Imaging Prostate Cancer: Clinical Utility of Prostate-Specific Membrane Antigen.

PURPOSE: Our goal was to review the pathway and pertinent materials leading to approval of prostate-specific membrane antigen (PSMA) scanning by the U.S. Food and Drug Administration (FDA). MATERIALS AND METHODS: Beginning with the pivotal trials and working backward, we summarize the evolution of PSMA scanning, beginning with the discovery of the molecule, the mechanism of action to identify prostate cancer, the route to the present-day test and some of the major publications leading to each step of the sequence. From the thousands of PSMA articles listed on PubMed®, the present review is focused on the 4 large U.S. trials incorporating university studies of the gallium-68 compound and commercial studies of the fluorine-18 compound. The review further focuses on the role of PSMA scanning for both initial staging of prostate cancer and diagnosis of recurrent prostate cancer. RESULTS: PSMA is a transmembrane-bound glycoprotein which is overexpressed by 100-1,000-fold in prostate cancer cells. Preclinical PSMA studies at Cornell and Johns Hopkins in the 1990s were followed by early human studies in Germany in the early 2010s, then pivotal clinical trials at University of California, Los Angeles and University of California, San Francisco, leading to the first FDA approval in December 2020 (68Ga-PSMA-11). In January 2021, a commercially available product (18F-DCFPyL) was approved on the basis of multisite registration trials (CONDOR and OSPREY). Sensitivity and specificity of PSMA scanning exceeds that of any other imaging method currently available for initial staging of prostate cancer and diagnosis of recurrent disease. The accuracy of PSMA scanning is attributed to the great image contrast (high signal-to-noise ratio), a property deriving from the high PSMA tracer uptake by prostate cancer cells. That property can be estimated quantitatively by a metric, the standardized uptake value. A follow-on PSMA compound, the theranostic lutetium-177, is currently pending FDA approval for treatment of metastases. CONCLUSIONS: PSMA scanning is a disruptive technology that promises to transform the way prostate cancer is initially staged, recurrence is diagnosed and some advanced cases are treated.

Active Surveillance of Prostate Cancer is a Viable Option for Men Younger than 60 Years.

PURPOSE: At most centers strict age criteria are lacking for eligibility for active surveillance of prostate cancer. Younger men are often counseled to undergo definitive treatment despite limited data on the outcomes of active surveillance in younger men. We compared clinical characteristics and outcomes in men who enrolled in active surveillance at age less than 60 vs 60 years old or older. MATERIALS AND METHODS: We retrospectively reviewed the records of 2 institutional cohorts of a total of 2,084 men in whom prostate cancer was managed by active surveillance between 1995 and 2016. We compared outcomes in men who began active surveillance at age 60 vs 60 years or older using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: We identified 417 and 1,667 men who began active surveillance at younger than 60 and 60 years old or older, respectively, who met study inclusion criteria. At a median followup of 6.2 years we found no significant difference between men younger than 60 and 60 years old or older in the 5-year rates of biopsy progression-free survival (83% vs 83%), treatment-free survival (74% vs 71%), metastasis-free survival (99.7% vs 99.0%) or prostate cancer specific survival (100% vs 99.7%). Of the younger men 131 (31%) ultimately underwent treatment, including for pathological progression in 67% and prostate specific antigen progression in 18%. On multivariate analysis significant predictors of biopsy progression and progression to treatment among younger men were 20% or greater involvement of any core on diagnostic biopsy (HR 2.21, p = 0.003) and prostate specific antigen density 0.15 ng/ml/ml or greater (HR 1.93, p = 0.01). CONCLUSIONS: Active surveillance is a viable option in select men younger than 60 years with low volume, low risk prostate cancer. However, patients must be surveyed closely and understand the significant likelihood of ultimately requiring treatment.

Diagnosing Testicular Torsion before Urological Consultation and Imaging: Validation of the TWIST Score.

