A Cancer “Kill Switch” Has Been Discovered in the Body


A Northwestern University team spent about eight years meticulously studying the human genome and all of its various chemicals and processes it uses to regulate itself, and it has discovered what it bills as a seemingly foolproof “self-destruct pathway,” that could be utilized for healing, to destroy any type of cancer cell one can think of.

The mechanism they found involves the creation of things called siRNAs, small RNA molecules that serve to interfere with a multitude of genes that are essential to the destructive proliferation of malignant, fast-growing cells. It is said that these siRNAs reportedly have little effect on our healthy, good cells. However, one might see already that if this cancer fighting strategy has risks, people should take a very close look at them.

They say insight was provided by two recent studies, and Marcus Peter, the research leader along with his colleagues have outlined in detail the series of events that the siRNA molecules trigger in our bodies.

They called this process of siRNA molecules causing cancer cell death DISE, or Death By Induced Survival gene Elmination. The team managed to identify six-nucleotide-long sequences that would be required for inducing this state of “DISE.”

It was explained that when researchers examined the nucleotide sequences of the various noncoding, non-protein translating RNA molecules our bodies produce naturally to selectively inhibit the expression of genes, they made the discovery that DISE-associated sequences are there, present at one end of several tumor suppressing RNA strands.

Yet another investigation concluded that those sequences can also be found throughout the genome, embedded in protein-coding sequences.

“We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system, which is about 500 million years old,” Peter said last year, in a statement. “It could be a fail-safe that forces rogue cells to commit suicide. We believe it is active in every cell protecting us from cancer.”

However, there was one small problem: they still had to determine just how the body produces these free siRNAs that are capable of producing DISE. That’s how complicated the body gets.

In another new study, a breakthrough came as it was published last month in eLife, and in that one Peter and his team observed the body making these molecules, as our cells basically chop a larger strand of RNA, that codes for a cell death cycle protein known as CD95L, into multiple siRNAs.

A series of experiments were conducted, and then they managed to show that the exact same cellular machinery could be utilized in converting other large protein-coding RNAs into these DISE siRNAs.

Even more remarkably, they found that somewhere around three percent of all the coding RNAs in our entire genome could be “processed” to serve the purpose.

“Now that we know the kill code, we can trigger the mechanism without having to use chemotherapy and without messing with the genome,” Peter said last month in a press conference.

Now, they want to make “next-generation medications” and “gene therapy,” and while this sounds like it makes a lot of sense, it’s true that people would be wise to keep their wits about them and know just what they are signing up for if they proceed with some new treatment resulting from this research.

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Obesity to Blame for Almost 1 in 20 Cancer Cases Globally


Excess body weight is responsible for about 4 percent of all cancer cases worldwide and an even larger proportion of malignancies diagnosed in developing countries, a new study suggests.

As of 2012, excess body weight accounted for approximately 544,300 cancers diagnosed annually around the world, researchers report in CA: A Cancer Journal for Clinicians, December 12. While overweight and obese individuals contributed to just 1 percent of cancer cases in low-income countries, they accounted for 7 to 8 percent of cancers diagnosed in some high-income Western countries and in Middle Eastern and North African nations.

“Not many people know about excess body weight and its link to cancer,” said lead study author Hyuna Sung of the American Cancer Society in Atlanta.

“Trying to achieve healthy weight and maintaining it is important and may reduce the risk of cancer,” Sung said by email.

But the proportion of people who are overweight and obese has been increasing worldwide since the 1970s, the researchers note. As of 2016, 40 percent of adults and 18 percent of school-age children were overweight or obese, for a total of almost 2 billion adults and 340 million kids worldwide.

While the proportion of people with excess body weight has increased rapidly in most countries and across all population groups, the surge has been most pronounced in some low- and middle-income countries that have adopted a Western lifestyle with too little exercise and too many unhealthy foods, the study team writes.

“The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy-dense, nutrient-poor foods, alongside reduced opportunities for physical activity,” Sung said.

Overweight and obesity has been definitively linked to an increased risk of 13 cancers affecting the breast, colon and rectum, uterus, esophagus, gallbladder, kidney, liver, ovary, pancreas, stomach, and thyroid, brain and spinal cord, and blood cells.

