New Study Reveals Many Cancer Patients Are Killed By Chemotherapy & Not The Cancer


  • Up until recently, chemotherapy and radiation have been the only two approved treatment methods for treating cancer by mainstream medicine, but as more research emerges, light is being shed on just how damaging these treatment methods can be and how often they are the cause of death and not the cancer itself. Upon this discovery, many doctors are starting to see how this is not always the best treatment method.

Researchers from Public Health England and Cancer Research UK recently performed a groundbreaking study, which examined the number of cancer patients who died within 30 days of beginning chemotherapy showing how the treatment, and not the cancer itself, was the cause of death.

When looking at those death rates across hospitals in the U.K., the researchers found an alarming mortality rate that was directly associated with the chemotherapy treatment.

“England around 8.4 per cent of patients with lung cancer, and 2.4 per cent of breast cancer patients died within a month,” the Telegraph reported.

“But in some hospitals the figure was far higher. In Milton Keynes the death rate for lung cancer treatment was 50.9 per cent, although it was based on a very small number of patients.”

Results of the study showed the one-month mortality rate at Lancashire Teaching Hospitals for those undergoing palliative, rather than curative chemotherapy was 28%. One in five patients receiving palliative care for breast cancer at Cambridge University Hospitals died from treatment.

In other areas including, Blackpool, Coventry, Derby, South Tyneside, Surrey, and Sussex, saw that deaths from lung cancer patients receiving chemotherapy were much higher than the national average.

Cancer Lead for Public Health England, Dr. Jem Rashbass, requested the study and said, according to the Telegraph: “Chemotherapy is a vital part of cancer treatment and is a large reason behind the improved survival rates over the last four decades.”

“However, it is powerful medication with significant side effects and often getting the balance right on which patients to treat aggressively can be hard.”

“Those hospitals whose death rates are outside the expected range have had the findings shared with them and we have asked them to review their practice and data.”

All women with breast cancer and all men and women with lung cancer residing in England, who were 24 years older and who started a cycle” of chemotherapy in 2014 were included in the analysis by the researchers of the study.

Could This Signify The End Of Chemo?

Finally, chemotherapy has been looked at with a skeptical eye, had this been studied sooner, it is easy to see how this method of treatment cannot distinguish between healthy cells and cancerous cells, therefore there are more ideal patients for this method of treatment and less ideal patients. The study published by the Lancet shows how the cell destroying property of chemo can eventually lead to death as there aren’t enough healthy cells to survive.

Because of these important findings, researchers have now advised physicians to exercise more caution in the process of vetting which patients should in fact receive chemotherapy and which, ideally should not. Older, infirm patients could potentially be better off without receiving palliative care.

“The statistics don’t suggest bad practice overall but there are some outliers,” noted Professor David Dodwell of the Institute of Oncology at St. James Hospital in Leeds.

“It could be data problems, and figures skewed because of just a few deaths, but nevertheless it could also be down to problems with clinical practice,” he continued.

“I think it’s important to make patients aware that there are potentially life threatening downsides to chemotherapy. And doctors should be more careful about who they treat with chemotherapy.”

It’s important to realize that doctors aren’t intending to harm their patients by prescribing this method of treatment, this is what they have been taught during their extensive years of schooling and education, this is the curriculum, so it’s the widely accepted treatment method for cancer even though it often doesn’t help at all and can make things worse as mentioned above.

The hospitals involved maintain their stance, after reviewing the information that chemotherapy is safe, with the caveat patient selection for the treatment should be more discretionary. Chemo does seem to work for many, but there is a more ideal patient for this method and it shouldn’t be prescribed to every cancer patient that walks through the door.

Professor David Cameron of the Edinburgh Cancer Centre at West General Hospital in Edinburgh, Scotland, noted,

“The concern is that with some of the patients dying within 30 days of being given chemo probably shouldn’t have been given the chemo. But how many? There is no easy way to answer that, but perhaps looking at those places/hospitals where the death rate was higher might help. Furthermore, if we give less chemo then some patients will die because they didn’t get enough chemo. It’s a fine balance and the more data we have the better we can be t making sure we get the balance right. “

U.S. Doctors, Take Note

Unfortunately, in the United States many patients are forced to undergo chemotherapy despite what they want for themselves. This has happened with many children whose parents are opting to seek out alternative cancer treatments.

One example involves, 17-year-old Cassandra C., who has Hodgkin lymphoma, has been denied her desire to pursue alternative treatment methods when it comes to her cancer treatment. The Connecticut Supreme Court ruled, on January 8th, that Cassandra (who declined chemotherapy treatment) will be forced to undergo the treatment anyway. She cited chemotherapy’s adverse health effects as her main reason for refusing.

Cassandra expressed that being forced into surgery and chemo has traumatized her, that it should be a given human right to decide what you want and don’t want for your own body.

Alternatives?

The most frustrating part about this whole thing is that there are in fact many alternative methods to treating cancer that are not recognized, accepted or provided with enough funding for thorough studies to be considered as an option in the first place.

Successful alternative methods that have been used to treat cancer is an entirely separate topic that involves a lot of research, but success has been reported using vegan methods, fasting methods, and more. Clinical trials have been conducted in these areas, but we don’t hear much about it. The science on this that’s emerging is fascinating, and we encourage all who are interested to look into it a little deeper if interested.

Below is a great clip from The THRIVE movement that gives us all something to thing about.

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Reducing Inappropriate Vancomycin Use in Cancer Patients


While he was an attending physician at Montefiore Medical Center in New York City, Adam F. Binder, MD, and his colleagues developed an initiative to encourage the appropriate use of intravenous vancomycin for cancer patients with neutropenic fever.

For this work, he was hailed as a Choosing Wisely Champion here at the recent American Society for Hematology (ASH) 2018 annual meeting.

This program is run by ASH in cooperation with the American Board of Internal Medicine Foundation (ABIM), which began the Choosing Wisely initiative in 2012. The annual Choosing Wisely Champions campaign recognizes the efforts of practitioners who are working to eliminate the costly and potentially harmful overuse of tests and procedures.

In a presentation about his work, Binder explained that febrile neutropenia is a relatively common adverse event associated with myelosuppressive cancer therapies, and current guidelines for empiric therapy do not recommend the use of vancomycin.  So he was rather concerned to find that clinicians were overprescribing vancomycin for neutropenic fever.

“There was some anecdotal concern from oncologists and the antibiotic stewardship team that we may have been overprescribing vancomycin,” he said. “Some of the preliminary data that turned this from just anecdotal to objective evidence came out of a larger project that was looking at methicillin-resistant Staphylococcus aureus (MRSA) screening as a way to de-escalate the use of vancomycin in patients presenting with pneumonia.”

For that project, they looked at a cohort of 88 patients with hematologic malignancies who either presented to the emergency department with neutropenic fever or developed it in hospital.

Of this group, 45 patients (51%) had an inappropriate initiation of vancomycin.

“If vancomycin was started in the ER and then discontinued when they got to the floor, that was considered to be inappropriate, because the oncology team made the decision that it wasn’t necessary,” explained Binder.

Next, Binder and colleagues identified what he believed were the top three barriers to more appropriate use of vancomycin. One was changing individual practice patterns. “Physicians get used to practicing a certain way, even though there’s evidence suggesting that vancomycin up front doesn’t improve overall mortality,” he said. “But some may feel comfortable starting broader and then de-escalating.”

Another challenge was the ever-changing residency staff. “We had residents rounding on service and switching every 2 to 4 weeks, and most were second- and third-year residents and most of them had never rounded on an oncology floor,” he said. “So they didn’t know the appropriate management of neutropenic fever.”

A third barrier was a lack of nursing empowerment in driving change or for enforcing guidelines.

An interdisciplinary team was created, which included an antibiotic stewardship team, pharmacists, and hematologists, and together they developed an institutional algorithm to guide prescriptions related to febrile neutropenia. They also conducted recurring educational initiatives emphasizing criteria for appropriate vancomycin initiation based on well-established guidelines.

“The whole team gave their input and having everyone’s consensus meant that it was more likely that the algorithm would be followed than if it had been developed by just a small group,” Binder commented.

Once the guidelines were in place, they wanted to make sure that they were easily accessible. “That’s one of the problems,” he said. “One of our concerns is that guidelines are put online and you can click on them to read them, but no one ever looks at them. We wanted to make sure that the guidelines were seen.”

To circumvent that problem, the guidelines were printed out and laminated and these boards were placed at all work stations. “So no matter where you were, and no matter where you sat down, you’d have them staring at you in the face,” Binder emphasized. “A year later and the boards are still up and people are still using them. It’s a nice example of sustainability.”

After this intervention was put in place, along with educational initiative, inappropriate initiation of vancomycin dropped to 34%. There was also a 1-day reduction in the duration of vancomycin therapy.

Binder said this is an improvement to what they had seen previously (51% inappropriate vancomycin), but there is still a lot of work to be done, “because 34% is still high.”

“This is really just the beginning,” he said. “The changes need to be sustainable, and we need to continue to look for new interventions. One of our next projects is to have a clinical decision-making tool within the order set.”

A Prescription for Healthy Living: How Diet and Exercise Can Help Cancer Patients


A patient’s treatment plan for fighting cancer doesn’t stop at the hospital door. Adopting a healthy lifestyle, in terms of diet and exercise, is especially important for cancer patients in reducing stress, minimizing side effects, and boosting energy levels to power through treatment and recovery.

