Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Essential Value of the International Committee of Medical Journal Editors (ICMJE)

Catherine D. DeAngelis, MD, University Distinguished Professor Emerita, Johns Hopkins University School of Medicine; Professor of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health; Editor in Chief Emerita, JAMA

Q: The internet has produced mass democratization of information provision and access with little quality control. You represented JAMA at the International Committee of Medical Journal Editors (ICMJE) for over 10 years. How important is the ICMJE in protecting quality and ethics?
A: Since 1978, when a group of high impact medical journal editors representing several countries first met, the ICMJE has played a major role in setting standards for the ethics, preparation, and formatting of biomedical manuscripts. The current membership consists of thirteen medical journal editors and representatives of selected related organizations including the National Library of Science and the World Association of Medical Editors (WAME). These individuals work together to improve the quality of medical science and the reporting of such science.
The ICMJE publishes recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals. These guidelines, primarily for authors, reviewers and editors, are available on line for anyone. ICMJE developed these recommendations to review best practices and ethical standards for the conduct and reporting of research and other material published in medical journals. The recommendations also help authors, editors, and others involved in peer review and biomedical publishing create and distribute accurate, clear, reproducible, and unbiased medical journal articles. These guidelines have also provided useful insights into the medical editing and publishing process for the media, patients and their families, and general readers.
One example of the important role the ICMJE has played in helping to assure the ethical publication of sound research occurred in September 2004 when the editors published a joint editorial regarding the registration of randomized clinical trials. At that time the law in the United States required that all clinical trials be registered in as soon as the first patient was enrolled. Very few such trials were registered because no one enforced the law. This put editors in a quandary because they had no idea if the submission of a manuscript that described a trial accounted for other trials using the same intervention (often a drug or medical device). In addition, editors looking at a manuscript’s trial did not know the results of those other trials or if the other trials were performed in different populations.
The joint editorial by the ICMJE editors announced that they would not publish any unregistered trials. This essentially meant that they also would not even review such manuscripts. The editors gave investigators a year to enroll the ongoing trials, but after September 2005 no unregistered trial would be published. This caused a great kerfuffle especially among the pharmaceutical and medical device manufacturers. However, the ICMJE prevailed and since September 2005 essentially all published clinical trials have been registered.
The numerous journals that follow the ICMJE recommendations are listed online and allow authors, reviewers, the media and others to know if the journal to which they plan to submit a manuscript or to review a publication follows the ethical and scientific guidelines.
The ICMJE has no legal jurisdiction. However, the respect shown for its leadership and the influence it has had on medical journalism for the past thirty-eight years cannot be questioned. The importance of having guidelines to assure honest reporting is more important than ever with the expanding use of online and print, non peer-reviewed publications by foundations and other institutions.
Hopefully the influence of the ICMJE will continue for as long as medical publications in any form exist.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Making Cancer Care Great Again

Michael L. Millenson, President of Health Quality Advisors LLC and an Adjunct Associate Professor of Medicine at Northwestern’s Feinberg School of Medicine

Q: Donald Trump’s campaign for the presidency included a promise to repeal “Obamacare” in its entirety. If he succeeds in fulfilling that promise, what impact can we expect on American cancer prevention and cancer treatment?

