Tag: 10/8/22

Categories : CancerTags :

Durvalumab Plus Radiotherapy Boosts NSCLC Survival Rate

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Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash

Durvalumab with radiotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC) without chemotherapy achieve had a much greater 12-month progression-free survival rate than expected, with tolerable adverse reactions.  This phase II clinical trial was reported at the IASLC 2022 World Conference on Lung Cancer in Vienna.

Immunotherapy plays an important role in NSCLC and combination of radiotherapy and immunotherapy have been reported to have a synergistic effect. Durvalumab after concurrent chemoradiotherapy has been standard of care with unresectable locally advanced NSCLC (stage III/postoperative recurrent NSCLC). But some patients are unable to complete concurrent curative radiation therapy and cannot receive durvalumab.

Dr M. Tachihara of Kobe University Graduate School of Medicine and colleagues developed the DOLPHIN study – the first Phase II study of immunotherapy combined with curative radiotherapy for unresectable locally advanced non-small cell lung cancer. 

The team enrolled 35 adult patients with unresectable locally advanced non-small cell lung cancer with an ECOG performance status (PS) 0-1, PD-L1≥1% (SP263 clone). Of the 35 patients (median age, 72 years), 88.6% were male, 54.3% had ECOG PS 0, 96.1% had a history of smoking, 57.1% had non-squamous histology, and 25.7% were postoperative recurrence.  

Patients received curative radiation therapy (60Gy) plus durvalumab 10 mg/kg every two weeks simultaneously, followed by maintenance with durvalumab for up to 12 months until disease progression (PD) or unacceptable toxicity.

Thirty-four patients were evaluated for safety, and 33 patients for efficacy. The 12-month progression-free survival rate by ICR was 72.1% (90% CI, 59.1-85.1) after a median follow-up of 18.7 months. Confirmed overall response rate was 90.9% (95% CI, 75.7-98.1, ICR-assessed) with complete and partial response rates of 36.4% and 54.5%, respectively. Median progression-free survival was not reached by ICR-assessed, and 24.1 months (95% CI, 16.0-NR) by investigator-assessed. Thirteen patients (39.4%) discontinued durvalumab; six patients due to progression disease and seven due to adverse events (AE). Grade 3/4 adverse events occurred in 47.1%; the most common adverse event of grade 3/4 was lung infection (11.8%) and pneumonitis (11.8%). Grade 5 adverse events of any cause occurred in 2 patients (5.9%), one with lung infection and one with broncho-oesophageal fistula because of tumour progression during follow-up.

“This DOLPHIN study is the first report of immunotherapy combined with curative radiotherapy for unresectable LA-NSCLC. The primary endpoint of 12-months PFS rate was met and much higher than expected value. It suggests that this treatment strategy is promising with tolerable adverse effects and appropriate as a study treatment for phase III trials,” said Dr. Tachihara.

Source: IASLC

Categories : Diseases, Syndromes and ConditionsTags :

Chronic Inflammation Link to Low Vitamin D Explains Some Controversies

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Vitamin D pills
Photo by Michele Blackwell on Unsplash

New genetic research shows a direct link between low vitamin D levels and high levels of inflammation, providing an important biomarker to identify people at higher risk of or severity of chronic illnesses with an inflammatory component, such as type 2 diabetes. The findings, published in the International Journal of Epidemiology, also helps to settle some of the controversies surrounding the ‘sunshine vitamin’.

The study drew on genetic data for 294 970 participants in the UK Biobank, using Mendelian randomisation to show the association between vitamin D and C-reactive protein levels, an indicator of inflammation.

University of South Australia’s Dr Ang Zhou, the study’s lead researcher, said that the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.

“This study examined vitamin D and C-reactive proteins and found a one-way relationship between low levels of vitamin D and high levels of C-reactive protein, expressed as inflammation.

“Boosting vitamin D in people with deficiencies may reduce chronic inflammation, helping them avoid a number of related diseases.”