More than 93 million American adults could be counted as obese in 2016, according to the most recently available data from the Centers for Disease Control and Prevention.  “Obesity not only increases the risks of developing cancer; it also increases the risks of complications in diagnosed patients,” says Jennifer Ligibel, MD, director of Dana-Farber’s Leonard P. Zakim Center for Integrative Therapies and Healthy Living.

Plus, in some common cancers, such as breast cancer and prostate cancer, many patients now tend to gain—rather than lose—weight during treatment.

“That contradicts a common misperception that people have had for many years,” Ligibel continues. “Some patients think, ‘I have cancer. I have to make sure I don’t lose weight,’ so they bulk up. But we have much better medications to help patients avoid nausea and weight loss during treatment now than we did even a few years ago.

“Many people become less active during their cancer treatment, and even afterward,” says Ligibel. “Some cancer treatments can also contribute to weight gain.”

Jennifer Ligibel, MD.

How Patients Can Evaluate and Manage Their Diet

Ligibel recommends following the American Cancer Society’s guidelines on nutrition and weight management. They emphasize a plant-based diet with most nutrients coming from fruits, vegetables, whole grains, lean meats and fish.

“When you look across a population of people who have healthy behaviors—they eat a plant-based diet, their weight is in the normal range—we know that those people are less likely to get cancer in the first place,” Ligibel says. “In some cases, they are also less likely to have it comes back after it develops.”Blueberries.

Why Exercise is Important

Exercise is crucial in helping patients lose and manage weight and also provides other critical health benefits.

“If you exercise during your cancer treatment, and afterward, that can help prevent some of the long-term side effects that patients can develop from cancer treatment,” Ligibel says. “Exercise has been shown to reduce side effects like fatigue and joint pains from cancer treatments. Patients also feel better when they exercise and experience less anxiety and depression.”

Exercise also helps to preserve muscle; muscle loss often happens during cancer treatment, and can make recovery difficult, Ligibel says.

Those very side effects—especially fatigue—can make it difficult for patients to feel motivated to exercise in the first place. What’s important is to start now, wherever you are in your treatment, and to start slowly.

“I tell patients that 10 percent of something is better than 100 percent of nothing,” says Nancy Campbell, a clinical exercise physiologist at the Zakim Center. “Patients don’t have to go to a gym, start training for a marathon or buy expensive equipment. All it takes is a walk out your door or around your house to get started.”

Campbell suggests using a fitness tracking device, be it a basic pedometer, a smart phone app or Fitbit. After wearing it for a few weeks, you should have a baseline of your activity during treatment weeks, non-treatment weeks and weekends.

“It gives patients a good gauge of how much activity they are doing and how to gradually increase it,” she explains. “As people start to feel better, they get excited and do more and sometimes may do too much too soon. The device gives you feedback to let you know if you need to add more activity. If patients are sedentary, some of the apps buzz to remind you to move around every hour.”

To rebuild your muscle tone, Campbell suggests signing up for the free Live Strong program offered by YMCA locations across the country. This 12-week physical fitness program is designed specifically for cancer patients.

“There are also plenty of things you can do on your own at home,” she says. “You can get creative with light weights, such as soup cans, at home. But get some professional guidance before you start.”

Yoga, too, has been shown to have significant benefits for cancer patients in terms of reducing fatigue, improving sleep and improving quality of life.

“The data shows us that staying active during treatment definitely helps,” Campbell says. “Just doing a little something can take the edge off the nausea and fatigue, improve your mood and help take your mind off of it all.”

Increase in ‘Fake News’ Placing Cancer Patients at Risk


A decline in public trust in physicians and the rise of misinformation and “fake news” spread via the Internet has led to an increase in the use of unproven, unconventional treatments by cancer patients, claims an editorial that says efforts to communicate genuine medical advances need to be redoubled.

The editorial, published in the September issue of the Lancet Oncology, says that the “collision” between greater patient autonomy, falling trust, and the rise in social media has led to an increase in self-diagnosis and the use of alternative therapies by cancer patients.

This, it warns, may result in patients refusing conventional, proven therapies and increase their risk for death compared with patients who follow recommended treatment regimens, as previously reported by Medscape Medical News.

The editorial urges all those working in the oncology world to tackle the “disinformation and…lies” that are spread across social media, news platforms, and marketing channels by focusing on the communication of accurate information.

It points to a National Institutes of Health website that aims to help users evaluate health information on the Internet, as well as the recent hiring of a digital nurse by UK charity Macmillan Cancer Support to debunk fake news via a question-and-answer service.

There is nothing new in having to deal with fake news and misinformation in oncology, says Martin Ledwick, head information nurse at the leading charity Cancer Research UK. “This is something that has been around for a long time, and as a charity, our position is to challenge where there isn’t a decent evidence base for a treatment that’s being promoted,” he told Medscape Medical News.

Ledwick explained that Cancer Research UK set up its online forum around 10 years ago partly because “we could see when we looked around at the time that there wasn’t really a properly moderated forum out there for cancer patients.

“You could see that people were having suggestions made to them about alternative therapies and things like that, and no one was really picking that up,” he commented.

Ledwick noted that Cancer Research UK’s science blog also “spends a lot of time debunking myths and reinforcing the value of proper evidence base before people make decisions.”

Their team of nurses staffing their helpline “respond to a lot of inquiries from people who have heard about something perhaps through the Internet and want to explore it but haven’t understood that it’s not as good as it looks,” he said.

Ledwick believes that the growth of the Internet in recent years has created “much more of a platform for ideas to spread” and that that has led to a shift in the nature of the inquiries they receive.

He said that complementary treatments are “usually pretty harmless.” As long as the people offering them “are not overclaiming about them,” there is no problem with people taking them, he said.

“What gets tricky is when you’ve got someone saying this will definitely work and getting people signing up to it for that reason,” he warns.

Another problem, Ledwick noted, is when patients think they can use alternative treatments instead of conventional therapies.

“That, I think, is a worry,” he said, “that sometimes people think, well, maybe I will put off having conventional treatment and see if this works first, because, to be honest, it won’t.

“If it’s not a scientifically based, properly researched therapy, you’re basing your choices in hearsay and anecdotes rather than proper evidence,” he warns.

Decline in Trust in Health Professionals

The editorial notes that a “major challenge” in oncology today is a decline in trust by the lay public in professional opinion, at the center of which is “a collision between personal autonomy, specious journalism, social media, widespread disinformation, and political marginalisation.”

The editorial states that together, these factors undermine the standing of science and academic endeavor, which, in oncology, has led to self-diagnosis and patients’ “demand for specific treatments irrespective of their doctors’ advice.”

Patients are also turning to “alternative unproven therapies,” and clinicians are practicing what has been termed “defensive medicine” to avoid lawsuits, primarily through the overuse of diagnostic tests.

The editorial points to two studies, one published earlier this year and one in 2017, that show that cancer patients who use complementary medicine are more likely to refuse surgery, radiotherapy, and chemotherapy and are more than twice as likely to die than those who receive conventional medicine.

“How has society got to this point, where unproven interventions are being chosen in preference to evidence-based, effective treatments?” the editorial asks.

“Unfortunately, disinformation and — frankly — lies are propagated widely and with the same magnitude as verified evidence due to the ease with which social media, ubiquitous online news platforms, and disreputable marketing exercises can populate information channels, which often do not have sufficient funding to employ subject-specific journalists to weed out facts from fiction,” it comments.

The editorial asserts that to tackle this problem and to stem the decline in public trust, greater efforts need to be made to communicate medical advances accurately to both patients and the lay public “to ensure genuine knowledge can be separated from false material.”

It adds that oncologists need to be better protected from “spurious legal proceedings, bureaucracy, and unnecessary stresses.

“If these challenges are not addressed soon, the great advances in science and medicine that have markedly improved human health worldwide could be easily undone and society will come to regret such inaction and reliance on unreliable sources of information,” it concludes.

5 Things Every Cancer Patient & Their Families Must Know


Cancer patients & their families often lament on how unprepared they are after receiving news of their diagnosis.

Keeping this in mind, our team of oncologists has prepared a guide that helps you navigate through your cancer. This is by no means exhaustive, but we hope you find it useful as you begin your treatment journey.

What is Cancer?

Cancer is caused when some abnormal cells of the body start growing in numbers uncontrollably, and overcrowd the healthy cells, thereby affecting the functioning of body organs.

Cancer can sometimes stay hidden for a long time (as seen in cases of pancreatic cancer) or be detected early on, either because of regular cancer screening/health-check-ups or through unusual symptoms experienced by the patient.

Symptoms Seen Commonly In Cancer Patients

Please note that symptoms may differ, depending on the site, type and size of cancer. The most common symptoms of cancer are listed below:

  • C: Change in bowel or bladder habits
  • A: A painless oral/skin sore that does not heal
  • U: Unusual bleeding or discharge from the Nipple, Vagina, in urine or in stools
  • T: Thickening or lump in the breast or elsewhere
  • I: Indigestion or difficulty in swallowing
  • O: Obvious change in a wart or mole
  • N: Nagging cough or hoarseness of voice

Also notable is that these symptoms are not necessarily indicative of cancer; neither are they comprehensive. It is best to talk to your doctor/general physician if/when you experience any unusual symptoms.

How Is Cancer Detected?

