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

Friday, January 30, 2015

A new trial down the “Hedgehog” pathway for men with high-risk prostate cancer


Nearly ten years ago, Johns Hopkins researchers David Berman and Philip Beachy discovered the hedgehog pathway in mice with prostate cancer.[1] This molecular pathway is turned on in the embryologic development of lung, pancreas, prostate, brain and other organs during normal development. In prostate cancer, this pathway is abnormally turned "on" as prostate cancer grows and spreads. Patrick C. Walsh, MD, describes the pathway, "It's like soil and seeds. The soil is the stroma of the prostate — the connective tissue that serves as its framework — and the cancer cells are the seeds." And the Hedgehog protein is compost, sunlight and water — everything the seeds need to grow. "If these cells spread but try to grow in poor soil, they can't survive. But if they can manufacture the Hedgehog signal, they can make the soil that they need — they can pack their lunch and take it with them."

In their original study, published in Nature,[1] Drs. Berman and Beachy demonstrated that giving drugs that could block the Hedgehog pathway, could shrink human prostate cancer tumors in animals. That model is now ready for prime-time testing in humans. Dr. Ashley Ross, MD, PhD, Assistant Professor in Urology, Oncology, and Pathology, is partnering with Emmanuel Antonarakis, MD, medical oncologist, are opening a randomized, placebo-controlled clinical trial of a highly selective Hedgehog pathway inhibitor, called LDE225 and made by Novartis. Dr. Ross explains the hypothesis of the trial:

Ashley E. Ross, MD, PhD
"By looking at gene expression patterns, we and others have found that the Hedgehog pathway appears up-regulated in men with disease that metastasizes after local therapy. Also, in men with advanced prostate cancer, Itraconazole, which inhibits the Hedgehog pathway, appears to slow the disease by a mechanism independent of the androgen receptor. Itraconazole is an antifungal drug. Recently, new, Hedgehog pathway specific drugs with much more favorable toxicity profiles are available."

Men with high-risk prostate cancer are badly in need of a drug that could potentially prevent cancer growth and metastasis. In these patients, there is always the possibility that, even after surgery or radiation therapy, some cancer cells have already escaped the prostate, are hiding somewhere in the body, and will repopulate. Use of a systemic Hedgehog inhibitor may help wipe out these "micrometastatic" cells. Dr. Ross explains,
"We need to start thinking of high-risk disease as a different type of cancer, a systemic disease, and we have to start treating them like we treat other cancers, with a systemic approach in addition to surgery and/or radiation."

The trial is open to radical prostatectomy patients at Johns Hopkins with high-risk prostate cancer: men with a Gleason score of 8 to 10, a PSA of 20 or greater, or clinical stage T3 disease. The men who receive the drug will take the pill for four weeks before radical prostatectomy. All of the men will undergo a repeat biopsy and will have a molecular profile done on their cancer cells before surgery, and then will have the radical prostatectomy specimens examined afterward. Dr. Ross explains, "It's a pharmacodynamic trial, to see if this new drug actually gets into the prostate and inhibits the Hedgehog pathway as we expect it should. Of course, men will be followed closely following prostatectomy and we will also monitor whether superior cancer control results are achieved in those who received LDE225."


 


 

This blog and quotations are extracted from:
Target: Hedgehog Pathway, New Trial Opens for Men with High-Risk Prostate Cancer in Discovery, Volume XI, Winter 2015.

Hedgehog Blockers:Can They Stop Advanced Prostate Cancer? Scientists One Step Closer To Finding Out in Prostate Cancer Discovery, Volume II, Autumn 2005.

 

[1] Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004 Oct 7;431(7009):707-12. Epub 2004 Sep 12.

 

Tuesday, January 27, 2015

Historical Contribution: 1963, King et al, The Bladder Neck in Childhood


1963
King LR, Mellins HZ, Scott WW. Radiographic Evaluation of the Bladder Neck in Childhood. Trans of Amer Assoc of Genito-urinary Sugeons. 1963. 55:7-12.


 

In the Transcripts of the American Association of Genitourinary Surgeons, Lowell King, Harry Mellins and William Wallace Scott detail the anatomy of voiding in 121 pediatric patients. Children ranged from one day to 17 years old. They found a number of interesting observations they describe in the manuscript:
  • Approximately 40% of normal girls will have a narrowed proximal urethra – this has no bearing on incidence of vesicoureteral reflux or clinical outcomes and can therefore be considered normal.
  • Of boys with outlet obstruction, about half of the patients had meatal stenosis and the other half had posterior urethral valves (PUV).
  • Of boys with recurrent urinary tract infections (UTI), approximately half had a congenital abnormality of the outlet – either PUV or an ureterocele. The rest had normal anatomy but functional deficits that led to residual urine and UTI.
In conclusion, King, Mellins and Scott found that there was a characteristic appearance of the bladder neck in pediatric patients with obstruction. However, "A narrow bladder neck relative to the proximal urethra as seen in the AP view is a common finding, and is certainly not a specific sign of bladder neck contracture."

 

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!