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20th October 2023
The potential for detection of colorectal cancer based on an analysis of the variability in a patient‘s gut microbiome has been highlighted in a study presented at United European Gastroenterology (UEG) Week.
The findings come from the Dutch microbiome project, which is a large-scale studying involving 8,208 participants. Researchers analysed the gut microbiome of those who developed pre-cancerous colorectal lesions before faecal sampling between 2000 and 2015, in addition to those who developed such lesions following sampling between 2015 and 2022.
They then compared the results with samples taken from individuals with a normal colonoscopy, as well as exploring the range of bacterial species present and their function within the gut by reconstructing their genomes from metagenomic data.
The team identified that when compared to those who had a normal colonoscopy, individuals who developed colonic lesions after faecal sampling displayed a greater diversity in their gut microbiome. In addition, the composition and function of the microbes differed in those with pre-existing or future lesions based on the type of lesion.
In terms of the specific organisms, researchers identified that those from the family of Lachnospiraceae and the genera Roseburia and Eubacterium were linked with the future development of lesions.
Significant variation in the gut microbiome of individuals who developed pre-cancerous colorectal lesions offers another potential avenue to explore to enhance the detection and prevention of colorectal cancer.
Commenting on the findings, study lead, Dr Ranko Gacesa, postdoctoral researcher at the University Medical Center Groningen in the Netherlands, said: ‘While we didn’t investigate mechanisms in this study, it is known from previous research that some of the bacterial species identified may have properties that could contribute to the development of colorectal lesions.
‘A bacterium called Bacteroides fragilis, for example, is known to produce a toxin that can lead to chronic low-grade inflammation in the gut. Prolonged inflammation is believed to be potentially genotoxic and carcinogenic, meaning it may cause genetic damage and promote cancer.’
In a discussion of the potential implications of the study findings, Dr Gacesa added: ‘The connection between the gut microbiome and pre-cancerous lesions has been underexplored, leaving uncertainty about whether gut bacteria can predict the future onset of colorectal cancer.
‘Our findings suggest that the microbiome could act as a valuable tool to improve existing tests, advancing early detection methods for pre-cancerous lesions and colorectal cancer.’
According to the World Health Organization, colorectal cancer is the third most common cancer and there were nearly two million cases and almost one million deaths in 2020, with a spike in diagnoses of the cancer at an advanced stage during the pandemic.
In addition, an increasing number of studies reveal how the progression of colorectal cancer is related to gut microbiome composition. In fact, the published literature related to the development of colorectal cancer has demonstrated that many bacteria affect tumour development and growth. It is also clear that gut microbiome can modulate the efficacy of conventional chemotherapy, through regulating cytotoxicity by participating in the metabolic process of anti-cancer drugs.
Air pollution contains particulate matter that can carry antibiotic resistance genes, which have been found to accelerate microbial threats to human health. Here, Rod Tucker considers the extent to which air pollution could serve as a primary vector and driving force behind the increasing levels of global antibiotic resistance.
There‘s no doubt that global antibiotic resistance represents a major health challenge and is responsible for a huge number of deaths. For example, in a systematic review looking at the global burden of bacterial antimicrobial resistance in 2019, the authors estimated there were 4.95 million associated deaths.
In addition, data published in 2018 from the European Centre for Disease Prevention and Control estimated that around 33,000 people die each year in the in the European Union and European Economic Area as a direct consequence of infections with antibiotic-resistant bacteria.
Although antibiotic resistance represents the failure of a particular drug, there are a number of underlying factors responsible. Perhaps the greatest risk comes from interconnected human, animal and environmental habitats that are likely to contribute towards the emergence, evolution and spread of antibiotic resistance. In fact, resistance emerges as a result of the local confluence that occurs when bacteria colonise different human and animal hosts, enabling the spread of antibiotic resistant genes.
In response to the global rise in antibiotic resistance, countries have introduced antimicrobial stewardship programmes. Such initiatives represent a coordinated approach to promote the appropriate use of antimicrobials and reduce both microbial resistance and the spread of infections caused by multidrug-resistant organisms.
Antimicrobial stewardship programmes are predicated on the notion that antibiotic use per se, is associated with the development of resistance. However, simply controlling usage may not be an effective means of reducing the rate at which resistance develops.
