Blood Clots & Nattokinase

[PCa] studies.

H. D-dimer.

I. Fibrinogen.

J. Warfarin & PCa Risk.

Caution: Nattokinase is an over-the-counter enzyme that dissolves blood clots. As of writing, there are six trials on clinicaltrials.gov, but none involve diagnosed deep vein thrombosis [DVT] or cancer. The author’s experience of nattokinase use for DVT and cancer should be viewed as anecdotal.

[A] Take home message.

Men at risk should keep an eye on D-dimer, which is elevated when there is a clot. If a clot is suspected, consider using nattokinase. This might speed up the breakdown of the clot. In the short term, this will increase D-dimer. Eventually, at an effective dose, D-dimer should fall close to zero. A maintenance dose might keep it there.

[B] Introduction.

A “deep vein thrombosis {DVT}, pulmonary embolism {PE}, or both, affects an estimated 300,000-600,000 individuals in the U.S. each year, causing considerable morbidity and mortality.” [Ba]

“The precise number of people affected by DVT/PE is unknown, although as many as 900,000 people could be affected (1 to 2 per 1,000) each year in the United States” [Bb]

I don’t know why the CDC (Centers for Disease Control and Prevention) is so muddy about the actual number, but let’s suppose that well over a thousand individuals – 500 men – experience an event each day in the U.S. It isn’t as though these people were suddenly hit by lightning; the condition takes time to build up. Did they really have to end up in the emergency room before their condition could be recognized & treated?

According to my doctor, tools are lacking & there are no acceptable drugs. While Warfarin can be used to treat a life threatening blood clot, it is otherwise too dangerous to use prophylactically.

From the doctor’s perspective, it seems, there is no point in detecting a condition for which there exists no treatment protocol. Therefore, he must wait until there is no option but to prescribe Warfarin (or comparable drug). Assuming that the patient is still alive.

From a patient’s perspective (& writing as someone whose DVT treatment began in the ER), it would be useful to have a heads-up. Useful, because a patient would then have time to discover and try nattokinase.

With nattokinase as an option, high-risk individuals could request a periodic D-dimer test (or purchase the test from Life Extension, in the U.S.). A result above the normal range is suggestive of a clot. A negative result means there is no clot. If D-dimer is elevated, nattokinase could be tried for 2-3 months before a retest.

The test is not foolproof – D-dimer can be elevated for unrelated reasons, but it is a reasonable approach for a high-risk individual.

See DVT risk factors (according to the Mayo Clinic): [Bc].

Here is the CDC again [Bb]:

“Sudden death is the first symptom in about one-quarter (25%) of people who have a PE” (pulmonary embolism)

“Estimates suggest that 60,000-100,000 Americans die of DVT/PE (also called venous thromboembolism)”.

“10 to 30% of people will die within one month of diagnosis”.

These are shocking statistics. Why wouldn’t a high-risk man consider the D-dimer/Nattokinase option?

Cancer is a risk factor for blood clots. Cancer-related clots can occur before cancer has even been suspected. If a clot occurs, it is prudent to be screened for cancer. And if one already has cancer, it is prudent to monitor D-dimer.

Cancer has a known disruptive effect on coagulation factors. It has been postulated that metastasis cannot occur in the absence of micro-clots. Circulating cancer cells that dock on a micro-clot escape detection and destruction. Although the great fear, I suppose, is to be rushed to the ER because a portion of a clot has broken away and traveled to the lungs, nonthreatening circulating micro-clots, just as lethally facilitate metastasis and death from cancer.

[C] Warfarin (Coumadin).

For a drug that is itself responsible for countless visits to the ER, and over 30,000 U.S. emergency hospitalizations each year, Warfarin nonetheless continues to be the treatment of choice for blood clots. About 33 million U.S. prescriptions are filled annually [Ca].

I suppose that many men who go to the ER because of a clot, & leave with a Warfarin prescription, expect the drug to dissolve the clot. It does no such thing. Warfarin slows the clotting process so that the problem clot ceases to grow faster than it can be broken down. In time, the body will have removed the clot.

