Study: Beta-Blockers May Help Lung Cancer Patients Live Longer
By Anna Azvolinsky, PhD1 |
January 11, 2013
1Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter
Lung cancer patients who take beta-adrenergic receptor antagonists
(beta-blockers) may survive longer and have a lower rate of tumor
spread.
This is the result of a retrospective study of 722 non–small-cell lung cancer (NSCLC) patients published in Annals of Oncology.  Ball-and-stick model of the beta-blocker propranolol(Drug information on propranololBeta-blockers target the beta receptors on heart muscles and smooth muscles and are commonly prescribed for hypertension, cardiac arrhythmias, and as secondary prevention after a heart attack. Zhongxing Liao, MD, and Daniel Gomez, MD, both from the department of radiation oncology at the MD Anderson Cancer Center in Houston, and colleagues compared outcomes of those NSCLC patients being treated with radiotherapy as their main line of treatment who were either not taking or regularly taking beta-blockers to treat another unrelated condition. While beta-blockers didn’t influence the locoregional progression-free survival, the 155 patients on beta-blockers at the time of their radiotherapy lung cancer treatment had better distant metastasis-free survival (P < .01) and disease-free survival (P < .01) compared to the 567 patients not taking beta-blockers. When adjusting for other factors including age, performance status, histology, concurrent chemotherapy, total tumor volume, stage of disease, those on beta-blockers did better in terms of distant metastasis-free survival (hazard ratio [HR], 0.67; P = .01), disease-free survival (HR, 0.74; P = .02), and overall survival (HR, 0.78; P = .02). There was no correlation, however, with locoregional progression-free survival (HR, 0.91, P = .63). There is nothing unique about the combination of radiation therapy as a modality and beta-blocker usage, according to Gomez. “It would not be unreasonable to propose that these results may be extrapolated to other modalities, such as chemotherapy or surgery.” This study is the first to show a link between improved survival and beta-blocker usage in lung cancer patients. Similar retrospective results have been shown for breast cancer, including triple-negative breast cancer and melanoma. Previous studies have also shown that beta-blockers may have antitumor activity, including in lung cancer models. One previous retrospective lung cancer study did not show any benefit of beta-blockers on patient outcomes. The authors note that the study did not take into account any other clinical factors other than beta-blocker usage and excluded patients with chronic obstructive pulmonary disease or coronary heart disease, both of which are common among cancer patients. Further studies, including prospective trials are needed to follow up and confirm these results. Weakness of the current study include missing data of other medications the patients may have taken during their cancer, data from only a single institution, and lack of data on beta-blocker usage prior to and post-radiation therapy. How beta-blockers may affect metastasis is not clear but may help to suppress chronic stress conditions that result from stress hormones, which have been shown to facilitate the spread of tumor cells from their primary site of origin. “We hypothesize that the mechanism of this benefit is by blocking the beta-adrenergic signaling pathway,” said Gomez. It has been demonstrated in both tissue culture and animal model experiments that blocking this pathway can affect the spread and growth of tumors. “Future molecular studies will help us to understand if the mechanism that we propose is correct, and thus if beta-blockers are indeed directly affecting the aggressiveness of this malignancy, or if these findings are due to the activation or inhibition of another pathway,” said Gomez. | |
Tuesday, January 15, 2013
CPRIT Foundation releases donor list
To view the full list in PDF form, click here.
Lawmakers, in a December Texas House Committee Meeting, voiced concern over opaqueness at the CPRIT Foundation. More hearings are supposed to take place, and an auditor report is due this month.
Meanwhile, the future of the $3 billion institute seems uncertain. Gov. Rick Perry, Lt. Gov. David Dewhurst and Speaker Joe Straus sent a letter last month to CPRIT's Oversight Committee calling on the agency to fully address concerns that have been raised about the organization.
Jimmy Mansour, the committee's chairman, and Dr. Joseph Bailes, the vice chairman, issued a joint statement Dec. 19 endorsing the call for a moratorium on CPRIT grants until public confidence has been restored.
Bayan Raji covers health care.
CPRIT Foundation: Names are coming out of the hiding...
http://www.dallasnews.com/news/state/headlines/20130111-dallas-nonprofit-among-donors-to-embattled-texas-cancer-fighting-agency-s-foundation.ece
The CPRIT Foundation released the donor list to state legislators and other officials who have raised questions whether the foundation was used as a “pay-to-play” vehicle for the state agency. CPRIT and officials of the foundation have rejected that charge.
A rider inserted into the state appropriations bill in 2009 says “an individual, an organization, or an employee, officer or director of an organization that makes a contribution to the CPRIT Foundation” is not eligible to receive grants from the agency. Ellen Read, a CPRIT spokesman, said that provision would prohibit any grants to the Crowley Cancer Foundation itself.
The CPRIT Foundation also disclosed that Shanahan is among several individuals and companies to which it issued refunds “in order to avoid any appearance of impropriety.” A $1,000 donation from Shanahan was refunded because he is “affiliated with Gradalis,” said Marc Palazzo, a CPRIT Foundation spokesman.
Glenn Smith, director of the liberal advocacy group Progress Texas Political Action Committee, said the problem with the CPRIT Foundation, which had not released its donor list until Thursday, is that “it’s a way to buy the favor that you want from the state.”
The donor list shows, as The News reported in November, that Dallas philanthropist Peter O’Donnell contributed $1.5 million to the CPRIT Foundation.
CPRIT confirmed in November that it awarded $11 million in June 2010 to a Dallas biotechnology firm, Peloton Therapeutics, without the required review of business or science experts.
O’Donnell has said he invested in Peloton in July 2011, more than a year after the CPRIT Oversight Committee ratified the award. He said he purchased 900,000 shares of Peloton stock and donated all of his shares, as well as his right to future shares, to UT Southwestern Medical Center in December 2011.
O’Donnell and his wife have contributed more than $240,000 to Perry’s state campaigns since 2000 and about $200,000 to Dewhurst’s, according to the Texas Ethics Commission.
The CPRIT Foundation released the donor list to state legislators and other officials who have raised questions whether the foundation was used as a “pay-to-play” vehicle for the state agency. CPRIT and officials of the foundation have rejected that charge.
A rider inserted into the state appropriations bill in 2009 says “an individual, an organization, or an employee, officer or director of an organization that makes a contribution to the CPRIT Foundation” is not eligible to receive grants from the agency. Ellen Read, a CPRIT spokesman, said that provision would prohibit any grants to the Crowley Cancer Foundation itself.
The CPRIT Foundation also disclosed that Shanahan is among several individuals and companies to which it issued refunds “in order to avoid any appearance of impropriety.” A $1,000 donation from Shanahan was refunded because he is “affiliated with Gradalis,” said Marc Palazzo, a CPRIT Foundation spokesman.
Glenn Smith, director of the liberal advocacy group Progress Texas Political Action Committee, said the problem with the CPRIT Foundation, which had not released its donor list until Thursday, is that “it’s a way to buy the favor that you want from the state.”
The donor list shows, as The News reported in November, that Dallas philanthropist Peter O’Donnell contributed $1.5 million to the CPRIT Foundation.
CPRIT confirmed in November that it awarded $11 million in June 2010 to a Dallas biotechnology firm, Peloton Therapeutics, without the required review of business or science experts.
O’Donnell has said he invested in Peloton in July 2011, more than a year after the CPRIT Oversight Committee ratified the award. He said he purchased 900,000 shares of Peloton stock and donated all of his shares, as well as his right to future shares, to UT Southwestern Medical Center in December 2011.
O’Donnell and his wife have contributed more than $240,000 to Perry’s state campaigns since 2000 and about $200,000 to Dewhurst’s, according to the Texas Ethics Commission.
MICROSATELLITE INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER?.
One will not think of this normally, but because of its good prognosis a biomarker, and because of its positive predictive value in terms of response to therapy, One may want to know its participation if any or share in triple negative breast cancer.
Microsatellite instability is almost standard of care a request in Colorectal cancer as it has entered the ASCO and NCCN guidelines. But is it exclusive to COLORECTAL cancers.
' Lynch syndrome (HNPCC or Hereditary nonpolyposis colorectal cancer ) is an autosomal dominant genetic condition which has a high risk of colon cancer[1] as well as other cancers including endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.'
This definition clearly exclude Breast Cancer however it would be of clinic interest to test triple negative breast cancer for these features in trying to further define the various group of this condition. Likelihood of finding anything is low. But may be we can find a cohort, a subtype that we can declare of good prognosis?
One will not think of this normally, but because of its good prognosis a biomarker, and because of its positive predictive value in terms of response to therapy, One may want to know its participation if any or share in triple negative breast cancer.
Microsatellite instability is almost standard of care a request in Colorectal cancer as it has entered the ASCO and NCCN guidelines. But is it exclusive to COLORECTAL cancers.
' Lynch syndrome (HNPCC or Hereditary nonpolyposis colorectal cancer ) is an autosomal dominant genetic condition which has a high risk of colon cancer[1] as well as other cancers including endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.'
This definition clearly exclude Breast Cancer however it would be of clinic interest to test triple negative breast cancer for these features in trying to further define the various group of this condition. Likelihood of finding anything is low. But may be we can find a cohort, a subtype that we can declare of good prognosis?
WHAT IS A DRIVER MUTATION ANYWAY?
In a cell, there are aberrancies which are bound to happen during cell division that are not critical cell functions and get by like any heterogeneity in our genes. These aberrancies with no impact in cell survivors are some time called or includes the "passenger" Mutations. life follows a flow of forces which, when unhindered, keeps living cells going strong. Until an alteration occurs affecting one pathways that belong to this main flow of force without clearly stopping it but causing enough distorsion to detour its normal evolution.
Such an alteration is driver mutation.
The effect of a driver mutation can be a stoppage in Maturity or acquisition of new capability while maintaining survival. It could be a loss of restrain or an unwelcome augmentation of autocrine function, A stimulation of enzymatic processes release at a promoter gene. All these scenarios depict a driver Mutation.
Our current standard of defining a Driver Mutation is not only linked to finding a Mutation (testing for EGFR, KRAS, BRAF and HER-2 in lung cancer) but also by weighing therapeutic response to selected target therapy. So if you find EGFR and gave related medication, you get a response. You conclude that EGFR was a driver. This kind of conclusion however leaves room to the fact that an overwhelming action can move things along without it being a driver.
We have to have more information. Finding a mutation could imply it is active or it may not. We need to dig deeper. Does it overwhelmingly stimulate other pathways? Does it induces more transcription factors more enzymes, more regulator proteins etc...
Gene sequencing of certain Axons has so far been great at finding Mutation, let's find better ways to gauge intensity of pathways and gene transcription to further define our "Drivers".
In a cell, there are aberrancies which are bound to happen during cell division that are not critical cell functions and get by like any heterogeneity in our genes. These aberrancies with no impact in cell survivors are some time called or includes the "passenger" Mutations. life follows a flow of forces which, when unhindered, keeps living cells going strong. Until an alteration occurs affecting one pathways that belong to this main flow of force without clearly stopping it but causing enough distorsion to detour its normal evolution.
Such an alteration is driver mutation.
The effect of a driver mutation can be a stoppage in Maturity or acquisition of new capability while maintaining survival. It could be a loss of restrain or an unwelcome augmentation of autocrine function, A stimulation of enzymatic processes release at a promoter gene. All these scenarios depict a driver Mutation.
Our current standard of defining a Driver Mutation is not only linked to finding a Mutation (testing for EGFR, KRAS, BRAF and HER-2 in lung cancer) but also by weighing therapeutic response to selected target therapy. So if you find EGFR and gave related medication, you get a response. You conclude that EGFR was a driver. This kind of conclusion however leaves room to the fact that an overwhelming action can move things along without it being a driver.
