Tuesday, May 5, 2015

Historical Contribution: 1969, Schwarz, et al., UTI Correlation to Fecal Bacteria


Schwarz H, Schirmer HKA, Ehlers B, Post B. Urinary Tract Infections: Correlation between Organisms Obtained Simultaneously from the Urine and Feces of Patients with Bacteriuria and Pyuria. J Urol. 1969. 101:765-767.


It was well established that gram-negative bacteria caused approximately 80% of UTI (urinary tract infections) and the colon was believed to be the source of most of these bacteria. In a study of 148 hospitalized individuals with bacteria in their urine, researchers from Johns Hopkins correlated the urinary organism with stool cultures from the same patients. Limited by difficulties in bacterial culture and identification of the time period, Dr. Schwarz and colleagues were able to demonstrate that urinary and fecal organisms were correlated in 60% to 100% of cases, depending on the bacteria. The authors then postulated that the colon was the most likely source of urinary bacteria, and perhaps, treating colonic flora could control the spread of infectious urinary organisms.


While we now know that the relationship between the colon, urinary bacteria and antimicrobial agents is more complex than a simple causal relationshipWe now understand that each patient has risk factors for infection, each bacteria has different methods for causing infection and there is certainly a difference between bacteruria (bacteria in the urine) and a UTI. However , manuscripts like this 1969 historical contribution, paved the way for a better understanding of UTI.


Visit the Centennial Website or click here to see more about the first 100 years at the Brady.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Tuesday, April 28, 2015

Historical Contribution: 1966: Gibbons, Transurethral Freezing of the Bladder

Gibbons RP. Transurethral Freezing of the Bladder: An Experimental Study. J Urol. 1966. 95;33-44.


Presented at the Urological Research Forum at the annual American Urological Association in New Orleans, 1965, Dr. Robert Gibbons presented early experiments to treat non-invasive urothelial cancers of the bladder. The proposed hypothesis was that by circumferentially destroying the mucosa of the bladder, the risk of subsequent, recurrent non-invasive cancers could be eliminated. Therefore Gibbons set out to find an acceptable freezing material and device to deliver a treatment that could treat these non-invasive bladder cancers.


Using a specially designed transurethral cooling device, Gibbons was able to deliver coolant to the entire surface of the bladder – effectively destroying the urothelial layer. 

The experiments were carried out in 30 dogs, and anatomic and pathological evaluation was carried out of the bladders at varying time points following treatment. By carefully tuning the cooling apparatus, Gibbons was able to achieve greater than 75% mucosal slough in many of the experiments. Importantly, Gibbons was never able to achieve 100% mucosal destruction, nor could he create reproducible outcomes by standardizing the coolant and methods to cool the bladder. Anatomic examination demonstrated reduced bladder capacity, new onset hydronephrosis and abdominal adhesions in many animals. Pathological evaluation demonstrated involvement of the submucosa in most specimens and often noticed full-thickness necrosis of the bladder wall in a number of cases. Unfortunately, this corresponded to peritoneal infections and death in a number of the experiments.


While this experiment could be considered a failure, this was an outstanding attempt to treat non-invasive bladder cancers. In 1965, there was no BCG or other intravesical treatment for the management of non-invasive urothelial cancers. Thermal ablation, or "freezing" of cancers was en vogue and being attempted in gastric, esophageal, retinal, brain and kidney cancers.


Visit the Centennial Website or click here to see more about the first 100 years at the Brady.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Wednesday, April 22, 2015

Is Testosterone Replacement Therapy "Feeding the Fire" of Prostate Cancer?

Testosterone replacement therapy (TRT) is the administration of testosterone to men with abnormally low testosterone, termed hypogonadism, or "low T," Men with symptoms of low testosterone, can often benefit from TRT. Common symptoms of hypogonadism in post-pubertal men commonly include decreased muscle mass, decreased energy, depressed mood, decreased libido, decreased spontaneous erections, and erectile dysfunction [Wang et al., 2008, Basaria, 2014].

While TRT has been used for decades the last decade has seen a dramatic increase in the use of TRT. The percentage of men in the Unites States over 40 years of age prescribed TRT increased from less than 1% in 2001 to nearly 3% in 2011 [Baillargeon et al., 2013]. The increase in TRT and lack of data from large, long term randomized controlled trials (RCT) has raised concern for unrecognized adverse health risks, including potential increases in cardiovascular disease and prostate cancer (PC).