The obvious problem is that the patient is vulnerable while on Warfarin. In the event of injury with serious bleeding, the patient might die before reaching the ER.

“An estimated 99,628 emergency hospitalizations for adverse drug events occur each year among older adults, most of which are for supratherapeutic effects. Warfarin was implicated in about one third of these hospitalizations” [Cb]

Initially, the Warfarin treatment period is 3-6 months, to give the clot time to be dissolved. However, if the patient suffers a subsequent clot, he will be on Warfarin for the rest of his life.

A major issue, IMO, is that Warfarin is a vitamin K inhibitor. Vitamin K is essential for the transport of calcium from blood to bone. A lack of vitamin K will result in calcification of the arteries & osteoporosis. [Cc]

Men on Warfarin should have vitamin K at hand. In the event of major bleeding, vitamin K will render Warfarin ineffective. (I have a friend whose prothrombin time [INR] moves below the therapeutic range if he has a small spinach salad the day before his monthly INR test.)

There are newer, more expensive drugs, & they do not require frequent visits to the “Coumadin Clinic” to check on the INR. However, they pose a problem to the ER, since, unlike Warfarin with vitamin K, they cannot easily be neutralized.

[D] Aspirin.

Many men take a daily low-dose aspirin to prevent heart attacks. The idea is to prevent clots forming in narrowed arteries feeding the heart. Arterial walls can be weakened by the deposits associated with heart disease. The body will act fast to repair damage. The first stage is the aggregation of platelets, to plug the wound. The second is the accretion of fibrin to form a clot. The result can be a blockage.

A low dose aspirin (81 mg) is all that is required to inhibit platelet aggregation.

Bayer was selling acetylsalicylic acid as Aspirin by 1899. Although willow bark (it contains salicylate) and the like had been used from antiquity, it is said that the U.S. Food and Drug Administration [FDA] would probably not approve aspirin today.

What is the FDA position on aspirin use for CVD (cardiovascular disease) [Da]?

“The FDA has reviewed the available data and does not believe the evidence supports the general use of aspirin for primary prevention of a heart attack or stroke. In fact, there are serious risks associated with the use of aspirin, including increased risk of bleeding in the stomach and brain, in situations where the benefit of aspirin for primary prevention has not been established.”
“The available evidence supports the use of aspirin for preventing another heart attack or stroke in patients who have already had a heart attack or stroke, or have other evidence of coronary artery disease, such as angina or a history of a coronary bypass operation or coronary angioplasty.”

However, a 2017 analysis of 11 clinical trials [Db] concluded that:

“Aspirin use in {peripheral vascular disease} might not be associated with improved cardiovascular outcomes …”

A 2015 survey [Dc] found that 52% of adults aged 45-75 were using aspirin.

“Among 2,039 respondents without a history of cardiovascular disease, current use of aspirin was 47%.”

Such widespread use of aspirin may be misguided, but it can provide valuable data for those investigating whether aspirin use can inhibit metastases. See: [G].

[E] Plasmin.

Plasmin is an enzyme that degrades fibrin. Its presence is supposed to ensure that blood clots do not outlive their usefulness or grow in an uncontrolled way. There are many factors involved in the coagulation cascade. When a DVT occurs, the reasons are less important than the fact that plasmin is under-performing.

The liver produces the plasmin precursor, plasminogen, which is actually drawn to a clot as it forms, and becomes incorporated into the clot. When activated, plasmin cleaves fibrin molecules at various points, “dissolving” the clot.

Sometimes, we could use a little extra plasmin to outpace unwanted coagulation. Nattokinase is an enzyme that has a similar structure. It breaks down fibrin in the same way.

[F] Nattokinase.

Nattokinase is an enzyme originally extracted from nattō, a traditional Japanese food made from fermented soybeans. [Fa] It has a similar structure to plasmin, & has similar fibrinolytic properties in the body. Given the popularity and long history of nattō, nattokinase is presumably safe, at least at levels normally ingested.

A 1990 Japanese paper [Fb] reported that nattokinase “capsules were … administered orally to dogs with experimentally induced thrombosis, and lysis of the thrombi was observed by angiography.”

