Ban the Term Animal ‘Model’

I have always been somewhat bemused by the term ‘animal model’ in research. As an animal lover and admirer, I have always bridled at the harsh denigration of animals to mere ‘models’ for our species.

Recently I read about the Arizona Cancer Evolution center, which compares and contrasts findings across the animal kingdom as a whole to learn generalisable lessons.[1] One interesting example concerns Peto’s paradox. This paradox turns on the observation that larger animals do not have higher cancer rates than humans, despite having many more cells. The resolution to the paradox comes from the finding that very large animals have a higher proportion of DNA repair and apoptosis genes. These genes help reduce somatic mutations or their effects, and compensate for the greater a priori risk.

Using animals as mere ‘models’ for humans is not only speciesist, but non-scientific. I hope we can get rid of this patronising and scientifically limiting term once and for all.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Tollis M, Boddy AM, Maley CC. Peto’s Paradox: how has evolution solved the problem of cancer prevention? BMC Biol. 2017; 15: 60.

Stop Taking Those Supplements: Just Stop

There is a strong natural human instinct to take precautions to delay the death the lies ahead for us all. So strong is this instinct that we are predisposed to believe in all sorts of measures with a superficial, but fundamentally facile, theoretical basis. Food supplements are such a measure.

So yet another study shows that they do no good, and in some cases they likely increase the very risks that they are designed to prevent.[1] A recent article by Chen and colleagues follows up a cohort of over 30,000 adults who completed a nutrition questionnaire yearly for six years. A healthy diet was associated with lowered cancer mortality risk, but supplements were not, and could even raise risks. With respect to minerals, NEVER take supplements, because it is the balance between metal couples (sodium/potassium; magnesium/calcium; copper/zinc) that is important. So it is not surprising that calcium supplements were harmful in the above study.

Studies of this type are subject to personal and recall bias but, in my opinion, these work against the findings. People who take care of their health usually have better outcomes than people at large, and recall bias is augmented if the bad endpoint materialises, whereas the overall results in this study were null.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Chen F, Du M, Blumberg JB, et al. Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults. Ann Intern Med. 2019; 170: 604-13.

How Many Cigarettes in a Bottle of Wine?

We have talked before about the effects alcohol has on health – ranging from studies showing protective effects against dementia and Alzheimer’s disease,[1] to increasing risk of structural brain changes and cognitive decline.[2] While there have been studies looking at association between alcohol and cancer rates,[3] the general public do not think of cancer when asked to list health risks of drinking (only 13% of adults surveyed were aware of the putative association between alcohol and cancer).[4] A recent paper in the BMC Public Health calculated the lifetime risk of developing alcohol-related cancers and equated this to the risk from smoking.[5]

The authors found that drinking one bottle of wine per week was associated with an increase in the absolute risk of developing cancer during a lifetime of 1.0% in non-smoking men, and 1.4% in non-smoking women. The gender difference was predominantly driven by an increased risk of developing breast cancer. They calculated that this was “equivalent” to a weekly smoking habit of five (for men) or ten (for women) cigarettes.

Although moderate alcohol intake is not equivalent to smoking, there is an argument to increase the level of public health awareness on the risk of cancer from drinking, especially among women. Using cigarettes as an equivalent may help communicate the message of risk more effectively.

— Peter Chilton, Research Fellow

References:

1. Lilford RJ. So Where Are We Up to With Alcohol And Health? NIHR CLAHRC West Midlands News Blog. 12 January 2018.
2. Lilford RJ. Alcohol and its Effects. NIHR CLAHRC West Midlands News Blog. 18 August 2017.
3. Lilford RJ. Oh Dear – Evidence Against Alcohol Accumulates. NIHR CLAHRC West Midlands News Blog. 7 December 2017.
4. Buykx P, Li J, Gavens L, et al. Public awareness of the link between alcohol and cancer in England in 2015: a population-based survey. BMC Public Health. 2016;16:1194.
5. Hydes TJ, Burton R, Inskip H, Bellis MA, Sheron N. A comparison of gender-linked population cancer risks between alcohol and tobacco: how many cigarettes are there in a bottle of wine? BMC Public Health. 2019.

