Liver Resection Improves Survival in Patients with Early Multinodular HCC

A recent study published has cast doubt on the 2022 Barcelona Clinic Liver Cancer (BCLC) algorithm that currently advises against liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules, each 3 cm or smaller. This research published in the Journal of American Medical Association suggests that liver resection should actually be considered a primary treatment option for these patients with improved survival rates when compared to other therapies.

The study compared the effectiveness of liver resection, percutaneous radiofrequency ablation (PRFA) and transarterial chemoembolization (TACE) in treating early multinodular HCC. This retrospective analysis utilized data from the HE.RC.O.LE.S register which included a total of  5,331 patients who underwent LR and the ITA.LI.CA database which encompassed a total of 7,056 patients treated with PRFA or TACE.

A matching-adjusted indirect comparison (MAIC) method was employed to balance the data and account for potential confounding factors among the three treatment groups. The analysis covered patient data from multiple centers which spanned between 2008 to 2020, with data analysis performed from January to December 2023.

The study analyzed a group of 720 patients with early multinodular HCC, of whom 543 were male (75.4%) and 177 female (24.6%) with 350 individuals older than 70 years (48.6%). Among these patients, 296 patients received LR, 240 underwent PRFA and 184 were treated with TACE.

After applying the MAIC method, LR demonstrated superior survival rates at 1, 3, and 5 years—89.11%, 70.98% and 56.44%, respectively. Also, PRFA showed survival rates of 94.01% at 1 year, 65.20% at 3 years and 39.93% at 5 years. TACE expressed 1-year, 3-year and 5-year survival rates of 90.88%, 48.95% and 29.24%, respectively.

The multivariable Cox survival analysis in the weighted population revealed a significant survival advantage for LR over PRFA and TACE. Also, the hazard ratio (HR) for PRFA when compared to LR which was 1.41 (95% CI, 1.07-1.86; P = .01) and for TACE against the LR, the HR was 1.86 (95% CI, 1.29-2.68; P = .001). The competing risk analysis also confirmed a lower risk of cancer-related death with LR when compared to the other treatments. The findings suggest that for patients with early multinodular HCC who are not eligible for liver transplantation, should undergo liver resection as the primary treatment option. PRFA and TACE should be considered alternative treatments when LR is not feasible.

Source:

Vitale, A., Romano, P., Cillo, U., Busti, M., Nezi, G., De Carlis, R., Ratti, F., Milana, F., Donadon, M., Marinelli, L., Razionale, F., Carissimi, F., Scotti, M. A., Ciuli, C., De Peppo, V., Russolillo, N., Giuffrida, M., De Stefano, F., … Peverada, J. (2024). Liver Resection vs Nonsurgical Treatments for Patients With Early Multinodular Hepatocellular Carcinoma. In JAMA Surgery. American Medical Association (AMA). https://doi.org/10.1001/jamasurg.2024.1184

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Adiposity in childhood affects risk of breast cancer by changing breast tissue composition, study suggests

Breast cancer is the most common cancer in women worldwide. With rates continuing to rise, there is an urgent need to identify new modifiable breast cancer risk factors. New research led by the University of Bristol suggests that higher adiposity in childhood leads to less dense breast tissue forming, which results in a reduced breast cancer risk. However, further research is needed to understand the mechanism of the overall protective effect of childhood adiposity to identify new targets for intervention and prevention.

The study, published in Nature Communications, explored the unexplained protective effect of higher body size in childhood on breast cancer risk using Mendelian randomization, to examine the connections between body size in childhood and adulthood, puberty onset timing, breast tissue density, and breast cancer risk.

The research team looked in more detail at one of the most plausible connections – breast tissue density. Higher breast density, measured with a mammogram, is an established risk factor for breast cancer, and is known to be affected by body size. When a mammogram shows dense breast tissue, it means there’s a higher proportion of glandular or fibrous tissue compared to fatty tissue. Conversely, when breast tissue is less dense, there’s more fatty tissue relative to glandular or fibrous tissue.

There is growing evidence that adiposity in childhood can lead to various adult diseases. However, in the case of breast cancer risk, observational epidemiological studies, and more recently studies that used genetic data, have shown that higher body size in childhood decreases the risk of developing this disease.

