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Thursday, December 12, 2024

'Why is colorectal cancer rising in younger age groups?'

 A new study has confirmed that the rate of colorectal cancer is rising in younger adults around the world, with England among the countries seeing the highest increase.

The paper in The Lancet Oncology used World Health Organization (WHO) data on colorectal cancer in people aged less than 50 to gauge the trend in incidence in this group versus older individuals.

The worrying finding was that early-onset colorectal cancer is on the rise in 27 out of 50 countries, typically advancing at a rate that outstrips cases in older patients, and stable in the remaining 23.

It is the first study to track a rise in early-onset bowel cancer outside high-income Western countries, including regions like Latin America, the Caribbean, Eastern Europe, and Asia.

The analysis found that England experienced the fourth fastest rise in the rate of early-onset bowel cancer in the decade to 2017 – at 3.6% per year – behind only New Zealand, Chile, and Puerto Rico, and just ahead of Norway.

The increase was most apparent in women in some countries, including England, but was seen most often in men in Puerto Rico and others – just one finding that leads the researchers behind the work to acknowledge that the reasons for the trend are hard to fathom. Notably, the increase seen in England was not matched in the other UK nations.

So, what could be behind the trend? Previous studies have suggested a wide range of risk factors for this type of cancer, including prolonged sitting, poor diet, consumption of sugary drinks and alcohol, as well as illnesses like obesity and diabetes.

The authors of the study note that, in many of the newly identified countries, increases in early-onset colorectal cancer seem to coincide with or follow on from periods of economic development, which they suggest could be linked to rapid changes in lifestyle and diet.

"Early-onset colorectal cancer is a growing global phenomenon, But, at the same time, it is still rare," said Dr Yin Cao from Washington University in St Louis, one of the researchers behind the work. "Even though it is increasing, I don't think people should be scared."

commentary on the paper from Cancer Research UK noted that changes may have happened earlier and more gradually in countries like the UK and the US, where the increases in early-onset colorectal cancer rates had already been documented, and changing rates could also be affected by changes in how and when the cancer is diagnosed.

"More research is needed to understand whether there are genuine differences between the nations, and how to address them," said Katrina Brown, a senior cancer intelligence manager at CRUK.

Overall, it's worth noting that the UK nations have a mid-table ranking of 16th to 19th for the overall rate of this type of cancer, and the charity thinks the regional differences between the devolved nations may be down to population differences.

Cao said the differences underscore the need to identify emerging and novel risk factors for early-onset colorectal cancers, which might mark them out from cases that start later in life.

It's a view echoed by Dr Sarah Bailey, of the University of Exeter Medical School in the UK and an advanced fellow at the National Institute for Health and Care Research (NIHR), who was not involved in the study.

"This high-quality study confirms that colorectal cancer rates are rising in younger adults in many countries," she said. "The reasons for this are not fully understood, but it is clear that we need to be searching for the underlying causes."

Bailey also pointed out that earlier diagnosis strategies for colorectal cancer, such as screening programmes and investigation of symptomatic patients in primary care, tend to target people aged 50 and over – the age range in which most new cases are diagnosed.

"As rates in younger adults increase, we will need to explore how we can expand our strategies to capture cases early in this group too."

https://pharmaphorum.com/news/why-colorectal-cancer-rising-younger-age-groups

NIH abandons trial of SIGA's mpox drug

 Another clinical trial has found that SIGA Technologies' antiviral drug tecovirimat is ineffective as a treatment for mpox, prompting the investigators to stop patient recruitment.

The study by researchers at the US National Institutes of Health (NIH) is the second to show no benefit with tecovirimat in the treatment of mpox in the space of a few weeks.

It's a major blow to efforts to counteract an ongoing outbreak of mpox, as tecovirimat – approved as TPOXX for smallpox, another virus in the same family – is being used off-label to treat the disease in many countries around the world.

