What is the evolutionary explanation for blood type antibodies? Blood transfusion is so recent in history, why do we have this ‘defense’ mechanism from the evolutionary perspective?

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Shorter answer

Already by 6 months of age, gut microbiota polysaccharides stimulate antibodies capable of binding ABO blood group antigens (1). In particular, anti-histo blood group B antibodies can bind gut microbiota (2) while the environmental trigger for anti-histo blood group A still remains undefined (3).

Thus, rather than indicative of defense, Cross-reactivity – Wikipedia as in structural similarity between microbial and histo-blood group antigens explains antibodies against the latter. The 20th century human invention of blood transfusion simply uncovers the scope of such cross-reactivity (4).

A dynamic snapshot of a person’s immunological history, circulating antibodies embody the immunological imprint of past antigenic encounters. However, which antigens specifically induce such circulating antibodies? Grouped under the umbrella term, Natural antibodies – Wikipedia, they’re found in circulation even in absence of explicit infection. In actuality, the term simply signifies unknown antigenic targets triggered such antibodies. Until recently, explicitly looking for such antigens was akin to looking for the proverbial needle in a haystack.

Now though Systems biology – Wikipedia approaches that combine high-throughput computational and Omics – Wikipedia techniques are beginning to trace out the broad overlaps in structure within the universe of antigens, overlaps that antibodies and other receptors of the Adaptive immune system – Wikipedia already so brilliantly glom onto when they bind their antigenic targets so specifically.

Such studies reveal how a contradiction of terms, specificity married to redundancy, could even come to be such a hallmark feature of the adaptive immune system receptors. For example, one study (5) suggests a universal architecture for the human anti-carbohydrate antibody repertoire, universal implying capacity to bind structurally similar Moiety (chemistry) – Wikipedia across living organisms, be they microbes or mammals.

Back in the mid-20th century, Arthur Mourant – Wikipedia proposed that modern-day geographic ABO distributions are the consequence of past epidemics (6). Though severely understudied, research spanning decades has in fact uncovered several examples of antibodies that cross-react on microbial and histo-blood group antigens.

  • Exposure to bacterial antigens stimulates anti-histo blood group antigen antibody titers (7), suggesting the two, bacterial and blood group antigens, are antigenically related.
  • As far back as 1971, researchers discovered that blood group O and A volunteers fed E.coli O86 had spike in anti-blood group B antibody titers (1), clearly indicating antigenic similarity between E.coli O86 and blood group B antigens.
  • Histo-blood group and viral antigen similarities have been reported for SARS Coronavirus – Wikipedia (Severe acute respiratory syndrome – Wikipedia) (8) and Crimean–Congo hemorrhagic fever – Wikipedia virus (9).

Such cross-reactivity can co-exist with immunological tolerance to one’s own histo-blood group antigens since sources of antibodies, the B cell – Wikipedia with receptors capable of binding them would get deleted through the process of developmentally dictated tolerance.

Longer Answer With Some Examples Of Antibodies Cross-Reactive to Histo-Blood Groups & Microbial Antigens

Table below from 10 lists some linkages between disease-causing/associated microbial agents and blood groups.

Malaria

O blood group is associated with resistance to severe malaria (11). As well, high percentage of O blood group individuals in malaria-endemic regions suggests selective advantage of having this blood group (12). Malaria seems to have exerted selective pressure in blood group distribution (13).

Cholera

Anti-Vibrio cholerae antibody response induced by cholera vaccines was lower in blood group O compared to A individuals (14, 15). Epidemiological studies have found O blood group correlates with cholera disease severity (16, 17) fueling the speculation cholera selection pressure may account for the extremely low and high prevalence of histo-blood groups O and B, respectively, among people living in the Gangetic Delta (18, 19).

FUT2 – Wikipedia Lewis Blood Group Antigen: Rotavirus & Norovirus

Rotavirus infectivity appears to be highly dependent on histo-blood groups (7). Non-B and FUT2 – Wikipedia secretor blood groups tend to be more susceptible to norovirus and rotavirus infection-associated gastroenteritis (13, 20, 21). In a test of norovirus vaccine candidates, anti-histo blood group antibody titers in placebo group individuals positively correlated with protection while vaccinees with higher pre-challenge anti-histo blood group antibody titers had lower frequency of severe disease (22). OTOH, FUT2 – Wikipedia secretor phenotype is associated with influenza, respiratory syncytial virus, echovirus (23).

HIV

Anti-histo blood group antibodies could even function to neutralize viruses such as HIV, albeit in a blood group-specific manner. For example, an anti-blood group A monoclonal antibody could neutralize HIV viruses isolated from peripheral blood lymphocytes from blood group A donors but not B or O donors (24, 25).

Vaccines

The biomedical literature is pockmarked with sporadic reports of various vaccines triggering increase in anti-histo blood group antibodies, pneumoccocal vaccine (26) and tetanus and diphtheria toxoids (27) being cases in point. Again antigenic similarity explains the data. Streptococcus pneumoniae‘s polysaccharide capsule and pig stomach pepsin used back then to produce toxoids, both contain an A-like substance (28).

Lifestyle & Diet Influence Anti-Histo Blood Group Antibodies

Some volunteers who took probiotic supplements developed high anti-histo blood group B antibody titers (28). Turned out some bacterial strains in these supplements had antigenic similarity to histo-blood group B antigens.

Children who are fed intravenously for a long time have low to practically non-existent ABO antibodies, especially anti-B (29). Being essentially ‘sterile’, such nutrition alters and reduces gut microbiota suggesting major source of triggers for anti-histo blood group antibodies are gut microbiota. Interesting then that mean ABO titers have declined dramatically among those on present-day diet of processed, ‘pasteurized’ food compared to historical controls (30).

Bibliography

1. Springer, G. F. “Blood-Group and Forssman Antigenic Determinants Shared between Microbes and Mammalian Cells1.” Progress in Allergy Vol. 15. Karger Publishers, 1971. 9-77.

2. Galili, U., et al. “Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora.” Infection and immunity 56.7 (1988): 1730-1737. https://www.ncbi.nlm.nih.gov/pmc…

3. Branch, Donald R. “Anti‐A and anti‐B: what are they and where do they come from?.” Transfusion 55.S2 (2015): S74-S79. https://www.researchgate.net/pro…

4. Blackwell, C. Caroline, et al. “Blood group phenotypes and infectious diseases.” Susceptibility to infectious diseases: the importance of host genetics 4 (2004).

5. Schneider, Christoph, et al. “The human IgG anti-carbohydrate repertoire exhibits a universal architecture and contains specificity for microbial attachment sites.” Science translational medicine 7.269 (2015): 269ra1-269ra1. https://www.ncbi.nlm.nih.gov/pmc…

6. Mourant, Arthur Ernest. “The Distribution of the Human Blood Groups.” The Distribution of the Human Blood Groups. (1954).

7. Cooling, Laura. “Blood groups in infection and host susceptibility.” Clinical microbiology reviews 28.3 (2015): 801-870. Blood Groups in Infection and Host Susceptibility

8. Guillon, Patrice, et al. “Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies.” Glycobiology 18.12 (2008): 1085-1093. https://www.researchgate.net/pro…

9. Güven, Ahmet Sami, et al. “Value of ABO blood group in predicting the severity of children with Crimean-Congo hemorrhagic fever.” International journal of clinical and experimental medicine 7.2 (2014): 416. https://www.ncbi.nlm.nih.gov/pmc…

10. Dotz, Viktoria, and Manfred Wuhrer. “Histo-blood group glycans in the context of personalized medicine.” Biochimica et Biophysica Acta (BBA)-General Subjects 1860.8 (2016): 1596-1607. https://www.researchgate.net/pro…

11. Timmann, Christian, et al. “Genome-wide association study indicates two novel resistance loci for severe malaria.” Nature 489.7416 (2012): 443-446.

12. Anstee, David J. “The relationship between blood groups and disease.” Blood 115.23 (2010): 4635-4643. https://www.researchgate.net/pro…

13. Tirumalai Kamala’s answer to What are the similarities of people having the same blood group?

14. Clemens, John D., et al. “ABO blood groups and cholera: new observations on specificity of risk and modification of vaccine efficacy.” The Journal of infectious diseases 159.4 (1989): 770-773.

15. Qadri, Firdausi, et al. “Peru-15, a live attenuated oral cholera vaccine, is safe and immunogenic in Bangladeshi toddlers and infants.” Vaccine 25.2 (2007): 231-238. https://www.researchgate.net/pro…

16. Barua, D., and A. S. Paguio. “ABO blood groups and cholera.” Annals of human biology 4.5 (1977): 489-492.

17. Glass, Roger I., et al. “Predisposition for cholera of individuals with o blood group possible evolutionary significance.” American journal of epidemiology 121.6 (1985): 791-796.

18. Harris, Jason B., and Regina C. LaRocque. “Cholera and ABO Blood Group: Understanding an Ancient Association.” The American Journal of Tropical Medicine and Hygiene 95.2 (2016): 263-264. https://pdfs.semanticscholar.org…

19. Kuhlmann, F. Matthew, et al. “Blood group O–dependent cellular responses to cholera toxin: parallel clinical and epidemiological links to severe cholera.” The American journal of tropical medicine and hygiene (2016): 16-0161.

20. Tirumalai Kamala’s answer to Why do my American friends get sick by norovirus every Thanksgiving, but I’ve never seen a Russian citizen gotten sick by norovirus in her homeland?

21. Payne, Daniel C., et al. “Epidemiologic association between FUT2 secretor status and severe rotavirus gastroenteritis in children in the United States.” JAMA pediatrics 169.11 (2015): 1040-1045. <i>FUT2</i> Secretor Status and Severe Rotavirus Gastroenteritis

22. Atmar, Robert L., et al. “Serological correlates of protection against a GII. 4 norovirus.” Clinical and Vaccine Immunology 22.8 (2015): 923-929. https://www.researchgate.net/pro…

23. Raza, M. W., et al. “Association between secretor status and respiratory viral illness.” Bmj 303.6806 (1991): 815-818. http://pubmedcentralcanada.ca/pm…

24. Arendrup, Maiken, et al. “Antibody to histo-blood group A antigen neutralizes HIV produced by lymphocytes from blood group A donors but not from blood group B or O donors.” Aids 5.4 (1991): 441-444.

25. Rother, Russell P., et al. “A novel mechanism of retrovirus inactivation in human serum mediated by anti-alpha-galactosyl natural antibody.” Journal of Experimental Medicine 182.5 (1995): 1345-1355. http://europepmc.org/backend/ptp…

26. Boyer, Kenneth M., et al. “Antibody response to group B streptococcus type III and AB blood group antigens induced by pneumococcal vaccine.” The Journal of pediatrics 98.3 (1981): 374-378.

27. Elliott, G. B. “Transiently dangerous universal blood donor.” Canadian Medical Association journal 70.5 (1954): 571. https://www.ncbi.nlm.nih.gov/pmc…

28. Daniel‐Johnson, Jennifer, et al. “Probiotic‐associated high‐titer anti‐B in a group A platelet donor as a cause of severe hemolytic transfusion reactions.” Transfusion 49.9 (2009): 1845-1849. https://www.ncbi.nlm.nih.gov/pmc…

29. Cooling, L. W., et al. “Abo Typing Discrepancies in Children Requiring Long-term Nutritional Support.” Transfusion 47 (2007): 9A-10A.

30. Mazda, T., et al. “Differences in ABO antibody levels among blood donors: a comparison between past and present Japanese, Laotian, and Thai populations.” Immunohematology/American Red Cross 23.1 (2006): 38-41.

https://www.quora.com/What-is-the-evolutionary-explanation-for-blood-type-antibodies/answer/Tirumalai-Kamala

What implications does Thomas Kuhn have for research methodology?

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The main message of The Structure of Scientific Revolutions – Wikipedia (SSR) could be restated as science is self-correcting though individual scientists may not be or science is rational though individual scientists may not be. A facetious one is an abbreviated version of Planck’s principle – Wikipedia, (Max Planck – Wikiquote),

‘Science advances one funeral at a time’

Perspective: Kuhn, The Apple Cart Upsetter

Kuhn’s singular and unprecedented insight came by questioning the then prevailing consensus that being progressive and cumulative constitute the dominant attributes of scientific progress. Progressive and cumulative imply steady, thoughtful, rational, unemotional, and yet the history of scientific progress suggests it has been anything but. There’s an eerie resonance to Kuhn’s synthesis in the The Sleepwalkers – Wikipedia, a 1959 book by Arthur Koestler – Wikipedia,

‘The progress of science is generally regarded as a kind of clean, rational advance along a straight ascending line; in fact it has followed a zigzag course, at times more bewildering than the evolution of political thought.’

Three years later, in 1962 Kuhn wrote (1, p.208, emphasis mine),

‘scientific development as a succession of tradition-bound periods punctuated by non-cumulative breaks

Kuhn’s thesis was a poke in the eye for philosophy titans like Karl Popper (Stanford Encyclopedia of Philosophy) who’d held sway until then with their contention that science was a unique human endeavor for objective pursuit of truth, that scientific progress, i.e., the discovery of new facts, followed from scientists calmly, objectively and rationally incorporating new data and adjusting their mental constructs accordingly in the form of new theories or hypotheses.

Kuhn comes along and says none of such accepted tropes about the scientific process are accurate, that instead

  • Science consists of periods of ‘normal’ science leavened by periods of crisis, with revolutionary science breaking the impasse, overturning and replacing the old paradigm with a new one. Thus, neither necessarily progressive nor cumulative though it could also be both.
  • Scientific education helps inculcate the unquestioning attitude and habits of ‘normal’ science (2).