This was highlighted in a 2018 analysis of the factors driving global antimicrobial resistance. It found that reducing antibiotic consumption would be unlikely to control antimicrobial resistance because the spread of resistant strains and resistance genes seemed to be the most important contributory factor.
So, if this is case, what are the most likely vectors of resistant genes?
In 2018, Chinese researchers profiled the relative abundances of 30 antibiotic resistance genes (ARGs) in urban air carried in particulate matter. They found that urban air is being polluted by ARGs and different cities are challenged with varying health risks due to airborne ARG exposure.
Moreover, fine particulate matter, with a diameter of 2.5 μm or less (i.e. PM2·5), is easily inhaled and therefore serves to increase the intake of airborne ARGs.
But to what extent is air pollution and the carriage of ARGs actually responsible for the spread of resistance?
A more recent study by Chinese researchers tried to answer this question. Writing in the journal Lancet Planetary Health, the team provided the first global estimates of antibiotic resistance and burden of premature deaths attributable to antibiotic resistance resulting from PM2·5 pollution.
They used data from multiple sources and included a number of potential confounders, such as levels of air pollution, antibiotic use, sanitation services, climate, year, and region, from a total of 116 countries collected between 2000 and 2018.
Using raw antibiotic-resistance data on nine pathogens and 43 types of antibiotic agents, the team identified significant global correlations between PM2·5 and antibiotic resistance (R2= 0.42 – 0.76, p<0.0001). Furthermore, these correlations appeared to strengthen over time.
The researchers also estimated that antibiotic resistance derived from PM2·5 led to an estimated 0.48 million premature deaths and 18.2 million years of life lost in 2018 worldwide. In other words, with a positive and robust association between PM2·5 and antibiotic resistance, the findings implied that globally, air pollution, and in particular PM2·5, was an important driving factor.
While the findings from the Lancet Planetary Health study are intriguing, this was an ecological study, which is more suited to the generation of hypotheses, and the finding of an association between air pollution and antibiotic resistance is not necessarily causal.
The authors of the paper also acknowledge some limitations. For instance, several low- and middle-income countries – the likes of which are most affected by antibiotic resistance – did not provide pathogen and antibiotic data.
In addition, the unrestricted use of antibiotics in animal farming was not examined in the study, which is a potentially important determinant of resistance in countries that also tend to have higher air pollution levels.
Finally, the authors also state that ‘some factors could be almost as important as PM2·5 in contributing to antibiotic resistance’. This is another way of stating the obvious: there are lots of other possible factors that could account for the observed association. As information on such data was unavailable, it could not be included in the statistical models.
While it is possible that air pollution is a factor linked to increased levels of antibiotic resistance, in the absence of experimental evidence to support this premise, it remains yet another factor to be considered and addressed, if possible, in the global fight to reduce the adverse outcomes associated with increased antibiotic resistance.
13th October 2023
The use of artificial intelligence (AI) software has shown a 100% detection rate for melanoma and saved over 1,000 face-to-face secondary care consultations during a 10-month period, according to a study presented at the recent European Academy of Dermatology and Venereology (EADV) Congress 2023.
The study was able to able to correctly detect all 59 cases of suspected melanoma between April 2022 and January 2023, as well as 99.5% of all skin cancers (189/190 cases) and 92.5% of pre-cancerous lesions (541/585).
The software assessed 22,356 patients with suspected skin cancers using three versions of an AI software. The first version tested in 2020-21 had an 85.9% detection rate for melanoma (195/227), 83.8% for all skin cancer (903/1,078) and 54.1% for pre-cancerous lesions (496/917).
Lead author Dr Kashini Andrew, a specialist registrar at University Hospitals Birmingham NHS Foundation Trust, commented: ‘The latest version of the software has saved over 1,000 face-to-face consultations in the secondary care setting between April 2022 and January 2023, freeing up more time for patients that need urgent attention.‘
The research team noted that the data is ‘incredibly encouraging‘, however, co-author and colleague, Dr Irshad Zaki, consultant dermatologist, said: ‘We would like to stress that AI should not be used as a standalone tool in skin cancer detection and that AI is not a substitute for consultant dermatologists.‘
Evidence of the need for appropriate clinical oversight was shown among the basal cell carcinoma cases as a single case was missed by the AI tool and later identified at a second read by what the researchers termed ‘a dermatologist “safety net“‘.