In the STOMP trial, tecovirimat did not reduce the time to lesion resolution or have an effect on pain compared to placebo in adults with mild to moderate clade 2 mpox and a low risk of developing severe disease in an interim analysis, according to the NIH. It was carried out in Argentina, Brazil, Japan, Mexico, Peru, Thailand, and the US.

The result follows the PALM 007 study carried out in the Democratic Republic of the Congo (DRC), at the epicentre of an outbreak deemed a public health emergency by the World Health Organization (WHO) – which found the drug was no better than placebo at mitigating mpox symptoms, as well as preventing serious outcomes including death, in patients with clade 1 mpox.

As a result of the preliminary STOMP data – which gave the chances of a positive outcome from the study at less than 1% – the NIH decided to stop patient enrolment into the trial, including an open-label study arm for participants with or at elevated risk of severe disease.

A clade 2 subtype of mpox caused an outbreak in 2022, and continues to circulate at low levels, but the current outbreak focused mainly on Central and East African countries is linked to a clade 1 strain, with a few cases also seen in international travellers who have visited the region.

"The initial STOMP findings provide valuable insight to inform clade 2 mpox medical countermeasures and underscore the critical importance of conducting well-designed randomised clinical trials during infectious disease outbreaks," commented Jeanne Marrazzo, director of the National Institute for Allergy and Infectious Diseases (NIAID).

"Before 2022, no treatment candidate had been studied in people with mpox, and this trial is a critical step in our systematic evaluation of existing antivirals like tecovirimat while pursuing novel antivirals and antibody-based mpox therapeutics," she added.

While the new study is a blow – given that tecovirimat remains the only recognised drug treatment for mpox – there are three vaccines available to help fight the outbreak from Bavarian Nordic, KM Biologics, and Emergent BioSolutions.

SIGA's chief executive, Diem Nguye,n said that antivirals are most effective when administered early in the course of an infection and tend to demonstrate the greatest benefit in patients with more severe disease.

For that reason "the STOMP results are not unexpected, as the study design was similar to the PALM 007 study, except it was in patients with mild to moderate clade 2 mpox compared to patients with clade 1 mpox."

He added: "It is important to note that approximately 75% of mpox patients in the randomised arms of the STOMP trial received tecovirimat more than five days after symptom onset, and higher-risk patients were included in an open-label arm."

It's not the end of the story just yet for tecovirimat for mpox, as three other trials are still ongoing – UNITY (Switzerland, Brazil, Argentina), Platinum-CAN (Canada), and EPOXI (EU) – although, Nguyen noted that these have similar designs and are likely to generate similar results.

https://pharmaphorum.com/news/nih-abandons-trial-sigas-mpox-drug

Satellite Footage Reveals Iranian "Mothership" Drone Carriers Exist, Just Not Near New Jersey

 Pentagon Deputy Press Secretary Sabrina Singh quickly rejected Republican Congressman Jefferson Van Drew of New Jersey's claim that mysterious Iranian "mothership" drone carriers off the US East Coast were launching drone swarms into New Jersey airspace.

Singh told reporters on Wednesday afternoon, hours after Van Drew's comments on Fox News, that "There is no Iranian ship off the coast of the United States ... and there is no so-called 'mothership' launching drones toward the United States."

Singh might be correct in her assessment because if Iran had drone carriers off the US East Coast, satellite intelligence firms would have likely published images of these carriers, sparking panic in corporate media—just as they did when Iranian warships sailed across the Atlantic Ocean to Venezuela several years ago.

It remains a mystery where the drones are originating from in New Jersey, one of the most restricted airspaces in the world, second only to the Baltimore-Washington metro area.

But what does not remain a mystery is that Iranian IRGC's (Islamic Revolutionary Guard Corps) drone carriers exist on the other side of the world.

Here's more color on the IRGC "motherships" via Covert Shores:

The Iranian IRGC's (Islamic Revolutionary Guard Corps) latest ambitious naval project, the drone carrier Shahid Bagheri (C-110-4), has sailed. The vessel appears to be on sea trials and may now be anchored outside Bandar Abbas harbor. Work on the The 240 metership, a converted merchant vessel, begun in 2022, and she was launched in 2023.