Changes in androgen use over time. From Baillargeon et al., 2013.

There is large body of both historic and modern data supporting a role for androgens in PC pathogenesis and progression.

In 1941, Huggins and Hodges proposed that PC growth was driven by androgens, after observing benefits of castration in PC patients [Huggins et al., 1941]. Current laboratory data demonstrate that many PC cell lines depend on testosterone for growth and spread.  [Kyprianou et al., 1990, Webber et al., 1996, Schwab et al., 2000]. In animal models, testosterone promotes PC tumor growth [Bladou et al., 1996, Ahmad et al., 2008].

The data supporting the androgen hypothesis has led to the dogma that TRT in PC patients is like "feeding the fire." Historically, there is data supporting this concept. In 1982 Fowler et al. reported on 52 men with metastatic PC patients who recieved testosterone. 38% of men had elevations in prostatic acid phosphatase (a blood test used to monitor PC), 2 men had measurable metastatic progression, and ther were 4 deaths [Fowler et al., 1982]. Importantly, these patients had advanced disease, and many had prior androgen deprivation [Fowler et al., 1982]. Thus, it would not be appropriate to apply these observations to men with clinically localized disease who receive early primary treatment and PSA monitoring.


There is currently no reliable data indicating an increase in PC in men without PC undergoing TRT.

The majority of studies on TRT and PC are small, and to date, there have been no prospective studies on TRT with sufficient patient numbers to determine increased PC risk. By one estimate, 6,000 patients receiving 5 years of TRT would be needed to detect a 30% increase in PC incidence [Bhasin et al., 2003]. In a systematic review of 40 prospective studies, there was no study which demonstrated an association between TRT and PC risk in men without prior PC. In addition, a meta-analysis of 19 studies, there was no significant increase in PC or significant PSA increases necessitating prostate biopsy. [Calof et al., 2005].


TRT in patients with localized PC appears safe, based on limited data

Using Medicare data, Kaplan and colleagues reported on 149,354 men, including 1,181 men who received TRT after a diagnosis with PC. Overall, TRT was not associated with PC deaths [Kaplan et al., 2014]. Similarly, Pastuszak and colleagues reported on 103 men who after prostatectomy were treated with TRT. There was an overall increase serum PSA, but no evidence of increased cancer recurrence over 36 months [Pastuszak et al., 2013]. In a smaller study, Morgentaler et al. examined 13 patients with untreated PC, enrolled in an active surveillence program and receiving TRT. After a median follow-up of 2.5 years, 2 men had worse pathology on subsequent biopsy, but no cases of disease or PSA progression were seen [Morgentaler et al., 2011].



Overall, there remains no clear answer to the question "Does testosterone promote prostate cancer development in humans?" Thus, TRT in men with prostate cancer remains controversial. There is clear evidence that androgens can promote PC in animal models. It is clear that the influence of testosterone on PC disease progression is of paramount importance to both patients and providers as they weight the potential benefits of TRT. Currently, there is a growing amount of evidence that TRT is safe in well-selected men with clinically localized PC. However, these results are based on TRT in a small number of patients. Furthermore, the heterogeneity in PC progression and aggressiveness may give rise to heterogeneity in the responsiveness of tumors to TRT. Thus, until the results of future RCTs are available, TRT should only be offered to select patients who are carefully monitored and well-informed about the potential risks and benefits.


This blog was written by Jason E. Michaud M.D., Ph.D., urology resident at the Brady Urological Institute, currently in his laboratory research year.