PURPOSE: The TWIST (Testicular Workup for Ischemia and Suspected Torsion) score uses urological history and physical examination to assess risk of testis torsion. Parameters include testis swelling (2 points), hard testis (2), absent cremasteric reflex (1), nausea/vomiting (1) and high riding testis (1). While TWIST has been validated when scored by urologists, its diagnostic accuracy among nonurological providers is unknown. We assessed the usefulness of the TWIST score when determined by nonurological nonphysician providers, mirroring emergency room evaluation of acute scrotal pain. MATERIALS AND METHODS: Children with unilateral acute scrotum were prospectively enrolled in a National Institutes of Health clinical trial. After undergoing basic history and physical examination training, emergency medical technicians calculated TWIST score and determined Tanner stage per pictorial diagram. Clinical torsion was confirmed by surgical exploration. All data were captured into REDCap™ and ROC curves were used to evaluate the diagnostic usefulness of TWIST. RESULTS: Of 128 patients (mean age 11.3 years) 44 (13.0 years) had torsion. TWIST score cutoff values of 0 and 6 derived from ROC analysis identified 31 high, 57 intermediate and 40 low risk cases (positive predictive value 93.5%, negative predictive value 100%). CONCLUSIONS: TWIST score assessed by nonurologists, such as emergency medical technicians, is accurate. Low risk patients do not require ultrasound to rule out torsion. High risk patients can proceed directly to surgery, with more than 50% avoiding ultrasound. In the future emergency medical technicians and/or emergency room triage personnel may be able to calculate TWIST score to guide radiological evaluation and immediate surgical intervention at initial assessment long before urological consultation.

Cryotherapy for partial gland ablation of prostate cancer: Oncologic and safety outcomes.

BACKGROUND: Partial gland ablation (PGA) is a new option for treatment of prostate cancer (PCa). Cryotherapy, an early method of PGA, has had favorable evaluations, but few studies have employed a strict protocol using biopsy endpoints in men with clinically significant prostate cancer (csPCa). METHODS: 143 men with unilateral csPCa were enrolled in a prospective, observational trial of outpatient PGA-cryotherapy. Treatment was a 2-cycle freeze of the affected prostate part. Participants were evaluated with MRI-guided biopsy (MRGB) at baseline and at 6 months and 18 months after treatment. Absence of csPCa upon MRGB was the primary endpoint; quality-of-life at baseline and at 6 months after treatment was assessed by EPIC-CP questionnaires in the domains of urinary and sexual function. RESULTS: Of the 143 participants, 136 (95%) completed MRGB at 6 months after treatment. In 103/136 (76%), the biopsy revealed no csPCa. Of the 103, 71 subsequently had an 18-month comprehensive biopsy; of the 71 with 18-month biopsies, 46 (65%) were found to have no csPCa. MRI lesions became undetectable in 96/130 (74%); declines in median serum PSA levels (6.9 to 2.5 ng/mL), PSA density (0.15 to 0.07), and prostate volume (42 to 34cc) were observed (all p < 0.01). Neither lesion disappearance on MRI nor PSA decline correlated with biopsy outcome. Urinary function was affected only slightly and sexual function moderately. CONCLUSION: In the near to intermediate term, partial gland ablation with cryotherapy was found to be a safe and moderately effective treatment of intermediate-risk prostate cancer. Eradication of cancer was better determined by MRI-guided biopsy than by MRI or PSA.

Impact of a negative confirmatory biopsy on risk of disease progression among men on active surveillance for prostate cancer.

OBJECTIVE: Most prostate cancer active surveillance (AS) protocols suggest a confirmatory biopsy within 12 to 18 months of diagnosis to mitigate the risk of unsampled high-grade disease. We investigate whether the results of confirmatory biopsy impact AS outcomes and could be used to tailor surveillance intensity. METHODS: We retrospectively reviewed our institutional database of prostate cancer patients managed by AS from 1997 to 2019 who underwent confirmatory biopsy and ≥3 biopsies overall. Biopsy progression was defined as either an increase in grade group or an increase in the proportion of positive biopsy cores to >34% and was compared between patients with a negative vs positive confirmatory biopsy using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: We identified 452 patients meeting inclusion criteria for this analysis, of whom 169 (37%) had a negative confirmatory biopsy. With a median follow-up of 6.8 years, 37% of patients progressed to treatment, most commonly due to biopsy progression. A negative confirmatory biopsy was significantly associated with biopsy progression-free survival in multivariable analysis (HR 0.54, 95% CI 0.34-0.88, P = 0.013), adjusting for known clinical and pathologic factors, including use of mpMRI prior to confirmatory biopsy. Negative confirmatory biopsy was also associated with an increased risk of adverse pathologic features at prostatectomy but not with biochemical recurrence among men who ultimately underwent definitive treatment. CONCLUSIONS: A negative confirmatory biopsy is associated with a lower risk of biopsy progression. While the increased risk of adverse pathology at time of definitive treatment sounds a small cautionary note regarding decreasing surveillance intensity, the majority of such patients have a favorable outcome on AS.

Partial Gland Ablation of Prostate Cancer: Effects of Repeat Treatment.

