November, 2000

Prostate Cancer Research in Cincinnati

Questions about quality of research are difficult to answer. Who determines whether research is good or bad? A tough question. But questions about quantity of research can be answered by counting the number of publications. Fortunately, there appears a correlation between quantity and quality: where publications are plentiful research is better than where publications are scarce. Publications can be counted in 'PubMed', the National Library of Medicine's search service that provides access to over 11 million citations in MEDLINE, PreMEDLINE, and other related databases:http://www.ncbi.nlm.nih.gov/entrez/.

1.3 million citations in PubMed are about cancer, and about 2.5% of those are about prostate cancer. If one enters as keywords 'prostate cancer' and 'Cincinnati', all citations about prostate cancer and with Cincinnati in the address of the principal (=first) author, will be listed. PubMed allows also searching with time limits. In our searches only the citations of the last ten years, the last five years, and the last two years were selected. Seven cities were entered, and the results are shown in two bar graphs. In both graphs the bars consist of three segments: blank at the top, stippled in the middle, and black at the bottom. The number of publications during the last two years are shown in the top (blank) part of the bar, those of the last five years are shown in the blank and stippled parts combined, and the full length of the bar represents all papers published during the last 10 years.

The first graph shows all publications about cancer in the seven cities. In Cleveland, Pittsburgh and Ann Arbor the publication rate is more than twice that in Columbus and Cincinnati. Indianapolis and Detroit are between these two groups. The second graph shows the publications about prostate cancer. There are again two groups, but with different cities. Cleveland, Detroit and Ann Arbor are leading --- the number of publications originating in Detroit is ten times that in Cincinnati! The relative size of the segments of the various bars suggests that prostate cancer research in Cincinnati has fallen behind. Five years ago, in October 1995, the number of publications about prostate cancer originating in Cincinnati was larger than that of Columbus, Indianapolis and Pittsburgh. In the last two years research in Cincinnati has dwindled.

Kees DeJong

About NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

COX-2 is BAD: Prostate 2000 Jan;42(1):73-8
Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma.
Gupta S et al.: Aberrant or increased expression of cyclooxygenase (COX)-2 has been implicated in the pathogenesis of many diseases including carcinogenesis. COX-2 has been shown to be over-expressed in some human cancers. we assessed COX-2 expression in samples of pair-matched benign and cancer tissue obtained from the same prostate cancer patient. Mean levels of COX-2 mRNA were 3.4-fold higher in prostate cancer tissue (n = 12) compared with the paired benign tissue. These data suggest that COX-2 inhibitors may be useful for prevention or therapy of prostate cancer in humans.

Inhibiting COX-2 is GOOD:  
BJU Int 2000 Oct;86(6):736-41
Cytoplasmic induction and over-expression of cyclooxygenase-2 in human prostate cancer: im- plications for prevention and treatment.
Madaan S et al.: OBJECTIVE: To assess the level and morphological distribution of cyclooxygenase (COX)-1 and -2 in human prostates and to determine any association with the Gleason grade of prostate cancer. COX-2 expression was significantly higher in poorly differentiated than in well differentiated tumours The regular use of nonsteroidal anti-inflammatory drugs is associated with a reduced incidence of cancers. The present results provide the basis for a potential role for COX-2 inhibitors in the prevention and treatment of prostate cancer.

Celebrex & Vioxx INHIBIT COX-2:  
Crit Rev Clin Lab Sci 2000 Oct;37(5):431-502
Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neo- plasia.
Fosslien E: Several types of human tumors overexpress cyclooxygenase (COX)-2 but not COX-1. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but COX-1 as well. selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib <Celebrex> and rofecoxib <Vioxx> are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1.

MICE Benefit:  
J Urol 2000 Sep;164(3 Pt 1):820-5
Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo.
Liu XH et al.: PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme which catalyzes the formation of prostaglandins from arachidonic acid <fat in meat>, is expressed in prostate cancer specimens and cell lines. A total of 28 male nude mice were inoculated subcutaneously with 1 million PC-3 cells. Tumors were palpable in all 28 animals 1 week after inoculation and mice were randomized to receive either vehicle (control) or NS398 <a COX-2 inhibitor>, NS398 induced a sustained inhibition of PC-3 tumor cell growth and a regression of existing tumors. NS398 had no effect on proliferation (PCNA), but induced apoptosis and decreased angiogenesis.

SULINDAC is also active:  
Biochem Pharmacol 1999 Oct 1;58(7):1097-107
Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines.
Lim JT et al.: We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (Exisulind, Prevatec) on a series of human prostate epithelial cell lines. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism These compounds may be useful in the prevention and treatment of human prostate cancer. CONCLUSION NSAIDs (COX-2 inhibitors and Sulindac) as medicines against Prostate Cancer are promising but unproven as clinical trials have not yet taken place.

=================           back to top             =================

October, 2000

Prostate Cancer Statistics of the USA

From the Statistics page of the American Cancer Society (www.cancer.org)

"An estimated 180,400 new cases of prostate cancer in the US during 2000. Prostate cancer incidence rates remain significantly higher in black men than in white men. … An estimated 31,900 deaths in 2000, the second leading cause of cancer death in men. … rates in black men remain more than twice as high as rates in white men. 
…the incidence of prostate cancer increases with age; more than 75% of all prostate cancers are diagnosed in men over age 65. Black Americans have the highest prostate cancer incidence rates in the world… strong familial predisposition may be responsible for 5%-10% of prostate cancers… Ninety two percent of men diagnosed with prostate cancer survive at least 5 years, 67% survive at least 10 years, and 52% survive 15 years. Fifty-eight percent of all prostate cancers are found while they are still localized (that is, confined to the prostate), and the 5-year relative survival rate for men with localized prostate cancer is 100%. Thirty-one percent of prostate cancers have already spread locally (to tissues near the prostate) at the time of diagnosis. The 5-year survival rate for these men is 94%. Among the 11% of men whose prostate cancers have already spread to distant parts of the body at the time of diagnosis, about 31% are expected to survive at least five years. 

