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Illegal vaccination is a big concern: Top doctors

Healthcare experts say that black marketing of Covid vaccination is happening and people are getting vaccinated by showing false comorbidity certificates.

Shalini Bhardwaj

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Who is responsible for resurging Covid-19 cases? How is black marketing of vaccination taking place? Top doctors and health experts—Dr Ishwar Gilada, consultant in HIV and infectious diseases, secretary-general of People’s Organisation and The Organised Medicine Academic Guild of India, Dr Anjan Trikha, chairman of Clinical Managerial Group Covid sector at AIIMS, Dr Dhiren Gupta, senior consultant and paediatrician at Sir Ganga Ram Hospital—answer all this and more. 

Q. Who is responsible for the explosive second Covid-19 wave?

Dr Trikha: You, me and the citizens of the country are responsible for this surge. A lot of people seem sick and tired of it and have taken things for granted and just don’t realise its implication. Although the side effects or the gravity of the disease is less compared to the last time, the numbers are increasing, ICUs are getting full. There’s no bed available in Maharashtra, Pune is a standing example, Nagpur is another example, and Delhi is not far off. People have to realise that we might have to come back to the same level of precautions that were there last April or May and then only we can beat it. The positive thing is that more and more people are getting vaccinated we presume that will lead to some kind of immunity amongst them but people have to keep taking precautions.

Q. Why have people taken norms and guidelines for granted?

Dr Gilada: I think our people didn’t expect the second or third wave to come. If you have seen a second or the third wave anywhere in the world, the second wave was stronger than the first wave and the third wave is always stronger than the first and second wave put together. So, we are going to also have a third wave, we are not going to stop at the second wave only. A good thing about the second wave is that it is a highly infectious virus but less lethal.

This time, people are not thronging the hospitals so only those who require hospitalisation are going to the hospitals and therefore doctors can concentrate on them. Otherwise, earlier as soon as people were getting tested positive, they would lock the beds in hospitals so there was a lot of shortage of beds at that time. 

About 15 days back Maharashtra was reporting 70% cases; currently, it is reporting 58% cases that means a 12% gap is taken by other states. What happens is, in Maharashtra, the cases are increasing at 10% every day or every two days there are 4,000 to 5,000 cases. Around 15 days back, there were only 44 cases in a day in Bihar and Uttar Pradesh was reporting 126 cases in a day. Now cases in UP have gone up 10 times and cases in Bihar have gone up 8 times in just two weeks. So, it doesn’t take much time for the small numbers to become big numbers. 

Look at the people who are masking, they are not covering their nose or mouth, if they want to talk they take off the mask. We need to change the attitude of the people. Most importantly we have always been blaming young people saying that young people are responsible for carrying the infection from society to home, home to society but if only blame game is there we are not going to solve the problem. I have worked in HIV for 35 years and know that blaming young people was a wrong strategy. Set a centre stage of programming, prioritising them is the strategy so now also we need to prioritise the young population all over. Programmes should be young people-centric and make them responsible for their own generation, the next generation and the senior generation. If they will be responsible only then we can control the pandemic. 

Last but not least, the vaccine is to prevent the third surge, not the second surge. We cannot prevent the second surge through vaccination.

Dr Gupta: I’m a clinician, though I’m a paediatrician, last year I managed around 2,000 plus adult patients online and I am taking care of the adult ward now. In the past six days, I have gotten a lot of adult Covid calls especially doctors who usually call me to get treated by me as I am an infectious disease expert. Our pace of vaccination is very slow, at this time last year our 30% of staff got infected including our fellows, resident doctors, nurses so 30% of the beds were occupied by our staff. Now, at present none of those people who got infected and later got vaccinated and have probably been exposed to the virus. But even if they are infected, they are not spreaders or super spreaders. As per my experience over the past 15 days in Delhi, probably hospitals seem safer as everybody is vaccinated as compared to last year when hospitals became the hub.

I found that the PGI dean got infected despite two vaccination doses. Let’s be responsible, not only as a citizen but as a scientific person, a doctor, and as a community person. People think that they are young and won’t get affected so they are taking the disease too lightly and are spreading it. They’re not concerned about Covid appropriate behaviour. Also, they think vaccination is meant for them. Recently, our Health Minister has said that we need not vaccinate everybody in due course of time but I think we need to vaccinate everybody in due course of time.

