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Precision Urology

A GENOMIC-BASED PROGRAM

A personalized, individualized, genomic-based program in managing prostate cancer. A novel approach which avoids unnecessary biopsies, gives comfort in putting patients in active surveillance, and makes the treatment much more specific and precise for the patient, including precision surgery, precision diagnostics, precision therapy, and targeted vaccines and drug therapy.

At Mount Sinai, our Precision UrologyTM approach involves integration of multiple variables and imaging data in a decision support system. This is key in assuring men with prostate cancer of our commitment to a patient-centric, personalized diagnostic approach and excellent outcome while minimizing the side effects of treatment. Precision UrologyTM reflects our utilization of advanced technologies and incorporation of molecular and genomic analysis to identify markers of aggressive disease. This allows us to rigorously stage disease to determine if intervention is needed and if so, tailor the treatment accordingly.

PRECISE MD

A Precise MD IHC panel on a Gleason 6 biopsy patient showing Androgen Receptor staining, Ki67 staining, p53 staining and ERG-FUSION staining suggesting high risk of progression.

The Precise Immuno Histochemistry Panel is intended for patients either newly diagnosed with prostate cancer (prostate needle biopsy) or post-surgery (prostatectomy). The assay is designed to provide additional information for identifying a patient's risk for disease progression using 4 specific markers including: the Androgen Receptor (steroid hormone receptor, elevated levels have been associated with increased risk of disease progression), Ki67 (proliferation marker, increased labeling index has been associated with recurrence and resistance to radiation therapy), TP53 (tumor suppressor, mutations in the P53 gene have been associated with a more aggressive form of prostate cancer) and ERG (oncogene, over-expression is associated with the fusion of the ERG gene with the TMPRSS2 gene and reflects a specific phenotype of cancer which by some reports is associated with a more aggressive disease). The goal is to provide a more complete understanding of the patients tumor at baseline, in order to guide an initial treatment decision (i.e. Active Surveillance vs. therapy) or subsequent treatment post surgery, i.e. clinical follow-up monitoring, adjuvant radiation, or hormonal therapy.

FUSION BIOPSIES

Current prostate cancer diagnostic techniques are being scrutinized due to lack of conclusive data from screening trials and concerns about large number of unnecessary biopsies that are being performed.Nearly a million biopsies are done annually, to detect only a quarter of a million prostate cancer cases, which means 75% biopsies are unnecessary. PSA is an imperfect biomarker, missing 15% cases of prostate cancer when PSA is normal and when PSA is abnormal only 12% cases are found to have cancer. This leads to unnecessary blind and random biopsies, of which a large number turn out to be negative or of indolent cancers and is also associated with underestimating the cancer stage and missing significant Gleason 7 cancer in up to 30% cases. PSA as a marker and systematic biopsy as a confirmation tool are far from perfect and there is an acute need for developing better biomarkers and increasing accuracy of our biopsy techniques. Thus, the current diagnostic tools are imperfect to distinguish between aggressive prostate cancers requiring treatment, from indolent cancers.

The MRI-TRUS fusion is done in two steps: first a multiparametric endorectal MRI is done, the studies are then loaded on to a software on which the radiologist marks the prostate gland and the regions of interest for biopsy in different slices and views of the MRI, known as segmentation. This information is then loaded on to the device. The second step involves real-time MRI-TRUS fusion to create a three-dimensional real-time reconstruction of the prostate on which the aiming and tracking of biopsy site is done. This technique can be done in an outpatient setting under local anesthesia within a few minutes. Currently five devices approved by the FDA are available for MRI-TRUS fusion biopsy. The Artemis device (Eigen, GrassValley, California, USA) has a mechanical arm with ultrasound transducer probe and is capable of tracking and recording biopsy locations.