Though the scientific enterprise may be open-minded, the individual scientist is very often not. Whether his work is predominantly theoretical or experimental, he usually seems to know, before his research project is well under way, all but the most intimate details of the result which that project will achieve. If the result is quickly forthcoming, well and good. If not, he will struggle with his apparatus and with his equations until, if at all possible, they will yield results which conform to the sort of pattern which he has foreseen from the start…a relatively dogmatic initiation into a pre-established problem-solving tradition that the student is neither invited nor equipped to evaluate

  • Criteria and methods scientists use to justify their choice of paradigms are habitually ambiguous and imprecise as well as inconsistent and changing.
  • ‘Normal’ scientists engage in puzzle-solving, using the prevailing paradigm as a road-map to solve remaining puzzles within a given field. Periods of ‘normal’ science thus consist of unquestioning adherence to the prevailing consensus of beliefs and methods, i.e., paradigm, and therefore as well unquestioning use of such methods in routine puzzle-solving until over time, anomalies accumulate, anomalies the prevailing paradigm fails to adequately explain and which thwart these scientists in achieving their puzzle solving goals. Tension over accumulating anomalies then leads that scientific field into a period of crisis, one eventually resolved by a revolution wherein a new theory supplants the older one by being able to adequately or better explain such anomalies. Why would such anomalies accumulate in the first place? According to Kuhn, if the scientific approach operates the way it should then, regardless of scientists, scientism and inherent biases attendant to the two, it should ferret out some undeniable truism, what Popper called verisimilitude (Verisimilitude – Wikipedia). What to do about the truism then becomes the question. Fits with the prevailing paradigm? Accept wholeheartedly. Doesn’t fit? Ignore or minimize and so anomalies accrue with time. Generation gap may also apply as in younger, presumably conceptually uncommitted or less committed, practitioners assessing the same data and the lay of the land with fresh, less biased eyes.
  • Aware of and driven by anomalies within their field, revolutionary scientists pursue answers that could explain them and in the process create revolutionary science (3).

Thus, rather than the Popperian view of science as ‘revolution in permanence‘ (4), Kuhn proposed ‘Periods of stable growth punctuated by revisionary revolutions‘ (5), with both defining scientific progress as the discovery of new facts. Which is more accurate? History of science suggests Kuhn’s.

Self-Inflicted Problem: What Did Kuhn Actually Mean By Paradigm?

Problem is Kuhn’s writing in the book he’s best known for was so ambiguous, it triggered and sustained a furore of criticism led by philosophical luminaries such as Karl Popper, Paul Feyerabend (Stanford Encyclopedia of Philosophy), Imre Lakatos (Stanford Encyclopedia of Philosophy) (4, 6, 7). Unfortunately Kuhn’s ambiguity and vague use of the word paradigm also encouraged popular culture to over-use it to the point of abuse and meaninglessness. A thorny issue fought over ever since is whether Kuhn offered prescriptions or descriptions of the scientific process.

Paul Feyerabend (Stanford Encyclopedia of Philosophy) famously wrote (6, page 198) of SSR,

Whenever I read Kuhn, I am troubled by the following question: are we here presented with methodological prescriptions which tell the scientist how to proceed; or are we given a description, void of any evaluative element, of those activities which are generally called “scientific”? Kuhn’s writings, it seems to me, do not lead to a straightforward answer. They are ambiguous in the sense that they are compatible with, and lend support to, both interpretations’

To which Thomas Kuhn (Stanford Encyclopedia of Philosophy) felt compelled to respond (6, page 237),

‘The answer, of course, is that they should be read in both ways at once. If I have a theory of how and why science works, it must necessarily have implications for the way in which scientists should behave if their enterprise is to flourish…scientists should behave essentially as they do if their concern is to improve scientific knowledge’

Margaret Masterman – Wikipedia from the Cambridge Language Research Unit carefully analyzed SSR and identified 21 different senses in which Kuhn used it, grouping them into 3 categories, metaphysical, sociological and construct. The last includes the nuts and bolts of a practicing scientist’s tool-kit including among others, standard textbooks, methods, reagents, analytical tools (8).

Sustained criticism forced Kuhn to re-analyze his position and clarify what he meant by paradigm (1, page 175, emphasis mine),

‘in much of the book the term ‘paradigm’ is used in two different senses. On the one hand, it stands for the entire constellation of beliefs, values, techniques, and so on shared by the members of a given community. On the other, it denotes one sort of element in that constellation, the concrete puzzle-solutions which, employed as models or examples, can replace explicit rules as a basis for the solution of the remaining puzzles of normal science’

In further revisions, Kuhn eventually divided his use of paradigm into two categories, disciplinary matrix, all the shared commitments of a scientific group, and exemplars as in concrete problem solutions, accepted by the group as, in a quite usual sense, paradigmatic (9). ‘Disciplinary’ as in the common possession of the practitioners of a professional discipline; ‘matrix’ as in being composed of ordered elements of various sorts, each requiring further specification. Obviously disciplinary matrix and exemplar never took off into popular culture the way paradigm did.

Meaning Kuhn intended paradigm to signify a given scientific field’s tacitly agreed upon worldview or mental construct, the corresponding tool-kit and language to define and interrogate it, and the authoritative, supportive examples of how to do science to solve remaining puzzles within that field.

Kuhn’s Prescriptions & Descriptions: How Scientists Do And Ought To Behave Go Hand In Hand

As a historian, sociologist and philosopher of science, to me Thomas Kuhn’s place is akin to that of behavioral scientists.

Classical economists schooled in the manner of Friedrich Hayek – Wikipedia or Milton Friedman – Wikipedia chose to regard individuals as rational actors making rational economic decisions. Others such as Richard Thaler – Wikipedia, Amos Tversky – Wikipedia, Daniel Kahneman – Wikipedia, Dan Ariely – Wikipedia, to name some notables, instead show that economical decision making is beset by cognitive biases that each and every one of us, the supposed rational actors, unwittingly bring to the decision making process, be it about economics or anything else for that matter.

In like manner, Kuhn may be best understood as a counterpoint to philosophers such as Karl Popper and sociologists such as Robert K. Merton – Wikipedia who envisaged scientific development as smooth, cumulative, progressive. Implicit in the latter analysis is the assumption that scientists as the players involved in the system are rational actors making unbiased decisions.

Problem with this notion is at least two-fold.

For one, we now know and understand much better in a way that wasn’t as explicitly understood in the days of Popper and Merton that we each operate within a maze of cognitive biases that constantly attend our every thought and decision. Or at least we more openly acknowledge that this is so.

For another, scientific culture gets established the same way others do, viz., individuals within the group behave and are expected to hew to a set of normative values tacitly assumed to be common to that group.

Habituation of ‘normal’ scientists, those accepting of the prevailing status quo, their habits of thought and thinking processes, their habitual experimental constructs, read-outs, and analyses, their scientific method, create a further, unbridgeable divide such that status quo acceptors and challengers live in ‘different worlds’ and their concepts are also ‘incommensurable’ (Commensurability (philosophy of science) – Wikipedia. Failure to communicate is then a predictable outcome. Language is after all an imperfect tool. Practitioners may use but imply very different meanings to the same terms. Seen in one light, per Kuhn, ‘normal’ scientists behave non-rationally, trying the same approach over and over again even when the outcome doesn’t support the prevailing paradigm. Seen in another light, the ‘revolutionary’ scientists are the non-rational actors, bucking the prevailing norm. Either view threatens the Popperian view of slow, steady, rational, relentless march of scientific progress, and philosophers continue to debate these opposing views.

For Kuhn, criteria and essentials of the scientific process go together as do how scientists do and ought to behave. Contingent on their commitment to improve scientific knowledge, Kuhn’s implications for research methodology is to make no change and to keep doing what scientists have been doing. After all, science has been spectacularly successful so far.

Bibliography

1. The Structure of Scientific Revolutions – Wikipedia, 2nd edition, Thomas S. Kuhn.

2. Kuhn, Thomas S. The function of dogma in scientific research. Na, 1963.

3. Maurice A. Finocchiaro. Essay-Review of Lakatos’ Criticism and the Growth of Knowledge. Studies in History and Philosophy of Science 3(1972 -73): 357-72.

4. Lakatos, Imre. “Criticism and the methodology of scientific research programmes.” Proceedings of the Aristotelian society. Vol. 69. Aristotelian Society, Wiley, 1968. Publications

5. Thomas Kuhn (Stanford Encyclopedia of Philosophy)

6. Musgrave, Alan, ed. Criticism and the Growth of Knowledge: Volume 4: Proceedings of the International Colloquium in the Philosophy of Science, London, 1965. Vol. 4. Cambridge University Press, 1970.

7. Lakatos, Imre. “Falsification and the methodology of scientific research programmes.” Can Theories be Refuted?. Springer Netherlands, 1976. 205-259. http://www.csun.edu/~vcsoc00i/cl…

8. Masterman, M. “The Nature of a Paradigm, w: Lakatos, I., Musgrave A.(eds.), Criticism and the Growth of Knowledge.” (1970).

9. Kuhn, Thomas S. “Second thoughts on paradigms.” The structure of scientific theories 2 (1974): 459-482. http://eu.pravo.hr/_download/rep…

https://www.quora.com/What-implications-does-Thomas-Kuhn-have-for-research-methodology/answer/Tirumalai-Kamala

What side effects does Perjeta have when administered without other chemotherapy drugs?

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Difficult to consider side effects of Perjeta aka Pertuzumab – Wikipedia in isolation because

  • It’s been tested in combination therapies, usually with Herceptin aka Trastuzumab – Wikipedia and also often Docetaxel – Wikipedia. Neutropenia – Wikipedia (low neutrophil count), febrile neutropenia, alopecia, nausea, fatigue, and infusion reactions are already common side effects of docetaxel.
  • Most clinical trial patients have usually been on other Rx previously, some of which may leave long-term adverse effects on various organ systems.

That said, side effects particular to drugs like Perjeta are dictated by expression pattern of their targets. Like Herceptin, Perjeta targets HER2/neu – Wikipedia, an extracellular human EGFR (Epidermal growth factor receptor – Wikipedia). Both used to treat HER2 positive breast cancer, Perjeta and Herceptin have complementary modes of action. Binding HER2’s extracellular domain, Perjeta prevents it from heterodimerzing with EGFR (Epidermal growth factor receptor – Wikipedia). This blocks transmission of proliferative signals into HER2-positive tumor cells.

Though targeting something expressed by some breast cancers, nevertheless Rx such as Perjeta and Herceptin are still non-specific since HER2 is also expressed by other tissue types.

  • Colonic epithelial cells hence diarrhea is possible.
    • Studies (1) have shown HER2 blockade can cause non-life threatening diarrhea, presumably as a result of excess chloride secretion by EGFR blockade on colonic epithelial cells.
    • 40 to 80% of patients who got Perjeta in clinical trials experienced diarrhea (2, 3, 4, 5, 6).
    • Specifically, grades 1 to 3 diarrhea (7, page 20, grades 1 thru’ 3 are milder, grade 4 is life-threatening, grade 5 is death) were a common symptom in 3 breast cancer trials testing Perjeta with other drugs, CLEOPATRA (n=804, 2) for metastatic, and NeoSphere (n=416, 3) and TRYPHAENA (n=223, 4) for early-stage.
    • Highest during the first Perjeta-containing cycle, diarrhea incidence decreased with subsequent cycles.
    • The data suggest diarrhea is more common when Perjeta‘s given since rate was 68% for Docetaxel plus Hercpetin and Perjeta compared to 49% for Docetaxel plus Hercpetin in CLEOPATRA (2).
  • Cardiac myocytes hence heart toxicity is possible (8).
    • However, the way these drugs affect heart function is highly reversible (9).
    • As well, low numbers of patients tend to be affected. For example, 6 of 92 (6.5%) in one trial (10).
  • Keratinocytes so rashes, and skin and nail infections, typically Staphylococcus aureus (11).
    • Detailed meta-analysis suggests Perjeta significantly increased risk of rash (12).

However, these trials and meta-analyses also conclude these side effects are well manageable.

Bibliography

1. Gao, Jennifer, and Sandra M. Swain. “Pertuzumab for the treatment of breast cancer: a safety review.” Expert opinion on drug safety 15.6 (2016): 853-863.

2. Baselga, José, et al. “Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.” New England Journal of Medicine 366.2 (2012): 109-119. http://www.nejm.org/doi/pdf/10.1…

3. Gianni, Luca, et al. “Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.” The lancet oncology 13.1 (2012): 25-32. http://www.rits.onc.jhmi.edu/dbb…

4. Schneeweiss, A., et al. “Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).” Annals of oncology 24.9 (2013): 2278-2284. https://www.researchgate.net/pro…

5. Cortés, Javier, et al. Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab: Activity and Tolerability in Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Journal of Clinical Oncology: Vol 30, No 14

6. Baselga, José, et al. Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy: Journal of Clinical Oncology: Vol 28, No 7

7. https://ctep.cancer.gov/protocol…

8. Valachis, Antonis, et al. “Cardiac toxicity in breast cancer patients treated with dual HER2 blockade.” International journal of cancer 133.9 (2013): 2245-2252. http://onlinelibrary.wiley.com/d…

9. Lenihan, D., et al. “Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab.” Annals of oncology 23.3 (2012): 791-800. https://www.researchgate.net/pro…

10. Portera, Chia C., et al. “Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2–positive metastatic breast cancer.” Clinical Cancer Research 14.9 (2008): 2710-2716. https://www.researchgate.net/pro…

11. Mortimer, Joanne E., et al. “Skin, nail, and staphylococcal infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy.” (2015): e11610-e11610.

12. Drucker, Aaron M., et al. “Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis.” Breast cancer research and treatment 135.2 (2012): 347-354.

https://www.quora.com/What-side-effects-does-Perjeta-have-when-administered-without-other-chemotherapy-drugs/answer/Tirumalai-Kamala

Is there an association between inflammation and cancer?

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Inflammation-cancer link is indirect and convoluted. Rather than inflammation per se, failure to resolve it is a common feature of early tumor development. In particular chronic inflammation (1, 2), specifically tumor-promoting inflammation is now considered a tumor-enabling characteristic (3).

This answer

I. Explains inflammation is a process, not an outcome, and why the distinction matters.

II. Explains how the inflammatory process could either help or hinder cancer growth. Dysregulated (unresolved and/or inappropriate) helps while regulated inflammation hinders.