Dr Kashini Andrew added: ‘This study has demonstrated how AI is rapidly improving and learning, with the high accuracy directly attributable to improvements in AI training techniques and the quality of data used to train the AI.
‘The role of AI in dermatology and the most appropriate pathway are debated. Further research with appropriate clinical oversight may allow the deployment of AI as a triage tool. However, any pathway must demonstrate cost-effectiveness, and AI is currently not a standalone tool in dermatology. Our data shows the great promise of AI in future provision of healthcare.’
This supports the findings of previous studies including a 2022 systematic review in which the researchers concluded that ‘the performance of artificial intelligence in melanoma is satisfactory and the future for potential applications is enormous‘.
12th October 2023
Non-melanoma skin cancer (NMSC) causes more global deaths than melanoma, despite its lower severity, and dark skin phenotypes were found to be at risk, according to research presented at the recent European Academy of Dermatology and Venereology (EADV) Congress 2023.
Using data from the World Health Organization International Agency for Research on Cancer data, the researchers looked at global skin cancer epidemiology, focusing particularly on population risk profiles and impact of dermatologist density on incidence and mortality.
They found that in 2020, NMSC was responsible for 63,731 deaths compared to the 57,043 deaths recorded from melanoma during the same year. However, as NMSC is often underreported in cancer registries, they noted that these figures may be underestimated.
Commenting on the top-line results, lead author of the study, Professor Thierry Passeron, professor and chair of dermatology in the University Hospital of Nice, said: ‘Although NMSC is less likely to be fatal than melanoma skin cancer, its prevalence is strikingly higher. In 2020, NMSC accounted for 78% of all skin cancer cases, resulting in over 63,700 deaths. In contrast, melanoma caused an estimated 57,000 fatalities in the same year. The significantly higher incidence of NMSC has, therefore, led to a more substantial overall impact.‘
Mapping of the data also identified a higher skin cancer incidence in fair-skinned and elderly populations from the USA, Germany, UK, France, Australia and Italy. In Africa, 11,281 skin cancer deaths were registered, demonstrating that even countries with a higher proportion of dark phenotypes are at risk.
Overall, individuals who were at a higher risk of melanoma were the elderly (relative risk, RR = 8.5), organ transplant recipients (RR = 8.0) and those with xeroderma pigmentosum (RR = 2,000). Those who worked outside were also deemed to have greater risk of NMSC than melanoma.
Commenting further on these findings, Professor Passeron said: ‘We have to get the message out that not only melanoma can be fatal, but NMSC also. It‘s crucial to note that individuals with melanin-rich skin are also at risk and are dying from skin cancer. There is a need to implement effective strategies to reduce the fatalities associated with all kinds of skin cancers.‘
When it came to dermatologist density, there was no evidence to suggest having more dermatologists per capita could reduce mortality rates. The researchers found that countries with fewer dermatologists, such as Australia, the UK and Canada, exhibited low mortality-to-incidence ratios.
Professor Passeron continued: ‘We therefore need to explore what strategies these countries are employing to reduce the impact of skin cancer in further depth. The involvement of other healthcare practitioners, such as GPs, in the identification and management of this disease may partly explain their success. There remains huge opportunity worldwide to elevate the role of GPs and other healthcare professionals in this process and train them to recognise suspicious lesions early.
‘In alignment with this, there is an ongoing need to develop awareness campaigns that educate the general public about the risks of sun exposure and other relevant risk factors. These campaigns should be tailored to at-risk populations, including those with fair skin, outdoor workers, the elderly and individuals who are immunosuppressed. Importantly, these efforts should also extend to populations that may not typically be considered at high risk, such as darker-skinned populations.’
NMSC has become a significant public health threat with a 2022 study showing that the incidence rate increased from 54.08 per 100,000 population in 1990 to 79.10 per 100,000 in 2019.
Widespread inequalities in the provision of aortic valve replacement (AVR) in England have been highlighted in a new study.
Published in the journal Open Heart, researchers assessed gender, ethnicity, and deprivation-based differences in the provision of AVR in England for adults with aortic stenosis.
Using English Hospital Episode Statistics between April 2016 and March 2019, they retrospectively identified 183,591 adults with aortic stenosis, of whom 31,436 subsequently underwent AVR.