Mouth Bacteria Linked to More Aggressive Colorectal Cancer

In the UK colorectal cancer is the fourth most common cancer and accounts for 11.5% of all cancers registered annually. Although research has shown that accumulating genetic mutations can cause this disease, there are other factors that can contribute. Around a third of colorectal cancers have been shown to be associated with F. nucleatum, a common mouth bacterium that is a key component of dental plaque – these cases are often the most aggressive. Previous research has shown that F. nucleatum produces FadA adhesion, which is able to trigger a signalling pathway that stimulates the growth of cancerous cells. It is unclear, however, why this only stimulates cancerous cells.

A recent paper by Rubinstein and colleagues found that non-cancerous cells lack Annexin A1, a protein that stimulates cancer growth.[1] In mice that had the Annexin A1 gene knocked out, growth of cancer cells was slower, with F. nucleatum being unable to bind to the cancer cells. Further, the researchers found that the presence of F. nucleatum increased the production of Annexin A1, which then attracted more of the bacteria, creating a positive feedback loop that aided the progression of cancer and sped up tumour growth.

Analysis of the genetics of 466 patients with colorectal cancer found that those with an increased level of Annexin A1 expression had a worse prognosis, irrespective of cancer grade or stage, age or sex. The authors propose that colorectal cancer follows a ‘two hit’ model, with mutations causing cancer, followed by F. nucleatum facilitating its progression.

It is hoped that Annexin A1 can be used as a biomarker to identify patients with aggressive colon cancer, and also a potential target for therapeutic treatment.

— Peter Chilton, Research Fellow

References:

1. Rubinstein MR, Baik JE, Lagana SM, et al. Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β‐catenin modulator Annexin A1. EMBO Reports. 2019; 20(3): e47638.

Counter Intuitive Findings in Cervical Cancer Surgery

In recent years there has been an increase in the use of minimally invasive surgeries for a number of cancers, with many, such as uterine, colorectal, or gastric cancers, showing similar survival rates to traditional open surgery. Although there hasn’t been much specific evidence for the use of minimally invasive hysterectomy in patients with cervical cancer, it has steadily become adopted in a number of countries. Traditional open surgery for hysterectomy has been associated with considerable perioperative and long-term complications, while minimally invasive hysterectomy has been shown to reduce risk of infection and improve recovery times.

The New England Journal of Medicine has recently published the results of two separate studies looking at differences in survival rates following minimally invasive surgery (laparoscopy) compared to open surgery (laparotomy) for radical hysterectomy in cervical cancer patients.[1][2] One study, by Ramirez, et al., was a randomised controlled trial conducted in 33 centres across the globe,[1] while the other by Melamed, et al., was an observational study using a US dataset.[2] Both looked at a similar subset of patients with a similar period of follow-up.

In the RCT 563 patients underwent one of the two types of hysterectomy, and follow-up at four and a half years showed a significant difference in disease-free survival – 86.0% of those who had undergone minimally invasive surgery compared to 96.5% who had undergone open surgery (difference of -10.6 percentage points, 95% CI -16.4 to -4.7). Further, the minimally invasive surgery was associated with a lower rate of overall survival at three years (93.8% vs. 99.0%) with a hazard ratio for death of 6.00 (95% CI 1.77-20.30).

In the other, observational, study, the authors looked at 2,461 women who underwent a hysterectomy and found that after four years 90.9% of those who had minimally invasive surgery survived, compared to 94.7% of those who had undergone open surgery (hazard ratio 1.65, 95% CI 1.22-2.22). Looking at a longer time period of data, the widespread adoption of minimally invasive surgery in 2006 coincided with a decline in the four year relative survival rate of 0.8% per year (p=0.01).

So, here we have another two studies where the results of the randomised trial broadly agree with those from the observational study,[3] and with a large and significant effect. Looking at the methods used this counter intuitive effect is not accounted for by a more complex excision being performed during the open surgery. Instead, it may be that something to do with the technique – could manipulation of the cervix during the laparoscopy, or exposure of the tumour to circulating CO₂, lead to the release of cancerous cells into the blood stream of the patient?

What we would like to know from News Blog readers is whether they know of any studies where someone has counted (using PCR or cell separation) to see if cancer cells are released into circulation when a tumour is manipulated. Please let us know.

— Peter Chilton, Research Fellow

References:

1. Ramirez PT, Frumovitz M, Pareja R, et al. Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer. New Engl J Med. 2018.
2. Melamed A, Margul DJ, Chen L, Keating NL. Survival after Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer. New Engl J Med. 2018.
3. Lilford RJ. RCTs versus Observational Studies: This Time in the Advertisement Industry. NIHR CLAHRC West Midlands News Blog. 29 June 2018.

