Tuesday, March 24, 2015

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


1968
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


1967
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


1965
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.

 

Follow the link here to access the Journal of Cellular Physiology.

Monday, March 2, 2015

MRI-Robot Helps Target Cancer

MRI (magnetic resonance imaging) has recently been demonstrated to help in the diagnosis of prostate cancer, especially in men with a prior negative biopsy or those meeting criteria for active surveillance (See our prior blog on MRI and Active Surveillance). Traditionally prostate biopsies are performed with ultrasound imaging – which is great at targeting the prostate, but not necessarily for finding prostate cancer. Fusing MRI and ultrasound imaging is a recent advance that has helped urologists make use of the precision of MRI for finding tumors and the targeting of ultrasound to sample them.

Fusing MRI and ultrasound images can be complex and does not always work perfectly. If the tumor could be targeted with MRI, the extra step of fusion could be avoided. However, MRI machines make use of extremely strong magnets and metal instruments cannot be near the machine when it is turned on. This makes it impossible to use metal needles or machines with any metal components (including electrical wiring).

Researchers at Johns Hopkins, led by Dan Stoianovici, PhD, Director of the Urology Robotics Program, have developed a completely MRI-compatible robot to target the prostate and cancers within it. The robot makes use of pneumatic system composed of rubber and plastic tubing, screws and gears to manipulate a MRI-compatible needle to target the prostate. "The robotic device mounts on the MRI table alongside the patient. The physician selects a suspicious region that the MRI has shown, and the robot automatically guides the needle to target and presets the depth of insertion."

"To the best of our knowledge, this is the only robot approved by the FDA to operate in the MR environment in general, not only for the prostate."

The MR-bot (MRI-robot) has been approved by the Food and Drug Administration (FDA) and Insitutional Review Board (IRB) of Johns Hopkins for a clinical trial in humans. Urologists Mohamad Allaf, MD and Ashley Ross, MD, PhD, perform the biopsies. The first few cases indicate that robotic biopsy is safe and feasible.


With more precise imaging and techniques, urologists may continue to improve the precision of prostate biopsies. This work was awarded best paper of the Engineering and Urology Society of the American Urological Association.


Read more about the MrBOT at: http://urobotics.urology.jhu.edu/projects/MrBot/





Portions of this story were extracted from "First-Ever MRI Robot Targets Potential Cancer Sites for Biopsy" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.

Wednesday, February 4, 2015

Penile Cancer: Carcinoma in situ


Carcinoma in situ (CIS) of the penis refers to a squamous cell cancer limited to the most superficial layers of the penile skin. This cancer is also known as Erythroplasia of Queyrat if on the glans (head) of the penis or Bowen Disease if on the shaft of the penis and was covered in a previous blog. While CIS is technically a non-invasive cancer and believed to have low metastatic potential, it has features of high-grade (potentially aggressive) cancer that warrants careful management.

History

CIS was inititally described by Queyrat in 1911 as a red, velvety, well-marginated lesion of the glans penis or prepuce (of uncircumcised men). Bowen described a similar lesion of the penile skin in 1912. The original description of Bowen disease related to subsequent internal malignancy, however subsequent studies have demonstrated that this relationship was nothing more than coincidence.[1]

 

Presentation and Prognosis

CIS has a similar clinical presentation whether on the glans penis or shaft. As described above, CIS can appear as a red, velvety, well-marginated lesion on the penis. Alternatively the lesion can be scaly, crusted or ulcerated – similar in appearance to eczema or psoriasis. Development of metastasis for CIS is incredibly rare – however 10-33% of CIS on the glans and 5% of CIS on the shaft can progress to more invasive, dangerous disease.[2,3]

 

Management

As CIS rarely metastasizes, treatment is focused on (1) confirmation of a non-invasive lesion, (2) resection of lesions with an adequate microscopic margin and (3) penis-sparing techniques if the lesion is on the glans. Confirmation of non-invasive malignancy may require multiple biopsies or complete excision of the area of concern. A 5mm margin if often adequate for lesions on the shaft, while circumcision will cure most cases of CIS on the prepuce. Lymph node dissection is only performed in cases suspicious for invasion or enlarged lymph nodes.