III. Shares some epidemiological data suggesting dysregulated inflammation could increase cancer risk.

IV. Explains how certain types of inflammation could hinder, even eliminate cancers, as William Coley – Wikipedia showed with his Coley’s toxins – Wikipedia.

V. Shares some epidemiological data suggesting certain types of inflammation could reduce cancer risk.

VI. Shares some epidemiological data suggesting reducing inflammation could reduce cancer risk.

I. Inflammation Is A Process, Not An Outcome

Inflammation, a normal physiological process (4), has been dealt a bad rap in popular culture where it’s usually used tacitly as synonymous with bad outcome when it’s actually a fundamental attribute of physiology, a dynamic immunological process that appears designed to

  • Manifest itself in response to homeostatic perturbation in a given tissue,
  • Help resolve such perturbation and help restore the tissue to its former homeostasis, and
  • Itself disappear.

The last clearly indicates inflammation is normally a self-limiting process with a finite end (5, 6, 7). For thousands of years, starting with its first apparent recorded report by the Roman encyclopedist, Aulus Cornelius Celsus – Wikipedia, inflammation was described using its cardinal features, redness (rubor), heat (calor), swelling (tumor) and pain (dolor) until 1852 when Rudolf Virchow – Wikipedia added loss of function (functio laesa, injured function) (8). Given its characteristic features, infections are stereotypical triggers of the inflammatory process.

Mild or severe, short-lived (acute) or prolonged (chronic), it’s a process whose features, course and consequences vary vastly in scope and length, and are contingent on the triggers that initiate it and the constraints of the tissues where it occurs. For example, being encased by the bony skull renders the soft brain tissue particularly ill-suited to effectively deal with some of inflammation’s characteristic consequences such as greater than normal influx of blood-derived cells and fluid, especially when it presents abruptly as an intense and relentless process as happens in Traumatic brain injury – Wikipedia.

Unfortunately, even in biomedicine, the word inflammation is also often misused to describe any number and variety of undesirable or adverse outcomes when it is instead a process. Such distortion of the fundamental framework ends up distorting experimental goals and design so no surprise if confusing results ensue.

Another problem of epidemic proportions plaguing our understanding of inflammation’s role in cancer is blanket over-reliance on pre-clinical mouse models which are increasingly recognized to poorly recapitulate human physiology (9, 10). Too often, such over-reliance dictates what to examine how and when. For example, mouse models did not predict pituitary gland inflammation (hypophysitis) and colitis as common, severe side effects of Ipilimumab – Wikipedia, an anti- CTLA-4 – Wikipedia mAb (monoclonal antibody) approved for use in human metastatic melanoma patients (11, 12) nor did they predict mAbs targeting Programmed cell death protein 1 – Wikipedia and PD-L1 – Wikipedia would be far more effective compared to those targeting CTLA-4.

II. Inflammation Could Either Help Or Hinder Cancer Growth

Disagreement about the role of tumor-infiltrating immunocytes is long-standing, starting from the very genesis of the field of modern immunology. While Rudolph Virchow saw ‘white’ cell, i.e., leukocyte, infiltrates in solid tumors and in 1863 ascribed to them a cancer-promoting role (1), Paul Ehrlich in 1909 proposed the human immune system eliminated nascent tumors (13). However, such opposing views can be reconciled by considering inflammation’s outcome, tumor-promoting or tumor-inhibiting/eradicating, to be inherently context-based. Doing so shifts the spotlight away from outcome to process.

Specifically, dysregulated (unresolved and/or inappropriate) inflammation as tumor-promoting/enabling and regulated inflammation as tumor-inhibiting. In 1972 Alexander Haddow speculated ‘tumor production is a possible overhealing‘ (14). In 1986 Harold F. Dvorak observed inflammation and cancer share some basic developmental features such as angiogenesis and leukocyte infiltration, and suggested tumors were ‘wounds that did not heal‘ (15). Enabling/promoting implies chronic tumor site activation of immunocytes (granulocytes, monocytes, macrophages, mast cells, even eventually lymphocytes) and also fibroblasts (16) that over time get hopelessly compromised and locked into an unproductive tissue repair/wound healing process that ends up promoting tumor growth (see below from 17). Predictably differentiating different types of inflammation locally as well as systemically is very much work in progress.

III. Epidemiological Data Suggesting Dysregulated Inflammation Could Increase Cancer Risk

Albeit indirect, some epidemiological studies estimate infection-driven cancer risk to be considerable.

  • Some infections can directly drive the genetic transformation process necessary for cancer. For example, EBV, HPV and HTLV-1 can directly induce cell transformation.
  • Other infections may lock in an unproductive chronic inflammation process that enables cancer in those predisposed to it. For example, hepatitis viruses drive chronic inflammation in infected tissues. Reasons for such predisposition could be genetic as well as environmental, with diet and lifestyle being the main drivers of the latter.
  • Estimates suggest 15 (18) to ~18% (19) of global cancer are infection-related with agents ranging from Helicobater pylori, HPV (human papilloma virus), hepatitis B and C viruses, EBV (Epstein-Barr virus), HIV and herpes, schistosomes, HTLV, and liver flukes. Tumor-promoting inflammation is suspected to be involved in all of them.
  • Success of prophylactic vaccines in preventing cancers caused by viral infections has led to the estimate that 10 to 20% of all human tumors could be outcomes of such infections (20, 21).
  • 25% of all human cancers are estimated to result from chronic inflammation (2).

IBDs (Inflammatory bowel disease – Wikipedia) such as UC and Crohn’s have 10-fold greater colorectal cancer risk (22, 23).

Abundant infiltration of renal cell carcinoma by CD4+ and CD8+ T cells with specific features is associated with worse prognosis (24, 25, 26).

Age, ethnicity, family history being the major risk factors for prostate cancer would seem to preclude a role for chronic inflammation except its rate rises within one generation of migrating to the US or Western Europe among low-risk Chinese and Japanese men (27). Diet and lifestyle would thus be the prime environmental factors with chronic inflammation linking them to prostate cancer, except the particulars of such inflammation are yet unresolved. This may be why epidemiological data on link between chronic inflammation and prostate cancer is a mixed bag, several supporting (28, 29, 30, 31, 32, 33, 34, 35), some not (36, 37, 38, 39, 40), with strongest supportive data from studies with larger number of subjects and with confirmed diagnosis of Prostatitis – Wikipedia.

Such contradictions emphasize the difficulty inherent to human studies, especially so for solid tumors. Reconstructing an entire process with recourse only to snapshots, be they biopsies or images, can only ever be fraught with uncertainty.

  • Different studies used different size biopsies and may have taken them at different stages of the cancer process.
  • Different studies used different qualitative approaches to categorize inflammation.

IV. Spontaneous Regressions, William Coley and Coley’s Toxins: Mimicking Acute Infections Could Eradicate Tumors

His observation of several cases of spontaneous tumor regressions in the context of acute infections, specifically infections that induced high fevers, drove William Coley – Wikipedia to a life-long endeavor of trying to eliminate tumors using infection-mimics in the form of his artisanal Coley’s toxins – Wikipedia (41). Though Coley’s ideas fell into disfavor and his legacy was ignored through much of the 20th century, the explication of the Adaptive immune system – Wikipedia starting in the 1960s and of the Innate immune system – Wikipedia starting in the 1990s reversed that trend with modern cancer immunotherapy a direct inheritor and beneficiary of his ideas.

V. Epidemiological Data That Certain Types Of Inflammation Could Reduce Cancer Risk

Ectopic lymph node-like structures in solid tissues are considered emblematic of chronic inflammation. However, their presence in lung and colorectal cancers is associated with improved prognosis (42, 43, 44). As well, such studies show up the limitation of terminology. Clearly even chronic inflammation isn’t inherently tumor-enabling. Process, not outcome and more than one type of chronic inflammation.

VI. Epidemiological Data That Reducing Inflammation Reduces Cancer Risk

Daily Aspirin &/Or NSAID Intake Reduces Risk Of Several Cancers

  • Several meta-analyses (55, 56, 57, 58, 59, 60) suggest daily aspirin but not other NSAID intake consistently shows some protection against prostate cancer incidence.
  • Meta-analysis – Wikipedia of cardiovascular trials found low daily dose (75 to 100mg) of aspirin may reduce cancer incidence and cancer mortality for many cancer types (61, 62).
  • Meta-analysis of data from 8 RCTs (Randomized controlled trial – Wikipedia) where patients took daily aspirin to prevent cardiovascular diseases also found lower incidence of cancers, not just colon but also brain, esophageal, lung, pancreatic, prostate and stomach, with the benefit becoming apparent after at least 5 years of daily aspirin while aspirin for >7.5 years reduced 20-year risk of cancer death by 30% for all solid cancers and by 60% for gastrointestinal cancers (63).

However, drawback of prolonged use of aspirin and NSAIDs is side effects such as stomach and brain bleeds.

Used to treat IBD for >50 years, a meta-analysis of 9 observational studies found drugs such as Mesalazine – Wikipedia reduce colitis-associated colorectal cancer risk by 49% (64).

Anti-Diabetic Drug Metformin – Wikipedia Might Reduce Cancer Risk In The Diabetic

  • Meta-analysis (65) of 11 studies including cohort and case-control studies on 4042 cancer cases and 529 cancer deaths found 31% reduction in cancer incidence and mortality risk among metformin takers.
  • Meta-analysis (66) of 47 independent studies including 65540 cancer cases in diabetic patients found metformin reduced overall cancer incidence and mortality by 31 and 34%, respectively, specifically risk for colorectal cancer.
  • Meta-analysis (67) of 24 independent metformin cohort and case-control studies on 386825 subjects found 30% reduced cancer risk for metformin users.

Metformin might inhibit tumor progression by altering tumor metabolism as well as tumor-associated inflammation (68).

Bibliography

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4. I learned from Guido Majno’s definition of Inflammation that a great definition is a work of genius. by Tirumalai Kamala on TK Talk

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11. Hodi, F. Stephen, et al. “Improved survival with ipilimumab in patients with metastatic melanoma.” N Engl j Med 2010.363 (2010): 711-723. http://www.nejm.org/doi/pdf/10.1…

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16. Marsh, Timothy, Kristian Pietras, and Sandra S. McAllister. “Fibroblasts as architects of cancer pathogenesis.” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1832.7 (2013): 1070-1078. Fibroblasts as architects of cancer pathogenesis

17. Kuraishy, Ali, Michael Karin, and Sergei I. Grivennikov. “Tumor promotion via injury-and death-induced inflammation.” Immunity 35.4 (2011): 467-477. http://www.stem-art.com/Library/…

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19. Parkin, Donald Maxwell. “The global health burden of infection‐associated cancers in the year 2002.” International journal of cancer 118.12 (2006): 3030-3044. http://onlinelibrary.wiley.com/d…

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21. Tuohy, Vincent K., and Ritika Jaini. “Prophylactic cancer vaccination by targeting functional non-self.” Annals of medicine 43.5 (2011): 356-365. https://www.ncbi.nlm.nih.gov/pmc…

22. Seril, Darren N., et al. “Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models.” Carcinogenesis 24.3 (2003): 353-362. https://www.researchgate.net/pro…

23. Itzkowitz, Steven H., and Xianyang Yio. “Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.” American Journal of Physiology-Gastrointestinal and Liver Physiology 287.1 (2004): G7-G17. http://ajpgi.physiology.org/cont…

24. Nakano, Osamu, et al. “Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma.” Cancer research 61.13 (2001): 5132-5136. http://cancerres.aacrjournals.or…

25. Granier, Clémence, et al. “Tim-3 expression on tumor-infiltrating PD-1+ CD8+ T cells correlates with poor clinical outcome in renal cell carcinoma.” Cancer Research (2016): canres-0274.

26. Giraldo, Nicolas A., et al. “Tumor-Infiltrating and Peripheral Blood T Cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.” Clinical Cancer Research (2017): clincanres-2848.

27. Peto, Julian. “Cancer epidemiology in the last century and the next decade.” Nature 411.6835 (2001): 390-395. http://www.ph.ucla.edu/EPI/facul…

28. Irani, Jacques, et al. “High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy.” Urology 54.3 (1999): 467-472.

29. Dennis, Leslie K., Charles F. Lynch, and James C. Torner. “Epidemiologic association between prostatitis and prostate cancer.” Urology 60.1 (2002): 78-83.

30. Roberts, Rosebud O., et al. “Prostatitis as a risk factor for prostate cancer.” Epidemiology 15.1 (2004): 93-99.

31. MacLennan, Gregory T., et al. “The influence of chronic inflammation in prostatic carcinogenesis: a 5-year followup study.” The Journal of urology 176.3 (2006): 1012-1016.

32. Karakiewicz, P. I., et al. “Chronic inflammation is negatively associated with prostate cancer and high‐grade prostatic intraepithelial neoplasia on needle biopsy.” International journal of clinical practice 61.3 (2007): 425-430.

33. Davidsson, Sabina, et al. “Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer.” Cancer Epidemiology and Prevention Biomarkers 20.10 (2011): 2280-2287. http://cebp.aacrjournals.org/con…

34. Jiang, Junyi, et al. “The role of prostatitis in prostate cancer: meta-analysis.” PloS one 8.12 (2013): e85179. http://journals.plos.org/plosone…

35. Gurel, Bora, et al. “Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial.” Cancer Epidemiology and Prevention Biomarkers 23.5 (2014): 847-856. https://www.researchgate.net/pro…

36. Pepe, Pietro, and Francesco Aragona. “Does an inflammatory pattern at primary biopsy suggest a lower risk for prostate cancer at repeated saturation prostate biopsy.” Urologia internationalis 87.2 (2011): 171-174.

37. Vral, Anne, et al. “Topographic and quantitative relationship between prostate inflammation, proliferative inflammatory atrophy and low-grade prostate intraepithelial neoplasia: a biopsy study in chronic prostatitis patients.” International journal of oncology 41.6 (2012): 1950-1958. https://www.researchgate.net/pro…

38. Engelhardt, P. F., et al. “Chronic asymptomatic inflammation of the prostate type IV and carcinoma of the prostate: Is there a correlation?.” Scandinavian journal of urology 47.3 (2013): 230-235.

