Faculty Bibliography

Brain arteriovenous malformations (bAVMs) are vascular anomalies characterized by direct arterial to venous shunting without an intervening capillary bed, predisposing patients to intracranial hemorrhage and subsequent neurological morbidity and mortality. Evidence suggests that development and evolution of bAVMs are influenced by ongoing molecular and inflammatory processes. Chronic inflammation within the AVM microenvironment has emerged as a key driver of dysregulated angiogenesis, vascular instability, and hemorrhage risk. The objective of this review is to examine the molecular and cellular mechanisms through which inflammatory pathways contribute to AVM development, rupture, and treatment response. A comprehensive search of the Web of Science database was performed from database inception through September 2024. Following removal of duplicate articles, titles and abstracts were screened and full texts were reviewed for relevance. Experimental, translational, and clinical studies investigating inflammatory signaling pathways, immune cell involvement, molecular biomarkers, and therapeutic implications in AVMs were included. A total of 342 studies were included in the final review. Current evidence demonstrates that inflammatory signaling plays a central role in AVM pathobiology. Pro-inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α promote endothelial activation, leukocyte recruitment, and abnormal angiogenesis within the AVM nidus. Dysregulation of signaling pathways such as VEGF, TGF-β/BMP, NF-κB, Notch, and KRAS/MAPK-ERK contributes to extracellular matrix degradation, vascular remodeling, and vessel fragility. Infiltration by macrophages and neutrophils further amplifies inflammatory cascades through the release of matrix metalloproteinases and reactive oxygen species, increasing rupture risk. In addition to its pathogenic role, inflammation also contributes to success of AVM obliteration using stereotactic radiosurgery through radiation-induced endothelial injury, immune cell recruitment, and progressive vascular fibrosis. Inflammation is a fundamental component of AVM formation, progression, and therapeutic response. Targeting these pathways, in combination with surgical or radiosurgical interventions, may offer new opportunities for improving AVM management and improving approaches in cerebrovascular neurosurgery.

OBJECTIVES/OBJECTIVE:To evaluate the incidence, timing, and clinical predictors of radiation-induced hematuria following robotic stereotactic body radiation therapy (SBRT) for localized prostate cancer. METHODS:This retrospective single-center cohort study included 397 patients treated with robotic SBRT between 2013 and 2019 for localized prostate cancer. All patients received 36.25 Gy in 5 fractions with the urethral sparing technique. Radiation-induced hematuria was defined as gross hematuria or clinically significant microscopic hematuria without alternative etiology. Incidence, time to first event, and related interventions were assessed. Severity was graded using CTCAE version 5.0. Candidate predictors were selected based on the literature. Cox proportional hazards modeling identified clinical predictors of radiation-induced hematuria. RESULTS:At a median follow-up of 56 months (IQR 29-79), 48 patients (12.1%) developed radiation-induced hematuria, occurring at a median of 30 months (IQR 19-49) after radiation treatment. Severe events (grade 3) were rare, affecting only 5 patients (1.3%). Diagnostic cystoscopy was performed in 35 patients (72.9%) and 6 patients (12.5%) required a total of 10 therapeutic interventions. Diabetes was the only independent predictor (HR 2.63, 95% CI 1.37-5.00, p = 0.004), while age, anticoagulant use, prostate volume, and Charlson Comorbidity Index showed no significant association. CONCLUSION/CONCLUSIONS:Radiation-induced hematuria following robotic SBRT is predominantly low-grade and late-occurring, confirming the favorable genitourinary toxicity profile. These findings help clinicians better understand this SBRT-related toxicity and provide more accurate patient counseling regarding timing and severity of potential hematuria. Diabetes was identified as an independent risk factor and may have clinical implications; however, whether optimization of glycemic control reduces hematuria risk remains uncertain and requires further investigation.