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Endogenous, H., Prostate Cancer Collaborative, G., Roddam, A.W., Allen, N.E., Appleby, P., and Key, T.J. (2008) Endogenous Sex Hormones and Prostate Cancer: A Collaborative Analysis of 18 Prospective Studies. J Natl Cancer Inst 100: 170-183.
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Garcia-Cruz, E., Piqueras, M., Ribal, M.J., Huguet, J., Serapiao, R., Peri, L. et al. (2012) Low Testosterone Level Predicts Prostate Cancer in Re-Biopsy in Patients with High Grade Prostatic Intraepithelial Neoplasia. BJU Int 110: E199-202.
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Harman, S.M., Metter Ej Fau - Tobin, J.D., Tobin Jd Fau - Pearson, J., Pearson J Fau - Blackman, M.R., and Blackman, M.R. (2001) Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men. Baltimore Longitudinal Study of Aging.
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Huggins, C. (1947) The Etiology of Benign Prostatic Hypertrophy. Bulletin of the New York Academy of Medicine 23: 696-704.
Huggins, C. and Hodges, C.V. (1941) Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate. 1941. Cancer Res 1: 293-297.
Imamoto, T., Suzuki, H., Fukasawa, S., Shimbo, M., Inahara, M., Komiya, A. et al. (2005) Pretreatment Serum Testosterone Level as a Predictive Factor of Pathological Stage in Localized Prostate Cancer Patients Treated with Radical Prostatectomy. Eur Urol 47: 308-312.
Kaplan, A.L., Trinh, Q.D., Sun, M., Carter, S.C., Nguyen, P.L., Shih, Y.C. et al. (2014) Testosterone Replacement Therapy Following the Diagnosis of Prostate Cancer: Outcomes and Utilization Trends. J Sex Med 11: 1063-1070.
Kyprianou, N., English, H.F., and Isaacs, J.T. (1990) Programmed Cell Death During Regression of Pc-82 Human Prostate Cancer Following Androgen Ablation. Cancer Res 50: 3748-3753.
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Leibowitz, R.L., Dorff, T.B., Tucker, S., Symanowski, J., and Vogelzang, N.J. (2010) Testosterone Replacement in Prostate Cancer Survivors with Hypogonadal Symptoms. BJU Int 105: 1397-1401.
Massengill, J.C., Sun, L., Moul, J.W., Wu, H., Mcleod, D.G., Amling, C. et al. (2003) Pretreatment Total Testosterone Level Predicts Pathological Stage in Patients with Localized Prostate Cancer Treated with Radical Prostatectomy. J Urol 169: 1670-1675.
Matsumoto, A.M. (2003) Fundamental Aspects of Hypogonadism in the Aging Male. Reviews in Urology 5: S3-S10.
Mearini, L., Zucchi, A., Nunzi, E., Villirillo, T., Bini, V., and Porena, M. (2013) Low Serum Testosterone Levels Are Predictive of Prostate Cancer. World J Urol 31: 247-252.
Miner, M., Barkin, J., and Rosenberg, M.T. (2014) Testosterone Deficiency: Myth, Facts, and Controversy. Can J Urol 21 Suppl 2: 39-54.
Morgentaler, A., Lipshultz, L.I., Bennett, R., Sweeney, M., Avila, D., Jr., and Khera, M. (2011) Testosterone Therapy in Men with Untreated Prostate Cancer. J Urol 185: 1256-1260.
Morgentaler, A. and Rhoden, E.L. (2006) Prevalence of Prostate Cancer among Hypogonadal Men with Prostate-Specific Antigen Levels of 4.0 Ng/Ml or Less. Urology 68: 1263-1267.
Morote, J., Ramirez, C., Gomez, E., Planas, J., Raventos, C.X., De Torres, I.M. et al. (2009) The Relationship between Total and Free Serum Testosterone and the Risk of Prostate Cancer and Tumour Aggressiveness. BJU Int 104: 486-489.
Muller, M., Den Tonkelaar, I., Thijssen, J.H., Grobbee, D.E., and Van Der Schouw, Y.T. (2003) Endogenous Sex Hormones in Men Aged 40-80 Years. Eur J Endocrinol 149: 583-589.
Muller, R.L., Gerber L Fau - Moreira, D.M., Moreira Dm Fau - Andriole, G., Andriole G Fau - Castro-Santamaria, R., Castro-Santamaria R Fau - Freedland, S.J., and Freedland, S.J. (2012) Serum Testosterone and Dihydrotestosterone and Prostate Cancer Risk in the Placebo Arm of the Reduction by Dutasteride of Prostate Cancer Events Trial.
Mulligan, T., Frick, M.F., Zuraw, Q.C., Stemhagen, A., and Mcwhirter, C. (2006) Prevalence of Hypogonadism in Males Aged at Least 45 Years: The Him Study. International Journal of Clinical Practice 60: 762-769.
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Pastuszak, A.W., Pearlman, A.M., Lai, W.S., Godoy, G., Sathyamoorthy, K., Liu, J.S. et al. (2013) Testosterone Replacement Therapy in Patients with Prostate Cancer after Radical Prostatectomy. J Urol 190: 639-644.
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San Francisco, I.F., Rojas, P.A., Dewolf, W.C., and Morgentaler, A. (2014) Low Free Testosterone Levels Predict Disease Reclassification in Men with Prostate Cancer Undergoing Active Surveillance. BJU Int 114: 229-235.
Schroder, F.H., Hugosson, J., Roobol, M.J., Tammela, T.L.J., Ciatto, S., Nelen, V. et al. (2012) Prostate-Cancer Mortality at 11 Years of Follow-Up. New England Journal of Medicine 366: 981-990.
Schwab, T.S., Stewart, T., Lehr, J., Pienta, K.J., Rhim, J.S., and Macoska, J.A. (2000) Phenotypic Characterization of Immortalized Normal and Primary Tumor-Derived Human Prostate Epithelial Cell Cultures. Prostate 44: 164-171.
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Wang, C., Nieschlag, E., Swerdloff, R., Behre, H.M., Hellstrom, W.J., Gooren, L.J. et al. (2008) Investigation, Treatment and Monitoring of Late-Onset Hypogonadism in Males: Isa, Issam, Eau, Eaa and Asa Recommendations. Eur J Endocrinol 159: 507-514.
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Wu, F.C., Tajar, A., Beynon, J.M., Pye, S.R., Silman, A.J., Finn, J.D. et al. (2010) Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. N Engl J Med 363: 123-135.
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Tuesday, March 31, 2015