OBJECTIVE: To evaluate the near-term clinical and pathological effects of repeat partial gland ablation (PGA) in men with intermediate-risk prostate cancer (PCa). MATERIALS AND METHODS: One hundred seventy men with focal lesions of PCa (all GG2 or GG3) underwent PGA with high-intensity focused ultrasound (HIFU) or cryotherapy (CRYO) in prospective trials. Residual PCa in or near the ablation zone was found in 37 men after a first PGA; 30 went on to receive a second PGA and were the subjects of study. At 3 timepoints, baseline and 6 months after first and second ablations, quality-of-life (QOL) questionnaires (IIEF, IPSS) and MRI-guided biopsies (MRGB) were performed. Biopsies were targeted and systematic at baseline and in follow-up, comprehensively about the ablation zone. RESULTS: All 30 patients completed QOL questionnaires and 26 had MRGB at the 3 timepoints. Mean QOL scores were not significantly different from the baseline after the first or second PGA. No operative complications were encountered; and "decisional regret" was reported in only 2/29 men after the repeat ablation. A decrease in semen volume was reported by 25% of patients. Repeat ablation was successful (absence of csPCa on MRGB) in 14/26 (53%) of men. PSA levels decreased and MRI lesions resolved after ablations, but neither was a reliable predictor of biopsy outcomes. CONCLUSION: When initial PGA fails, repeat PGA is a reasonable consideration, because in near-term follow-up, secondary procedures appear to be safe, causing only minimal detriment to urinary and sexual function, with csPCa becoming undetectable by MRGB in approximately half the patients.

Endothelial colony forming cells and mesenchymal progenitor cells form blood vessels and increase blood flow in ischemic muscle.

Here we investigated whether endothelial colony forming cells (ECFC) and mesenchymal progenitor cells (MPC) form vascular networks and restore blood flow in ischemic skeletal muscle, and whether host myeloid cells play a role. ECFC + MPC, ECFC alone, MPC alone, or vehicle alone were injected into the hind limb ischemic muscle one day after ligation of femoral artery and vein. At day 5, hind limbs injected with ECFC + MPC showed greater blood flow recovery compared with ECFC, MPC, or vehicle. Tail vein injection of human endothelial specific Ulex europaeus agglutinin-I demonstrated an increased number of perfused human vessels in ECFC + MPC compared with ECFC. In vivo bioluminescence imaging showed ECFC persisted for 14 days in ECFC + MPC-injected hind limbs. Flow cytometric analysis of ischemic muscles at day 2 revealed increased myeloid lineage cells in ECFC + MPC-injected muscles compared to vehicle-injected muscles. Neutrophils declined by day 7, while the number of myeloid cells, macrophages, and monocytes did not. Systemic myeloid cell depletion with anti-Gr-1 antibody blocked the improved blood flow observed with ECFC + MPC and reduced ECFC and MPC retention. Our data suggest that ECFC + MPC delivery could be used to reestablish blood flow in ischemic tissues, and this may be enhanced by coordinated recruitment of host myeloid cells.

Primary genitourinary melanoma: Epidemiology and disease-specific survival in a large population-based cohort.

BACKGROUND: Primary genitourinary (GU) melanoma is a rare disease, which is poorly characterized. OBJECTIVE: To examine clinical characteristics and survival outcomes of primary GU melanoma among men and women. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study using the Surveillance, Epidemiology, and End Results database (1973-2010) was used to identify primary GU melanoma cases by tumor site and histology codes. We examined associations of GU melanoma with demographic, clinical, and pathologic characteristics, as well as disease-specific survival (DSS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: DSS was calculated using the Kaplan-Meier method. Cox-proportional hazard models were used to calculate hazard ratios and 95% CI for factors associated with worse DSS. RESULTS AND LIMITATIONS: A total of 1,586 histologically confirmed cases of primary GU melanoma were identified with a median age of 66.1 years (IQR: 55-80). Incidence of primary GU melanoma was 0.2cases/million among men and 1.80cases/million among women. Overall, 60.1% of patients had localized disease at presentation and 90.5% of patients had cancer-directed surgery. Patients with urothelial melanoma had the worst 5- and 10-year DSS (39% and 29%, respectively). Women with vulvar/vaginal melanoma had worse 5- and 10-year DSS compared to men with penile/scrotal melanoma. In multivariate analysis, decreased survival was associated with increasing age, distant stage, and lymph node involvement. Results are limited by the lack of standardized staging for primary GU melanoma and the retrospective design of our study. CONCLUSIONS: Patients with primary GU melanoma present with advanced stage and have a poor prognosis. Women have worse DSS compared to men. DSS is negatively associated with advanced age at diagnosis, higher stage, and lymph node involvement. PATIENT SUMMARY: Clinicians and patients must be aware of the poor disease-specific outcomes associated with primary GU melanoma. Most importantly, women fare worse than men and mucosal melanomas have worse outcomes compared to cutaneous melanomas.