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Friday, June 27, 2008

Blog Updates for June 2008

June 1/08. In PSA Screening and Early Detection - Part 2 added: Thus for a given level of PSA a smaller prostate is associated with a higher likelihood of prostate cancer than a larger prostate. In particular a rule of thumb is that for each cubic centimeter (cc) of benign prostate tissue that 0.067 ng/ml of PSA will be produced. Thus for a prostate of 40cc one would expect a PSA of 40 x 0.067 = 2.68 ng/ml so if the PSA were 4.0 ng/ml then there is 4.0 - 2.68 = 1.32 ng/ml that is unexplained and might be due to cancer cells or other factor listed here. See [link].

June 1. In Tesosterone Metabolism and Prostate Cancer we add: Although reducing testosterone is a major approach taken in prostate cancer therapy isolated experiences with Testosterone Replacement Therapy (TRT) in prostate cancer patients have, contrary to the above models, not consistently shown an adverse effect. This suggests that a better model is required to truly understand what is going on.

June 1. In the Links section in the right margin we added a link on the Treatments: line labelled (2) after the Focal link which summarizes 2007 International Task Force on Prostate Cancer and the Focal Lesion Paradigm conclusions. See [link]

June 3. In the post on Testosterone Metabolism we add: One recent result that would tend to reinforce the idea that testosterone fuels prostate cancer is the finding that in response to drugs that suppress testosterone and other androgens (a common treatment for advanced cancer which tends to work for a period of time typically becomes ineffective after a period of time), metastatic prostate cancers develop genetic pathways enabling them to generate their own testosterone. See [PMID: 18519708] [full text] or [News Release].

Also added:
In a 1997 paper entitled Bcl2 Is the Guardian of Microtubule Integrity investigators hypothesize that the action of the drug taxol is related to reducing bcl-2 and associate it with an increase in bax.

June 3. In Soy we added: Even if it were beneficial for preventing prostate cancer or even if it were beneficial in earlier stage disease there remains the possibility that it could be detrimental for later stage disease. Although not a formal study, clinical observations by Dr. Leibowitz, a medical oncologist, were that he was able to reverse PSA rises in some patients by simply removing soy and phytoestrogens from their diet. See Dr. Leibowitz on soy. Also see Willet Divides Prostate Cancer into Four.

June 4. In Bradford Hill Criteria of Causation we added: Sometimes it can be difficult to distinguish which cause is the real one. For example, it might appear that prostate cancer patients with diabetes are at higher risk of mortality (from prostate cancer or other cause); however, a paper at 2008 ASCO found that that was because diabetics tend to be overweight. When they controlled for weight, e.g. compare diabetics and non-diabetics who are normal weight and compare diabetics and non-diabetics who are overweight, they found that diabetics had the same risk as non-diabetics. Being overweight was the true risk factor.

June 4. In AUA 2007 Conference Summaries we added: Update: highlights from the May 2008 AUA meeting conference are summarized at [urotoday] and [urologytimes].

June 4. In the Historical Developments post (which also includes future developments) we added: The Prostate Cancer Foundation founded by financier Michael Milken has used a portfolio approach for issuing $19 million in research grants and a review of the areas illustrates the topics thought to have the greatest upcoming promise. See Prostate Cancer Foundation Grants More Than $19 Million to Cancer Research Programs . The topics are:
  • Progression Biomarkers whose development would increase the pace of all future research since one would know sooner when experimental drugs are working
  • blocking ETS Gene Fusions to arrest prostate cancer, since it was found that tumors create their own androgens
  • since it was discovered that tumors produce their own androgens simply reducing them in the blood is insufficient so this project would look into reducingthem in the tumor itself
  • better characterize models that predict when new drugs are working in order to speed up research
  • study nutrition, obesity, diabetes, bone fracture and heart disease for patients receiving treatment for advanced prostate cancer
  • epigenetic cellular alterations are genetic mutations that are independent of DNA sequence. Study and work toward the new medications which block these.
  • discover blood markers indicating an immune response to prostate cancer and use this to develop immunotherapy treatments
  • study prostate cancer stem cells

June 4. In Testosterone Metabolism we add: A 2008 UrologyTimes article cites four studies: [PMID: 15310998], [PMID: 15643240], [PMID: 17509298], [PMID: 17183557] in which Testosterone replacement therapy was administered to prostate cancer patients beneficially. On the other hand, in the same article Dr. Lamm pointed out: In a "meta-analysis of nine studies, 11 of 987 patients given TRT developed prostate cancer versus zero of 129 control group patients [PMID: 14749457]. While not statistically significant, these figures raise the possibility that TRT fuels prostate cancer development" [reference modified to point to pubmed]

Dr. Morgensterm interprets this as "levels of androgens in the prostate do not reflect levels in the blood". He further says, referring to [PMID: 17169647] which he authored: "This is a new and exciting area that has turned on its head our idea about the relationship between testosterone and prostate cancer," Dr. Morgentaler said. "In fact, the latest data show the opposite of what we used to believe: It's not that high testosterone is a problem with prostate cancer. Actually, low testosterone appears to be a problem."