The following tests help in the detection of cancer and the determination of its stage:

  1. Lab Tests: Typically, blood and urine tests are performed to detect a few common cancer types. These also help in detecting recurrences in some cases, through tumour marker studies.
  2. MRI Scans: These scans reveal a detailed internal image of body tissues.
  3. Ultrasound Tests: These provide an image of an internal part of the body through echoed sound waves.
  4. X-rays: X-rays are sometimes the first tests done to detect any bony abnormality. Chest X-rays also help in detecting if cancer has spread to the lungs.
  5. PET-CT Scans: These tests help detect cancerous areas as glowing hotspots in any part of the body. Such spots are then tested with a biopsy to confirm the presence of cancer. These also help in confirming whether the cancer has spread to other parts of the body.
  6. Biopsies: In a biopsy, a small piece of lump is extracted from the cancerous area, and checked for the presence of cancer cells. A biopsy is often a confirmatory test to diagnose cancer.

Once a biopsy report confirms cancer, a diagnosis is made.

What A Cancer Diagnosis Reveals

  1. Type Of Cancer: This is dependent on the body organ where the cancer first originated.
  2. Grade Of Cancer: Grade helps in predicting how fast the cancer will grow and spread. Higher-grade cancer grows fast and often requires aggressive treatment protocols.
  3. Stage Of Cancer: Cancer stage can be 0,1,2,3 or 4. A 4th stage cancer implies that a cancer has spread wide from its site of origin.
  4. Metastatis (Y/N): Cancer is termed metastatic once it has spread to other body parts. For example: a lung cancer can spread to the brain, etc.

Cancer Treatment Options

Cancer treatment options are comprised of one or more of the following:

  1. Surgery: A surgery is often performed to remove the tumor from a body part. It is most effective when the cancer is localized (early stage) and non-metastatic.
  2. Radiation Therapy: Radiation treatment involves killing of cancer cells by subjecting the tumour to X-ray radiation. It can either be from external or internal sources.
  3. Chemotherapy: Chemotherapy involves the administration of drugs to kill cancer. These drugs are very toxic in nature and sometimes attack healthy cells as well. Therefore, patients on chemo drugs often experience severe side effects.
  4. Targeted Drugs: Targeted therapies only affect the cancerous cells in the body and exclude all healthy cells from their effects. Therefore, they have less severe side effects as compared to chemo drugs. There are several targeted therapies available in the market today, for certain types of cancers.
  5. Immunotherapy: This is a cutting-edge treatment option in cancer care today, and it involves training the immune system of the body to attack cancer cells.
  6. Other Advanced Therapies: The field of cancer research has seen major clinical advancements in the last decade. Hundreds of cutting-edge therapies are in development presently, and will be approved in the coming years. It is worthwhile to check if there are any clinical trials recruiting near you for these therapies.

Development of a gene panel for next-generation sequencing of clinically relevant mutations in cell-free DNA from cancer patients


Abstract

Background:

When tumour tissue is unavailable, cell-free DNA (cfDNA)can serve as a surrogate for genetic analyses. Because mutated alleles in cfDNA are usually below 1%, next-generation sequencing (NGS)must be narrowed to target only clinically relevant genes. In this proof-of-concept study, we developed a panel to use in ultra-deep sequencing to identify such mutations in cfDNA.

Methods:

Our panel (‘SiRe’) covers 568 mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα)involved in non-small-cell lung cancer (NSCLC), gastrointestinal stromal tumour, colorectal carcinoma and melanoma. We evaluated the panel performance in three steps. First, we analysed its analytical sensitivity on cell line DNA and by using an artificial reference standard with multiple mutations in different genes. Second, we analysed cfDNA from cancer patients at presentation (n=42), treatment response (n=12) and tumour progression (n=11); all patients had paired tumour tissue and cfDNA previously genotyped with a Taqman-derived assay (TDA). Third, we tested blood samples prospectively collected from NSCLC patients (n=79) to assess the performance of SiRe in clinical practice.

Results:

SiRe had a high analytical performance and a 0.01% lower limit of detection. In the retrospective series, SiRe detected 40 EGFR, 11 KRAS, 1 NRAS and 5 BRAF mutations (96.8% concordance with TDA). In the baseline samples, SiRe had 100% specificity and 79% sensitivity relative to tumour tissue. Finally, in the prospective series, SiRe detected 8.7% (4/46) of EGFR mutations at baseline and 42.9% (9/21) of EGFR p.T790M in patients at tumour progression.

Conclusions:

SiRe is a feasible NGS panel for cfDNA analysis in clinical practice.

Main

Precision medicine, coupled with the tissue-based assessment of biomarkers predictive of treatment outcome, has transformed pathology practice (Papadopoulos et al, 2006). RAS and BRAF mutation testing in colorectal cancer (CRC; Di Nicolantonio et al, 2008; Lièvre et al, 2008), EGFR in non-small-cell lung cancer (NSCLC; Lynch et al, 2004) BRAF in melanoma (Chapman et al, 2011) and cKIT and PDGFRα in gastrointestinal stromal tumours (GIST; Antonescu, 2008) has added a genotypic element to the phenotypic diagnostics of solid tumours. However, tumour tissue is not always available or may be insufficient for molecular testing, especially when cancer is diagnosed at advanced stages on small biopsy specimens. On other occasions, due to tumour location or small size, tissue sampling can be challenging and risky, particularly in extensively treated patients. As an alternative to cancer tissue, predictive biomarkers can be non-invasively assessed in cell-free DNA (cfDNA; Schwarzenbach et al, 2011; Crowley et al, 2013).

Using a Taqman-derived assay (TDA) we previously identified EGFR mutations in NSCLC (Karachaliou et al, 2015) and BRAF mutations in melanoma patients (Gonzalez-Cao et al, 2015) with a specificity of 100% and with sensitivities of 69% and 78%, respectively. One of the factors contributing to this high sensitivity was the concomitant analysis, in each patient, of serum- and plasma-derived cfDNA (Karachaliou et al, 2015; Gonzalez-Cao et al, 2015). This performance may be further improved by next-generation sequencing (NGS), which can be multiplexed across several genes to cover less common and even novel variants (Malapelle et al, 2016a). Large gene panels or whole-exome approaches to screen for a large number of genomic regions may not be easily implemented in cfDNA analysis (Cancer Genome Atlas Research Network, 2014). Conversely, small NGS panels tailored to target a limited number of actionable genes can be an effective tool in daily clinical practice (Paweletz et al, 2016). This strategy, known as ‘ultra-deep sequencing’, can significantly increase sensitivity, which is essential considering that circulating tumour DNA represents only a small fraction (<0.5%) of the total cfDNA (Mead et al, 2011) in most patients with solid tumours. Since the low threshold levels of mutant alleles required to detect clinically relevant alterations may easily lead to false-positive results (van Dijk et al, 2014), implementation of the ultra-deep sequencing of cfDNA in the clinical setting must be validated in terms of blood collection, cfDNA extraction, automated library preparation, sequencing and variant calling (Gargis et al, 2012; Malapelle et al, 2016c).

In this proof-of-concept study, we report the development, performance evaluation and implementation in a clinical setting of a narrow gene panel that targets 568 clinically relevant mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα) involved in non Small cell lung cancer, gastroIntestinal stromal tumour, metastatic coloRectal carcinoma and mElanoma (whose acronym is SiRe). This panel has a high sensitivity and specificity and enables the detection and quantification of mutations in cfDNA purified from the plasma and serum of patients with different types of solid tumours.

Materials and methods

Design of the SiRe panel

The Ion AmpliSeq Designer suite v5.3.1 with hg19 was used as reference genome to develop a customised panel targeting six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα) that are associated with treatment outcome in NSCLC, GIST, CRC and metastatic melanoma (Lynch et al, 2004; Antonescu, 2008; Di Nicolantonio et al, 2008; Lièvre et al, 2008; Chapman et al, 2011). A single primer pool leading to the selection of 42 amplicons (ranging from 125 to 175 bp) enabled us to cover all COSMIC annotated mutations (n=568) in the selected exons of the target genes. The complete reference range of SiRe is reported in Supplementary Material (Supplementary Table S1). The amplicon design (available on request) covering 5.2 kb of genomic DNA was optimised for the simultaneous analysis of 16 samples with the 316v2 chip (Thermofisher, Foster City, CA, USA) on a Personal Genome Machine Torrent (Thermofisher).

Study design, patients and samples

The panel performance was evaluated in three steps (Figure 1). First, the analytical sensitivity of the assay was assessed on DNA from two cell lines and by using an artificial reference standard with multiple mutations in different genes. Second, clinical sensitivity and specificity was determined using archival cfDNA from 63 cancer patients (Table 1) with paired tumour tissue, previously genotyped with a TDA. As exploratory analysis, to confirm that our NGS approach cover the mutations in cKit and PDGFRα genes, two GIST samples (bloods and tissues) were tested with SiRe and the relative data are reported only in Supplementary Material. Third, the performance of the panel in daily clinical practice was assessed using blood samples prospectively collected from patients with advanced NSCLC. Written informed consent was obtained from all patients and documented in accordance with the general authorisation to process personal data for scientific research purposes from ‘The Italian Data Protection Authority’ (http://www.garanteprivacy.it/web/guest/home/docweb/-/docwebdisplay/export/2485392). All information regarding human material was managed using anonymous numerical codes, and all samples were handled in compliance with the Helsinki Declaration (http://www.wma.net/en/30publications/10policies/b3/).