More recently, some research has also tied excess weight to risk for prostate tumors as well as cancers of the mouth and throat.

National wealth is the most apparent systematic driver of population obesity, the study authors note.

The economic transition to a wealthier economy brings with it an environment that precipitates obesity; each $10,000 increase in average per capita national income is associated with a 0.4 increase in body mass index among adults, the study authors note.

However, obesity is uncommon in some high-income Asia-Pacific countries, which is likely a result of consuming healthier foods like lean fish and veggies and eating fewer calories, as well as active transportation and walking as part of daily activity, the authors point out.

Still, the report offers fresh evidence of the need for policies that promote healthy eating and exercise habits as a way to battle obesity and reduce the global burden of cancer, the authors argue.

Dietary interventions might include eliminating trans-fats through the development of legislation to ban their use in the food chain; reducing sugar consumption through effective taxation on sugar-sweetened beverages; implementing subsidies to increase the intake of fruits and vegetables; and limiting portion and package size to reduce energy intake and the risk of excess body weight.

Activity interventions might include encouraging urban planning that promotes high-density housing with sidewalks, accessible public transportation and widespread availability of open spaces, parks and places to walk and cycle.

“Based on cancer alone, this report makes the case for allotting significant resources to addressing the global obesity epidemic, and those efforts have to address multiple factors that are creating ‘obesigenic’ societies,” said Dr. Graham A. Colditz of Washington University School of Medicine in St. Louis.

“The actions of individuals are important when it comes to weight – eating a healthy diet and exercising regularly, for example,” Colditz, who wasn’t involved in the report, said by email. “But unless those actions are supported by policies, infrastructure, schools, and employers, they’re less likely to take hold and be broadly successful over time.”

Source:Medscape

Chemo Disturbs Sleep in Breast Cancer Patients


Patients treated with chemotherapy have disturbed sleep-wake activity, a prospective study from Hong Kong and Australia confirms.

“The first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe,” the researchers write in Sleep, online December 14.

“Nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production,” they add.

Dr. Lap Ah Tse of the Jockey Club School of Public Health and Primary Care of the Chinese University of Hong Kong and colleagues investigated the patterns of sleep, sleep-wake activity rhythm, and first morning void urinary melatonin levels in 180 patients undergoing adjuvant chemotherapy for stage I-III primary breast cancer.

At baseline, the median participant age was 53, and most were married with high school or higher education; 76% reported sleep disturbance (Pittsburgh Sleep Quality Index (PSQI) 5 or higher); 85% had good performance status; and 72% had undergone mastectomy.

Guided by their disease condition and preference, patients received one of three adjuvant chemotherapy regimens: six cycles of FEC-T (5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel; 44% received this), four cycles of doxorubicin plus cyclophosphamide (29%), or four cycles of docetaxel plus cyclophosphamide (27%).

Participants completed a baseline questionnaire about sociodemographics and lifestyle, including age, education level, family income, marital status, and drinking history; they completed the PSQI to evaluate their subjective sleep quality; and the researchers reviewed their medical records.

The patients wore wrist actigraph monitors GENEActiv Original (Activinsights Company, UK) on the non-dominant hand for a week before chemotherapy, and during the first week of the first cycle. Afterwards, those treated with doxorubicin plus cyclophosphamide or with docetaxel plus cyclophosphamide wore the monitor during the first week of the fourth cycle (end of chemotherapy), and those on FEC-T wore the monitor during the first week of the third cycle (end of FEC). They collected their first morning void urine samples before treatment as well as during their first and the last cycle.

The actigraphy data were extracted to determine sleep efficiency, sleep duration, total nighttime wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase.

Researchers also assessed urinary 6-sulfatoxymelatonin (aMT6s) levels.

Linear mixed-effects models were used to calculate the changes in actigraphy values as well as first morning urinary aMT6s before and during chemotherapy, and univariable and multivariable models were used for all actigraphy values and urinary aMT6s. The multivariable linear mixed-effects models were adjusted for cancer stage; age; body mass index; menopausal status; performance status; surgery type; comorbidities; corticosteroid use; sociodemographics; alcohol consumption; and chemotherapy.