We have to have more information. Finding a mutation could imply it is active or it may not. We need to dig deeper. Does it overwhelmingly stimulate other pathways? Does it induces more transcription factors more enzymes, more regulator proteins etc...
Gene sequencing of certain Axons has so far been great at finding Mutation, let's find better ways to gauge intensity of pathways and gene transcription to further define our "Drivers".
Monday, January 14, 2013
NF-kB PATHWAY AND CANCER SURVIVAL, (Inhibitor: Parthenolide)
All refractory cancers seem to have one strong characteristic. They survive even when the kitchen sink is thrown at them. By kitchen sink, I mean all kinds of combination chemotherapy. In fact, times and again we have seen that only one medication turns out to be working as comparative studies end up showing equivalency between a combination therapy Vs a monotherapy. The story of DTIC in Melanoma is an example that combination therapy Vs DTIC alone, there was no difference in survival. The reasons for this drug resistance is multiple. The cell may have an MDR (Multiple drug Resistance) protein that effectively shut down cellular processes to the various drugs, but can't mount an elective resistance to DTIC. Or the cell may activate its NF-kB pathways to survive.
As cells live their lives in our body they come in contact with all kinds of neighbors and enemies, including drugs constantly thrown around in our body. The cells register the invasion, exposure or attack and send the message through a pathway of survival called NF-kB. Signals from this pathways are interpreted quickly and our body modulate the attack in the general sense of survival. To achieve this, some transcription genes are amplified to make more blockers to the invasion (ie. Bcl-2), some transcription genes are shut down to reduce susceptibility to the attack. The NF-kB pathway is in this a critical pathway of adaptation to life. It is central to all immune diseases, it is critical to resistance to diseases, it is the force to reckon with when you give a drug to treat anything including cancer. You got to stop NF-kB from working effectively to achieve your goal. Because, unlike the MDR and Flippase which are determined in their place of action and mechanism, this pathway is constantly searching for an answer against therapy by modulating various transcription factors! You see here now why attempts to target this pathway are so important.
To assure versatility in its action, NF-kB knows it cannot do it on its own, it "cross-talks" to many other pathways and important molecules. One of which is the STAT3 for rapid transcription of whatever protein is needed to decrease Apoptosis and protect the cell. NF-kB a constant, moving and changing fighter which will do anything to decrease activities that can lead to death of the cell. So far Phosphorylating it has been with limited success. May be its inhibitors need to be given with Velcade or Cabozantinib.
Allez Hop! another mighty combination to try in a difficult disease has been created!
Taxol/cisplatin/Velcade and Parthenolide for triple negative Breast cancer!
(Instead of Parthenolide, may be IL-2 could work)
All refractory cancers seem to have one strong characteristic. They survive even when the kitchen sink is thrown at them. By kitchen sink, I mean all kinds of combination chemotherapy. In fact, times and again we have seen that only one medication turns out to be working as comparative studies end up showing equivalency between a combination therapy Vs a monotherapy. The story of DTIC in Melanoma is an example that combination therapy Vs DTIC alone, there was no difference in survival. The reasons for this drug resistance is multiple. The cell may have an MDR (Multiple drug Resistance) protein that effectively shut down cellular processes to the various drugs, but can't mount an elective resistance to DTIC. Or the cell may activate its NF-kB pathways to survive.
As cells live their lives in our body they come in contact with all kinds of neighbors and enemies, including drugs constantly thrown around in our body. The cells register the invasion, exposure or attack and send the message through a pathway of survival called NF-kB. Signals from this pathways are interpreted quickly and our body modulate the attack in the general sense of survival. To achieve this, some transcription genes are amplified to make more blockers to the invasion (ie. Bcl-2), some transcription genes are shut down to reduce susceptibility to the attack. The NF-kB pathway is in this a critical pathway of adaptation to life. It is central to all immune diseases, it is critical to resistance to diseases, it is the force to reckon with when you give a drug to treat anything including cancer. You got to stop NF-kB from working effectively to achieve your goal. Because, unlike the MDR and Flippase which are determined in their place of action and mechanism, this pathway is constantly searching for an answer against therapy by modulating various transcription factors! You see here now why attempts to target this pathway are so important.
To assure versatility in its action, NF-kB knows it cannot do it on its own, it "cross-talks" to many other pathways and important molecules. One of which is the STAT3 for rapid transcription of whatever protein is needed to decrease Apoptosis and protect the cell. NF-kB a constant, moving and changing fighter which will do anything to decrease activities that can lead to death of the cell. So far Phosphorylating it has been with limited success. May be its inhibitors need to be given with Velcade or Cabozantinib.
Allez Hop! another mighty combination to try in a difficult disease has been created!
Taxol/cisplatin/Velcade and Parthenolide for triple negative Breast cancer!
(Instead of Parthenolide, may be IL-2 could work)
Lack of Clear Evidence for Sentinel Node Biopsy in Melanoma?
Sentinel lymph node (SLN) biopsy has become a common
procedure in melanoma and has been endorsed by professional guidelines.
It is considered to be a minimally invasive and highly
accurate procedure that allows for appropriate regional nodal staging
and identification of patients without nodal metastases.
However, in a feature published online January 8 in BMJ, freelance journalist Ingrid Torjesen, from London, United Kingdom, describes SLN biopsy as an "expensive and invasive procedure" and reports that thousands of melanoma patients around the world are having it done despite a lack of clear evidence that it will improve outcomes.
She focuses on the Multicenter Selective Lymphadenectomy Trial (MSLT-I), which was designed to determine the ability of SLN biopsy to identify patients with clinically occult nodal metastases and to evaluate the effectiveness of immediate completion lymph node dissection (CLND) in patients with positive SLNs.
The 5-year follow-up of the MSLT-I, published in 2006 ( N Engl J Med. 2006;355:1307-1317), failed to show a survival advantage from SLN biopsy. However, it did confirm that SLN biopsy was highly accurate in identifying positive nodes in patients with melanomas 1.2 to 3.5 mm thick, and that SLN biopsy followed by CLND was associated with prolonged disease-free survival.
In addition, clinically node-negative patients with SLN metastases who underwent CLND had significantly better melanoma-specific 5-year survival rates than those who had delayed CLND for clinically detected nodal relapse.
SLN biopsy is now commonly used in Australia, Canada, the United States, and Western Europe, but is not routinely used in the United Kingdom.
A guideline issued jointly by the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SOS) recommends SLN biopsy for patients with melanomas of intermediate thickness. The procedure has also been endorsed by the American Joint Committee on Cancer as a valuable staging procedure for those at risk of developing clinically occult nodal metastases.
Why No Interim Results?
In her report, Torjesen states that the results of the MSLT-I were controversial, and that critics said it was not surprising "to see an improved disease-free survival in the biopsy arm [because] patients whose disease was most likely to progress had had their regional nodes removed."
She notes that the fourth interim analysis of the MSLT-I data (showing 7-year follow-up data), which was expected in 2008, and the fifth and final analysis (with 10-year data), expected in 2011, will settle the question once and for all.
So why haven't they been published, Torjesen asks.
"A minimum of 10 years of follow-up is required to see the full benefit of the technique," said Alistair Cochran, MD, MB ChB, distinguished professor of pathology, laboratory medicine, and surgery at the University of California Los Angeles School of Medicine.
"The 10-year data have been analyzed and are being prepared for submission, hopefully within the next month or so," Dr. Cochran told Medscape Medical News.
Dr. Cochran was involved in developing the technique, is a coauthor of the ASCO/SOS guidelines, and has worked with Donald Morton, MD, lead author of the MSLT-I.
Sandra Wong, MD, associate professor of surgery at the University of Michigan Health Systems in Ann Arbor, and lead author of the ASCO/SOS guidelines, agrees. "In a lot of studies, the follow-up time just isn't long enough," she told Medscape Medical News. "Melanoma is not like a lot of other cancers, where you start seeing recurrences within the first 2 years. I have patients who are a decade out and they are having a recurrence. It's just a very different disease process," she explained.
Lacking Balance
Dr. Cochran pointed out that Torjesen relies heavily on comments from J. Meiron Thomas, MS, FRCP, FRCS, who is a consultant surgeon at the Royal Marsden Hospital London and chair of surgical oncology at Imperial College, London, United Kingdom.
Dr. Thomas has been very vocal in his criticism of SLN biopsy and has published maybe 15 or 16 papers on the subject, Dr. Cochran explained. "This is a picture of a tennis match.... We publish something and then Dr. Thomas prints a rebuttal. We have eventually left him to it and figured time will tell," he noted.
"I don't know if bias is the right word, but the paper seems to only represent 1 side of the debate," said Dr. Wong. "That side is a very minority opinion, and Dr. Thomas is a vocal critic," she added.
Dr. Wong noted that when "we try to set up debates at national meetings, we can never get anyone to take the con side. Not even a 'soft' con."
This report is not offering any new information or insight, said Daniel Coit, MD, a surgical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. It "is really just a rehash of arguments and commentaries that have been made for quite some time," he explained.
Dr. Coit emphasized Donald Morton, who introduced the technique and who has, so to speak, the biggest stake in it "is the one person who has done more than anyone else to critically evaluate the technique, with these 2 large randomized prospective trials.... While there are many critics — and Steve Rosenberg [mentioned in the report] and Meiron Thomas have an absolute right to interpret the data of others — neither has actually created any data of their own to contribute to this," he explained.
"It is very easy to take pot shots, but very hard to create new data," Dr. Coit added. "And Don Morton has created a wealth of data."
All of the arguments made in the report are cogent. "This is not a procedure that affects survival, it is a procedure that provides important prognostic information," he noted.
"As a society, we have to decide if we want to pay for it, just as we decide if we are going to pay for CT scans or PET scans," Dr. Coit added.
Professional Advancement and Company Profits?
Torjesen implies that the uptake of SLN biopsy has been largely driven by professional advancement and commercial profit. She states that "whole professional careers and businesses have been built on sentinel node biopsy for melanoma. Professional pride and company profits are now at stake."
Dr. Cochran explained that it is highly doubtful that the use of SLN biopsy has been endorsed simply to advance careers or to generate profit. "I don't think that the popularity of the technique can be put down to the commercialization," he said. "I'm sure that there is some money to be made, but nothing like the money that can be made by pharmaceutical companies from some of their new drugs."
Dr. Wong agrees that there is some cost associated with the procedure, but it is not very expensive overall and not a huge profit maker. "It's not like chemotherapy or using excessive imaging," she noted.
"If you're really cynical, you can say that if melanoma surgeons stopped doing this, they would lose a large part of their practice," she added. "But that's cynical because this is a procedure that can help overall survival or help make an accurate diagnosis," she said.
Harms of Overtreatment
Torjesen raises concerns about overtreatment in her report. "It is generally accepted that only 20% of patients who have sentinel node biopsy will have positive sentinel nodes, and only 20% of those will have metastatic disease in the nonsentinel nodes," she states. "Therefore, 96% of patients who have sentinel node biopsy will have unnecessary surgery," she writes.
Dr. Cochran agrees that the prophylactic removal of lymph nodes can cause serious morbidity, but pointed out that some people can be saved by it. "The other alternative is to watch and wait, but we've found that the number of involved lymph nodes in patients who have been observed is about 3 times as high as those treated with sentinel node biopsy," he said. "We know that with time, the disease progresses. I think most physicians are uncomfortable with letting things be and letting nature take its course," he explained.
