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By Pooja Toshniwal Paharia Jun 11 2024 Reviewed by Lily Ramsey, LLM

In a recent study published in Cancer Discovery, researchers developed and validated a blood-based, cell-free deoxyribonucleic acid (cfDNA) fragmentome assay for lung cancer detection, which, if the results were positive, would be followed by low-dose computed tomography (LDCT).

Study:  Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection . Image Credit: MMD Creative/Shutterstock.com Introduction

Lung cancer is a major death cause, and yearly screening is crucial. However, chest LDCT has low adoption due to patient barriers like inadequate awareness, radiation concerns, and limited availability.

Other challenges include poor smoking history recording, a lack of defined practices, and specialist follow-up.

A blood-based lung malignancy screening test, like the fragmentome technique, could increase screening rates by analyzing specific chromatin configurations in peripheral blood. About the study

In the present DELFI-L101 study, researchers developed a hematological test using machine learning to analyze DNA fragmentomes and identify individuals at risk of lung cancer. Individuals testing positive would undergo LDCT.

Beginning March 2021, the researchers enrolled 958 individuals aged 50–80 with ≥20 pack-years of smoking across 47 United States (US) facilities. Eligibility features resembled the LDCT screening criteria of the 2015 National Health Interview Survey (NHIS).

They excluded individuals with cancer therapy within one year, a history of hematologic malignancy or myelodysplasia, organ tissue transplantation, blood product transfusion within 120 days of enrollment, pregnancy, and participation in other trials.

The team divided the study participants into three groups: A (lung cancer), B (non-cancer controls), and C (cancer other than lung cancer). Related StoriesResearch reveals new pathways for treating never-smoker lung cancerCanada's plan to eliminate cervical cancer by 2040: HPV-based screening and vaccination keyLung cancer screening yields early diagnoses and increased cure rates in veterans

The American Joint Committee on Cancer's Cancer Staging Manual (AJCC) criteria ascertained the disease stage. Changes in cfDNA fragmentation patterns (fragmentomes) in blood revealed genomic and chromatin features of lung cancer.

The researchers trained the classifier on 576 cases and controls before validating it on another 382 cases and controls.

They used whole genome sequences from the training dataset to assess fragmentations in 504 non-overlapping-type 5.0 MB sections with strong mappability. Each region included 80,000 pieces and covered a genome size of 2.50 GB.

The team examined genome-wide alterations to Hi-C open-type (A compartment) and closed-type (B compartment) chromatin.

They created the classifier using principal component analysis (PCA) and logistic regressions, incorporating chromosomal arm-level changes, cfDNA fractions derived from the mitochondrial genome, and cfDNA fragment length distributions.

The researchers performed Monte Carlo simulations on 15 million individuals under three scenarios: Base Scenario: Current practices without hematological screening. Low Scenario: 10% uptake of hematological screening for individuals eligible for pulmonary cancer screening but not subjected to low-dose CT in the first year, increasing to 25% in five years. High Scenario: 20% uptake of hematological screening for the same group in the first year, increasing to 50% in five years. Results

The researchers observed 58% test specificity, 84% sensitivity, and 99.8% negative predictive value (NPV). Applying the rest to the screening-eligible group with 0.7% lung cancer prevalence, the number needed to screen (NNS) was 143.

Study validations showed negative and positive results related to NNS with LDCT imaging to detect 414 and 76 cases, respectively, yielding a 5.5 relative risk value. The positive predictive value (PPV) was almost double that of the LDCT qualifying requirements alone.

The cfDNA fragmentomes of lung squamous cell carcinoma (LUSC) patients comprised a component resembling cfDNA profiles from non-cancer individuals and another resembling A/B-type compartments noted in LUSC tissues.

Non-cancer individuals showed cfDNA patterns approximating lymphoblastoid Hi-C findings. Within common locations, fragmentations among samples provided by individuals with cancer presence and absence were similar.

Lung cancer patients had increased cell-free DNA representations fpr 1q, 3q, 5p, 8q, and 12p, as well as lower 1p, 3p, 4q, 5q, 10q, and 17p levels. Their cfDNA fragmentations differed from controls, revealing more closely packed chromatin in cfDNA of closed LUSC spaces, while lymphoblastoid reference regions showed the reverse impact.

