A platform-independent AI tumor lineage and site (ATLAS) classifier.

Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98-99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.

Automated prostate gland segmentation in challenging clinical cases: comparison of three artificial intelligence methods.

OBJECTIVE: Automated methods for prostate segmentation on MRI are typically developed under ideal scanning and anatomical conditions. This study evaluates three different prostate segmentation AI algorithms in a challenging population of patients with prior treatments, variable anatomic characteristics, complex clinical history, or atypical MRI acquisition parameters. MATERIALS AND METHODS: A single institution retrospective database was queried for the following conditions at prostate MRI: prior prostate-specific oncologic treatment, transurethral resection of the prostate (TURP), abdominal perineal resection (APR), hip prosthesis (HP), diversity of prostate volumes (large ≥ 150 cc, small ≤ 25 cc), whole gland tumor burden, magnet strength, noted poor quality, and various scanners (outside/vendors). Final inclusion criteria required availability of axial T2-weighted (T2W) sequence and corresponding prostate organ segmentation from an expert radiologist. Three previously developed algorithms were evaluated: (1) deep learning (DL)-based model, (2) commercially available shape-based model, and (3) federated DL-based model. Dice Similarity Coefficient (DSC) was calculated compared to expert. DSC by model and scan factors were evaluated with Wilcox signed-rank test and linear mixed effects (LMER) model. RESULTS: 683 scans (651 patients) met inclusion criteria (mean prostate volume 60.1 cc [9.05-329 cc]). Overall DSC scores for models 1, 2, and 3 were 0.916 (0.707-0.971), 0.873 (0-0.997), and 0.894 (0.025-0.961), respectively, with DL-based models demonstrating significantly higher performance (p < 0.01). In sub-group analysis by factors, Model 1 outperformed Model 2 (all p < 0.05) and Model 3 (all p < 0.001). Performance of all models was negatively impacted by prostate volume and poor signal quality (p < 0.01). Shape-based factors influenced DL models (p < 0.001) while signal factors influenced all (p < 0.001). CONCLUSION: Factors affecting anatomical and signal conditions of the prostate gland can adversely impact both DL and non-deep learning-based segmentation models.

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy.

PURPOSE: NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. RESULTS: Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. CONCLUSIONS: The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

Predicting 18F-DCFPyL-PET/CT Scan Positivity in Prostate Cancer Patients with Biochemical Recurrence.

RATIONALE AND OBJECTIVES: To analyze variables that can predict the positivity of 18F-DCFPyL- positron emission tomography/computed tomography (PET/CT) and extent of disease in patients with biochemically recurrent (BCR) prostate cancer after primary local therapy with either radical prostatectomy or radiation therapy. MATERIALS AND METHODS: This is a retrospective analysis of a prospective single institutional review board-approved study. We included 199 patients with biochemical recurrence and negative conventional imaging after primary local therapies (radical prostatectomy n = 127, radiation therapy n = 72). All patients underwent 18F-DCFPyL-PET/CT. Univariate and multivariate logistic regression analyses were used to determine predictors of a positive scan for both cohort of patients. Regression-based coefficients were used to develop nomograms predicting scan positivity and extra-pelvic disease. Decision curve analysis (DCA) was implemented to quantify nomogram's clinical benefit. RESULTS: Of the 127 (63%) post-radical prostatectomy patients, 91 patients had positive scans - 61 of those with intrapelvic lesions and 30 with extra-pelvic lesions (i.e., retroperitoneal or distant nodes and/or bone/organ lesions). Of the 72 post-radiation therapy patients, 65 patients had positive scans - 39 of them had intrapelvic lesions and 26 extra-pelvic lesions. In the radical prostatectomy cohort, multivariate regression analysis revealed original International Society of Urological Pathology category, prostate-specific antigen (PSA), prostate-specific antigen doubling time (PSAdt), and time from BCR (mo) to scan were predictors for scan positivity and presence of extra-pelvic disease, with an area under the curve of 80% and 78%, respectively. Positive versus negative tumor margin after radical prostatectomy was not related to scan positivity or to the presence of positive extra-pelvic foci. In the radiation therapy cohort, multivariate regression analysis revealed that PSA, PSAdt, and time to BCR (mo) were predictors of extra-pelvic disease, with area under the curve of 82%. Because only seven patients in the radiation therapy cohort had negative scans, a prediction model for scan positivity could not be analyzed and only the presence of extra-pelvic disease was evaluated. CONCLUSION: PSA and PSAdt are consistently significant predictors of 18F-DCFPyL PET/CT positivity and extra-pelvic disease in BCR prostate cancer patients. Stratifying the patient population into primary local treatment group enables the use of other variables as predictors, such as time since BCR. This nomogram may guide selection of the most suitable candidates for 18F-DCFPyL-PET/CT imaging.