39. Yli‐Hemminki, Tytti H., et al. “Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate‐specific antigen (PSA) concentration in the Finnish prostate cancer screening trial.” BJU international 112.6 (2013): 735-741. http://onlinelibrary.wiley.com/d…

40. Moreira, Daniel M., et al. “Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the REDUCE study.” Cancer 120.2 (2014): 190-196. Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: Results from the REDUCE study – Moreira – 2013 – Cancer – Wiley Online Library

41. Tirumalai Kamala’s answer to What is the relationship between tumors and immune tolerance?

42. Dieu-Nosjean, Marie-Caroline, et al. “Long-term survival for patients with non–small-cell lung cancer with intratumoral lymphoid structures.” Journal of Clinical Oncology 26.27 (2008): 4410-4417. Long-Term Survival for Patients With Non-Small-Cell Lung Cancer With Intratumoral Lymphoid Structures

43. de Chaisemartin, Luc, et al. “Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer.” Cancer research 71.20 (2011): 6391-6399. http://cancerres.aacrjournals.or…

44. Coppola, Domenico, et al. “Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling.” The American journal of pathology 179.1 (2011): 37-45. http://ac.els-cdn.com/S000294401…

45. Naito, Yoshitaka, et al. “CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer.” Cancer research 58.16 (1998): 3491-3494. http://cancerres.aacrjournals.or…

46. Galon, Jérôme, et al. “Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.” Science 313.5795 (2006): 1960-1964. https://www.researchgate.net/pro…

47. Laghi, Luigi, et al. “CD3+ cells at the invasive margin of deeply invading (pT3–T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study.” The lancet oncology 10.9 (2009): 877-884.

48. Loi, Sherene, et al. “Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.” Journal of clinical oncology 31.7 (2013): 860-867. Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98: Journal of Clinical Oncology: Vol 31, No 7

49. Ali, H. R., et al. “Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients.” Annals of oncology (2014): mdu191. https://oup.silverchair-cdn.com/…

50. Loi, S., et al. “Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.” Annals of oncology 25.8 (2014): 1544-1550. https://www.researchgate.net/pro…

51. Adams, Sylvia, et al. “Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.” Journal of clinical oncology 32.27 (2014): 2959-2966. Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199: Journal of Clinical Oncology: Vol 32, No 27

52. Salgado, Roberto, et al. “Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial.” JAMA oncology 1.4 (2015): 448-455. https://www.researchgate.net/pro…

53. Pages, F., et al. “Immune infiltration in human tumors: a prognostic factor that should not be ignored.” Oncogene 29.8 (2010): 1093-1102. http://www.nature.com/onc/journa…

54. Nelson, Brad H. “The impact of T‐cell immunity on ovarian cancer outcomes.” Immunological reviews 222.1 (2008): 101-116.

55. Jafari, Siavash, Mahyar Etminan, and Kourosh Afshar. “Nonsteroidal anti-inflammatory drugs and prostate cancer: a systematic review of the literature and meta-analysis.” Can Urol Assoc J 3.4 (2009): 323-330. http://citeseerx.ist.psu.edu/vie…

56. Mahmud, Salaheddin M., Eduardo L. Franco, and Armen G. Aprikian. “Use of nonsteroidal anti‐inflammatory drugs and prostate cancer risk: A meta‐analysis.” International journal of cancer 127.7 (2010): 1680-1691. http://onlinelibrary.wiley.com/d…

57. Bosetti, Cristina, et al. “Aspirin and urologic cancer risk: an update.” Nature Reviews Urology 9.2 (2012): 102-110.

58. Liu, Yanqiong, et al. “Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis.” BMC medicine 12.1 (2014): 55. Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis

59. Huang, Tian-bao, et al. “Aspirin use and the risk of prostate cancer: a meta-analysis of 24 epidemiologic studies.” International urology and nephrology 46.9 (2014): 1715-1728. https://www.researchgate.net/pro…

60. Vidal, Adriana C., et al. “Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study.” Clinical Cancer Research 21.4 (2015): 756-762. http://clincancerres.aacrjournal…

61. Sostres, Carlos, Carla Jerusalen Gargallo, and Angel Lanas. “Aspirin, cyclooxygenase inhibition and colorectal cancer.” World J Gastrointest Pharmacol Ther 5.1 (2014): 40-9. http://www.wjgnet.com/esps/DownL…

62. Thun, Michael J., Eric J. Jacobs, and Carlo Patrono. “The role of aspirin in cancer prevention.” Nature reviews Clinical oncology 9.5 (2012): 259-267. http://vetbiotech.um.ac.ir/param…

63. Rothwell, Peter M., et al. “Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.” The Lancet 377.9759 (2011): 31-41. https://www.researchgate.net/pro…

64. Velayos, Fernando S., et al. “Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study.” Gastroenterology 130.7 (2006): 1941-1949.

65. DeCensi, Andrea, et al. “Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis.” Cancer prevention research (2010): 1940-6207. http://cancerpreventionresearch….

66. Gandini, Sara, et al. “Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders.” Cancer prevention research (2014). http://cancerpreventionresearch….

67. Thakkar, Bindiya, et al. “Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies.” Metabolism 62.7 (2013): 922-934. http://ac.els-cdn.com/S002604951…

68. Pulito, Claudio, et al. “Metformin: on ongoing journey across diabetes, cancer therapy and prevention.” Metabolites 3.4 (2013): 1051-1075. http://www.mdpi.com/2218-1989/3/…

https://www.quora.com/Is-there-an-association-between-inflammation-and-cancer/answer/Tirumalai-Kamala

What are the various applications of polyclonal antibodies?

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Some definitions first for a general audience

Polyclonal antibodies – Wikipedia: Usually the serum product of an immunized animal. Heterogeneous because they comprise

  • Various antibodies specific for a variety of antigens, some specific for different epitopes of the same antigen,
  • Different antibody classes and sub-classes, i.e., Isotype (immunology) – Wikipedia, and
  • Wide range of antibody concentrations (Antibody titer – Wikipedia) and affinities for their respective antigens.

Monoclonal antibody – Wikipedia (mAbs): Products of a hybridoma clone (Hybridoma technology – Wikipedia), derived from a single antibody-secreting B cell fused to a myeloma cell line. Homogeneous. In essence, product of a cellular factory spewing out that one mAb. Thus, the secreted antibody is mono-specific, with a single affinity to the single epitope it binds on the antigen, and is of a single antibody class (Immunoglobulin class switching – Wikipedia).

Epitope: Site that an antibody binds on an antigen.

Affinity: Strength of antibody binding to antigen.

Avidity: Sum of affinities of multiple antigen-binding sites on an antibody.

Polyclonal antibodies: Pros & Cons

Unlike mAbs, polyclonal antibodies

  • Can be produced faster and more cheaply.
  • Can bind their target antigens under a variety of salt and pH concentrations so are more stable.
  • Comprise antibodies specific for different epitopes of a given antigen. Outcome is higher antibody affinity, i.e., antigen-binding sensitivity.
  • Easier to couple to a variety of labels such as enzymes, Fluorophore – Wikipedia, etc.

Such attributes make polyclonal antibodies a better option in assays

  • For binding proteins sensitive to conformational changes or denaturation, or which are polymorphic.
  • In Immunoprecipitation – Wikipedia (IP) and Chromatin immunoprecipitation – Wikipedia (ChIP) assays.
  • For detecting low concentrations of a given protein.
  • As capture antibody in sandwich ELISA – Wikipedia (Enzyme-Linked Immunosorbent Assay), one of the most widely used assays to detect and quantify antigens. For capture and not for detection. ELISA assays using them for detection are more susceptible to dramatic changes when diluting sera since a polyclonal serum contains varying antigen specificities and affinities at different concentrations (titers). OTOH, diluting mAbs doesn’t affect their affinity/avidity so easier to interpret that a change in reaction results from change in antigen concentration. While mAbs have a single specificity, heterogeneity of polyclonal antibodies means varying affinities even against the same epitope which makes assessing their specificity much more complicated. Unlike polyclonal antibodies, using mAbs for detection in ELISAs allows calibration, and therefore, standardization.

However, major drawbacks of polyclonal antibodies are

  • Batch-to-batch variability since each batch is typically product of one or few immunized animals. OTOH, being products of immortalized cells, practically limitless amounts of mAbs can be produced.
  • Binding multiple epitopes on a given antigen increases scope for cross-reactivity. This necessitates affinity purification (Affinity chromatography – Wikipedia) before using them in assays.
  • Consequence of polyclonal antibodies comprising different antigenic specificities and affinities is higher background signal in various assays, i.e., lower specificity.

Some Therapeutic Applications of Polyclonal antibodies

Polyclonal antibodies are widely used for Immunosuppression – Wikipedia to prevent acute rejection in transplant recipients. In transplants, one of the major logistical problems is severe, chronic shortage of living donors. As a result, criteria have steadily expanded to include organs previously precluded from consideration. These include greater tissue mismatches, and organ and tissue donations after cardiac death. Problem with using expanded criteria organs is higher probability of rejection. This necessitates using more powerful immunosuppressive therapy, often lifelong.

Some polyclonal antibody preparations have become mainstays among immunosuppressive regimens used to prevent early, acute rejection in solid organ transplants. Two main types of polyclonal antibody preparations are widely used, one sourced from rabbits, the other from horses (Anti-thymocyte globulin – Wikipedia). They are (1, 2, 3, 4, 5, 6)

  • Thymoglobulin®, a rabbit anthymocyte globulin (rATG).
  • ATG-Fresenius, a rabbit anthymocyte globulin.
  • ATGAM® or eATG, equine antithymocyte globulin.
  • Lymphoglobulin®, horse ATG.

Thymoglobulin®, a rabbit anthymocyte globulin (rATG)

  • First licensed in April 1984 in Europe and in 1999 in USA (6).
  • Manufactured by Genzyme/Sanofi.
  • Is polyclonal IgG anti-human thymocyte globulin.
  • Rabbits are immunized with human Thymocyte – Wikipedia (developing T cells).
  • Is widely used in solid organ transplants.
  • Was given to ~ half of all new kidney transplant recipients in the US between 2000 and 2009 (7).
  • Initially used in kidney transplants, today it’s used in a variety of solid organ transplants such as liver, heart, lung, pancreas, intestinal as well as hematopoietic stem cell transplantation and aplastic anemia (1, 5).

ATG-Fresenius

  • Manufactured by Neovii Biotech (formerly Fresenius Biotech) (4).
  • Rabbits are immunized with a human Jurkat cells – Wikipedia line.

ATGAM® or eATG, equine antithymocyte globulin (5)

  • Horses are immunized with human T cells and their antibodies harvested from their serum.
  • Developed by Peter Medawar – Wikipedia in the 1950s.
  • Thomas Starzl – Wikipedia started using it in the 1960s.
  • Registered for use in kidney transplantation in the US since 1981.
  • First commercially available ATG in Europe and USA.
  • Manufactured by Pfizer (previously Pharmacia Upjohn).

Lymphoglobulin®, Horse ATG

  • Manufactured by Genzyme/Sanofi.

To avoid early, acute rejection, high-risk transplant recipients, usually defined as glucocorticoid-resistant, are typically given these antibodies starting shortly before the transplant and continuing immediately afterward for a few weeks.

While exact mechanism by which these complex reagents immunosuppress is unknown, ADCC (Antibody-dependent cell-mediated cytotoxicity – Wikipedia) likely causes rapid and widespead lysis of T cells though elimination of other cells such as NK cells is also possible. This Rx also entails serious risks which include Cytokine release syndrome – Wikipedia, Thrombocytopenia – Wikipedia, Leukopenia – Wikipedia, higher infection risk, and many others (2, 3, 4, 5, 8, 9).

Bibliography

1. Gaber, A. Osama, et al. “Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology.” Drugs 70.6 (2010): 691-732. https://www.researchgate.net/pro…

2. Penninga, Luit. Immunosuppressive Polyclonal and Monoclonal T-cell Antibody Induction Therapy for Solid Organ Transplant Recipients: Systematic Reviews with Meta-analyses and Trial Sequential Analyses of Randomised Clinical Trials: Ph. D. Thesis. Afsnit 7812, Blegdamsvej 9, 2100 Ø, 2014. http://citeseerx.ist.psu.edu/vie…

3. Chen, Huifang, Qian, Shiguang. “Current Immunosuppressive Therapy in Organ Transplantation.” CURRENT IMMUNOSUPPRESSIVE THERAPY IN ORGAN TRANSPLANTATION: 51. https://www.researchgate.net/pro…

4. Nishihori, Taiga, et al. “Antithymocyte globulin in allogeneic hematopoietic cell transplantation: benefits and limitations.” Immunotherapy 8.4 (2016): 435-447.

5. https://www.fda.gov/downloads/Ap…

6. Thymoglobulin

7. Cai, J., and P. I. Terasaki. “The current trend of induction and maintenance treatment in patient of different PRA levels: a report on OPTN/UNOS Kidney Transplant Registry data.” Clinical transplants (2009): 45-52.

8. Bamoulid, Jamal, et al. “Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects.” Nephrology Dialysis Transplantation (2016): gfw368.)

9. Malvezzi, Paolo, Thomas Jouve, and Lionel Rostaing. “Induction by anti-thymocyte globulins in kidney transplantation: a review of the literature and current usage.” Journal of nephropathology 4.4 (2015): 110. https://www.researchgate.net/pro…

https://www.quora.com/What-are-the-various-applications-of-polyclonal-antibodies/answer/Tirumalai-Kamala

Why are some clinical trials finished, but the results not reported?

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Short answer

  • Too many exemptions. Legal requirements for reporting results of completed clinical trials contain so many exemptions that most trials entered into Home – ClinicalTrials.gov are exempt.
  • Enforcement too lax. The US FDA and NIH are tasked with enforcing these reporting rules but not only do they themselves flout them, they also do little to ensure compliance. For example, a 2015 investigation (1) found not a single researcher or trial sponsor had been fined or penalized since the law came into effect in 2008.