Q. Do you think that if we vaccinate children, then it will become easy to get herd immunity?

Dr Gupta: Children may not get a severe disease but they are spreaders and what I found, as I closely monitor the families and paediatric patients, grandparents are very closely attached to their grandchildren. So, we need to vaccinate all populations and that should be the strategy probably.

As for vaccination, my feeling is very clear. Firstly, we should pitch in all the doctors whether they are MBBS, MD or final-year students. Doctors should pitch in to vaccinate in their respective clinics and we should not be rationed, rationing should not be there that only you can charge Rs 50 only, you can charge Rs 100. Let it be open.

Q. Do you think mass vaccination is a solution?

Dr Trikha: I feel that looking at the number of people and their general behaviour in the society, how much we respect our loss, how much we respect the basic hygiene of our city, considering all these it is going to be a very tough call. I sincerely think we do a good job if people do not overcrowd places. Vaccination is not the only issue the government has to think about, they have to think about elections and after the election results, you will see what will happen. The issue of vaccinating children was brought up but children cannot get vaccinated as there is no data to support that the vaccine has been used on children in the trials. Only two studies have been started in the US where they are taking care of children between 14 to 17 because as per international definitions you can have a 17-year-old vaccinated and he comes into the subgroup of a child. Unless you have data, you don’t know what will happen and we need not start vaccinating children unless we think that it is pretty safe. Vaccination has to be voluntary. We have to be persistent about vaccination and I’m sure things are improving. Vaccinating children is still a far-off thing. There was a lot of controversy regarding pregnant women that is settling down. Mass vaccination doesn’t seem like a viable solution

Q. Are we getting reinfection cases also because there are a lot of covid patients?

Dr Gilada: Whether you get infected and develop antibodies or whether you take the vaccine and develop antibodies, the antibodies will last a maximum of six to eight months or maybe 10 months and that is very important even from the vaccination point of view. If the vaccination effect is going to last only for eight to ten months that means whatever number of people we need to vaccinate that entire thing has to be completed in eight to ten months. We have only six to seven months whatever targeted people are there may be 60,00,00,000 70,00,00,000 at two doses that is 1, 20,00,00,000 process has to be finished within six to eight months and if it is not done then all of second round of the vaccine has to be repeated. Similarly, those who were infected six to eight months back are getting reinfected and that is also possible currently. There are new variants and strains, there are people who are fully vaccinated and despite that, they are getting infected. You should know that the vaccination will not work on 30 to 40% of people, so despite getting vaccinated that person will still get infected and there cannot be news on that but because of social media and electronic media such news are spread and therefore people are not taking the vaccine.

The most important thing is also to wrap up the vaccination. We need 24×7 vaccination, we should have the vaccination at private and public hospitals, at mobile clinics, and at workplaces. Initially, we did not understand whether the vaccine will give a lot of severe reactions or not therefore we were asking people to wait for half an hour to prevent overcrowding in that waiting area. People who are just vaccinated can get infected from next door people so we need to change all those things in light of currently available experience which is approved as an emergency authorisation. Black marketing is happening in terms of vaccination as people are showing false comorbidity certificates to get vaccinated. Some vaccination centres are even keeping a doctor there who is giving false comorbidity certificates. How do you confirm the documentation? You cannot see comorbidity; anybody could say they’ve it. No certification can be authentic.

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RESEARCH: INTERMITTENT FASTING WORKS FOR WEIGHT LOSS, HEALTH CHANGES

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According to a new study review led by University of Illinois Chicago researchers, intermittent fasting can produce clinically significant weight loss as well as improve metabolic health in individuals with obesity.

The findings of the study were published in the journal Annual Review of Nutrition. “We noted that intermittent fasting is not better than regular dieting; both produce the same amount of weight loss and similar changes in blood pressure, cholesterol and inflammation,” said Krista Varady, professor of nutrition at the UIC College of Applied Health Sciences and author of “Cardiometabolic Benefits of Intermittent Fasting.”