Historical Contribution: 1971, Chung and Coffey, The Prostate Nuclei

Biochemical characterization of prostatic nuclei. I. Androgen-induced changes in nuclear proteins L. W. Chung and D. S. Coffey Biochim Biophys Acta 1971 247: 570-83


Based on prior work, Dr. Coffey and colleagues demonstrated that the DNA, RNA and protein synthesis of the prostate gland varied with androgen levels (see the Historical Contribution: 1968). In this 1971 investigation (written in two parts), Drs. Chung and Coffey analyzed the nuclei and DNA content of rats following castration. They found that nuclei from prostate cells could easily be recovered in rats who were castrate (approximately 60%). However, in normal rats and those who received testosterone replacement (after castration) – the proportion of nuclei recovered was dramatically lower (13-15%). Thorough investigation determined a number of factors that contributed to the difference in prostate nuclei:
  1. Magnesium levels and the nuclear membranes are affected by testosterone levels. Aberrations in these normal cellular processes resulted in lower nuclei yield.
  2. Testosterone levels also affect the size of the nuclei (it had previously been demonstrated that testosterone affected the size of the whole prostate cell). Just as the prostate cell shrinks under castrate levels, so too does the prostate cell nucleus.
  3. Nuclear protein to DNA content (as measured by nuclear proteins and nuclear membrane proteins) is decreased with low testosterone levels and,
  4. … can be restored to normal after testosterone supplementation.

This series of elegant experiments can be found in Biochimica et Biophysica Acta. It is a wonderful example of Dr. Coffey's thoughtful and inventive approach to deciphering the prostate.


Visit the Centennial Website or click here to see more about the first 100 years at the Brady.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Tuesday, March 24, 2015

Historical Contribution: 1968, Coffey et al, DNA, Androgens and Prostate Growth

Coffey DS, Shimazaki J, Williams-Ashman HG. Polymerization of Deoxyribonucleotides in Realtion to Androgen-Induced Prostatic Growth. Ach Biochem Biophys. 1968. 124(1):184-98.


Donald S. Coffey, PhD
Long before becoming the Director of the Research Laboratories in the Department of Urology in 1974, Dr. Donald Coffey started a long career of investigation and discovery in the realm of benign and malignant prostatic growth. Based on observations that restoration of androgens after castration often results in regrowth of androgen-sensitive tissues, Coffey postulated that hyperplastic and hypertrophic changes in prostatic tissue could be detected in changes in DNA content.

In this 1968 manuscript, Dr. Coffey found that large doses of testosterone, when given to normal rats, only resulted in small increases in prostatic DNA content and DNA polymerase activity, and high levels of prostatic DNA activity and DNA polymerase levels are only present when the cells undergo active proliferation. The data supporting these conclusions demonstrates that following castration, the rat prostate decreases in size and DNA content. With exogenous testosterone, the prostate will grow and DNA content restored to normal levels… for some time. Even if excessive amounts of testosterone are administered, eventually the prostatic DNA content will plateau. DNA polymerase activity mirrored this effect, paralleling "the enhancement of "DNA synthesis" by intact prostatic cells."