Compared with baseline, sleep efficiency during the first and last cycle decreased by 10% and 5%, respectively; rhythm decreased by 27% during the first cycle and 21% during the last cycle; and during the first and last cycles, aMT6s levels decreased by 11% and 15%, respectively, compared to baseline.

“This study provides the first epidemiological evidence that nocturnal melatonin secretion is progressively impaired over the course of chemotherapy in breast cancer patients receiving chemotherapy,” the authors write.

The authors note that disturbed sleep with weak sleep-wake activity rhythm is a common problem among breast cancer survivors who have chemotherapy.

“This longitudinal study suggests that sleep, sleep-wake activity rhythm, and nocturnal melatonin production are rapidly disrupted after the administration of the first cycle of adjuvant chemotherapy in breast cancer patients,” they write.

“Sleep disturbance is associated with poor quality of life, fatigue, and depression in breast cancer patients. Weak sleep-wake activity rhythm is evident to be a prognostic risk factor associated with poor survival of cancer patients and the side effects of anti-cancer treatment,” they add. “Furthermore, disruptions in sleep and sleep-wake activity rhythm may disrupt the production of nocturnal melatonin, which is an endogenous hormone playing a pivotal role in alleviating oxidative stress and regulating the immune and hematological system.”

Systemic treatment of pancreatic cancer revisited


Abstract

Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%. To date, neither personalized medicine nor immunotherapy, the 2 recent revolutions of cancer treatment, have delivered major positive results in the treatment of pancreatic cancer; and it is especially clear that immune checkpoint inhibitors will not become a major tool in the treatment of pancreatic cancer. There are many ongoing studies, including those exploring combinations of chemotherapy with immunotherapy. Vaccines or T cells modified with a chimeric antigen receptor (CAR-T cells) could also play a role in the treatment of cancer in the future. The aim of this review is to discuss recent improvements in standard of care, major obstacles to overcome, recent results of new treatment combinations, and the most interesting innovative approaches.

Selecting chemotherapy for pancreatic cancer: Far away or so close?


Abstract

Pancreatic cancer is a lethal disease with a very poor prognosis. In contrast to treatments for many other tumor types, cytotoxic agents are still the first-line drugs for pancreatic cancer in both the palliative and adjuvant settings. Some progress has been made in recent years, but most large phase 3 studies have not shown significant improvements in survival. Because the available drugs and regimens are limited in both type and effect, the selection of chemotherapy based on clinicopathologic characteristics may be consequential for pancreatic cancer. In the present report, we focused on 7 landmark clinical trials for pancreatic cancer. We observed that FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) and NG (nab-paclitaxel and gemcitabine), 2 first-line regimens, exerted opposite effects on metastatic pancreatic cancer patients with different baseline carbohydrate antigen 19-9 (CA19-9) levels. This suggested that not only the performance status but possibly also CA19-9 levels should be considered when making a therapeutic choice for patients with advanced pancreatic cancer. Moreover, we found that patients with a diagnosis of pancreatic cancer who have undergone a surgical resection with a negative margin (R0) may benefit more from fluorouracil and/or oral prodrugs of fluorouracil-based adjuvant therapy than from gemcitabine. Conversely, gemcitabine or gemcitabine-based regimens may be more effective for patients with a positive resection margin (R1). Based on these findings, we propose flowcharts for selecting chemotherapy for both advanced and resected pancreatic cancer. Furthermore, we present possible mechanisms and interpretations underlying the selection of chemotherapy for pancreatic cancer and propose the tumor burden as a key variable in this process. Regardless of the possible bias and exact treatment selection process, this study offers an opportunity to improve patient outcomes by using agents currently used in the therapy of pancreatic cancer. Although these conclusions are based on indirect evidence, we provide insights and possibilities to drive the selection of chemotherapy for pancreatic cancer.

Liquid Biopsy Tracks Herceptin Resistance in HER2+ Gastric Cancer


Liquid biopsy of circulating tumor DNA (ctDNA) is an “efficient” way to monitor resistance to trastuzumab (Herceptin, Genentech) and spot emerging resistance mechanisms in metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, according to a study from China.

