Tag: Stomach

Gut bacteria and tryptophan diet can play a protective role against pathogenic E. coli

[ad_1]

Gut bacteria and a diet rich in the amino acid tryptophan can play a protective role against pathogenic E. coli, which can cause severe stomach upset, cramps, fever, intestinal bleeding and renal failure, according to a study published March 13 in Nature.

The research reveals how dietary tryptophan – an amino acid found mostly in animal products, nuts, seeds, whole grains and legumes – can be broken down by gut bacteria into small molecules called metabolites. It turns out a few of these metabolites can bind to a receptor on gut epithelial (surface) cells, triggering a pathway that ultimately reduces the production of proteins that E. coli use to attach to the gut lining where they cause infection. When E. coli fail to attach and colonize the gut, the pathogen benignly moves through and passes out of the body.

The research describes a previously unknown role in the gut for a receptor, DRD2. DRD2 has otherwise been known as a dopamine (neurotransmitter) receptor in the central and peripheral nervous systems.

It’s actually two completely different areas that this receptor could play a role in, which was not appreciated prior to our findings. We essentially think that DRD2 is moonlighting in the gut as a microbial metabolite sensor, and then its downstream effect is to help protect against infection.”

Pamela Chang, associate professor of immunology in the College of Veterinary Medicine and of chemical biology in the College of Arts and Sciences

Samantha Scott, a postdoctoral researcher in Chang’s lab, is first author of the study, “Dopamine Receptor D2 Confers Colonization Resistance via Microbial Metabolites.”

Now that Chang, Scott and colleagues have identified a specific pathway to help prevent E. coli infection, they may now begin studying the DRD2 receptor and components of its downstream pathway for therapeutic targets.

In the study, the researchers used mice infected with Citrobacter rodentium, a bacterium that closely resembles E. coli, since certain pathogenic E. coli don’t infect mice. Through experiments, the researchers identified that there was less pathogen and inflammation (a sign of an active immune system and infection) after mice were fed a tryptophan-supplemented diet. Then, to show that gut bacteria were having an effect, they gave the mice antibiotics to deplete microbes in the gut, and found that the mice were infected by C. rodentium in spite of eating a tryptophan diet, confirming that protection from tryptophan was dependent on the gut bacteria.

Then, using mass spectrometry, they ran a screen to find the chemical identities of tryptophan metabolites in a gut sample, and identified three such metabolites that were significantly increased when given a tryptophan diet. Again, based on pathogen levels and inflammation, when these three metabolites alone were fed to the mice, they had the same protective effect as giving the mice a full tryptophan diet.

Switching gears, the researchers used bioinformatics to find which proteins (and receptors) might bind to the tryptophan metabolites, and from a long list they identified three related receptors within the same family of dopamine receptors. Using a human intestinal cell line in the lab, they were able to isolate receptor DRD2 as the one that had the protective effect against infection in the presence of tryptophan metabolites.

Having identified the metabolites and the receptor, they analyzed the downstream pathway of DRD2 in human gut epithelial cells. Ultimately, they found that when the DRD2 pathway was activated, the host’s ability to produce an actin regulatory protein was compromised. C. rodentium (and E. coli) require actin to attach themselves to gut epithelial cells, where they colonize and inject virulence factors and toxins into the cells that cause symptoms. But without actin polymerization they can’t attach and the pathogen passes through and clears.

The experiments revealed a new role of dopamine receptor DRD2 in the gut that controls actin proteins and affects a previously unknown pathway for preventing a pathogenic bacteria’s ability to colonize the gut.

Jingjing Fu, a former postdoctoral researcher in Chang’s lab, is a co-author.

The study was supported by the Arnold and Mabel Beckman Foundation, a President’s Council of Cornell Women Affinito-Stewart Grant, the National Institutes of Health and a Cornell Institute of Host-Microbe Interactions and Disease Postdoctoral Fellowship.

Source:

Journal reference:

Scott, S. A., et al. (2024). Dopamine receptor D2 confers colonization resistance via microbial metabolites. Nature. doi.org/10.1038/s41586-024-07179-5

[ad_2]

Source link

March 14, 2024
New analysis sheds light on cancer incidence and mortality trends in the UK

[ad_1]

In a recent study published in BMJ, researchers investigated trends in cancer incidence and deaths in the United Kingdom (UK) among individuals aged between 35 and 69 years.

Study: 25 year trends in cancer incidence and mortality among adults aged 35-69 years in the UK, 1993-2018: retrospective secondary analysis. Image Credit: Image Point Fr/Shutterstock.com

Background

Over the last 25 years, the UK has seen remarkable improvements in cancer risk factors, including a decline in smoking prevalence as a result of tariff rises, advertising restrictions, and smoke-free laws. Diet and exercise are leading to an increase in the number of overweight or obese individuals.

Between 1993 and 2018, three screening programs for cervical, breast, and bowel cancer were implemented, with the ability to detect non-harmful cases. However, there is limited recent research on cancer incidences and deaths among those aged 35 to 69.

About the study

In the present study, researchers examined changes in cancer incidences and deaths in the United Kingdom between 1993 and 2018 for individuals aged 35 to 69 years.