More on the Hygiene Hypothesis and Exposure to Coliform Organisms from the Birth Canal

The putative advantages of a deep draught of coliform organisms during a baby’s journey into the world has been discussed in a previous News Blog, with respect to prevention of allergy.[1] It now seems that it is not just allergy, but also cancer – more specifically the acute leukaemia of childhood – that is influenced by the process of birth.[2] And again, bypassing the birth canal by means of Caesarean section increases risk. The mechanism seems to conform with the three hits hypothesis, described in a past News Blog.[3] Here the hits might be:

1. Genetic predisposition.
2. Failure to ‘benefit’ from exposure to coliforms during birth.
3. Subsequent severe infection.

Regarding the third ‘hit’ above, it is known that acute lymphoblastic leukaemia of children occurs in semi-epidemic fashion, suggesting that an acute infection is the trigger.

Some decades ago I carried out a decision-analysis that argued that when the risk of intra-partum C-section exceeded a threshold of around 35%, then a planned C-section was the best option for mother and baby.[4] For the mother because intra-partum C-section is more risky than planned C-section; and for the baby because situations where intra-partum C-section is common usually imply that the baby is also at increased risk – for example if the baby is coming by the breach. However, I can now see that my decision-analysis was incomplete – maybe I should have factored in the ‘unknown unknowns’.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Exposure of the Baby to a Rich Mixture of Coliform Organisms from the Birth Canal. NIHR CLAHRC West Midlands News Blog. 22 April 2016.
2. Greaves M. A causal mechanisms for childhood acute lymphoblastic leukaemia. Nat Rev Cancer. 2018.
3. Lilford RJ. Three Hits Hypothesis. NIHR CLAHRC West Midlands News Blog. 7 April 2017.
4. Lilford RJ, van Coeverden de Groot HA, Moore PJ, Bingham P. The relative risks of caesarean section (intrapartum and elective) and vaginal delivery: a detailed analysis to exclude the effects of medical disorders and other acute pre-existing physiological disturbances. Br J Obstet Gynaecol. 1990; 97(10): 883-92.

Using Polio to Treat Cancer

Up until the mid-1950s polio was epidemic across many countries with an estimated 500,000 people paralysed or killed each year. Two vaccines were developed (one by Jonas Salk launched in 1957, the other by Albert Sabin in 1962), which lead to a dramatic decline in cases, and eventually eradication in many high-income countries. Following this the World Health Organization, UNICEF and the Rotary Foundation began an eradication campaign in 1988, and as a result there were only 22 reported polio cases worldwide in 2017. However, recent research has suggested that polio may be able to help patients with grade IV malignant gliomas.[1] Such patients have low survival rates – less than 20 months following diagnosis, and less than 12 months for recurrent gliomas. Current therapies are ineffective, inconsistent in improving survival and have many toxic effects. The trial was conducted using PVSRIPO, a modified live attenuated poliovirus type 1 vaccine. This is able to recognise CD155, a poliovirus receptor that is widely expressed in tumour cells. In total 61 patients were given a dose of PVSRIPO and followed up. Although 19% of patients had moderate-severe (grade 3 or higher) adverse events attributed to PVSRIPO, the overall survival of patients reached a plateau of 21% (95% CI 11-33) at 24 months, which was sustained at 36 months. This was higher than the rate among historical controls.

References:

1. Desjardins A, Gromeier M, Herndon JE, et al. Recurrent Glioblastoma Treated with Recombinant Poliovirus. New Engl J Med. 2018.

Modern Chemotherapy for Severe Mental Disorders in a Prayer Camp

I thank Prof Swaran Singh for drawing my attention to a randomised trial of traditional faith healing with chemotherapy versus traditional faith healing alone for patients with serious psychiatric disorders.[1] The study took place in a faith-based healing centre. Belief in spiritual origins for mental illness is common in many countries. A randomised trial was conducted to evaluate the additional benefits of pharmacotherapy for patients with a range of psychotic conditions. The outcome of the trial was based on the brief psychiatric rating scale. Patients in the intervention group had much better outcomes than patients in the control group over the first six weeks following randomisation. That is to say, adding chemotherapy to faith healing produced a marked improvement in outcome.