OBJECTIVE:Indeterminate lesions on prostate-specific membrane antigen (PSMA)-PET are challenging to address. We aimed to develop, implement, and evaluate a multidisciplinary consensus algorithm that integrates existing interpretation systems with multimodality imaging and clinicopathological information for interpreting indeterminate bone and lymph node lesions on PSMA-PET. MATERIALS AND METHODS/METHODS:This was a retrospective single-center study on a prospectively implemented algorithm. We included all consecutive prostate cancer patients whose PSMA-PET findings for indeterminate bone lesions or lymph nodes were discussed at a multidisciplinary tumor board (MDT) in 2024-2025. An algorithm determining the level of suspicion for metastasis was developed in a multidisciplinary fashion, incorporating lesion location, conventional imaging features, PSMA-PET characteristics, and clinicopathological information. The application of the algorithm and outcomes were documented, compared against a composite reference standard. Comparisons were made with PSMA-RADS and PROMISE V2 PSMA-expression scores. RESULTS:81 patients (median age 68, interquartile range 64-75) were included. Algorithm results were benign (48.1% [39/81]), equivocal (4.9% [4/81]), metastasis (40.7% [33/81]), and mixed (benign and metastatic lesions, 6.2% [5/81]). The algorithm was correct in 94.1% (64 of 68 patients with a sufficient reference standard). The algorithm was discordant with PSMA-RADS in 54.3% (44/81) and with PROMISE V2 PSMA-expression score in 71.6% (58/81). The frequency of equivocal lesions was lower using the algorithm (4.9% [4/81]) compared with PSMA-RADS (53.1% [43/81]) and PSMA-expression score (64.2% [52/81]). CONCLUSION/CONCLUSIONS:A multidisciplinary consensus algorithm for interpreting indeterminate bone lesions and lymph nodes on PSMA-PET was developed and implemented. Integrating clinicopathological information and multimodality imaging in an MDT setting reduced equivocal interpretations. KEY POINTS/CONCLUSIONS:Question While prostate-specific membrane antigen (PSMA)-PET has become essential in the management of prostate cancer, indeterminate bone lesions and lymph nodes remain challenging to address. Findings A multidisciplinary algorithm for interpreting indeterminate bone lesions and lymph nodes on PSMA-PET, incorporating clinicopathological information and multimodality imaging, reduced the frequency of equivocal interpretations. Clinical relevance An algorithm for interpreting indeterminate bone lesions and lymph nodes on PSMA-PET, incorporating clinicopathological information and multimodality imaging in a multidisciplinary tumor board setting, decreases the frequency of equivocal interpretations and can potentially help management decisions.

Stereotactic body radiotherapy (SBRT) is established as standard therapy for organ-confined prostate cancer (PC) based on 5-yr phase 2-3 outcomes, but 10-yr data are lacking. Here, we report 10-yr results of a trial conducted at 21 centers. Patients were treated from January 2008 to April 2010. SBRT was delivered on a noncoplanar robotic platform with real-time motion management, to a total dose of 40 Gy in five fractions. Adjuvant hormone therapy was not allowed. Late toxicities (>90 d) were assessed with Common Terminology Criteria for Adverse Events version 3 (CTCAE v3). Biochemical failure is defined as nadir+2. Relapses are defined as biochemical or clinical failure or salvage/systemic PC therapy. Out of 310 evaluable patients, median age 68 yr; 172 were low-risk (LR), and 138 patients were intermediate-risk (IR). Median follow-up was 9 yr. Ten-yr cumulative grade 3 gastrointestinal (GI) or genitourinary (GU) toxicities were 1.4% and 1.5% in the LR and IR cohorts, respectively. There were no grade 4-5 events observed. Ten year grade 2+ GI and GU toxicity rates were 2.1% and 14% respectively. Overall survival in 10 yr was 84%. Overall, relapse-free survival (RFS) was 90%; 94% in the LR cohort, 86% in the IR cohort, and 92% versus 77% in the favorable vs unfavorable intermediate subgroups. In this multi-institutional trial, the 10-yr follow-up demonstrates that prostate SBRT yields minimal toxicity and favorable RFS.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Most patients with high-risk localized prostate cancer (HRLPC) do not undergo stereotactic body radiotherapy (SBRT) in part because of the limited evidence of long-term outcomes. We report long-term efficacy and toxicity outcomes for men treated with SBRT for HRLPC. METHODS:Individual patient data from ten prospective clinical studies evaluating SBRT for HRLPC across nine institutions were pooled in the Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate consortium. The Kaplan-Meier method was used to estimate 5-yr biochemical recurrence (BCR) and distant metastasis (DM), stratified by receipt of intensified treatment (≥12 mo of androgen deprivation therapy [ADT] with extremely dose-escalated [≥8 Gy/fraction] prostate-directed SBRT). The impact of intensified treatment on BCR-free survival and DM-free survival was evaluated using multivariable Cox proportional hazards models. Late Common Terminology Criteria for Adverse Events grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity was analyzed using time-to-event models. KEY FINDINGS AND LIMITATIONS/UNASSIGNED:In 440 patients with a median follow-up time of 60.4 mo, 5-yr BCR and DM rates were 22% (95% confidence interval [CI] = 17-26%] and 9.2% (95% CI = 6.2-12%), respectively. In the 93 patients (21%) who received intensified treatment, 5-yr BCR and DM rates were 7.4% (95% CI = 1.7-13%) and 3.7% (95% CI = 0-7.9%), respectively. Receipt of intensified therapy was associated with a significant reduction in both BCR (hazard ratio [HR] = 0.38 [95% CI = 0.20-0.74], p = 0.005) and DM (HR = 0.43 [95% CI = 0.18-0.99], p = 0.049). For the overall cohort, 5-yr rates of grade ≥2 GU and GI toxicity were 23% (95% CI = 19-27%) and 10% (95% CI = 7-13%), respectively. Limitations include heterogeneous treatment techniques and the nonrandomized nature of the study. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:The safety and efficacy profile of SBRT for HRLPC remains favorable at long-term follow-up, and SBRT should be integrated into shared decision-making for treatment of HRLPC.