A: Donald Trump, emboldened by eliminating ISIS, ending illegal immigration and energizing the economy, will eradicate cancer. Or at the very least, I predict, he will append it to his list of promised achievements as president.
Our current chief executive, dubbed “No Drama Obama” by his staff during the 2008 campaign, couldn’t resist the heady promise of a cancer “moonshot.” Trump, who’s declared, “I will take care of ISIS,” “close up those borders” and “jump-start America,” will likely rev up the rhetoric back to Nixonian “War on Cancer” levels.
A candidate whose campaign centered on his personal pledge to “make America great again” will surely be galvanized by the chance to make cancer care “great,” too.
The current Cancer Moonshot initiative, featured in President Barack Obama’s last State of the Union Address, is codified in a presidential memorandum of Jan. 28, 2016 and placed within the Office of the Vice President. While fighting cancer was of deep personal interest to Vice President Joe Biden, Vice President-elect Mike Pence was governor of Indiana, where pharmaceutical giant Eli Lilly has a major portfolio of oncology products. Coincidentally, Lilly in October introduced a new version of its PACE Continuous Innovation Indicator (CII), a customizable, online tool to review progress against cancer in order to inform public policy and accelerate innovation.
The current executive director of the Cancer Moonshot initiative, Greg Simon, was an aide to former Vice President Al Gore. But Simon is also a cancer survivor and entrepreneur who once worked for New York City-based Pfizer. He came to his current post from FasterCures, a foundation whose work has strong support among Congressional Republicans.
Whether enthusiasm for anti-cancer combat entails increased funding remains to be seen. However, a Trump administration may downplay cancer prevention. Recent research among a population of mostly white Americans aged 25 to 79 found that lifestyle changes related to smoking, drinking, diet and physical activity can reduce the risk of dying from cancer by 14 to 61 percent. Given the central role played in Trump’s electoral triumph by a working class population more prone to those behaviors, I wouldn’t expect a lot of new government nagging.
And while the Centers for Disease Control and Prevention has recommended that pre-teens be vaccinated against the HPV virus, linked to a series of cancers transmitted through sexual activity, I wouldn’t expect this to be an area where President Trump speaks out publicly, either.
Some current cancer patients are reportedly “frantic and scared” that Trump’s vow to ax Obamacare (a/k/a the Affordable Care Act) will sweep away its ban on lifetime dollar limits on coverage and its protection against denying coverage to those with pre-existing conditions. Trump has said he plans to keep both those prohibitions, but those who are sick remain worried. If the provisions are repealed, said a 32-year-old mom with breast cancer, “I can’t afford treatment and I die.”
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Control American Drug Costs

Brian Klepper PhD, Health Care Analyst, CEO of Health Value Direct and an advisor to The Lundberg Institute

Q: Many newer (as well as many older) drugs are of great value in treating many diseases. But the prices charged seem very high and rising, causing serious concern for many. Is there anything the United States can do to control these costs?

A: We can do a lot to control drug costs, but success will take the cooperation of Congress and the legislatures, which are fundamentally in the drug industry’s pocket.
The industry lavishes money on Congress to buy that favor. Open Secrets data show that the pharmaceutical/health products sector, the most politically influential industry, gave Congress $3.3 billion in campaign contributions between 1997-2015. That largess averages out to $183 million annually over that 18-year period, or a stunning $343,000 per legislator per year. Within these dynamics, every relevant law and rule is spun to favor the interests of the drug industry over those of the American people.
In an excellent recent JAMA article on the sources of US drug pricing, Kesselheim et al. point out that influence over policy has translated into two core problems: “granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits.”
Consider Congress’ prohibition against Medicare negotiating drug prices. Millions of patients’ medications are subsidized by Medicare, which pays whatever price is demanded. It’s hard to imagine a better deal than the purchaser allowing the manufacturer to set any price, with the guarantee that the bill will be paid.
These dynamics translate to harsh realities. Federal programs are required to cover most products – including those with sub-optimal performance – priced at whatever the market will bear. To a large degree, the commercial health plan sector follows suit. No rational market rules guide the way we currently buy drugs. We don’t require pricing to be tethered to what’s paid in other industrialized, international markets, or tied to the value delivered in care avoided or Quality-Adjusted Life Years gained.
For perspective, consider a 2015 JAMA Int Med study showing that between 2008-2012, 86 percent of the drugs approved with surrogate endpoints and 57 percent of cancer drugs approved by the FDA “have unknown effects on overall survival or fail to show gains in survival.” In other words, the authors write, “most cancer drug approvals have not been shown to, or do not, improve clinically relevant end points.” Realizations like this make clear the need to identify the measurable improvements that existing or new drugs represent. That would provide a rational way to value and price a drug.
Recently efforts have been afoot to tie pricing or purchasing decisions to known value. For example:

  • The American Society of Clinical Oncology recently unveiled its drug value framework, which evaluates new cancer therapies based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost.
  • The Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center is also focused on the price and value of drugs, under the belief that more rational pricing could increase patient access to important medications while driving innovation.
  • The Institute for Clinical and Economic Review (ICER) independently assesses the value of new drugs, guided by four questions:
    1. How well does the drug work?
    2. How much better is it than what we already have?
    3. How much could it save us?
    4. How much would it cost to treat everyone who needs it?