The interesting feature of this trial was that it combined modern medical treatment with traditional healing methods. Thus it is not a head-to-head of the two different approaches; rather it is a trial of both methods compared with traditional methods alone.

Although the study produces interesting findings, the traditional methods did not sit comfortably with the medical approach; for instance patients were often put in chains so that they could not escape or harm themselves or others. This invokes the deeper question about whether the two methods (allopathic and traditional) can really exist side-by-side on a routine basis. Many providers of psychiatric services would find it difficult to live with a situation in which patients for whom they felt responsible were also subjected to practices that they consider degrading, if not outright harmful. The question can be fairly asked as to whether medical practitioners in the study were endorsing or even colluding in these practices. I tackled the moral and epistemological Implications of trying to integrate enlightenment science and spiritual practices within the same system of care, in a recent news blog.[2] The above research paper seems to reinforce my opinion that integration of modern medicine and traditional practices is much more than simply a technical issue. While clinical trials such as the one cited above can produce useful information, they cannot, by themselves, resolve the deeper issues.

— Richard Lilford, CLAHRC WM Director

References:

1. Ofori-Atta A, Attafuah J, Jack H, et al. Joining Psychiatric Care and Faith Healing in a Prayer Camp in Ghana: Randomised trial. Br J Psychiatry. 2018; 212: 34-41.
2. Lilford RJ. Traditional Healers and Mental Health. NIHR CLAHRC West Midlands News Blog. 12 January 2018.

Intraperitoneal Chemotherapy for Ovarian Cancer

The CLAHRC WM Director hates ovarian cancer – it spreads throughout the abdominal cavity and is horrible to behold it at surgery. He has often wondered if topical chemotherapy could help control this dreaded disease. In the UK one in 52 women will be diagnosed with ovarian cancer within their lifetime, with around 7,400 new cases and around 4,100 deaths in 2014.[1] Standard treatment is surgery to excise the tumour, followed by intravenously administered chemotherapy, or vice-versa. Can topical (intraperitoneal) chemotherapy improve outcomes compared to the standard intravenous method? Previous research of combined intravenous and intraperitoneal chemotherapy has shown an increase in overall survival in patients with ovarian cancer, but there are a number of limitations that have affected widespread adoption. Researchers in the Netherlands conducted a study to see if delivering the intraperitoneal chemotherapy immediately after surgery could show similar effectiveness, while overcoming these limitations.[2]

This was a randomised trial of 245 patients with ovarian cancer who had already undergone three cycles of chemotherapy. Patients underwent surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) administered at the end of the procedure or not, followed by another three cycles of chemotherapy. HIPEC is where the abdomen is heated prior to applying the chemotherapy drugs. This hyperthermia results in a number of cellular reactions, including increasing the penetration of chemotherapy drugs into the tissue, impairing the ability of cancer cells to repair DNA, thus increasing their sensitivity, and inducing apoptosis.

Results showed significantly fewer deaths and disease recurrence in those patients who underwent HIPEC immediately during surgery, than in those who did not (hazard ratio 0.66, 95% CI 0.50-0.87; p=0.003). Further the patients in the HIPEC group had a median recurrence-free survival of 14.2 months, compared to 10.7 months. At follow-up (median of 4.7 years), 62% of patients who had undergone surgery without HIPEC had died, compared to 50% of patients who had received HIPEC (p=0.02). Median survival was 45.7 months compared to 33.9 months. Adverse events were similar in both groups.

— Peter Chilton, Research Fellow

References:

1. Cancer Research UK. Ovarian Cancer Statistics. 2018.
2. van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. New Engl J Med. 2018; 378: 230-40.

Oh Dear – Evidence Against Alcohol Accumulates

Yes, more research [1] [2] on alcohol – increases in cancers of mouth, throat and oesophagus. Not good places to have cancer. Direct contact of C2-H5-OH with the membrane is the likely causal mechanism. So here is an hypothesis – the more dilute a given amount of alcohol, the better. So I think beer > wine > spirits, ceteris paribus. I guess this has been tested? But next week I may have some more reassuring news for us oenophiles.

— Richard Lilford, CLAHRC WM Director

References:

1. LoConte NK, Brewster AM, Kaur JS, Merrill JK, Alberg AJ. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. J Clin Oncol. 2017; 35: 1-11.
2. The Lancet. Alcohol and cancer. Lancet. 2017. 390: 2215.