Saturday, February 29, 2020

UCI neuro-oncologist uses comprehensive approach to battle brain cancer

When you're facing a cancer diagnosis with an average survival span of 12 to 18 months, every milestone is a victory. That makes each wedding invitation, graduation announcement and birthday photo that UCI neuro-oncologist Dr. Daniela Bota receives from her patients a cherished validation of her 12 years of groundbreaking research on glioblastoma multiforme, the most aggressive form of brain cancer. "Because of our work, these people have been able to move on with their lives," she says.

Bota has pushed the boundaries of innovation in her quest to increase the survival rates of individuals with brain tumors, especially glioblastomas. The esteemed physician-scientist has taken a truly comprehensive approach to battling this rare disease, which has a five year survival rate of only 10 percent and claimed the lives of U.S. Sens. Ted Kennedy and John McCain. Bota has conducted clinical trials of multiple cutting-edge treatments that are improving the quantity as well as the quality of life for glioblastoma patients at UCI and beyond.

'So much potential, so much growth'

Bota grew up in Romania, in a family of engineers. It was assumed she'd follow them into the profession – she was a national mathematics champion in her youth – but Bota had another path in mind. "I wanted to make a more significant contribution," she says. "I wanted to combine my analytical side with a place where I could help others. I ended up becoming an M.D.-Ph.D. to blend both."

At USC, Bota earned a doctorate in molecular biology, focusing on neural degeneration. She then went to the University of Kansas for medical school and a residency in neurology. During her shifts, Bota found herself caring for people with brain tumors – and discovered a new direction for her medical career.

The generosity and gratitude of brain tumor patients make it so rewarding to care for them. I see it again and again at UCI. Many of these patients have a terminal diagnosis, but they're volunteering their time and energy to participate in our clinical trials to help us build a better treatment and, hopefully, in the future, a cure."  Dr. Daniela Bota, UCI neuro-oncologist

After a neuro-oncology fellowship at Duke University, Bota joined the faculty of UCI's School of Medicine and the Chao Family Comprehensive Cancer Center in November 2007. "Both my career and UCI in general have grown so tremendously over the dozen years since," says Bota, who's now co-director of the UCI Health Comprehensive Brain Tumor Program. "There has been so much potential, so much growth, so many changes and so much scientific revolution helping us move forward in so many different directions. It's a very exciting time."

A comprehensive approach

The word "comprehensive" carries significant weight in the realm of cancer care centers. The "comprehensive" designation from the National Cancer Institute recognizes an added depth and breadth of research that bridges multiple scientific areas. Just 51 cancer centers in the U.S. carry the designation; the Chao Family Comprehensive Cancer Center is the only one in Orange County. "We offer one of the most innovative and complex portfolios of clinical trials anywhere in the world," Bota says.

Her own multipronged attack against glioblastoma multiforme reflects the center's comprehensive approach. Bota's work on the experimental drug marizomib has generated significant attention and hope. Unlike traditional chemotherapy drugs, marizomib can penetrate the blood-brain barrier – the filtering mechanism that prevents many blood-borne substances from passing into brain tissues – and inhibit cancer growth without causing damage to other parts of the brain.

Over the past 12 years, Bota has shepherded marizomib from preclinical development all the way through a 700-person international phase III clinical trial now underway. "We have a number of patients from our clinical trials who are surviving this tumor for longer periods of time than usually expected," she says.

Amanda Johnson, a 32-year-old freelance writer in Mission Viejo, has been receiving marizomib for two years under Bota's care. Her large glioblastoma tumor – which straddled both sides of her brain – has shrunk so much that it's no longer measurable. She has returned to work on her novel and even joined a gym. "I feel so happy just to be alive," Johnson says.

Larry Johnson, her father, told Fox News, "I don't think [Amanda] has come to realize how important her survival is to other people and families who are going to find themselves in a similar situation."

Bota strives to reach a point where such cases will be so commonplace that they don't make the news. "That's what success looks like – not having a prominent publication or being part of a game-changing discovery," she says. "It's having patients like Amanda still be here and doing well."

Vaccine trials and right to try
To achieve that goal, Bota tenaciously pursues multiple avenues of treatment. She has been a leader in the use of Optune, a device worn on the head that generates an electrical field that disrupts the growth of cancer cells. "We were among the first in the country to explore and use this technology," Bota says. "Now we're working with physicians from other countries to help them adopt it in their practices."