Figure 1
Figure 1

Study design.cfDNAs (A) extracted with the QIAsymphony virus/pathogen kit (B) from paired (P) plasma and (S) serum (C) samples were analysed by quantitative 5′-nuclease TaqMan PCR (D) and by the NGS SiRe panel (E). Any discordance between the two techniques was evaluated by dPCR (F). After preclinical validation, the SiRe panel was applied in clinical practice in cases in which tissues were not available to select patients for TKI treatment, at baseline (G), and to evaluate the selection of resistant clones after disease progression (H).

Table 1: Characteristics of the patients included in the retrospective (left) and prospective (right) clinical validation of the SiRe panel

DNA purification

DNA from the two cell lines was isolated using the QIAamp Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Circulating-free DNA was purified as follows: 15 ml blood was withdrawn from patients and collected in Vacutainer tubes (BD, Plymouth, UK). Plasma and serum were isolated by centrifugation twice at 2300 r.p.m. for 10 min. The supernatant (serum or plasma) was aliquoted and used immediately for cfDNA isolation or stored at −80 °C. Cell-free DNA was purified from serum and plasma for each patient (1.2 ml). In the rare instances that the volume of the serum and plasma sample obtained from a patient was between 1 and 1.2 ml, PBS up to 1.2 ml was added to the samples, which were then purified using the QIAsymphony robot (Qiagen) and the QIAsymphony DSPVirus/Pathogen Midi Kit, according to the manufacturer’s instructions, and cfDNA was eluted in a final volume of 30 μl. Since correct preanalytical handling of blood specimens is crucial to maintain the sample informative, the process was standardised (in terms of blood collection, sample centrifugation and cfDNA extraction) in the Department of Public Health of the University of Naples Federico II, and all procedures were performed in-house by a nurse belonging to the laboratory staff.

Sample sequencing

We analysed the serum and plasma cfDNAs of each patient enrolled in the study. Libraries were constructed and purified on the Ion Chef (Thermofisher), and eight samples (corresponding to 4 patients) were added per run. Library generation was as follows: 6 μl of cfDNA were dispensed on Ion Code plates and amplified using Ion AmpliSeq DL8 (Thermofisher). We used 22 cycles for cfDNA amplification and 6 cycles for library reamplification after barcoding, under the thermal conditions defined by the manufacturer. Purified libraries derived from eight cfDNA samples were diluted to 60 pM and combined with eight additional cfDNA-derived libraries to obtain a 16 Ion Code pooled library. The two-pooled libraries were re-loaded into the Ion Chef instrument, and templates were prepared using the Ion PGM Hi-Q IC Kit (Thermofisher). Finally, templates were loaded into the 316v2 chip and sequenced on PGM.

Data analysis

Signal processing and base calling were carried out using the default base-caller parameters on Torrent Suite [v.5.0.2] and coverage analysis was performed using SiRe designed bed files with coverage plug-in (v.5.0.2.0). BAM files were visually inspected with the Golden Helix Genome Browser v.2.0.7 (Bozeman,MT, USA). Variants were automatically annotated using variant caller plug-in (v.5.0.2.1) at specific optimised parameters of the SiRe panel (Supplementary Table S2). In particular, only variants with 5X allele coverage and a quality score 20, within an amplicon that covered at least 1000X alleles, were called, and the frequency of each mutant allele was recorded.

Preclinical assessment

Genomic DNA from the HCC827 (EGFR p.E746-A750del; KRAS wt) and A549 (EGFR wt; KRAS p.G12S) cell lines was used to assess analytical performance. Both cell lines were obtained from the National Research Council/Institute of Experimental Endocrinology and Oncology on courtesy of Dr Pierlorenzo Pallante (Naples, Italy). The analytical sensitivity of the assay for point mutation and indel detection was determined by diluting DNA from the appropriate mutated cell line (A549 for point mutations and HCC827 for indels) into increasing concentrations of DNA from the appropriate wt cell line (HCC827 for point mutations and A549 for indels). DNA dilutions ranged between 1 : 10 and 1 : 10 000, which correspond to allelic fractions from 1 : 20 to 1 : 20 000 of the mutated allele (both cell lines are heterozygous). Each dilution was analysed in duplicate to estimate inter-run assay reproducibility, and the library obtained from each dilution was sequenced twice to evaluate intra-run assay reproducibility. In addition, customised Horizon Diagnostics Multiplex gDNA reference standard, with mutation in EGFR (p.E746_A750del and p.G719S), KRAS (p.G12D), NRAS (p.Q61L) and BRAF (p.V600E), each of them at three different dilution points (1, 0.5 and 0.1%), were assessed to provide stronger evidence on SiRe analytical performance.

Clinical validation

We determined the specificity and sensitivity of our assay by analysing archival serum and plasma cfDNA from 40 cancer patients at presentation attending the Quiron Dexeus University Hospital (33 NSCLC, 2 CRC and 5 metastatic melanoma) with paired tumour tissue. In addition, we tested archival serum and plasma cfDNAs from 12 responder patients and 11 patients at the time of tumour progression after treatment (18 NSCLC, 2 CRC and 3 metastatic melanoma; Table 1). All of the 63 cfDNA samples and tumour tissues had previously been genotyped for EGFR, KRAS, NRAS and BRAF mutations using a TDA (Gonzalez-Cao et al, 2015; Karachaliou et al, 2015). In the case of tumour tissues, genotyping had been confirmed by standard PCR followed by Sanger sequencing. Cases showing discordance between the NGS SiRe panel and the TDA were further investigated by digital PCR (dPCR) on a QuantStudio 3D Digital PCR System platform (Thermofisher) as previously described (Malapelle et al, 2016b).

Performance of the SiRe panel in prospective clinical samples

To evaluate the performance of the SiRe panel in the clinical setting, we prospectively genotyped 79 advanced NSCLC patients (37 men and 42 women; mean age: 65 years) using blood samples collected at the Department of Public Health of the University of Naples Federico II. According to the European Medicines Agency guidelines, mutations related to EGFR disease were tested in patients when tissue was not available at presentation (n=46), or at tumour progression (n=33) in patients previously treated with erlotinib (n=14), gefitinib (n=14) or afatinib (n=5) in the attempt to detect the emergence of resistance secondary mutations. In 21 of the 33 cases with tumour progression, first-line TKI administration had been based on the demonstration of an EGFR mutation in tissue, whereas in the remaining 12/33 cases, TKI treatment had been administrated in second line without evidence of EGFR mutations.

Results

Panel design and preclinical performance evaluation

The SiRe panel was designed to cover 568 clinically relevant mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα) involved in NSCLC, GIST, CRC and metastatic melanoma (see Supplementary Table S1). The panel was intended for use in cfDNA purified from patients with advanced cancer. On cell line derived DNA, the SiRe panel detected the EGFR deletion p.E746_A750del and the KRAS point mutation p.G12S at a level as low as one copy of the mutated allele in a background of 20000 copies of wild-type alleles (0.005% mutated allele fraction), with 100% of intra- and inter-run reproducibility. In addition, regarding the results obtained on multiplex gDNA reference standard (Horizon Diagnostics), p.E746_A750del and p.G719S point mutation in EGFR, p.G12D mutation in KRAS exon 2, p.Q61L mutation in NRAS exon 3 and p.V600E mutation in BRAF exon 15 were correctly identified for each different dilution point.

This high analytical performance was achieved thanks to the use of optimised parameters set in variant caller plug-in (v.5.0.2.1) which detected low abundant mutated alleles with a specificity of 100% (see Supplementary Table S2).

Clinical sensitivity and specificity of the SiRe panel in cfDNA samples

The retrospective series of cfDNAs (Supplementary Table S3) was constituted by 126 paired serum and plasma samples from 63 patients. In each run, up to 16 paired serum and plasma samples from eight patients on 316v2 were processed. Run median output was 257Mbases, median read length was 124 bp, mean read depth was 2821 × and coverage uniformity was 97%. Technical performance data relative to each processed sample are reported in Supplementary Material (Supplementary Table S4). When the 63 samples were tested with the SiRe panel, the cfDNA of all eight patients with wild-type tumour tissue was negative (specificity 100%, CI 64.6-100%). In the remaining 55 patients with EGFR, KRAS, NRAS or BRAF mutations in tumour tissue, the SiRe panel detected the same mutation in the serum and/or plasma cfDNA in 46 cases (sensitivity 83.6%, CI 67.3–94.3%; Table 2).

Table 2: Concordance of Taqman-derived assay (TDA) and the SiRe panel NGS in retrospective serum and plasma cfDNA samples

Comparison of the SiRe panel with a TDA in cfDNA samples

We compared the performance of the SiRe panel for mutation analysis in cfDNA with that of a previously reported TDA (Karachaliou et al, 2015; Gonzalez-Cao et al, 2015) in 63 samples: (i) the 40 cfDNA samples obtained at presentation mentioned above; (ii) archival serum and plasma cfDNAs from 12 patients in response to different types of antitumour drugs; and 11 patients mutations in the cfDNA of 46 of 63 patients. The test was positive in both serum and plasma cfDNA in 35 patients (76.1%), positive in plasma but not in serum in 5 patients (10.9%), and positive in serum but not in plasma in 6 patients (13%). An EGFR sensitising mutation and the p.T790M resistance mutation were detected simultaneously in 10 patients at progression to EGFR TKIs.