The researchers used data from genome-wide association studies (GWAS) and Mendelian Randomization analysis. They were able to demonstrate that over 50 per cent of the protective effect that higher childhood body size has on breast cancer risk is explained by the changes in dense breast tissue.

The research team suggest that a higher body size in childhood, around the start of puberty, leads to less dense tissue forming in the breast. The dense area is the part of the breast (glandular and fibrous tissue) where cancer normally develops.

Having less dense area in the breast subsequently leads to a reduced breast cancer risk in adulthood. This is the proposed mechanism by which higher childhood body size decreases breast cancer risk. However, the biological mechanism/pathway is more complex than this, and identifying smaller steps in this process using genetic data is a part of uncovering the basis of this unexplained causal relationship.

Dr Marina Vabistsevits from the University of Bristol’s MRC Integrative Epidemiology Unit (MRC IEU) and Bristol Medical School: Population Health Sciences (PHS), and corresponding authors, said: “Studying the mechanism of childhood adiposity protective effect is important, as weight gain in childhood cannot be considered to be a preventative measure for breast cancer.

“Investigating how this overall ‘protection’ works is crucial to understand the underlying mechanisms leading to and preventing cancer, as it might help identify new targets for intervention and prevention.”

Reference:

Vabistsevits, M., Davey Smith, G., Richardson, T.G. et al. Mammographic density mediates the protective effect of early-life body size on breast cancer risk. Nat Commun 15, 4021 (2024). https://doi.org/10.1038/s41467-024-48105-7.

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Restricted first-trimester fetal size Tied to mental and Psychomotor Developmental Delay in childhood: Study

Restricted first-trimester fetal size tied to mental and psychomotor developmental delay in childhood suggests a study published in the BMC Medicine.

Early pregnancy is a critical window for neural system programming; however, the association of first-trimester fetal size with children’s neurodevelopment remains to be assessed. This study aimed to explore the association between first-trimester fetal size and children’s neurodevelopment and to examine whether intrauterine accelerated growth could compensate for the detrimental effects of first-trimester restricted growth on childhood neurodevelopment. The participants were from a birth cohort enrolled from March 2014 to March 2019 in Wuhan, China. A total of 2058 fetuses with crown to rump length (CRL) (a proxy of first-trimester fetal size) measurements in the first trimester and neurodevelopmental assessment at age 2 years were included. We measured the first-trimester CRL and defined three fetal growth patterns based on the growth rate of estimated fetal weight from mid to late pregnancy. The neurodevelopment was assessed using the Bayley Scales of Infant Development of China Revision at 2 years. Results: Each unit (a Z score) increase of first-trimester CRL was associated with increased scores in mental developmental index (MDI) (adjusted beta estimate = 1.19, (95% CI: 0.42, 1.95), P = 0.03) and psychomotor developmental index (PDI) (adjusted beta estimate = 1.36, (95% CI: 0.46, 2.26), P < 0.01) at age 2 years, respectively. No significant association was observed between fetal growth rate and PDI. For children with restricted first-trimester fetal size (the lowest tertile of first-trimester CRL), those with “intrauterine accelerated growth” pattern (higher growth rates) had significantly higher MDI (adjusted beta estimate = 6.14, (95% CI: 3.80, 8.49), P < 0.001) but indistinguishable PDI compared to those with “intrauterine faltering growth” pattern (lower growth rates). Main limitations of this study included potential misclassification of gestational age due to recall bias of the last menstrual period and residual confounding. The current study suggests that restricted first-trimester fetal size is associated with mental and psychomotor developmental delay in childhood. However, in children with restricted first-trimester fetal size, intrauterine accelerated growth was associated with improved mental development but had little effect on psychomotor development. Additional studies are needed to validate the results in diverse populations.