The researchers examined cancer registration, deaths, and nationwide population-level data from the Public Health Wales, Office for National Statistics (ONS), North Ireland Cancer Registry, Public Health Scotland, the General Register Office for North Ireland, and National Health Service (NHS) England.

They investigated 23 cancer locations in the United Kingdom to determine cancer incidence and deaths among individuals aged 35 to 69 who received cancer diagnoses or died from cancers between 1993 and 2018.

The team used the International Classification of Diseases, Tenth Revision (ICD-10) codes to diagnose cancers. The primary outcomes were changes in cancer incidences and deaths based on age across time.

Sex-specific cancer groups were evaluated without breast and prostate cancers to examine general trends in the absence of the most prevalent cancer site for each gender.

Mesothelioma was a new particular code released in ICD-10, and there were no credible mortality statistics available for this site before 2001; hence, the researchers did not include this kind of malignancy.

They included non-malignant brain and spinal cord tumor codes, despite their benign character, because their presence in the cranial cavity can lead to death.

The researchers omitted non-melanoma skin cancer from the incidence statistics due to incomplete documentation of these tumors, making the data unreliable. To account for yearly volatility in low-case sites, the researchers estimated three-year rolling average age-standardized rates per 100,000 population. They used generalized linear modeling for analysis.

Results

Cancer incidence among individuals aged 35 to 69 years increased by 57% (86,297 from 55,014) for males and 48% (88,970 from 60,187) for women, with an average yearly growth of 0.80% for both genders.

Between 2003 and 2013, prostate and breast cancers grew in both sexes, with the male age-standardized incidence rate falling before 2000 and rising among women. Less frequent malignancies, such as melanoma, skin, liver, mouth, and kidney, have also shown alarming rises.

For males aged 35 to 69 years, the highest mean yearly percentage elevations were for malignancies of hepatic tissues (4.70%), prostate (4.20%), and skin melanomas (4.20%). The highest yearly declines were for stomach (4.2%), bladder (4.10%), and lung (2.10%) cancers.

For females, the highest average yearly percentage increases were for the liver (3.90%), skin melanomas (3.50%), and mouth (3.30%) cancers, whereas the highest annual declines were for bladder (3.60%) and stomach (3.10%).

Over the past 25 years, cancer fatalities were reduced by 20% (26,322 from 32,878) in men and 17% (23,719 from 28,516) in women. Age-standardized mortality rates for all malignancies were decreased by 37% (2.0% each year) in men and 33% (1.6% per year) in women.

The study discovered that after omitting prostate cancer from mortality trends, men’s death rates fell considerably, whereas women’s mortality decreased by 1.3% each year. The highest decline in mortality happened before 2000, with 14% in males and 11% in females.

The most significant declines were shown in bladder, mesothelioma, and stomach malignancies in males, as well as stomach, cervical, and non-Hodgkin lymphoma in women.

For males, the cancers with mean yearly percentage decreases in death rates of ≥1.0% per year were stomach (5.10%), mesothelioma (4.20%), bladder (3.20%), lung (3.10%), non-Hodgkin lymphoma (2.90%), testis (2.80%), Hodgkin lymphoma (2.60%), larynx (2.50%), bowel (2.50%), prostate (1.80%), myeloma (1.70%), and leukemia (1.60%).

For females, the cancers with mean yearly reductions in death rates of ≥1.0% were of the stomach (4.20%), cervix (3.60%), non-Hodgkin lymphomas (3.20%), ovaries (2.80%), breast (2.80%), myeloma (2.30%), bowel (2.20%), mesothelioma (2.0%), laryngeal tissues (2.0%), leukemia (2.0%), bladder (1.60%), esophagus (1.20%), and kidneys (1.00%).

In both sexes, liver (2.70%) and mouth (1.20%) malignancies had mean yearly mortality increases of ≥1.0%.

Conclusion

The study findings showed that cancer mortality in males and females aged 35 to 69 years decreased significantly over the last 25 years, primarily due to cancer prevention, early diagnosis, improved diagnostic testing, and successful treatment.

However, an increase in nonsmoking risk factors may result in a rise in some malignancies. The research provides a baseline for the coming years, assessing the influence of coronavirus disease 2019 (COVID-19) on cancer incidences and outcomes.

There are increased concerns regarding specific cancer sites, with the highest concern being the need to expedite the decline in female lung cancer.

[ad_2]

Source link

March 14, 2024
Biocompatible, bioresorbable sticker detects anastomotic leaks

[ad_1]

Researchers led by Northwestern University and Washington University School of Medicine in St. Louis have developed a new, first-of-its-kind sticker that enables clinicians to monitor the health of patients’ organs and deep tissues with a simple ultrasound device.

When attached to an organ, the soft, tiny sticker changes in shape in response to the body’s changing pH levels, which can serve as an early warning sign for post-surgery complications such as anastomotic leaks. Clinicians then can view these shape changes in real time through ultrasound imaging.

Currently, no existing methods can reliably and non-invasively detect anastomotic leaks -; a life-threatening condition that occurs when gastrointestinal fluids escape the digestive system. By revealing the leakage of these fluids with high sensitivity and high specificity, the non-invasive sticker can enable earlier interventions than previously possible. Then, when the patient has fully recovered, the biocompatible, bioresorbable sticker simply dissolves away -; bypassing the need for surgical extraction.