Dr. Cochran added that at some point it will be possible to tell which patients with a positive SLN have metastatic disease, "but we are not there yet."
It is hoped that the follow-up MSLT-II will answer some of those questions. That study is also being run by Dr. Morton, and will evaluate the potential benefits of regional lymphadenectomy for melanoma patients with positive sentinel nodes.
The MSLT-II will establish whether "every patient with a positive SLN needs a full dissection," said Dr. Wong.
If lymph node surgery in melanoma is ultimately scaled back, it would not be without precedent. In recent years, surgical oncologists have learned that not all women with positive sentinel axillary lymph nodes need completion dissection. The Z0011 trial, conducted by the American College of Surgeons Oncology Group, showed that women with minimal lymph node involvement did not suffer from inferior survival when they only underwent sentinel node biopsy and did not undergo completion dissection.
In addition, new agents have been shown to be very effective in metastatic disease; that's why the staging is so important, Dr. Wong explained. "You may have a patient who walks in with a stage I melanoma clinically, but may actually be a stage III once we do the procedure. If we lose these data, we won't know which patients will benefit from these new treatments," she noted.
In general, the jury is still out as far as SLN biopsy goes. "But everyone is doing it, and I don't think there is too much debate," Dr. Wong said. "It is hard to tell a patient that you don't want to do it if they are in the 1 to 4 mm stage. They want to know."
Dr. Coit agrees. "I don't think any clinicians regularly using this procedure propose it to patients as anything other than a method that will provide more information on how likely melanoma is to occur," he said.
The main question right now is which patients are least likely to benefit from the procedure, he added. "We are taking a long hard look at who this prognostic information will likely help, this procedure will help, but also who it will not be of benefit to."
Medscape Medical News requested a comment on this report from BMJ, but had not received a response by press time.
BMJ. 2013;346:e8645. Full text
===========================
FROM MEDSCAPE NEWS, BE AWARE OF THIS CONTROVERSY!
However, in a feature published online January 8 in BMJ, freelance journalist Ingrid Torjesen, from London, United Kingdom, describes SLN biopsy as an "expensive and invasive procedure" and reports that thousands of melanoma patients around the world are having it done despite a lack of clear evidence that it will improve outcomes.
She focuses on the Multicenter Selective Lymphadenectomy Trial (MSLT-I), which was designed to determine the ability of SLN biopsy to identify patients with clinically occult nodal metastases and to evaluate the effectiveness of immediate completion lymph node dissection (CLND) in patients with positive SLNs.
The 5-year follow-up of the MSLT-I, published in 2006 ( N Engl J Med. 2006;355:1307-1317), failed to show a survival advantage from SLN biopsy. However, it did confirm that SLN biopsy was highly accurate in identifying positive nodes in patients with melanomas 1.2 to 3.5 mm thick, and that SLN biopsy followed by CLND was associated with prolonged disease-free survival.
In addition, clinically node-negative patients with SLN metastases who underwent CLND had significantly better melanoma-specific 5-year survival rates than those who had delayed CLND for clinically detected nodal relapse.
SLN biopsy is now commonly used in Australia, Canada, the United States, and Western Europe, but is not routinely used in the United Kingdom.
A guideline issued jointly by the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SOS) recommends SLN biopsy for patients with melanomas of intermediate thickness. The procedure has also been endorsed by the American Joint Committee on Cancer as a valuable staging procedure for those at risk of developing clinically occult nodal metastases.
Why No Interim Results?
In her report, Torjesen states that the results of the MSLT-I were controversial, and that critics said it was not surprising "to see an improved disease-free survival in the biopsy arm [because] patients whose disease was most likely to progress had had their regional nodes removed."
She notes that the fourth interim analysis of the MSLT-I data (showing 7-year follow-up data), which was expected in 2008, and the fifth and final analysis (with 10-year data), expected in 2011, will settle the question once and for all.
So why haven't they been published, Torjesen asks.
"A minimum of 10 years of follow-up is required to see the full benefit of the technique," said Alistair Cochran, MD, MB ChB, distinguished professor of pathology, laboratory medicine, and surgery at the University of California Los Angeles School of Medicine.
"The 10-year data have been analyzed and are being prepared for submission, hopefully within the next month or so," Dr. Cochran told Medscape Medical News.
Dr. Cochran was involved in developing the technique, is a coauthor of the ASCO/SOS guidelines, and has worked with Donald Morton, MD, lead author of the MSLT-I.
Sandra Wong, MD, associate professor of surgery at the University of Michigan Health Systems in Ann Arbor, and lead author of the ASCO/SOS guidelines, agrees. "In a lot of studies, the follow-up time just isn't long enough," she told Medscape Medical News. "Melanoma is not like a lot of other cancers, where you start seeing recurrences within the first 2 years. I have patients who are a decade out and they are having a recurrence. It's just a very different disease process," she explained.
Lacking Balance
Dr. Cochran pointed out that Torjesen relies heavily on comments from J. Meiron Thomas, MS, FRCP, FRCS, who is a consultant surgeon at the Royal Marsden Hospital London and chair of surgical oncology at Imperial College, London, United Kingdom.
Dr. Thomas has been very vocal in his criticism of SLN biopsy and has published maybe 15 or 16 papers on the subject, Dr. Cochran explained. "This is a picture of a tennis match.... We publish something and then Dr. Thomas prints a rebuttal. We have eventually left him to it and figured time will tell," he noted.
"I don't know if bias is the right word, but the paper seems to only represent 1 side of the debate," said Dr. Wong. "That side is a very minority opinion, and Dr. Thomas is a vocal critic," she added.
Dr. Wong noted that when "we try to set up debates at national meetings, we can never get anyone to take the con side. Not even a 'soft' con."
This report is not offering any new information or insight, said Daniel Coit, MD, a surgical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. It "is really just a rehash of arguments and commentaries that have been made for quite some time," he explained.
Dr. Coit emphasized Donald Morton, who introduced the technique and who has, so to speak, the biggest stake in it "is the one person who has done more than anyone else to critically evaluate the technique, with these 2 large randomized prospective trials.... While there are many critics — and Steve Rosenberg [mentioned in the report] and Meiron Thomas have an absolute right to interpret the data of others — neither has actually created any data of their own to contribute to this," he explained.
"It is very easy to take pot shots, but very hard to create new data," Dr. Coit added. "And Don Morton has created a wealth of data."
All of the arguments made in the report are cogent. "This is not a procedure that affects survival, it is a procedure that provides important prognostic information," he noted.
"As a society, we have to decide if we want to pay for it, just as we decide if we are going to pay for CT scans or PET scans," Dr. Coit added.
Professional Advancement and Company Profits?
Torjesen implies that the uptake of SLN biopsy has been largely driven by professional advancement and commercial profit. She states that "whole professional careers and businesses have been built on sentinel node biopsy for melanoma. Professional pride and company profits are now at stake."
Dr. Cochran explained that it is highly doubtful that the use of SLN biopsy has been endorsed simply to advance careers or to generate profit. "I don't think that the popularity of the technique can be put down to the commercialization," he said. "I'm sure that there is some money to be made, but nothing like the money that can be made by pharmaceutical companies from some of their new drugs."
Dr. Wong agrees that there is some cost associated with the procedure, but it is not very expensive overall and not a huge profit maker. "It's not like chemotherapy or using excessive imaging," she noted.
"If you're really cynical, you can say that if melanoma surgeons stopped doing this, they would lose a large part of their practice," she added. "But that's cynical because this is a procedure that can help overall survival or help make an accurate diagnosis," she said.
Harms of Overtreatment
Torjesen raises concerns about overtreatment in her report. "It is generally accepted that only 20% of patients who have sentinel node biopsy will have positive sentinel nodes, and only 20% of those will have metastatic disease in the nonsentinel nodes," she states. "Therefore, 96% of patients who have sentinel node biopsy will have unnecessary surgery," she writes.
Dr. Cochran agrees that the prophylactic removal of lymph nodes can cause serious morbidity, but pointed out that some people can be saved by it. "The other alternative is to watch and wait, but we've found that the number of involved lymph nodes in patients who have been observed is about 3 times as high as those treated with sentinel node biopsy," he said. "We know that with time, the disease progresses. I think most physicians are uncomfortable with letting things be and letting nature take its course," he explained.
Dr. Cochran added that at some point it will be possible to tell which patients with a positive SLN have metastatic disease, "but we are not there yet."
It is hoped that the follow-up MSLT-II will answer some of those questions. That study is also being run by Dr. Morton, and will evaluate the potential benefits of regional lymphadenectomy for melanoma patients with positive sentinel nodes.
The MSLT-II will establish whether "every patient with a positive SLN needs a full dissection," said Dr. Wong.
If lymph node surgery in melanoma is ultimately scaled back, it would not be without precedent. In recent years, surgical oncologists have learned that not all women with positive sentinel axillary lymph nodes need completion dissection. The Z0011 trial, conducted by the American College of Surgeons Oncology Group, showed that women with minimal lymph node involvement did not suffer from inferior survival when they only underwent sentinel node biopsy and did not undergo completion dissection.
In addition, new agents have been shown to be very effective in metastatic disease; that's why the staging is so important, Dr. Wong explained. "You may have a patient who walks in with a stage I melanoma clinically, but may actually be a stage III once we do the procedure. If we lose these data, we won't know which patients will benefit from these new treatments," she noted.
In general, the jury is still out as far as SLN biopsy goes. "But everyone is doing it, and I don't think there is too much debate," Dr. Wong said. "It is hard to tell a patient that you don't want to do it if they are in the 1 to 4 mm stage. They want to know."
Dr. Coit agrees. "I don't think any clinicians regularly using this procedure propose it to patients as anything other than a method that will provide more information on how likely melanoma is to occur," he said.
The main question right now is which patients are least likely to benefit from the procedure, he added. "We are taking a long hard look at who this prognostic information will likely help, this procedure will help, but also who it will not be of benefit to."
Medscape Medical News requested a comment on this report from BMJ, but had not received a response by press time.
BMJ. 2013;346:e8645. Full text
===========================
FROM MEDSCAPE NEWS, BE AWARE OF THIS CONTROVERSY!