Up to 23% of gastric cancers are HER2+, but the response rate of these tumors to trastuzumab is limited, and any resistance to the drug happens rapidly during treatment, De-Shen Wang, MD, PhD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, told Medscape Medical News.

“Currently, the underlying mechanism of trastuzumab resistance remains unclear, and strategies to overcome resistance are urgently needed,” said Wang.

“We found that liquid biopsy-based ctDNA profiling could promisingly predict the tumor shrinkage and progression, and the underlying mechanism for innate resistance and acquired resistance of Herceptin might be different due to the differences of observed HER2 copy numbers,” Wang added.

The study was published online in the journal Gut.

Researchers evaluated the consistency between molecular alterations in solid tumor biopsies and liquid (plasma) biopsies by sequencing a panel of 416 cancer-related genes from 78 patients with gastric cancer (46 HER2+ and 32 HER2–). They also performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track resistance during trastuzumab treatment and validate candidate resistance genes identified.

The molecular alterations detected in plasma provided a “good representation of the status of the tumor tissue, particularly at advanced stages,” the authors report in their article.

HER2 somatic copy number alterations (SCNA) were “highly consistent” with fluorescence in situ hybridization data, and the detected HER2 copy number variation was better than the plasma carcinoembryonic antigen level at predicting tumor shrinkage and progression, they note.

Most patients with innate trastuzumab resistance had high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance, they found.

PIK3CA/R1/C3 or ERBB2/4 mutations contributed “greatly” to resistance and led to worse progression free survival, whereas ERBB4 S774G mutation increased sensitivity to trastuzumab, Wang said.

The researchers also identified and confirmed NF1 as a resistance-related gene and found evidence that the combination of the HER2 inhibitor lapatinib (Tykerb, GlaxoSmithKline) and MEK/ERK inhibitor selumetinib (AstraZeneca) might overcome trastuzumab resistance.

“We propose that ctDNA profiling could provide helpful information to monitor the occurrence, dissect the potential molecular mechanisms, and provide helpful clues to therapy development for Herceptin resistance,” Wang told Medscape Medical News.

However, the technique, and this study, has several limitations, the authors note. First, although the 416-gene panel covered the majority of solid tumor-related genes, patients might have developed a mutation in a gene not covered by the panel. It’s also possible that the function of a protein encoded by a certain gene was regulated at the transcriptional, translational, or even post-translational level, and thus was not detected by DNA sequencing, they explain.

Second, they note that cell-free DNA (cfDNA) from plasma contains both cfDNA released from normal cells and ctDNA from limited tumor cells, leading to a lower tumor DNA content in the whole plasma cfDNA sample in most cases, which generates large amounts of “noise” and limits ctDNA detection sensitivity.

“A higher sequencing coverage depth might improve the detection sensitivity of ctDNA profiling to a certain extent but would not completely solve the problem due to the limited number of original tumor DNA molecules present in the cfDNA sample,” the authors suggest.

Obesity to Blame for Almost 1 in 20 Cancer Cases Globally


Excess body weight is responsible for about 4 percent of all cancer cases worldwide and an even larger proportion of malignancies diagnosed in developing countries, a new study suggests.

As of 2012, excess body weight accounted for approximately 544,300 cancers diagnosed annually around the world, researchers report in CA: A Cancer Journal for Clinicians, December 12. While overweight and obese individuals contributed to just 1 percent of cancer cases in low-income countries, they accounted for 7 to 8 percent of cancers diagnosed in some high-income Western countries and in Middle Eastern and North African nations.

“Not many people know about excess body weight and its link to cancer,” said lead study author Hyuna Sung of the American Cancer Society in Atlanta.

“Trying to achieve healthy weight and maintaining it is important and may reduce the risk of cancer,” Sung said by email.

But the proportion of people who are overweight and obese has been increasing worldwide since the 1970s, the researchers note. As of 2016, 40 percent of adults and 18 percent of school-age children were overweight or obese, for a total of almost 2 billion adults and 340 million kids worldwide.