Women had lower odds of receiving AVR compared with men (odds ratio (OR) 0.65; 95% CI 0.63 to 0.66), as did those of black (OR 0.70; 95% CI 0.60 to 0.82) or south Asian (OR 0.75; 95% CI 0.69 to 0.82) ethnicity compared to people of white ethnicity.
When examining AVR based on social deprivation, individuals residing in areas of high social deprivation were less likely to receive the procedure than those in the least deprived areas (OR 0.8; 95% CI 0.75 to 0.86).
Researchers also looked at whether the procedure was performed in a timely manner – meaning it was performed during an elective admission and without evidence of cardiac decompensation on or before AVR.
Timely replacement occurred in 65% of those of white ethnicities compared with 55% of both those of black and south Asian ethnicities. Furthermore, 77% of the those from the least deprived area had a timely procedure compared with only 58% of the most deprived regions.
Based on these findings, the researched suggested that ‘further research is needed to investigate the reasons for under provision of AVR in certain person groups and to identify whether disparity is related to structural or systemic inequities, genetic inequalities or differences in patient behaviours or preferences’.
10th October 2023
The psychological burden and subsequent impact on quality of life of skin diseases such as acne, hidradenitis suppurativa and urticaria has been revealed in a large pan-European study published in the Journal of the European Academy of Dermatology and Venereology (EADV).
Adding to the existing evidence derived from studies in which adult patients have been recruited from either hospitals or clinical centres, the researchers aimed to broaden the evidence base and include people with a wide range of skin diseases who do not undergo a clinical consultation.
Of the 19,015 participants who responded to the ‘Burden of skin diseases in Europe‘ survey, around 50% of participants with acne, alopecia, or chronic urticaria, and about 40% of those with atopic dermatitis, skin cancers, or psoriasis reported a modest to extremely large effect of the disease on their quality of life.
This was particularly impaired in people with hidradenitis suppurativa, with almost 60% reporting that their quality of life was extremely or very much impaired.
Some 88.1% considered their condition to be embarrassing in their personal life, and 83% reported the same in their work life.
In addition, 14.5% felt to have been rejected by others because of their skin condition, and 19.2% reported having ‘been looked at with disgust‘. Anxiety and depression were frequently reported by patients with each of the skin diseases studied.
Commenting on the findings, Professor Myrto Trakatelli, chair of EADV‘s advocacy working group, said: ‘Skin diseases are systematically underestimated, and only a small number of interventions on tackling associated stigmatisation have been published.
‘Urgent action must be taken to raise awareness of the impact that skin diseases have on individuals, economies and society and to ensure that patients receive the holistic care they need, including mental health support.
‘Eliminating stigma across the field is of paramount importance to really improve the life of the many patients living with skin diseases, so we call on policymakers to take concerted action to address both the physical and psychological burden of skin diseases.’
Despite their high prevalence and psychological and physical impact, skin diseases receive limited policy, research and funding attention, according to the EADV.
Researchers recruited a representative sample of the European general population aged 18 years or older. A total of 19,915 people responded to the survey, with nearly half (44.7%) being male.
When a respondent declared they had experienced one or more skin problems or diseases during the previous 12 months, they completed the Dermatology Life Quality Index questionnaire and answered questions regarding the impact of their skin disease or diseases on their daily and work lives, anxiety, depression, and stigmatisation.
Some 35.4% had only one skin disease, 24.3% reported having at least two, and 26.3% had four or more.
When looking at the specific conditions, patients with hidradenitis suppurativa reported a high level of personal (67.3%) and professional (63.7%) impact, as well as stigmatisation at 35% and 37% for rejection and disgust, respectively.
The impact on work life was a particular problem for those with acne (47.5%) and urticaria (59.7%).
What‘s more, acne was most frequently associated with time requirements to take care of the disease (65.7%) and side effects of treatment were reported to be especially burdensome in patients with acne (50.9%) and urticaria (53.9%).
A high proportion of those with acne and vitiligo reported stigmatisation, in particular feelings of disgust at 38.2% and 40.4%, respectively.
Commenting on the findings, Professor Marie-Aleth Richard, EADV board member and lead author of the research, said: ‘This study highlights the alarming psychosocial challenge faced by individuals with skin diseases and underscores the need to provide psychological support to patients, and to mitigate the stigmatisation that patients endure in their personal and professional lives.
‘With a profound impact on mental health, these common diseases exert a significant toll on patients’ quality of life.’