Sunday, January 13, 2013
Effective Treatment of Psoriasis with Narrow-Band UVB Phototherapy Is Linked to Suppression of the IFN and Th17 Pathways
Emőke Rácz,
Errol P Prens, Dorota Kurek, Marius Kant, Dick de Ridder,
Sabine Mourits, Ewout M Baerveldt, Zeliha Ozgur, Wilfred F J van IJcken,
Jon D Laman, Frank J Staal and Leslie van der Fits
BACK TO ARTICLETable 2. Effect of narrow-band ultraviolet-B (NB-UVB) phototherapy on pathways known to be therapeutic targets in psoriasis, or targets of UVB radiation
| Molecules affected by NB-UVB within these pathways | |||
|---|---|---|---|
| Pathway | P-value | Upregulated | Downregulated |
| Therapeutic target in psoriasis | |||
| Glucocorticoid receptor signaling | 1.1E−03 | PIK3R1, PIK3C2G, HSPA2, BCL2, IL1R2, TGFBR2, TSC22D3, KAT2B, AKT3, NCOR2, ADRB2, UBE2I | IL8, STAT3, STAT1 |
| VDR/RXR activation | 4.2E−03 | IGFBP5, NCOR2, CST6 | DEFB4, SERPINB1, KLK6, HSD17B2 |
| NF-κB signaling | 2.3E−02 | IL1R2, CSNK2A2, IL18, PIK3R1, PIK3C2G, AKT3, IL1F7 | IL1F9 |
| Induced by UV in normal skin | |||
| p53 signaling | 2.1E−03 | KAT2B, TP53INP1, PIK3R1, PIK3C2G, AKT3, CCND1, BCL2 | SCO2 |
| p38 MAPK signaling | 3.5E−03 | IL1R2, TGFBR2, IL18, H3F3B, IL1F7, EEF2K | IL1F9, STAT1 |
| EGF signaling | 5.4E−03 | CSNK2A2, PIK3R1, PIK3C2G | STAT3, STAT1 |
| IGF-1 signaling | 2.4E−02 | CSNK2A2, PIK3R1, PIK3C2G, AKT3, IGFBP5, IGFBP7 | |
| Proposed as therapeutic target in psoriasis | |||
| LXR/RXR activation | 2.5E−04 | IL1R2, APOE, IL18, IL1F7, NCOR2 | IL1F9, LDLR, CCL7 |
| IL-10 signaling | 4.2E−03 | IL1R2, IL18, IL1F7 | IL4R, IL1F9, STAT3 |
| PPAR signaling | 1.8E−02 | IL1R2, IL18, IL1F7, NCOR2, PDGFC | IL1F9 |
| IL-4 signaling | 2.2E−02 | PIK3R1, PIK3C2G, AKT3 | IL4R, IL13RA1 |
| Other | |||
| GM-CSF signaling | 1.5E−04 | PIK3R1, PIK3C2G, AKT3, CCND1 | CSF2RB, LYN, STAT3, STAT1 |
| Acute-phase response signaling | 3.2E−04 | PIK3R1, SOCS6, IL1F7, IL18, AKT3 | C1S, SERPINA3, STAT3, C1R, IL1F9, SOD2, CRABP2, CFB |
| IFN signaling | 6.3E−04 | IFIT1, OAS1, IFNGR1, MX1, STAT1 | |
| PDGF signaling | 2.1E−03 | CSNK2A2, PIK3R1, CAV1, PIK3C2G, PDGFC | STAT3, STAT1 |
| JAK/Stat signaling | 4.2E−03 | PIK3R1, SOCS6, PIK3C2G, AKT3, | STAT3, STAT1 |
| IL-6 signaling | 7.2E−03 | IL1R2, CSNK2A2, IL18, IL1F7 | IL8, IL1F9, STAT3 |
| Complement system | 9.5E−03 | CD59 | C1R, C1S, CFB |
| LPS/IL-1-mediated inhibition of RXR function | 1.9E−02 | IL1R2, GSTA3, APOE, ALDH3A2, CAT, HS3ST6, ABCC4 | ALDH1A3, PAPSS2, HS3ST3A1 |
| VEGF signaling | 1.9E−02 | PIK3R1, PIK3C2G, AKT3, BCL2 | HIF1A, ACTN1 |
| Wnt/β-catenin signaling | 2.2E−02 | TGFBR2, CSNK2A2, FRZB, DKK3, SOX10, AKT3, CCND1 | SOX9, FZD5 |
| Xenobiotic metabolism signaling | 3.2E−02 | GSTA3, ALDH3A2, PIK3R1, MAF, CAT, PIK3C2G, HS3ST6, NCOR2, | ALDH1A3, UGT1A9, HS3ST3A1 |
| Fc ∑ RI signaling | 3.6E−02 | FYN, VAV3, PIK3R1, PIK3C2G, AKT3 | LYN |
| IL-2 signaling | 4.3E−02 | CSNK2A2, PIK3R1, PIK3C2G, AKT3 | |
ASPECTS OF TARGET THERAPY IN TRIPLE NEGATIVE BREAST CANCER.
As one goes in deeper into treating Breast cancer with triple negative characteristics, one quickly realize it is imperative to further assess genome and pathway drivers in order to get to effective therapy. This type of Breast cancer is driven by polygenic stimulators and prognostic factors. Recent developments has pointed to STAT1 and its relationship with AKT3 and MAP3-K1. In the article posted here, MAGI3-AKT3 reshuffling is plenty discussed. One of the challenge is to find an effective AKT3 inhibitor. The potential inhibitors have been tested in Melanoma where AKT3 pathway is amplified in 70% of cancer cells. Generally, an amplification of pathways is linked to overexpression of promoter genes and transcription genes. This is were gene Methylation can help silence these promoters, and can prove an effective way controlling these disease processes. Once again, we believe that an Interfeon and /or Interleukin combined to an mTor (Afinitor), plus or minus a Taxane would be effective in Triple Negative Breast Cancer.
As one goes in deeper into treating Breast cancer with triple negative characteristics, one quickly realize it is imperative to further assess genome and pathway drivers in order to get to effective therapy. This type of Breast cancer is driven by polygenic stimulators and prognostic factors. Recent developments has pointed to STAT1 and its relationship with AKT3 and MAP3-K1. In the article posted here, MAGI3-AKT3 reshuffling is plenty discussed. One of the challenge is to find an effective AKT3 inhibitor. The potential inhibitors have been tested in Melanoma where AKT3 pathway is amplified in 70% of cancer cells. Generally, an amplification of pathways is linked to overexpression of promoter genes and transcription genes. This is were gene Methylation can help silence these promoters, and can prove an effective way controlling these disease processes. Once again, we believe that an Interfeon and /or Interleukin combined to an mTor (Afinitor), plus or minus a Taxane would be effective in Triple Negative Breast Cancer.
Breast cancer’s many drivers
By Elizabeth Cooney, Broad Communications,
June 20th, 2012
-
A breast cancer cell, shown in a color-enhanced scanning electron
micrograph.
Image courtesy of Anne Weston via Wellcome Images
Breast cancer is not a single disease, but a collection of diseases
with dozens of different mutations that crop up with varying frequency
across different breast cancer subtypes. Deeper exploration of the
genetic changes that drive breast cancer is revealing new complexity in
the leading cause of cancer death in women worldwide.
In one of the largest breast cancer sequencing efforts to date, scientists from the Broad Institute, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute have discovered surprising alterations in genes that were not previously associated with breast cancer. They report their results in the June 21 issue of Nature, which is publishing a series of papers characterizing the genomic landscape of breast cancer.
One of the team’s new findings, a recurrent fusion of the genes MAGI3 and AKT3 in what is known as a translocation event, was observed in tumors from a rare but aggressive form of breast cancer known as triple-negative breast cancer. This cancer does not respond to conventional hormone therapy because its tumors lack three receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (known as HER2). But the biological pathway that is affected by the MAGI3-AKT3 reshuffling is already the target of experimental drugs.
The other new alteration reported by the team occurred in two transcription factor genes. Recurrent mutations were detected in the gene CBFB and deletions of its partner RUNX1. Cancer-causing rearrangements of these two genes are common in blood cancers, such as acute myeloid leukemia, but their discovery in breast cancer marks the first time they have been seen in a solid cancer.
“These genes wouldn’t top the list of genes you think would be mutated in breast cancer,” said Alfredo Hidalgo Miranda, co-senior author of the paper and head of the cancer genomics laboratory at the National Institute of Genomic Medicine, known by its Spanish acronym INMEGEN. “That’s exactly the point of doing this type of analysis. It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process.”
The scientists studied two kinds of samples. They sequenced the whole exomes – the tiny fraction of the genome that encodes proteins – of 103 breast cancer tumors and DNA from normal tissue from patients in Mexico and Vietnam. They also sequenced the entire genomes of 22 breast cancer tumors and matched normal tissue.
Their analysis confirmed the presence of previously known mutations, but it also turned up the unsuspected alterations.
“One of the lessons here is the real diversity of mutations in breast cancer. I think it’s clear there are going to be roughly 50 or so different mutated genes in breast cancer,” said Matthew Meyerson, co-senior author of the paper, Broad senior associate member, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School. “There’s a big diversity of driver genes in cancer. We don’t understand what all of them are, but larger data sets will enable us to identify them.”
The mutations in CBFB and RUNX1 point to the importance of understanding cell differentiation – how cells become specialized – and transcription factors that regulate that process of cell differentiation in epithelial tissue, which lines the inner and outer surfaces of the body. Further studies are needed to unravel that relationship, the authors concluded.
For the current study, inspecting the novel fusion gene MAGI1-AKT3 more closely showed not only that the translocation can transform normal cells into cancer cells, but also that the protein produced by the gene is insensitive to certain drugs now in clinical trials, yet sensitive to others.
In general, fusion genes are created within the same chromosome or across different chromosomes when parts of one gene join parts of another to become a novel gene that wouldn’t normally exist. Like the CBFB and RUNX1 mutations, translocations are also more common in blood cancers but until now have rarely been detected in solid tumors, especially breast cancer.
This particular MAGI1-AKT3 fusion gene produces a fusion protein that acts in the PI 3-kinase pathway as an oncogene, or a gene that drives cancer, revealing a new target for potential therapy. The kinase pathway controls a multitude of cellular functions. When a gene is mutated in this pathway, the result is uncontrolled cell growth, a hallmark of cancer.
Other gene mutations in this pathway are well-known, but MAGI1-AKT3 is a first.
“This is the first translocation event resulting in an oncogenic fusion protein that has been identified in this pathway,” said Alex Toker, a professor in the department of pathology at Beth Israel Deaconess and Harvard Medical School. “That’s important because this is one of the most frequently mutated pathways in human cancer, especially in women’s cancers such as breast, ovarian, and endometrial cancer.”
The most frequently mutated pathway is also the most studied and, from a pharmaceutical perspective, among the most “druggable.”
In laboratory dishes, tests confirmed that the novel structure of proteins encoded by the fusion gene provided no place for some drugs to bind but offered targets for other drugs.
“There are many additional studies that need to be performed using mouse models of disease that would recapitulate the expression of this protein in the mammary gland, in addition to the mechanism by which this protein promotes the effects associated with malignancy,” Toker said. “These are all experiments that are under way.”
Once the mechanism at work in triple-negative breast cancer is understood through animal models, the next step would be to test chemical compounds to see how effective they might be at targeting cells that harbor this fusion gene’s protein.
Beyond these scientific findings, the study also represents a closer look at the Latino population, thanks to the collaboration between the Broad and INMEGEN forged through the Slim Initiative in Genomic Medicine.
“The Slim Initiative in Genomic Medicine aims to support the discovery of the genetic basis of diseases such as type 2 diabetes mellitus and several types of cancer which have a profound public health impact in Mexico and Latin America,” said Roberto Tapia-Conyer, director general of the Carlos Slim Health Institute. “This novel bi-national scientific collaboration is contributing to put the Latin American genome on the map of the second generation worldwide genome studies.”
INMEGEN scientists had previously built a large breast cancer study and then scientists at both the Broad and INMEGEN exchanged clinical, biological, and computational information.
“From the Mexican point of view, you can say the Latino population has not been extensively characterized using genomic methods,” Hidalgo Miranda said. “This is a significant contribution to the knowledge of the architecture of breast tumors in this particular population.”
The study represented a first opportunity to study the genetic basis of breast cancer in Mexico. Larger studies will be required to determine whether differences in the spectrum of mutations exist between different populations, but this was an important first step toward that goal.