“The results obtained suggest that NK {nattokinase} represents a possible drug for use not only in the treatment of embolism but also in the prevention of the disease, since NK has a proven safety and can be mass-produced.”

From 2009 (Taiwan) [Fc]: “we hypothesized that nattokinase could reduce certain factors of blood clotting and lipids that are associated with an increase risk for cardiovascular disease (CVD)”

“After 2 months of administration, fibrinogen, factor VII, and factor VIII decreased 9%, 14%, and 17%, respectively, for the Healthy Group; 7%, 13%, and 19%, respectively, for the Cardiovascular Group; and 10%, 7%, and 19%, respectively, for the Dialysis Group, whereas blood lipids were unaffected by nattokinase.”

In a 2015 study [Fd] of the effect of a single dose on “12 healthy young males”:

“Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly … Factor VIII activity declined at 4 and 6 hours .., blood antithrombin concentration was higher at 2 and 4 hours .. and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration … All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.”

But is nattokinase safe?

There are no studies regarding appropriate use and safety. Nattokinase is increasingly being used as a prophylactic, just as aspirin is. Ideally, one’s GP should be involved, but good luck with that. The standard dose is 2,000 fibrinolytic units. A much larger dose might be required if there is cancer. As with vitamin D, it is pointless guessing at a therapeutic dose.

