Simon’s prostate log

cancer diary

5. Clear scan results and CRP

Appointment with urologist today. My scans appear to be clear of any further cancer i.e no metastasis.

He put some of the images that I had bought with me from my scans onto a screen and explained the dark bits. Appears that I have a fair bit of degenerative arthritis as well as a small cyst on my left kidney (no problem). We discussed the details of the Radical Prostatectomy and Jeremy Goad drew me some more excellent pictures by way of explanation. The operation takes about 3 hours. He cuts the urethra, removes the prostate and then sews the urethra back onto the bladder. The risk of impotence is because the nerves go very close to the wall of the rectum and he has to cut close to this wall. In his opinion there is no real defensible advantage to robots or laprascopic surgery other than a quicker recovery time. But I think I prefer an experienced human without too many degrees of separation from what is in front of him. I don’t want my fate determined by a mouse. I’ll need a catheter for a couple of weeks.

Told him about the blood and it all appeared normal.

Mentioned Martin Ashdown’s CRP work and the idea of waiting while I had 6 consecutive blood tests to establish the immune cycle. He seemed quite interested. Martin’s email had arrived this morning while I was struggling with CAD to complete my wiring assignment.

We agreed that we would tentatively book in the 11th December for surgery and that would probably leave time for the 6 consecutive blood tests after my needle biopsy heals. Healing should take another 2 weeks.

Martin’s email as follows:

Hi Simon….

below are 4 abstracts FYI. As discussed we are conducting cancer clinical trials at the Mayo Clinic (US), Royal Women’s hospital Melbourne and soon to start at Peter MacCallum also here in Melbourne.
We are using serial measurements of the blood assay – high sensitive C- Reactive Protein (hs-CRP) to establish the best time to apply chemotherapy.

Our work suggests that in order to obtain a complete response chemotherapy (and probably radiotherapy ) needs to be applied at the correct point (a narrow approx’ 12 hr window) in a patients repeating ~7 day regulated immune response cycle. CRP is known to be elevated and rise with disease progression in a number of cancer types. CRP is also appreciated to rise and fall with initiation and termination of the immune response.

Our work has demonstrated that CRP is repeatedly oscillating up & down over an approx 7 day cycle in response to the tumor burden in a variety of malignancies. This oscillation suggests a continuous repeating process of the patient’s immune system switching “on & off” in response to the tumor. Mouse experiments have shown that appropriately timed chemotherapy can “jam” this response “on” leading to total tumor irradication in advanced disease.

Also our work suggests that when chemotherapy is spectacularly successful in a late stage or advanced pateint, it is due to the chemotherapy fortuitously modulating a pre-existing suppressed anti-tumor immune response and not direct tumor toxicity. The 4th abstract discusses the immune suppression in prostate cancer patients. CRP when meausred serially (near daily) appears to be a good, cheap, robust surrogate biomarker to time therapy.

WRT your situation….and if you are interested I would suggest that you get six sequential hs-CRP’s done ( on a Monday, Wed, Fri, Sat, Mon, Wed) thru your GP & local Dorevitch. This may show elevated and oscillating CRP. I would do this once all the after-effects of your needle biopsies have resolved. This may also provide some information to your surgeon pre-op in light of the recent publications…abstracts below. I would be happy to chat to your surgeon to better explain what we are doing in the clinic. If you have any further questions ….don’t hesitate to call

best regards

martin.

Cancer. 2008 Jun;112(11):2377-83. (full text)
C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial.

Beer TM, Lalani AS, Lee S, Mori M, Eilers KM, Curd JG, Henner WD, Ryan CW, Venner P, Ruether JD, Chi KN; ASCENT Investigators.

Division of Hematology & Medical Oncology, Oregon Health & Sciences University, Portland, OR 97239, USA. beert@ohsu.edu

BACKGROUND: Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy. METHODS: Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline. RESULTS: C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52-5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60-0.92 [P = .007]). CONCLUSIONS.: Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel-based therapy. (c) 2008 American Cancer Society.

Urol Int. 2008;80(2):129-33. Epub 2008 Mar 19. (full text)

Simple stratification of survival using bone scan and serum C-reactive protein in prostate cancer patients with metastases.

Nakashima J, Kikuchi E, Miyajima A, Nakagawa K, Oya M, Ohigashi T, Murai M.

Department of Urology, Keio University School of Medicine, Tokyo, Japan. njun@sc.itc.keio.ac.jp

BACKGROUND: IL-6 has been reported to be a significant prognostic factor for prostate cancer and induces synthesis of C-reactive protein (CRP) by hepatocytes. The present study was undertaken to evaluate the clinical value of serum CRP in prostate cancer patients with metastases. METHODS: The prognostic significance of serum CRP as well as tumor histology, extent of disease (EOD) on bone scan, serum levels of prostate-specific antigen (PSA) and alkaline phosphatase (ALP) and hemoglobin was assessed using Cox’s proportional hazards model analyses in 126 prostate cancer patients with metastases treated with endocrine therapy. RESULTS: Serum levels of CRP, PSA and ALP significantly increased and hemoglobin significantly decreased with advancing EOD grade. Univariate analysis demonstrated that EOD, CRP, PSA, ALP, hemoglobin and tumor histology are significantly associated with disease-specific survival. Multivariate analysis demonstrated that serum CRP and EOD were significant prognostic factors. The 5-year survival rates in low-risk patients (CRP < or = 0.15 mg/dl and EOD 0.15 mg/dl and EOD > or = 2) were 74 and 24%, respectively. CONCLUSION: These results indicate that a combination of serum CRP and EOD can identify patients with a poor prognosis who may be candidates for innovative treatments among prostate cancer patients with metastases.