Follow the link here to access the manuscript from Archives of Biochemistry and Biophysics.

Visit the Centennial Website or click here to see more about the first 100 years at the Brady.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 



Tuesday, March 10, 2015

Historical Contribution: 1967, Schirmer and Scott, Prostate Cancer and Irradiation

Schirmer HKA, Scott WW. Prostatic Cancer and Irradiation: Its Possible Mode of Action and its Clinical Indication. Southern Med Journal. 1967. 60;6:578-82.

HKA Schirmer (2nd from left, last row) 
and WW Scott (2nd from right, 1st row), 1986-87.
The Brady Urological Institute is well known for its advances in surgical treatment of prostatic disease, dating back to Hugh Hampton Young's perineal prostatectomy in 1904. The Brady was also a pioneer in radiation treatment for prostate cancer. In 1917, in the first Journal of Urology, HH Young demonstrated interstitial radiation (brachytherapy) for the treatment of prostate cancer. In this week's Historical Contribution, Horst Schirmer and William Scott embarked upon experimentation in freshly retrieved prostate cancer tissue to examine the possible effects of radiation therapy upon the tissue.

Based on the observations that (1) cancer cells derive chemical energy from lactic acid fermentation rather than oxidative metabolism (i.e. the Warburg effect; see FIGURE 2), (2) radiation preferentially affects cells undergoing aerobic metabolism, and (3) the catalase enzyme can attenuate the response of cells to radiation by reducing hydroxyl radical and molecular oxygen; Schirmer and Scott investigated the levels of catalase in normal prostate, well- and poorly-differentiated prostate cancers. They found that the catalase activity of normal prostate was 35 fold higher than catalase activity in prostate cancer. In addition, they found that well-differentiated prostate cancers had 6-fold higher catalase activity than poorly-differentiated cancers. They found corresponding decreases in oxygen consumption (i.e. respiration) and increases in glycolysis.

In the second part of this manuscript, Schirmer and Scott review three patients (of 16 treated at Hopkins) treated with prostate irradiation. Interestingly, all three patients had poorly differentiated prostate cancer and were treated with between 4500 and 5000 rads (a dose we now know to be biologically inadequate for prostate cancer). However, all three men experienced clinical improvement in prostate size and urinary symptoms. However, oncologic follow-up was short and the one patient who died of diffuse metastatic disease had residual, viable prostate cancer on histologic examination of the gland after his death.

Follow the link here to access the Southern Medical Journal.


Tuesday, March 3, 2015

Historical Contribution: 1965, Williams-Ashman, Androgens, Nucleic Acid & Protein Synthesis in Male Organs

Williams-Ashman HG. Androgenic Control of Nucleic Acid and Protein Synthesis in Male Accessory Genital Organs. Jour of Cellular and Comp Physiology. 1965. 66;2:111-24.


Howard Guy Williams-Ashman, PhD, was an internationally recognized authority on sex hormones and the biochemistry, biosynthesis, regulation and mode of action in both normal reproduction and malignant conditions. Dr. Williams-Ashman trained under Charles Huggins at the University of Chicago. For five years (1964-1969), he served as the Director of the Brady Laboratory for Reproductive Physiology at Johns Hopkins before returning to the University of Chicago. In this manuscript from 1965, Williams-Ashman discusses the reactions between RNA (ribonucleic acid) and protein synthesis in the prostate and seminal vesicle (SV).

Dr. Williams-Ashman starts by highlighting a number of important clinical observations: natural estrogens exert effects at much lower doses than androgens, physiologic actions of estrogens are quicker than those to androgens, sex genotype has little influence of reactivity to androgens and estrogens, and determining target tissues for androgens and estrogens can be challenging. He then reviews the scientific discoveries leading to the current understanding of androgens and development of the prostate and SV. He finishes by summarizing these data, stating:

"…androgenic hormones initiate and maintain the functional differentiation of the prostate gland and seminal vesicles… [through] primary changes in the ribosomal population density and in the levels of template RNA's."

The changes in RNA polymerase activity may be among the first detectable metabolic changes following castration. In addition, although they were not yet discovered, he hypothesized that the androgen receptor would be "proteinaceous" and the resulting discussion between Drs. Williams-Ashman and several leading researchers in the field provides wonderful, historical insight into the understanding of sex hormones, sex hormone receptors and the interplay in extragenital tissues.


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