She is also spearheading two clinical trials on cancer vaccines. "Brain tumors hide behind the blood-brain barrier, so the body doesn't recognize them as not being a normal part of the body," Bota explains. "With our vaccines, we extract cellular markers from the patient's tumor and inject them back into the patient to stimulate the immune system to recognize those tumors, attack them and, if possible, eliminate them."

She adds: "Both studies have been well-received in our neuro-oncological community, which is highly promising. And a significant benefit is that the vaccines function with minimal or no toxicity."

In January 2019, one of Bota's patients who was ineligible for both clinical trials was able to access one of the vaccines through the first successful application of the national Right to Try Act. Passed in May 2018, it allows people with terminal illnesses, in consultation with their doctors, to seek treatment with experimental drugs not yet approved by the Food and Drug Administration directly from pharmaceutical companies. "The law puts patients in charge of their care; they initiate contact with the manufacturer and request therapy," Bota says. "It gives patients who don't qualify for clinical trials another option."

"We offer one of the most innovative and complex portfolios of clinical trials anywhere in the world."

Sharing her expertise
Bota eagerly offers her knowledge beyond the doors of the Chao Family Comprehensive Cancer Center. Whenever she and her husband, Robert, a local psychiatrist, travel back to their home country of Romania, she consults with medical colleagues there, as there are no certified neuro-oncologists in the nation. On days when the couple work on their farm in the Transylvanian Alps, locals come to them – often on foot – for medical advice. The two hope to eventually establish a clinic in the area. "I want to make sure that Romania also benefits from my medical expertise," Bota says.

Back on campus, in her capacity as senior associate dean for clinical research, she uses her vast clinical trial experience to help colleagues in UCI's School of Medicine advance their own research projects into the clinical arena.

"I'm excited by the ability to impact the lives of so many people through this role," Bota says. "Whether it's for burns or vascular disorders or other conditions, people come to UCI for the same reason: We can offer what community hospitals cannot. Being able to make that happen, to create new options for our patients, is what wakes me up in the morning."

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Cancer chemical from common gut microbe

Many common gut bacteria carry cancer-causing mutations, says a new study published in the journal Nature on the 27th February 2020.

There are trillions of bacteria living in and on the human body. The gut bacteria within human individuals play a unique role in both health and disease. They prime immunity during the formative 2-week period just after birth, they prevent the invasion and overgrowth of pathogenic bacterial species and maintain the integrity of the intestinal epithelium, among other things.

A potential pathogen that occurs commonly in the human gut is the bacterium Escherichia coli (E. coli).

Mutations and tumor development

Cancer cells develop because of specific mutations in the DNA, which cause unbridled proliferation and loss of mature characteristics, in many cases, resulting eventually in tumor growth.  Mutations are often caused by exposure to ultraviolet light or smoking. Repeated exposures increase the chances of harmful mutations accumulating within a cell, causing cancerous transformation.

It is known that every type of DNA damage causes a visible pattern of DNA damage called a mutational signature or footprint. Many such footprints are already known, which record the effect of agents such as ultraviolet exposure or smoking. Thus, the exposure history can often be known by looking at the mutational footprint. However, the mutagenic effects of gut bacteria were unknown until recently.

As researcher Ruben van Boxtel explains, “These signatures can have great value in determining causes of cancer and may even direct treatment strategies. We can identify such mutational footprints in several forms of cancer, also in pediatric cancer. This time we wondered if the genotoxic bacteria also leave their unique distinguishing mark in the DNA.”

The study
In the current study, the investigators looked at intestinal organoids, which are tiny masses of intestinal tissue grown as a mini-organ in the laboratory, to test whether a specific strain of E. coli induces DNA mutations. This strain is found in a fifth of all adults.

The researchers cultured gut organoids which were then exposed for five months to this strain of E. coli, which produces a genotoxin, a chemical that harms the human DNA. The chemical involved is called colibactin. The gene-modifying effects of this toxin mean that it could harm humans by causing mutations.

After 5 months of exposure, the organoid cells were subjected to DNA extraction, and the kind, as well as the number of mutations due to the bacterial presence, was analyzed.


The results

The researchers found that there was indeed a unique pattern to the mutations that occurred within the organoid cells. In other words, the tested strain of E. coli did cause a distinctive mutation pattern to occur within human cells.