The EADV states that as ‘the patient journey is frequently complex, with many avoiding medical consultations‘, there will be an ‘underestimated true burden‘.
6th October 2023
Taking a pre-radiation biopsy of circulating tumour DNA (ctDNA) in patients with oligometastatic non-small cell lung cancer (NSCLC) may help identify those most likely to benefit from locally consolidative radiotherapy (RT), according the findings of recent study.
Published in the journal NPJ Precision Oncology, the researchers sought to risk-stratify and identify the patients with oligometastatic NSCLC most likely to benefit from locally consolidative RT, which could help to achieve prolonged remission.
They performed 1,880 liquid biopsies and approximately 20% of patients (n = 309) had their ctDNA measured prior to RT and after their diagnosis of oligometastatic disease.
Patients with undetectable ctDNA before RT had significantly improved progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.030).
In contrast, patients with detectable ctDNA pre-RT had a median PFS of 5.4 months versus 8.8 months for those with undetectable levels (Hazard ratio, HR = 1.57, 95% CI 1.15 – 2.13, p = 0.004). There were similar findings for OS, with a median OS of 16.8 months versus 25 months (HR = 1.65, 95% CI 1.05 – 2.61, p = 0.030). Multivariate analysis, including additional parameters, revealed a similar trend.
Based on these findings, the authors wrote: ’Our analysis reveals that ctDNA testing performed pre-RT can risk-stratify those patients with truly oligometastatic NSCLC from those who likely harbour widespread micrometastatic disease (below current imaging limits of detection).’
Senior study author Aadel Chaudhuri, an assistant professor of radiation oncology at the Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine in St Louis, said: ‘Our findings suggest the level of ctDNA, rather than the number of tumours themselves, is a more precise measure of disease burden.’
The authors added: ‘This approach should be prospectively evaluated in a clinical trial that redefines oligometastatic NSCLC to include a discrete liquid biopsy metric encompassing a low or undetectable ctDNA level.‘
Stereotactic radiotherapy courses for men with intermediate risk, localised prostate cancer is as effective as standard care, according to the findings of a new trial presented at the recent American Society for Radiation oncology (ASTRO) annual meeting.
The phase 3 PACE B (Prostate Advances in Comparative Evidence) study found that using stereotactic body radiation therapy (SBRT) was non-inferior to standard treatment with moderately fractionated radiation in men with non-metastatic prostate cancer. SBRT had a five-year disease control rate of 96% compared to 95% for conventional radiation.
Researchers from the Royal Marsden Hospital in London, enrolled 874 men with a median age of 69.8 years from 38 centres in Canada and the UK.
Participants were randomly assigned to receive either SBRT (n = 443), which involved the delivery of five fractions over one to two weeks (36.25 Gy total dose), or a standard course of radiation (n = 441) with 39 fractions over 7.5 weeks (78 Gy) or 20 fractions over four weeks (62 Gy). The men were then followed for a median of 73.1 months.
The trial explored whether patients remained free of biochemical clinical failure (BCF), which was defined as an increase in PSA levels, distant metastases or other evidence that the cancer was returning, or death from prostate cancer.
After five years after treatment with either modality, men treated with SBRT had a BCF-event-free rate of 95.7%, compared to 94.6% for those treated with standard care radiation. This demonstrated that SBRT was non-inferior to CRT (p-value for non-inferiority = 0.007).
Side effects were low in both groups, and not significantly different between treatment arms. At five years post-treatment, 5.5% of patients who received SBRT experienced grade 2 or higher side effects affecting the genital or urinary organs, compared to 3.2% in the conventional group (p = 0.14). Only one person in each arm of the study experienced grade 2 or higher gastrointestinal side effects (p = 0.99).
In discussing these findings, Professor Nicholas van As, consultant clinical oncologist, medical director of The Royal Marsden NHS Foundation Trust and the study lead, said: ‘Standard radiation treatment is already highly effective and is very well tolerated in people with localised prostate cancer.
‘But, for a healthcare system and for patients, to have this treatment delivered just as effectively in five days as opposed to four weeks has huge implications.‘
Stereotactic radiotherapy delivers treatment with high precision from a number of different angles around the body and helps to reduce adverse effects in the surrounding tissue. A study from earlier in 2023 found MRI-guided stereotactic radiotherapy reduced physician-reported toxic GU and gastrointestinal adverse effects than CT-guided stereotactic radiotherapy in men with prostate cancer.