In other words, methodologies to achieve value-based drug pricing are well within reach, but the industry will resist with all its power and influence. Secretary Clinton is focused on this area, and believes that leadership can mobilize the agents of reform to make meaningful change achievable. That is what it will take.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Expanded-Compassionate Use of an Investigational Drug

Vivek Subbiah, MD, Assistant Professor, Department of Investigational Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Q: You have exhausted surgical, radiation, and standard chemotherapy options for a patient with an advanced epithelial malignancy. Yet the patient has a strong will to live and to advance science during palliative care.  No active clinical trial is available. How would you evaluate pre-clinical data to try to identify an investigational drug for “expanded-compassionate” use?

A: Thank you for the question. This is a challenging situation. It is subjective and complex.
My answer – “it depends”. Let me give you 2 scenarios.
Scenario A: A 30-year-old surgeon, recently married with the love of his life who has just graduated from a neurosurgery residency, is expecting his first child and diagnosed with Stage IV non-small cell lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. Has a strong will to live.
Scenario B: An 85-year-old man, who has a wife in the nursing home and a son in California and another son in Australia has been diagnosed with Stage IV non-small lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. He lives alone and has a declining PS with multiple co-morbid conditions.
In the first case, yes, as an experimental investigator I would go to any lengths to try to provide investigational drug for expanded-compassionate use.
In the second case, I would likely arrange a family meeting to discuss the reality and lean towards providing best supportive palliative care.
Breakthroughs in oncology or any other field infers that successful outcome in the face of what was considered impossible. We all live in the future. If we do not take risky experiments, breakthroughs cannot be made. It could be argued that there is a 1 in 100 chance that the investigational agent for expanded compassionate use works. I would say that the chance is ONE and not zero. For his mother, father, wife and future child it is HOPE. It is with this hope that we live in.
How do I evaluate the pre-clinical and/ or clinical data for justifying compassionate use?
I refer you to the webpage of Personalized Cancer Therapy at MD Anderson. Here there are quite a few resources to define actionability of a gene. I am highlighting the main aspects from that site as below:
Actionable Gene: A gene is deemed actionable if 1) there are clinically available drugs that directly or indirectly target tumors with genomic alterations in the gene of interest with minimally preclinical evidence of their use in tumors with alterations in the gene of interest, and/or 2) there are clinical trials specifically selecting for patients with tumors harboring genomic alterations in the gene of interest.
Actionable Variant: A variant is deemed actionable if all of the following criteria are met: 1) the variant occurs in a gene deemed actionable, 2) the alteration type (mutations, amplification, etc) for that gene is deemed actionable, and 3) there is either published literature or data from the MD Anderson Zayed al Nahyan Institute for Personalized Cancer Therapy (IPCT) functional genomics platform that the alteration is likely to be tumor promoting (e.g. activating mutation in an oncogene or inactivating mutation in a tumor suppressor), or there is evidence that the variant confers sensitivity or resistance to a clinically available therapy.

Table 1
Precision oncology decision support level of evidence classification: level of evidence for drug effectiveness in a specific tumor type harboring a specific biomarker*

Level 1
1A | Drug is FDA-approved for the same tumor type harboring a specific biomarker.
1B | An adequately powered, prospective study with biomarker selection/stratification, or a meta-analysis/overview demonstrates a biomarker, predicts tumor response to a drug or that the drug is clinically effective in a biomarker-selected cohort in the same tumor type.
Level 2
2A | Large-scale study demonstrates a biomarker is associated with tumor response to the drug in the same tumor type. This could be a prospective trial where biomarker study is the secondary objective or an adequately powered retrospective cohort study or a case-control study.
2B | Clinical data that the biomarker predicts tumor response to drug in a different tumor type.
Level 3
3A | Single or few unusual responder(s), or case studies, show a biomarker is associated with response to drug, supported by scientific rationale.
3B | Preclinical data (in vitro or in vivo models or functional genomics) demonstrates that a biomarker predicts response of cells to drug treatment.
Bottomline, is that clinical studies provide highest level of evidence and pre-clinical studies lowest level of evidence (but at least provide some evidence for hope in the face of nothing).
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The “Hutch” and Improving Baseball: World Series Edition

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center, and Professor of Medicine at the University of Washington School of Medicine, Seattle, Washington.