The study will be published on Friday (March 8) in the journal Science. The paper outlines evaluations across small and large animal models to validate three different types of stickers made of hydrogel materials tailored for the ability to detect anastomotic leaks from the stomach, the small intestine and the pancreas.

“These leaks can arise from subtle perforations in the tissue, often as imperceptible gaps between two sides of a surgical incision,” said Northwestern’s John A. Rogers, who led device development with postdoctoral fellow Jiaqi Liu. “These types of defects cannot be seen directly with ultrasound imaging tools. They also escape detection by even the most sophisticated CT and MRI scans. We developed an engineering approach and a set of advanced materials to address this unmet need in patient monitoring. The technology has the potential to eliminate risks, reduce costs and expand accessibility to rapid, non-invasive assessments for improved patient outcomes.”

“Right now, there is no good way whatsoever to detect these kinds of leaks,” said gastrointestinal surgeon Dr. Chet Hammill, who led the clinical evaluation and animal model studies at Washington University with collaborator Dr. Matthew MacEwan, an assistant professor of neurosurgery. “The majority of operations in the abdomen -; when you have to remove something and sew it back together -; carry a risk of leaking. We can’t fully prevent those complications, but maybe we can catch them earlier to minimize harm. Even if we could detect a leak 24- or 48-hours earlier, we could catch complications before the patient becomes really sick. This new technology has potential to completely change the way we monitor patients after surgery.”

A bioelectronics pioneer, Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery, with appointments at the McCormick School of Engineering and Northwestern University Feinberg School of Medicine. He also directs the Querrey Simpson Institute for Bioelectronics. At the time of the research, Hammill was an associate professor of surgery at Washington University. Rogers, Hammill and MacEwan co-led the research with Heling Wang, an associate professor at Tsinghua University in Beijing.

The importance of being early

All gastrointestinal surgeries carry the risk of anastomotic leaks. If the leak is not detected early enough, the patient has a 30% chance of spending up to six months in the hospital and a 20% chance of dying, according to Hammill. For patients recovering from pancreatic surgery, the risks are even higher. Hammill says a staggering 40-60% of patients suffer complications after pancreas-related surgeries.

The biggest problem is there’s no way to predict who will develop such complications. And, by the time the patient is experiencing symptoms, they already are incredibly ill.

“Patients might have some vague symptoms associated with the leak,” Hammill said. “But they have just gone through big surgery, so it’s hard to know if the symptoms are abnormal. If we can catch it early, then we can drain the fluid. If we catch it later, the patient can get sepsis and end up in the ICU. For patients with pancreatic cancer, they might only have six months to live as it is. Now, they are spending half that time in the hospital.”

In search of improved outcomes for his patients, Hammill contacted Rogers, whose laboratory specializes in developing engineering solutions to address health challenges. Rogers’ team had already developed a suite of bioresorbable electronic devices to serve as temporary implants, including dissolving pacemakers, nerve stimulators and implantable painkillers.

The bioresorbable systems piqued Hammill’s interest. The greatest odds of developing an anastomotic leak occur either three days or two weeks after surgery.

“We like to monitor patients for complications for about 30 days,” Hammill said. “Having a device that lasts a month and then disappears sounded ideal.”

Enhancing ultrasound

Instead of developing new imaging systems, Rogers speculated that his team might be able to enhance current imaging methods -; allowing them to “see” features that otherwise would be invisible. Ultrasound technology already has many advantages: it’s inexpensive, readily available, does not require cumbersome equipment and does not expose patients to radiation or other risks.

But, of course, there is a major drawback. Ultrasound technology -; which uses sound waves to determine the position, shape and structure of organs -; cannot reliably differentiate between various bodily fluids. Blood and gastric fluid, for example, appear the same.

“The acoustic properties of the leaking fluids are very similar to those of naturally occurring biofluids and surrounding tissues,” Rogers said. “The clinical need, however, demands chemical specificity, beyond the scope of fundamental mechanisms that create contrast in ultrasound images.”

Ultimately, Rogers’ team devised an approach to overcome this limitation by using tiny sensor devices designed to be readable by ultrasound imaging. Specifically, they created a small, tissue-adhesive sticker out of a flexible, chemically responsive, soft hydrogel material. Then, they embedded tiny, paper-thin metal disks into the thin layers of this hydrogel. When the sticker encounters acidic fluids, such as stomach acid, it swells. When the sticker encounters caustic fluids, such as pancreatic fluids, it contracts.

Making the invisible visible

As the hydrogel swells or shrinks in response to changing pH, the metal disks either move apart or closer together, respectively. Then, the ultrasound can view these subtle changes in placement.

“Because the acoustic properties of the metal disks are much different than those of the surrounding tissue, they provide very strong contrast in ultrasound images,” Rogers said. “In this way, we can essentially ‘tag’ an organ for monitoring.” Because the need for monitoring extends only during a postsurgical recovery, Rogers team designed these stickers with bioresorbable materials. They simply disappear naturally and harmlessly in the body after they are no longer needed.