A biomarker combination that includes interleukin-6 (IL-6) together with the established markers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) has shown excellent discriminatory ability in CT-negative patients with mild traumatic brain injury (mTBI).
The new study led by Monash University and The Alfred Emergency Department in Melbourne, Australia, and published in the journal Neurology, found that this combination of protein biomarkers showed sensitivity and specificity in distinguishing patients with mTBI who were under the age of 50 and presented to an emergency department within six hours of injury.
Study lead and Monash Trauma Group principal investigator Dr Stuart McDonald said: ‘Concussion diagnosis is notoriously challenging in many cases because clinicians rely on subjective observations of physical signs and self-reported symptoms, neither of which are specific to concussion and often exhibit subtlety and rapid evolution.
‘Consequently, even in the ED, individuals can be discharged without a definitive diagnosis. Our findings showed that the panel of biomarkers we assessed performed really well even in patients that lacked the more overt signs of concussion, such as loss of consciousness or post-traumatic amnesia.‘
In 2018, the US FDA approved a blood test using the Banyan Brain Trauma Indicator, which measures GFAP and UCH-L1 to help determine the need for a CT scan in suspected mTBI.
Researchers in the current study sought to determine if there was a better combination of biomarkers that could more accurately be linked to mTBI and thus help diagnose the condition in CT negative patients.
If approved, a blood test identifying these three biomarkers could improve the accuracy diagnostic process of mTBI when used alongside existing measures such as physical signs and symptom self-reporting.
The researchers measured a number of biomarkers, including IL-6, GFAP and UCH-L1 within six hours of of injury. The values of each biomarker were then compared to those seen in uninjured controls.
The results showed that adding plasma IL-6 to the standard panel which includes only GFAP and UCH-L1 showed incredible sensitivity and specificity in distinguishing individuals with mTBI (n=74) compared to control (n=44) within six hours of injury.
The biomarker performance was similar between sexes and for participants with and without loss of consciousness and/or post traumatic amnesia.
Co-study lead and Monash University Professor Biswadev Mitra, who is director of emergency medicine research at The Alfred, said that ‘if further research validated these results‘ and the biomarkers were granted regulatory approval, ‘they could increase diagnosis certainty not just for clinicians but for patients too, enabling earlier management‘.
He added: ‘Within the ED, we believe the test might prove useful in providing certainty in difficult-to-assess cases, especially when a patient may be unwilling or unable to communicate their symptoms. One example could be in cases of domestic violence, where the test might reveal a mild brain injury that could otherwise go unnoticed.‘
In the same patients studied a week after their concussion, the researchers found the biomarker neurofilament light (NfL) was elevated and had comparable diagnostic properties as the acute markers (AUC=0.81, 95%CI=0.72-0.90).
Dr McDonald said this suggested NfL could be particularly suited for assisting concussion diagnosis in cases of delayed assessments.
‘Beyond the ED, measures of blood NfL may be most beneficial when individuals consult a GP multiple days after an impact, especially in situations where diagnostic certainty is crucial for making safe return-to-work or return-to-play decisions, such as in military or sports settings,‘ Dr McDonald added.
4th October 2023
Changes in the gut microbiome are known to affect the response to immunotherapy in patients with melanoma, but whether it is therefore possible that modulating gut dysbiosis could halt disease progression remains unclear. Clinical writer Rod Tucker investigates.
Cutaneous melanoma is the 17th most common cancer worldwide and the last 40 years has seen a steady increase in the number of cases, with a more than eight-fold increase from 1985 to 2018.
A further cause for concern is that melanoma has invasive metastatic growth patterns and is one of the most aggressive types of skin cancer.
Fortunately, in recent years, the introduction of immunotherapies has marked a major advancement in the treatment of melanoma. As a result, immunotherapy is now considered to be a promising new approach for the treatment of metastatic melanoma.
Curiously, one factor that appears to influence the outcome of immunotherapy in patients with melanoma is their gut microbiome.
This vast microbial community resides symbiotically within the human gut, contributing to homeostasis and regulating immune function. The terms microbiota and microbiome are often used interchangeably, although, strictly speaking, the ‘microbiome’ refers to a collection of genomes from all of the microorganisms, the microbial structural elements and metabolites.