The ship's distinctive outline is visible in Sentinel 2 satellite imagery from yesterday. Other sources suggest that the ship is still in the vicinity. The flight deck is now marked, possibly flight tests of some sort can be expected.

The ship has a unique angled flight deck on the port (left) side which heads across towards the starboard (right) side. This novel arrangement is a workaround to avoid the need to remove the pre-existing superstructure left over from the ship's past life as a merchant vessel.

The angled flight deck, with a ski-jump ramp at the front, shows that the ship is intended for fixed-wing operations. The aircraft, highly likely primarily drones (UAVs), will be landing as well as taking off, so will not be one-way types. Previous Iranian drone carriers have only been able to launch large drones, not recover them.

The utility of such a ship in the IRGC's fleet is open to question, but shows both the ambition of the country's regime, and the trend towards drone carriers.

In a separate report, these drone carriers were spotted early last week in the Strait of Hormuz, 7,500 miles away from New Jersey. 

Sal Mercogliano, a professor at Campbell University and the host of the What Is Going On With Shipping? show on YouTube, provided additional color on Iran's drone carriers and the likelihood that these vessels are not parked off the US East Coast. 

So, where are these drones coming from?

https://www.zerohedge.com/military/satellite-footage-reveals-iranian-mothership-drone-carriers-exist-just-not-near-new-jersey

"Moderate Jihad": Syrians 'Excited' Over Public Executions

 by Paul Joseph Watson via Modernity,news,

After lauding how the overthrow of Assad in Syria would bring about “moderate jihad,” the BBC highlighted how thousands of ‘excited’ Syrians turned out to see a public execution.

Since Syrian rebel leader Abu Mohammed al-Jolani led his militants to topple Assad’s government, the legacy media has been busy rebranding al-Jolani and his cohorts as westernized and tolerant, with al-Jolani even adopting the rhetoric of corporate HR departments by declaring, “Diversity is a strength.”

Earlier this week, the BBC said that al-Jolani and his HTS fighters wanted to usher in a form of “moderate jihad,” despite the fact that the rebel leader was previously affiliated with ISIS and Al-Qaeda, was radicalized by 9/11, and previously planted roadside IEDs targeting US troops in Iraq.

Apparently, one manifestation of this “moderate jihad” is the lust for extrajudicial public executions.

The BBC’s Jeremy Bowen reported on how a huge group of Syrians had gathered to see one of Assad’s military intelligence operatives be publicly hanged.

Thousands of Syrians almost caused a stampede as they congregated expecting to see the individual executed.

The BBC reported that the crowd were “jostling for the best position, not wanting to miss a thing,” and shared a “real strong sense of excitement, expectation” at the prospect of witnessing the hanging.

“They don’t just want justice to be done, they want to see it being done,” said Bowen.

Another example of “moderate jihad” unfolded in Syria when Hayat Tahrir al-Sham (HTS) destroyed the tomb of the late president Hafez al-Assad, which also contained the remains of his wife and eldest son, by burning it to the ground.

Meanwhile, since the overthrow of Assad, innumerable horrific videos have emerged of Syrian rebel militants executing alleged Assad sympathizers in cold blood.

If this is “moderate jihad,” one wonders what hardcore jihad would look like.

https://www.zerohedge.com/geopolitical/moderate-jihad-syrians-excited-over-public-executions

FDA Issues Safety Alert on Liver Disease Drug

 Postmarketing data on obeticholic acid (Ocaliva: Alfasigma) identified a risk for serious liver injury in primary biliary cholangitis (PBC) patients without cirrhosis, the FDA said in a safety communication

opens in a new tab or window on Thursday.

The agency's review of a mandated clinical trial "found that some cases of liver injury in patients without cirrhosis resulted in liver transplant. This risk was notably higher for patients taking Ocaliva compared with a placebo," the FDA said.