Reference:

Chen, X., Liu, H., Li, Y. et al. First-trimester fetal size, accelerated growth in utero, and child neurodevelopment in a cohort study. BMC Med 22, 181 (2024). https://doi.org/10.1186/s12916-024-03390-3

Keywords:

Restricted, first-trimester, fetal size, mental, psychomotor, developmental delay, childhood, study, BMC Medicine, Chen, X., Liu, H., Li, Y, Child neurodevelopment, First-trimester fetal size, Intrauterine accelerated growth, Cohort study

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Mucoadhesive antifungal delivery vehicles as effective as topical agents for the treatment of oral candidiasis: Study

Mucoadhesive antifungal delivery vehicles are as effective as topical agents for the treatment of oral candidiasis suggests a study published in Oral Diseases.

This systematic review and meta-analysis aimed to evaluate the clinical and mycological effectiveness of mucoadhesives as vehicles for drugs or natural products in the treatment of oral candidiasis. The search for articles was carried out in the Medline/PubMed, SCOPUS, EMBASE, Web of Science, Cochrane Library, and SciELO databases before August 2023. We selected the studies, extracted the data, evaluated the study quality, graded the evidence, performed the risk of bias, and carried out meta-analysis. Results: A total of 389 potentially relevant articles were identified, and 11 studies (1869 participants) met the inclusion criteria of the systematic review. The overall risk of bias was considered low. The most common presentation of mucoadhesives was tablets, with miconazole being the most frequently drug used in the delivery system. Mucoadhesives demonstrated comparable efficacy with topical or systemic antifungal agents, with no significant differences between treatments in terms of clinical (RR = 0.907; 95CI = 0.3–1.297; p = 0.591; I2 = 64.648) or mycological (RR = 0.95; 95CI = 0.667–1.360; p = 0.789; I2 = 73.271) efficacy. Mucoadhesives may be a suitable alternative to conventional treatments, with the advantage of reducing the frequency of application by up to 5 times and the daily dosage by up to 20 times.

Reference:

Sugio, C. Y. C., Garcia, A. A. M. N., Kitamoto, K. A. A., Santiago Júnior, J. F., Soares, S., Porto, V. C., Urban, V. M., Ferrari, P. C., Fernandes, M. H., & Neppelenbroek, K. H. (2024). Mucoadhesive delivery systems for oral candidiasis treatment: A systematic review and meta-analysis. Oral Diseases, 00, 1–17. https://doi.org/10.1111/odi.14928

Keywords:

Mucoadhesive antifungal delivery vehicles are as effective as topical agents for the treatment of oral candidiasis suggests a study published in Oral Diseases.

This systematic review and meta-analysis aimed to evaluate the clinical and mycological effectiveness of mucoadhesives as vehicles for drugs or natural products in the treatment of oral candidiasis. The search for articles was carried out in the Medline/PubMed, SCOPUS, EMBASE, Web of Science, Cochrane Library, and SciELO databases before August 2023. We selected the studies, extracted the data, evaluated the study quality, graded the evidence, performed the risk of bias, and carried out meta-analysis. Results: A total of 389 potentially relevant articles were identified, and 11 studies (1869 participants) met the inclusion criteria of the systematic review. The overall risk of bias was considered low. The most common presentation of mucoadhesives was tablets, with miconazole being the most frequently drug used in the delivery system. Mucoadhesives demonstrated comparable efficacy with topical or systemic antifungal agents, with no significant differences between treatments in terms of clinical (RR = 0.907; 95CI = 0.3–1.297; p = 0.591; I2 = 64.648) or mycological (RR = 0.95; 95CI = 0.667–1.360; p = 0.789; I2 = 73.271) efficacy. Mucoadhesives may be a suitable alternative to conventional treatments, with the advantage of reducing the frequency of application by up to 5 times and the daily dosage by up to 20 times.


Reference:

Sugio, C. Y. C., Garcia, A. A. M. N., Kitamoto, K. A. A., Santiago Júnior, J. F., Soares, S., Porto, V. C., Urban, V. M., Ferrari, P. C., Fernandes, M. H., & Neppelenbroek, K. H. (2024). Mucoadhesive delivery systems for oral candidiasis treatment: A systematic review and meta-analysis. Oral Diseases, 00, 1–17. https://doi.org/10.1111/odi.14928


Keywords:

Mucoadhesive, antifungal, delivery, vehicles, effective, topical, agents, treatment, oral candidiasis, study, Sugio, C. Y. C., Garcia, A. A. M. N., Kitamoto, K. A. A., Santiago Júnior, J. F., Soares, S., Porto, V. C., Urban, V. M., Ferrari, P. C., Fernandes, M. H., & Neppelenbroek, K. H

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Quitting smoking during pregnancy may have a positive effect on placental weight: Study

The researchers in Bergen and Exeter used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and a similar study in the UK, the Avon Longitudinal Study of Parents and Children (ALSPAC), to investigate the relationship between smoking and placental weight. The aim was to determine to what extent expectant mothers who quit smoking could impact the weight of the placenta at the time of birth.