Computational collaborator Yonggang Huang, the Jan and Marcia Achenbach Professorship in Mechanical Engineering and professor of civil and environmental engineering at McCormick, used acoustic and mechanical simulation techniques to help guide optimized choices in materials and device layouts to ensure high visibility in ultrasound images, even for stickers located at deep positions within the body.

“CT and MRI scans just take a picture,” Hammill added. “The fluid might show up in a CT image, but there’s always fluid collections after surgery. We don’t know if it’s actually a leak or normal abdominal fluid. The information that we get from the new patch is much, much more valuable. If we can see that the pH is altered, then we know that something isn’t right.”

Rogers team constructed stickers of varying sizes. The largest measures 12 millimeters in diameter, while the smallest is just 4 millimeters in diameter. Considering that the metal disks are each 1 millimeter or smaller, Rogers realized that it might be difficult for radiologists to assess the images manually. To overcome this challenge, his team also developed software that can automatically analyze the images to detect with high accuracy any relative movement of the disks.

Improving quality of life

To evaluate the efficacy of the new sticker, Hammill’s team tested it in both small and large animal models. In the studies, ultrasound imaging consistently detected changes in the shape-shifting sticker -; even when it was 10 centimeters deep inside of tissues. When exposed to fluids with abnormally high or low pH levels, the sticker altered its shape within minutes.

Rogers and Hammill imagine that the device could be implanted at the end of a surgical procedure. Or, because it’s small and flexible, the device also fits (rolled up) inside a syringe, which clinicians can use to inject the tag into the body.

“These tags are so small and thin and soft that surgeons can easily place collections of them at different locations,” Rogers said. “For example, if an incision extends by a few centimeters in length, an array of these tags can be placed along the length of the site to develop a map of pH for precisely locating the position of the leak.”

“It’s obviously an early prototype, but I can envision the final product where, at the end of surgery, you just place these little patches for monitoring,” Hammill said. “It does its job and then completely disappears. This could have a huge impact on patients, their recovery time and, ultimately, their quality of life.”

Next, Rogers and his team are exploring similar tags that could detect internal bleeding or temperature changes. “Detecting changes in pH is a good starting point,” Rogers said. “But this platform can extend to other types of applications by use of hydrogels that respond to other changes in local chemistry, or to temperature or other properties of clinical relevance.”

Source:

Northwestern University

Journal reference:

Liu, J., et al. (2024) Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis. Science. doi.org/10.1126/science.adk9880.

[ad_2]

Source link

March 7, 2024
UK lags in cancer treatment compared to other countries
[ad_1]
People in the UK were treated with chemotherapy and radiotherapy less often than in comparable countries and faced long waits for treatments, according to two new studies published in The Lancet Oncology.

In the first research of its kind, investigators at University College London examined data from over 780,000 people with cancer diagnosed between 2012 and 2017 in four comparable countries (Australia, Canada, Norway and the UK). Eight cancer types were included: oesophageal, stomach, colon, rectal, liver, pancreatic, lung and ovarian cancer.

The two studies by the International Cancer Benchmarking Partnership (ICBP) are the first to examine treatment differences for eight cancer types in countries across three continents. Building on previous research, the findings provide further insights into why cancer survival in the UK lags behind internationally.

The research concluded that:
- There was stark variation in the treatment of all eight cancer types and people with cancer in the UK received chemotherapy and radiotherapy less often than other countries. Fewer lung cancer patients in the UK (27.7%) were treated with chemotherapy compared to Canada (35.0%), Norway (45.3%) and Australia (41.4%)
- Older patients were least likely to be treated with chemotherapy and radiotherapy, particularly in the UK. For example, 2.4% of UK patients aged 85 and over received chemotherapy, compared to 8.1% in Australia and 14% in Ontario, Canada
- Countries with better cancer survival typically had higher use of chemotherapy and radiotherapy and shorter waits to start treatment in this study. For example, 5-year net survival for stage 3 colon cancer was higher in Norway (70.7%), Canada (69.9%) and Australia (70.1%) than in the UK (63.3%)
- Overall, people living in Norway and Australia started chemotherapy and radiotherapy in the quickest time
- Patients in the UK faced long waits for treatment, and this varied depending on where people live. The average time to start chemotherapy was shortest in England (48 days) and longest in Scotland (65 days). Northern Ireland had the shortest average time to start radiotherapy (53 days) and Scotland (79 days) and Wales (81 days) had the longest
The UK should be striving for world-leading cancer outcomes. All cancer patients, no matter where they live, deserve to receive the highest quality care. But this research shows that UK patients are treated with chemotherapy and radiotherapy less often than comparable countries.

When it comes to treating cancer, timing really matters. Behind these statistics are people waiting anxiously to begin treatment that is key to boosting their chances of survival.

We can learn a great deal from other countries who have stepped up and substantially improved cancer services. With a general election on the horizon, the UK Government has a real opportunity to buck the trends we see in this research and do better for people affected by cancer.”

Michelle Mitchell, Chief Executive, Cancer Research UK

Although not every patient will require them, chemotherapy and radiotherapy are key treatment options – it’s estimated around 4 in 10 people with cancer in the UK should receive radiotherapy as part of their care. With cancer cases projected to rise in the UK, demand for these treatments will substantially increase. And a wider range of people, including older people with more complex healthcare needs, will require cancer treatment.