Many would prefer to use nattokinase rather than Warfarin, but it takes a bit of nerve to switch without one’s doctor’s approval. My GP agreed, even though one vein had not cleared. He sympathized with my desire to resume vitamin K2 supplementation for prostate cancer. He also knew that I would be back immediately if leg pain recurred. The dose I chose was 6,000 fibrinolytic units. Within a week there was warmth in my calf – the dose was too low. I doubled the dose and leg temperature became normal in a few days. Within a couple of months, D-dimer was <20 ug FEU/mL, the lowest LabCorp result (reference interval: 0.00-0.49) {“In conjunction with a non-high clinical probability assessment, a normal (<0.50 ug FEU/mL) result excludes deep vein thrombosis (DVT) and pulmonary embolism (PE) with high sensitivity.”} I have noticed that Warfarin users tend to be blasé, as though unaware of its poor safety record. A couple of prostate cancer papers, while reporting benefit, state that Warfarin is not safe enough to be used as PCa chemotherapy. The level of morbidity and mortality is unacceptable. That should be a wake-up call to those stuck on it for life. [G] Aspirin and Prostate Cancer [PCa] studies. [Ga] (2002 - U.S. - Health Professionals Follow-up Study [HPFS] - Giovannucci) A "cohort of 47,882" "2,479 new cases of prostate cancer were ascertained. Of these, 608 were diagnosed as advanced (extraprostatic) prostate cancer and 258 as metastatic prostate cancer. We found no association between aspirin use and total prostate cancer." But: "For metastatic prostate cancer, we observed a suggestive decrease in risk among men reporting greater frequency of aspirin use. The multivariate relative risk of metastatic prostate cancer among men using aspirin 22 or more days/month was 0.73 ... compared with nonusers." A 27% reduction for metastatic PCa. [Gb] (2011 - Health Professionals Follow-up Study [HPFS] - Giovannucci - again) "In a prospective cohort study of 51,529 health professionals": "A total of 4,858 men were diagnosed with prostate cancer during the 18-year study period. Men taking ≥ 2 adult-strength aspirin tablets a week had a 10% lower risk of prostate cancer ... For regionally advanced cancer, we observed no significant associations with aspirin use. For high-grade and lethal disease, men taking ≥ 6 adult-strength tablets/week experienced similar reductions in risk (HR=0.72 ...)" "For lethal prostate cancer (M1 at diagnosis or the development of bony metastases or fatal prostate cancer during follow-up), we observed a significant inverse trend ... for increasing number of tablets per week whereby men who consumed less than two adult-strength tablets per week (equivalent to one baby aspirin daily) had a non-significant 3% lower risk of lethal prostate cancer ... that further decreased to 20% for 2–5 tablets a week ... and 29% ... for 6 or more tablets per week, when compared to non-users." [Gc] (2012 - Health Professionals Follow-up Study [HPFS] - Chan (& Giovannucci) "This is the first study reporting on aspirin consumption after a prostate cancer diagnosis and its association with the development of lethal prostate cancer. We observed no association between post-diagnostic aspirin use and metastatic or fatal prostate cancer." A "potential mechanism for reducing fatal disease may be through aspirin's anti-platelet effects to reduce blood–borne metastases. One may speculate that such metastases may have already occurred by the time of diagnosis, eliminating aspirin's potential effect through that mechanism." "Our data do not support an association between aspirin use after a prostate cancer diagnosis and the development of lethal prostate cancer." However, one might argue that there is benefit in preventing further metastases. [Gd] (2013 - Swedish Prescribed Drug Register) (Amazing that the Swedes can track low-dose aspirin use!) "Except for a borderline result in prostate cancer (OR ∼0.9 ...), aspirin use was associated with a lower rate of metastatic disease (ORs ∼0.6–0.8) {for colorectal, lung and breast cancers}." "… we found evidence that the use of low-dose aspirin in the year prior to diagnosis was associated with better tumour extent for colorectal and lung cancers, but not for prostate and breast cancers, and was associated with lower metastatic disease for colorectal, lung and breast cancers." [Ge] (2014 - U.S.) "We hypothesized that {anticoagulant} therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC." "Aspirin use was ... associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7% ...)" "On subset analysis of patients with Gleason score (GS) 9-10 histology, aspirin resulted in improved 5-year OS (88% vs. 37% ...)" !!! [Gf] (2015 - U.S. - African American men ) "We identified 289 African American men with prostate cancer who were treated with definitive radiation therapy to a dose of ≥7560 cGy." {The authors tried to make this hard to read. "ASA+" means aspirin users; "ASA-" means aspirin non-users. "DMPFS" is distant progression-free survival. "PCSS" = prostate cancer-specific survival.} "ASA use was associated with a significant reduction in biochemical recurrences (hazard ratio [HR] 0.56 ...). The 7-year DMPFS was 98.4% for ASA+ and 91.8% for ASA- men ... On multivariate analysis, ASA use was associated with a decreased risk of distant metastases (HR 0.23 ...). The 7-year PCSS was 99.3% for ASA+ and 96.9% for ASA- men ..." [Gg] (2012 - U.S.) "This study comprised 5,955 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database with localized adenocarcinoma of the prostate treated with radical prostatectomy (RP) or radiotherapy (RT). Of them, 2,175 (37%) were receiving ACs {anticoagulants} (warfarin, clopidogrel, enoxaparin, and/or aspirin)." "AC therapy, particularly aspirin, was associated with a reduced risk of {prostate cancer-specific mortality} in men treated with RT or RP for prostate cancer." "Multivariable analysis indicated that aspirin use was independently associated with a lower risk of {prostate cancer-specific mortality} (adjusted hazard ratio, 0.43 ...)" [Gh] (2012 - U.K.) "Post-diagnostic low-dose aspirin use was identified in 52 % of 1,184 prostate cancer-specific deaths and 39 % of 3,531 matched controls ..." "Compared with no use, patients with 1-11 prescriptions and 12 or more prescriptions had adjusted ORs of 1.07 ... and 0.97 .., respectively." "We found no evidence of an association between low-dose aspirin use before or after diagnosis and risk of prostate cancer-specific mortality, after potential confounders were accounted for, in UK prostate cancer patients." Prescriptions for low-dose aspirin? {After 43 years in the U.S., people still ask me where I am from. But to the English, I now sound like an America. On a vacation in England in 2004, my wife wanted some low dose aspirin for the return flight. (Her brother & father had both died because of blood clots.) So we went into 'Boots, the Chemist" but could not find the stuff. I approached someone who seemed to be in charge, & explained that we were looking for Baby Aspirin. She sighed, & looked at me as if to say "Americans & their infantile euphemisms!." "You mean 75 mg aspirin!" If I had my wits about me, I would have said: "No, no - 81 mg aspirin.", which is the U.S. low dose. Anyway, she walked over to a locked cabinet & found what we needed. No prescription required.} [Gi] (2014 - Ireland) Prescriptions again - but a different conclusion. "Men with stage I-III prostate cancer were identified from Irish National Cancer Registry records, which have been linked to national prescribing data from the Irish General Medical Services scheme. Aspirin use in the year preceding prostate cancer diagnosis was identified from this linked prescription-claims data." "In adjusted analyses, aspirin use was associated with a small, but non-significant, reduced risk of prostate cancer-specific mortality (HR = 0.88 ...)" "In dose-response analyses, stronger associations with prostate cancer-specific mortality were observed in men with higher aspirin dosing intensity (HR = 0.73 ...) and in men receiving >75 mg of aspirin (HR = 0.61 …)”