The study was recently published in the journal BMC Pregnancy and Childbirth.

Previous research has demonstrated a clear relationship between smoking and reduced birth weight in offspring, likely due to impaired placental function resulting from smoking. However, whether smoking affects the weight of the placenta was controversial and debated among specialists.

Heavier placenta and fetal vulnerability

The researchers used genetic analyses to solve this enigma and found increased placental weight in women who continued to smoke throughout pregnancy compared to those who quit smoking. The study revealed that the placenta increased by 182 g for mothers smoking in the first trimester and 202 g for those smoking until the end of pregnancy. But while a large placenta is usually associated with healthy pregnancy, the researchers found that smoking was causing a lower birth weight relative to the weight of the placenta.

This mismatch may be a sign of an increased vulnerability for the fetus and suggests that the placenta tries to compensate for the harmful effect of smoking by increasing its weight to match the demands of the fetus.

Quitting helps restore the balance

Cathrine Ebbing is Professor at the Department of Clinical Science, UiB, and fetal medicine specialist at Haukeland University Hospital. She did not directly participate in the study and provides her expert commentary. “A malfunctioning placenta leading to growth restriction of the fetus is dangerous and can cause long-term health consequences for the mother and child. The study by our colleagues in Bergen and Exeter is remarkable as it provides strong causal evidence that smoking is directly harmful to the development of the placenta. It is also encouraging and motivating as it shows that quitting smoking during pregnancy has a direct positive effect on the balance between placental weight and birthweight, with possible effects on the health of both mother and child.”

Reference:

Jaitner A, Vaudel M, Tsaneva-Atanasova K, Njølstad PR, Jacobsson B, Bowden J, Johansson S, Freathy RM. Smoking during pregnancy and its effect on placental weight: A Mendelian randomization study. medRxiv [Preprint]. 2023 Aug 25:2023.08.24.23294537. doi: 10.1101/2023.08.24.23294537. 

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Respiratory drive heterogeneity linked to systemic inflammation and vascular permeability in ARDS: Study

Recently published research paper investigates the correlation between systemic inflammation, vascular permeability markers, respiratory drive, and clinical outcomes in acute respiratory distress syndrome (ARDS). The study aims to understand how these factors contribute to the heterogeneity of respiratory drive in ARDS patients and their impact on clinical outcomes. The paper includes detailed methods and results obtained from a multicenter trial, where ARDS patients were enrolled and relevant data and plasma biomarkers were collected for the study.

Study Findings

The results indicate that 54.8% of the included ARDS patients had detectable respiratory drive, and markers of vascular permeability and systemic inflammation were found to be independently associated with higher respiratory drive, even after accounting for other factors such as acid–base state, oxygenation, respiratory mechanics, and sedation depth. The study observed that sedation depth was significantly associated with respiratory drive, and this relationship might be explained in part by differences in inflammation and vascular permeability.

It was found that patients with moderate respiratory drive had lower mortality compared to those with either lower or higher drive. The paper also delves into potential mechanisms by which vascular permeability and systemic inflammation influence ventilatory control, impacting respiratory drive in critical illness. However, the study acknowledges several limitations, including its observational nature, the complex and bidirectional relationship between inflammation, endothelial injury, and respiratory drive, and the absence of some relevant measurements such as pain.

Study Implications

Overall, the study provides valuable insights into the association between systemic inflammation, vascular permeability, and respiratory drive in ARDS patients. It highlights the potential impact of targeting specific levels of respiratory drive in clinical care and emphasizes the need for further research to understand the complex pathways modulating control of breathing, inflammation, and endothelial barrier function in critically ill patients.

