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Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer.In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting.Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths.24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term.Insightec and the National Cancer Institute.

S1. Segmentation map of a subset of lower Gleason tissue specimens, demonstrates regional differences between tumor and normal tissue, and between the two different Gleason grades S2. Example MALDI ion images of 2 long chain acylcarnitine species S3. Annotated H&E and serial frozen sections of human prostate tissue S4. Scores plot from PLSDA multivariate analysis of LESA MS data from tumor and normal prostate tissue Table 1. Pathological description of specimens used for MALDI MSI, cases were staged according to AJCC TNM 8th edition

Diagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the “Gleason score.” This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4+3) compared with GS (3+4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support image-guided prostate biopsy.Implications:In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.

Rationale and Objectives There have been multiple investigations defining and reporting the effectiveness of focal cryoablation as a treatment option for organ-confined prostate cancer. However, the impact of cryo-needle/probe placement accuracy within the tumor and gland has not been extensively studied. We analyzed how variations in the placement of the cryo-needles, specifically errors leading to incomplete ablation, may affect prostate cancer's resulting cryoablation. Materials and Methods We performed a study based on isothermal models using Monte Carlo simulations to analyze the impact of needle placement errors on tumor coverage and the probability of positive ablation margin. We modeled the placement error as a Gaussian noise on the cryo-needle position. The analysis used retrospective MRI data of 15 patients with biopsy-proven, unifocal, and MRI visible prostate cancer to calculate the impact of placement error on the volume of the tumor encompassed by the −40°C and −20°C isotherms using one to four cryo-needles. Results When the standard deviation of the placement error reached 3 mm, the tumor coverage was still above 97% with the −20°C isotherm, and above 81% with the −40°C isotherm using two cryo-needles or more. The probability of positive margin was significantly lower considering the −20°C isotherm (0.04 for three needles) than using the −40°C isotherm (0.66 for three needles). Conclusion The results indicated that accurate cryo-needle placement is essential for the success of focal cryoablation of prostate cancer. The analysis shows that an admissible targeting error depends on the lethal temperature considered and the number of cryo-needles used.