So the dose seems to matter. Note that a low dose is sufficient to prevent platelet aggregation, but an increasing dose would have more effect on inflammation.

[Gj] (2014 – U.S. – men with nonmetastatic prostate cancer)

“… the Cancer Prevention Study-II Nutrition Cohort in 1992 or 1993 and June 2009. Aspirin use was reported at enrollment, in 1997, and every 2 years thereafter. During follow-up through 2010, there were 441 prostate cancer deaths among 8,427 prostate cancer cases with information on prediagnosis aspirin use and 301 prostate cancer deaths among 7,118 prostate cancer cases with information on postdiagnosis aspirin use.”

Modest protection against lesser cancer, but:

“… among men diagnosed with high-risk cancers (≥ T3 and/or Gleason score ≥ 8), postdiagnosis daily aspirin use was associated with lower {prostate cancer-specific mortality} (HR = 0.60 …), with no clear difference by dose (low-dose, typically 81 mg per day, HR = 0.50 .., higher dose, HR = 0.73 …)”

[Gk] (2014 – Canadian study using UK data)

Similar to [B2] – failed to find benefit.

[Gl] (2017 – U.S. – Physicians’ Health Study )

“In 1981/82, the Physicians’ Health Study randomized 22,071 healthy male physicians to aspirin, β-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2,015 for PC patients.”

“502 men developed lethal PC by 2009”

“Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68 … past: HR 0.54 … compared to never users.”

“In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68 …) and overall mortality (HR 0.72 …)”.

[H] D-dimer.

If you go to the ER with chest pain, they will probably do a D-dimer test. If D-dimer is normal, they will discount the possibility of a clot to the lungs. D-dimer can be elevated for other reasons, but will always be elevated if a clot is present.

D-dimer is a protein fragment that is present in the blood when plasmin acts to degrade a blood clot by fibrinolysis. [Ha]

Blood clots are essentially fibrin. While circulating plasmin will break down fibrin. It is a slow process, for obvious reasons. When there is internal bleeding, one would not want a rapid breakdown of the resulting clot. But with the persistent build-up of a DVT, the plasmin effect is far too slow.

[I] Fibrinogen.

Fibrinogen is the precursor of fibrin. It therefore represents clotting potential. Fibrinogen levels may be elevated due to chronic subclinical inflammation, but should return to normal if inflammation is brought under control.

[J] Warfarin & PCa Risk.

In Warfarin users who are later diagnosed with PCa, some will have suffered a blood clot because of the (occult) cancer. Warfarin use would then appear to increase the risk of PCa – at least in the short term. Men who began using Warfarin before PCa affected coagulation, would have a different risk pattern. Warfarin-PCa studies necessarily commingle these two populations and muddy the picture. & so it is useful to distinguish short-term users from long-term. One-year use could be associated with increased risk, while 4-year use in linked to lower risk.

If dysfunctional coagulation is necessary for metastasis, cancer-related clots might be associated with increased mortality – which would show up in short-term Warfarin users.

A 2007 Canadian study [Ja] reported that men who had used Warfarin for 4 years had 20% less risk for PCa:

“Our results suggest that warfarin has an antitumour effect that is specific to prostate cancer.“

A 2010 U.S. study [Jb] found that anticoagulant “therapy was associated with an improvement in biochemical control in patients with prostate cancer who received {radiotherapy} with curative intent. The effect was most prominent in patients who had high-risk disease.”

