Iatrogenic nerve injury is a risk in many surgical procedures. We present our experience with a novel fluorescent agent to enhance the visualization of at-risk nerves during a prostatectomy in a canine model. Illuminare-1 is an intravenously administered myelin-binding fluorophore. After IRB approval and successfully visualizing target nerves in murine and porcine tests, we undertook a robotically-assisted prostatectomy on a dog, which has comparable genitourinary anatomy to a human. Dogs were positioned supine, anesthetized, the abdomen was insufflated, and the peri-prostatic and obturator nerves were exposed with a DaVinci SI Surgical System. A modified FDA-approved laparoscope with white and blue (370 – 425nm wave length) light settings was positioned via an assistant port to illuminate these nerves. A bolus of 1mg/kg of Illuminare-1 was administered intravenously with uninterrupted visualization of the presumed nerves. Fluorescent structures were resected for histological assessment. With 1mg/kg of Illuminare-1, nerves rapidly fluoresced under blue light, displaying a distinct hue. Fluorescence was seen within 90 seconds of administration and sustained for over three hours in the obturator and smaller periprostatic nerves. Tiny linear structures that were not initially seen under white light conditions were clearly identified as fluorescent tissue after injection with Illuminare-1. Seven fluorescent peri-prostatic structures were resected and all were histologically confirmed to be myelinated nerves. The cross-sectional nerve fiber diameters ranged from 64 – 247nm. Illuminare-1 enhanced the visualization of the neurovascular bundle in a dog. Phase-1 in-human trials with Illuminare-1 will follow to address the unmet need to reduce unintended surgical morbidity.
The biologic mechanism of tissue ablation with Tookad soluble vascular targeted photodynamic therapy (TS-VTP) is well suited for treating tumors in sensitive organs such as the human genitourinary tract. Preclinical collaborative studies conducted at the Weizmann Institute and Memorial Sloan Kettering have provided insight for the development of TS-VTP as a treatment modality for prostate, kidney and urothelial cancers that are now being tested in prospective clinical trials.
MSK trial 17-070 is a Phase 2b study of the efficacy of TS-VTP for the treatment of intermediate risk, unilateral prostate cancer. Men with suitable cancers are being treated with VTP therapy by interstitial technique through fiberoptic diffusers placed into the prostate gland under ultrasound guidance in order to illuminate a volume of targeted tissue based on tumor localization from prior biopsy. Tissue effects, tolerability and serum biomarkers of response are being monitored as important secondary endpoints.
MSK protocol 18-140 is a Phase 1 clinical trial investigating the safety and tolerability of TS-VTP for the treatment of urothelial cancer involving the bladder and upper urinary tract. In this study, patients with transitional cell carcinoma found in the bladder, ureter or renal pelvis of the kidney are treated by endoluminal technique with fiberoptic diffusers placed in proximity to the tumors to achieve tumor ablative effects. The identification of adverse events is the primary goal of the study however tissue effects, tolerability and urinary biomarkers of response are also being monitored.
Preliminary findings from both of these studies as well as other clinical trials in TS-VTP treatment will be presented.
Vascular targeted photodynamic therapy with TOOKAD-from local ablation to systemic cancer treatment
Background:
Local therapies that allow for safe ablation of primary lesions and trigger anti-tumor immunity with minimal side effects, may be particularly effective in management of early-stage cancer. Vascular-targeted photodynamic therapy (VTP) with TOOKAD®, recently granted EMA approval as a first-line treatment for localized prostate cancer, has been shown by us to also trigger anti-tumor immunity. Our recent preclinical and current clinical studies aim to test the hypothesis that synchronizing TOOKAD®VTP with immune-modulation that attenuates the pro-tumor immunity, will result in systemic micrometastases annihilation and a high cure rate.
Methods:
4T1-Luc, adenosquamous JA and Met-Lu cells were orthotopically grafted in the mammary pad, esophagus and prostate of immune-competent mice and rats, respectively. Seven days postgrafting, tumors were treated with TOOKAD®VTP, with or without immune-modulators. Immune profiles were examined by 10-X genomics, FACS analysis and immunohistochemistry. Animal survival and lung and lower abdomen metastases counts were followed up for 3 months. Clinical protocols were composed based on the preclinical data and utilized in the clinical studies that will be described in other lectures of this session.
Results:
TOOKAD®VTP triggered anti-tumor immunity sufficient to achieve 60-90% cure in various cancer models. However, primary lesion annihilation did not prevent disease progression in the more aggressive cancers such as 4T1-Luc breast cancer. TOOKAD®VTP synchronized with metronomic administration of immune-modulators was associated with a 60-90% disease-free animals and resistance to re-challenge. The rate of success was highly pending on the exact synchronization of the immune modulating agents with the VTP timing. The required modulators match the deciphered immune profiles. This combined immuno-VTP therapy concept has been translated to clinical trials currently ongoing at Memorial Sloan Kettering Cancer Center.
Conclusion:
Application of TOOKAD®VTP to localized tumors combined with immune modulation appears to provide novel means to treat early disseminated cancers.
Objective: To investigate and diagnose testicular pathology in patients with testicular dysfunction using the technique of ultrasound power spectrum analysis. Methods: Testicular ultrasound studies with power spectrum tissue characterization analysis were performed on men with testicular abnormalities as well as normal controls. Semen analysis, biopsy data, microscopic intra-operative findings and data pertaining to testicular function were collected for each surgically evaluated subject. Ultrasound data were analyzed for power spectrum characteristics of microscopic scatterer size and concentration within discrete areas of testicular tissue. Results: Patients with varicoceles and greater than 2x106 sperm/ml on semen analysis had larger average scatterer size (107.7 micrometers ) and lower scatterer concentration (-15.02 dB) than non-obstructed, azoospermic patients with varicoceles (92.4 micrometers and -11.41 dB, respectively). Subjects with obstructed azoospermia had slightly larger average tissue scatterer size (108.1 micrometers ) and lower concentration (-15.73 dB) while normal control data revealed intermediate values of size (102.3 micrometers ) and concentration (-13.1 dB) of scatterers. Spectral data from pure testicular seminoma lesions had the lowest average scatterer size (82.3 micrometers ) with low relative concentration (-14.7 dB). Summary: Ultrasound tissue characterization based on RF spectrum analysis may distinguish different types of testicular pathology including obstructed and non-obstructed azoospermia and tissue changes due to varicocele and tumor.
Conference Committee Involvement (1)
17th International Photodynamic Association World Congress
28 June 2019 | Cambridge, Massachusetts, United States
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