This research contributes to the understanding of respiratory drive heterogeneity in ARDS patients and sheds light on the potential implications for clinical care and future research in this area.

Key Points

– The research paper aims to investigate the correlation between systemic inflammation, vascular permeability markers, respiratory drive, and clinical outcomes in acute respiratory distress syndrome (ARDS) patients. The study involved a multicenter trial with ARDS patients where relevant data and plasma biomarkers were collected.

– The findings indicate that markers of vascular permeability and systemic inflammation were independently associated with higher respiratory drive in ARDS patients, even after considering factors such as acid–base state, oxygenation, respiratory mechanics, and sedation depth. Patients with moderate respiratory drive had lower mortality compared to those with either lower or higher drive. The study also explores potential mechanisms by which vascular permeability and systemic inflammation influence ventilatory control in critical illness.

– The study suggests the importance of targeting specific levels of respiratory drive in clinical care and the need for further research to understand the complex pathways modulating control of breathing, inflammation, and endothelial barrier function in critically ill patients. It contributes valuable insights into respiratory drive heterogeneity in ARDS patients and highlights implications for clinical care and future research in this area.

Reference –

Baedorf-Kassis, E., Murn, M., Dzierba, A.L. et al. Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome. Crit Care 28, 136 (2024). https://doi.org/10.1186/s13054-024-04920-4

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Groundbreaking study shows novel peel combination as safe and effective for hand lentigines

USA: In a groundbreaking study published in Dermatologic Surgery, dermatologists have unveiled a promising new treatment for hand lentigines, or age spots. The research indicates that a series of three chemical peels, combining 15% trichloroacetic acid (TCA) with 3% glycolic acid (GA), prove to be effective and safe in reducing the appearance of these common skin blemishes.

The study stated that a series of three 15% TCA + 3% GA peels are safe and effective in treating hand lentigines.

“Patients who received a series of TCA + GA peels over three treatments at intervals of 4 weeks showed significant improvements compared to untreated hands,” the researchers reported. They noted that the procedure was well-tolerated, with no adverse events observed and minimal pain reported.

Hand lentigines, characterized by small, dark spots on the skin, are often associated with aging and prolonged sun exposure. While various treatments exist, finding a safe and effective approach, particularly for the delicate skin of the hands, has been a challenge.

Improving the appearance of lentigines on the hands is an important component of hand rejuvenation. Soft tissue fillers revolumize hands but do not address pigmentary changes. Kachiu Lee, Department of Dermatology, Temple University, Philadelphia, Pennsylvania, and colleagues aimed to investigate the efficacy of a 15% trichloroacetic acid + 3% glycolic acid combination peel in improving the appearance of hand lentigines.

For this purpose, the researchers performed a prospective evaluator-blinded, split-hand study using a 15% TCA + 3% GA peel for treating hand lentigines. Subjects received three treatments at 4-week intervals on one hand, with the other hand serving as an untreated control.

Final photographs were taken 12 weeks following the last treatment. Improvement in hand lentigines was graded using a 5-point scale by two blinded board-certified dermatologists. 90% of the patients completed the study; the mean age was 64.4 years.

The study led to the following findings:

  • The mean pain scores were 3.8 on a 10-point scale (1 = no pain, 10 = extremely painful).
  • Blinded evaluators correctly identified the after-treatment photographs in 88% of the patients.
  • Physician and patient-graded mean improvement of lentigines was significant for treated versus control hands.
  • There were no adverse events.

The findings showed that a series of chemical peels (15% TCA + 3% GA) offer an effective and safe treatment for improving the appearance of lentigines in the hands. It is a cost-effective option versus energy-based devices and has fewer side effects and downtime compared with cryotherapy.

“This cosmetic treatment can be combined with other modalities, such as soft tissue fillers aimed at revolumization, to improve the overall appearance of photoaged hands,” the researchers concluded.

These findings represent a significant advancement in dermatology, offering dermatologists and patients a non-invasive and reliable option for addressing hand lentigines. With further research and clinical validation, triple peels may soon become a standard treatment modality, helping individuals reclaim confidence in the appearance of their hands and overall skin health.