While some cancer patients need time to prepare for treatment, others are forced to wait too long. This can result in people’s cancers continuing to grow and spread, potentially impacting the success of their treatment and further exacerbating their stress and anxiety levels.

Cancer Research UK said that concerning delays to begin treatment in the UK are partly a result of the UK Government’s lack of long-term planning on cancer in recent decades. Countries with more robust cancer strategies backed by sufficient funding have seen larger improvements in survival than the UK.

There are a range of factors driving international differences in the use of chemotherapy and radiotherapy. Cancer Research UK said that workforce and capacity pressures across the UK health system are barriers to delivering world-class treatment for patients.

As outlined in the charity’s recently published manifesto, ‘Longer, better lives’, the UK’s cancer crisis could be turned around with a long-term plan to deliver investment and reform needed in the NHS.

As part of this, Cancer Research UK is calling for a strategic approach to addressing treatment variation. Better data collection and investment in clinical audit and quality improvement would help us understand and tackle why access to timely, quality treatment differs.

Clinical lead for the International Cancer Benchmarking Partnership and an ovarian cancer surgeon, Dr John Butler, said:

“For many aggressive cancers – such as ovarian, lung and pancreatic cancer, it’s vital that people are diagnosed and start treatment as soon as possible. Lower use of chemotherapy and radiotherapy in the UK could impact people’s chances of survival, especially for older patients.

“Although we have made progress, the last benchmark showed that cancer survival in the UK is still around 10 to 15 years behind leading countries. This study captures missed opportunities for patients in the UK to receive life-prolonging treatment.

“The next phase of our research will explore these treatment differences in more depth and look to understand the impact of the Covid pandemic on cancer patient’s care.”

Lead researcher from University College London, Professor Georgios Lyratzopoulos, said:

“This study builds on over a decade of ICBP research into how cancer diagnosis and care varies internationally. We already know that the cancer survival in the UK has fallen behind countries like Australia and Canada, and this analysis of two key cancer treatments highlights one of the likely reasons.

“With cancer cases projected to rise in the UK, the NHS must be equipped to deliver the best care for patients. The cancer treatment landscape is changing at pace, but capacity issues and system pressures mean that not all patients can feel the benefit of specialist cancer treatments.

“To improve the UK’s cancer outcomes, we need to continue to investigate what is driving international variation in treatment – better data collection is key to this.”

Source:

Journal reference:

McPhail, S., et al. (2024) Use of chemotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study. The Lancet Oncology. doi.org/10.1016/S1470-2045(24)00031-7.
[ad_2]

Source link
February 27, 2024
Early advanced therapy significantly improves Crohn’s disease outcomes

[ad_1]

A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced therapy to all patients straight after diagnosis can drastically improve outcomes, including by reducing the number of people requiring urgent abdominal surgery for treatment of their disease by ten-fold.

The PROFILE trial, led by researchers at the University of Cambridge, involved 386 patients with newly-diagnosed active Crohn’s disease. Recruiting from 40 hospitals across the UK, and supported by the National Institute for Health and Care Research (NIHR) Clinical Research Network, it sought to test whether a biomarker – a genetic signature – could predict which patients were at greatest risk of relapses of their condition, and to test two different approaches to treating the disease.

Crohn’s disease is a life-long condition characterised by inflammation of the digestive tract. It affects around one in 350 people in the UK. Even at its mildest, it can cause symptoms that have a major impact on quality of life including: stomach pain, diarrhoea, weight loss and fatigue. Typically patients experience ‘flares’ of inflammation, where their condition worsens for a time, producing more symptoms and progressive bowel damage. As many as one in 10 patients will require urgent abdominal surgery to treat their condition within their first year of diagnosis.

The findings of the PROFILE trial, sponsored by Cambridge University Hospitals (CUH) NHS Foundation Trust and the University of Cambridge, are published today in The Lancet Gastroenterology and Hepatology. While the biomarker did not prove useful in selecting treatments for individual patients, a ‘top-down’ treatment strategy involving use of the drug infliximab straight after diagnosis, showed dramatic results.

Infliximab works by blocking a protein found in the body’s immune system, TNF (tumour necrosis factor)-alpha, which plays an important role in inflammation. The drug is administered through regular intravenous infusions directly into the bloodstream or injections under the skin. However, due to historical concerns about cost and side-effects – including an increased risk of infection related to immunosuppression – it is currently only offered when patients experience regular flare-ups that do not respond to less potent treatments.

In the PROFILE trial, patients were assigned at random to one of two treatment groups. Each group was given a different treatment strategy and patients were followed up over the course of a year.

The first group was treated using an ‘accelerated step-up’ approach, which is the conventional treatment strategy used in the UK and across most countries around the world. In this group, patients only started on infliximab if their disease was progressing and not responding to other simpler treatments.

The second group, however, was treated using ‘top-down’ therapy – that is, they were provided with infliximab as soon as possible after their diagnosis, regardless of the severity of their symptoms.

The results were dramatic: 80% of people receiving the top-down therapy had both symptoms and inflammatory markers controlled throughout the course of the entire year compared to only 15% of people receiving the accelerated step-up therapy.