PI-RADS Version 2.0 Versus Version 2.1: Comparison of Prostate Cancer Gleason Grade Upgrade and Downgrade Rates From MRI-Targeted Biopsy to Radical Prostatectomy.

BACKGROUND. Precise risk stratification through MRI/ultrasound (US) fusion-guided targeted biopsy (TBx) can guide optimal prostate cancer (PCa) management. OBJECTIVE. The purpose of this study was to compare PI-RADS version 2.0 (v2.0) and PI-RADS version 2.1 (v2.1) in terms of the rates of International Society of Urological Pathology (ISUP) grade group (GG) upgrade and downgrade from TBx to radical prostatectomy (RP). METHODS. This study entailed a retrospective post hoc analysis of patients who underwent 3-T prostate MRI at a single institution from May 2015 to March 2023 as part of three prospective clinical trials. Trial participants who underwent MRI followed by MRI/US fusion-guided TBx and RP within a 1-year interval were identified. A single genitourinary radiologist performed clinical interpretations of the MRI examinations using PI-RADS v2.0 from May 2015 to March 2019 and PI-RADS v2.1 from April 2019 to March 2023. Upgrade and downgrade rates from TBx to RP were compared using chi-square tests. Clinically significant cancer was defined as ISUP GG2 or greater. RESULTS. The final analysis included 308 patients (median age, 65 years; median PSA density, 0.16 ng/mL2). The v2.0 group (n = 177) and v2.1 group (n = 131) showed no significant difference in terms of upgrade rate (29% vs 22%, respectively; p = .15), downgrade rate (19% vs 21%, p = .76), clinically significant upgrade rate (14% vs 10%, p = .27), or clinically significant downgrade rate (1% vs 1%, p > .99). The upgrade rate and downgrade rate were also not significantly different between the v2.0 and v2.1 groups when stratifying by index lesion PI-RADS category or index lesion zone, as well as when assessed only in patients without a prior PCa diagnosis (all p > .01). Among patients with GG2 or GG3 at RP (n = 121 for v2.0; n = 103 for v2.1), the concordance rate between TBx and RP was not significantly different between the v2.0 and v2.1 groups (53% vs 57%, p = .51). CONCLUSION. Upgrade and downgrade rates from TBx to RP were not significantly different between patients whose MRI examinations were clinically interpreted using v2.0 or v2.1. CLINICAL IMPACT. Implementation of the most recent PI-RADS update did not improve the incongruence in PCa grade assessment between TBx and surgery.

Evaluation of a Deep Learning-based Algorithm for Post-Radiotherapy Prostate Cancer Local Recurrence Detection Using Biparametric MRI.

OBJECTIVE: To evaluate a biparametric MRI (bpMRI)-based artificial intelligence (AI) model for the detection of local prostate cancer (PCa) recurrence in patients with radiotherapy history. MATERIALS AND METHODS: This study included post-radiotherapy patients undergoing multiparametric MRI and subsequent MRI/US fusion-guided and/or systematic biopsy. Histopathology results were used as ground truth. The recurrent cancer detection sensitivity of a bpMRI-based AI model, which was developed on a large dataset to primarily identify lesions in treatment-naïve patients, was compared to a prospective radiologist assessment using the Wald test. Subanalysis was conducted on patients stratified by the treatment modality (external beam radiation treatment [EBRT] and brachytherapy) and the prostate volume quartiles. RESULTS: Of the 62 patients included (median age = 70 years; median PSA = 3.51 ng/ml; median prostate volume = 27.55 ml), 56 recurrent PCa foci were identified within 46 patients. The AI model detected 40 lesions in 35 patients. The AI model performance was lower than the prospective radiology interpretation (Rad) on a patient-(AI: 76.1% vs. Rad: 91.3%, p = 0.02) and lesion-level (AI: 71.4% vs. Rad: 87.5%, p = 0.01). The mean number of false positives per patient was 0.35 (range: 0-2). The AI model performance was higher in EBRT group both on patient-level (EBRT: 81.5% [22/27] vs. brachytherapy: 68.4% [13/19]) and lesion-level (EBRT: 79.4% [27/34] vs. brachytherapy: 59.1% [13/22]). In patients with gland volumes >34 ml (n = 25), detection sensitivities were 100% (11/11) and 94.1% (16/17) on patient- and lesion-level, respectively. CONCLUSION: The reported bpMRI-based AI model detected the majority of locally recurrent prostate cancer after radiotherapy. Further testing including external validation of this model is warranted prior to clinical implementation.