As reported in Table 2, there was a high concordance (Cohen’s Kappa 0.85) between the results obtained with the NGS SiRe panel and the TDA, although the performance of the SiRe was slightly better. All 42 patients with mutation-positive cfDNA at TDA were also positive with the SiRe panel, and the 17 negative samples with the panel were also negative at TDA. In addition, NGS detected mutations in the cfDNA of four patients, whereas TDA did not. The mutations in these four patients appeared also in paired tumour tissue. One was a p.L597R mutation in BRAF not covered by the TDA, and was confirmed by dPCR (Supplementary Figure S2). The remaining three mutations were a p.L861Q mutation in EGFR and two KRAS mutations, p.G12C and p.G12A. Both TDA and NGS using the SiRe panel enable quantification of the mutated alleles (Figure 2). There was a significant correlation in the levels of serum cfDNA between the two techniques (r=0.64). In contrast, correlation was lower in the case of plasma (r=0.35), but improved significantly when three outlier samples were removed (r=0.61).

Figure 2
Figure 2

Quantification of mutated allele fractions.Comparison of the quantification of mutated allele fractions by Taqman Derived Assay vs SiRe NGS in serum (A) and plasma (B) cfDNA. In the case of plasma, three outliers were removed and results re-plotted (C).

Evaluation of the SiRe panel for prospective analysis of clinical samples

The performance of the SiRe panel in the clinical setting was evaluated by prospectively testing the serum and plasma cfDNA of patients with advanced NSCLC for whom no tissue was available in order to select them for TKI treatment. Seventy-nine patients were tested, 46 at presentation and 33 at the time of tumour progression after first-line TKI treatment (Table 1). The NGS procedure was adequate for variant calling in the 79 cfDNA paired serum and plasma samples. The run metrics parameters were not dissimilar from those of the retrospective samples. In fact, in prospective cfDNA samples, the median output was 210Mbases, the median read length 125.57 bp, the mean read depth 3385.45 and coverage uniformity 97.49%. Among the 46 patients analysed at baseline (Supplementary Table S5), we detected four EGFR mutations (8.7%), one point mutation in exon 18 (p.G719A), two deletions in exon 19 (both p.E746_A750delELREA) and one insertion in exon 20 (p.H773-V774insH). In all four patients, the mutant alleles were detected in both serum and plasma cfDNA and were confirmed by digital PCR (data not shown).

Regarding samples at progression (Supplementary Table S6), the SiRe panel did not detect mutations in 12 patients, whose tissues had been identified as EGFR wild type in biopsies at presentation. In contrast, among the 21 patients EGFR positive in baseline tissue, the SiRe panel confirmed the same mutation in cfDNA in 19 cases (Table 3). Thus, sensitivity and specificity in this cohort of patients at progression were within the range of those observed in the retrospective cohort. Interestingly, in 9 of those 19 cases (47%), we observed the emergence of the EGFR p.T790M mutation in addition to the original EGFR activating mutation. The appearance of EGFR p.T790M mutation in relation to TKIs treatment regimen was reported in Figure 3. Of the 28 mutations (sensitising+p.T790M) detected, 10 (35.70%) were present in both serum and plasma, 7 (25%) in plasma alone and 11 (39.3%) in serum alone. All mutations detected by the SiRe panel at progression were confirmed by dPCR.

Table 3: Comparison of the mutational status in FFPE tumour tissue at presentation with the results of the SiRe panel in archival cfDNA purified from serum and plasma baseline (n=42, left) and at response or after tumour progression (n=23, right)
Figure 3
Figure 3

Frequency of the EGFR p.T790M mutation (green: T790M−; red T790M+) after progression to thyrosine kinase inhibitors (TKIs) in the serum and plasma cfDNA of EGFR-mutated patients evaluated with SiRe panel NGS.A full colour version of this figure is available at the British Journal of Cancer journal online.

Discussion

In this proof-of-concept study, we demonstrate that the performance of ultra-deep sequencing using a narrow NGS panel on Ion Torrent PGM is excellent, and that this procedure can be used for the routine testing of relevant tumour mutations in cfDNA. The high sensitivity (90.5%) and analytical specificity (100%) of this panel equal or even surpass those of such other procedures as real-time PCR-based methods. Unlike earlier NGS applications that cover large genomic regions (Cancer Genome Atlas Research Network, 2014), our small gene panel (5.2 kb) focuses on biomarkers that are currently used in the clinical setting.

The ultra-deep sequencing procedure reported herein has various advantages. In fact, using a single panel, we were able to detect up to 568 relevant mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα). These mutations included less common, but actionable variants such as the BRAF p.L597R mutation in melanoma (case #38 in Supplementary Table S3). Sequencing with the SiRe panel was more efficient than real-time PCR target techniques in detecting deletions (n=2) and point mutations (n=6) on cfDNA samples. In addition, NGS per se is a time-effective procedure for analysing large numbers of samples, thereby optimising the work flow in molecular pathology laboratories (Malapelle et al, 2016a). With our procedure, different types of samples (DNA from tumour tissues and cfDNAs from biological fluids) from patients affected by different types of diseases (e.g., NSCLC, GIST, CRC and melanoma) can be processed simultaneously. Consequently, sample batching is more effective and does not require a minimum number of a given tumour type. As a result, turnaround time (TAT) can be as short as three working days, as recommended by international guidelines (Lindeman et al, 2013). The recently developed Ion Chef automated library preparation station, which has a better procedure reproducibility and standardisation than manual procedures, also contributes to the short TAT (Malapelle et al, 2016a).

The Ion Torrent PGM protocols, panels and variant caller do not detect low abundant mutations diluted in a large amount of WT DNA. Therefore, we used several in-house strategies specifically tailored to cfDNA. Firstly, we reduced the number of genes and exons vs commercially available tests, and we modified the thresholds for variant calling, in particular all the variants with 5X allele coverage and a quality score 20, within an amplicon that covered at least 1000X alleles, were called (Supplementary Table S2).

We also adapted the Ion Chef template preparation protocol by pooling two 16-sample libraries in each run. Thus, using this well standardised procedure, we were able to sequence simultaneously up to 32 paired plasma/serum samples in less than 3 h on the PGM, with a consequent reduction in the total consumable cost. In a previous study (Malapelle et al, 2016a)we showed that by using a commercially available 22 gene panel(AmpliSeq Colon and Lung Cancer Panel)on the Ion Torrent PGM, the consumable cost was €196 per sample. Using the modified protocol that we developed in this current study the cost per sample was lowered to 98 euro for simultaneously analysis of six different genes. This is comparable with the cost of the most commercially available Real Time PCR based kits.

The simultaneous analysis of paired plasma/serum samples is a crucial feature of this new procedure since the sensitivity of somatic mutation analysis in cfDNA increases when serum and plasma are analysed together (Gonzalez-Cao et al, 2015; Karachaliou et al, 2015). Our results are in agreement with this finding. In fact, of the 89 patients found to carry mutations in cfDNA, 58 (65.17%)were positive in both serum and plasma, 15 (16.85%) in plasma alone and 16 (17.98%)in serum alone.

From the technical point of view, even when sequencing 16 samples simultaneously in a run, the SiRe panel had optimal run metrics in our daily clinical practice in terms of both mean depth reads and uniformity of coverage, which resulted in a high assay sensitivity in cfDNA vs tumour tissue (90.5%) and a specificity of 100%. This is a very high degree of concordance, particularly given the 91.7% concordance between paired surgical resection and cytological samples (Sun et al, 2013). Thanks to the high sensitivity of our assay, the EGFR mutational rate of 8.7% that we identified in NSCLC patients prospectively tested on cfDNA at baseline is in keeping with previous data on tissue samples (Malapelle et al, 2013). Similarly, the frequency of the EGFR p.T790M mutation, which was detected in the cfDNA of 9 of 19 (47.4%) patients progressing after TKI treatment (n=5 gefitinib, n=3 afatinib, n=1 erlotinib), is in line with data obtained on tissues samples collected after disease progression (Karachaliou et al, 2015).

The performance of our methodology compares favorably with that of NGS for mutational analysis in the blood of cancer patients. An Ion Torrent-derived sequencing of five genes in cfDNA purified from never smoking lung cancer patients achieved a modest 58% sensitivity and 87% specificity (Couraud et al, 2014). An analysis of 23 amplicons in five genes using cfDNA from breast cancer patients identified 10 mutations but missed 6 identified by droplet digital PCR (Guttery et al, 2015). When restricted to EGFR, deep sequencing achieved 61–80% sensitivity and 94–98% specificity in advanced NSCLC (Uchida et al, 2015). The 90.5% sensitivity of our assay also exceeds the 77% recently reported when NSCLC plasma-derived cfDNA was analysed on an Illumina NGS platform with a panel covering amplicons of 11 clinically relevant genes (Paweletz et al, 2016). Despite the variations inherent to the platforms used, such as the library preparation and the longer TAT (6 days), the Illumina-based NGS approach featured similar run metrics and analytical parameters as our assay, which supports the use of ultra-deep sequencing in the clinical setting (Paweletz et al, 2016). It is conceivable that the higher sensitivity achieved by our panel is due not only to technical differences but also to the simultaneous testing of serum and plasma in each patient.