BJU Int. 2005 May;95(7):961-2. – (full text)

Comment in: BJU Int. 2005 Aug;96(3):441; author reply 441.

C-reactive protein is significantly associated with prostate-specific antigen and metastatic disease in prostate cancer.

Lehrer S, Diamond EJ, Mamkine B, Droller MJ, Stone NN, Stock RG.

Department of Radiation Oncology, Mount Sinai Medical Center, New York, NY 10029, USA. stevenlehrer@hotmail.com

OBJECTIVE: To further analyse the relationship of c-reactive protein (CRP) levels to prostate cancer, by measuring CRP in men with prostate cancer and benign prostatic hypertrophy (BPH), as chronic inflammation has long been linked to cancers with an infectious cause and CRP is a nonspecific marker for inflammation, associated with prostate cancer incidence and progression. PATIENTS AND METHODS: Data from 114 men, most of whom had had radioactive seeds implanted, were evaluated from November 1990 to April 2002. In addition, 27 men were included who had biopsy-confirmed BPH. CRP was assessed with an automated chemiluminometric high-sensitivity assay kit. RESULTS: There was no significant difference in CRP levels in men with localized prostate cancer or BPH but levels were significantly higher in men with bone metastases. There was also a significant correlation of CRP level with prostate-specific antigen (PSA) in those with cancer. Because PSA is correlated with disease stage, multiple linear regression was used with CRP as the dependent variable, and PSA and disease stage as independent variables. The regression was significant overall (P < 0.001) and the effect of disease stage on CRP (P < 0.001) was independent of the effect of PSA level (P = 0.001). CONCLUSION: The strong association of CRP with PSA, independent of tumour stage, suggests that inflammation might be fundamental in prostate cancer, and that chronic inflammation may be a legitimate target for prostate cancer chemoprevention and treatment.

Clin Cancer Res. 2007 Dec 1;13(23):6947-58. (full text) .

CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer.
Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, Thompson TC, Old LJ, Wang RF.

Department of Pathology, The Center for Cell and Gene Therapy, Baylor Colleg of Medicine, Houston, Texas 77030, USA.

PURPOSE: Although elevated proportions of CD4(+)CD25(+) regulatory T (Treg) cells have been shown in several types of cancers, very little is known about the existence and function of CD8(+) Treg cells in prostate cancer. In this study, we investigated prostate tumor-derived CD8(+) Treg cells and their function. EXPERIMENTAL DESIGN: Tumor-infiltrating lymphocytes (TIL) from fresh tumor specimens of patients with prostate cancer were generated and subjected to phenotypic and suppressive function analyses. In particular, we investigated the role and function CD8(+) Treg cells in prostate cancer. RESULTS: We show that high percentages of CD4(+)CD25(+) T cells are probably present in the majority (70%) of prostate TILs. Remarkably, both CD4(+) and CD8(+) T-cell subpopulations possessed potent suppressive activity. T-cell cloning and fluorescence-activated cell sorting analyses showed the presence of CD8(+)CD25(+) Treg cell clones that expressed FoxP3 and suppressed naïve T-cell proliferation, in addition to the previously known CD4(+)CD25(+) Treg cells. These CD8(+) Treg cells suppressed naïve T-cell proliferation mainly through a cell contact-dependent mechanism. Importantly, the suppressive function of CD8(+) Treg cells could be reversed by human Toll-like receptor 8 (TLR8) signaling. CONCLUSION: Our study shows that like CD4(+)CD25(+) Treg cells, CD8(+) Foxp3(+) Treg cells present in prostate tumor-derived TILs suppress immune responses and that their suppressive function can be regulated by TLR8 ligands, raising the possibility that the manipulation of Treg cell function by TLR8 ligands could improve the efficacy of immunotherapy for prostate cancer patients.

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7 Comments

  1. That is great news about the scan.

  2. Well, that’s excellent news 🙂

    If you call a 3 hr operation excellent news…

    Sounds like you’ll be good for a drink roundabout xmas then!

  3. admin

    November 12, 2008 at 1:41 pm

    Well, I’m unlikely to be heaving rocks in the Warrumbungles – where I would certainly prefer to be.

  4. Great news about the clear result Simon, and to read about your involvement in the immune cycle study.

    Nice to know you have friends and family around you.

    Sounds all together like you’re in good hands.

  5. Excellent! Great news!

  6. Thanks Sime for documenting all of this, it really does help me to understand what you and Susan are going through. My most loving thoughts will be with you on the11th!

  7. The kids and I were very pleased to hear this first good news since this saga began.

    Thanks for the scientific detail – much appreciated – the immune cycle stuff sounds really interesting.

    I’m sure you’d prefer to be in the ‘Bungles but it sounds like you are in excellent hands.

    We’ll be thinking of you on the 11th – much love.

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