Two-thirds (67%) of patients in the ‘top-down’ group had no ulcers seen on their endoscopy camera test at the end of the trial – something known as endoscopic remission. Endoscopic remission is considered very important as this has been consistently associated with decreased risk of later complications in Crohn’s disease. Most previous clinical trials of therapies have been considered highly successful based on getting 20 to 30% of patients into endoscopic remission.

As well as these findings, patients in the top-down arm also had higher quality of life scores, less use of steroid medication and lower number of hospitalisations.

Strikingly, while around one in 20 patients (5%) in the conventional treatment arm of the trial required urgent abdominal surgery for their Crohn’s disease, only one in 193 (0.5%) receiving the ‘top-down’ therapy required such surgery.

Dr Nuru Noor from the Department of Medicine at the University of Cambridge, one of the study’s lead researchers and first author of the trial, said: “Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore ‘good enough’. But our findings redefine what should be considered early treatment.

“As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking – and has likely been ticking for some time – in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible. We’ve shown that by treating earlier, we can achieve better outcomes for patients than have previously been reported.”

In fact, say the researchers, the improvements seen among the trial patients receiving ‘top-down’ therapy might be even more stark compared to usual clinical care. Few patients with Crohn’s disease in standard clinical care receive the rapid, ‘accelerated step-up’ approach provided by the trial protocol, and so the benefits of implementing a ‘top-down’ approach in standard clinical care might be even more pronounced.

Crucially, the team found no difference in risk of serious infection between treatment strategies, suggesting that infliximab straight after diagnosis was well tolerated, contrary to previous concerns about its safety. In addition, the cost of the drug, which is now an off-patent, generic and ‘biosimilar’ medicine, has fallen considerably from around £15,000 to around £3,000 per patient per year.

Up until now, the view has been ‘Why would you use a more expensive treatment strategy and potentially over-treat people if there’s a chance they might do fine anyway?’

As we’ve shown, and as previous studies have demonstrated, there’s actually a pretty high risk that an individual with Crohn’s disease will experience disease flares and complications even in the first year after diagnosis.

We now know we can prevent the majority of adverse outcomes, including need for urgent surgery, by providing a treatment strategy that is safe and becoming increasingly affordable. If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer ‘top-down’ therapy straight after diagnosis rather than having to wait and use ‘step-up’ treatment.”

Professor Miles Parkes, Chief Investigator of the PROFILE trial, Director of the NIHR Cambridge Biomedical Research Centre

The PROFILE team are now actively working on an analysis of the health economics to see whether the benefits of the therapy outweigh its cost.

Professor Parkes added: “It’s not just those five per cent of people requiring surgery that we need to think about. In the ‘step-up’ arm lots of people experienced disease flares without necessarily needing surgery. And every time somebody flares, they require several consultations with specialist doctors and nurses, clinical investigations such as scans and colonoscopies, time off work, time out of education and so on – all leading to major impacts on quality of life for individuals.”

While there are other anti-TNF drugs, such as adalimumab, that work in a similar manner to infliximab and are significantly cheaper, more research is required to understand if it would be as clinically effective.

Ruth Wakeman, Director of Services, Advocacy & Evidence at Crohn’s & Colitis UK said: “Crohn’s Disease affects over 200,000 people in the UK and we know that many of them have symptoms for a long time before they are diagnosed. But diagnosis is not the end of their journey, and the trial and error involved in finding the right treatment can be challenging and distressing.

“This study shows what a dramatic difference early treatment with advanced therapy can make to newly-diagnosed patients. People with Crohn’s don’t want to be stuck in hospital or having surgery, they want to be out in the world, living their lives. Anything that speeds up the path to remission can only be a good thing.”

The research was funded by Wellcome and PredictImmune Ltd and supported by the NIHR Cambridge Biomedical Research Centre.

“If the drug had been offered in the first place, things could have been very different.”

Toby Moore, 28, was just ten years old when it became clear there was something wrong.

“I was at primary school at the time and was getting lots of abdominal pain, lots of going to the toilet and vomiting, low energy levels – I was effectively unable to consume any food or drink without some kind of problem. It was just terrible.”

He visited the GP repeatedly over six months, where among other things he was told it was due to the stress of Year Six exams. He says that for his mother and father, it was probably the most challenging time of their lives as parents.

“I was eventually referred to a paediatric gastroenterologist specialist who within 30 seconds of looking at me said, ‘Right. I think you have Crohn’s disease. I’d like to do these tests,’ and off we went.”

The specialist was correct. He put Toby on an ‘elemental diet’ to manage his condition, which meant that for six weeks he could eat no food or drinks (other than water), only prescription shakes aimed at allowing his digestive system to heal. Toby then had to reintroduce different foods into his diet to see if they could identify what triggered his condition.

Not long afterwards, he had a ‘flare up’, with his symptoms worsening significantly. His local Peterborough hospital was unable to help and so he was referred to the Royal Free Hospital in London. There, his parents had to make the difficult decision of whether he should receive abdominal surgery or go onto biologic medication. They chose the latter, and Toby was put on infliximab.

“If you asked my parents now, they’d call it a light switch drug. I was infused with it on a Thursday and by the Sunday I was a different person. I was eating, drinking, my symptoms had stopped. It was unbelievable. Arguably, if that had been offered in the first place instead of the lighter approach, things could have been very different.”