According to the analysis published in the Annual Review of Nutrition, all forms of fasting reviewed produced mild to moderate weight loss, 1 to 8 percent from baseline weight, which represents results that are similar to that of more traditional, calorie-restrictive diets.

Intermittent fasting regimens may also benefit health by decreasing blood pressure and insulin resistance, and in some cases, cholesterol and triglyceride levels are also lowered. Other health benefits, such as improved appetite regulation and positive changes in the gut microbiome, have also been demonstrated.

The review looked at over 25 research studies involving three types of intermittent fasting: alternate-day fasting, which typically involves a feast day alternated with a fast day where 500 calories are consumed in one meal, 5:2 diet—a modified version of alternate-day fasting that involves five feast days and two fast days per week, time-restricted eating—which confines eating to a specified number of hours per day usually four to 10 hours with no calorie restrictions during the eating period.

Various studies of time-restricted eating show participants with obesity losing an average of 3 percent of their body weight, regardless of the time of the eating window.

Studies showed alternate day fasting resulted in weight loss of 3% to 8% of body weight over three to eight weeks, with results peaking at 12 weeks. Individuals on alternate day fasting typically do not overeat or binge on feast days, which results in mild to moderate weight loss, according to the review.

Studies for the 5:2 diet showed similar results to alternate-day fasting, which surprised the study’s reviewers. The subjects who participate in the 5:2 diet fast much less frequently than alternate-day fasting participants do, but the results of weight loss results are similar.

Weight loss in both the alternate day and 5:2 fasting are comparable to more traditional daily calorie-restrictive diets. And, both fasting diets showed individuals were able to maintain an average of 7% weight loss for a year.

“You’re fooling your body into eating a little bit less and that’s why people are losing weight,” Varady said.

Varady added the review set out to debunk some myths regarding intermittent fasting. Intermittent fasting does not negatively affect metabolism, nor does it cause disordered eating, according to the studies reviewed.

“Fasting people are worried about feeling lethargic and not being able to concentrate. Even though you are not eating, it won’t affect your energy,” Varady said. “A lot of people experience a boost of energy on fasting days. Don’t worry, you won’t feel crappy. You may even feel better.”

The study review includes a summary of practical considerations for those who may want to try intermittent fasting. Among the considerations are:

Adjustment time—side effects such as headaches, dizziness, and constipation subside after one to two weeks of fasting. Increased water intake can help alleviate headaches caused by dehydration during this time.

Exercise—moderate to high-intensity endurance or resistance training during food abstention can be done, and some study participants reported having more energy on fast days. However, studies recommend those following alternate day fasting eat their fasting day meal after exercise.

Diet during fasting—there are no specific recommendations for food consumption during intermittent fasting, but eating fruits, vegetables, and whole grains can help boost fibre intake and help relieve constipation that sometimes accompanies fasting.

Alcohol and caffeine—for those using an alternate day or 5:2 fasting plan, alcohol is not recommended on fast days as the limited calories should be used on healthy foods that provide nutrition.

There are several groups who should not intermittent fast, according to the studies. Those individuals include: those who are pregnant or lactating, children who are under 12, those with a history of disordered eating, those with a body mass index, or BMI, less than 18.5, shift workers—studies have shown they may struggle with fasting regimens because of shifting work schedules, and those who need to take the medication with food at regimented times.

“People love intermittent fasting because it’s easy. People need to find diets that they can stick to long term. It’s definitely effective for weight loss and it’s gained popularity because there are no special foods or apps necessary. You can also combine it with other diets, like Keto,” Varady said.

It’s definitely effective for weight loss and it has gained popularity because there are no special foods or apps necessary. You can also combine it with other diets, like Keto.

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Optimal blood pressure helps our brains age slower: Study

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People with elevated blood pressure that falls within the normal recommended range are at risk of accelerated brain ageing, according to new research from The Australian National University (ANU).

The research also found optimal blood pressure helps our brains stay at least six months younger than our actual age. The researchers are now calling for national health guidelines to be updated to reflect their important findings. The ANU study, published in Frontiers in Aging Neuroscience, found participants with high blood pressure had older and therefore less healthy brains, increasing their risk of heart disease, stroke, and dementia.