Besides being an alternative to molecular diagnosis at presentation when tumour tissue is not available, liquid biopsy is also a noninvasive test with which to monitor response to targeted therapy and to detect the emergence of resistance mutations in genes such as EGFR (Sundaresan et al, 2016) and ESR1 (Chu et al, 2016). Monitoring would consist in quantifying the mutant allelic fractions in cfDNA over time, which can be reliably assessed by our NGS assay. The SiRe panel detects the appearance of resistance mutations such as EGFR p.T790M (Figure 3). Finally, the non-synonymous mutation burden correlates with a good response to immunotherapy in NSCLC (Rizvi et al, 2015) and other tumours, and NGS has been proposed as a tool with which to design customised immunotherapies that target common driver mutations (Nielsen et al, 2016). Our panel, which covers several exons in frequently mutated genes, can be useful also in this setting.

In conclusion, we have developed and translate in clinical setting an NGS assay based on a narrow gene panel. The assay detects relevant mutations in cfDNA purified from the serum and plasma of patients with the tumours most commonly tested for molecular alterations (such as NSCLC, CRC and metastatic melanoma). The SiRe panel has excellent sensitivity and specificity, and is hence suitable for testing blood samples in the clinical setting. Finally, it enables the application of NGS on a prospective basis in daily molecular predictive pathology practice, particularly when tumour tissue is not available, and is a tool with which to monitor disease course.

Omega-3 Builds Muscle Mass in Cancer Patients


For cancer patients, supplementation with omega-3 fats could help them maintain and even regain lost muscle mass, according to a new study. Most patients who took a daily supplement for 10 weeks either maintained or gained muscle mass. Patients who didn’t take anything either maintained or lost muscle mass.

omega-3-capsules-3-24

MSNBC reports:

“[Omega-3’s] interfere with inflammation, thereby reducing its effect on muscle … Loss of muscle mass and fat is bad for cancer patients because it hampers their ability to respond to cancer treatments.”

Dr. Mercola’s Comments:

If you’ve known anyone with advanced cancer, chances are they have experienced cachexia, also called catabolic wasting. Cachexia, or more precisely cancer anorexia-cachexia syndrome (CACS), is a clinical wasting syndrome characterized by unintended and progressive weight loss. Both muscle and fat tend to be lost.

More than 80 percent of patients with advanced cancer develop cachexia, especially those with solid tumors. Cachexia is more common among children and elderly patients, and it becomes more pronounced as the cancer progresses.

Patients experience anorexia, chronic nausea, early satiety, and changes in how foods taste to them, making previously enjoyed foods less palatable. If you’ve ever had a friend or family member with cachexia, your loved one may have seemed to “waste away” before your very eyes.

Cancer patients can have other adverse effects, associated with the cachexia:

Anemia Hyperlipidemia and insulin resistance
Fatigue and weakness after minimal activity Psychological distress
Systemic inflammation Diminished quality of life
Edema

Cachexia is a SERIOUS and complex metabolic syndrome—it is estimated to be responsible for one-fifth to one-third of all cancer deaths.

This may be explained, at least in part, by a 2010 study in mice that showed the wasting can result in damage to the heart. This is quite significant because prior to now, most clinicians believed cachexia did not affect the heart muscle in the way it does skeletal muscle.

This study demonstrated that cancer cachexia impairs heart function by causing “increased fibrosis, disrupted myocardial structure, and altered composition of contractile proteins of cardiac muscle.”

What Causes Cachexia?

It used to be thought that cancer increased your metabolic demand and suppressed your appetite, resulting in malnutrition. However, new research shows there is more to it than that.

Cancer actually alters your metabolism from an anabolic one (muscle building) to a catabolic one (muscle breakdown). Recent research shows that cancer raises your resting metabolic rate, and supplemental general nutrition does not alleviate it.

Today, clinicians believe that tissue wasting results from a variety of tumor products, immune factors, and cytokines.

According to an article in Life Extension:

“The cytokines interleukin-1 (IL-1), IL-6, interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and brain-derived neurotrophic factor appear to increase and play a role in the progression of cachexia in cancer, as well as in other diseases associated with bodily wasting.”

Basically, you end up with an energy deficit, so your body is forced to use your muscles, internal organs and fat for energy. Add to that the ravaging side effects of common cancer treatments, such as chemotherapy and radiotherapy, and it is easy to understand why your loved one looks malnourished and even emaciated.

Numerous Other Studies Show the Positive Effects of Omega-3s on Cachexia

This is not the first study showing that omega-3 fatty acids may help to reverse cancer-induced cachexia. Studies in mice have been very favorable, and studies in humans have been largely favorable.

The “not favorable” human studies often involve treatment with insufficient doses of omega-3 fatty acids, or treatment over too short of a time. Because these studies have been done mostly on late-stage cancer patients (since they are the ones with the worst cachexia), there is a relatively high attrition rate, which skews the results toward “unfavorable.”

The bottom line is, the sooner you bump up your omega-3 levels, the better your long-term outcome will be.

Here are a few of the specific studies:

  • A 2004 study of human patients with advanced malignancy found that, although the majority of patients did not gain weight with the fish oil, a subset of patients had weight stabilization or weight gain. The researchers theorized that the length of time patients receive omega-3 supplementation is a factor—the longer, the more significant the positive effect. They also suggested inadequate dose as the explanation for part of the lack of effect in some patients.
  • A study in 1996 of eighteen human pancreatic cancer patients showed that taking fish oil capsules resulted in less muscle wasting, and many actually gained lean body mass.
  • A 2000 study investigating the effects of a combination of omega-3 fatty acids AND vitamin E found the combination produced a significant immunomodulating effect, and the omega-3 prolonged patient survival.
  • A 1990 scientific study of cachexia-inducing tumors in mice showed that when part of the carbohydrate calories in their diet was replaced by fish oil, their weight loss was inhibited.
  • A 1991 study found that fish oil concentrate inhibited skeletal muscle degradation and even reduced tumor size in mice.

Krill Oil—NOT Fish Oil—Is Your Best Source of Omega-3 Fatty Acids

The time to begin supplementing your diet with these important fatty acids is NOW, rather that waiting until you have cancer or another serious disease.

The average American diet is seriously deficient in the animal based omega-3 fats, DHA and EPA. Except for certain types of fish, there are very few sources of these important fats.

Unfortunately, fish supplies around the world are found more contaminated every year as increasing numbers of fish test positive for mercury, PCBs, toxic metals like lead and arsenic, and radioactive substances like strontium. If you have cancer, the LAST thing you want to do is place additional stress on your body by taking in toxic heavy metals.

Your safest and most cost effective choice for bumping up your omega-3 fatty acids is taking a high-quality Antarctic krill oil.

Krill oil is superior to fish oil because it contains phospholipids, a very powerful antioxidant called astaxanthin, and omega-3s bonded together in a way that keeps them safe from oxidation and easily absorbed by your body. Krill oil is 48 times more potent than fish oil. Many popular fish oil brands are already oxidized before you open the bottle.

And harvesting krill is more sustainable and earth-friendly than harvesting fish.

Your risk of getting mercury contamination from krill is extremely low, since krill are so small they don’t have the chance to accumulate toxins before being harvested.

Plant based omega-3 sources like flax, hemp and chia are high in ALA and are important sources of nutrients, as we all need ALA. However, the key point to remember is that ALA has to be converted by your body into far more essential EPA and DHA by an enzyme in which the vast majority of us are deficient.

So, I believe it is essential to get some of your omega-3 fatty acids from animal sources.

There are studies that even show ALA from flaxseed can actually increase your risk of cancer. Personally, I regularly include ALA omega-3 plant based foods in my diet, like flax and hemp, but these are always combined with animal-based omega-3 fats.

Other Important Nutritional Aspects, for Those Who Have Cancer

No one wants to battle cancer.

But if you find yourself in this unfortunate position, many of the lifestyle suggestions for preventing cancer apply to treating it as well.

Besides omega-3 fatty acids, you should also address the following:

  • Optimize your vitamin D. Vitamin D influences virtually every cell in your body and is one of nature’s most potent cancer-fighters. Vitamin D is actually able to enter cancer cells and trigger apoptosis (cell death).

    If you have cancer, your vitamin D level should be between 70 and 100 ng/ml. Vitamin D works synergistically with every cancer treatment I’m aware of, with no adverse effects. I invite you to watch my one-hour free lecture on vitamin D to learn how to best optimize your vitamin D level.

  • Eat the right foods for your Nutritional Type. If you are not familiar with this approach, start by taking my FREE Nutritional Type Test here.
  • Avoid sugar, grains, processed foods, chemicals, and artificial sweeteners. Sugar fuels the growth of cancer cells. Normalizing your insulin creates an environment that is unfriendly to cancer cells.
  • Use organic coconut oil every day. Coconut oil is rich in medium chain triglycerides (MCTs), which offer a wide variety of health benefits and may also be effective in preventing or reversing cachexia.
  • Avoid charring your meats. Charcoal or flame broiled meat is linked with increased cancer growth
  • Avoid unfermented soy products. Unfermented soy is high in plant estrogens, or phytoestrogens, also known as isoflavones. In some studies, soy appears to work in concert with human estrogen to increase cell proliferation, which increases mutations and cancerous cells.
  • Drink a quart of organic green vegetable juice daily. Please review my juicing instructions for more detailed information about this.
  • Avoid drinking alcohol, or at least limit your alcoholic drinks to one per day.
  • Drink plenty of pure water every day.
  • Get some sort of exercise daily. Exercise will help you maintain your muscle mass, thereby slowing down cachexia. Realizing cancer can really diminish your energy level, you may have to experiment a bit to find forms of exercise you can tolerate, but it is important to do it, nevertheless. Exercise has been proven to extend the lives of cancer patients.
  • Avoid electromagnetic fields as much as possible. Minimize cell phone use, and make sure your cordless phone base station is as far from your sleeping area as possible. Keep medical radiation exposure as low as possible. Even electric blankets can increase your cancer risk.