Penis-sparing treatments

Lesions of the glans penis can be difficult to treat surgically without distorting normal penile anatomy or sensation. A number of topical treatments including 5-fluorouracil, 5% imiquimod, laser ablation (YAG or KTP lasers) and radiation therapy have all been used with success.[4-10] For patients with large tumors or lesions refractory to topical treatment, local skin excision can be performed with skin grafting as needed.

Penile lesion (CIS) completely excised (left) and with a skin graft using non-hair bearing skin of the groin (right).


For patients with CIS involving the glans, partial or complete excision with partial or complete resurfacing can be performed.[11,12]



A. CIS on the glans penis, B. Glanular skin removed, C. Skin graft placed on the glans, D. Final, cosmetically pleasant result.  From Palminteri etal. [12]

These penile surgeries often involve a multidisciplinary approach including a urologic oncologist, plastic (reconstructive) surgeon and excellent pathologists to ensure eradication of the disease.  Penile cancer is a rare disease and balancing the risks of cancer with penile reconstruction and function is best done at a center with experience treating this disease.


  1. Anderson SL, Nielson A, and Reymann F: Relationship between Bowen disease and internal malignant tumors. Arch Dermatol 1973; 108: pp. 367.
  2. Buechner SA: Common skin disorders of the penis. BJU Int 2002; 90: pp. 498-506.
  3. Bleeker MCG, Heideman DAM, Snijders PJF, et al: Penile cancer: epidemiology, pathogenesis, and prevention. World J Urol 2009; 27: pp. 141-150.
  4. Harrington KJ, Price PM, Fry L, Witherow RO. Erythroplasia of Queyrat treated with isotretinoin. Lancet. Oct 16 1993;342(8877):994-5. 
  5. Micali G, Nasca MR, De Pasquale R. Erythroplasia of Queyrat treated with imiquimod 5% cream. J Am Acad Dermatol. Nov 2006;55(5):901-3. 
  6. Conejo-Mir JS, Munoz MA, Linares M, Rodriguez L, Serrano A. Carbon dioxide laser treatment of erythroplasia of Queyrat: a revisited treatment to this condition. J Eur Acad Dermatol Venereol. Sep 2005;19(5):643-4. 
  7. Arlette JP. Treatment of Bowen's disease and erythroplasia of Queyrat. Br J Dermatol. Nov 2003;149 Suppl 66:43-9. 
  8. Orengo I, Rosen T, Guill CK. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol. Oct 2002;47(4 Suppl):S225-8. 
  9. Micali G, Lacarrubba F, Dinotta F, Massimino D, Nasca MR. Treating skin cancer with topical cream. Expert Opin Pharmacother. Jun 2010;11(9):1515-27. 
  10. Grabstald H, and Kelley CD: Radiation therapy of penile cancer. Urology 1980; 15: pp. 575-576.
  11. Pompeo AC, Zequi Sde C, Pompeo AS. Penile cancer: organ-sparing surgery. Curr Opin Urol. 2015 Mar;25(2):121-8. doi: 10.1097/MOU.0000000000000149.
  12. Palminteri E, Berdondini E, Lazzeri M, Mirri F, Barbagli G. Resurfacing and reconstruction of the glans penis. Eur Urol. 2007 Sep;52(3):893-8. Epub 2007 Jan 22.

Tuesday, February 3, 2015

Historical Contribution: 1964, Schirmer & Walton, Hypothermia and Kidney Function


1964
Schirmer HKA, Walton K. The Effet of Hypothermia upon Respiration and Anerobic Glycolysis of Dog Kidney. Invest Urol. 1964. 1;6:604-9.