“I remember the excitement when the first signatures appeared on the computer screen,” says Axel Rosendahl Huber. “We had hoped for some indication of a signature that we could follow up on in other experiments, but the patterns were more striking than any signature we had analyzed before.”

The signature consisted of two mutations that occurred together, one being the change of an adenine base (A) to any of the other four DNA bases, and the other the loss of a single A in long polyA stretches. There was also another additional A on the other strand of the DNA helix, located at a distance of 3-4 bases away from the site of mutation.


Delving deeper

At the final stage, the team began to explore the way colibactin caused DNA damage. They found out its molecular structure and how this acted upon the DNA. The chief finding was that colibactin could bind two A’s simultaneously, causing a crosslink to form between them. This could, in their opinion, explain why the colibactin caused its unique mutational pattern.

The next step was to trace this signature in other cells, namely, the cells of patients with cancer. Furthermore, the researchers did not skimp on this. They examined thousands of mutations in over 5,000 cancers, of many different types.

One exciting finding stood out: more than 5% of bowel cancers showed this footprint, but it was present in less than one in hundred of other cancer DNAs. Among these, the tissue was known to be exposed to the same bacterium – such as cancer of the mouth or the urinary bladder.

Ominously, this tell-tale pattern was also found within the DNA of patients with colon cancer, which may well indicate a link between the bacteria and the disease. Jens Puschhof says, “It is known that E. coli can infect these organs, and we are keen to explore if its genotoxicity may act in other organs beyond the colon.”


Implications

This study marks the first time a direct connection has been found between the human microbiome and the mutations that cause cancers to develop.

The frightening thing is that, in the words of Hans Clever of the Hubrecht Institute, which ran the study, “There are probiotics currently on the market that contain genotoxic strains of E. coli. Some of these probiotics are also used in clinical trials as we speak. These E. coli strains should be critically re-evaluated in the lab.”

He explains that despite the short-term relief for certain painful conditions such as fibromyalgia or irritable bowel syndrome, when used for a short period, they could cause cancer after decades.

The finding of this mutation signature could help screen patients for their chances of developing a tumor, based on the presence of this genotoxic strain. It is estimated that it occurs in up to a fifth of healthy individuals. It is even possible that using the right antibiotics, these bacteria could be eradicated, and the chances of tumor development markedly reduced. Or at least, it could help detect these tumors very early in their course.


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Weight gain after breast cancer is a greater problem than previously thought

New study findings suggest that weight gain after breast cancer is a greater problem than previously thought. The first national survey on weight after breast cancer in Australia, published in BMC Cancer journal, found close to two-thirds (63.7%) of women reported weight gain at an average of nine kilograms after a breast cancer diagnosis, and overall nearly one-in-five women (17%) added more than 20 kilograms.

Researchers from NICM Health Research Institute, Western Sydney University and ICON Cancer Centre, Sydney Adventist Hospital, Wahroonga, surveyed 309 women with breast cancer living in Australia using an anonymous, self-administered online cross-sectional survey between November 2017 and January 2018. The national sample consisted mainly of members from Breast Cancer Network Australia (BCNA).

The majority of women surveyed (77%) reported gaining weight within the first 12-18 months after diagnosis, which could be the ideal 'window of opportunity' to provide additional support for weight management among women with breast cancer says Dr. Ee, lead author, general practitioner and senior research fellow at NICM Health Research Institute, Western Sydney University.

As well as significant weight gain, we also found high levels of concern about weight among our survey participants. Timing may be the key in helping women to manage weight after a diagnosis of breast cancer.

 Cancer services and general practitioners play an important role in having early conversations with women, and referring them to a team of qualified healthcare professionals such as dieticians and exercise physiologists with experience in cancer."

 Dr. Ee, lead author, general practitioner and senior research fellow at NICM Health Research Institute, Western Sydney University

The survey also found:

The proportion of women who were overweight or obese increased from 48% at time of diagnosis to 67% at the time of the survey, with the proportion of women who were obese almost doubling from 17% to 32%.


The majority (69%) of women gained weight in excess of the rates reported in age-matched controls without breast cancer - an additional 2.42 kilograms over five years.


Professor John Boyages AM, co-author and radiation oncologist at Icon Cancer Centre says that all women should be prescribed exercise after being diagnosed with breast cancer, according to the Clinical Oncology Society of Australia (COSA) guidelines.