Q: You are known to be good at clever solutions to daunting problems, and a baseball fan to boot. What should we do about the conflicted designated hitter (DH)?
A: The last six months have been contentious across our land, with anger and hostility replacing civility and tolerance. Families and friends are pitted against each other. Religions and cultures are torn apart.
Can we save our nation from the additional conflict at World Series time, the designator hitter (DH) divide?
As the World Series is upon us, the wound will continue to fester.
Here is a solution that will both satisfy baseball “purists” (National League) and “progressives.” There are four easy steps.

  1. Make the DH available and optional for all games, all season long, in both leagues.
  2. Before each game, a designated specific team decides whether or not the DH will be used in that game.
  3. Which team gets to choose will always be the same, but is based on an anticipated upcoming decision by Major League Baseball (MLB). If MLB wants to soften home field advantage, then the visitor always picks. If MLB wants to strengthen home field advantage (and thus, shorten more games by 1/2 inning), then the home team always gets to pick.
  4. Major league rosters are allowed to grow from 25-26 to accommodate this change.

This change makes the use of the DH part of the everyday lineup strategy. If I’m the manager that gets to pick, if your DH is better than mine (think David Ortiz), then no DH for your team. If my team’s pitcher that day can hit (think Bumgarner) and yours can’t, no DH. If my team’s pitcher can’t hit or run (think Colon), then DH it is. This revised rule also can take into account lefty/righter pitcher/hitter match ups. And think about the Sabermetrics field-they will go into a frenzy developing the best algorithms for deciding the yea/nay DH decision.
Four simple steps, and our (at least this part of) country is healed.
Still curious?
Fred Hutchinson (Hutch) was a great (perhaps Seattle’s greatest ever) baseball player and major league manager. A chain smoker, he died of metastatic lung cancer at age 45. His brother, a surgeon, initiated the Fred Hutchinson Cancer Research Center (aka the Hutch) in his honor. The starting pitcher for the Chicago Cubs in the 2016 World Series is Jon Lester, a cancer survivor (since 2006), successfully treated at “the Hutch”.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Decide to Offer a New Lab Test

Jared N. Schwartz, MD PhD LLC Past President, College of American Pathologists; Opinions his own; Charlotte, NC.

Q: Pathologists are faced with the need to set up additional lab tests routinely. Immunotherapy for cancer is the current rage. How does a pathologist decide whether and how to offer a new test such as PD-L1 Expression Testing?
A: The decision to introduce a new test or remove an old test is not as easy as one would think. There are many variables that must be taken into consideration. Concerning your question i.e. when to introduce a “new” test that may be used to direct therapy in a patient with cancer is an especially important task for the pathologist.
In my own experience using your example the subject would probably arise at a tumor board or multidisciplinary conference. This is setting where pathologists, oncologists, radiologists, surgeons and other medical specialists discuss possible or already identified cancer patients for input and recommendations on evaluation, more specific diagnostic information, treatment options and follow-up plans.
Today with the rapidly expanding complexities resulting from the introduction and availability of new biomarkers be they genomic, proteomic etc. that aid in diagnostic, prognostic and/or therapeutic decisions the burden of proof to introduce a test into your lab is very high. The more so if the “claims” being made are the specific biomarker results which are important and maybe critical in enhancing patient outcomes. The point is that the initial but critical decision of whether a new test should be available and introduced into your lab will be a team effort with input from users of test (the utility) and those responsible for ensuring the test can in fact be performed accurately in your specific lab environment (your validation).
The FDA has already approved PD-LD1. Its value is backed up by numerous clinical studies published in peer-reviewed journals, suggesting that “at this time” having the test results for PD-L1 are important for the treating physician to have in a timely manner.
Now the question is do you send the test request out to another laboratory or introduce it into your own? There are many questions to be answered by lab director in order to make that determination. A short example list of important questions below in no specific order:
What would the number of requests for PD-L1 be in your lab?
Are these numbers high enough to ensure on-going experience in performing test?
Does your lab have skilled staff that can be trained to perform test?
Do you have the resources to ensure your staff have the time to introduce, validate and ensure ongoing quality control of the test?
What will be the costs to provide the test in-house or sent to outside lab?
What is turn-around-time expected from your ordering physicians?
Do you have ability to meet their expectations?
If volume is questionable can an outside lab meet the turn-around time expectations?
What process would you use to select an outside testing lab?
If you decide to perform test what method would you select?
What process would you use to validate, maintain quality control and select appropriate ongoing proficiency and competency testing as per CLIA?
The answers to these questions and others depending on your clinical setting would help you and your colleagues determine if the test for PD-L1 should be performed in-house or sent to another laboratory.
Important to remember: this decision needs to be revisited depending on changes to the answers to above questions occurring over time.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Preventing Hair Loss from Cancer Chemotherapy