The study also raises the possibility that having adequate vitamin D concentrations may mitigate complications arising from obesity and reduce the risk or severity of chronic illnesses with an inflammatory component, such as CVDs, diabetes, and autoimmune diseases.

Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, said that these results offer an explanation for some of the controversies in reported associations with vitamin D.

“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit.” Prof Hyppönen said.

“These findings highlight the importance of avoiding clinical vitamin D deficiency, and provide further evidence for the wide-ranging effects of hormonal vitamin D.”

Source: University of South Australia

Categories : CancerTags :

Collagen’s Role in Breast Cancer Includes Triggering Metastasis

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Breast cancer cells
Breast cancer cells. Image source: National Cancer Institute on Unsplash

Type XII collagen plays a key role in regulating the organisation of the tumour matrix, according to research published in the journal Nature Communications. The study investigators also discovered that high levels of collagen XII can trigger metastasis.

Cancer cells continually interact with the tumour microenvironment one component of which is the extracellular matrix. Collagen is an important part of this tumour microenvironment, but just how it influences tumours has not been understood.

“There’s still a lot we don’t know about the role of the extracellular matrix in cancer metastasis. Our study shows that collagen XII plays an important role in breast cancer progression and metastasis,” said Associate Professor Thomas Cox, senior author of the study.

“Imagine cancer cells as seeds, and the tumour microenvironment as the soil. By studying the soil – the extracellular matrix – we can begin to understand what makes some tumours more aggressive than others, and by extension, begin to develop new ways to treat cancer,” he explained.

The research also suggests that measuring the level of collagen XII in a patient’s tumour biopsy could potentially be used as an additional screening tool to identify aggressive breast cancers with higher rates of metastasis, such as in the triple-negative type of breast cancer. Furthermore, collagen XII might be a possible target for future treatments.

The extracellular matrix is a 3D meshwork of around 300–400 core molecules, including several collagen proteins. This matrix provides structural and functional support to cells and tissues in all parts of the body.

In this study, the researchers catalogued how the tumour matrix changes over time and have generated a comprehensive database of these changes, which has been made freely available to researchers.

The team focused on collagen XII, one of 28 types of collagen in the body. Collagen XII plays an important role in organising other collagens and can have profound effects on the 3D structure of the extracellular matrix.

The researchers studied tumours in mouse models from the earliest pre-clinical stages of cancer, right through to late-stage tumours. They found that as the tumours developed, many matrix molecules changed, and importantly the level of collagen XII was also increased.

“Collagen XII seems to be altering the properties of the tumour and makes it more aggressive,” said first author Michael Papanicolaou. “It changes how collagens are organised to support cancer cells escaping from the tumour and moving to other sites like the lungs.”

The team then genetically manipulated collagen XII production, looking at the effects of metastasis to other organs. They found that as levels of collagen XII increased, so did metastasis. These findings were then confirmed in human tumour biopsies, which showed that high levels of collagen XII are associated with higher metastasis and poorer overall survival rates.

Further research will focus on studying more human samples, and investigating possible therapeutic pathways.

Source: Garvan Institute of Medical Research

Categories : Cardiovascular Disease Surgeries & ProceduresTags :

Aspirin and Antiplatelets after Coronary Artery Grafts are a Double-edged Sword

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Source: Wikimedia Commons CC0

A new analysis published in JAMA shows that a combination of aspirin and another antiplatelet agent can prevent clotting after coronary artery bypass grafts but also increases the risk of potentially dangerous bleeding. This double-edged finding from investigators suggests physicians should carefully weigh the use of these medications after this procedure.

A Weill Cornell Medicine and NewYork-Presbyterian team led by Dr Mario Gaudino, a coronary artery bypass surgeon, examined data from 1668 grafts in which surgeons use a saphenous vein graft to circumvent blocked coronary arteries. It is common for blood clots to form within the grafted vein, for which patients are typically given aspirin. Some evidence suggests that aspirin along with a prescription strength antiplatelet agent such as ticagrelor can more effectively prevent this clotting.