Participants with elevated blood pressure, but within the normal range, also had older-looking brains and were at risk of health problems. “This thinking that one’s brain becomes unhealthy because of high blood pressure later in life is not completely true,” Professor Nicolas Cherbuin, Head of the ANU Centre for Research on Ageing, Health, and Wellbeing, said.

“It starts earlier and it starts in people who have normal blood pressure.” Normal blood pressure is defined by pressure below 120/80, whereas an optimal and healthier blood pressure is closer to 110/70.

The new research comes after a large international study found the number of people over 30 with high blood pressure has doubled globally. Cardiologist and co-author of the study, Professor Walter Abhayaratna, said if we maintain optimal blood pressure our brains will remain younger and healthier as we age.

“It’s important we introduce lifestyle and diet changes early on in life to prevent our blood pressure from rising too much, rather than waiting for it to become a problem,” he said.

“Compared to a person with a high blood pressure of 135/85, someone with an optimal reading of 110/70 was found to have a brain age that appears more than six months younger by the time they reach middle age.”

The ANU team, in collaboration with colleagues in Australia, New Zealand, and Germany, examined more than 2,000 brain scans of 686 healthy individuals aged 44 to 76. The blood pressure of the participants was measured up to four times across a 12-year period. The brain scan and blood pressure data were used to determine a person’s brain age, which is a measure of brain health.

Lead author, Professor Cherbuin, said the findings highlight a particular concern for young people aged in their 20s and 30s because it takes time for the effects of increased blood pressure to impact the brain.

“By detecting the impact of increased blood pressure on the brain health of people in their 40s and older, we have to assume the effects of elevated blood pressure must build up over many years and could start in their 20s. This means that a young person’s brain is already vulnerable,” he said.

Professor Abhayaratna said the research findings show the need for everyone, including young people, to check their blood pressure regularly. “Australian adults should take the opportunity to check their blood pressure at least once a year when they see their GP, with an aim to ensure that their target blood pressure is closer to 110/70, particularly in younger and middle age groups,” he said.

“If your blood pressure levels are elevated, you should take the opportunity to speak with your GP about ways to reduce your blood pressure, including the modification of lifestyle factors such as diet and physical activity,” he added.

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HOW TO TACKLE ANTIMICROBIAL RESISTANCE IN INDIA

Dr Rahul Pandit

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A recent ICMR report has left healthcare providers, patients, and infection control experts worried about the rising Antimicrobial Resistance in India. The report says that more than 50 percent of ICU patients in recent times have been battling a type of Pneumonia caused by the bacteria ‘Klebsiella Pneumonia’, which will not respond to even powerful antibiotics like Carbapenem. Another antibiotic, Imipenem, will not affect a mutated form of E-coli in 3 out of 10 cases. This means mutations in microbes, be it bacteria, viruses, or fungi—are rendering medicines useless when the patients most need them.

Given the pandemic and the extensive use of antibiotics to fight Covid-19, antibiotic resistance has been accelerated. Many experts are of the opinion that our approach to treating Covid-19 in hospitals could be exacerbating the problem.

Having said that, India with its combination of a large population, rising incomes that facilitate the purchase of antibiotics, high burden of infectious diseases, and easy over-the-counter access to antibiotics —is an important locus for the generation of resistance genes. This was the state even before the pandemic hit us.

Antibiotic resistance leads to longer hospital stays, higher medical costs, and increased mortality. We have already seen the rise of secondary infections and rare fungal infections such as mucor mycosis or black fungus, white fungus, and yellow fungus, taking a toll on Covid-19 patients during the second wave. Several studies attribute this to the injudicious use of steroids and other antibiotics medicines.

Moreover, even before the pandemic, India experienced over 56,000 newborn deaths each year due to Sepsis that is caused by organisms that are resistant to first-line antibiotics. Also, an estimated 170,000 deaths from Pneumonia in children under five, can be averted with timely access to effective antibiotics. While rising rates of resistant infections are a threat, many deaths are attributable to the lack of access to basic antibiotics.