Clinical Trial Results Under-reporting: A Chronic Problem Of Epidemic Proportions

Under-reporting of clinical trial results has long been chronic and widespread for decades (2).

A 2016 analysis (3) of the fate of 5918 abstracts presented at the American Society of Anesthesiologists annual meetings from 2001 to 2004 found

  • 1052 presented results of human RCTs.
  • Only 54%, 568 of 1052, were published within 10 years of the initial presentation.
  • RCTs with positive data (defined as one showing a statistically significant result in favor of the experimental group) were 42% more likely to be published compared to those with negative data.
  • Positive or negative data notwithstanding, most of these studies were small with median 40 to 50 participants, which only adds insult to injury. Not only is scope of false inference already considerable, such inferences would be drawn from tiny, utterly unrepresentative slices of the whole, greatly increasing scope of false positives (4).

A 2016 analysis (5) of drugs and biologics tested in pivotal trials from 1998 to 2008 found

  • 54% of them failed.
  • Trial results were published for only 40% of the ones that failed.

Eventually the epidemic scale of the problem prompted the US government to enact the 2007 US FDA Amendments Act (FDAAA), which (6, emphasis mine)

‘requires that the results from clinical trials of Food and Drug Administration–approved drugs and devices conducted in the United States must be made publicly available at Home – ClinicalTrials.gov within 1 y of the completion of the trial, whether the results are published or not.’

So Much Promised, So Little Achieved: Laws Mean Nothing If They Aren’t Enforced

A 2016 analysis (7) found that of 13327 completed or terminated clinical trials from January 1 2008 until August 31, 2012,

  • 51 top academic and non-profit institutions posted clinical trial results on Home – ClinicalTrials.gov only 13% of the time even two years after they’re finished when the legal requirement is to do so within one year of completion.
  • Researchers published their findings in medical journals within two years only 29% of the time.

A 2017 analysis (8) of breast cancer trials registered at Home – ClinicalTrials.gov from 2000 to 2012 found no improvement in reporting. Rather it found

  • Trials with statistically significant outcome more likely to be published.
  • Under-reporting of clinical trial results.
  • Delay in publication of statistically non-significant results.

Situation is not much different even for posting trial results on the Home – ClinicalTrials.gov webpage. One study (9) examined 17536 studies with results posted at Home – ClinicalTrials.gov, 2823 of which were completed randomized phase II or III trials.

  • 1400 of 2823 completed trials (~50%) reported the treatment effect estimate and/or p value. Of these, 844 (60%) had statistically significant results.
  • 1423 trials only posted data without reporting results, which, however, could be calculated, at least in theory. Calculation was possible for 929 (65%), not for 494 (35%), either due to insufficient reporting, data censoring or repeat measurements. Of these 929, only 342 (37%) had statistically significant results.
  • Key comparison then is the large difference in statistically significant results between those who posted their treatment effect estimate and/or p value (844 of 1400, 60%) versus those who didn’t (342 of 929, 37%).
  • Thus, positive result bias is prevalent not just in publications but even in merely reporting them to Home – ClinicalTrials.gov.
  • Irony is posting results to Home – ClinicalTrials.gov is likely far more valuable to the public
    • Site is freely accessible worldwide unlike scientific journals which are more often hidden behind exorbitantly priced paywalls.
    • A 2013 Plos Medicine analysis (6) found posted Home – ClinicalTrials.gov results for 212 published studies were far more complete, especially in reporting potentially adverse events, information of vital importance to patients.

The American health news web-site Stat (website) – Wikipedia, published results of a 2015 investigation (1) that showed

  • Top flouters weren’t merely prestigious ones like Memorial Sloan Kettering, Stanford, Eli Lilly and GlaxoSmithKline but ironically the enforcers themselves. Yes, even NIH routinely flouted the rule it’s supposed to enforce (see below from 1).
  • Such high-profile exposure caught the attention of the US Senate with one senator chiding the NIH for failing to do its job (10).
  • Even then US Vice-President Joe Biden called for defunding federal grant recipients who didn’t comply with the law.
  • In the short-term, reporting of clinical trials results jumped 25% over the same period the previous years.

Later in 2016, the US government posted new regulations (11) requiring public reporting of many more clinical trials, including some for drugs and devices that never reach the market. Problem is these rules don’t go far enough. There are too many exemptions.

  • Trials entered into Home – ClinicalTrials.gov before 2008 are exempt.
  • So are ‘privately funded studies — including small trials examining just the safety of a new drug, small feasibility studies of medical devices, and behavioral intervention studies‘ (1).
  • Thus the rules only apply to a fraction of registered trials.
  • The 2015 STAT news investigation (1) found they only applied to a mere 4.5%, ~9000 of ~200000 trials.

Rampant Publication bias – Wikipedia, defined as ‘published research which is systematically unrepresentative of the population of completed studies‘ (12), and originally described in 1979 as the file drawer problem (13). The usual suspects of employers (universities, academic institutes, biotech/pharma, hospitals, medical centers, etc), journal editors, peer reviewers, funding agencies, even mass media, seem to continue to strongly prefer positive and novel results. Cost of basing treatments on not the whole picture but on a small, biased slice of it is harm to patients (14, 15, 16, 17). Treatments based on a single RCT could later turn out to be useless or even dangerous (18).

Bibliography

1. STAT, Charles Piller, December 13, 2015. Patients endangered as law is ignored

2. Rotonda, Tavola. “Underreporting research is scientific misconduct.” Jama 263 (1990): 1405-1408.; Antes, Gerd, and Iain Chalmers. “Under-reporting of clinical trials is unethical.” The Lancet 361.9362 (2003): 978-979.

3. Chong, Simon W., et al. “The relationship between study findings and publication outcome in anesthesia research: a retrospective observational study examining publication bias.” Canadian Journal of Anesthesia/Journal canadien d’anesthésie 63.6 (2016): 682-690.

4. Dumas-Mallet, Estelle, et al. “Low statistical power in biomedical science: a review of three human research domains.” Royal Society Open Science 4.2 (2017): 160254. http://rsos.royalsocietypublishi…

5. Hwang, Thomas J., et al. “Failure of investigational drugs in late-stage clinical development and publication of trial results.” JAMA Internal Medicine 176.12 (2016): 1826-1833.

6. Riveros, Carolina, et al. “Timing and completeness of trial results posted at ClinicalTrials. gov and published in journals.” PLoS Med 10.12 (2013): e1001566. http://journals.plos.org/plosmed…

7. Chen, Ruijun, et al. “Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers.” bmj 352 (2016): i637. http://www.bmj.com/content/bmj/3…

8. Song, Seung Yeon, et al. “The significance of the trial outcome was associated with publication rate and time to publication.” Journal of Clinical Epidemiology (2017).

9. Dechartres, Agnes, et al. “Reporting of statistically significant results at ClinicalTrials. gov for completed superiority randomized controlled trials.” BMC medicine 14.1 (2016): 192. Reporting of statistically significant results at ClinicalTrials.gov for completed superiority randomized controlled trials

10. STAT, Charles Piller, February 19, 2016. Senator Charles Grassley urges better clinical trials reporting

11. https://s3.amazonaws.com/public-…

12. Rothstein HR, Sutton AJ, Borenstein M. Publication bias in meta-analysis. In: Rothstein HR, Sutton AJ, Borenstein M (Eds). Publication Bias in Meta-Analysis: Prevention, Assesment and Adjustments. John Wiley & Sons, Inc. 2006.

13. Rosenthal, Robert. “The file drawer problem and tolerance for null results.” Psychological bulletin 86.3 (1979): 638. http://datacolada.org/wp-content…

14. Horton, Richard. “Offline: What is medicine’s 5 sigma?.” The Lancet 385.9976 (2015): 1380. http://www.thelancet.com/pdfs/jo…

15. Smaldino, Paul E., and Richard McElreath. “The natural selection of bad science.” Royal Society Open Science 3.9 (2016): 160384. https://www.researchgate.net/pro…

16. Higginson, Andrew D., and Marcus R. Munafò. “Current incentives for scientists lead to underpowered studies with erroneous conclusions.” PLoS Biology 14.11 (2016): e2000995. http://journals.plos.org/plosbio…

17. Nissen, Silas Boye, et al. “Publication bias and the canonization of false facts.” Elife 5 (2016): e21451. https://elifesciences.org/conten…

18. Prasad, Vinay, et al. “A decade of reversal: an analysis of 146 contradicted medical practices.” Mayo Clinic Proceedings. Vol. 88. No. 8. Elsevier, 2013. https://www.researchgate.net/pro…

https://www.quora.com/Why-are-some-clinical-trials-finished-but-the-results-not-reported/answer/Tirumalai-Kamala

Does processed milk cause multiple sclerosis flare up?

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Brief History Of Nebulous Connection Between Milk & MS (Multiple Sclerosis)

Sparse data on this subject consists of

  • An US epidemiological study that compared 1949 to 1967 MS mortality rates and food consumption data, and found high correlation (0.8 to 0.9) with milk consumption (1).
  • A couple of cross-sectional epidemiological studies from 1976 (2) and 1992 (3) that compared MS prevalence and dairy product consumption. The second one looked across 29 populations in 27 countries and suggested MS progression could be influenced by factors in liquid cow’s milk but not in processed milk.

The story then appeared to lie dormant for the next several years until revived by a 2000 rat EAE (Experimental autoimmune encephalomyelitis – Wikipedia) model study (4). This study mechanistically showed Butyrophilin – Wikipedia, a milk fat globule membrane protein expressed only by the lactating mammary gland,

Similar experiments in a mouse model (5) also showed Butyrophilin could prevent MOG-induced EAE, i.e., that this milk component could protect against EAE.

Problem is though originally developed in the 1950s to supposedly mimic human MS, these rodent (mainly rat and mouse) models simply don’t mimic human MS very well (6), haven’t yielded much insight or practical therapies and yet have taken over basic MS research and remain the mainstay in the field.

Meantime, a couple of small human studies from France (n=44 MS versus 30 controls, 7) and the US (n= 35 MS versus 25 controls, 8) yielded contradictory data

  • The French study (7) found MS patients with higher circulating antibody levels cross-reactive to MOG and Butyrophilin.
  • The US study (8) found MS patients and controls had similar levels of circulating antibodies cross-reactive to MOG and Butyrophilin. However, this US study also compared anti-MOG and -Butyrophilin antibody responses in blood as well as CSF (Cerebrospinal fluid – Wikipedia) of MS patients and found they were specific for different epitopes (parts) of Butyrophilin, the one dominating in the CSF also cross-reacting to a homologous MOG peptide in 34% of MS patients, i.e., possible Molecular mimicry – Wikipedia between MOG and Butyrophilin.

In addition to these two human studies contradicting each other, these purely observational studies examined circulating antibody levels, i.e., B cell – Wikipedia, not T, cell response as the animal model studies did. Apples and oranges.

While Butyrophilin’s plausible role in MS progression lies in its high sequence similarity to MOG (9), i.e., Molecular mimicry – Wikipedia, data from these two small human studies are inconclusive and so far there’s no other data on milk proteins’ role in MS prognosis or disease course (10).

How Milk Or Any Other Factor Might Trigger Or Flare MS (Multiple Sclerosis)

Though there are many suspects, confirmed triggers for MS are still unknown. Most convincing data exist not for dietary factors such as milk but for vitamin D levels and its receptor polymorphisms, history of Epstein-Barr virus infection including Infectious mononucleosis – Wikipedia and smoking (11, 12).

No matter the trigger though, how might MS disease cascade follow? Prime suspect is molecular mimicry, i.e., molecular level similarity between such triggers and the target of autoimmune attack in MS, typically proteins such as MOG expressed on Oligodendrocyte – Wikipedia, myelin sheath cells.

  • However, even this is insufficient. Consider milk for example. Many more people drink milk than get MS. If molecular mimicry alone sufficed, they should all have MS and they don’t.
  • Clearly other factors are also involved. No matter the degree of molecular mimicry, nothing can ensue if a person’s immune system can’t ‘see’ it.
    • An immunologically necessary condition would thus be the HLA (Human leukocyte antigen – Wikipedia) haplotype. However, HLA haplotype alone wouldn’t suffice because far more people share HLA haplotypes than develop MS.
    • Breakdown in T cell tolerance is also necessary. After all, during their development in the thymus, T cells with the capacity to recognize oligodendrocyte proteins should get deleted. Obviously that process seems to fall short in MS patients.
  • Thus target antigen (and molecular mimic)-specific T cells should be present and such target(s) of immune attack should be properly processed and presented to these T cells. However, though appropriate HLA haplotype and CNS (Central nervous system – Wikipedia) protein(s)-specific T cells are the necessary building blocks for MS autoimmune pathology, their presence alone doesn’t suffice either.
  • Context is also necessary, i.e., predisposing and/or conditioning factors necessary to drive the pathological immune response necessary for MS expression. Totality of such factors, sufficient to explain MS in each and every case, still remain undefined.

Bibliography

1. Agranoff, BernardW, and David Goldberg. “Diet and the geographical distribution of multiple sclerosis.” The Lancet 304.7888 (1974): 1061-1066. https://deepblue.lib.umich.edu/b…

2. Butcher, J. “The distribution of multiple sclerosis in relation to the dairy industry and milk consumption.” The New Zealand Medical Journal 83.566 (1976): 427-430)

3. Malosse, D., et al. “Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study.” Neuroepidemiology 11.4-6 (1993): 304-312.

4. Stefferl, Andreas, et al. “Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis.” The Journal of Immunology 165.5 (2000): 2859-2865. http://www.jimmunol.org/content/…

5. Mañá, Paula, et al. “Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin.” International immunology 16.3 (2004): 489-499. https://www.researchgate.net/pro…

6. Tirumalai Kamala’s answer to Why can chemicals that block the alpha tumour necrosis factor make multiple sclerosis worse? Do inhibiting cytokines make inflammation worse?

7. De March, A. Kennel, et al. “Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis.” Journal of neuroimmunology 135.1 (2003): 117-125.