June 5. In Testosterone Metabolism we add:
5AR is involved in a number of different prostate cancer and non-prostate cancer examples:

  • Fat and Genistein. Even though models one and model two may be incomplete they may still be adequate for explaining certain phenomena. For example, [PMID: 18483578] uses this model, as seen in this figure to hypothesize the effects of fat and genistein on prostate cancer. "A high dietary fat intake, a risk factor of prostate cancer, induces prostate 5a-reductase-2 [i.e. 5AR] gene expression and subsequently stimulates prostate growth." On the other side 5AR and the associated growth can be inhibited by genistein, a phytoestrogen. As the two opposing forces are thought to both act on 5AR this model seems sufficient to describe these dynamics if the hypotheses of the paper are correct.
  • BPH. Inhibition of 5a-reductase [i.e. 5AR] activity by medication is used in the treatment of BPH.
  • Male-pattern baldness. Inhibition of 5a-reductase [i.e. 5AR] activity by medication is used in the treatment of male pattern baldness.
  • Diagnostics. Regions of higher blood flow within the prostate are thought to be higher risk areas of prostate cancer. Thus if we would locate regions of higher blood flow using imaging one could focus the biopsy sampling on those regions to increase the likelihood of detecting prostate cancer. Contrast agents are drugs which make it easier to image this blood flow. The imaging itself, is done via ordinary grey scale ultrasound or color doppler ultrasound or power doppler ultrasound. Color is thought to make it easier to detect the blood flow and power doppler is a variation that is thought to be less dependent on the angle of the reflected sound waves. (For comparison of ultrasound types see this table from this 2006 review by Halpern. A promising new method to enhance this further, which has been investigated [PMID: 16183033] [full text] and is currently the subject of further clinical trials at Thomas Jefferson University, makes use of the fact that 5AR inhibitors appear to reduce blood flow within healthy prostate tissue but do not reduce it in cancerous tissue. This would mean that by administering 5AR agents such as dutasteride two weeks prior to biopsy imaged blood flow is more likely to indicate prostate cancer.
  • Prostate Cancer Prevention. The use of 5AR inhibitors "in prostate cancer prevention is still controversial although it can decrease the incidence of prostate cancer." [PMID: 18483578]. In fact in the PCPT trial 18.4% of the men on finasteride vs. 24.4% of the controls developed prostate cancer -- a nearly 25% drop. (There was a greater number of advanced prostate cancer cases but that was thought to be due to the fact that as mentioned above 5AR inhibitors make it easier to detect cancer so we have to correct for the fact that a greater percentage would have been detected in the Finasteride group.)

June 6. In Testosterone Metabolism and Prostate Cancer we add: A third bcl inhibitor that is currently under investigation is WL-276 [PMID: 18519699] [full text].

June 8. In PSA Screening and Early Detection - Part 3. Current Environment we add the Annals of Internal Medicine paper reference and the references to its figures: Results that appear to support screening are also said to suffer from lead-time and length-time bias (requires sign-in but sign-in is free) also described in this 1997 Annals of Internal Medicine paper where bias is illustrated in a set of three diagrams: [1] [2] [3].

June 8. In Testosterone Metabolism and Prostate Cancer we add the introduction to Friedman's hormone receptor model: In Friedman's words "testosterone, estrogen and progesterone can be either helpful, harmful, or not do much at all. It all depends on the amount of each hormone receptor within the prostate cancer cell. Each hormone has receptors that acts in contradictory manner (in effect the cells drive with one foot on the gas pedal and one foot on the brake pedal). Since in vivo you are dealing with a heterogenous population, even if 99% of the cancer cells die in the presence of any one hormone, the 1% left will thrive in that environment. Also, for different individuals, one hormone treatment might initially be extremely helpful and for another be extremely hurtful."

June 8. In Nerve Sparing Turns 25 we add this Dr. Walsh Interview. Also added this to the Links in the right margin on the Webcasts: line.

June 9. In Questions to Ask Doctor added this link to another such list:

June 12. In PSA Screening and Early Detection - Part 2 added this reference treatment of prostatitis in the Factors Affecting PSA section.

June 15. In Testosterone Metabolism and Prostate Cancer and in How Healthy Men Can Reduce Their Risk we add this [New York Times, June 15, 2008] reference to Finasteride and Prostate Cancer Prevention.

June 17. In the Urinary Incontinence post added this reference to a voiding diary.