Another important aspect is the use of antibiotics in the poultry and animal industry. This is much larger than what we imagine and obviously contributes to the growing menace of resistance.

So, how do we control and tackle growing Antimicrobial Resistance (AMR) in India?

We need to balance excessive and inappropriate use, a key driver of antibiotic resistance while ensuring live-saving medicines are available to those who need them. There is also a need to improve vaccination coverage, access to clean water, adequate sanitation, and improved hygiene.

However, efforts must be made to bring about behavioral changes in terms of hygiene practices, self-medication efforts, and proper health education. Vaccination has been shown to reduce the transmission of AMR infections and the volume of antibiotics consumed due to both, appropriate treatment of bacterial infections and viral infections.

India has undertaken many activities like Mission Indradhanush — to address low vaccination coverage and strengthened micro-planning and additional mechanisms to improve monitoring & accountability. Yet, improvements in coverage are still needed. Moreover, antibiotic stewardship programs are very much needed, to help providers and clinicians make the best clinical decisions possible for an antibiotic prescription. Antibiotic stewardship is the systemic effort to ensure effective treatment of infections, and therefore combat AMR, by monitoring and advising on antibiotic prescription and use. Another aspect is the appropriate management of antibiotics throughout the supply chain—from manufacturing to consumption. Effluents from pharma manufacturing contain active antibiotics, resistant bacteria, and resistant genes; they contaminate rivers, streams, and wells, including waters that are used for drinking and bathing. This increases both the emergence of resistant bacteria in local populations and also its spread. In addition, even lower levels of contamination in wastewater can cause resistant bacteria. In the same light, researchers have noted that contamination in areas where there is an antibiotic manufacturing industry led to an increase in bacterium causing resistance to Carbapenems.

Another source of environmental contamination is contaminated hospital waste. Untreated hospital waste may contain antibiotics and resistant bacteria. Where disposal mechanisms are inadequate, such waste puts staff and patients at increased risk from AMR. Hence, a concerted approach that incorporates diverse stakeholders to tackle and control the spread of antibiotics is essential.

The author is Director of Critical Care at Fortis Hospital, Mumbai and a member of Maharashtra’s Covid-19 Taskforce

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STUDY EXPLORES ADVERSE COMPLICATIONS FOR COVID POSITIVE PREGNANT WOMEN, THEIR NEWBORNS

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A new study, which finds an increased risk of poorer outcomes for the newborns and symptomatic women with Covid-19, adds further weight to the argument for pregnant women to be vaccinated for the virus.

The peer-reviewed findings were published in The Journal of Maternal-Fetal and Neonatal Medicine. Assessing 2,471 women in the third trimester of their pregnancy, close to their delivery, researchers found “significant differences” for symptomatic Covid-positive patients including higher rates of gestational diabetes, lower white blood cell counts, and heavier bleeding during delivery, whilst respiratory complications were witnessed in their babies. Thankfully in the group of patients—which included 172 covid positive women (56 of whom were symptomatic)—monitored at the Mayanei Hayeshua Medical Center in Israel, only one person needed mechanical ventilation, and there were no maternal deaths.

They show, lead Dr Elior Eliasi stated that Covid-19 in the third trimester of pregnancy “has clinical implications, albeit at lower rates than expected once asymptomatic patients are taken into account.”

The analysis found that there was no significant increase in cesarean delivery in women, who were Covid-19 positive and the incidence of preterm deliveries was not significantly different among the three groups (healthy, covid positive asymptomatic, covid positive symptomatic). Most pregnancy and delivery outcomes were similar between Covid-positive and -negative parturients (a woman about to give birth; in labour).

Dr Eliasi said, “However, There were significant differences between the Covid-positive and healthy controls included higher rates of GDM (gestational diabetes), low lymphocyte counts (white blood cell count) which were significantly lower, postpartum hemorrhage (bleeding during birth), and neonatal respiratory complications.”

“Our findings support the importance of vaccinating all pregnant women at all stages of pregnancy,” he added.

The study looked at births at the hospital between 26 March and 30 September 2020. A total of 93 percent of women admitted to the labour ward during this period were negative for Covid-19. Of the Covid-positive patients, 67 percent were asymptomatic.