Contributors to the work also include, from the Broad and its Harvard-affiliated hospitals: Shantanu Banerji (co-first author), Kristian Cibulskis (co-first author), Kristin K. Brown (co-first author), Scott L. Carter, Abbie M. Frederick, Michael S. Lawrence, Andrey Y. Sivachenko, Carrie Sougnez, Lihua Zou, Maria L. Cortes, Shouyong Peng, Kristin G. Ardlie, Daniel Auclair, Fujiko Duke, Joshua Francis, Joonil Jung, Robert C. Onofrio, Melissa Parkin, Nam H. Pho, Alex. H. Ramos, Steven E. Schumacher, Nicolas Stransky, Kristin M. Thompson, Jose Baselga, Rameen Beroukhim, Kornelia Polyak, Dennis C. Sgroi, Andrea L. Richardson, Eric S. Lander, Stacey B. Gabriel, Levi A. Garraway, Todd R. Golub, and Gad Getz (co-senior author). From Mexico: Claudia Rangel-Escareno (co-first author), Juan C. Fernandez-Lopez, Veronica Bautista-Pina, Antonio Maffuz-Aziz, Valeria Quintanar-Jurado, Rosa Rebollar-Vega, Sergio Rodriguez-Cuevas, Sandra L. Romero-Cordoba, Laura Uribe-Figueroa, Gerardo Jimenez-Sanchez, and Jorge Melendez-Zajgla.
The research was conducted as part of the Slim Initiative in Genomic Medicine, a project funded by the Carlos Slim Health Institute in Mexico. The work was also supported by grants from the National Institutes of Health and the National Cancer Institute.
About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
About the Carlos Slim Health Institute
The Carlos Slim Health Institute is a non-profit organization created in 2007 by the initiative of Mr. Carlos Slim-Helú with the purpose of generating solutions in order to help solving Mexico’s and Latin America’s main public health problems focusing on the most deprived populations.
The institute seeks to achieve its objectives by fostering alliances with Mexican and foreign public, private and social institutions in order to support the adoption of innovative, sustainable and replicable solutions aimed at improving the health of the population, such as the use of mobile technologies in health care, on-line based distance learning, translating scientific research into applicable tools, etc. http://www.salud.carlosslim.org
About the National Institute of Genomic Medicine
The National Institute of Genomic Medicine (INMEGEN) was founded in 2004 and became the 11th National Institute of Health in Mexico. INMEGEN's mission is to contribute to the healthcare of the Mexican population by developing cutting-edge scientific research and well-trained human resources. The goal is to apply the knowledge of genomic medicine through innovation, state-of-the-art technology, and strategic partnerships, all the while complying with universal ethical principles.
INMEGEN's main research areas focus on principal complex diseases in Mexico, all based on the genomic characterization of the Mexican population. Examples of these areas are genomics of metabolic diseases (diabetes mellitus and obesity), cancer research, infectious and cardiovascular diseases, as well as nutrigenomics and pharmacogenomics.
One of the features of INMEGEN¹s innovative culture is scientific research and development of technology, which leads to goods and services that can then be used to contribute to better health care for the Mexican people in the knowledge-based economy.
www.inmegen.gob.mx
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Boston Children’s Hospital as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.
In one of the largest breast cancer sequencing efforts to date, scientists from the Broad Institute, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute have discovered surprising alterations in genes that were not previously associated with breast cancer. They report their results in the June 21 issue of Nature, which is publishing a series of papers characterizing the genomic landscape of breast cancer.
One of the team’s new findings, a recurrent fusion of the genes MAGI3 and AKT3 in what is known as a translocation event, was observed in tumors from a rare but aggressive form of breast cancer known as triple-negative breast cancer. This cancer does not respond to conventional hormone therapy because its tumors lack three receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (known as HER2). But the biological pathway that is affected by the MAGI3-AKT3 reshuffling is already the target of experimental drugs.
The other new alteration reported by the team occurred in two transcription factor genes. Recurrent mutations were detected in the gene CBFB and deletions of its partner RUNX1. Cancer-causing rearrangements of these two genes are common in blood cancers, such as acute myeloid leukemia, but their discovery in breast cancer marks the first time they have been seen in a solid cancer.
“These genes wouldn’t top the list of genes you think would be mutated in breast cancer,” said Alfredo Hidalgo Miranda, co-senior author of the paper and head of the cancer genomics laboratory at the National Institute of Genomic Medicine, known by its Spanish acronym INMEGEN. “That’s exactly the point of doing this type of analysis. It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process.”
The scientists studied two kinds of samples. They sequenced the whole exomes – the tiny fraction of the genome that encodes proteins – of 103 breast cancer tumors and DNA from normal tissue from patients in Mexico and Vietnam. They also sequenced the entire genomes of 22 breast cancer tumors and matched normal tissue.
Their analysis confirmed the presence of previously known mutations, but it also turned up the unsuspected alterations.
“One of the lessons here is the real diversity of mutations in breast cancer. I think it’s clear there are going to be roughly 50 or so different mutated genes in breast cancer,” said Matthew Meyerson, co-senior author of the paper, Broad senior associate member, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School. “There’s a big diversity of driver genes in cancer. We don’t understand what all of them are, but larger data sets will enable us to identify them.”
The mutations in CBFB and RUNX1 point to the importance of understanding cell differentiation – how cells become specialized – and transcription factors that regulate that process of cell differentiation in epithelial tissue, which lines the inner and outer surfaces of the body. Further studies are needed to unravel that relationship, the authors concluded.
For the current study, inspecting the novel fusion gene MAGI1-AKT3 more closely showed not only that the translocation can transform normal cells into cancer cells, but also that the protein produced by the gene is insensitive to certain drugs now in clinical trials, yet sensitive to others.
In general, fusion genes are created within the same chromosome or across different chromosomes when parts of one gene join parts of another to become a novel gene that wouldn’t normally exist. Like the CBFB and RUNX1 mutations, translocations are also more common in blood cancers but until now have rarely been detected in solid tumors, especially breast cancer.
This particular MAGI1-AKT3 fusion gene produces a fusion protein that acts in the PI 3-kinase pathway as an oncogene, or a gene that drives cancer, revealing a new target for potential therapy. The kinase pathway controls a multitude of cellular functions. When a gene is mutated in this pathway, the result is uncontrolled cell growth, a hallmark of cancer.
Other gene mutations in this pathway are well-known, but MAGI1-AKT3 is a first.
“This is the first translocation event resulting in an oncogenic fusion protein that has been identified in this pathway,” said Alex Toker, a professor in the department of pathology at Beth Israel Deaconess and Harvard Medical School. “That’s important because this is one of the most frequently mutated pathways in human cancer, especially in women’s cancers such as breast, ovarian, and endometrial cancer.”
The most frequently mutated pathway is also the most studied and, from a pharmaceutical perspective, among the most “druggable.”
In laboratory dishes, tests confirmed that the novel structure of proteins encoded by the fusion gene provided no place for some drugs to bind but offered targets for other drugs.
“There are many additional studies that need to be performed using mouse models of disease that would recapitulate the expression of this protein in the mammary gland, in addition to the mechanism by which this protein promotes the effects associated with malignancy,” Toker said. “These are all experiments that are under way.”
Once the mechanism at work in triple-negative breast cancer is understood through animal models, the next step would be to test chemical compounds to see how effective they might be at targeting cells that harbor this fusion gene’s protein.
Beyond these scientific findings, the study also represents a closer look at the Latino population, thanks to the collaboration between the Broad and INMEGEN forged through the Slim Initiative in Genomic Medicine.
“The Slim Initiative in Genomic Medicine aims to support the discovery of the genetic basis of diseases such as type 2 diabetes mellitus and several types of cancer which have a profound public health impact in Mexico and Latin America,” said Roberto Tapia-Conyer, director general of the Carlos Slim Health Institute. “This novel bi-national scientific collaboration is contributing to put the Latin American genome on the map of the second generation worldwide genome studies.”
INMEGEN scientists had previously built a large breast cancer study and then scientists at both the Broad and INMEGEN exchanged clinical, biological, and computational information.
“From the Mexican point of view, you can say the Latino population has not been extensively characterized using genomic methods,” Hidalgo Miranda said. “This is a significant contribution to the knowledge of the architecture of breast tumors in this particular population.”
The study represented a first opportunity to study the genetic basis of breast cancer in Mexico. Larger studies will be required to determine whether differences in the spectrum of mutations exist between different populations, but this was an important first step toward that goal.
Contributors to the work also include, from the Broad and its Harvard-affiliated hospitals: Shantanu Banerji (co-first author), Kristian Cibulskis (co-first author), Kristin K. Brown (co-first author), Scott L. Carter, Abbie M. Frederick, Michael S. Lawrence, Andrey Y. Sivachenko, Carrie Sougnez, Lihua Zou, Maria L. Cortes, Shouyong Peng, Kristin G. Ardlie, Daniel Auclair, Fujiko Duke, Joshua Francis, Joonil Jung, Robert C. Onofrio, Melissa Parkin, Nam H. Pho, Alex. H. Ramos, Steven E. Schumacher, Nicolas Stransky, Kristin M. Thompson, Jose Baselga, Rameen Beroukhim, Kornelia Polyak, Dennis C. Sgroi, Andrea L. Richardson, Eric S. Lander, Stacey B. Gabriel, Levi A. Garraway, Todd R. Golub, and Gad Getz (co-senior author). From Mexico: Claudia Rangel-Escareno (co-first author), Juan C. Fernandez-Lopez, Veronica Bautista-Pina, Antonio Maffuz-Aziz, Valeria Quintanar-Jurado, Rosa Rebollar-Vega, Sergio Rodriguez-Cuevas, Sandra L. Romero-Cordoba, Laura Uribe-Figueroa, Gerardo Jimenez-Sanchez, and Jorge Melendez-Zajgla.
The research was conducted as part of the Slim Initiative in Genomic Medicine, a project funded by the Carlos Slim Health Institute in Mexico. The work was also supported by grants from the National Institutes of Health and the National Cancer Institute.
About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
About the Carlos Slim Health Institute
The Carlos Slim Health Institute is a non-profit organization created in 2007 by the initiative of Mr. Carlos Slim-Helú with the purpose of generating solutions in order to help solving Mexico’s and Latin America’s main public health problems focusing on the most deprived populations.
The institute seeks to achieve its objectives by fostering alliances with Mexican and foreign public, private and social institutions in order to support the adoption of innovative, sustainable and replicable solutions aimed at improving the health of the population, such as the use of mobile technologies in health care, on-line based distance learning, translating scientific research into applicable tools, etc. http://www.salud.carlosslim.org
About the National Institute of Genomic Medicine
The National Institute of Genomic Medicine (INMEGEN) was founded in 2004 and became the 11th National Institute of Health in Mexico. INMEGEN's mission is to contribute to the healthcare of the Mexican population by developing cutting-edge scientific research and well-trained human resources. The goal is to apply the knowledge of genomic medicine through innovation, state-of-the-art technology, and strategic partnerships, all the while complying with universal ethical principles.
INMEGEN's main research areas focus on principal complex diseases in Mexico, all based on the genomic characterization of the Mexican population. Examples of these areas are genomics of metabolic diseases (diabetes mellitus and obesity), cancer research, infectious and cardiovascular diseases, as well as nutrigenomics and pharmacogenomics.
One of the features of INMEGEN¹s innovative culture is scientific research and development of technology, which leads to goods and services that can then be used to contribute to better health care for the Mexican people in the knowledge-based economy.
www.inmegen.gob.mx
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Boston Children’s Hospital as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.