The FDA in 2016 granted accelerated approvalopens in a new tab or window to the farnesoid X receptor (FXR) agonist as a second-line treatment for adults with PBC, either in combination with ursodeoxycholic acid (UDCA) for those with an inadequate response to the standard therapy or as a single agent in patients unable to tolerate UDCA.

But previous safety concernsopens in a new tab or window in PBC patients with advanced cirrhosis led to a narrower indicationopens in a new tab or window in May 2021 and a contraindication for that group with advanced cirrhosis. The drug is currently limited to PBC patients without cirrhosis or with compensated cirrhosis but no evidence of portal hypertension.

Yet postmarketing trial data of patients appropriately indicated for obeticholic acid showed a higher risk of liver transplant or death compared with patients receiving placebo (HR 4.77, 95% CI 1.03-22.09), with seven of 81 patients on obeticholic acid needing a liver transplant versus one of 68 placebo recipients. Furthermore, there were four deaths in the obeticholic acid group versus one in the placebo group.

And FDA's review found that some PBC patients with advanced cirrhosis still received the drug after the change to the prescribing information. In data from after the contraindication was added, 20 cases of serious liver injury in patients prescribed obeticholic acid were reported to the FDA Adverse Event Reporting System database, including 13 in the U.S. These included seven liver transplants, eight evaluations or listings for liver transplant, and six cases of liver-related death.

"Although we were not able to assess the appropriateness of Ocaliva use for most of these cases because of limited information, we identified three U.S. cases of liver-related events that occurred in patients for whom Ocaliva should have been discontinued based on progression of their liver disease as indicated in the 2021 safety labeling changes," said FDA. "This shows the importance of ongoing monitoring of liver tests and prompt action to withdraw Ocaliva if there is evidence of progression towards cirrhosis."

FDA urged clinicians to conduct frequent liver tests to check for signs of early liver damage in patients on obeticholic acid and said to discontinue treatment if there is any sign of liver disease progression or lack of efficacy.

Physicians should also alert their patients about specific or general symptoms of liver damage that may indicate need for medical attention, the agency said.

Specific symptoms: swollen belly, jaundice, bloody/black stools, coughing/vomiting blood, and changes in mental status (e.g., confusion, slurred speech, personality changes, increased sleepiness).

General symptoms if severe or that do not resolve in a few days: belly pain, nausea/vomiting, diarrhea, loss of appetite, weight loss, new or worsening tiredness, weakness, fever/chills, lightheadedness, and less frequent urination.

PBC is a rare and chronic liver disease that disproportionately affects women. The condition causes the small bile ducts in the liver to become inflamed and destroyed, resulting in damage to liver cells as bile remains trapped. Untreated, PBC can lead to cirrhosis, liver failure, and death.

The agency last month declined to grant full approval to obeticholic acidopens in a new tab or window for PBC, a decision that followed a meeting of the agency's Gastrointestinal Drugs Advisory Committee, which agreed that the FXR agonist did not have a favorable benefit-risk profileopens in a new tab or window as a second-line agent in PBC patients without contraindications. On whether the available data supported a clinical benefit, 13 of the 14 panelists said no.

It is unclear if the agency will seek to withdraw the drug in the future, as it has done with multiple cancer drugsopens in a new tab or window that failed confirmatory trialsopens in a new tab or window. In September, the European Commission revoked obeticholic acid's marketing authorizationopens in a new tab or window for PBC.

COBALTopens in a new tab or window, the main trial supporting a potential full approval, was hampered by unblinding and treatment crossover but nonetheless failed to demonstrate a significant benefit in the full study population and showed trends of excess liver transplants and death in patients assigned to obeticholic acid without contraindications.

Notably, the FDA this year granted accelerated approval to two other drugs -- seladelpar (Livdelzi)opens in a new tab or window and elafibranor (Iqirvo)opens in a new tab or window -- for PBC.

https://www.medpagetoday.com/gastroenterology/generalhepatology/113355

Could Psoriasis Treatment Be This Simple?

 A derivative of the diuretic drug amiloride (Midamor) blocked key inflammatory pathways in mouse models of psoriasis, including xenografts of psoriatic human skin, as well as in cultured patient skin samples, researchers said.