At the cut-off of 0.2, ten-fold cross-validation with ten repeats within the training population yielded 50% overall specificity and sensitivities of 75%, 90%, 96%, and 97% for stages I, II, III, and IV, respectively. Sensitivity was constant across ages, with younger people having higher specificity. Using the 2015 NHIS data yielded 80% sensitivity and 58% specificity.

From the ‘base’ scenario (24,489 cases), lung cancer cases identified by screening increased to 63,523 (the ‘low’ scenario) and 100,346 (the ‘high’ scenario). In contrast, stage I cases increased by 4.80% and 9.70%, while stage IV diagnoses decreased by 4.20% and 8.70%, respectively.

In total, 4,720 deaths from lung malignancies could be averted in the ‘base’ scenario, 7,652 in the ‘low’ scenario, and 14,264 deaths in the ‘high’ scenario. LDCT use in screening could reduce the number of tests required to identify lung cancers from 202 (‘base’ scenario) to 150 (‘low’ scenario) and 139 (‘high’ scenario). Conclusion

Based on the study findings, the DNA fragmentome assay provides a novel, accurate, affordable, blood-based tool for initial lung cancer evaluation with LDCT follow-ups.

The assay could contribute to preventing lung cancer-related deaths, with moderate adoption rates possibly lowering late-stage diagnoses and fatalities. Journal reference:

Peter Mazzone et al., (2024) Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection, Cancer Discov (2024), doi: https://doi.org/10.1158/2159-8290.CD-24-0519.https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-0519/745696/Clinical-validation-of-a-cell-free-DNA-fragmentome?searchresult=1

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Fourteen children arrested on suspicion of manslaughter over Gateshead fire released on bail

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Fourteen children arrested on suspicion of manslaughter over Gateshead fire released on bail

All 14 children arrested on suspicion of manslaughter after a boy died in a fire have been released on police bail, officers said.

Layton Carr, 14, was found dead near the site of a fire at Fairfield industrial park in the Bill Quay area of Gateshead on Friday.

Northumbria Police said on Saturday that they had arrested 11 boys and three girls in connection with the incident.

In an update on Sunday, a Northumbria Police spokesman said: “All those arrested have since been released on police bail pending further inquiries.”

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Teenager dies in industrial estate fire

Firefighters raced to the industrial site shortly after 8pm on Friday, putting out the blaze a short time later.

Police then issued an appeal for Carr, who was believed to be in the area at that time.

In a statement on Saturday, the force said that “sadly, following searches, a body believed to be that of 14-year-old Layton Carr was located deceased inside the building”.

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David Thompson, headteacher of Hebburn Comprehensive School, where Layton was a pupil, said the school community was “heartbroken”.

Mr Thompson described him as a “valued and much-loved member of Year 9” and said he would be “greatly missed by everyone”.

He added that the school’s “sincere condolences” were with Layton’s family and that the community would “rally together to support one another through this tragedy”.

A fundraising page on GoFundMe has been set up to help Layton’s mother pay for funeral costs.

Pic: Gofundme
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Pic: Gofundme

Organiser Stephanie Simpson said: “The last thing Georgia needs to stress trying to pay for a funeral for her Boy Any donations will help thank you.”

One tribute in a Facebook post read: “Can’t believe I’m writing this my nephew RIP Layton 💔 forever 14 you’ll be a massive miss, thinking of my sister and 2 beautiful nieces right now.”

Detective Chief Inspector Louise Jenkins, of Northumbria Police, also said: “This is an extremely tragic incident where a boy has sadly lost his life.”

She added that the force’s “thoughts are with Layton’s family as they begin to attempt to process the loss of their loved one”.

They are working to establish “the full circumstances surrounding the incident” and officers will be in the area to “offer reassurance to the public”, she added.

A cordon remains in place at the site while police carry out enquiries.

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Football bodies could be forced to pay towards brain injury care costs of ex-players

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Football bodies could be forced to pay towards brain injury care costs of ex-players

Football bodies could be forced to pay towards the care costs of ex-players who have been diagnosed with brain conditions, under proposals set to be considered by MPs.

Campaigners are drafting amendments to the Football Governance Bill, which would treat conditions caused by heading balls as an “industrial injuries issue”.