On average the increased risk of incidence of adverse outcomes was 13.8 percent higher for asymptomatic covid patients and 19.6 percent higher for those symptomatic.

“More data is now needed to better delineate the differences between pregnancy outcomes seen in certain populations, potentially related to different viral characteristics (subtypes, viral load), patient epigenetics, or other factors. Additionally, the effects of maternal infection on the fetus both in terms of symptomatic maternal illness and vertical viral transmission remain to be further investigated,” the authors stated.

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RESEARCHERS TAKE STEPS TOWARD MORE EFFECTIVE FITNESS TRACKERS, GREATER PHYSICAL ACTIVITY

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As the popularity of fitness trackers has increased, so have the opportunities to use such devices to not only track fitness goals but also increase the motivation to meet those goals.

Researchers in the College of Engineering and the College of Health and Human Development at Penn State have teamed up to use control systems engineering tools to tailor motivational messages sent to individual device users. The results of their study were published in Health Psychology. “One of the really exciting advances of the last 15 years has been the advent of wearable and portable consumer technology that can be used to help promote physical activity,” said David Conroy, professor of kinesiology and human development and family studies, and co-principal investigator on the paper.

David added, “You can get real-time feedback from these devices and monitor your goals, and you can even push people messages, depending on what their goals are and what their behaviour is. We know that those messages work well for improving behaviour on average. But nobody is average, and we don’t know how to make sure each individual consistently gets the greatest benefit from a limited number of messages.”

Conroy said that researchers have tried several strategies, including messages that are specific to certain population segments; messages based on recent behaviour—for example, sending one of two different messages depending on if a user did or did not meet their goals the previous day; and customising the messages by putting in a person’s name or something they might like. So far, none of these approaches has proven to be consistently effective in improving the messages’ effects.

The new messaging approach developed by Conroy and Constantino Lagoa, co-principal investigator and professor of electrical engineering, applies tools used regularly in controlled systems engineering to behaviour science.

“Essentially, we’re using the same mathematical tools that people in control engineering usually use to model behaviours as differential equations,” Lagoa said. “We’re using those models to design feedback controllers that take into account the current state of the person and together with the model decide what is the best time to send the messages.”

Conroy emphasised that establishing the correct dosing—meaning the type of message and its timing, frequency and context—is a critical part of this approach.

“We’re really prioritising understanding the dosing so that we only send the right message at the right time and in the right context so people get the benefits that they’re looking for,” he said. “We don’t want to disrupt them without them getting the payoff that they’re looking for.”

The researchers refer to this individualised approach as precision behavioural medicine. “This is one of the first studies that were able to leverage data collected from each individual and zoom in on his or her personal response,” Lagoa said.

One of the main examples of how the researchers personalised the messages was by considering the weather in the area of the user, noting that certain messages were more effective for certain individuals on rainy days, hot days and so on.

The researchers acknowledged the potential concern people may have about trading privacy for personalization but said that the automation means that the data can be used and then discarded, as opposed to stored, and the location settings only need to be approximate to know the weather and customise the messaging appropriately. They also said, if their approach is commercialised, users would be able to adjust their settings to select how much information to share, and they plan on conducting more research before applying their approach to a larger population.

“We’ve established here is there’s a new tool to use with an established problem,” Conroy said. “Our next project will focus on establishing efficacy: Does this work better than sending messages at random or not sending messages at all? But once we establish efficacy, I would imagine that it’d be very attractive to device manufacturers to consider this kind of approach.”

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Strategy for overcoming colorectal cancer’s immunotherapy resistance

Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionised cancer treatment; however, the medications aren’t effective in a large number of patients, including those with colorectal cancer.

New research published in the journal PNAS that was led by investigators at Massachusetts General Hospital (MGH) and the University of Geneva (UNIGE) provides insights into why some types of colorectal cancer don’t respond to immune checkpoint inhibitors and offer a strategy to overcome their resistance. “Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide,” said senior and co-corresponding author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH. He added, “A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver.”

Jain explains that most colorectal cancers that spread to the liver do not respond to immune checkpoint inhibitors. When the team injected these colorectal cancer cells under the skin in the hind flank of mice (the most commonly used method for studying cancer in these animals), the cells responded well to immune checkpoint inhibitors, unlike what happens in patients.