Richard B. Schwab, MD. Associate Clinical Professor of Medicine, Moores Cancer Center, University of California, San Diego, School of Medicine

Q: Loss of hair is a predictable adverse effect of much chemotherapy. Although “only cosmetic” this can be a troubling event for some patients. What is your opinion about the new devices or methods available to diminish chemotherapy-induced alopecia?
A: Scalp cooling to reduce chemotherapy-induced alopecia has been available for many years. This approach is effective for taxane-based chemotherapy regimens and, in my experience, can have benefit even with anthracycline-based regimens. There is good safety data for acute toxicity (for example frostbite hasn’t been an issue) but there is no good data on how exclusion of chemotherapy from the scalp might affect the risk of recurrence in this area of the body. Fortunately scalp recurrences are extremely rare, which is the major reason why data on scalp recurrence risk with cooling is not likely to ever be available. Regardless, I always educate my patients about this hypothetical risk. Given that the benefit of adjuvant chemotherapy for some breast cancer patients can be modest, this approach to reduce toxicity is quite reasonable.
In the past Penguin Cold Caps were used by some of my patients, under their own arrangements. This approach is quite burdensome requiring patients to bring in caps on dry ice and have an assistant with them to exchange these caps frequently during the infusion, and for some hours after as well. The total duration of recommended use varies with chemotherapy regimen but is about 5-6 hours per treatment. More recently Dignitana has obtained FDA approval for their system. The advantage of their system is that cap exchanges are not needed. A disadvantage is that centers offering this system need to lease a machine and thereby become involved in the business of scalp cooling. Given that insurance rarely reimburses any costs associated with the treatment of chemotherapy-induced alopecia this is a significant issue. Patients can expect to pay approximate $500 per treatment so a typical course of chemotherapy, with 4 treatments, scalp cooling will cost an additional $2000.
Now centers must consider how to handle scalp cooling. If a center leases a Dignitana system there will be a financial incentive for utilization. Additionally centers will need to consider how to handle this for patients that cannot afford the added cost. Is reduction of hair loss a good use of limited charity resources? Additionally logistical issues could develop. Each system can only accommodate 2 users at a time so patients using this system will face additional scheduling limitations. Is waiting to start chemotherapy at a time when scalp cooling is available acceptable or will additional systems need to be leased to prevent delays in therapy?
Obviously numerous additional questions will arise if scalp cooling becomes more popular. For now, it seems to me that this is a good thing for our patients. Fortunately cure rates for breast cancer patients are relatively high and are rising. This gives us the luxury to focus more and more on reducing the toxicity of breast cancer treatment. Scalp cooling is undoubtedly an effective way to reduce one of the most troubling toxicities of chemotherapy for our patients.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Mutational Oncology: The Basics

Vivian B. Douglas, PhD. Associate Knowledge Engineer, CollabRx San Francisco, California