While the proportion of people with excess body weight has increased rapidly in most countries and across all population groups, the surge has been most pronounced in some low- and middle-income countries that have adopted a Western lifestyle with too little exercise and too many unhealthy foods, the study team writes.

“The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy-dense, nutrient-poor foods, alongside reduced opportunities for physical activity,” Sung said.

Overweight and obesity has been definitively linked to an increased risk of 13 cancers affecting the breast, colon and rectum, uterus, esophagus, gallbladder, kidney, liver, ovary, pancreas, stomach, and thyroid, brain and spinal cord, and blood cells.

More recently, some research has also tied excess weight to risk for prostate tumors as well as cancers of the mouth and throat.

National wealth is the most apparent systematic driver of population obesity, the study authors note.

The economic transition to a wealthier economy brings with it an environment that precipitates obesity; each $10,000 increase in average per capita national income is associated with a 0.4 increase in body mass index among adults, the study authors note.

However, obesity is uncommon in some high-income Asia-Pacific countries, which is likely a result of consuming healthier foods like lean fish and veggies and eating fewer calories, as well as active transportation and walking as part of daily activity, the authors point out.

Still, the report offers fresh evidence of the need for policies that promote healthy eating and exercise habits as a way to battle obesity and reduce the global burden of cancer, the authors argue.

Dietary interventions might include eliminating trans-fats through the development of legislation to ban their use in the food chain; reducing sugar consumption through effective taxation on sugar-sweetened beverages; implementing subsidies to increase the intake of fruits and vegetables; and limiting portion and package size to reduce energy intake and the risk of excess body weight.

Activity interventions might include encouraging urban planning that promotes high-density housing with sidewalks, accessible public transportation and widespread availability of open spaces, parks and places to walk and cycle.

“Based on cancer alone, this report makes the case for allotting significant resources to addressing the global obesity epidemic, and those efforts have to address multiple factors that are creating ‘obesigenic’ societies,” said Dr. Graham A. Colditz of Washington University School of Medicine in St. Louis.

“The actions of individuals are important when it comes to weight – eating a healthy diet and exercising regularly, for example,” Colditz, who wasn’t involved in the report, said by email. “But unless those actions are supported by policies, infrastructure, schools, and employers, they’re less likely to take hold and be broadly successful over time.”

Million-Strong Study Supports CRC Screening Every 10 Years


Clinicians following guideline recommendations to screen for colorectal cancer once every 10 years can reassure their patients that the time interval is effective and does not put them at increased risk, conclude US investigators.

Researchers evaluated more than 1.2 million Californians aged 50 to 75 years who were enrolled in a health plan. They compared unscreened individuals with those who had a negative colonoscopy result over a 10-year period.

The results showed that the relative risk of developing colorectal cancer in people with a negative result at 10 years was 46% lower than that for unscreened individuals; the relative risk of colorectal cancer death was 88% lower.

The research was published online December 17 in JAMA Internal Medicine.

Lead author Jeffrey K. Lee, MD, Division of Research, Kaiser Permanente Northern California, Oakland, said in a press release: “Our study shows that, following a colonoscopy with normal findings, there is a reduced risk of developing and dying from colorectal cancer for at least 10 years.”

These findings suggest, said Lee, that physicians “can feel confident” about the guideline-recommended 10-year rescreening interval after a negative colonoscopy in which no colorectal cancer or polyps were found.

“There is now solid evidence supporting that recommendation,” he said.

Senior author Douglas A. Corley, MD, PhD, MPH, also of Kaiser Permanente Northern California, added: “This large study is the first with a high enough number of average-risk individuals to evaluate cancer risks after colonoscopy examinations, compared with no screening.”

The study provides “greater certainty regarding the appropriate timing for rescreening after a negative colonoscopy,” he said.

Asked for comment, Robert A. Smith, PhD, vice president of cancer screening, American Cancer Society in Atlanta, Georgia, said that “the new data show that a 10-year interval is pretty effective.”

Approximately 63% of eligible individuals in the United States undergo colorectal cancer screening, Smith told Medscape Medical News. In the majority of cases, screening is opportunistic, with patients referred as a result of another encounter, he explained.