Paper(s) cited:
Banerji S et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature DOI: 10.1038/nature11154
A network module-based method for identifying cancer prognostic signatures
Genome Biology 2012, 13:R112 doi:10.1186/gb-2012-13-12-r112
Published: 10 December 2012
Published: 10 December 2012
Abstract (provisional)
Discovering robust prognostic gene signatures as biomarkers using genomics data can
be challenging. We have developed a simple but efficient method for discovering prognostic
biomarkers in cancer gene expression data sets using modules derived from a highly
reliable gene functional interaction network. When applied to breast cancer, we discover
a novel 31-gene signature associated with patient survival. The signature replicates
across five independent gene expression studies, and outperforms 48 published gene
signatures. When applied to ovarian cancer, the algorithm identifies a 75-gene signature
associated with patient survival. A Cytoscape plugin implementation of the signature
discovery method is available at http://wiki.reactome.org/index.php/Reactome_FI_Cytoscape_Plugin.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
=================================================================
At CRBCM we are waiting for the final article. These types of article shed a light on how we
can finally identify some of the driver mutation in basal like breast cancer. Will wait to comment as soon as the final article is reviewed.
Saturday, January 12, 2013
Fighting cancer with cell phones: Innovation to save lives in Africa By Teo Kermeliotis, for CNN updated 9:00 AM EST, Mon November 26, 2012 |
Fighting cancer with cell phones: Innovation to save lives in Africa
- A Canada-backed body is sponsoring health innovators to pursue creative ideas
- The goal is to improve access to care in developing countries
- Grants of $100,000 have been given to 68 projects, 38 of which will be implemented in Africa
- Successful projects will be able to apply for funding of up to $1 million
More than 50,000 women die each year of cervical cancer in Africa, according to World Health Organization estimates, as more than 80% of the cases are detected in late stages.
In countries such as Tanzania, where nearly 4,500 women
die annually from the disease, the problem is exacerbated by an acute
shortage of medical experts and a lack of quality screening services,
especially in rural areas.
But now a group of
Canadian and Tanzanian health innovators have joined forces to apply
simple and safe mobile technologies to improve cervical cancer screening
and thus potentially reduce mortality rates in the East African
country.
The idea is to send teams
of two trained non-physician healthcare workers in remote Tanzania to
examine women living several hours away from health centers. The nurses,
who will be equipped with cervical screening and treatment tools as
well as standard smartphones, will take a photograph of the cervix with
their phone and send it via SMS to a medical expert in a specialized
clinic.
Trained doctors will then
be able to review the image immediately and text the diagnosis back to
the health worker, as well as give instructions about treatment.
"That's the beauty of it
-- for early grade cancers, those will be able to be treated right in
the field, right in the rural area," says Dr Karen Yeates, of Queen's University, Ontario, the principal investigator of The Kilimanjaro Cervical Screening Project.
The effectiveness of the
idea will be put to the test in the coming months as Yeates was named
Thursday amongst the 68 innovators to receive $100,000 Canadian grants
to pursue bold concepts for tackling health issues in developing
countries.
In total, some $7
million has been awarded to 51 innovators in 18 low and middle-income
countries, and to 17 Canadian projects, by Grand Challenges Canada,
a group sponsoring breakthrough concepts to improve health in poor
parts of the world. Thirty-eight of these projects will be implemented
in Africa.
"This is probably the
largest pipeline of innovation in global health from the developing
world," says Peter Singer, chief executive of Grand Challenges Canada,
which is funded by the Canadian government. "It shows that poor
countries are very rich in ideas because talent is everywhere,
opportunity is not, and what we are trying to do is to bring opportunity
to talent to improve health."
Poor countries are very rich in ideas because talent is everywhere,
opportunity is not and what we are trying to do is to bring opportunity
to talent to improve health.
Peter Singer, Grand Challenges Canada, CEO
Peter Singer, Grand Challenges Canada, CEO
Amongst the Africa-based projects is a new trading system in Kenya
where researchers will create a barcoded vaccination card that people
can redeem for farm seeds and fertilizer as part of efforts to encourage
vaccination of children.
Benson Wamalwa, of the
University of Nairobi, says the project "would powerfully incentivize
parents to seek and adhere to their children's immunization schedule
even when hard pressed financially to reach a distant vaccination
center. The idea is a practical solution that would significantly boost
small farm productivity and incomes for poor households while
safeguarding the general health of children in farming villages through
up-to-date immunizations."
Other programs include restoring native freshwater prawns
in Senegal to eat the populations of snails that are responsible for
the spreading of the parasitic disease schistosomiasis; paying youth in
Uganda to collect and sort garbage and deliver it to a plant for
conversion to fertilizer and biogas in order to improve sanitation; and
anti-diarrhea kits for children hitching a ride on Coca-Cola's
distribution chain to improve the availability of life-saving drugs.
Grand Challenges Canada says it will repeat its Stars in Global Health
program every six months, funding hundreds of projects over the coming
years. It also plans to work with partners to provide scale-up funding
of up to $1 million to those ideas that are proved to be successful so
that they can have a bigger impact in a more sustainable way.
Singer says that many of
the traditional approaches when it comes to aid have proved to be
inadequate. Instead, he argues, fostering innovation and investing in
the ideas of the people can be an effective exit strategy from poverty.
"There are only two ways
for a country to develop, there's only two sources of wealth in the
world," he says. "Either you mine the ground for resources and minerals,
if you do that in a non-corrupt manner, or you mine the brains of your
citizens for their bold ideas and help them to create social
enterprises, to create businesses that can improve the local conditions
in a broader scale."
He adds: "I do think
that these innovators can help the problems of their community -- in
fact, they are the only thing that can."
SCATTERED NEWS
1. Adding Velcade may increase remission rates in AML.
This was suggested in a study at Massachusetts general Hospital.
2. CD25 was a new prognosis Biomarker in Adult B-ALL.
3. Ibrutinib in combination with Rituxan is effective in CLL
420 mg PO daily with weekly 375mg/m2 of Rituxan for 4 weeks
Rituxan was then continued monthly for 6 months
RR of 83% noted.
4. Preliminary suggestions that patients taking Statins may have a reduced risk of Hepatoma.
5 Pazopanib may be no inferior to Sutent as first line therapy in Metastatic renal cell cancer.
6. Axinitib failed to meet primary end point in Metastatic Renal cell cancer.
1. Adding Velcade may increase remission rates in AML.
This was suggested in a study at Massachusetts general Hospital.
2. CD25 was a new prognosis Biomarker in Adult B-ALL.
3. Ibrutinib in combination with Rituxan is effective in CLL
420 mg PO daily with weekly 375mg/m2 of Rituxan for 4 weeks
Rituxan was then continued monthly for 6 months
RR of 83% noted.
4. Preliminary suggestions that patients taking Statins may have a reduced risk of Hepatoma.
5 Pazopanib may be no inferior to Sutent as first line therapy in Metastatic renal cell cancer.
6. Axinitib failed to meet primary end point in Metastatic Renal cell cancer.
ETIRINOTECAN PEGOL WAS GRANTED FAST TRACK BY THE FDA FOR METASTATIC BREAST CANCER REFRACTORY TO TAXANE, ANTHRACYCLINES AND XELODA.
This is the same setting indicated for Ixabepilone (Ixempra) and other Microtubule disrupting agents.
E. Pegol has anti topoIsomerase I activity. reportedly designed using Nectar's polymer conjugate technology. Call BEACON III to enroll patients.
As a topo-Isomerase inhibitor, I wonder if Bcl-2 status of patients would be critical in interpreting results?
will see if Researcher are looking at this as way to establish refractoriness?
This is the same setting indicated for Ixabepilone (Ixempra) and other Microtubule disrupting agents.
E. Pegol has anti topoIsomerase I activity. reportedly designed using Nectar's polymer conjugate technology. Call BEACON III to enroll patients.
As a topo-Isomerase inhibitor, I wonder if Bcl-2 status of patients would be critical in interpreting results?
will see if Researcher are looking at this as way to establish refractoriness?
IS T-DM1 THE NEXT BIG THING IN HER-2 POSITIVE BREAST CANCER, METASTATIC SETTING.
A conjugate drug associating Trastuzumab and DM1, a chemotherapy reported to have 500 times the effect of Taxol, was able to swing 6 month benefit of SURVIVAL as compared to a combination of Lapatinib and Xeloda in women with Metastatic HER-2 positive breast cancer. Improving SURVIVAL is rarely achieved by most current recommended therapy. This position this drug to be the next big thing in breast cancer responding to this characteristic. The Oncology community is still waiting on the FDA to approve the drug last I checked. T-DM-1 is a large molecule and must be engulfed by the cell by Endocytosis increasing delivery of DM-1 intracellularly, people have suggested this is a "smart Bomb" and Genentech had requested to FAST-TRACK the drug. FDA did not comply, and some are filing petition to push this government institution to move forward! Until the FDA approves, the drug is not available to the public!
A conjugate drug associating Trastuzumab and DM1, a chemotherapy reported to have 500 times the effect of Taxol, was able to swing 6 month benefit of SURVIVAL as compared to a combination of Lapatinib and Xeloda in women with Metastatic HER-2 positive breast cancer. Improving SURVIVAL is rarely achieved by most current recommended therapy. This position this drug to be the next big thing in breast cancer responding to this characteristic. The Oncology community is still waiting on the FDA to approve the drug last I checked. T-DM-1 is a large molecule and must be engulfed by the cell by Endocytosis increasing delivery of DM-1 intracellularly, people have suggested this is a "smart Bomb" and Genentech had requested to FAST-TRACK the drug. FDA did not comply, and some are filing petition to push this government institution to move forward! Until the FDA approves, the drug is not available to the public!
Novel Cancer Hypothesis Suggests Antioxidants Are Harmful, from Medscape
Drug & Reference Information
A new hypothesis that focuses on reactive oxygen species (ROS) proposes that antioxidant levels within cancer cells are a
problem and are responsible for resistance to treatment.
The theory destroys any reason for taking antioxidative nutritional supplements, because they "more likely cause than prevent cancer," according to Nobel laureate James Watson, PhD, from Cold Spring Harbor Laboratory, New York.
Dr. Watson, who shared the Nobel prize for unraveling the structure of DNA, regards this theory as being "among my most important work since the double helix," notes a press release from his institution, where he has been director since 1968.
The theory was published online January 8 in Open Biology.
Dr. Watson explains that the vast majority of agents used to directly kill cancer cells, including ionizing radiation, most chemotherapeutic agents, and some targeted therapies, work by generating — either directly or indirectly — ROS that block key steps in the cell cycle.
This generation of ROS creates a hypoxic environment in which cancers cells undergo a transformation from epithelial to mesenchymal cells (EMT).
These transformed cells almost inevitably posses very high amounts of antioxidants, which effectively block the effects of anticancer treatments, Dr. Watson notes. Once a cancer becomes resistant to chemotherapy, it usually is equally resistant to ionizing radiation, he points out.
In addition, these transformed EMT cancer cells generate free-floating mesenchymal cells, which have the flexibility and movement that allows them to metastasize to other body locations (brain, liver, lung). "Only when they have moved do most cancers become life-threatening," Dr. Watson notes.
Interestingly, the widely used antidiabetic drug metformin has been shown to preferentially kill mesenchymal stem cells. "In a still much unappreciated article published 3 years ago," metformin added to chemotherapy "induced prolonged remission if not real cures" in mouse models of cancer ( Cancer Res. 2009;69:7507-7511), Dr. Watson writes. He notes that clinical trials are currently looking to see if adding metformin to chemotherapy provides clinical benefits, but adds that diabetics who have been using metformin regularly have a reduced incidence of many cancers.
Resistance to Therapy From Antioxidants in Cancer Cells
Dr. Watson proposes that anticancer therapies work by generating ROS, which cause apoptosis. However, as cancer cells evolve, they produce antioxidant proteins that block this effect, such as glutathione, superoxide dismutase, catalase, and thioredoxin.