Q: Many mature clinicians find “Mutational Oncology” to be a bit mysterious. Please help them understand. As they pertain to cancer, what are somatic (as opposed to germ line) mutations, transitions, transversions, “point”, “missense”, “nonsense”, insertion, deletion, and copy numbers and why does it matter?
A: With the plethora of molecular alterations that commonly occur in cancer, it can be confusing to understand what causes them and how these alterations affect the proteins that these genes encode. To begin, in cancer a somatic alteration refers to a non-inherited molecular alteration, which can occur spontaneously during replication or may be due to DNA damage or mistakes during DNA damage repair, and is only detectable in the tumor. These mutations are not passed to offspring. In contrast, a germ line mutation is heritable and detectable in nearly all tissues.
Many types of alterations occur in cancer. For example, a point mutation is the modification of a single base in a DNA coding sequence. A point mutation may be a transversion (replacement of a purine base with a pyrimidine and vice versa) or more commonly, a transition (replacement of a purine with a purine or pyrimidine with a pyrimidine). These single-base modifications can have several different effects. One common type of mutation is a missense mutation, in which the resulting base substitution changes the coding sequence for one amino acid to another. Another type of single base substitution may lead to a change from a coding amino acid to a termination codon, resulting in premature truncation of the protein. A point mutation may also result in the insertion or deletion of a base resulting in a change of the reading frame (a frameshift mutation) during protein translation. Finally, a single base substitution may not have an effect and will code for the same amino acid; this effect is known as a silent mutation.
These seemingly simple changes in DNA coding sequences can have profound effects on protein function. If the coding sequence of a protein is altered, this can lead to a number of different altered behaviors including inactivation or activation, mislocalization, or altered transcription (which can affect mRNA and protein expression). For example, the well-known missense mutations BRAF V600E and EGFR T790M mutations change these proteins from their normal functioning state to a hyperactive state. In the case of a truncating or frameshift mutations, this can result in the loss of key portions of the protein that are critical to its function. For example, a truncating mutation that results in the loss of a kinase domain in a tyrosine kinase protein will completely abrogate that function of the protein. It is these functional characterizations that lead to the classification of variants as deleterious/pathogenic or benign.
Knowing the tumor profile of a patient can aid in treatment decisions, aid in the identification of potential targeted therapies that may be beneficial, and identify clinical trials that can be beneficial to the patient. Additionally, genetic testing for certain germline mutations can identify patients that have an increased risk for developing certain cancers, a well-known example being BRCA testing for breast cancer risk. Another perhaps more critical role in personalized medicine that genetic profiling of patient tumors plays is the guidance on treatments that should not be used for a particular patient. In particular, some mutations can render a tumor resistant to certain drugs and others can lead to acquired resistance after an initial response. In the era of personalized medicine, determination of mutation type and the effect of that mutation on protein function can be a critical part of cancer treatment.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Most Relied Upon Journals in Precision Oncology

George Lundberg, MS, MD, ScD, MASCP, FCAP, Chief Medical Officer and Editor in Chief, CollabRx, a Rennova Health Company; Editor at Large, Medscape; Executive Adviser, Cureus; Consulting Professor of Pathology and Health Research and Policy, Stanford University; President and Chair, The Lundberg Institute; @glundberg

Q: The medical world is running amuck with new information, some credible, some not. What are the most reliable sources of information in Precision Oncology?

A: “Half of knowledge is knowing where to find knowledge”.
No one knows how many medical journals/periodicals there are in the world. Estimates range from 20,000 to 40,000.
Many are general medical journals; many more are specialty or sub-specialty journals. Their foci may be scientific, clinical, or even marketing. A few are strictly on paper; most also have an internet version, either a replicate of the print version, or a hybrid; some are exclusively electronic.
There are many parameters used to evaluate medical journals: exclusionary indexing systems, circulation, readership, revenue, advertising, paid subscription or open access, author fees, profitability, volume of information, frequency of publication, speed to publication, reference citation scores and indices, open and click through rates, page views, library catalogs, public media attention, owner/publisher status, primary language, location, tradition, brand name recognition, and others.
Of course the internet “changed everything “ so now there are “legitimate” as well as “predatory” online-only, open access journals.
CollabRx works in the field of Precision Oncology. We rely heavily on availability and veracity of the published literature. CollabRx enjoys the voluntary contributions of scores of unpaid editorial board members.
So, in 2016, I made the following request of sixty-six (66) of our editorial board members, paid staff and a few other esteemed experts:
Twenty nine individuals (44%) responded. A total of 70 journals were named. ONLY 10 journals had 10 or more advocates. This was a single pass survey.
The top 10 are:
New England Journal of Medicine-28;
Journal of Clinical Oncology- 27;
Lancet Oncology- 15;
Cancer Clinical Research-15;
Cancer Research-13;
Nature Medicine-12;
Cancer Discovery-12;
Journal of the American Medical Association- 11;
JAMA Oncology-10.
Eight (8) journals drew 5-9 advocates.
Science-9; Blood-9; Science Translational Medicine -8; Cancer Cell-7; Oncotarget-7; Journal of the National Cancer Institute – 7; Molecular Cancer Therapeutics-7; Cell-6.
Sixteen (16) publications enjoyed 2-4 advocates.
Cancer-4; Cell Reports; Breast Cancer Research; British Journal of Cancer; Annals of Internal Medicine; Nature Review Clinical Oncology-3 each; these attracted 2 each: European Urology; Clinical Cancer Research; Annals of Hematology/Oncology; Proceedings of the National Academy of Sciences; PLoS ONE; PLoS; Journal of Precision Medicine; Journal of Thoracic Oncology; Nature Genetics; New York Times.
The remainder (36) were named by a single advocate.
AJCP; AACR; Annals of Oncology; Arch Path Lab Med; BMC Cancer; Brit J Urol; Cancer Genetics; Cancer Immunology and Immunotherapy; Cancer Science; Clin Adc in Hem and Onc; Euro J Cancer; HemOnc Today; Haematologica; Immunity; Int J of Cancer; JCI; J Comm and Supportive Oncology; JID; J of Onco Pract; JNCCN; J or Urol; Leukemia; Mayo Cl Proc; Molecular Cancer Research; Molecular Cell; Molecular Oncology; Nature Biotech; Nature Cancer Biology; Nature Review Drug Discovery; Nature Methods; Oncogene; Oncologist; Pig Cell Mel Res; PLoS Genetics; Urology; Prostate Diseases; WSJ.
The data source is: EXPERT OPINION. This may be as good a way as any to evaluate a medical publication, as long as you can engage “the best experts”. Was your favorite source included or missing?
Write to me at to add other favorites or to argue that some that are included here are unfairly ranked or should be delisted.
Medical and Scientific Journalology is a big deal. Once scientific work has been accomplished, unless it is written about, no one else will ever learn from it. The economics and sociology of medical publishing are also big deals, and are very much in flux. This blog may address other publishing issues as time goes by, especially topics like “paywalls” for readers and publication costs borne by the authors.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Length and Quality of Life in Cancer Patient Treatment