A Phase 1 Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer.

PURPOSE: NCT03253744 was a phase 1 trial to identify the maximum tolerated dose (MTD) of image-guided, focal, salvage stereotactic body radiation therapy (SBRT) for patients with locally radiorecurrent prostate cancer. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: The trial design included 3 dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions delivered ≥48 hours apart. The prescription dose was delivered to the magnetic resonance- and prostate-specific membrane antigen imaging-defined tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until 2 years after completion of SBRT using Common Terminology Criteria for Adverse Events, version 5.0, criteria. Escalation was halted if 2 dose-limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT and any grade 3 genitourinary (GU) or grade 4 gastrointestinal (GI) toxicity thereafter. RESULTS: Between August 2018 and May 2022, 8 patients underwent salvage focal SBRT, with a median follow-up of 35 months. No dose-limiting toxic effects were observed on DL1. Two patients were enrolled in DL2 and experienced grade 3 GU toxicities, prompting de-escalation and expansion (n = 6) at the MTD (DL1). The most common toxicities observed were grade ≥2 GU toxicities, with only a single grade 2 GI toxicity and no grade ≥3 GI toxicities. One patient experienced biochemical failure (prostate-specific antigen nadir + 2.0) at 33 months. CONCLUSIONS: The MTD for focal salvage SBRT for isolated intraprostatic radiorecurrence was 40 Gy in 5 fractions, producing a 100% 24-month biochemical progression free survival, with 1 poststudy failure at 33 months. The most frequent clinically significant toxicity was late grade ≥2 GU toxicity.

Safety of Radiation Therapy in Patients With Prostate Cancer and Inflammatory Bowel Disease: A Systematic Review.

PURPOSE: Inflammatory bowel disease (IBD) has historically been considered a relative contraindication for pelvic radiation therapy (RT). To date, no systematic review has summarized the toxicity profile of RT for patients with prostate cancer and comorbid IBD. METHODS AND MATERIALS: A PRISMA-guided systematic search was conducted on PubMed/Embase for original investigations that reported gastrointestinal (GI; rectal/bowel) toxicity in patients with IBD undergoing RT for prostate cancer. The substantial heterogeneity in patient population, follow-up, and toxicity reporting practices precluded a formal meta-analysis; however, a summary of the individual study-level data and crude pooled rates was described. RESULTS: Twelve retrospective studies with 194 patients were included: 5 examined predominantly low-dose-rate brachytherapy (BT) monotherapy, 1 predominantly high-dose-rate BT monotherapy, 3 mixed external beam RT (3-dimensional conformal or intensity modulated RT [IMRT]) + low-dose-rate BT, 1 IMRT + high-dose-rate BT, and 2 stereotactic RT. Among these studies, patients with active IBD, patients receiving pelvic RT, and patients with prior abdominopelvic surgery were underrepresented. In all but 1 publication, the rate of late grade 3+ GI toxicities was <5%. The crude pooled rate of acute and late grade 2+ GI events was 15.3% (n = 27/177 evaluable patients; range, 0%-100%) and 11.3% (n = 20/177 evaluable patients; range, 0%-38.5%), respectively. Crude rates of acute and late grade 3+ GI events were 3.4% (6 cases; range, 0%-23%) and 2.3% (4 cases; range, 0%-15%). CONCLUSIONS: Prostate RT in patients with comorbid IBD appears to be associated with low rates of grade 3+ GI toxicity; however, patients must be counseled regarding the possibility for lower-grade toxicities. These data cannot be generalized to the underrepresented subpopulations mentioned above, and individualize decision-making is recommended for those high-risk cases. Several strategies should be considered to minimize the probability of toxicity in this susceptible population, including careful patient selection, minimizing elective (nodal) treatment volumes, using rectal sparing techniques, and employing contemporary RT advancements to minimize exposure to GI organs at risk (eg, IMRT, magnetic resonance imaging-based target delineation, and high-quality daily image guidance).

A Phase 1 Trial of Highly Conformal, Hypofractionated Postprostatectomy Radiation Therapy.