If Warfarin use inhibits metastasis, the benefit would show up more in high-risk cases.

From a 2010 Canadian study [Jc]:

“Prolonged warfarin use may decrease the risk of prostate cancer. We aimed to assess the effect of warfarin on histological grade and clinical stage of prostate cancer at diagnosis.”

“Compared with non-users, men with at least 2 years of cumulative warfarin use in the 5 year period preceding the diagnosis of prostate cancer were at a lower risk of a poor prognosis composite score at the time of their prostate cancer diagnosis” – 60% less risk.

“However, an increased risk of poor prognosis disease was observed with 4 years of cumulative warfarin use compared to never use” – double the risk.

That’s puzzling. Of course, Warfarin users are often not in the best of health. Even so, this is an outlier finding.

Another Canadian study from 2013 [Jd]:

“Recent evidence suggests that warfarin use may be associated with a reduced risk of prostate cancer. We aimed to determine whether exposure to warfarin is also associated with a reduced risk of prostate cancer death.”

The risk of PCa death with one year of Warfarin use (versus never) was increased by 77%, whereas five-year use reduced risk by 36%. This is consistent with short-term users having had cancer-related clots, & possibly therefore, more serious disease.

A 2016 Finnish paper [Je] reported increased risk with low-dose short-term use. Similarly, for metastatic PCa, there was increased risk, which disappeared with continued use.

Again, this supports the idea that recent Warfarin use includes men with PCa-related clots & a higher risk of diagnosis.

With a wash-out period (longer use) there was no longer any increased risk. Unfortunately, in this population, there seems not to have been reduced risk either.

Incidentally, regardless of any PCa survival benefit of Warfarin, there is a consensus that Warfarin is too dangerous to use as a PCa chemotherapy drug.

-Palinurus

[Ba] https://www.ncbi.nlm.nih.gov/pubmed/20331949

[Bb] https://www.cdc.gov/ncbddd/dvt/data.html

[Bc] http://www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/basics/risk-factors/con-2003192

[Ca] http://www.repertoiremag.com/warfarin-still-the-gold-standard.html

[Cb] http://www.nejm.org/doi/full/10.1056/NEJMsa1103053?viewType=Print

[Cc] https://www.ncbi.nlm.nih.gov/pubmed/26674156

[Da] https://www.fda.gov/drugs/resourcesforyou/consumers/ucm390574.htm

[Db] http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175283

[Dc] http://www.ajpmonline.org/article/S0749-3797(14)00661-8/fulltext

[Fa] https://en.wikipedia.org/wiki/Nattokinase

[Fb] https://www.ncbi.nlm.nih.gov/pubmed/2123064

[Fc] https://www.ncbi.nlm.nih.gov/pubmed/19358933

[Fd] https://www.ncbi.nlm.nih.gov/pubmed/26109079

[Ga] http://cebp.aacrjournals.org/content/11/10/1108.long

[Gb] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445018/

[Gc] http://cancerpreventionresearch.aacrjournals.org/content/5/10/1223.long

[Gd] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790151/

[Ge] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049786/

[Gf] https://www.ncbi.nlm.nih.gov/pubmed/26429642

[Gg] https://www.ncbi.nlm.nih.gov/pubmed/22927523

[Gh] https://www.ncbi.nlm.nih.gov/pubmed/24310109

[Gi] https://www.ncbi.nlm.nih.gov/pubmed/24356627

[Gj] https://www.ncbi.nlm.nih.gov/pubmed/25332245

[Gk] https://www.ncbi.nlm.nih.gov/pubmed/25463991

[Gl] https://www.ncbi.nlm.nih.gov/pubmed/28189429

[Ha] https://en.wikipedia.org/wiki/D-dimer

[Ja] https://www.ncbi.nlm.nih.gov/pubmed/17466896

[Jb] http://onlinelibrary.wiley.com/doi/10.1002/cncr.24890/full

[Jc] https://www.ncbi.nlm.nih.gov/pubmed/20437456

[Jd] https://www.ncbi.nlm.nih.gov/pubmed/23494728

[Je] https://www.ncbi.nlm.nih.gov/pubmed/27628763