Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management

Stent Implantation Preferred Strategy For Previously Untreated Non-complex Coronary Artery Disease, States Study

Novel drug-coated balloons (DCB) did not outshine standard treatment with second generation drug-eluting stents (DES) as they were expected to, in a surprise finding of the first randomised trial to compare clinical outcomes in previously untreated patients with non-complex disease undergoing percutaneous coronary intervention (PCI). The study was presented in a Hot Line Session at this year's ESC Congress 2024 in London, UK (30 Aug – 2 Sept).

"Drug-coated balloon angioplasty failed to achieve non­inferiority compared to standard treatment with second-generation thin strut drug-eluting stents, mainly due to the need for more repeat procedures (revascularisation)," said senior author Dr Ling Tao from Xijing Hospital, Xi'an, China.

Each year, millions of people around the world undergo PCI, a non-surgical intervention to treat blockages in the coronary arteries (that supply blood to the heart).

The conventional treatment of coronary artery disease (CAD) usually involves a procedure known as balloon angioplasty, during which a deflated balloon attached to a catheter is inserted into a narrowed artery. Once in position, the balloon is inflated, opening up the narrowed blood vessel and restoring blood flow to the heart, followed by the deployment of a DES to provide an immediate scaffold and to reduce the long-term risk of restenosis (a re-narrowing of the treated artery and recurrence of symptoms that may require additional repair).

"While PCI with DES is highly effective, 2% of patients experience in-stent restenosis annually after the procedure," explained Dr Tao. "Because of the metallic scaffold left behind, a DES may distort and permanently cage the coronary vessel from adaptive remodeling, impeding vessel pulsatility, interfering with cell signaling and mechano-transduction, and promoting chronic inflammation. Such stent related adverse events have fuelled interest in alternative stent free methods of local drug delivery, such as using drug coated balloons."

Previous studies have shown the strategy of DCB angioplasty with the option of stenting in case of an unsatisfactory result to be just as effective as DES for previously untreated small vessel CAD (diameter ≤ 3.0 mm). However, the long­term efficacy and safety of this strategy in previously untreated coronary lesions, regardless of coronary artery diameter, remains uncertain.

To find out more, the REC­CAGEFREE I randomised, non­inferiority trial enrolled patients requiring PCI who had previously untreated, non­complex CAD (irrespective of target vessel diameter) from 43 sites across China.

Between February, 2021, and May, 2022, a total of 2,272 patients (aged 18 and older) who had achieved a successful target vessel pre-dilation were randomly assigned in a 1:1 ratio to receive either treatment with paclitaxel coated balloon angioplasty with the option of rescue stenting due to an unsatisfactory result (DCB; 1,133 patients), or deployment of a second-generation, thin strut, sirolimus eluting stent (DES; 1,139 patients). The average age of patients was 61 years, 69% were men, 27% had diabetes, and 6% were insulin dependent.

In total, around 9% (106/1,133) of patients had to undergo rescue DES after unsatisfactory DCB angioplasty.

The primary endpoint of the 2-year combined rate of cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation (Device oriented Composite Endpoint [DoCE]) was 6.4% (72 patients) for DCB and 3.4% (38 patients) for DES, with an absolute risk difference of 3.04% (which was above the prespecified 2.68% threshold for non-inferiority). This was mainly due to higher rates of clinically and physiologically indicated target lesion revascularisation with DCBs (3.1% vs 1.2%, difference:1.90%).

However, sub-group analysis found that there was a notable heterogeneity in the treatment effect across vessel diameters, which requires further confirmation in adequately designed trials. While DES was the more favourable option in the non-small vessel disease subpopulation (device diameter > 3.0 mm), in the small vessel disease subpopulation (≤3.0 mm), with more than 1,000 patients, the results were in line with previous studies showing that DCB and DES had similar rates of DoCE through the two-year follow-up (p-value for the interaction between treatment (DCB or DES) and the small vessel disease subgroup was 0.02)

"Our results show that the attempted strategy of "leave nothing behind" by using paclitaxel-coated balloons in de novo non-complex coronary artery disease was disproven, and DES implantation should continue to be the standard of care for these patients," said Dr Tao.

Rapper & Hypeman's Cause Of Death Revealed

(Photo by Hanna Lassen/Getty Images for Jimmy Choo)

Almost a month after the shocking death of rapper, hip-hop hype man and radio host Fatman Scoop, Connecticut's state's medical examiner's office has released his official cause of death.

If you remember, the beloved hype-man collapsed at a concert in Connecticut and was rushed to the hospital. Footage shared by TMZ showed Scoop appearing to suffer a medical emergency and collapsing onstage mid-performance. In a subsequent Facebook post, Hamden Mayor Lauren Garrett confirmed that Scoop "had a medical emergency onstage" and was taken by ambulance to the hospital.