"As doctors we really need to actively think about weight, nutrition and exercise and advise about possible interventions," said Professor Boyages.

"Breast cancer is the most common cancer in women worldwide and in Australia, and weight gain is common after breast cancer treatment. Many patients assume they will lose weight. Weight gain adds to self-esteem problems, increases the risk of heart disease and other cancers and several reports suggest it may affect prognosis and also increases the risk of arm swelling (lymphoedema). Prescribing a healthy lifestyle is just as important as prescribing tablets."

Dr. Ee further says that after diagnosis of breast cancer, many women experience fatigue, which can be a barrier to staying active, and studies show exercise is an effective treatment for fatigue. However, for this to be feasible and sustainable, she says supervision by an experienced exercise physiologist is invaluable.

BCNA CEO Kirsten Pilatti says many studies highlight the importance of specialists such as exercise physiologists and nutritionists for breast cancer treatment plans, however they are often an unfunded component of follow-up care.

"For many breast cancer survivors, the cost of accessing the expertise of these specialists puts them beyond their reach. We want a system that helps women and men diagnosed with breast cancer to come out and be able to move on with their life, not be crushed by the experience," said Ms Pilatti.

The researchers will next analyze the survey data to investigate reasons why women are gaining weight after breast cancer, with several risk factors reported in other studies, including the type of treatment that women receive, and whether or not they were menopausal before diagnosis and treatment.

 
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Administering immunotherapy alongside chemoradiation for advanced NSCLC appears to be safe and tolerable

Research from Rutgers Cancer Institute of New Jersey shows administering the immunotherapy drug pembrolizumab together with chemotherapy given at the same time as radiation treatment (chemoradiation) is safe and tolerable as a first-line therapy for patients with stage 3 non-small cell lung cancer (NSCLC). The work, stemming from a multi-center phase 1 clinical trial led by Rutgers Cancer Institute, is published in the February 20 online edition of JAMA Oncology.

"Locally advanced NSCLC accounts for 20 to 25 percent of all new diagnoses of NSCLC, with five-year overall survival rates of between 25 to 30 percent when standard therapy is given. Current standard treatment in which an immunotherapy drug is administered after chemoradiaton offers a 57 percent progression-free survival rate compared to 43.5 percent when chemoradiation is given alone. Our team wanted to examine the safety and tolerability of the immunotherapy drug pembrolizumab when administered concurrently with chemoradiation, as we've learned from first-line treatment of stage 4 disease that we see better patient outcomes the earlier immunotherapy is given," shares Rutgers Cancer Institute radiation oncologist Salma Jabbour, MD, who is the lead and corresponding author of the current work.

Typically, the human body's immune system recognizes abnormal cells in the body and destroys them. Cancer cells frequently create proteins (PD-L1, programmed cell death ligand-1) on the cell surface that act as signals to turn off this part of the immune system. Pembrolizumab is a drug approved by the Food and Drug Administration to treat melanoma and other forms of cancer that targets PD-1 receptors, which act as a signaling 'switch.' Pembrolizumab blocks this action and turns the 'switch' back on, allowing the immune system to recognize cancer cells as foreign and attack them.

For a 27 month period between 2016 and 2018, 23 participants were enrolled (52 percent were women; median age 69 years). Five cohorts evaluating different timing and dosing of pembrolizumab combined with chemotherapy (carboplatin and paclitaxel weekly) and definitive radiation therapy (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced, stage 3 disease were examined. Median follow-up time was 16 months.

Results show the combined treatment is feasible and well tolerated with a 12-month progression-free survival of 69.7 percent. Clinical benefit accounted for 94.6 percent at a median of 12.6 months. Of 19 evaluable patients (those who received 2 or more cycles of pembrolizumab) for response, the best response to therapy was a partial response seen in 73.7 percent, followed by 15.8 percent with a complete response, and 5.3 percent with stable disease. Local progression occurred in one patient, and of the six who developed metastatic disease, the median time to metastatic disease was 14.7 months. While there was an increased rate of pneumonitis, the authors note that patients with this form of lung inflammation responded to high-dose steroid treatment.