Targeting of lesions on multiparametric- MRI

The initial study at UCLA in 171 patients who underwent prostate biopsies using the Artemis platform which included 106 (active surveillance) patients and 65 (increasing PSA, prior negative conventional biopsy)patients. Prostate cancer was detected in 53% of the men. Fusion biopsy based targeted cores had higher yield of 21% as compared to 7% for systemic biopsy cores and higher number of gleason 7 cores 36% vs 24%.

Future perspectives

Multi-parametric MRI is capable of showing the location, extent and aggressiveness of prostate cancer. This capability of MRI is expected to end the era of unnecessary blind prostate biopsies and pave the way for future image-guided biopsies. It will help tailor therapies based on each patient's unique individual requirements and lead to improvements in health care and reduce complications, patient anxiety and discomfort.

3TESLA MULTIPARAMETRIC MRI

The ideal MRI for prostate cancer detection and staging comprises T1(for demonstrating high signal blood products) and T2 (demonstrating the anatomy) weighted imaging and functional imaging which includes diffusion weighted imaging and dynamic contrast enhanced imaging with the use of pelvic phased-array coil along with an endorectal coil on a high field-strength magnet. To obtain sub millimeter-resolution T2 weighted images necessary for local staging 3mm thin sections with a 14cm field of few are require. The cancer commonly demonstrates decreased signal intensity relative to the high-signal intensity normal peripheral zone on T2 weighted images. For detection of prostate cancer the sensitivity ranges from 60 to 96%, but has poor specificity. But, for detecting extracapsular extension or seminal vesical invasion the sensitivity and specificity of MRI is 73% to 80% and 97-100% respectively . Diffusion weighted imaging allows the mapping of diffusion of water molecules within tissue. Apparent diffusion co-efficient is helpful in differentiating between low, intermediate and high risk Gleason scores. DW-MRI along with T2 weighted imaging has 89% sensitivity and 91% specificity.

There are a few limitations of MRI such as post-biopsy hemorrhage, different MP-MRI sequence, and magnetic susceptibility in the tissue, could vary the MP-MRI results, affecting values such as ADC which may hamper tumor detection, leading to either under or overestimation of tumor presence and extent. With the increase in number of biopsy cores in the recent years, a longer delay of 6-8 weeks is recommended between biopsy and MR imaging to avoid post-biopsy changes. However, MR imaging adds value to both DRE and transrectal US-guided biopsy (P < .01 for each) in cancer detection and localization in the prostate.

At our institution multi-parametric MRI findings are used for better surgical management and improving the functional outcomes in each individual patient based on his own unique individual disease characteristics. The information from MRI helps in making informed decisions during surgery for achieving oncological goals of cancer extirpation (negative surgical margins) and preservation of periprostatic tissue and nerves to improve the functional outcomes (continence and sexual functions).

Prostate cancer with extraprostatic extension. (a) Axial and coronal (b) T2 weighted images demonstrate extraprostatic extension in the left lateral base invading left neurovascular bundle. There is also seminal vesicle invasion (marked in red) as seen on axial T2WI obtained more superiorly (c).

Localization of prostate cancer using multiparametric MRI combining T2WI, DWI and DCE (a)T2 weighted image shows hypointense lesion in right peripheral zone (arrow). (b) Corresponding ADC map shows restricted diffusion with low ADC in tumor compared to normal peripheral zone. (c) a Color coded map obtained with DCE-MRI overlaid on T2WI shows marked enhancement in the same region, as well as hypervascularity in central gland.

GENETIC ANALYSIS

Our researchers are working to unravel the genetic factors linked to prostate cancer. Genetic screening can pick up mutations in an individual's genetic code that may increase the risk of advanced prostate cancer. We combine genetic information with advanced imaging and immunhistochemistry to determine prostate cancer risk and staging. We design prostate cancer screening plans tailored to each patient's risk profile.