The current study, said Smith, “probably reinforces in people’s minds the importance of screening…. It’s widely accepted that colorectal cancer screening is a good thing.”

On the other hand, some patients either do not undergo colonoscopy or do not prepare for the procedure properly and end up having to cancel.

“A concern is raised that we have uneven quality of colonoscopy in this country,” he said.

“Just because you’ve had a normal examination doesn’t mean that there aren’t some lesions in there that were overlooked but could potentially grow to become malignancies in the interval before your next examination is due,” Smith continued.

Echoing previous suggestions that “a reasonable and safe thing to do is a fecal immunochemical test, say, at 5 years,” Smith argued that “a high-sensitivity stool test would have the opportunity to pick those [malignancies] up.”

Study Details

Although current guidelines recommend that individuals with a negative colonoscopy result be rescreened after 10 years, the California investigators say the evidence supporting this is “modest” and that that recommendation is based on estimates of colonoscopy sensitivity and the time it takes for adenoma to progress.

Clinicians following guideline recommendations to screen for colorectal cancer once every 10 years can reassure their patients that the time interval is effective and does not put them at increased risk, conclude US investigators.

Researchers evaluated more than 1.2 million Californians aged 50 to 75 years who were enrolled in a health plan. They compared unscreened individuals with those who had a negative colonoscopy result over a 10-year period.

The results showed that the relative risk of developing colorectal cancer in people with a negative result at 10 years was 46% lower than that for unscreened individuals; the relative risk of colorectal cancer death was 88% lower.

The research was published online December 17 in JAMA Internal Medicine.

Lead author Jeffrey K. Lee, MD, Division of Research, Kaiser Permanente Northern California, Oakland, said in a press release: “Our study shows that, following a colonoscopy with normal findings, there is a reduced risk of developing and dying from colorectal cancer for at least 10 years.”

These findings suggest, said Lee, that physicians “can feel confident” about the guideline-recommended 10-year rescreening interval after a negative colonoscopy in which no colorectal cancer or polyps were found.

“There is now solid evidence supporting that recommendation,” he said.

Senior author Douglas A. Corley, MD, PhD, MPH, also of Kaiser Permanente Northern California, added: “This large study is the first with a high enough number of average-risk individuals to evaluate cancer risks after colonoscopy examinations, compared with no screening.”

The study provides “greater certainty regarding the appropriate timing for rescreening after a negative colonoscopy,” he said.

Asked for comment, Robert A. Smith, PhD, vice president of cancer screening, American Cancer Society in Atlanta, Georgia, said that “the new data show that a 10-year interval is pretty effective.”

Approximately 63% of eligible individuals in the United States undergo colorectal cancer screening, Smith told Medscape Medical News. In the majority of cases, screening is opportunistic, with patients referred as a result of another encounter, he explained.

The current study, said Smith, “probably reinforces in people’s minds the importance of screening…. It’s widely accepted that colorectal cancer screening is a good thing.”

On the other hand, some patients either do not undergo colonoscopy or do not prepare for the procedure properly and end up having to cancel.

“A concern is raised that we have uneven quality of colonoscopy in this country,” he said.

“Just because you’ve had a normal examination doesn’t mean that there aren’t some lesions in there that were overlooked but could potentially grow to become malignancies in the interval before your next examination is due,” Smith continued.

Echoing previous suggestions that “a reasonable and safe thing to do is a fecal immunochemical test, say, at 5 years,” Smith argued that “a high-sensitivity stool test would have the opportunity to pick those [malignancies] up.”

Study Details

Although current guidelines recommend that individuals with a negative colonoscopy result be rescreened after 10 years, the California investigators say the evidence supporting this is “modest” and that that recommendation is based on estimates of colonoscopy sensitivity and the time it takes for adenoma to progress.

Cancer “Kill Switch


A Northwestern University team spent about eight years meticulously studying the human genome and all of its various chemicals and processes it uses to regulate itself, and it has discovered what it bills as a seemingly foolproof “self-destruct pathway,” that could be utilized for healing, to destroy any type of cancer cell one can think of.