Toby was on infliximab for several years, but was taken off the drug in late secondary school when he became unwell – “not in a Crohn’s disease way, something else was going on”. He was taken into hospital, where the doctors immediately stopped the treatment, concerned it was a trigger.

Toby was transferred to Addenbrooke’s Hospital, where Dr Miles Parkes took over his treatment. It turned out that Toby also had large vessel vasculitis, another autoimmune condition. Whereas Crohn’s affects your digestive system, this affects blood vessels. It causes the aorta, the main blood vessel in your body, to become narrowed, which causes symptoms including weight loss, unexplained lower back pain and fatigue.

Since then, Toby has been on a number of different biologic treatments, each working for a while before their effects wear off, he experiences another flare up, and is prescribed a different drug. Were it not for the drugs, he says his life would be very different.

“It can be quite debilitating, especially when it’s flaring up, as I’m sure you can imagine, when you have minimal control over certain bodily functions. It’s not the most pleasant.”

His current medication, upadacitinib, involves taking a daily pill. It has helped him manage his condition – flare ups aside – allowing him to live a relatively normal life, hold down a steady job as a chef in a local hospice , close to where he lives, and start a family. But he still has to be very careful.

“Where possible I try to avoid stressful situations that life throws at you. When you live at your mum and dad’s life’s a bit more simple, you’ve got a few less responsibilities, so stress is slightly less, but when you go out into the big wide world – and I’ve got a two-and-a-half year old daughter now – that obviously adds a new dynamic to your life!”

Toby has nothing but praise for the NHS. “They’ve been just phenomenal. Miles is very good at nipping things in the bud straight away. He always actions things, he doesn’t just say, ‘Well, we’ll see how you are in a month’. So it never gets too out of control. My opinion of the NHS is really, really high. They’ve been a lifeline for me.”

Source:

Journal reference:

Noor, N. M., et al. (2024) A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial. The Lancet Gastroenterology & Hepatology. doi.org/10.1016/S2468-1253(24)00034-7.

[ad_2]

Source link

February 22, 2024
Can dietary patterns impact stomach cancer risk?

[ad_1]

In a recent review published in Frontiers in Oncology, researchers investigated eating patterns and indices related to gastric cancer and explored their association with stomach cancer risk.

Study: Review of dietary patterns and gastric cancer risk: epidemiology and biological evidence. Image Credit: Peakstock/Shutterstock.com

Background

Gastric cancer is a common cancer worldwide, accounting for considerable global mortality. Despite attempts to minimize Helicobacter pylori prevalence and enhance food storage, the incidence and fatality rates of stomach cancer have decreased.

Epidemiological studies have found links between eating habits and stomach cancer risk. Individual dietary components, on the other hand, have produced inconsistent results in terms of the stated risk of stomach cancer.

Assessing eating patterns yields more reliable effect estimates and outcomes, emphasizing the need for comprehensive cancer prevention recommendations.

About the review

In the present review, researchers reviewed existing data on the impact of diet on gastric cancer risk.

Diet patterns can be posteriori (formed from cohort population data) or a priori (created using existing information about food, nutrients, and illness). Posteriori patterns are determined using statistical approaches such as principal component analysis, factor analysis, and cluster analysis.

A priori patterns may derive from country-specific standards, chronic disease-preventive diets, or cultural eating habits.

Association between a posteriori eating patterns and stomach cancer

In case-control studies, healthy eating patterns minimized the risk of stomach cancer, but an “unhealthy” dietary pattern raised the risk.

A comprehensive meta-analysis revealed that greater compliance with “prudent” diet patterns was related to a lower incidence of stomach cancer [odds ratio (OR) 0.8].

In contrast, increased compliance with Western diets increased the risk of total stomach cancer (odds ratio, 1.5). The association between poor eating habits and stomach cancer risk was more robust for cardia stomach cancers (OR, 2.1) than for distal stomach cancers (OR, 1.4).

Other meta-analyses showed that individuals consuming healthy foods had decreased stomach cancer risks (OR, 0.7) considerably.

In contrast, following unhealthy diets increased stomach cancer risk (OR, 1.6). A 2017 meta-analysis found that “Western” diets increase gastric cancer risk.

However, meta-analytical research of 13 case-control studies and eight studies of the prospective cohort type found that those abiding by “prudent” diets had a lower chance of developing stomach cancer.

A priori dietary patterns, dietary indices, and gastric cancer

The relationship between eating habits and stomach cancer risk is complicated and nuanced. There is limited research on the link between high health eating index (HEI) or alternate HEI (AHEI) scores and the risk of stomach cancer.

A comprehensive review and meta-analysis found that higher adherence to HEI and AHEI dietary patterns was associated with a lower risk of total cancer-specific mortality.

New case-control research from Iran found that eating the dietary approaches to stop hypertension (DASH) diet was related to a 54% lower incidence of stomach cancer.

The DASH diet’s components, such as excessive salt intake, red meat consumption, and fruits, have been linked to an increased risk of stomach cancer.

A Markov cohort state-transition model projected that a low sodium-DASH diet reduced stomach cancer risk by 25% in men and 21% in women.