Magic mushrooms are helping cancer patients deal with the fear of dying 


A single dose works in a profound way.

 

Dinah Bazer was diagnosed with ovarian cancer in the spring of 2010. The Brooklyn resident, an ice skating teacher and former bank IT programmer in her 60s, was devastated.

Luckily, doctors were able to successfully treat her disease with chemotherapy, but the dread of a reoccurrence just wouldn’t go away. It was like waiting for the other shoe to drop. “I was totally consumed with fear and anxiety,” she said on a recent call with a group of reporters.

 So in 2011, Bazer enrolled in a trial at New York University, where researchers were looking to test a substance that they hoped would have a seemingly “mystical” ability to lift depression and anxiety connected to fear about life’s end.

The drug they were testing wasn’t one dreamed up in a lab. It’s the essential component of psychoactive magic mushrooms, psilocybin.

1730-psyco-2

 

In a living-room-like setting at the Bluestone Centre at the NYU College of Dentistry, accompanied by trained therapists, Bazer took a pill. At first she couldn’t know whether it was the drug or a placebo, but once the effects started to come on, it would be clear.

Sure enough, within about 40 minutes, she started to ‘trip’.

“I visualised my fear as physical mass in my body,” a black concentration, she said. She became angry, volcanic. She screamed. “Get the f- out!”

And then this woman who said she had been an atheist her entire adult life – and still is – had a strange sensation.

“I was bathed in God’s love, and that continued for hours,” she said. “I really had no other way to describe this incredibly powerful experience.”

The feeling faded, but so did her fear, depression, and anxiety. They have not returned.

Spring for psychedelics

Bazer was a participant in one of two controlled clinical trials of the effects of psilocybin on patients dealing with depression and distress related to facing the end of life.

Aside from a few smaller pilot studies, these two trials – one by researchers from Johns Hopkins University and the other, which Bazer participated in, at NYU – were the first major ones of their kind.

The results from both studies were published in the Journal of Psychopharmacology on December 1, along with 10 commentaries by prominent experts in the field of psychiatry.

The results from both trials were encouraging enough that the scientists involved hope they’ll be able to get consent from the Food and Drug Administration to move forward to a large-scale Phase 3 study, the third and final set of human trials that is needed before the FDA considers approving a new drug.

“This is a potential pathway to clinical approval,” said Roland Griffiths, a professor of psychiatry and behavioural sciences at JHU School of Medicine, who led the JHU study and is one of the pioneers in the modern era of psychedelic research.

“But that [approval] requires the next step of going to the FDA and getting permission to move forward.”

The recent announcement that the FDA would allow trials using MDMA – the chemical name for the drug commonly known as Molly or Ecstasy – to treat post-traumatic stress disorder to move to Phase 3 gives him hope, too, especially since he says MDMA might have even more ‘baggage’ than psilocybin when it comes to getting approval.

In a certain sense, this is a renewal of research into the power of psychedelic substances, according to Griffiths and Stephen Ross, an associate professor at NYU’s School of Medicine, who led the NYU study.

In the 1950s and 60s, psychiatrists were enthralled by the power of LSD, psilocybin, and other hallucinogens – substances that seemed able to reorganise the way that patients viewed the world and, they say, appeared to help them overcome struggles with alcoholism and other addictions.

But the drug prohibition era put an end to that research for decades.

Scientists have only recently begun to experiment again with these substances. Griffiths told Business Insider he started looking into experiments with healthy volunteers around 2000, at a time that such a suggestion shocked review boards, which thought it would be far too dangerous.

But slowly, he was able to convince them. He began to recruit volunteers who hadn’t tried LSD or magic mushrooms.

This was one of the hardest parts, he says, since he wanted people naive to psychedelics, but most of the people he found who weren’t scared of the idea had already experimented some.

1730-psyco-4

Psilocybe Pelliculosa mushrooms. 

A single dose

After the researchers studied a number of healthy people, certain things about psilocybin’s effects became clear. In a therapeutic setting, they didn’t find any serious, long-lasting adverse effects of the drug. That doesn’t mean that they found it to be totally risk-free, however.

Griffiths is also the senior researcher on another paper published December 1 in the Journal of Psychopharmacology that surveyed people who took hallucinogens outside a clinical setting about their worst experiences.

Some people said they had gone through difficult or dangerous experiences, some of which caused them to seek psychological treatment later. (That’s a small percentage of psychedelic use cases, and many of those same people still said their experiences were important and meaningful, but it’s worth being aware of.)

But in a clinical setting, a high percentage of volunteers reported that the experience was one of the most meaningful they’d had in their life, calling it spiritual – something that inspired reverence and increased their overall life satisfaction.

Most compelling was that this substance appeared capable of reliably and consistently inducing what are known as “mystical experiences”.

These profound effects were so powerful that eventually Griffiths and other researchers tried psilocybin on people struggling to cope with anxiety about the end of life because they’d been diagnosed with a life-threatening illness or disease like cancer.

We don’t have a good way to treat the existential anxiety and depression that’s prominent in cancer patients who don’t respond well to traditional treatment, Griffiths told Business Insider.

Yet a single dose of psilocybin did seem helpful, in a profound way.

The researchers gave patients a dose that was about 20 milligrams of psilocybin for a person weighing 70 kilograms, or 154 pounds. Griffiths’ previous work has shown that people who have ‘bad trips’ frequently take more – a median of 30 mg, which is approximately 4 grams of dried mushrooms.

It takes about 20 to 40 minutes for people to start feeling the effects. Patients listened to music during their experience.

Griffiths says their playlist included a mixture of classical music, including Henryk Gorecki, Bach, and Beethoven; Indian chant, including Russill Paul’s “Om Namah Shivaya”; new age works; and world music, so the researchers could study the ‘best’ music for the experience.

The effects of psilocybin fade after about four hours – one of the reasons researchers like to work with that drug instead of LSD, which can last up to 12 hours.

Afterward, patients talked and wrote about what they’d gone through.

Even six months after the experience, 80 percent of the 51 participants in the JHU study showed significant decreases in depression and anxiety, as measured by what’s considered a gold standard psychiatric evaluation.

The NYU team says that between 60 percent and 80 percent of its 29 participants had similarly reduced anxiety and depression six and a half months after a single psychedelic trip.

These findings correspond with results from other pilot studies on psilocybin so far.

These studies on treating depression and anxiety related to cancer have been promising enough that researchers began small studies on using psilocybin to treat more common forms of depression. And so far, those results have been encouraging.

Traditional medicine for these conditions is taken over time, has side effects, and often isn’t much better than a placebo. In this case, one dose seemed able to make a huge difference.

Griffiths says one way psychedelic researchers have characterised this is as the inverse of PTSD. With PTSD, one terrible experience can change the way a person’s brain causes them to perceive the world, with long-lasting effects.

This is like the opposite of that – a single meaningful experience that people highly value and has transformational, enduring effects.

“I don’t think we have any models in psychiatry like that,” Griffiths said on the call with press. “It’s more like a surgical intervention.”

Still, it’s early in the research process. Hundreds of people have now safely received doses of psilocybin, but the drug is still considered a Schedule I drug by the Drug Enforcement Agency, meaning it legally has no accepted medical use.

Any researcher will tell you that before they can truly say psilocybin is a safe and effective drug, it needs to get through the strenuous FDA approval process.

And with psilocybin and other psychedelics, there’s still a massive unanswered question, one that we may be far away from understanding: how do they work?

1730-psyco-3Human Connectome Project, Science, March 2012

Mystical experiences in the brain

We know that people who take psilocybin and other hallucinogens – in these studies, participants consumed synthetic psilocybin, not the mushroom form – report that they have mystical or spiritual experiences, things they consider significant. But we don’t know what causes those experiences.

As Griffiths explained to me, we still don’t know what in the brain is responsible for consciousness itself. We don’t really have a good way to scientifically characterise the things that transform consciousness.

“We’re at very primitive levels of understanding deeper experiences of this type,” he said.

We have theories. One interesting one has to do with a network in the brain known as the default mode network, something we associate with self-referential thought – thinking about ourselves. In depressed people, activity in this brain network goes way up, perhaps because of some sort of self-obsession or rumination associated with depression.

But at certain times, this activity drops. Meditation seems to be associated with a strong drop in brain activity in this network, which seems to correspond with the idea of ego dissolution that is the goal of some meditative practices, according to Griffiths.

He says he actually became interested in studying psilocybin because of his long-standing meditation practice, which made him think about consciousness and the meanings of spiritual experiences (though he says he was initially a skeptic about hallucinogens).

Psilocybin seems to cause a drop in default mode network activity that’s very similar to that induced by certain meditators.

But the induced mystical experience is so profound that Griffiths thinks that decrease in activity can’t be all that’s going on.

“I’m very suspicious of simplistic stories,” he said.