The fact that the gut microbiome influences a patient’s response to chemotherapy, was first revealed in a 2013 study using mouse models. Researchers observed that among either antibiotic-treated or germ-free mice, tumour-infiltrating myeloid-derived cells responded poorly to chemotherapy.
Later work confirmed this relationship. Again, using mouse melanoma models, it was shown that supplementing with oral bifidobacterium, improved tumour control to the same degree as programmed cell death protein 1 ligand 1-specific antibody therapy.
This effect was also observed in humans in a 2017 study. Researchers examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 (anti-PD-1) immunotherapy. They were able to show via immune profiling, that there was an enhanced systemic and anti-tumour immunity in responding patients who had a favourable gut microbiome.
In fact, it became clear that there was a significant association between commensal microbial composition and clinical response in patients with metastatic melanoma.
Taken together, these findings made clear that a patient’s gut microbiome was able to influence their response to immune checkpoint inhibitor therapy. But the observations only raised more questions.
For example, was the diversity of the gut microbiome linked to the development of melanoma? Furthermore, did melanoma progress because of a gut dysbiosis? And, if the two were linked, could this information be used either prognostically or even therapeutically?
Some answers to these emerging questions came from a recent study. Researchers were interested in exploring if there were any differences in the gut microbiome of patients with melanoma compared to healthy controls and between those at an early and late stage of the cancer.
The study, which was published in the journal JAMA Dermatology, characterised and compared gut microbiota profiles between healthy volunteers and patients with melanoma either at an early (stages 0 to II) or at a late stage (III to IV) of their disease.
A total of 228 participants were enrolled, of whom 49 were healthy controls, 38 had early stage disease and 141 had with late stage disease.
When comparing the microbiomes of individuals with melanoma against healthy controls, there were significant differences in alpha diversity with a higher number of unique species present among the healthy control group (p = 0.06).
But when looking at the beta diversity, which measures the differences between the two groups, healthy control samples formed distinct or distant communities as compared with patients who had melanoma (p <0.001). In fact, healthy controls had a greater abundance of the bacterial phyla Actinomycetota and Firmicutes.
One interesting observation was the higher level of species from the bacterial genus Fusobacterium, was significantly more abundant in the melanoma group compared to controls. This species has been found to be present at higher levels in patients with colorectal cancer and is associated with a shorter survival. Nevertheless, in the current study, while higher in melanoma patients, the difference was no longer significant after statistical adjustment.
When researchers compared the microbiome of those with early and late-stage melanoma, they found both a significantly higher alpha and beta diversity in those in the earliest stage of their cancer. In other words, it seems that melanoma progression is associated with a reduction in the diversity of the gut microbiome.
So, if microbiome diversity reduces as malignant melanoma progresses, could improving the alpha diversity prevent the subsequent development of the cancer?
It is an intriguing thought that simply by enhancing the range of microorganisms within the gut, it could be possible to halt melanoma progression. And this idea may not be as far fetched as it might sound.
There is emerging evidence to suggest that improving the gut microbiome, might represent an effective adjunct to immunotherapy. For example, in a study from 2021, researchers showed that the use of faecal microbiota transplantation in 10 patients with anti-PD-1-refractory metastatic melanoma elicited a clinical responses in three patients: two achieved a partial response and one complete response.
More recently, in a second trial, researchers found that faecal microbiota transplantation from healthy donors to 20 patients with advanced melanoma who were in receipt of anti-PD-1 therapy, gave rise to an objective response rate of 65% and a complete response rate of 4%.
While faecal transplantation may not appeal to many, an alternative approach could be to increase alpha diversity with probiotics. In a case report of two patients with metastatic melanoma whose cancer progressed on immune checkpoint inhibitors, the combination of the Camu Camu probiotic with immunotherapy produced a both a complete and near complete response to therapy.
There is no doubt that the evidence to date has been able to shine a light on the importance of the gut microbiome in shaping a patient’s response to immunotherapy. Unfortunately, so far, research has only been able to demonstrates an association rather than causality. For instance, it remains unclear as to whether the reduced alpha diversity is actually the cause or merely a consequence, of melanoma progression. Research is also be hampered by the absence of what constitutes an ’optimal’ gut microbiome composition.
Despite these limitations, in the current era of precision medicine, a strategy that involves modulation therapy to improve the alpha diversity of the gut microbiome could play an important role in the future management of melanoma.
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