To address this discrepancy, the investigators decided to take an approach that is referred to as orthotopic (meaning “the normal place in the body”) by injecting the cancer cells in the relevant anatomical sites—for example, the colon, where primary colorectal cancer cells grow, and the liver, where these cells metastasize.

“We found that these colorectal cancer mouse models were profoundly resistant to immune checkpoint inhibitors, similar to what is seen in patients,” said co-corresponding author Dai Fukumura. He added, “Our results highlight how the environment in which cancer cells grow can influence the effectiveness of immunotherapy. Also, and most important, they indicate that these orthotopic cancer models should be used to study resistance to immune checkpoint blockade as observed in patients with colorectal cancer.”

To determine how liver metastases are resistant to immune checkpoint blockade, Jain and his colleagues investigated the composition of immune cells present in liver metastases in mice and compared it with that of colorectal cancer cells injected under the skin. “We found that liver metastases lacked certain immune cells–called dendritic cells—that are required for the activation of other immune cells known as cytotoxic T lymphocytes, which can kill cancer cells,” said lead author William W. Ho. “We saw a similar situation in patients–their liver metastases showed a lack of dendritic cells and activated T lymphocytes.”

When the team augmented the number of dendritic cells within liver metastases (by giving mice a growth factor called Flt3L), the treatment led to an increase in cytotoxic T lymphocytes within the tumors and caused the tumors to become sensitive to immune checkpoint inhibitors.

He added, “Our study highlights the importance of orthotopic tumor models in immunotherapy studies and underscores the relevance of dendritic cells for effective immune checkpoint blockade,” says co-corresponding author Mikael J. Pittet.

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Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionised cancer treatment; however, the medications aren’t effective in a large number of patients, including those with colorectal cancer.

New research published in the journal PNAS that was led by investigators at Massachusetts General Hospital (MGH) and the University of Geneva (UNIGE) provides insights into why some types of colorectal cancer don’t respond to immune checkpoint inhibitors and offer a strategy to overcome their resistance. “Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide,” said senior and co-corresponding author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH. He added, “A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver.”

Jain explains that most colorectal cancers that spread to the liver do not respond to immune checkpoint inhibitors. When the team injected these colorectal cancer cells under the skin in the hind flank of mice (the most commonly used method for studying cancer in these animals), the cells responded well to immune checkpoint inhibitors, unlike what happens in patients.

To address this discrepancy, the investigators decided to take an approach that is referred to as orthotopic (meaning “the normal place in the body”) by injecting the cancer cells in the relevant anatomical sites—for example, the colon, where primary colorectal cancer cells grow, and the liver, where these cells metastasize.

“We found that these colorectal cancer mouse models were profoundly resistant to immune checkpoint inhibitors, similar to what is seen in patients,” said co-corresponding author Dai Fukumura. He added, “Our results highlight how the environment in which cancer cells grow can influence the effectiveness of immunotherapy. Also, and most important, they indicate that these orthotopic cancer models should be used to study resistance to immune checkpoint blockade as observed in patients with colorectal cancer.”

To determine how liver metastases are resistant to immune checkpoint blockade, Jain and his colleagues investigated the composition of immune cells present in liver metastases in mice and compared it with that of colorectal cancer cells injected under the skin. “We found that liver metastases lacked certain immune cells–called dendritic cells—that are required for the activation of other immune cells known as cytotoxic T lymphocytes, which can kill cancer cells,” said lead author William W. Ho. “We saw a similar situation in patients–their liver metastases showed a lack of dendritic cells and activated T lymphocytes.”

When the team augmented the number of dendritic cells within liver metastases (by giving mice a growth factor called Flt3L), the treatment led to an increase in cytotoxic T lymphocytes within the tumors and caused the tumors to become sensitive to immune checkpoint inhibitors.

He added, “Our study highlights the importance of orthotopic tumor models in immunotherapy studies and underscores the relevance of dendritic cells for effective immune checkpoint blockade,” says co-corresponding author Mikael J. Pittet.

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