The mechanism they found involves the creation of things called siRNAs, small RNA molecules that serve to interfere with a multitude of genes that are essential to the destructive proliferation of malignant, fast-growing cells. It is said that these siRNAs reportedly have little effect on our healthy, good cells. However, one might see already that if this cancer fighting strategy has risks, people should take a very close look at them.

They say insight was provided by two recent studies, and Marcus Peter, the research leader along with his colleagues have outlined in detail the series of events that the siRNA molecules trigger in our bodies.

They called this process of siRNA molecules causing cancer cell death DISE, or Death By Induced Survival gene Elmination. The team managed to identify six-nucleotide-long sequences that would be required for inducing this state of “DISE.”

It was explained that when researchers examined the nucleotide sequences of the various noncoding, non-protein translating RNA molecules our bodies produce naturally to selectively inhibit the expression of genes, they made the discovery that DISE-associated sequences are there, present at one end of several tumor suppressing RNA strands.

Yet another investigation concluded that those sequences can also be found throughout the genome, embedded in protein-coding sequences.

“We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system, which is about 500 million years old,” Peter said last year, in a statement. “It could be a fail-safe that forces rogue cells to commit suicide. We believe it is active in every cell protecting us from cancer.”

However, there was one small problem: they still had to determine just how the body produces these free siRNAs that are capable of producing DISE. That’s how complicated the body gets.

In another new study, a breakthrough came as it was published last month in eLife, and in that one Peter and his team observed the body making these molecules, as our cells basically chop a larger strand of RNA, that codes for a cell death cycle protein known as CD95L, into multiple siRNAs.

A series of experiments were conducted, and then they managed to show that the exact same cellular machinery could be utilized in converting other large protein-coding RNAs into these DISE siRNAs.

Even more remarkably, they found that somewhere around three percent of all the coding RNAs in our entire genome could be “processed” to serve the purpose.

“Now that we know the kill code, we can trigger the mechanism without having to use chemotherapy and without messing with the genome,” Peter said last month in a press conference.

Now, they want to make “next-generation medications” and “gene therapy,” and while this sounds like it makes a lot of sense, it’s true that people would be wise to keep their wits about them and know just what they are signing up for if they proceed with some new treatment resulting from this research.

Major Trial: Partial Breast Radiation Good for Early Breast Cancer


Accelerated partial breast irradiation (PBI), although not 100% equivalent to whole-breast irradiation (WBI) for disease control in patients with early- stage breast cancer, yields outcomes so similar that it may be considered a viable treatment option for many patients, a long-term follow-up of the largest trial of its kind indicates.

“In an effort to improve quality of life for our patients, we studied whether or not we could reduce overall treatment times significantly down to a week or less by doing a technique known as partial breast irradiation, meaning limiting radiation only to the lumpectomy cavity region and accelerating treatment down to 5 days or less,” Frank Vicini, MD, MPH, Radiation Oncology Institute, Pontiac, Michigan, told a press briefing held here during the San Antonio Breast Cancer Symposium (SABCS) 2018.

“And while [we] cannot declare that WBI and PBI are equivalent in controlling local-in-breast tumor recurrence…the absolute difference in the 10-year cumulative incidence of IBTR [ipsilateral breast tumor recurrence] was only 0.7%…. So PBI may be an acceptable alternative to WBI for a proportion of women who undergo breast-conserving surgery,” he concluded.

The NRG (NSABP B-39/RTOG 0413) trial randomly assigned 4216 women who had recently undergone lumpectomy to receive either WBI or accelerated PBI. Women enrolled in the study had zero to three positive axillary nodes on study entry.

Twenty-five percent of the group had ductal carcinoma in situ (DCIS), 65% had stage I breast cancer, and 10% had stage II disease. The majority of women also had hormone receptor—positive tumors.

Women who were assigned to the WBI arm following adjuvant chemotherapy received daily treatment with 2.0 Gy/fraction of radiation totaling 50 Gy with a sequential boost to the surgical site.

Duration of WBI was 5 to 6 weeks, which was the standard of care at the time the trial was designed.

Those assigned to accelerated PBI prior to adjuvant chemotherapy received twice-daily treatment with 3.4 to 3.85 Gy given as either brachytherapy or 3D external-beam radiation.