 This study demonstrates that the combination of immunotherapy with chemoradiation has the potential to improve cure rates for patients with stage 3 non-small cell lung cancer."   Dr. Salma Jabbour, professor of radiation oncology at Rutgers Robert Wood Johnson Medical School

Given the risk of pneumonitis when pembrolizumab is given with chemoradiation, the authors note further evaluation of the treatment combination through clinical trials is warranted, where careful radiation design to limit key lung parameters and biomarkers can be implemented. They add study limitations include the small sample size and limited follow-up duration.


For a 27 month period between 2016 and 2018, 23 participants were enrolled (52 percent were women; median age 69 years). Five cohorts evaluating different timing and dosing of pembrolizumab combined with chemotherapy (carboplatin and paclitaxel weekly) and definitive radiation therapy (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced, stage 3 disease were examined. Median follow-up time was 16 months.

Results show the combined treatment is feasible and well tolerated with a 12-month progression-free survival of 69.7 percent. Clinical benefit accounted for 94.6 percent at a median of 12.6 months. Of 19 evaluable patients (those who received 2 or more cycles of pembrolizumab) for response, the best response to therapy was a partial response seen in 73.7 percent, followed by 15.8 percent with a complete response, and 5.3 percent with stable disease. Local progression occurred in one patient, and of the six who developed metastatic disease, the median time to metastatic disease was 14.7 months. While there was an increased rate of pneumonitis, the authors note that patients with this form of lung inflammation responded to high-dose steroid treatment.

    This study demonstrates that the combination of immunotherapy with chemoradiation has the potential to improve cure rates for patients with stage 3 non-small cell lung cancer."

    Dr. Salma Jabbour, professor of radiation oncology at Rutgers Robert Wood Johnson Medical School

Given the risk of pneumonitis when pembrolizumab is given with chemoradiation, the authors note further evaluation of the treatment combination through clinical trials is warranted, where careful radiation design to limit key lung parameters and biomarkers can be implemented. They add study limitations include the small sample size and limited follow-up duration.



This is only for your information, kindly take the advice of your doctor for medicines, exercises and so on.     

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Spending time in nature may lower stress, anxiety

Spending as little as 10 minutes in a natural setting may help college students feel happier, and reduce the effects of physical and mental stress, according to a review of studies. 

The research, published in the journal Frontiers in Psychology, aims to provide an easily-achievable dosage that physicians can prescribe as a preventative measure against high levels of stress, anxiety, depression and other mental health issues. "It does not take much time for the positive benefits to kick in - we are talking 10 minutes outside in a space with nature," said Gen Meredith from Cornell University in the US. 

"We firmly believe that every student, no matter what subject or how high their workload, has that much discretionary time each day, or at least a few times per week," Meredith said. The researchers performed a review of studies that examined the effects of nature on college students aged 15-30. The aim of the research was to discover the right amount of time students should be spending outside, and what they should be doing while they are there. 

The researchers found that the range of 10-50 minutes in natural spaces was the most effective to improve mood, focus and physiological markers like blood pressure and heart rate. "It is not that there is a decline after 50 minutes, but rather that the physiological and self-reported psychological benefits tend to plateau after that," said Donald Rakow, an associate professor at Cornell University.
While outside, students only need to be sitting or walking to enjoy the positive effects, the two primary activities the researchers examined in an effort to provide accessible recommendations when the results are applied at schools. "We wanted to keep this access to nature as simple and achievable as possible," said Rakow. 

"While there is a lot of literature on longer outdoor programmes, we wanted to quantify doses in minutes, not days," he said. When it comes to more urban universities, research suggests that adding green elements to a built space can produce the same results, the researchers said. It is the time spent in nature, not necessarily nature itself, that is beneficial, they said. "This is an opportunity to challenge our thinking around what nature can be," said Meredith. 

The impetus for this work is a movement toward prescribing time in nature as a way to prevent or improve stress and anxiety, while also supporting physical and mental health outcomes, according to the researchers. They are hoping that when it is applied at universities, it becomes part of the routine and is consumed in regular doses, like a pill. "Prescribing a dose can legitimise the physician's recommendation and give a tangible goal," said Meredith. 

"It is different than just saying: Go outside. There is something specific that a student can aim for," said Meredith. Many students who are managing psychological issues are looking for non-pharmacological ways of improving their well-being, Rakow said. "This nature dose is an upstream 'prevention' approach to, hopefully, reduce the number of people getting to the point where a pharmacological approach becomes necessary," he added.

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