According to People magazine, the Connecticut Medical Examiner's Office announced on Wednesday (Sept. 25) that Scoop (born Isaac Freeman III) died due to hypertensive and atherosclerotic cardiovascular disease, with a determination that his death was natural and no foul play was involved.

What Did the Disease Do to Scoop's Body?

Hypertensive atherosclerotic cardiovascular disease is a condition that occurs when high blood pressure (hypertension) and atherosclerosis (a buildup of plaque in the arteries) combine to increase the risk of heart attack, stroke, and other cardiovascular complications:

HypertensionHigh blood pressure can damage the lining of arteries, making them more susceptible to atherosclerosis. This can lead to heart and blood vessel damage over time.

AtherosclerosisAtherosclerosis is a condition that occurs when plaque builds up in the walls of arteries, which can narrow or block the arteries and reduce blood flow. Atherosclerosis can start in childhood and slowly worsen.

Other risk factors for atherosclerosis include:High cholesterol, High triglycerides, Smoking, Diabetes, Obesity, and Inflammation.

Signs & Symptoms You Shouldn't Ignore

Chest PainChest pain can also be a sign of anything from muscle strain to a heart attack. If you're experiencing a chest pain you cannot explain, it may be a symptom of atherosclerosis in your coronary arteries. Complications that arise with a narrowing of these arteries include coronary artery disease and heart attack. It is important to see a doctor if you are experiencing chest pain of any kind.

ConfusionNarrowing of the carotid arteries can lead to sudden confusion and disorientation. This altered level of consciousness can be distressing if you're aware of it. Memory problems can also sometimes occur alongside confusion which, in their extreme state, are known as delirium. The individual may also appear slower than usual. These symptoms could be a sign of anything from anxiety to a brain tumor or atherosclerosis.

Muscle WeaknessMuscle weakness can affect the face, the body, or both at the same time. If muscle weakness appears in the face, it may cause drooping of the eyelid or ptosis, or difficulty smiling. On the other hand, when the muscle weakness is all over the body, it can be hard to distinguish from fatigue, which can come from mental ailments such as anxiety and depression, or physical ailments such as an imbalance in the body. General muscle weakness is also an early sign of atherosclerosis in the peripheral arteries.

Trouble SpeakingTrouble speaking or forming words generally denotes a problem in the brain. Doctors are not always able to diagnose atherosclerosis before the stroke occurs. Difficulty forming words, as well as a possible change in character, could be a direct result of atherosclerosis in the cartoid arteries. If someone is exhibiting slurred speech or cannot think of simple words, it is important to see a doctor right away.

Treatments for hypertensive atherosclerotic cardiovascular disease include:

Medications to lower cholesterol, such as statins

Quitting smoking

Losing weight

Exercising

Eating a heart-healthy diet

Atherosclerosis and hypertension are distinct disease entities; everyone who has hypertension does not manifest extensive atherosclerosis, nor is atherosclerosis always or even usually accompanied by hypertension.

Hypertensive vascular disease involves both large and small arteries as well as arterioles and is characterized by fibromuscular thickening of the intima and media with luminal narrowing of the small arteries and arterioles. The physical stress of hypertension on the arterial wall also results in the aggravation and acceleration of atherosclerosis, particularly of the coronary and cerebral vessels. Other major complications of hypertensive vascular disease include rupture and thrombotic occlusion of blood vessels, especially in the brain.

Family, Friends, and Fans are Still Mourning His Death

In a statement following his death, Scoop's booking agency MN2S said it was "heartbroken" by his sudden passing.

"Scoop was a beloved figure in the music world, whose work was loved by countless fans across the globe," the agency said at the time. "His iconic voice, infectious energy and great personality made an indelible mark on the industry, and his legacy will live on through his timeless music."

Freeman's peers, friends and family gathered near the Harlem projects where he was raised at the Apollo Theater on Sept. 12 for a celebration of life ceremony hosted by SiriusXM's Sway Calloway, with Teddy Riley, Jim Jones, A$AP Ferg, Busta Rhymes, Kid Kapri, LL Cool J and Angie Martinez among those paying tribute.

His family cherished him as "the laughter in our lives, a constant source of support, unwavering strength and courage," his relatives said.

"His music made us dance and embrace life with positivity," his family members said. "His joy was infectious and the generosity he extended to all will be deeply missed but never forgotten."

Study Uncovers Hidden Proteins Fueling Heart Disease And Stroke

Research reveals potential drug targets for heart disease and stroke, using a combination of genetic and observational data to separate causal from non-causal proteins.