The fact that cancer cells largely driven by RAS and Myc are among the most difficult of cancers to treat could be due to their high levels of ROS-destroying antioxidants, Dr. Watson argues. High antioxidative levels might also explain the effective incurability of pancreatic cancer, he adds.
If this theory is correct, then drugs that lower antioxidant levels within cancer cells would be therapeutic. In fact, the ROS-generating agent arsenic trioxide has been shown to reduce levels of glutathione and thioredoxin. Arsenic trioxide is currently being used to treat promyeloblastic leukemia, but this theory suggests that the drug could be useful in many major cancers.
Nutritional Antioxidants Could Be Harmful
One far-reaching implication of this theory is that antioxidants as nutritional supplements, including beta-carotene, vitamins A, C, and E, and selenium, could be harmful in cancer.
For years, such supplements have been widely hyped for cancer prevention and/or treatment, as has encouragement to eat colorful fruit and berries, which contain antioxidants.
The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.
However, Dr. Watson warns that recent data strongly hint
that much of the untreatability of late-stage cancer might be the
result of "its possession of too many antioxidants, [so] the
time has come to seriously ask whether antioxidant use more likely
causes than prevents cancer."
Many nutritional intervention trials have shown no obvious effectiveness in preventing gastrointestinal cancer or in lengthening mortality, he writes. "In fact, they seem to slightly shorten the lives of those who take them."
Hence, he concludes, "blueberries best be eaten because they taste good, not because their consumption will lead to less cancer."
Very Complex Process
Maurie Markman, MD, national director for medical oncology at the Cancer Treatment Centers of America, who writes the Medscape Markman on Oncology blog, was asked to comment on the theory.
"The importance of the critical relationship between oxidating activity and antioxidants in the normal functioning of cells has been recognized by many investigators, and it is not surprising that this process would be quite relevant in cancer. However, it must be emphasized that this is a very complex process and the balance between these powerful influences at the cellular level is certain to be very carefully controlled. Further, it should be noted that antioxidants are components of our normal diets. Finally, while a provocative concept, it is most unlikely that a simple approach to somehow removing antioxidants from the body will be a useful strategy in cancer management," he explained.
Open Biol. 2013;2:120144. Full text
The theory destroys any reason for taking antioxidative nutritional supplements, because they "more likely cause than prevent cancer," according to Nobel laureate James Watson, PhD, from Cold Spring Harbor Laboratory, New York.
Dr. Watson, who shared the Nobel prize for unraveling the structure of DNA, regards this theory as being "among my most important work since the double helix," notes a press release from his institution, where he has been director since 1968.
The theory was published online January 8 in Open Biology.
Dr. Watson explains that the vast majority of agents used to directly kill cancer cells, including ionizing radiation, most chemotherapeutic agents, and some targeted therapies, work by generating — either directly or indirectly — ROS that block key steps in the cell cycle.
This generation of ROS creates a hypoxic environment in which cancers cells undergo a transformation from epithelial to mesenchymal cells (EMT).
These transformed cells almost inevitably posses very high amounts of antioxidants, which effectively block the effects of anticancer treatments, Dr. Watson notes. Once a cancer becomes resistant to chemotherapy, it usually is equally resistant to ionizing radiation, he points out.
In addition, these transformed EMT cancer cells generate free-floating mesenchymal cells, which have the flexibility and movement that allows them to metastasize to other body locations (brain, liver, lung). "Only when they have moved do most cancers become life-threatening," Dr. Watson notes.
Interestingly, the widely used antidiabetic drug metformin has been shown to preferentially kill mesenchymal stem cells. "In a still much unappreciated article published 3 years ago," metformin added to chemotherapy "induced prolonged remission if not real cures" in mouse models of cancer ( Cancer Res. 2009;69:7507-7511), Dr. Watson writes. He notes that clinical trials are currently looking to see if adding metformin to chemotherapy provides clinical benefits, but adds that diabetics who have been using metformin regularly have a reduced incidence of many cancers.
Resistance to Therapy From Antioxidants in Cancer Cells
Dr. Watson proposes that anticancer therapies work by generating ROS, which cause apoptosis. However, as cancer cells evolve, they produce antioxidant proteins that block this effect, such as glutathione, superoxide dismutase, catalase, and thioredoxin.
The fact that cancer cells largely driven by RAS and Myc are among the most difficult of cancers to treat could be due to their high levels of ROS-destroying antioxidants, Dr. Watson argues. High antioxidative levels might also explain the effective incurability of pancreatic cancer, he adds.
If this theory is correct, then drugs that lower antioxidant levels within cancer cells would be therapeutic. In fact, the ROS-generating agent arsenic trioxide has been shown to reduce levels of glutathione and thioredoxin. Arsenic trioxide is currently being used to treat promyeloblastic leukemia, but this theory suggests that the drug could be useful in many major cancers.
Nutritional Antioxidants Could Be Harmful
One far-reaching implication of this theory is that antioxidants as nutritional supplements, including beta-carotene, vitamins A, C, and E, and selenium, could be harmful in cancer.
For years, such supplements have been widely hyped for cancer prevention and/or treatment, as has encouragement to eat colorful fruit and berries, which contain antioxidants.
Many nutritional intervention trials have shown no obvious effectiveness in preventing gastrointestinal cancer or in lengthening mortality, he writes. "In fact, they seem to slightly shorten the lives of those who take them."
Hence, he concludes, "blueberries best be eaten because they taste good, not because their consumption will lead to less cancer."
Very Complex Process
Maurie Markman, MD, national director for medical oncology at the Cancer Treatment Centers of America, who writes the Medscape Markman on Oncology blog, was asked to comment on the theory.
"The importance of the critical relationship between oxidating activity and antioxidants in the normal functioning of cells has been recognized by many investigators, and it is not surprising that this process would be quite relevant in cancer. However, it must be emphasized that this is a very complex process and the balance between these powerful influences at the cellular level is certain to be very carefully controlled. Further, it should be noted that antioxidants are components of our normal diets. Finally, while a provocative concept, it is most unlikely that a simple approach to somehow removing antioxidants from the body will be a useful strategy in cancer management," he explained.
Open Biol. 2013;2:120144. Full text
Friday, January 11, 2013
Salivary Gland Biopsy May Diagnose Parkinson's Disease
Editors' Recommendations
Drug & Reference Information
Salivary gland biopsy appears to be a diagnostic test for Parkinson's disease, a new study suggests.
A biopsy of the submandibular gland that shows the presence of the abnormal protein alpha-synuclein is highly indicative of Parkinson's, as distinct from other neurodegenerative disorders that can mimic the disease, said lead study author, Charles Adler, MD, PhD, from the Mayo Clinic Arizona, Scottsdale, Arizona.
"There is currently no diagnostic test for Parkinson's disease in living patients. The only way to make the diagnosis is at autopsy, when you can see an abnormal protein, alpha-synuclein, in certain brain regions," Dr. Adler, a fellow of the American Academy of Neurology, told Medscape Medical News.
Their preliminary findings were released January 10; full results will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego.
Densest Concentration
Dr. Adler and his team have been working on determining whether there is evidence of alpha-synuclein in other organs of the body so that they could develop a diagnostic test in living patients.
"We previously published the fact that the submandibular
gland has one of the densest concentrations of alpha-synuclein in
an organ outside the brain. When we tested this in an
autopsy study of 28 Parkinson's disease patients, we found that all
28 of them had alpha-synuclein in the submandibular gland,"
he said.
The discovery led the researchers to biopsy the submandibular gland in living patients with Parkinson's disease to see whether this protein was present. If it was, then the biopsy could potentially be used as a diagnostic test, they reasoned.
The current study involved 11 patients, average age, 67.8 years (range, 61 to 76 years), with a mean duration of Parkinson's disease of 10.4 years (range, 6 to 14 years). All patients were responsive to dopaminergic medication and did not have dementia or any known salivary gland disorders.
The researchers used local anesthesia to perform core needle biopsies of 1 submandibular gland percutaneously using 18- or 16-gauge needles. They extracted up to 5 needle samples 240 to 535 μm thick, as well as samples from 2 to 5 minor salivary glands. The biopsies necessitated 1 to 3 stitches.
The patients tolerated the biopsies very well, Dr. Adler said. Three patients had 1 adverse event each, including a swollen cheek, a sore throat, and excess fluid that was expelled from the needle biopsy site after a sneeze.
Nine of the 11 patients showed evidence of alpha-synuclein in their salivary gland biopsy specimens.
"This really was a feasibility study, and it was important to do this in people who we felt had a higher certainty of having Parkinson's disease. They had symptoms for a long time and they were responsive to medication," Dr. Adler said.
Next Steps
The next step is to perform biopsy in patients who have had Parkinson's disease symptoms for a shorter duration.
"In people with more recent onset of disease, the accuracy of our clinical diagnosis is not as high. A lot of people who look like they have Parkinson's disease early on really don't have it, so we'd like to see if this biopsy test would be able to prove the presence of PD in earlier-onset, shorter-duration patients," he said.
Making a more accurate diagnosis in living individuals may improve the outcome of clinical trials, as well as the outcome of invasive procedures that are currently done for people with Parkinson's disease, he added.
"Doing the biopsy and finding the abnormal protein would tell us that we are in fact treating Parkinson's disease because before, we wouldn't be quite sure. There are a number of different studies, including data from our own which we haven't published yet, showing that the accuracy of the clinical diagnosis ranges anywhere from about 50% when somebody first presents with what looks like Parkinson's disease, up to about 80 to 90% for somebody who has had the disease for 5 or 10 years," Dr. Adler said.
"So, even at 10 years, accuracy is still not 100% for what we see clinically because there are many different neurodegenerative diseases that look like Parkinson's disease."
This study was funded by the Michael J. Fox Foundation for Parkinson's Research. Dr. Adler has disclosed no relevant financial relationships.
American Academy of Neurology 65th Annual Meeting. Abstract 1777. Released January 10, 2013.
A biopsy of the submandibular gland that shows the presence of the abnormal protein alpha-synuclein is highly indicative of Parkinson's, as distinct from other neurodegenerative disorders that can mimic the disease, said lead study author, Charles Adler, MD, PhD, from the Mayo Clinic Arizona, Scottsdale, Arizona.
"There is currently no diagnostic test for Parkinson's disease in living patients. The only way to make the diagnosis is at autopsy, when you can see an abnormal protein, alpha-synuclein, in certain brain regions," Dr. Adler, a fellow of the American Academy of Neurology, told Medscape Medical News.
Their preliminary findings were released January 10; full results will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego.
Densest Concentration
Dr. Adler and his team have been working on determining whether there is evidence of alpha-synuclein in other organs of the body so that they could develop a diagnostic test in living patients.
|
Dr. Charles Adler
|
The discovery led the researchers to biopsy the submandibular gland in living patients with Parkinson's disease to see whether this protein was present. If it was, then the biopsy could potentially be used as a diagnostic test, they reasoned.
The current study involved 11 patients, average age, 67.8 years (range, 61 to 76 years), with a mean duration of Parkinson's disease of 10.4 years (range, 6 to 14 years). All patients were responsive to dopaminergic medication and did not have dementia or any known salivary gland disorders.
The researchers used local anesthesia to perform core needle biopsies of 1 submandibular gland percutaneously using 18- or 16-gauge needles. They extracted up to 5 needle samples 240 to 535 μm thick, as well as samples from 2 to 5 minor salivary glands. The biopsies necessitated 1 to 3 stitches.
The patients tolerated the biopsies very well, Dr. Adler said. Three patients had 1 adverse event each, including a swollen cheek, a sore throat, and excess fluid that was expelled from the needle biopsy site after a sneeze.