8. Guggenmos, Johannes, et al. “Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis.” The Journal of Immunology 172.1 (2004): 661-668. http://www.jimmunol.org/content/…

9. Vojdani, Aristo. “Molecular mimicry as a mechanism for food immune reactivities and autoimmunity.” Altern Ther Health Med 21.Suppl 1 (2015): 34-45. http://bant.org.uk/wp-content/up…

10. Von Geldern, Gloria, and Ellen M. Mowry. “The influence of nutritional factors on the prognosis of multiple sclerosis.” Nature Reviews Neurology 8.12 (2012): 678-689.

11. Belbasis, Lazaros, et al. “Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses.” The Lancet Neurology 14.3 (2015): 263-273.

12. Tirumalai Kamala’s answer to Why does Colorado have the highest rate of multiple sclerosis?

https://www.quora.com/Does-processed-milk-cause-multiple-sclerosis-flare-up/answer/Tirumalai-Kamala

What experiments can we do with TILs to work out the mechanism of action of checkpoint inhibitors?

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Typical targets of checkpoint inhibitors (usually humanized monoclonal antibodies) are molecules such as Programmed cell death protein 1 – Wikipedia (PD-1), PD-L1 – Wikipedia, CTLA-4 – Wikipedia. Applying checkpoint inhibitors (Cancer immunotherapy – Wikipedia) when such molecules are expressed by cells within a given tumor is akin to releasing the brakes of tumor antigen-specific Tumor-infiltrating lymphocytes – Wikipedia (TILs) present within them, empowering them to eliminate such tumors. This is the purported mechanism of action (MOA) of checkpoint inhibitors. However, their major problem is non-specificity, as in potential for off-target responses since they could release the brakes off of all T cells that express them, not just those that are tumor antigen-specific. To be able to effectively harness TILs to destroy any given tumor,

  1. Tumor should have TILs within it in the first place.
  2. Tumor should express ‘neoantigens’, i.e., tumor-specific antigens.
  3. TILs being used in immunotherapy (1) should be specific for peptides derived from antigens specifically expressed by tumor (2).

2 and 3 present formidable challenges because unless both conditions are met, cancer immunotherapy could end up attacking the body itself, with tragic results, since even death is possible. For example, while details haven’t been divulged, higher than anticipated clinical trial deaths have led leading cancer immunotherapy company, Juno Therapeutics – Wikipedia, to recently scrap its lead CAR-T therapy (1).

Thus, checkpoint inhibitors notwithstanding, to assess whether TILs might be induced to specifically target a given tumor, the experimental process entails

  1. Assessing whether the tumor has TILs and if yes, then isolating them.
  2. Assessing whether tumor expresses tumor-specific antigens by comparing tumor and matched healthy tissue.
  3. Confirming tumor cells themselves can indeed process and present these tumor-specific antigens within MHC class I (to tumor-specific cytotoxic CD8+ T cells) or MHC class II (to tumor-specific helper CD4+ T cells) molecules, an extremely technically challenging task made even more arduous by the following caveats,
    1. Even if a given tumor expresses several tumor-specific antigens, it might not present peptides derived from them since tumors are known to have aberrant antigen processing and presentation pathways (2).
    2. Differentiating immunologically relevant from irrelevant peptides is turning out to be more complex than envisaged (3).
    3. MHC class II-binding peptides are longer and bind more promiscuously compared to those that bind class I, making binding predictions much more technically challenging.
    4. Tumor cells rarely express MHC class II.
  4. Assessing whether isolated TILs are tumor-specific, i.e., specifically bind tumor-derived pMHC (peptides bound to Major histocompatibility complex – Wikipedia (MHC)).
  5. Assessing effect of checkpoint inhibitors on such tumor-specific TILs. If tumor-specific TILs don’t express the targets of such checkpoint inhibitors and yet also don’t attack and eliminate the tumor,
    1. They could be T regs (Regulatory T cell – Wikipedia) in which case it may be difficult to impossible to engineer effective anti-tumor immunity using them.
    2. If not Tregs, may need to assess whether such TILs express novel ‘brakes’, targets for novel checkpoint inhibitors.

Plenty of obstacles stand in the way of these experimental imperatives. Steps 3 and 4 the most fiendishly complicated, no one method exists to reliably assess both in a high-throughput fashion nor are existing In silico – Wikipedia approaches fool-proof (4). There are other hurdles as well.

  • Not all tumors express abundant tumor-specific antigens (4, 5, 6, 7).
  • Some tumors can mutate ferociously, i.e., cancer Immunoediting – Wikipedia (8, 9), which reduces the likelihood of finding tumor-specific TILs.
  • Rather than being tumor antigen-specific, some TILs may be specific for antigens that both tumor and normal tissue cells express (cross-reactivity).
    • T cells function by recognizing and binding pMHC through their T-cell receptor – Wikipedia (TCR). Central tolerance – Wikipedia, the developmental process of eliminating T cells reactive to cells of the body in which they develop, is incomplete.
    • The TCR is inherently cross-reactive, capable of binding >1 pMHC, i.e., can bind peptides derived from different antigens presented by the same MHC molecule (cross-reactivity) (10).
  • Thus, possible for checkpoint inhibitors to trigger autoimmunity.

However, promise of this approach is sustained by examples of tumor-specific TILs (11) having been found in

  • Human non-small cell lung cancer (12).
  • Human melanoma (13, 14, 15, 16, 17, 18, 19).
  • Human AML (Acute Myeloid Leukemia) (20).
  • Human CLL (Chronic Lymphocytic Leukemia) (21, 22).

Bibliography

1. http://www.xconomy.com/seattle/2…

2. Leone, Patrizia, et al. “MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells.” Journal of the National Cancer Institute 105.16 (2013): 1172-1187. https://oup.silverchair-cdn.com/…

3. Gilchuk, Pavlo, et al. “Discovering protective CD8 T cell epitopes—no single immunologic property predicts it!.” Current opinion in immunology 34 (2015): 43-51. https://www.researchgate.net/pro…

4. Gfeller, David, et al. “Current tools for predicting cancer-specific T cell immunity.” OncoImmunology 5.7 (2016): e1177691. https://www.researchgate.net/pro…

5. Alexandrov, Ludmil B., et al. “Signatures of mutational processes in human cancer.” Nature 500.7463 (2013): 415-421. https://www.researchgate.net/pro…

6. Gubin, Matthew M., et al. “Tumor neoantigens: building a framework for personalized cancer immunotherapy.” The Journal of clinical investigation 125.9 (2015): 3413-3421. Tumor neoantigens: building a framework for personalized cancer immunotherapy

7. Schumacher, Ton N., and Robert D. Schreiber. “Neoantigens in cancer immunotherapy.” Science 348.6230 (2015): 69-74. http://pmpathway.wustl.edu/files…

8. Matsushita, Hirokazu, et al. “Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.” Nature 482.7385 (2012): 400-404. https://www.researchgate.net/pro…

9. Rooney, Michael S., et al. “Molecular and genetic properties of tumors associated with local immune cytolytic activity.” Cell 160.1 (2015): 48-61. http://wulab.dfci.harvard.edu/si…

10. Tirumalai Kamala’s answer to How is it possible that a T Cell Receptor (TCR) recognises as few as 1-3 residues of the MHC-associated peptide?

11. McGranahan, Nicholas, et al. “Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.” Science 351.6280 (2016): 1463-1469. https://www.ncbi.nlm.nih.gov/pmc…

12. Rizvi, Naiyer A., et al. “Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer.” Science 348.6230 (2015): 124-128. https://www.ncbi.nlm.nih.gov/pmc…

13. Kvistborg, Pia, et al. “TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients.” Oncoimmunology 1.4 (2012): 409-418. http://www.tandfonline.com/doi/p…

14. Andersen, Rikke Sick, et al. “High frequency of T cells specific for cryptic epitopes in melanoma patients.” Oncoimmunology 2.7 (2013): e25374.; http://www.tandfonline.com/doi/p…

15. Robbins, Paul F., et al. “Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells.” Nature medicine 19.6 (2013): 747-752. http://ggdpathway.wustl.edu/file…

16. Lu, Yong-Chen, et al. “Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions.” Clinical Cancer Research 20.13 (2014): 3401-3410. http://clincancerres.aacrjournal…

17. Frøsig, Thomas Mørch, et al. “Broadening the repertoire of melanoma-associated T-cell epitopes.” Cancer Immunology, Immunotherapy 64.5 (2015): 609-620. https://www.researchgate.net/pro…

18. Linnemann, Carsten, et al. “High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma.” Nature medicine 21.1 (2015): 81-85.

19. Cohen, Cyrille J., et al. “Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes.” The Journal of clinical investigation 125.10 (2015): 3981-3991. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes

20. Berlin, C., et al. “Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy.” Leukemia 29.3 (2015): 647-659.

21. Rajasagi, Mohini, et al. “Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia.” Blood 124.3 (2014): 453-462. ; http://www.bloodjournal.org/cont…

22. Kowalewski, Daniel J., et al. “HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL).” Proceedings of the National Academy of Sciences 112.2 (2015): E166-E175. http://www.pnas.org/content/112/…

https://www.quora.com/What-experiments-can-we-do-with-TILs-to-work-out-the-mechanism-of-action-of-checkpoint-inhibitors/answer/Tirumalai-Kamala

Is the placebo effect very powerful?

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The https://en.wikipedia.org/wiki/Pl… effect is powerful enough to be the bane of the https://en.wikipedia.org/wiki/Ra… (RCT), https://en.wikipedia.org/wiki/Bi…, and really of modern medicine itself. A dynamic attribute since it can be seemingly manipulated at will, it maybe more accurate to call it the Placebo Response, as proposed by https://en.wikipedia.org/wiki/Fa…. Their considerable scientific and economic impact is evidence of the shadow placebo responses cast on all of medicine.

Answer highlights

  • Placebo responses operate even for legitimate drugs and therapies.
  • Placebos elicit beneficial responses even when patients take them knowingly.
  • Placebo responses are becoming stronger, driving up drug development costs.
  • How placebo responses could be leveraged to make medicine more effective, cheaper and safer.
  • Examples that illustrate how just about anything to do with a Rx, colors, sizes, numbers, pills versus injections, even diligence in taking placebos, can trigger placebo response and influence its magnitude.

Longer answer for those interested in the details

Scientific Impact Of Placebo Responses

Placebo responses tend to be more pronounced in

  • Patient-reported outcomes rather than those independently-assessed (1).
  • Questionnaire- rather than clinical biomarker-based outcomes (2, 3).

No surprise since psychology is known to play an outsized role in pain and mental health conditions such as depression, which tend to lack objective diagnostic tests and are instead subjectively diagnosed on the basis of periodically revised, fuzzy questionnaires. Problem is most diseases lack biomarkers with proven therapeutic value.

However, even physiological attributes such as blood glucose levels entail placebo responses. Their concentrations in type II diabetes patients change commensurate to how their awareness of time is experimentally manipulated, lower and higher for those looking at clocks tweaked to run 2X slower or faster, respectively* (4). Blood glucose levels! Now that’s an objectively measured response. Already then, we can start to dimly discern the margins of modern biomedicine’s colossal problem. Unsubtly and arbitrarily splitting body (physiology) and mind (psychology) as a matter of course, it may not even be playing with a full deck since almost daily such new pieces of data force us to confront just how intertwined they actually are.

Placebo Responses: Outcome Of Expectation, Conditioning & Rx-Associated Communication/Ritual

Drugs and therapies are supposed to work specifically by targeting specific molecules and pathways involved in different diseases. Placebos, usually sugar pills, are supposed to mimic certain drug attributes. How? Three components working in tandem appear to explain not just how placebos work but also how placebo responses operate even for specific drugs and therapies.

Expectation is the outcome of learning, part of a general conditioning process of knowing one is getting Rx. The myriad components involved in getting Rx can be construed as Rx-associated communication/ritual (the physician, nurses, other care staff; are they warm, caring, supportive; do they explain what’s happening and what they’re doing; how much time they spend with the patient), etc.. Expectations and conditioning can mutually reinforce each other.

Paradigm shift lies in realizing placebo responses are ever-operational, even with legitimate drugs and therapies. Confused? The ‘open-hidden’ experiment design perfected by Benedetti’s team is not only clever but also groundbreaking because it reveals placebo response is an inherent part of response to medications and therapies.

In the original archetype of the ‘open-hidden’ experiment design (5), the powerful opioid painkiller https://en.wikipedia.org/wiki/Fe… was more effective when given openly by a doctor compared to being given secretly. Since then, the observation has been replicated in anxiety and Parkinson’s (6, 7). Knowingly getting a medication or therapy seems to set up expectations that make the medication or therapy more effective, i.e., by tapping Rx’s latent placebo response (8, See below from 9).

https://en.wikipedia.org/wiki/Te…, another leading placebo response researcher, has turned another conventional wisdom about placebos on their head. Giving patients placebos typically entails deception. Naturally this presents an ethical dilemma. If there are indeed bonafide benefits to placebos, how to reap them if doing so violates ethics?

Kaptchuk’s revolutionary idea is to turn this notion of secrecy on its head and to instead give placebos knowingly. Convention dictates knowingly taking placebos should blunt, even eliminate their benefit. Turns out to be not so. First for IBS (n=80, 10) then for lower back pain (n=97, 11), research on small patient groups shows knowingly taking a placebo in the context of an ongoing, supportive, caring, warm patient-physician relationship benefits patients. Rx-associated communication or ritual is a vital part of how placebo responses are triggered and sustained (12).

Economic Impact Of Placebo Responses

Decades-long evidence (13, 14, 15) suggests clinical trial placebo responses are becoming more powerful, especially for painkiller drug candidates (16) and especially in the US (17).

  • Placebo responses in anti-depressant trials were twice as strong in the 2000s compared to those in the 1980s (18). Even more compelling is the observation that this improvement occurred not for the more subjective patient self-rating but rather for the comparatively more objective observer rating (1).
  • Similar placebo response improvement when testing anti-psychotic drugs (19).
  • Placebo response magnitude change may vary by disease since it increased more weakly from 1991 to 2005 in trials for bipolar disorder (20).

Why could placebo responses be strengthening?