Reference:

Alajmi, Ali MD*; Niaz, Ghassan MD*,†; Chen, Christine BA‡; Lee, Kachiu MD, MPH*,§. A 15% Trichloroacetic Acid + 3% Glycolic Acid Chemical Peel Series Improves Appearance of Hand Lentigines: An Evaluator-Blinded, Split-Hand Prospective Trial. Dermatologic Surgery 50(5):p 467-470, May 2024. | DOI: 10.1097/DSS.0000000000004114

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Cortisol levels not glycated haemoglobin at time of admission to ICU linked to mortality: Study

Cortisol levels not glycated hemoglobin at time of admission to ICU linked to mortality suggests a study published in the Saudi Medical Journal.

A study research the effects of blood cortisol and hemoglobinA1c (HBA1C) levels on mortality in patients admitted to the intensive care unit (ICU) and whether these factors could be used as reliable indicators for mortality risk assessment in these patients. After receiving approval from the ethics committee, 79 patients admitted to ICU were included in the study. From patient files, we collected data on demographics (age, gender), presence of diabetes mellitus, and levels of cortisol, HbA1C, glucose, and lactate measured during hospitalization, along with acute physiology and chronic health evaluation (APACHE) II scores calculated within the first 24 hours. In our study, we planned to investigate the relationship between patients’ cortisol and HbA1C levels and mortality. RESULTS: A total of 79 patients were included in the study. The mortality rate of the patients included in the study was 65.8%. In the model established with all variables, only cortisol level (p=0.017) and APACHE II score (p=0.005) were defined to affect mortality. Cortisol levels at the time of admission to the ICU were found to affect mortality and can be considered a predictive factor, while HBA1C levels showed no such effect. Our findings indicate that neither cortisol nor HBA1C levels had an impact on the duration of mechanical ventilation or length of stay in the ICU.

Reference:

Sen, Oznur, et al. “Effect of Cortisol and Glycosylated-hemoglobin Levels On Mortality in Intensive Care Unit.” Saudi Medical Journal, vol. 45, no. 5, 2024, pp. 476-480.

Keywords:

Cortisol levels, glycated, hemoglobin, time, admission, ICU, linked, mortality, study, Sen, Oznur

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Sleep apnea linked to memory and thinking problems, reveals study

People who experience sleep apnea may be more likely to also have memory or thinking problems, according to a preliminary study released today, March 3, 2024, that will be presented at the American Academy of Neurology’s 76th Annual Meeting taking place April 13-18, 2024, in person in Denver and online. The study shows a positive association but did not determine whether sleep apnea causes cognitive decline.

Sleep apnea is when people stop and restart breathing repeatedly during sleep which can lower oxygen levels in the blood. Symptoms include snorting, gasping and breathing pauses. People with the disorder may also experience morning headaches or have trouble focusing on tasks.

“Sleep apnea is a common disorder that is often underdiagnosed, yet treatments are available,” said study author Dominique Low, MD, MPH, of Boston Medical Center in Massachusetts, and a member of the American Academy of Neurology. “Our study found participants who had sleep apnea symptoms had greater odds of having memory or thinking problems.”

The study involved 4,257 people. Participants completed a questionnaire asking about sleep quality as well as memory and thinking problems. For sleep, participants were asked about snorting, gasping or breathing pauses in their sleep. For memory and thinking, participants were asked questions related to difficulty remembering, periods of confusion, difficulty concentrating or problems with decision making.

Of all participants, 1,079 reported symptoms of sleep apnea. Of those with symptoms, 357 people, or 33%, reported memory or thinking problems compared to 628 people, or 20% of people without sleep apnea symptoms.

After adjusting for other factors that could affect memory and thinking problems, such as age, race, gender and education, researchers found that people who reported sleep apnea symptoms were about 50% more likely to also report having memory or thinking problems compared to people who did not have sleep apnea symptoms.

“These findings highlight the importance of early screening for sleep apnea,” said Low. “Effective treatments like continuous positive airway pressure (CPAP) machines are readily available. Quality sleep, along with eating a healthy diet, regular exercise, social engagement and cognitive stimulation, may ultimately reduce a person’s risk of thinking and memory problems, improving their quality of life.”

Reference:

Sleep apnea symptoms linked to memory and thinking problems, American Academy of Neurology, Meeting: 2024 American Academy of Neurology’s 76th Annual Meeting.