Nine of the 11 patients showed evidence of alpha-synuclein in their salivary gland biopsy specimens.
"This really was a feasibility study, and it was important to do this in people who we felt had a higher certainty of having Parkinson's disease. They had symptoms for a long time and they were responsive to medication," Dr. Adler said.
Next Steps
The next step is to perform biopsy in patients who have had Parkinson's disease symptoms for a shorter duration.
"In people with more recent onset of disease, the accuracy of our clinical diagnosis is not as high. A lot of people who look like they have Parkinson's disease early on really don't have it, so we'd like to see if this biopsy test would be able to prove the presence of PD in earlier-onset, shorter-duration patients," he said.
Making a more accurate diagnosis in living individuals may improve the outcome of clinical trials, as well as the outcome of invasive procedures that are currently done for people with Parkinson's disease, he added.
"Doing the biopsy and finding the abnormal protein would tell us that we are in fact treating Parkinson's disease because before, we wouldn't be quite sure. There are a number of different studies, including data from our own which we haven't published yet, showing that the accuracy of the clinical diagnosis ranges anywhere from about 50% when somebody first presents with what looks like Parkinson's disease, up to about 80 to 90% for somebody who has had the disease for 5 or 10 years," Dr. Adler said.
"So, even at 10 years, accuracy is still not 100% for what we see clinically because there are many different neurodegenerative diseases that look like Parkinson's disease."
This study was funded by the Michael J. Fox Foundation for Parkinson's Research. Dr. Adler has disclosed no relevant financial relationships.
American Academy of Neurology 65th Annual Meeting. Abstract 1777. Released January 10, 2013.
==================================================================
Interesting! from Medscape!
Interesting! from Medscape!
INTERFERON AND AFINITOR, A POTENTIAL COMBINATION FOR TRIPPLE NEGATIVE BREAST CANCER.
In a recent report about the genome of triple Negative Breast Cancer, researchers reported that there are 3 genes discovered at greater the 10% in this disease. One of which was STAT1. In a discussion with Reporters, DR Baumback-Reardon reported "one of the genes down regulated in the Kenyan tumors (with triple negative Breast cancers), STAT1 , is especially noteworthy in that it is has tumor suppression and immune regulating activity". Interferon has these 2 abilities combined just perfectly.
The Mammallian Target of Rapamycin (mTor) which affect Mitochondrial function are known to affect STAT1. It would be of Interest to see if this combination of Interferon alpha would be useful to stop Breast Cancer of triple negative nature in its track.
Adding Afinitor to exametestane has already proven a rescue option in patient AI refractory disease
but science is pushing us to believe Afinitor has a long way helping in other areas!
IS STAT1 EXPRESSION A DRIVER GENOME VARIABLE IN TRIPLE NEGATIVE BREAST CANCER?
IT IS ALSO KNOWN THAT MTOR INHIBITOR HAVE ACTIVITY IN BRAC-1 CELL TUMORS WHICH IS 85% OF TRIPLE NEGATIVE BREAST CANCER IN SOME REPORTS
In a recent report about the genome of triple Negative Breast Cancer, researchers reported that there are 3 genes discovered at greater the 10% in this disease. One of which was STAT1. In a discussion with Reporters, DR Baumback-Reardon reported "one of the genes down regulated in the Kenyan tumors (with triple negative Breast cancers), STAT1 , is especially noteworthy in that it is has tumor suppression and immune regulating activity". Interferon has these 2 abilities combined just perfectly.
The Mammallian Target of Rapamycin (mTor) which affect Mitochondrial function are known to affect STAT1. It would be of Interest to see if this combination of Interferon alpha would be useful to stop Breast Cancer of triple negative nature in its track.
Adding Afinitor to exametestane has already proven a rescue option in patient AI refractory disease
but science is pushing us to believe Afinitor has a long way helping in other areas!
IS STAT1 EXPRESSION A DRIVER GENOME VARIABLE IN TRIPLE NEGATIVE BREAST CANCER?
IT IS ALSO KNOWN THAT MTOR INHIBITOR HAVE ACTIVITY IN BRAC-1 CELL TUMORS WHICH IS 85% OF TRIPLE NEGATIVE BREAST CANCER IN SOME REPORTS
FDA APPROVES MANY DRUGS
1.CABOZANTINIB, A AMULTIKINASE INHIBITOR,
with action on RET, VEGFR2, RET,
It gave a Progression free survival of 11months Vs 4 months for placebo
Indication: Metastatic Medullary Thyroid cancer
the study was not powered to show survival benefit.
THIS THE SAME DRUG WHICH OF INTEREST IN OVARIAN CANCER (AFLIBERCEPT,ANOTHER DRUG OF INTEREST, HAS BEEN COMBINED TO TAXOTERE IN THIS DISEASE )
2.Earlier Use of Abiraterone approved
in April 2011, this drug was approved fur use after failure of Taxotere and prednisone
(continue Prednisone while on Abiraterone)
Now the drug can be used before Docetaxel.
side effect include fatigue joint pain and swelling, hot flush, diarrhea, vomiting high blood pressure cough bruising and Urinary tract infection.
3.Other news
Treatment Sequencing in Metastatic prostate cancer
1. Local therapy for early disease (Radiation Vs Surgery)
2. Androgen Deprivation +/- RT (with pelvic disease)
3. consider Sipuleucel-T, an autologous cellular immunotherapy for treatement of asymptomatic or minimally symptomatic metastatic disease (3 doses Q2weeks)
4. or go to Abiraterone (Apharadin, Enzalutamide)
5. Docetaxel and prednisone
6. Cabazitaxel
with bone involvement demonstrated Zometa or Denosumab indicated.
4. OTHER NEWS.
clinical importance
Circulating Breast cancer cells of <5 cells by 7.5 cc of blood Vs >5 cells, progression free survival
21,9 months Vs 10.9 months. CTC (circulating tumor cells) is held by some as the best predictor of recurrence.
This technology is being pushed in Melanoma, here surrogate for cell counts are MART-1, MAGE-A3 and GalNAC-T. At 57 months follow-up, 15 of 32 patients with 2 or more markers at diagnosis had recurrent disease! That is 47%.
From Oncology/Biotech News.
1.CABOZANTINIB, A AMULTIKINASE INHIBITOR,
with action on RET, VEGFR2, RET,
It gave a Progression free survival of 11months Vs 4 months for placebo
Indication: Metastatic Medullary Thyroid cancer
the study was not powered to show survival benefit.
THIS THE SAME DRUG WHICH OF INTEREST IN OVARIAN CANCER (AFLIBERCEPT,ANOTHER DRUG OF INTEREST, HAS BEEN COMBINED TO TAXOTERE IN THIS DISEASE )
2.Earlier Use of Abiraterone approved
in April 2011, this drug was approved fur use after failure of Taxotere and prednisone
(continue Prednisone while on Abiraterone)
Now the drug can be used before Docetaxel.
side effect include fatigue joint pain and swelling, hot flush, diarrhea, vomiting high blood pressure cough bruising and Urinary tract infection.
3.Other news
Treatment Sequencing in Metastatic prostate cancer
1. Local therapy for early disease (Radiation Vs Surgery)
2. Androgen Deprivation +/- RT (with pelvic disease)
3. consider Sipuleucel-T, an autologous cellular immunotherapy for treatement of asymptomatic or minimally symptomatic metastatic disease (3 doses Q2weeks)
4. or go to Abiraterone (Apharadin, Enzalutamide)
5. Docetaxel and prednisone
6. Cabazitaxel
with bone involvement demonstrated Zometa or Denosumab indicated.
4. OTHER NEWS.
clinical importance
Circulating Breast cancer cells of <5 cells by 7.5 cc of blood Vs >5 cells, progression free survival
21,9 months Vs 10.9 months. CTC (circulating tumor cells) is held by some as the best predictor of recurrence.
This technology is being pushed in Melanoma, here surrogate for cell counts are MART-1, MAGE-A3 and GalNAC-T. At 57 months follow-up, 15 of 32 patients with 2 or more markers at diagnosis had recurrent disease! That is 47%.
From Oncology/Biotech News.
Thursday, January 10, 2013
"NEVER MIND DRUG RESISTANCE" IN CLINICAL ONCOLOGY.
As we are advancing toward the cure, one of the thing that should change is our general attitude in Oncology clinical practice and clinic trial build up, is to stop dismissing drug resistance as an important component or criteria to include in our drug selection. With that dismissal comes however a significant effect on outcome.
It is known that addressing mechanisms of resistance to drug improves outcome. This is entering now clinical practice when it comes down to use of Tamoxifen and related pathway modulators, and the P450 Isoforms CYP2.
In each individual cancer patient there Resistance mechanism due to the host, and those due strictly to the cancer cells. The complexity of this resistance lead to its dismissal. We kind of walk away from this hoping it is not coming to haunt us! Unfortunately it does.
Variable Host factors include rate of absorption of the intended drug, rapid metabolism, excretion, poor tolerance and ability to deliver at the site of the intended action.
Variable Cancer cellular Factors include blood vessel variations, loss of surface receptors or transporters, presence of MDR (multiple drug resistance factor), gene heterogeneity/heterozygosity , and ability to compartmentalize the drug once absorbed by simple diffusion, active transport or Endocytosis.
There are Variable factors inherent to the drug itself, its molecular size (immunotoxin requires Endocytosis), liposolubility and hydrosolubility.
The worse of the resistance mechanism is of course the MDR that we try very much to forget. Yet we know something about it. We know it works with ATP interaction, we know it is a Technetium Sestamibi substrate and can be visualized radiologically, we know there are various kinds. Some kinds can only handle neutral electrically charged molecules, some more effective in neutralizing cationic or anionic molecules. And of course we know what drug behave electrically opposite to the MDR tendency. Suffice is to say that knowing more about the mechanism of resistance we face in individual cancer provide an opportunity to increase outcome. The future will require this level of discernment.
As we are advancing toward the cure, one of the thing that should change is our general attitude in Oncology clinical practice and clinic trial build up, is to stop dismissing drug resistance as an important component or criteria to include in our drug selection. With that dismissal comes however a significant effect on outcome.
It is known that addressing mechanisms of resistance to drug improves outcome. This is entering now clinical practice when it comes down to use of Tamoxifen and related pathway modulators, and the P450 Isoforms CYP2.
In each individual cancer patient there Resistance mechanism due to the host, and those due strictly to the cancer cells. The complexity of this resistance lead to its dismissal. We kind of walk away from this hoping it is not coming to haunt us! Unfortunately it does.
Variable Host factors include rate of absorption of the intended drug, rapid metabolism, excretion, poor tolerance and ability to deliver at the site of the intended action.
Variable Cancer cellular Factors include blood vessel variations, loss of surface receptors or transporters, presence of MDR (multiple drug resistance factor), gene heterogeneity/heterozygosity , and ability to compartmentalize the drug once absorbed by simple diffusion, active transport or Endocytosis.
There are Variable factors inherent to the drug itself, its molecular size (immunotoxin requires Endocytosis), liposolubility and hydrosolubility.
The worse of the resistance mechanism is of course the MDR that we try very much to forget. Yet we know something about it. We know it works with ATP interaction, we know it is a Technetium Sestamibi substrate and can be visualized radiologically, we know there are various kinds. Some kinds can only handle neutral electrically charged molecules, some more effective in neutralizing cationic or anionic molecules. And of course we know what drug behave electrically opposite to the MDR tendency. Suffice is to say that knowing more about the mechanism of resistance we face in individual cancer provide an opportunity to increase outcome. The future will require this level of discernment.
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