Skin cells taken from human psoriasis patients, reconstructed into tissue and grafted onto immunodeficient mice, "showed pronounced psoriasiform hyperplasia" when treated with a placebo solution, but when benzyl amiloride was applied, no such abnormal growth was seen, according to M. Peter Marinkovich, MD, of Stanford University in Palo Alto, California, and colleagues.

In addition, experiments with cultured psoriatic skin cells showed that the agent prevented cell growth driven by epidermal growth factor, the group reported in Science Translational Medicineopens in a new tab or window. The live-animal studies also showed that benzyl amiloride, also known as benzamil, effectively inhibited skin inflammation when given systemically as well as topically.

These studies "demonstrate the potential of the sodium channel inhibitor benzamil as a prototype for an effective, cost-efficient, and targeted therapeutic for skin inflammation," Marinkovich and colleagues wrote. "Future studies will ultimately determine the tolerability and efficacy of sodium channel inhibitors for translating these findings to the clinic."

The investigators didn't begin by thinking that a sodium channel blocker would be effective in psoriasis. Rather, they ended up with it through a computational analysis of previously published gene expression profiles for existing psoriasis treatments, the results of which (called Prototype Ranked Lists or PRLs) were then compared with expression profiles generated from psoriasis patients' cells, also compiled into PRLs. It's then possible to identify existing drugs that might work to oppose pathologic gene expression.

Thus, the group explained, "a meta-analysis of publicly available datasets from disease PRLs of lesional skin of 200 patients with psoriasis was compared with that of drug PRL gene expression signatures. This identified the drug benzamil ... as a therapeutic candidate. Benzamil showed a marked anticorrelation with psoriasis, which implicated down-regulation of pathways involving epidermal signaling and epidermal-immune cross-talk."

Benzamil is not itself an FDA-approved drug, but it's widely available for research purposes. It's considerably more potent than amiloride, which, in the above analysis and also in the published literature, had no suggestion of being effective in psoriasis. As the authors noted, benzamil's potential toxicity as well as clinical efficacy obviously needs to be explored in additional studies.

Key to the drug's effect is its inhibition of a pathway involving Rac1, shorthand for Ras-related C3 botulinum toxin substrate 1. "Previous work has shown that epidermal-specific Rac1 and STAT3 activation can promote abnormal IL [interleukin]-17- and IL-23-mediated immune activity and induce a phenotype in mice closely resembling human psoriasis," the researchers wrote. In 2016, a group with many of the same authors reported another xenograft studyopens in a new tab or window showing that inhibiting Rac1 in a different way was able to "rescue" psoriatic cell growth and inflammation.

Overall, this line of research and the new benzamil study indicate that "modulation of sodium flux in keratinocytes can regulate Rac1 activity by decreasing submembranous pH."

Marinkovich and colleagues remarked that further tweaks to the benzamil molecule might lead to an even better drug candidate. Even as is, benzamil is particularly attractive as a topical treatment, they wrote, since it should be safer than the "high-potency steroids" now often used to control psoriatic lesions and would also lack unwanted systemic immunosuppression.

Disclosures

The study was funded by the National Institute of General Medical Sciences.

Several co-authors reported serving as co-founders and/or holding stock in companies licensing technology related to the study; four of them are listed as inventors on patent applications for benzyl amiloride as a psoriasis therapy. Others reported relationships with numerous established pharmaceutical and electronics companies.

Primary Source

Science Translational Medicine

Source Reference: opens in a new tab or windowWinge MCG, et al "Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation" Sci Transl Med 2024; DOI: 10.1126/scitranslmed.ade5915.


https://www.medpagetoday.com/dermatology/psoriasis/113348

Ryan Routh's Lawyer Indicates Possible Insanity Defense In Trump Assassination Attempt Case

 by Jacob Burg and Sam Dorman via The Epoch Times (emphasis ours),

FORT PIERCE, Fla.—An attorney for Ryan Routh, the man suspected of attempting to assassinate then-presidential candidate Donald Trump earlier this year, indicated in court on Dec. 11 that he was showing signs of mental illness.