 

The first deliberate partial nephrectomy for the excision of a tumor was credited to Vincenz Czerny in 1887. Numerous studies over the next decades defined the surgical anatomy and feasibility of partial nephrectomy for a variety of localized kidney processes (including cancer). Lack of early diagnostics and technical challenges prevented the operation from being widely utilized in the early 1900's. While these early researchers investigated repair mechanisms of the kidney, advances in the understanding of segmental blood supply and renal hypothermia to prevent ischemic damage were not introduced until the 1950's and 1960's.[1] 
Horst Schirmer, MD

In 1964, Horst Schirmer and Kenneth Walton of the Brady Urological Institute investigated the effects of hypothermia on the kidney. Prior work demonstrated that, with local cooling, renal function would only be temporarily depressed and irreversible damage (under normothermic conditions) could be limited. They investigated ox'ygen consumption and glycolysis in the kidneys of dogs. They found:

  • With decreasing temperature, the reduction in glycolysis associated with ischemia was tempered (33% at 27C, 17% at 17C and near zero at 7C).
  • After achieving hypothermia of 7C, normal function returned after 1 hour.
  • Interruption of blood flow for 4 hours resulted in:
    • 75% reduction in function in the normothermic kidney
    • Unchanged function in the cooled (7C) kidney
  • By examining both tissue from the cortex and medulla of the kidney, the cortex is nearly 7x more active than the medulla – providing evidence that cortical cooling is sufficient to provide effective hypothermia.

 

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

 


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! 



[1] Herr HW.A history of partial nephrectomy for renal tumors.J Urol. 2005 Mar;173(3):705-8.

Monday, February 2, 2015

Getting closer to an “quantitative” diagnosis of prostate cancer


Histomorphometry is the study of the microscopic organization and structure of tissue in a quantitative manner under the microscope. This process was briefly described in a prior blog, and often involves computer-assisted technology to provide objective measures cellular architecture to aide in diagnosis – a process that is often based on subjective classification of microscopic features.

Most cancers, prostate cancer included, are diagnosed by a pathologist – who examines tissue under a microscope to determine the presence and aggressiveness of a cancer. The future of digital pathology will likely use prostate cancer quantitative histomorphometry using computer-assisted scanned image features and may serve as a new and innovative predictive tool to improve determination of aggressive phenotypes of cancer. In prior work, Dr. Robert Veltri, PhD, of the Brady Urological Institute, demonstrated that a special "spectrophotometer" microscope was accurate and capable of predicting stage, recurrence and progression of prostate cancer when examining portions of prostate cancer slides.[1] 


An original, high-powered image of prostate cancer (a) is segmented into areas of individual nuclei (b), classified into individual sets (c) and segmented by the computer-alogorithm.  From Ali etal [2].

With collaborator, Anant Madabhushi, PhD, and his team at Case Western Reserve University, Dr. Veltri is working to develop new techniques to examine the entire slide image in a high-throughput process. These novel tools could form the basis of future software tools to conduct, in cooperation with the pathologist, automated, rapid and reproducible identification and quantification of tissue histology morphologic and molecular events – enabling machine-based predictions of tumor aggressiveness and outcomes such as recurrence, metastasis and survival.

 

In a recent experiment, Drs. Veltri and Madabhushi examined 80 prostate cancers looking at a variety of cellular features. Through a complex computer algorithm termed adaptive active contour scheme (AdACM), they were able to distinguish features of nuclei, gland architecture, and texture and then identify the best features to discriminate Gleason grade patterns. Using these features, AdACM was able to distinguish Gleason score patterns with an accuracy of 86%.[2]


Different computer-generated features to model architecture of prostate cancer in a core of tissue from a prostate biopsy. From Ali etal [2].

This is just some of the exciting research ongoing at the Brady Urological Institute at Johns Hopkins that will improve the way we diagnose and treat prostate cancer.

 

[1] Ali S, Veltri R, Epstein JI, Christudass C, Madabhushi A.Adaptive energy selective active contour with shape priors for nuclear segmentation and gleason grading of prostate cancer.Med Image Comput Comput Assist Interv. 2011;14(Pt 1):661-9.

[2] Ali S, Veltri R, Epstein JI, Christhunesa Christudass CS, Madabhushi A. Selective Invocation of Shape Priors for Deformable Segmentation and Morphologic Classification of Prostate Cancer Tissue Microarrays. CMIG, December, 2014. dx.doi.org/10.1016/j.compmedimag.2014.11.001