Meta-analyses indicate that Mediterranean diet (MD) followers are less likely to develop stomach cancer.

MD vitamins and fibers reduce H. pylori colonization, whereas polyphenol-rich foods and extra-virgin olive oil (EVOO) reduce inflammation by inhibiting free radicals and lowering oxidative stress.

Omega-3 fatty acids reduce triglyceride levels and inflammation, methionine reduces body weight and insulin resistance, branched-chain amino acids improve insulin sensitivity, and short-chain fatty acids reduce trimethylamine N-oxide (TMAO) and inflammation and regulate autoimmunity factors.

Patterns based on biological markers

Inflammation increases gastric cancer risk, particularly among men. Pro-inflammatory foods increase the incidence of intestinal and diffuse cancer subtypes.

The upregulation of cytokines and chemokines, which recruit several hematopoietic and progenitor cell types to inflamed stomach tissues, may cause chronic inflammation.

Gastric cancer-related inflammation includes inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α). IL-1 has an anti-tumor impact, whereas IL-6 is associated with tumor progression, invasion, and metastasis.

The ketogenic diet (KD) is associated with anti-cancer treatment in advanced gastric cancer patients. The KD alters glucose metabolism and inhibits insulin signaling and insulin-like growth factor 1 (IGF-1), the primary energy source for tumor cells. KD reduces nicotinamide adenine dinucleotide phosphate (NADPH) generation to increase oxidative stress in tumor cells.

Ad libitum KD therapy inhibits hypoxia-related and growth-driven proteins, influencing tumor progression.

Ketones enter cancer cells by monocarboxylate transporters (MCTs), limit lactate export, reduce cancer survival time, and prevent the activation of NLR family pyrin domain containing 3 (NLRP3), nuclear factor kappa B (NF-kB) and Signal transducer and activator of transcription 3 (STAT3) activation, lowering IL-1β expression.

The review findings indicate that dietary patterns can influence gastric cancer risk by influencing metabolites, gut microbiota, inflammation, and immune function.

Inconsistency in results might be owing to various factors such as meal types, recollection bias, overall energy consumption, and other confounders. Large-scale prospective cohort studies could improve the validity of the findings.

[ad_2]

Source link

February 22, 2024
New immunotherapy borrows cancer’s tricks to unleash powerful T cells

[ad_1]

Immunotherapies using engineered T cells have ushered in a new era in cancer treatment, but they have their limits. They may cause side effects or stop working, and they do not work at all against 90% of cancers.

Now, scientists at UC San Francisco and Northwestern Medicine may have found a way around these limitations by borrowing a few tricks from cancer itself.

By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potentcy to engineered T cells. The team inserted a gene for this unique mutation into normal human T cells, which made them more than 100 times more potent at killing cancer cells. They kept the tumors at bay for many months, showing no signs of becoming toxic.

While current immunotherapies work only against cancers of the blood and bone marrow, the new approach was able to kill solid tumors derived from skin, lung and stomach tissues in mice. The team has already begun working toward testing this new approach in people.

The breakthrough was inspired by the martial arts principle of using an opponent’s strength against them, said Kole Roybal, PhD, a co-author of the study and associate professor in microbiology and immunology.

We’ve used the mutations that give cancer cells their staying power to engineer what we call a ‘Judo T-cell therapy’ that can survive and thrive in the harsh conditions that tumors create.”

Kole Roybal, PhD, co-author of the study and associate professor in microbiology and immunology

The study appears Feb. 7 in Nature.

A solution hiding in plain sight

Immunology has proved difficult against most cancers because a solid tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit. Often, cancerous tumors hijack the body’s immune system, causing it to defend, rather than attack, the cancer.

Not only does this impair the ability of regular T cells to target cancer cells, it also undermines the effectiveness of engineered T cells that are used in immunotherapies, which quickly tire against the tumor’s defenses. For immunotherapy treatments to work under those conditions, “We need to give healthy T cells abilities that are beyond what they can naturally achieve,” said Roybal, who is also a member of the Gladstone Institute of Genomic Immunology.

Using such T cells from patients with lymphoma, the UCSF and Northwestern teams screened 71 mutations, eventually isolating one that proved both potent and non-toxic, subjecting it to a rigorous set of safety tests.

“This approach performs better than anything we’ve seen before,” said Jaehyuk Choi, MD, PhD, an associate professor of medical dermatology, as well as biochemistry and molecular genetics, at Northwestern University Feinberg School of Medicine.

“Our discoveries empower T cells to kill multiple cancer types and have the potential to offer cures to people who have a poor prognosis,” he said, noting that because cell therapies live and grow inside the patient, they can provide long-term immunity against cancer.

In collaboration with the Parker Institute for Cancer Immunotherapy and venture capital firm Venrock, Roybal and Choi have launched a new company, Moonlight Bio, to realize the potential of their “judo” approach. Their first project is developing a lung cancer therapy that they hope to begin testing in people within the next few years.

“We see this as the starting point,” Roybal said. “There’s so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases.”

Source:

University of California – San Francisco

Journal reference:

Garcia, J., et al. (2024). Naturally occurring T cell mutations enhance engineered T cell therapies. Nature. doi.org/10.1038/s41586-024-07018-7.

[ad_2]

Source link

February 8, 2024