  • Could be simply because trials now last longer then they used to (21). Longer Rx-associated communication/ritual = Stronger Placebo responses.
  • Over the same time period, drug advertisements have undergone a sea change. The US legalized direct-to-consumer prescription drug advertising in 1997, which also exists in New Zealand. One unanticipated consequence? Social conditioning may be strengthening placebo responses.

Consequences of stronger placebo responses

  • Clinical trials are the necessary gatekeeper for new drug approvals. More powerful placebo responses increase the bar new drugs have to clear. No surprise new drug approvals have slowed down dramatically in recent years. Clearly some role there for the increasingly more powerful placebo responses.
  • Publication bias predicates that ‘real’ placebo response in RCTs remains unknowable. Studies with a significant drug to placebo difference are more likely to get published. Published placebo responses are thus likely lower than in studies that never got/get published. Ergo, actual placebo responses may be even higher than those revealed by clinical trial results that do get published. If this is the case with new drug candidates, no wonder new drug approvals have declined steeply in recent years.
  • One consequence of increasingly powerful placebo responses is a move away from the classic RCTs to newer designs such as comparative effectiveness research (CER) trials, which compare novel drugs to approved ones or to standard therapy, i.e., all participants get active Rx. Problem is such trials ‘increase the placebo response without being able to control for it‘ (9). Statistical analyses of such trials are also much challenging since they require showing the test compound is non-inferior to the standard Rx. As Enck et al point out (9, emphasis mine),

‘A non-inferiority trial tests the null hypothesis that the novel drug is inferior by the equivalence margin. If this null hypothesis is rejected, the novel compound can be regarded as clinically equivalent. This, on average, requires a fourfold larger sample size compared to classical RCTs and is one of the reasons why drug companies are increasingly concerned by the growing costs of drug development

How Placebo Responses Could Be Leveraged To Make Medicine More Effective, Cheaper & Safer

  • Pigeonholing placebos and placebo responses as undesirable or hindrance is problematic. Placebos are supposedly inert substances that should do nothing yet they do. OTOH, even genuine medicines induce placebo responses which increase their effectiveness. A way to reconcile this seeming contradiction would be by viewing placebo responses as an inevitable part of a virtuous feedback loop between psychology and physiology.
  • Expectations are outcome of learning, i.e., part of a conditioning process. Benefits of conditioning are well-known for allergies (22, 23) and nausea (24). See below from 9 how conditioning works.
  • Maybe encouraging placebo responses could make modern biomedicine more effective (9) by
    • Reducing healthcare costs since patients could interchangeably take drugs and placebos, and still benefit.
    • Minimizing harm from drug side effects since patients would be taking lower doses of drugs.
  • Now that would augur a true biomedical revolution. Conundrum is how to do this reproducibly since placebo’s evil twin, https://en.wikipedia.org/wiki/No…, lurks in the wings. Tapping the same pathways could yield harm just as easily as benefit and we simply don’t know enough about the feedback loops between psychology and physiology to manipulate them at will. For example, https://en.wikipedia.org/wiki/Na… can block analgesic (anti-pain) placebo response induced by opioid-driven but not non-opioid https://en.wikipedia.org/wiki/No… (NSAID) (25).

Placebo Responses: Research suggests placebo response magnitude depends on just about anything to do with Rx (26).

  • Rx Appearance (27). A systematic 1996 review (28) found red, yellow and orange pills worked better as stimulants while blue and green pills worked better as tranquilizers. Out of 49 nervous system drugs, stimulants were more often red or orange while sedatives were more often green, blue or purple.
  • Rx Frequency/number. A meta-analysis (29) of anti-duodenal ulcer RCTs found a difference in whether participants took 4 (51 trials) or 2 (28 trials) pills a day. After 4 weeks, 44% (805 of 1821) of those who took 4 placebo pills per day had healed duodenal ulcers compared to 36% (545 of 1504) of those who took 2, statistically a highly significant difference.
  • Rx Form. A meta-analysis (30) of 22 trials found placebo injections (32%, 279 of 862 patients) to be more effective against migraine (feeling better one hour later) compared to placebo pills (26%, 222 of 865 patients), statistically a highly significant difference.
  • Placebo-Taking Compliance Reduces Mortality Rates. BEST (Beta Blocker Evaluation of Survival Trial) participants (31) who took >75% of their prescribed placebos had significantly better outcomes (291 of 1038, 28%, died) compared to less compliant placebo-takers (55 of 136, 40%, died). A meta-analysis (32) of 21 RCT or cohort studies on conditions ranging from cancer-associated infections to heart attack to HIV found similar differences, lower mortality rates (4.3%, 581 of 13429 participants) for compliant placebo-takers compared to those less compliant (6.2%, 415 of 6204 participants).
  • Influence of Doctors (8, 9, 12, See below from 33 using data from 34).

Placebo Responses: Age, Culture, Ethnicity, Gender, etc. Also Matter

However, hastily generalizing such results could also be in error.

  • Different colors seem to matter differently in different countries, i.e., cultural differences are also at play (35).
  • An Italian study found women responded more strongly to blue sleeping pills compared to men who preferred orange ones (36).
  • Placebo injections may be more effective than pills at treating migraines in the US (33.6%, 151 of 449 patients for injections versus 22.3%, 25 of 112 patients for pills), not in Europe (25.1%, 80 of 318 patients for injections versus 27.1%, 182 of 670 patients for pills) (37).
  • Meta-analysis of 100 old RCTs of https://en.wikipedia.org/wiki/H2… on https://en.wikipedia.org/wiki/Pe… found placebo effects that ranged from 6% in Brazil, ~20% in Denmark and the Netherlands to >60% in Germany (38).
  • Again, would be wrong to conclude Germans are inherently more predisposed to strong placebo effects since the same analysis found them with among the lowest placebo effect for anti-hypertensive Rx.
  • Rotation-induced nausea is a condition with well-established ethnic differences (24).

Even Surgeries Aren’t Immune To Placebo Responses

Unlike medications, especially for subjective symptoms such as pain, surgery is usually done for tangible reasons yet even it isn’t immune to placebo responses, some attributable to bonafide placebo response power and some attesting to the futility of certain prevalent and expensive surgical procedures.

  • Back in the 1950s, ligating the internal mammary artery became a popular procedure to alleviate https://en.wikipedia.org/wiki/An…, the idea being restricting blood flow to a nearby region would improve supply going to the coronary arteries. Small placebo-controlled studies (39, 40) of this procedure found similar improvement (significantly less pain, lower nitroglycerine use) regardless whether patients got the ligation or just a skin incision.
  • Highly cited placebo-controlled studies (41, 42) on surgical Rx for osteoporosis found no difference in improvement magnitude (modest pain score improvement, physical function) between patients who got either https://en.wikipedia.org/wiki/Pe… (n=38, 68) or sham Rx (n=40, 63).
  • Highly cited placebo-controlled US-based studies (43, 44) on https://en.wikipedia.org/wiki/Os… found no difference in improvement magnitude between patients who got either arthroscopic debridement/ (https://en.wikipedia.org/wiki/Ar…), https://en.wikipedia.org/wiki/Ar… or simulated debridement (placebo, 3 small stab wounds in the knee). Even two years later, all patients had similar 6 point improvement on a 100 point scale that measured walking and bending. At the time these studies were done (1996-2002), 650,000 such arthroscopies were performed in the US each year, for an average cost of ~US $5000 each, obviously a colossal waste. An example of not the power of placebos but rather of uselessness of certain prevalent medical procedures.

* A preliminary study with few participants (n=47) that desperately needs replication. Also poor form to show data as Mean + Standard Error of the Mean (46). What that means is that actual variation within each group was much higher than what the authors chose to show, i.e., much more actual overlap between groups.

Bibliography

  1. Rief, Winfried, et al. “Meta-analysis of the placebo response in antidepressant trials.” Journal of affective disorders 118.1 (2009): 1-8. https://www.researchgate.net/pro…

2. Hróbjartsson, Asbjørn, and Peter C. Gøtzsche. “Placebo interventions for all clinical conditions.” The Cochrane Library (2010). http://nordic.cochrane.org/sites…

3. Howick, Jeremy, et al. “Are treatments more effective than placebos? A systematic review and meta-analysis.” PloS one 8.5 (2013): e62599. http://journals.plos.org/plosone…

4. Park, Chanmo, et al. “Blood sugar level follows perceived time rather than actual time in people with type 2 diabetes.” Proceedings of the National Academy of Sciences (2016): 201603444. http://www.pnas.org/content/113/…

5. Benedetti, Fabrizio, et al. “Open versus hidden medical treatments: the patient’s knowledge about a therapy affects the therapy outcome.” Prevention & Treatment 6.1 (2003): 1a.

6. Colloca, Luana, et al. “Overt versus covert treatment for pain, anxiety, and Parkinson’s disease.” The Lancet Neurology 3.11 (2004): 679-684. https://www.researchgate.net/pro…

7. Benedetti, F., E. Carlino, and A. Pollo. “Hidden administration of drugs.” Clinical Pharmacology & Therapeutics 90.5 (2011): 651-661. http://www.isdbweb.org/app/webro…

8. Schedlowski, Manfred, et al. “Neuro-bio-behavioral mechanisms of placebo and nocebo responses: implications for clinical trials and clinical practice.” Pharmacological reviews 67.3 (2015): 697-730. http://pharmrev.aspetjournals.or…

9. Enck, Paul, et al. “The placebo response in medicine: minimize, maximize or personalize?.” Nature reviews Drug discovery 12.3 (2013): 191-204.

10. Kaptchuk, Ted J., et al. “Placebos without deception: a randomized controlled trial in irritable bowel syndrome.” PloS one 5.12 (2010): e15591. http://journals.plos.org/plosone…

11. Carvalho, Cláudia, et al. “Open-label placebo treatment in chronic low back pain: a randomized controlled trial.” Pain 157.12 (2016): 2766. https://www.ncbi.nlm.nih.gov/pmc…

12. Welch, John S. “Ritual in western medicine and its role in placebo healing.” Journal of Religion and Health 42.1 (2003): 21-33.

13. The New York Times, Daniel Goleman, August 17, 1993. http://www.nytimes.com/1993/08/1…

14. Silberman, Steve. “Placebos are getting more effective. Drugmakers are desperate to know why.” Wired Magazine 17 (2009): 1-8. http://www.southdevonacupuncture…

15. Tuttle, Alexander H., et al. “Increasing placebo responses over time in US clinical trials of neuropathic pain.” Pain 156.12 (2015): 2616-2626.

16. Vase, Lene, Martina Amanzio, and Donald D. Price. “Nocebo vs. placebo: The challenges of trial design in analgesia research.” Clinical Pharmacology & Therapeutics 97.2 (2015): 143-150.

17. Quartz, Akshat Rathi, October 16, 2015. https://qz.com/525995/why-the-pl…

18. Walsh, B. Timothy, et al. “Placebo response in studies of major depression: variable, substantial, and growing.” Jama 287.14 (2002): 1840-1847. http://211.103.242.133:8080/ziyu…

19. Leucht, S., et al. “How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials.” Molecular psychiatry 14.4 (2009): 429-447. http://www.nature.com/mp/journal…

20. Sysko, Robyn, and B. Timothy Walsh. “A systematic review of placebo response in studies of bipolar mania.” The Journal of clinical psychiatry 68.8 (2007): 1213-1217.

21. Quessy, Steve N., and Michael C. Rowbotham. “Placebo response in neuropathic pain trials.” Pain 138.3 (2008): 479-483.

22. Vits, Sabine, et al. “Cognitive factors mediate placebo responses in patients with house dust mite allergy.” PLoS One 8.11 (2013): e79576. http://journals.plos.org/plosone…

23. Bartels, Danielle JP, et al. “Role of conditioning and verbal suggestion in placebo and nocebo effects on itch.” PloS one 9.3 (2014): e91727. http://journals.plos.org/plosone…

24. Quinn, Veronica F., and Ben Colagiuri. “Placebo interventions for nausea: a systematic review.” Annals of Behavioral Medicine 49.3 (2015): 449-462.

25. Amanzio, Martina, and Fabrizio Benedetti. “Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.” Journal of Neuroscience 19.1 (1999): 484-494.

26. Enck, Paul, Sibylle Klosterhalfen, and Katja Weimer. “Unsolved, Forgotten, and Ignored Features of the Placebo Response in Medicine.” Clinical Therapeutics (2016).

27. Buckalew, Louis W., and Kenneth E. Coffield. “An investigation of drug expectancy as a function of capsule color and size and preparation form.” Journal of clinical psychopharmacology 2.4 (1982): 245-248.

28. De Craen, Anton JM, et al. “Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness.” Bmj 313.7072 (1996): 1624-1626. http://pubmedcentralcanada.ca/pm…

29. De Craen, Anton JM, et al. “Placebo effect in the treatment of duodenal ulcer.” British journal of clinical pharmacology 48.6 (1999): 853-860. https://www.researchgate.net/pro…

30. de Craen, Anton JM, et al. “Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos.” Journal of neurology 247.3 (2000): 183-188.

31. Pressman, Alice, et al. “Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST).” Contemporary clinical trials 33.3 (2012): 492-498. https://www.ncbi.nlm.nih.gov/pmc…

32. Simpson, Scot H., et al. “A meta-analysis of the association between adherence to drug therapy and mortality.” Bmj 333.7557 (2006): 15. http://www.bmj.com/content/bmj/3…

33. Moerman, Daniel E. “Edible symbols: The effectiveness of placebos.” Annals of the New York Academy of Sciences 364.1 (1981): 256-268.

34. Sarles, H., R. Camatte, and J. Sahel. “A study of the variations in the response regarding duodenal ulcer when treated with placebo by different investigators.” Digestion 16.4 (1977): 289-292.

35. Bhugra, Dinesh, et al. “Colour, culture and placebo response.” International Journal of Social Psychiatry 61.6 (2015): 615-617.

36. Cattaneo, Angelo D., Paolo E. Lucchelli, and Giorgio Filippucci. “Sedative effects of placebo treatment.” European Journal of Clinical Pharmacology 3.1 (1970): 43-45.