June 17. In Questions to Ask Doctor we found a new site with the indicated laboratory test checklist as it had disappeared from the prior site: Questions about lab tests from the Canadian Society of Medical Laboratory Science:

June 18. Added to Free Monthly Prostate Cancer Magazines and Journals referring to the most cited urology journals (Prostate, J of Urology, Eur J of Urology): The same three journals have the highest SCImago Journal & Country (SJR) rank for 2006 among urology focused journals. See [SJR Urology] for the complete list. (This list includes some non-urology journals which we excluded in concluding which were the top three.)

June 18. In Advice to the Newly Diagnosed we add: When treated with conservative therapy (watchful waiting or active surveillance) or androgen withdrawl Albertsen (papers) et al presented 20 year outcomes in [PMID: 15870412] [Full Text] summarized in this Mortality after conservative therapy or androgen withdrawl figure which classifies mortality by age and Gleason Score.

June 19. Added Canadian Prostate Health Council prostate cancer prevention brochure [CPHC] to the links in the Key Posts section to the right and colored both it and the PCRI link red.

June 20. In How Healthy Men Can Reduce Their Risk we add: As discussed in [PMID: 18559852] [Full Text], Epidemiological evidence [PMID: 16278466], [PMID: 16425098] and migratory patterns [PMID: 2066247] [Full Text] suggest that lifestyle modifications can impact the progression of prostate cancer. Further confirmation has come from a June 2008 molecular study [PMID: 18559852] [Full Text] that found that after such interventions that gene expression of "protein metabolism and modification, intracellular protein traffic, and protein phosphorylation" had been modified. We point out some patient-oriented brochures that summarize steps that seem likely to affect the progression of prostate cancer.

June 22. Added to Links section on right in the Medical/Uro: line this link to the [AUA 2008] meeting posters.

June 24. Added to the Factors Affecting PSA section of PSA Screening and Early Detection - Part 2. In particular PSA:

increases with age. It is well known that PSA increases as one gets older and it has even been recommended that PSA cutoff levels be age-dependent. [PMID: 18522630]

decreases with liver and lipid profile tests. PSA varies inversely with alanine aminotransferase (ALT), high-density lipoprotein (HDL) and with fasting blood sugar. It has also been observed to vary inversely with certain other liver and lipid profile tests; however, those associations ceased to be significant when all variables were taken into account at the same time. See [PMID: 18522630].

June 24. Added to the Pros and Cons of Screening section of PSA Screening and Early Detection - Part 3. Current Environment: in favor of screening is that the studies that are "against screening should be considered inadequate upon closer scrutiny since they were conducted in a patient cohort that was too old, the follow-up period was too short, and inappropriate endpoints were set." [PMID: 18560799].

Also in the Recent Results section of the same post: A 2008 study of US screening and urologist density to be published in Prostate Cancer Prostatic Disease [PMID: 18268527] "found that prostate cancer mortality rates correlated inversely with urologist population densities (P<0.01) and PSA screening (P<0.01) suggesting that screening and treatment reduce prostate cancer mortality."

June 25. In How Healthy Men Can Reduce Their Risk we add: Several companies are now offering prostate cancer genetic testing. Proactive Genomics offers the $300 Focus5 (TM) genetic test based on [PMID: 18199855] and deCODE diagnostics offers the ProCa(TM) genetic test for prostate cancer for $500 direct to the patient based on [PMID: 18264098]. [References: eyeondna, Medscape]. California and New York are demanding that direct-to-patient genetic testing companies show that tests ordered by their states' residents have been ordered by physicians; however, one genetic testing company has countered by pointing out that they process the information and do not do any testing themselves (its done in approved labs) so that their activities fall outside the scope of any state regulation. Wired article of June, 2008.

June 25. Under Advice to the Newly Diagnosed we add: Merglen et al [PMID: 17923593] reviewed "all 844 patients having a diagnosis of localized prostate cancer between January 1, 1989, and December 31, 1998, in Geneva, Switzerland" and found that "ten-year specific survival was 83% (95% confidence interval [CI], 73%-93%), 75% (95% CI, 67%-83%), and 72% (95% CI, 66%-80%) for patients who underwent surgery, radiotherapy, and watchful waiting, respectively (P < .001)." However, since this was an observational rather than randomized study its possible that the surgery patients were healthier (as healthier patients are more likely to be streamed toward surgery) and the better results among the surgery patients may have been due to their superior health status or other selection bias rather than the treatment itself. Also there have been significant advancements in both surgery and radiation in the last 10 years which might invalidate such comparisons. Also there could be problems related to attribution of cause of death since death certificates are known to be unreliable. [PMID: 18574097] [extract]. Thus again we cannot really say with any certainty that on the basis of this study that one treatment is truly better than the other even though it might have, on the surface, seemed to favor surgery.

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