Even people who don’t really find the experience ‘mystical’ still seem to undergo a reorganisation in the brain that changes their perception of the world, something that seems beyond explanation so far. Even harder to understand are the long-term changes caused by the drug.

1730-psyco-1Visualisation of the brain connections in the brain of a person on psilocybin (right) and the brain of a person not given the drug (left). Credit: Journal of the Royal Society Interface

Looking forward

The patients in the studies published December 1 were all dealing with cancer-related end-of-life anxiety, and it should be stressed that, for now, those are the only people whom we have some idea of how psilocybin affects in a clinical sense.

The two studies had relatively similar designs, though there were some differences. The NYU study had more of an organised psychotherapy component, and the people who observed the participants were trained therapists.

In the JHU study, which involved more participants, some of the observers were psychologists, while others had no formal training.

In both studies, participants had two interventions: one with a full dose of psilocybin, and another with a sort of placebo. NYU used niacin, a form of vitamin B, as a placebo. JHU gave participants psilocybin both times, but one was a very low non-psychoactive dose: 1 mg/70 kg instead of 20 mg.

Griffiths says that since participants knew they would get psilocybin both times, they had some ability to distinguish the difference between when they expected to feel better because they’d “taken psilocybin” and when they actually had the full psychedelic experience.

And while these are the largest studies of their type so far, they’re still pretty small.

Researchers say they’ll need to see similar results in a larger number of patients dealing with end-of-life anxiety, most likely from cancer at first.

Griffiths and Ross both said they expect other studies will then look at patients dealing with terminal illnesses and existential anxiety – though there is definitely a chance that if psilocybin proves effective in these cases, it could work for other cases of depression and other kinds of anxiety. They’re beginning to design trials for that research now.

“This is just a long and continuing process,” Griffiths said. “When I initiated this research, most of my colleagues were skeptical … people thought I had gone a little nuts. … Now I get calls all the time from students who are familiar with what I’m doing and say, ‘I want to do that’.”

“I would think in time, whether it’s 10 years or 20 years, we’re going to have learned how to optimise the use of these compounds, and we’re going to have really good models for using them therapeutically,” he said. “Some of this past baggage will fall away.”

This Doctor’s 25 Years of Research Showed: Cancer Patients Live 4X Longer by Refusing Chemotherapy


Chemotherapy is one of the most expensive medical treatments in the world today, but is it actually…effective? Thanks to alternative media and documentaries like the ‘Truth About Cancer’ series, more and more people are beginning to question not only its efficacy, but also whether it actually does more harm than good.

Believe it or not that questioned may have been answered more than 40 years ago, when a shocking study was released that could have ended the chemo experiment — if anyone had been paying attention.

hardin b. jones cancer

Dr. Hardin B. Jones. Via Yale.edu

Dr. Hardin B. Jones, a former Professor of Medical Physics and Physiology at Berkeley, California, concluded after over 25 years of research not only that chemotherapy, radiation and surgery do not work and do not prolong a cancer patient’s life, but patients receiving these types of oncological treatments in many cases die much sooner than those who choose to be untreated. Treated patients also die a much more painful death.

“People who refused chemotherapy treatment live an average of 12 and a half years longer than the people who are receiving chemotherapy,” wrote Dr. Jones in the journal of the New York Academy of Sciences.

In 1969 he presented his research at the American Cancer Society’s Science Writers’ Seminar, and the unbelievable findings still send shockwaves through the cancer industry to this day.

Chemotherapy does not work the way it is supposed to 

Because chemotherapy kills the healthy cells sooner than it affects the cancer cells, the body is left weakened and defenseless against the disease. Adding major side effects of the toxins of the treatment on top, the human body is left barely holding on to life with no immune system to heal itself.

“It is not the cancer that kills the victim. It’s the breakdown of the defense mechanism that eventually brings death,” told Jones to MIDNIGHT. He and his wife considered what they would do if they were to develop cancer and both agreed that they would stay clear of mainstream treatments and instead do everything to keep the body in as healthy of a state as possible.

Jones’ Studies on Treatment with Vitamins

Jones’ research showed great potential for nutritional treatment. Doctors A. Hoffer and Linus Pauling analyzed andreported on Jones’ multiple studies. The findings show that on average cancer patients who followed a regimen of vitamins and minerals had 4 times longer survival times than patients who were not following the protocol. Their conclusion was that all cancer patients need to start this protocol as soon as possible. For people who would like to prevent cancer, it would be beneficial to also be on the same protocol just using lower dosages. The regimen included: a daily dose of 12 g Vitamin C, Vitamin B3, B6 and other B-Vitamins, folic acid, Vitamin E, beta carotene, selenium, zinc, and sometimes other minerals (note: natural vitamins and minerals are almost always the best choice; not all are created equal). Other parts of the treatment were following a healthy diet, and taking care of the patients’ mental health.

Jones’ Other Conclusions about Cancer

In 1969, the American Cancer Society published Jones’ aforementioned presentation from the 11th Science Writers’ Seminar. Cancer biology was one of the main research topics for Jones and the subject of this talk.

“A Report on Cancer” delivered these conclusions analyzing years of his research:

There is a strong link between carcinogens and cancer.

Jones stated that the more the person was exposed to a carcinogen, the higher their risk of developing cancer is. Different carcinogens have a slightly different effect and timeframe, but the stronger the individual dose of carcinogen is, the less time it takes for cancer to develop. With so many carcinogens in today’s food, air and water, it’s no wonder why cancer rates have been on the rise.

hardSurgery and radiation survival data is biased and faulty

Jones provides multiple examples of errors in the data when it comes to comparing rates in survival of those patients who went through surgery and/or radiation versus those who were untreated. Most studies he had seen did not count patients who died before the completion of their treatment.

Their deaths were omitted from the data as “rejected.” By defining two groups as treated and untreated, the treated group had to have finished the treatment in order to be counted in the study. The study looked at whether or not the patient survived after the surgery or operation was over, and those who died during these two types of treatment did not “meet the criteria” to be in the “treated” group, and were omitted. The longer the study was, and the more steps it had and the more errors were in the study, stated Jones.

The complete list of Jones’s papers (written over a 41-year period) is available online in The Bancroft Library of Berkeley, California.

Has Chemo’s Efficacy Changed? 

If you’ve ever met a cancer survivor you know that there are plenty of them out there who have undergone chemo treatments and survived (of course there seem to be far more natural survivors that are not counted).

And with the right nutritional protocol, emotional support, mindset, and other factors it is indeed possible to live on and heal the body after chemo. That being said, key recent studies have not exactly been in chemotherapy’s favor. Even though some have defended the procedure because of recent “advancements,” the survival rate has remained questionable at best, if not dismal compared to natural and holistic treatments being undertaken at specialty clinics and in people’s homes.

According to a major study conducted by the Department of Radiation Oncology at Northern Sydney Cancer Centre and published in the December 2004 issue of Clinical Oncology, chemotherapy’s real impact on the survival of American adults is a mere 2.1%, and that’s only for up to five years, not a “true survival rate.” With so much risk and so many nasty side effects surrounding chemo, do you think it’s worth the risk?

 

This article is for informational purposes only and should not constitute medical advice. It is not intended to treat, cure or prevent any diseases. Speak to a doctor before making any major changes. 

New treatment uses altered blood cells to attack leukaemia


Scientists have figured out how to reprogram the blood of cancer patients to attack their leukaemia, and 19 of the 30 patients who received the treatment remain in complete remission.

blood-transfusion

A team of researchers led by immunotherapist Carl June from the University of Pennsylvania in the US has announced the results of a new treatment for leukaemia patients that turns their own blood cells against their disease.

The researchers chose to work with patients who were dealing with particularly aggressive cases of leukaemia. All of the participants in the study had cancers that had returned at least four times before.

According to Elizabeth Lopatto at the Verge, the treatment works by first having a patient’s T cells – a type of white blood cell that plays a crucial role in the body’s immune response – harvested through a blood transfusion process. These T cells are then engineered to seek out a particular protein called a B cell receptor, found on the surface of the patient’s B cells. B cells are another type of white blood cell that’s specifically targeted by leukaemia.

The patient’s altered T cells will then be transplanted back into their blood stream so they can start hunting B cell receptor proteins, and kill the leukaemia and the B cells they’re attached to.

Of course, this means that the patient’s entire supply of B cells will be wiped out by this treatment. Because the main role of B cells is to produce antibodies to fight anything that might threaten our bodies, including viruses and bacteria, the patients will be left extremely vulnerable until they can generate more. This is something that hospitals will need to be aware of if the treatment ends up being used more widely, but the benefit of this treatment is that it only has to be administered once for it to work.

According to the study, which was published in the New England Journal of Medicine, of the 30 children and adults that received the treatment, complete remission was achieved in 27 patients (90 percent). Remission was sustained past the six-month point in 19 of the 30 patients. One of the early success stories is a nine-year-old girl called Emily Whitehead, who started the treatment when she was six. She’s been cancer-free now for two years.

“This is unlike almost all cell and gene therapies in that it’s actually ahead of the schedule we set for ourselves when we first started treating patients,” June told Lopatto at the Verge. “We pinch ourselves because, you know, until recently we didn’t know if we got lucky or if it would last. Our initial patients are still in remission, so we know it’s durable and reproducible. That’s something that makes us excited every day.”

The team is now working on easing the side effects of the treatment, which include fever, nausea, muscle pain and difficulty breathing.