathan Newby, the leader of the Alliance’s cassava research team.

“These form the genetic backbone for breeding new varieties and finding and understanding natural resistance to disease. It’s critical that material facing threats from witches’ broom is collected, screened for disease, and quickly transported to in vitro storage facilities for research.”

Out of about 300 cassava varieties they tested, the Alliance’s cassava breeders have found multiple varieties that display resistance to witches’ broom in Southeast Asia. Cassava in Future Seeds and other gene banks may also prove to have some level of resistance. While the pathogen is new to South America, it is unlikely that many plants have natural resistance, but scientists hope some natural resistance exists.

“This all takes time and resources,” said Embrapa’s Simoni. “You can’t do an experiment this week and have the results next week. That’s not how it works. We’re working to quickly bring together as many international experts as possible to confront this challenge together. We also need to ensure Africa is prepared, as the impact of witches’ broom there could be profound. We have to act now. This is science for prevention.”

The witches’ broom work builds on decades of collaboration between the Alliance and Embrapa, which recently entered a new phase focused on further strengthening ties between the organizations.

“The Alliance and Embrapa expect to make significant contributions not only to witches’ broom response and research but on other mutual interests, including food security, climate action and food system transformation,” said Maya Rajasekharan, the Alliance’s Managing Director for the Americas.

A fastidious fungus

Alliance scientists and partners are at the forefront of CWBD’s troubling rise in recent years. In addition to identifying C. theobromae as the cause of witches’ broom in Southeast Asia (which was previously thought to be a bacterial or viral infection), researchers also grew the fungus in laboratory conditions, a first-time feat that took researchers two months. This allows researchers to better understand how the fungus functions, test it under controlled conditions on cassava plants, potentially devise treatment methods, and breed CWBD-resistant varieties.

“It’s from a family called ‘fastidious fungi’ and it lives up to its name,” said Wilmer Cuellar, who leads the Alliance’s Crop Protection Team.

“It’s hard to identify, very difficult to isolate, and scientists needed decades to associate it with witches’ broom.”

Once Cuellar’s lab sequenced C. theobromae, they discovered it had been infecting cassava in Southeast Asia since at least the 2000s, and cacao since the 1960s. The incidence of witches’ broom disease appears cyclical and often flares up after long rainy seasons. The region is currently facing another major outbreak that started in 2022 in at least a half-dozen countries that produce cassava for starch, a multibillion-dollar business critical to smallholder farmers there.

Cuellar is concerned C. theobromae may behave differently in the Amazon. Humid conditions are far more constant there than in Southeast Asia, potentially creating an environment where the fungus could thrive and quickly spread. While predicting where CWBD will arrive next, it could potentially continue its path through South America’s northern Atlantic countries, including Colombia, which has its largest growing areas in the country’s north.

“The terrain is totally different in South America and the fungus will likely fly,” Cuellar said. “We’re already seeing it spread rapidly with more severe symptoms. This is a big problem.”