Patients who underwent accelerated PBI received a total of 10 treatments over 5 to 10 days.

“The primary endpoint was to determine whether or not PBI results in IBTR — both DCIS and invasive breast cancer — was the same as it was for WBI,” Vicini noted.

At a median follow-up of 10.2 years, Vicini and colleagues documented a total of 161 IBTRs as first events — 90 among women treated with accelerated PBI, and 71 for those treated with WBI.

On the basis of the upper limit of the hazard ratio confidence interval, “PBI did not meet the criteria for equivalence to WBI in controlling IBTR,” Vicini reported.

On the other hand, the 10-year cumulative incidence of IBTR was very low in both groups, at 4.6% for patients in the accelerated PBI arm vs 3.9% for those in the WBI arm.

Furthermore, the difference in recurrence-free interval rates between the two arms — 91.8% in the accelerated PBI group vs 93.4% in the WBI group — was also negligible, at only 1.6%, Vicini added.

There were no differences in distant disease-free interval (DDFI), overall survival (OS), or disease-free survival (DSF).

For example, at 10 years, 96.7% of patients in the accelerated PBI arm were free of distant disease, as were 97.1% of patients in the WBI arm.

At the same follow-up point, 90.6% of patients in the accelerated PBI arm were still alive, as were 91.3% of those treated with WBI.

DSF rates were also very similar between the two treatment arms, Vicini noted.

Rates of grade 3 toxicity were similar between the two treatment groups, at 9.6% in the accelerated PBI group and 7.1% for those who received WBI. Rates of higher-grade toxicities were also very low and were similar between the two treatment groups.

Additional analyses are currently underway to evaluate secondary endpoints, including quality of life and cosmetic outcomes, Vicini noted.

“There have been many studies looking at quality of life [after radiotherapy], and you can imagine that quality of life is better with PBI — it’s pretty intuitive,” Vicini noted.

“And there is a pretty dramatic difference in the treatment interval from 5 to 7 weeks [with WBI] down to a week or less [with PBI], so as long as the control rates are the same, the trend in oncology now is ‘less is better,’ ” he added.

Furthermore, DDFI, OS, and DFS were not different between the two arms. Arguably, these endpoints are more important than recurrence, Vicini suggested, even though recurrence is an important event for patients.

“These findings suggest that the less burdensome radiation method of accelerated PBI may be an acceptable choice for many women,” Vicini said.

“So I think this is a very important study and it certainly is important to patients,” he concluded.

PBI Not Commonly Used

Asked by Medscape Medical News to comment on the findings, press briefing moderator Virginia Kaklamani, MD, University of Texas Health, San Antonio, noted that the majority of patients in the United States who are similar to those in the current study are still undergoing WBI. “PBI is not as common as it should be,” she noted.

“In the end, this is detrimental to patients, because if they have WBI, they have to come in for radiation therapy for at least 5 and sometimes 7 weeks, whereas otherwise [with PBI], they would be coming in for 5 to 10 days,” Kaklamani added.

She felt that findings from the current study “absolutely” should provide reassurance that radiation oncologists can offer accelerated PBI to patients who meet the same criteria as those included in the current study.

“We have many trials evaluating shorter radiation intervals,” Kaklamani noted.

“And the medical community needs to be implementing more PBI, and patients should also be asking for it,” she suggested.

Reshma Jagsi, MD, DPhil, professor and deputy chair, Department or Radiation Oncology, University of Michigan in Ann Arbor, felt that high-quality randomized trials such as this one in which shorter courses of accelerated PBI were compared to WBI are “critically important” to help inform treatment decisions that women who are diagnosed with breast cancer must make each year.

“These decisions depend on the patient’s own values and preferences,” Jagsi told Medscape Medical News in an email.

For example, some women might prefer to come in twice a day for a week rather than daily for many weeks to minimize disruption of their work schedule or because of problems involving transportation, whereas others might quite reasonably decide otherwise.

“The contribution of trials like these is to arm each woman with the precise risk information she needs to make the decision that is right for her,” Jagsi wrote.

“These trialists have made an enormous contribution through this work,” he concluded.