==================================================

Information in this newsletter, presented with the name of magazine; title of article, and the name of the first author, has been downloaded from "PubMed", also known as "MedLine". More information can be found by going to the Web page of the "National Institutes of Health": www.nih.gov/, clicking on "Health Information", and then on "PubMed".

In Greater Cincinnati Each Working Day 
SIX Men are Diagnosed with PCa 
and 
ONE man Dies

Detailed PCa statistics in the USA are collected in a few states and metropolitan areas representing about 10% of the US population (SEER program); Ohio and Greater Cincinnati are not included in the SEER program. PCa statistics of Greater Cincinnati are thus an educated guess! 
Assuming 1) that incidence and mortality are proportional to the national data, and 2) that in 2000 the population of Greater Cincinnati and the USA are 2 and 300 million respectively, the Greater Cincinnati statistics would be for this year:

new cases: 1,200
diagnosed and still alive: 6,500 
deaths: 200 

=========================

Increased 5-year survival results are from diagnosing earlier, not from Reductions in Mortality, says JAMA

There has been publicity about increasing 5-year survival rates in cancer. Is this a sign of success? In a study published in the Journal of the American Medical Association (JAMA 2000 Jun 14;283(22):2975-8), it was concluded, "Although 5-year survival is a valid measure for comparing cancer therapies in a randomized trial, our analysis shows that changes in 5-year survival over time bear little relationship to changes in cancer mortality. Instead, they appear primarily related to changing patterns of diagnosis." 

Olive Oil and Tomatoes: Good for you!

European Journal of Cancer Prevention 2000 Apr;9(2):119-23 
Fraction of prostate cancer incidence attributed to diet in Athens, Greece. 
Bosetti C et al.) - Diet appears to be a major determinant in the incidence of prostate cancer. In a case-control study conducted in Athens, Greece, we found that dairy products, butter and seed oils were positively associated with risk of prostate cancer, whereas cooked and raw tomatoes were inversely associated. … The incidence of prostate cancer in Greece could be reduced by about two-fifths if the population increased the consumption of tomatoes and reduced the intake of dairy products, and substituted olive oil for other added lipids.

GLEASON GRADE & GLEASON SCORE
(from Phoenix5 at http://www.phoenix5.org/grading.html)

This is Dr. Gleason's own simplified drawing of the five grades of prostate cancer in his system. The less the cancerous cells appear like normal cells, the more malignant the cancer. Grade 1 appears at the top and grade 5 is at the bottom.

Two numbers, each from 1-5, are assigned successively to the two most predominant or prevalent patterns of differentiation present in the examined tissue sample. These are added together to produce the Gleason Score. High numbers (e.g., 7-10) indicate poor differentiation and therefore more malignant.

Tissues are obtained by biopsy of the prostate but it must be remembered that even with the biopsy, there is no certainty that the sample is fully representative. A tumor may be missed or it may be hit.

It can also be seen that assigning grades is not an exact science. A pathologist who may give a grading that is too high or too low. That is why a second opinion (of the same samples) is highly recommended. 

=================           back to top             =================

September, 2000 

Hormonal Therapy leads to Osteoporosis

J Urol 2000 Jan;163(1):181-6 
Progressive osteoporosis during androgen deprivation therapy for prostate cancer.  
Daniell HW, et al -.… Bone loss during androgen ablation therapy for prostate cancer has rarely been quantitated. … RESULTS: Average age corrected baseline femoral neck bone mineral density was higher in controls than in treated men and remained essentially un-changed for 2 years. Following orchiectomy average bone mineral density decreased 2.4% and 7.6%, respectively, during years 1 and 2 (2-year loss 2.5% to 17.0%), with similar losses documented in men undergoing chemical castration. Average bone mineral density decreased 1.4% to 2.6% per year 3 to 8 years after uninterrupted androgen deprivation … CONCLUSIONS: Chemical or surgical castration in men with prostate cancer is usually followed by greatly accelerated bone loss which may be super-imposed on a bone mass already depleted before hormonal therapy. 

Fosamax (alendronate) fights Osteoporosis

N Engl J Med 2000 Aug 31;343(9):604-10 
Alendronate for the treatment of osteoporosis in men.  
Orwoll E, et al - Despite its association with disability, death, and increased medical costs, osteoporosis in men has been relatively neglected as a subject of study. There have been no large, controlled trials of treatment in men. METHODS: In a two-year double-blind trial, we studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis. …
RESULTS: … The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites. The incidence of vertebral fractures was lower in the alendronate group than in the placebo group (0.8 percent vs. 7.1 percent). Men in the placebo group had a 2.4 mm decrease in height, as compared with a decrease of 0.6 mm in the alendronate group. Alendronate was generally well tolerated. 
CONCLUSIONS: In men with osteoporosis, alendronate significantly increases spine, hip, and total-body bone mineral density and helps prevent vertebral fractures and decreases in height.

Fosamax 70 mg once a Week  == Fosamax 10 mg once a day

Aging (Milano) 2000 Feb;12(1):1-12 
Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis.  
Schnitzer T, et al - Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. All three treatment groups similarly reduced biochemical markers of bone. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group.  

=================           back to top             =================