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SEQUOIA-HCM trial meets primary endpoint in obstructive hypertrophic cardiomyopathy

Even though mortality and hospitalisation rates have improved, the quality of life for those living with hypertrophic cardiomyopathy (HCM) can be compromised with limiting symptoms such as exertional dyspnoea and decreased exercise capacity. A major cause of this in HCM patients is left ventricular outflow tract (LVOT) obstruction, which results in elevated intracardiac pressures. This study demonstrated that aficamten enhanced HCM patients’ exercise capacity with significant improvement in peak oxygen uptake (pVO2), improvement in limiting symptoms, and decreases in LVOT pressure gradients. The late breaking research presented at Heart Failure 2024, a scientific congress of the European Society of Cardiology (ESC).

“The SEQUOIA-HCM trial demonstrated that aficamten can reliably and safely eliminate LVOT obstruction in patients with obstructive HCM using a simple and stepwise dosing regimen, and was associated with substantial improvements in clinically relevant endpoints such as exercise capacity and symptoms,” said principal investigator Professor Martin Maron of the Lahey Hospital and Medical Center, Burlington, Massachusetts, US. “HCM patients are often on multiple medications, which frequently provide suboptimal benefit, while aficamten was highly effective at providing clinical improvement as combination therapy, but also as monotherapy.”

HCM occurs in approximately one in 200 to 500 individuals, with 70% of patients having obstructive disease. The condition causes the walls of the left ventricle to become thick and stiff, which can also result in obstruction to blood flow out of the heart and increased intracardiac pressures.

Aficamten is a cardiac myosin inhibitor that was previously shown to reduce LVOT gradients in a phase 2 trial. The phase 3 SEQUOIA-HCM trial evaluated the efficacy and safety of aficamten versus placebo in adults with symptomatic obstructive HCM. The primary endpoint was the change in pVO2, assessed using cardiopulmonary exercise testing, from baseline to week 24. Secondary endpoints at 24 weeks included the change in KCCQ score; the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA); change in Valsalva LVOT gradient; the proportion of patients with Valsalva LVOT gradient <30 mmHg; and eligibility for invasive septal reduction.

SEQUOIA-HCM included 282 patients from 101 sites in 14 countries in North America, Asia, and Europe, making it the largest-ever obstructive HCM trial. All participants had reduced exercise capacity due to obstructive HCM. Patients were randomised 1:1 to aficamten or placebo on top of their background medical therapy. The starting dose of aficamten was 5 mg once daily with opportunities at weeks 2, 4, and 6 to increase the dose in 5 mg increments to a maximum dose of 20 mg. Dose adjustments were made according to left ventricular ejection fraction and LVOT gradients assessed using echocardiography.

The mean increase in pVO2 from baseline to 24 weeks was 1.8 ml/kg/min with aficamten compared to 0.0 ml/kg/min with placebo (least-squares mean difference between groups, 1.7 ml/kg/min; 95% confidence interval [CI] 1.0, 2.4; p<0.001). Regarding secondary endpoints at 24 weeks, aficamten resulted in a least-squares mean difference of 7 points in KCCQ score relative to placebo (95% CI 5, 10; p<0.0001). A ≥1 NYHA class improvement was observed in 58.5% of patients on aficamten and 24.3% of patients on placebo (p<0.0001). Aficamten led to a 50 mmHg greater reduction in Valsalva LVOT gradient versus placebo (95% CI -57, -44; p<0.0001). Some 49.3% of patients on aficamten achieved a Valsalva LVOT gradient <30 mmHg versus 3.6% of patients on placebo (p<0.0001). The aficamten group had 78 fewer days eligible for invasive septal reduction compared with the placebo group (p<0.0001).

Professor Maron said: “It was impressive to see that the beneficial effects of aficamten occurred rapidly and consistently over the treatment period and that the doses could be adjusted effectively and safely using only site read echocardiographic measures. It was also reassuring to see that in the very small number of patients found to have an ejection fraction below 50% on aficamten, there was no associated heart failure or the need for dose interruption, and that the effect on ejection fraction was reversible with treatment discontinuation.”

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