The proposals seek to require the football industry to provide the necessary financial support.

Campaigners say existing support is not fit for purpose, including the Brain Health Fund which was set up with an initial £1m by the Professional Footballers’ Association (PFA), supported by the Premier League.

But the Premier League said the fund has supported 121 families with at-home adaptations and care home fees.

From England‘s 1966 World Cup-winning team, both Jack and Bobby Charlton died with dementia, as did Martin Peters, Ray Wilson and Nobby Stiles.

Neil Ruddock speaks to Sky's Rob Harris outside parliament
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Neil Ruddock speaks to Sky’s Rob Harris outside parliament

Ex-players, including former Liverpool defender Neil Ruddock, went to parliament last week to lobby MPs.

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Ruddock told Sky News he had joined campaigners “for the families who’ve gone through hell”.

“A professional footballer, greatest job in the world, but no one knew the dangers, and that’s scary,” he said.

“Every time someone heads a ball it’s got to be dangerous to you. You know, I used to head 100 balls a day in training. I didn’t realise that might affect my future.”

A study co-funded by the PFA and the Football Association (FA) in 2019 found footballers were three and a half times more likely to die of a neurodegenerative disease than members of the public of the same age.

‘In denial’

Among those calling on football authorities to contribute towards the care costs of ex-players who have gone on to develop conditions such as Alzheimer’s and dementia is Labour MP Chris Evans.

Mr Evans, who represents Caerphilly in South Wales, hopes to amend the Bill to establish a care and financial support scheme for ex-footballers and told a recent event in parliament that affected ex-players “deserve to be compensated”.

Greater Manchester Mayor Andy Burnham, who helped to draft the amendment, said the game was “in denial about the whole thing”.

Mr Burnham called for it to be seen as “an industrial injuries issue in the same way with mining”.

In January, David Beckham lent his support to calls for greater support for footballers affected by dementia.

One of the amendments says that “the industry rather than the public should bear the financial burden”.

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A spokesperson for the FA said it was taking a “leading role in reviewing and improving the safety of our game” and that it had “already taken many proactive steps to review and address potential risk factors”.

An English Football League spokesperson said it was “working closely with other football bodies” to ensure both professional and grassroots football are “as safe as it can be”.

The PFA and Premier League declined to comment.

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Terror arrests came in context of raised warnings about Iran, with ongoing chaos in its own backyard

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Terror arrests came in context of raised warnings about Iran, with ongoing chaos in its own backyard

These are two separate and unrelated investigations by counter-terror officers.

But the common thread is nationality – seven out of the eight people arrested are Iranian.

And that comes in the context of increased warnings from government and the security services about Iranian activity on British soil.

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Counter terror officers raid property

Last year, the director general of MI5, Ken McCallum, said his organisation and police had responded to 20 Iran-backed plots presenting potentially lethal threats to British citizens and UK residents since January 2022.

He linked that increase to the ongoing situation in Iran’s own backyard.

“As events unfold in the Middle East, we will give our fullest attention to the risk of an increase in – or a broadening of – Iranian state aggression in the UK,” he said.

The implication is that even as Iran grapples with a rapidly changing situation in its own region, having seen its proxies, Hezbollah in Lebanon and Hamas in Gaza, decimated and itself coming under Israeli attack, it may seek avenues further abroad.

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The government reiterated this warning only a few weeks ago, with security minister Dan Jarvis addressing parliament.

“The threat from Iran sits in a wider context of the growing, diversifying and evolving threat that the UK faces from malign activity by a number of states,” Jarvis said.

“The threat from states has become increasingly interconnected in nature, blurring the lines between: domestic and international; online and offline; and states and their proxies.

“Turning specifically to Iran, the regime has become increasingly emboldened, asserting itself more aggressively to advance their objectives and undermine ours.”

Read more:
Anybody working for Iran in UK must register or face jail, government announces

As part of that address, Jarvis highlighted the National Security Act 2023, which “criminalises assisting a foreign intelligence service”, among other things.

So it was notable that this was the act used in one of this weekend’s investigations.

The suspects were detained under section 27 of the same act, which allows police to arrest those suspected of being “involved in foreign power threat activity”.

Those powers are apparently being put to use.

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