BACKGROUND AND PURPOSE/UNASSIGNED:To evaluate the dosimetric and toxicity profiles of stereotactic body radiotherapy (SBRT) for prostate cancer, comparing cohorts with and without intraprostatic boost (IPB) to assess feasibility and safety of IPB, with particular attention to urethral and bladder dose and toxicity. MATERIALS AND METHODS/UNASSIGNED:This retrospective cohort study analyzed 349 patients with localized prostate cancer treated between 2018 and 2023. Of these, 266 received SBRT with IPB, and 83 received SBRT without IPB. Patients were treated using a robotic SBRT platform with fiducial tracking. Dosimetric parameters for the urethra, including D0.03cc, D0.3cc, and V40Gy, and for the bladder, including D0.03cc, D5cc, D10cc, and V37Gy, were evaluated. Acute and late toxicities were assessed using CTCAE criteria. RESULTS/UNASSIGNED:For the urethra, median values for D0.03cc, D0.3cc, and V40Gy, and for the bladder, median values D0.03cc, D5cc, D10cc, and V37Gy were compared and no statistically significant differences were observed between the two cohorts. Late urinary toxicity of grade 3 or higher occurred in 2.25 % of patients in the IPB group and 2.47 % in the no IPB group, with no grade 3 acute toxicities reported. DISCUSSION/UNASSIGNED:These findings support the use of SBRT using an IPB as a feasible and safe approach to achieve focal dose escalation to dominant intra-prostatic lesions (DILs) without significantly increasing urethra or bladder dose or toxicity. Future research should focus on standardizing DIL contouring, exploring adaptive planning techniques to increase accuracy, and prospectively studying toxicity and quality of life in patients treated with IPB with SBRT.

PURPOSE/OBJECTIVES/UNASSIGNED:SBRT is a standard of care treatment for localized prostate cancer. Whole gland dose escalation remains controversial. Concomitant intraprostatic boost (IPB) may offer an acceptable compromise for dose escalation. In this series, we report changes in International Prostate Symptom Scores (IPSS) over a 12-month period following SBRT with IPB in patients treated in a large academic institution. MATERIALS/METHODS/UNASSIGNED:Seventy-four patients treated from October 2018 to March 2022 with robotic stereotactic body radiotherapy completed IPSS questionnaires. IPSS were evaluated for patients at three timepoints: pre-treatment, post-treatment (defined as 3 months after SBRT completion), and at follow-up (defined as within 12 months after SBRT completion). The patients were stratified into two cohorts: patients who experienced minimally important difference (MID) in their post-treatment IPSS and those who did not. Urethral and bladder doses were retrospectively extracted from the treatment planning software and compared between the two cohorts using Wilcoxon rank sum test. RESULTS/UNASSIGNED:Of the 74 patients, 46 (62%) experienced MID in scores (cohort A), while 28 (38%) did not (cohort B). Patient characteristics in the two cohorts such as risk stratification and initial PSA were well-balanced. Median IPSS for cohort A were 5 (range: 0-21) pre-treatment, 12 (range: 3-28) post-treatment, and 8 (range: 1-32) at 12 months. For cohort B, the scores were 9.5 (range: 0-29), 7 (range: 1-19), and 8.5 (range: 0-32), respectively. In addition, there was a statistically significant difference in D0.03cc to the bladder in cohort A compared to cohort B (41.9 Gy vs 40.2 Gy; p < 0.001). CONCLUSION/UNASSIGNED:IPB is well tolerated with acceptable change in urinary quality of life metrics as measured by IPSS. Max dose to the bladder remains the only significant difference in patients who experienced MID in their urinary quality of life.