Professor Michael Baum, Professor Emeritus of Surgery & Visiting Professor of Medical Humanities. University College, London, UK.

Q: Although you have practiced as a surgeon in the British National Health Service (NHS) for most of your career, how is it that you’ve been such an outspoken critic of the “21st C cures act” that was passed through congress last year? What possible relevance might this have for your NHS?
A: All first year medical students should be taught the raison d’être for the practice of their chosen profession. Simply stated this distills down to three principles: the maintenance of health (well-being) for those who are free of disease and, for those with life threatening disease, the improvement of quality of life (QoL) and length of life (LoL). Therefore for patients diagnosed with cancer, QoL and LoL should be the primary outcome measures for all randomized clinical trials (RCTs) of innovative treatment. All other outcome measures have to be considered surrogates that may or may not translate into improvements in the primary outcomes. These may be used for legitimate reasons, such as aborting a trial early if surrogates all point in the wrong direction, but more often than not these surrogates are used to replace the primary outcome measures in order to fast track the adoption of what look like “promising” new interventions.
At its best, even significant improvements in cancer specific mortality might be abrogated by deaths directly related to the toxicities of treatment. At its worst is the assumption that some third or fourth level indices of “activity” of the novel treatment are accepted as evidence sufficiently compelling to bring the treatment to market.
In a recent JAMA Internal Medicine study, Prasad et al used meta-analysis to study the association of surrogate end points and overall survival in oncology. In 52% of examined studies the correlation was low; 25% showed medium correlation: only 23% showed a high level. Well over half the time surrogate end points failed to impact the gold standard of overall survival. This disconnect will have profound influences on safety, efficacy, and cost of oncology drugs that is already reaching fever pitch after the passing of the U.S. Congressional “21st Century Cures” bill last year.
In an accompanying JAMA Internal Medicine editor’s note, Rita F. Redberg MD MSc commented, “We must reduce drug approvals based on unreliable surrogates and change practice when critical studies show no survival benefit… In our rush to find new effective treatments, we should not harm our patients with ineffective toxic ones.”
We recognize that surrogate end points continue to figure prominently in oncology studies, usually promoted as meaningful outcomes in desperate situations where it is better to have cancers respond than not respond, and it is better to live progression-free than with progression. But without QoL measures to account for the offsetting toxicity of such gains, and without financial data to account for the cost, we really don’t know what has been achieved for patients who ended up surviving for identical amounts of time.
As someone who has practised in the British NHS all his professional life why should that worry me? Sadly ill-considered lunacies from the USA often follow the prevailing winds to our shores. Last year Lord Saatchi tried to drive through the House of Lords a “Medical Innovations” bill that was considered a “Quacks Charter”, based on the same fundamental misconceptions. It was a close call but fortunately it came to nothing.
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