Letter: Measured and genetically predicted protein levels and cardiovascular diseases in UK Biobank and China Kadoorie Biobank. Image Credit: Lightspring / Shutterstock

In a recent study published in the journal Nature Cardiovascular Research, researchers assessed the association between 2,919 distinct plasma proteins and cardiovascular disease (CVD) outcomes in the UK Biobank (UKB) and China Kadoorie Biobank (CKB), identifying potential causal proteins for novel drug targets.

Background

Many studies have measured plasma protein levels in individuals with CVD outcomes. However, due to the interrelated nature of proteins, observational studies often struggle to pinpoint those with true causal relevance.

One approach to address this is through Mendelian randomization (MR) and genetic analyses, investigating whether genetic loci regulating protein levels are also associated with CVD outcomes.

Previous research has found hundreds of proteins linked to myocardial infarction (MI) (a heart attack caused by blocked blood flow to the heart), ischemic stroke (IS) (a stroke caused by a blockage in blood vessels supplying the brain), and heart failure (HF) (a condition where the heart cannot pump blood efficiently), with a limited number showing evidence of causality.

Further research is needed to better understand these causal relationships and discover new therapeutic targets for CVD treatment.

About the study

The UKB is a large, multicenter, prospective cohort study conducted across the UK between 2006 and 2010, involving over 500,000 individuals aged 40-69. Data from 52,164 participants with valid proteomics data were included. The North West Multicentre Research Ethics Committee (UK) and the Swedish Ethical Review Authority granted ethical approval, with participants providing written informed consent. Baseline measurements, including plasma levels of glucose, cholesterol, and creatinine, were collected alongside blood pressure and estimated glomerular filtration rate (eGFR).

Participants' ethnicity was categorized, and socioeconomic status was assessed using the Townsend social deprivation index. Smoking status was recorded as never, previous, or current smokers. Disease outcomes, including MI, IS, and HF, were classified using the International Classification of Diseases (ICD-10) codes. Plasma levels of 2,923 proteins were initially measured using the Olink EXPLORE assay, with 2,919 passing quality control.

The CKB study included 512,000 Chinese adults recruited between 2004 and 2008. Data were collected on smoking, medical history, and education. Plasma proteins were measured using the same analytical platform as in UKB. Key findings from UKB were successfully replicated in CKB, strengthening the study's conclusions.

Study results

In the UKB, 126 proteins were found to be significantly associated with all three CVD outcomes. Of these, 118 were associated with at least one CVD outcome in the replication phase conducted in CKB. Among these, 87 proteins were linked to more than one CVD, while 31 proteins were related to all three CVD outcomes (MI, IS, and HF) at a significance level of P < 0.05.

Using Mendelian randomization (MR) analysis, genetically predicted levels of 33 proteins were linked to coronary heart disease (CHD), with the top proteins being Lipoprotein(a) (LPA), Cadherin EGF LAG Seven-Pass G-Type Receptor 2 (CELSR2), Apolipoprotein E (APOE), Feline Sarcoma Oncogene (FES), and Vesicle-Associated Membrane Protein 5 (VAMP5). Four proteins were linked to IS, while 18 proteins were associated with HF, with LPA, CELSR2, and Fibroblast Growth Factor 5 (FGF5) emerging as key players in CHD and HF. Sensitivity analyses using multiple cis-SNPs for MR analysis produced results consistent with the initial findings, enhancing the robustness of these associations.

Colocalization analysis provided further evidence, showing that 10 proteins had strong shared causal variants with CVD outcomes. Notably, CELSR2 and FGF5 were associated with both CHD and HF, while FURIN was linked to both CHD and stroke. These proteins, especially FURIN, were identified as promising targets for future drug development, supported by additional findings in subclinical CVD markers.

Interestingly, observational analyses demonstrated a weaker relationship between protein levels and CVD outcomes compared to MR results. Only 6% of proteins associated with CVD outcomes in the observational analyses were found to have causal relationships in the MR analysis, suggesting that many observational associations were non-causal. This discrepancy is likely due to biases such as residual confounding and reverse causality in observational studies.

Proteins like FGF5, Protein C Receptor (PROCR), and FURIN showed consistent evidence of causal involvement in CVD outcomes across both observational and genetic analyses, highlighting their potential as therapeutic targets. FGF5 was implicated in hypertension and carotid artery distensibility, while FURIN, a protease involved in protein activation, was associated with both MI and IS.

Conclusions

To summarize, the study identified numerous proteins associated with CVD outcomes, but genetic analyses revealed that only a small subset showed evidence of causality. Key proteins such as FGF5, PROCR, and FURIN emerged as potential targets for CVD prevention and treatment.

The findings highlight the importance of distinguishing between observational and causal associations in protein studies. Although many observational associations were non-causal, the use of Mendelian randomization and colocalization analyses provided a clearer understanding of which proteins may have direct roles in CVD pathogenesis, offering promising directions for future drug development.

---