DA VINCI ROBOT

The daVinci Surgical System is a sophisticated robotic platform designed to expand the surgeon's capabilities and offer a state-of-the-art minimally invasive option for prostate surgery. With daVinci, small incisions are used to insert miniaturized wristed instruments and a highdefinition 3D camera. Seated comfortably at the daVinci console, Dr. Tewari views a magnified, high-resolution 3D image of the surgical site inside your body. At the same time, the latest robotic and computer technologies scale, filter and seamlessly translate Dr. Tewari's hand movements into precise micro-movements of the daVinci instruments. Although it is often called a "robot", the daVinci System cannot move or operate on its own, Dr. Tewari is 100% in control.

NEUROSAFE

Despite hard-earned successes in screening, diagnosis and management, prostate cancer remains a persistent and pervasive clinical affliction. The epidemiological impact of prostate cancer is illustrated by it being the most common non-cutaneous cancer affecting American men, with an estimated 233,000 new cases with subsequent mortality in 29,480 patients in the United States in 2014(Siegel, Ma, Zou, & Jemal, n.d.). The advent of prostate-specific antigen (PSA) screening as well as the expansion in the therapeutic armamentarium over the years has however shifted the clinical burden from mortality to morbidity. The disease process is habitually indolent and prostate cancer exhibits excellent survival rates with 98.9% of diagnosed patients surviving for 5 years. In 2011 there were approximately 2,707,821 men living with prostate cancer in the United States (SEER Stat Fact Sheets: Prostate Cancer), highlighting the significance of quality-of-life considerations in the disease management. Of the available modalities, radical prostatectomy (RP) is considered the standard treatment option and a rapid diffusion over the past decade has led to robot-assisted laparoscopic radical prostatectomy (RALP) commanding the lion's share, making it the surgery-of-choice in prostatic carcinoma(Box & Ahlering, 2008; Stitzenberg, Wong, Nielsen, Egleston, & Uzzo, 2012). However the extant adverse effects of urinary incontinence and impotence exhort continuing search for better techniques to afford the patient the highest possible health-related quality-of-life (HRQoL) following surgery.

One of the primary factors benefitting functional outcomes following RP is preservation of the prostatic neurovascular bundle (NVB) (Budaus et al., 2009; Eastham et al., 1996) but cancer control being the foremost guiding principle in any therapeutic strategy, tumour eradication and nerve sparing (NS) become a delicate juggling act for the clinician. In recent years, research elucidating the intricate anatomy of the prostatic neurovascular bundle and pre-operative risk stratification of patients has enhanced the oncological safety of NS procedures. Evolution of intra-operative frozen section (IFS) analysis in the form of Neurovascular Structure-adjacent Frozen-section Examination or NeuroSAFE has the potential to further augment these gains. Research on prostatic NVB anatomy has come a long way since the description of corpus cavernosal nerve supply by Walsh and Donker in 1982 and our group has previously described that unlike a thread entering a bead at a distinct singular point, the prostatic NVB enmeshes the gland in an intricate trizonal hammock of nerves. In the same study we also explicated a detailed surgical technique of the aforementioned neural hammock sparing along with a comprehensive pre-operative EPE risk stratification of patients in 4 instead of 2 groups, enabling us to transform the previously binary decision of NS vs. No NS to an incremental one. This ensures that, within limits of oncological safety, all our patients receive a measure of nerve sparing. The risk stratification algorithm has been since modified by our group to predict EPE risk with greater accuracy and the results will be published in another paper. The complex network of nerves that envelope the prostate gland, increase the opportunities of nerve rescue for a surgeon, however the sites of oncological surveillance increase concomitantly.

It is herein that real-time analysis of the entire neurovascular tissue adjacent circumference would safeguard the maximum number of nerves while achieving comprehensive histological surgical margins. Initially demonstrated primarily in open RPs, the NeuroSAFE approach has yet to see widespread acceptance by the RALP community despite exposition of a tailored, time-neutral approach for the Da Vinci robotic system by the original authors. Continuing our tradition of relentlessly working toward achievement of the highest HRQoL for our patients, we have included the NeuroSAFE technique in our package in addition to our athermal, traction-free, risk stratified, graded nerve sparing approach which is now the standard of care at our institute.



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