Ryan Wesley Routh participates in a rally in central Kyiv, Ukraine, on April 30, 2022. Efrem Lukatsky/ AP Photo

During a status conference with Judge Aileen Cannon, defense attorney Kristy Militello said that witnesses had described Routh as hallucinating and delusional. Militello said it could take months to interview experts to evaluate Routh’s mental health.

Cannon seemed skeptical and concerned that the court needed a more concrete or specific timeline for getting expert input. The defense also said it sought access to Routh’s childhood school records in an apparent attempt to capture his mental health history.

Assistant U.S. Attorney John Shipley Jr. criticized the idea that the defense would need to go through decades-old school records.

Insanity is at the moment of the crime,” Shipley said, emphasizing Routh’s ability to distinguish between right and wrong at the time of the criminal offense.

Pretrial considerations of Routh’s mental fitness could add to potential delays in the case, which Cannon scheduled for a trial in February. Earlier this week, the defense expressed concern about the breadth of material in pretrial discovery and requested that Cannon delay the trial until at least December 2025.

The prosecution said it was open to delay but that a delay that long was unwarranted.

In a filing on Dec. 10, Shipley told Cannon that while discovery was “indeed substantial,” much of the discovery involved content from Routh’s personal devices. Of the 18 cellphones the defense highlighted in their motion to delay, 17 belonged to the defendant, Shipley said.

“And while defense counsel may not be personally familiar with these devices, the lion’s share of their contents likely has little relevance to any serious defense,” his filing read.

During the Dec. 11 status conference, Militello, the defense attorney, said Routh may have forgotten some of the contents, which could also include information the defense attorneys were unaware of.

During the hearing, the prosecution expressed concern about Routh potentially tainting the jury pool with public statements defending himself. In both Shipley’s file and at the hearing, the prosecution referenced a recorded phone call Routh made from jail.

“In a recorded October 15, 2024 call from FDC-Miami, for example, Routh told a family member that he seeks publicity to aid his case at trial and to put out the word to jurors that he is, in his view, an honorable person,” Shipley’s filing read.

Cannon asked Shipley on Dec. 11 whether he could provide the recording for the court, and Shipley said he could. After the hearing, the court docket showed a filing in which the U.S. attorney’s office notified the court of its filing of a DVD with the recording to the court’s clerk.

“With any delay comes the increased risk that Routh, through his deliberate pre-trial publicity campaign, will impermissibly influence the jury poll, which at minimum will make it harder for this Court to seat an impartial jury,” Shipley said in his filing on Dec. 10.

He suggested during the status conference that the trial, with jury selection, could take longer than two weeks.

So far, the discovery has included electronic data downloaded from 18 phones, expert analyses, electronic data from multiple tablets and laptops, video surveillance, financial records, about 3,000 photographs, travel records, and other items.

Reading thousands of pages of materials, watching untold hours of video, and analyzing tens of thousands of digital pages of information will require many months,” the defense’s filing read.

The prosecution said it was trying to line up multiple experts, including a ballistics expert who could speak to the range available to Routh.

The dispute over trial delay follows a separate pretrial dispute over Cannon’s impartiality. Routh moved for Cannon to recuse herself after she was randomly assigned to his case in September.

Cannon has overseen two cases involving Trump, including his classified documents case, which she dismissed in July over the legality of special counsel Jack Smith’s appointment.

Cannon denied Routh’s recusal motion, stating on Oct. 29, “I have never spoken to or met former President Trump except in connection with his required presence at an official judicial proceeding, through counsel.”

Routh, 58, has been charged with attempted assassination, along with other counts such as assaulting a Secret Service agent.

He faces potential life imprisonment, the Department of Justice said in a statement.

https://www.zerohedge.com/political/ryan-rouths-lawyer-indicates-possible-insanity-defense-trump-assassination-attempt-case