“We found that, yes, this dual therapy significantly reduces the risk that the grafts will fail. However, for the first time, we have shown that this approach also carries a significant risk of clinically important bleeding,” said Dr Gaudino. “So, the benefit comes at a price.”

Taken together, these results indicate physicians should base their decisions on patients’ individual circumstances and avoid using this approach for those with conditions that put them at risk of bleeding, he said.

In more than 90% of coronary artery bypass grafts, surgeons take a graft from one of the patient’s saphenous veins, which return blood up the leg. However, within a year, up to a quarter of these grafts become obstructed.

While studies have examined the benefit of aspirin and ticagrelor, known as dual antiplatelet therapy (DAPT), these studies were small and had conflicting conclusions. The team contacted researchers on four such trials to obtain access to their raw data. They aggregated the data and effectively created a much larger study capable of generating more robust conclusions.

They found a failure rate of approximately 11% in patients who received a combination of aspirin and ticagrelor, while blockages occurred in 20% of grafts when patients received only aspirin. However, compared to aspirin alone, DAPT brought on more bleeding events that, while generally not life threatening, required medical attention.

In these previous trials, patients received DAPT for a full year. However, most graft failure occurs in the first few months after surgery. Dr Gaudino plans a further test of aspirin and ticagrelor over one to three months to see if a shortened course offers the same benefit with less risk of bleeding.

Source: Weill Cornell Medicine

Categories : GastrointestinalTags :

Body Posture, Stomach Motility Affect Oral Pill Bioavailability

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Photo by danilo.alvesd on Unsplash

While oral administration of a pill or capsule is a simple and cheap route, it is also the most complex way for the human body to absorb an active pharmaceutical ingredient, due to the stomach environment’s influence on bioavailability. Using highly detailed computer simulations, researchers have now found that stomach motility and posture (leaning right, left or backwards) significantly affect bioavailability.

The rate of dissolution and gastric emptying of the dissolved active pharmaceutical ingredient (API) into the duodenum is modulated by gastric motility, physical properties of the pill, and the contents of the stomach. This results in varying rates of pill dissolution and nonuniform emptying of the drug into the duodenum and, occasionally, gastric dumping in the case of modified-release dosage. Current in vitro procedures for assessing dissolution of oral drugs do not simulate this process well.

In Physics of Fluids, researchers used a biomimetic computer simulation based on the realistic anatomy and morphology of the stomach (a ‘StomachSim’) to investigate and quantify the effect of body posture and stomach motility on drug bioavailability over the first few minutes of absoprtion.

 The simulations show that changes in posture can potentially have a significant (up to 83%) effect on the emptying rate of the API into the duodenum. A 45 degree lean to the left greatly reduced the amount of active ingredient per cycle released into the duodenum, while a lean to the right dramatically increased it over the upright case.

Similarly, the researchers found that a reduction in antral contractility associated with gastroparesis significantly reduced the dissolution of the pill as well as emptying of the API into the duodenum. The simulations show that for an equivalent motility index, the reduction in gastric emptying due to neuropathic gastroparesis is larger by a factor of about five compared to myopathic gastroparesis.

“Oral administration is surprisingly complex despite being the most common choice for drug administration,” said co-author Rajat Mittal. “When the pill reaches the stomach, the motion of the stomach walls and the flow of contents inside determine the rate at which it dissolves. The properties of the pill and the stomach contents also play a major role.

“However, current experimental or clinical procedures for assessing the dissolution of oral drugs are limited in their ability to study this, which makes it a challenge to understand how the dissolution is affected in different stomach disorders, such as gastroparesis, which slows down the emptying of the stomach.”

Together, these issues pose several challenges for the design of drug delivery.

“In this work, we demonstrate a novel computer simulation platform that offers the potential for overcoming these limitations,” said Mittal. “Our models can generate biorelevant data on drug dissolution that can provide useful and unique insights into the complex physiological processes behind the oral administration of pills.”

The researchers note that the simulation required a lot of computational time, only capturing the first few minutes of the process, and are working on faster methods to capture differences over the period of an hour.

Source: American Institute of Physics