37. de Craen, Anton JM, et al. “Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos.” Journal of neurology 247.3 (2000): 183-188.

38. MOERMAN, DE. “GENERAL MEDICAL EFFECTIVENESS AND HUMAN-BIOLOGY-PLACEBO-EFFECTS IN THE TREATMENT OF ULCER DISEASE.” AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY. Vol. 54. No. 2. DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012: WILEY-LISS, 1981.

39. Cobb, Leonard A., et al. “An evaluation of internal-mammary-artery ligation by a double-blind technic.” New England Journal of Medicine 260.22 (1959): 1115-1118.

40. Dimond, E. Grey, C. Frederick Kittle, and James E. Crockett. “Comparison of internal mammary artery ligation and sham operation for angina pectoris∗.” The American journal of cardiology 5.4 (1960): 483-486.

41. Buchbinder, Rachelle, et al. “A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures.” New England Journal of Medicine 361.6 (2009): 557-568. http://www.nejm.org/doi/pdf/10.1…

42. Kallmes, David F., et al. “A randomized trial of vertebroplasty for osteoporotic spinal fractures.” New England Journal of Medicine 361.6 (2009): 569-579. http://www.nejm.org/doi/pdf/10.1…

43. Moseley Jr, J. Bruce, et al. “Arthroscopic treatment of osteoarthritis of the knee: a prospective, randomized, placebo-controlled trial: results of a pilot study.” The American journal of sports medicine 24.1 (1996): 28-34.

44. Moseley, J. Bruce, et al. “A controlled trial of arthroscopic surgery for osteoarthritis of the knee.” New England Journal of Medicine 347.2 (2002): 81-88. https://www.researchgate.net/pro…

https://www.quora.com/Is-the-placebo-effect-very-powerful/answer/Tirumalai-Kamala

How can I minimise pain after an intramuscular injection?

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Short answer

Pain a few days after an intramuscular (IM) injection could mean it wasn’t done properly. Question lacks the critical detail of injection site since there are four major sites of IM injection (see below from 1), and each has specific pros and cons, and different propensity for complications such as post-injection pain.

It’s the responsibility of the doctor who administered the injection to prescribe medications and/or other treatment to reduce post-injection pain.

Longer answer below for those interested in learning about IM injections in general, and sources of and approaches to minimize post-injection pain.

Brief Background On Intramuscular (IM) Injection Techniques

There are two main techniques used in IM injections to try to ensure injection is deposited in the muscle, and that injected material stays locked in it and doesn’t seep out into surrounding area along the needle track. They are the Z-track (see below from 2, 3) and air-lock techniques.

In the air-lock technique (3), a small amount of air is drawn up into the syringe along with the medication, the skin is stretched flat between two fingers and held taut, needle is plunged in at a right angle, injection includes medication followed by air, needle is withdrawn and taut skin is released. Rationale is the air locks in the medication in the muscle, hence air-lock, preventing it from seeping out into surrounding tissue along the needle track.

Possible Sources Of Pain After IM Injection

  • Aspiration is when the injector pushes the needle in but pulls back the syringe plunger before injecting the medication, rationale being to see if blood appears in the syringe meaning a blood vessel got punctured, i.e., need to try again. However, problems with aspiration are
    • No scientific support (4).
    • Can cause local tissue trauma and lingering pain (5, 6, 7, 8).
    • Is frequently done far too quickly to even be effective (4).
    • Isn’t recommended by National Immunization Technical Advisory Committees (9).
  • Inexperienced and/or unskilled injectors may end up injecting subcutaneously (SC) rather than IM, and cause undue local tissue trauma (10, 11).
  • Wrong choice of needle length can also increase chance of SC rather than IM injection. This is because ratio of subcutaneous to muscle varies by gender, age and weight, being higher in women (12, 13, 14, 15, 16, 17), older people and the obese (18, 19, 20, 21, 22). For example, a study infers a 12 to 25mm needle suffices for a thin person while a very obese person requires 76mm long needle for an IM injection (23).
  • Wiping needle with alcohol before injecting tracks it through the subcutaneous layer, which can be painful (24).

How To Minimize Pain After IM Injection

  • For something that’s a mainstay of routine medicine, shocking really that few sufficiently large, carefully controlled studies have compared different sites and techniques for their capacity to minimize pain after IM injection (25).
  • Consensus is slowly building that Ventrogluteal may cause less pain.
    • It isn’t close to large blood vessels, nerves, bone (1, 2, 10, 11, 25, 26, 27, 28, 29).
    • Being covered by relatively less subcutaneous tissue (15, 30) is another advantage since this reduces chances of accidental subcutaneous delivery (2, 27, 28).
    • However, there’s still insufficient conclusive data supporting it over Dorsogluteal (22).
  • OTOH, Dorsogluteal, though still much more commonly used compared to Ventrogluteal, has known risks such as
    • Sciatic nerve injury (26, 29).
    • Proximity to major blood vessels.
    • Increased thickness of subcutaneous tissue in this area compared to others (24), especially ventrogluteal (15, 30).
  • Injection techniques: A couple of small controlled studies (n=90 females aged between 18 and 60 years of age, 31; n=60; 32) suggest the air-lock technique can reduce tissue trauma and pain from IM injections.
  • Relaxed muscles can reduce injection site discomfort and pain (24). This means appropriately positioning the body, particularly the limbs, before IM injection. Studies (33, 34) suggest
    • Placing the hand on the hip relaxes the deltoid muscle.
    • Internal rotation of the femur relaxes the gluteal muscles.
  • No pain at initial point of needle contact on skin (24, 35). If there is pain, better to move needle 2 to 3mm at a time until reaching a painless point on the skin. Rationale is differential skin innervation, i.e., hitting upon a skin site with fewer or no pain receptors.
  • A randomized study (n=100) showed that changing needle after drawing up the medication and before injecting can minimize pain by ensuring needle tip used for injection remains sharp and free of medicine residue (36).
  • Briefly applying manual pressure to injection site before IM injection can minimize post-injection pain (6; n=48, 45 experimental and control, respectively, 37; n=74, one injection per arm, manual pressure randomly assigned, 38; n=63, 60 experimental and control, respectively, 39).

Bibliography

1. Ogston-Tuck, Sherri. “Intramuscular injection technique: an evidence-based approach.” Nursing Standard 29.4 (2014): 52-59.

2. Chadwick, Angelina, and Neil Withnell. “How to administer intramuscular injections.” Nursing Standard 30.8 (2015): 36-39.

3. Gabhann, L’am Mac. “A comparison of two depot injection techniques.” Nursing Standard 12.37 (1998): 39-41.

4. Ipp, Moshe, Jonathan Sam, and Patricia C. Parkin. “Needle aspiration and intramuscular vaccination.” Archives of pediatrics & adolescent medicine 160.4 (2006): 451-451.

5. Ipp, Moshe, et al. “Vaccine-related pain: randomised controlled trial of two injection techniques.” Archives of disease in childhood 92.12 (2007): 1105-1108.

6. Taddio, Anna, et al. “Physical interventions and injection techniques for reducing injection pain during routine childhood immunizations: systematic review of randomized controlled trials and quasi-randomized controlled trials.” Clinical Therapeutics 31 (2009): S48-S76.

7. Taddio, Anna, et al. “Reducing the pain of childhood vaccination: an evidence-based clinical practice guideline.” Canadian Medical Association Journal 182.18 (2010): E843-E855. https://www.researchgate.net/pro…

8. Davidson, Kathleen Marie, and Liam Rourke. “Teaching best-evidence: Deltoid intramuscular injection technique.” Journal of Nursing Education and Practice 3.7 (2013): 120. http://www.sciedupress.com/journ…

9. Cook, Ian F. “Best vaccination practice and medically attended injection site events following deltoid intramuscular injection.” Human vaccines & immunotherapeutics 11.5 (2015): 1184-1191. https://pdfs.semanticscholar.org…

10. Wynaden, Dianne, et al. “Establishing best practice guidelines for administration of intra muscular injections in the adult: a systematic review of the literature.” Contemporary nurse 20.2 (2005): 267-277.

11. Cocoman, A., and J. Murray. “Intramuscular injections: a review of best practice for mental health nurses.” Journal of psychiatric and mental health nursing 15.5 (2008): 424-434.

12. Haramati, Nogah, et al. “Injection granulomas. Intramuscle or intrafat?.” Archives of family medicine 3.2 (1994): 146-148.

13. Poland, Gregory A., et al. “Determination of deltoid fat pad thickness: implications for needle length in adult immunization.” Jama 277.21 (1997): 1709-1711. https://www.researchgate.net/pro…

14. Cook, I. F., M. Williamson, and D. Pond. “Definition of needle length required for intramuscular deltoid injection in elderly adults: an ultrasonographic study.” Vaccine 24.7 (2006): 937-940.

15. Chan, V. O., et al. “Intramuscular injections into the buttocks: are they truly intramuscular?.” European journal of radiology 58.3 (2006): 480-484.

16. Burbridge, Brent E. “Computed tomographic measurement of gluteal subcutaneous fat thickness in reference to failure of gluteal intramuscular injections.” Canadian Association of Radiologists Journal 58.2 (2007): 72. https://www.researchgate.net/pro…

17. Shankar, Nachiket, et al. “Influence of skin-to-muscle and muscle-to-bone thickness on depth of needle penetration in adults at the deltoid intramuscular injection site.” medical journal armed forces india 70.4 (2014): 338-343. http://medind.nic.in/maa/t14/i4/…

18. Greenway, Kathleen. “Using the ventrogluteal site for intramuscular injection.” Nursing Standard 18.25 (2004): 39-42. https://www.researchgate.net/pro…

19. Nisbet, Andrew Charles. “Intramuscular gluteal injections in the increasingly obese population: retrospective study.” Bmj 332.7542 (2006): 637-638. http://www.bmj.com/content/bmj/3…

20. Zaybak, Ayten, et al. “Does obesity prevent the needle from reaching muscle in intramuscular injections?.” Journal of advanced nursing 58.6 (2007): 552-556.

21. Sakamaki, Sakiko, et al. “The relationship between body mass index, thickness of subcutaneous fat, and the gluteus muscle as the intramuscular injection site.” Health 2013 (2013). http://file.scirp.org/pdf/Health…

22. Brown, Joe, Mark Gillespie, and Simon Chard. “The dorso–ventro debate: in search of empirical evidence.” British Journal of Nursing 24.22 (2015): 1132-1139. https://www.guidelines.ch/file/g…

23. Kaya, Nurten, et al. “The reliability of site determination methods in ventrogluteal area injection: A cross-sectional study.” International journal of nursing studies 52.1 (2015): 355-360. https://www.researchgate.net/pro…

24. Nicoll, Leslie H., and Amy Hesby. “Intramuscular injection: an integrative research review and guideline for evidence-based practice.” Applied Nursing Research 15.3 (2002): 149-162. http://lms.westernhealth.nl.ca/s…

25. Malkin, Bridget. “Are techniques used for intramuscular injection based on research evidence.” Nursing times 104.50/51 (2008): 48-51. https://www.choiceforum.org/docs…

26. Small, Sandra P. “Preventing sciatic nerve injury from intramuscular injections: literature review.” Journal of advanced nursing 47.3 (2004): 287-296.

27. Ferreira Oliveira, Laura, et al. “Ventrogluteal region, an alternative location to apply benzathine penicillin.” Revista Eletronica de Enfermagem 17.4 (2015). https://www.fen.ufg.br/revista/v…

28. Coskun, Halise, Cenk Kilic, and Cicek Senture. “The evaluation of dorsogluteal and ventrogluteal injection sites: a cadaver study.” Journal of clinical nursing (2016).

29. Mishra, P., and M. D. Stringer. “Sciatic nerve injury from intramuscular injection: a persistent and global problem.” International journal of clinical practice 64.11 (2010): 1573-1579.

30. Beecroft, P. C., and S. A. Redick. “Clarification of ventrogluteal site.” Pediatric nursing 16.4 (1989): 396-396.

31. Najafidolatabad, Shahla, Janmohamad Malekzadeh, and Zinat Mohebbinovbandegani. “Comparison of the pain severity, drug leakage and ecchymosis rates caused by the application on tramadol intramuscular injection in Z-track and Air-lock techniques.” Investigación y Educación en Enfermería 28.2 (2010): 24-33. https://www.researchgate.net/pro…

32. Yilmaz, Dilek K., et al. “The effect of air-lock technique on pain at the site of intramuscular injection.” Saudi medical journal 37.3 (2016): 304. https://www.ncbi.nlm.nih.gov/pmc…

33. Kruszwski, Ann Z., Susan Havens Lang, and Jean E. Johnson. “Effect of positioning on discomfort from intramuscular injections in the dorsogluteal site.” Nursing Research 28.2 (1979): 103-105.

34. Rettig, Frannie M., and Janet R. Southby. “Using different body positions to reduce discomfort from dorsogluteal injection.” Nursing Research 31.4 (1982): 219-221.

35. Jablecki, C. K. “Alternative technique for medication injections.” Nursing research 49.5 (2000): 244.

36. Ağaç, Emine, and Ülkü Yapucu Güneş. “Effect on pain of changing the needle prior to administering medicine intramuscularly: a randomized controlled trial.” Journal of advanced nursing 67.3 (2011): 563-568. http://www.hadassah.org.il/media…

37. Barnhill, Barbara J., et al. “Using pressure to decrease the pain of intramuscular injections.” Journal of pain and symptom management 12.1 (1996): 52-58.

38. Chung, Joanne WY, Winnie MY Ng, and Thomas KS Wong. “An experimental study on the use of manual pressure to reduce pain in intramuscular injections.” Journal of clinical nursing 11.4 (2002): 457-461.

39. Öztürk, Deniz, et al. “The effect of the application of manual pressure before the administration of intramuscular injections on students’ perceptions of postinjection pain: a semi‐experimental study.” Journal of Clinical Nursing (2016).

https://www.quora.com/How-can-I-minimise-pain-after-an-intramuscular-injection/answer/Tirumalai-Kamala