Purpose: This phase 1 trial aimed to identify the maximally tolerated hypofractionated dose schedule for postoperative radiation therapy (PORT) after radical prostatectomy. Secondary objectives included biochemical control and quality of life (QoL) measures. Methods and Materials: Patients were treated on 1 of 3 dose levels (DLs): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Treatment was delivered to the prostate bed without pelvic nodal irradiation. Dose escalation followed a standard 3 + 3 design with an expansion for 6 additional patients at the maximally tolerated hypofractionated dose schedule. Acute dose-limiting toxicity (DLT) was defined as grade 3 toxicity lasting >4 days within 21 days of PORT completion; late DLT was defined as grade 4 gastrointestinal (GI) or genitourinary (GU) toxicity. Results: Between January 2018 and August 2019, 15 patients underwent radiation treatment: 3 on DL1, 3 on DL2, and 9 on DL3. The median follow-up was 24 months. There were no DLTs, and the maximally tolerated hypofractionated dose schedule was identified as DL3. Two of the 15 patients (13.3%) experienced biochemical failure (prostate-specific antigen >0.1). Ten of 15 patients (67%) had grade 2+ acute toxicities, consisting of transient GI toxicities. Three patients experienced late grade 2+ GI toxicity, and 5 patients experienced late grade 2+ GU toxicity. Late grade 3 GU toxicity occurred in 2 patients. There were no grade 4+ acute or late toxicities. There were no significant differences in GI measures of QoL, however, there was an increase in GU symptoms and corresponding decrease in GU QoL between 12 and 24 months. Conclusions: The maximum tolerated hypofractionated dose schedule for hypofractionated PORT to the prostate bed was determined to be 44.2 Gy in 10 daily fractions. The most frequent clinically significant toxicities were late grade 2+ GU toxicities, which corresponded to a worsening of late GU QoL.

A Nationwide Medical Student Assessment of Oncology Education.

Cancer is the second leading cause of death in the USA, but there is minimal data on how oncology is taught to medical students. The purpose of this study is to characterize oncology education at US medical schools. An electronic survey was sent between December 2014 and February 2015 to a convenience sample of medical students who either attended the American Society for Radiation Oncology annual meeting or serve as delegates to the American Association of Medical Colleges. Information on various aspects of oncology instruction at participants' medical schools was collected. Seventy-six responses from students in 28 states were received. Among the six most common causes of death in the USA, cancer reportedly received the fourth most curricular time. During the first, second, and third years of medical school, participants most commonly reported 6-10, 16-20, and 6-10 h of oncology teaching, respectively. Participants were less confident in their understanding of cancer treatment than workup/diagnosis or basic science/natural history of cancer (p < 0.01). During the preclinical years, pathologists, scientists/Ph.D.'s, and medical oncologists reportedly performed the majority of teaching, whereas during the clinical clerkships, medical and surgical oncologists reportedly performed the majority of teaching. Radiation oncologists were significantly less involved during both periods (p < 0.01). Most schools did not require any oncology-oriented clerkship. During each mandatory rotation, <20 % of patients had a primary diagnosis of cancer. Oncology education is often underemphasized and fragmented with wide variability in content and structure between medical schools, suggesting a need for reform.

Medical student mentorship in radiation oncology at a single academic institution: A 10-year analysis.

PURPOSE: Mentorship has been identified by medical students, residents, and faculty as an important component of specialty selection and research productivity in radiation oncology. This study quantitatively analyzes the impact of a mentorship program in radiation oncology targeted to medical students at our institution. METHODS AND MATERIALS: We performed a retrospective review of 76 current or former medical students who were mentored by faculty radiation oncologists at our institution between 2004 and 2013. Data were collected from the medical school's Office of Student Affairs and from internal departmental records. Mentees were organized by mentorship tracks, which included a clinical track and a research track. For each track, data were compiled and analyzed for student specialty selection, and Fisher exact tests were used to determine the relative significance of exposure to clinical, research, or both tracks on student likelihood of pursuing residency in radiation oncology relative to other specialties. We further tracked the research productivity of mentees in the program, as determined by the number publications that were coauthored by mentees and mentors each year. RESULTS: The absolute number of mentees has grown each year, with a total of 76 mentees, including 58 alumni, at the end of 2013. Mentees in the program have produced a total of 53 manuscripts, given 75 presentations at national conferences, and received numerous national and internal medical school research awards. Of the 58 alumni, 17 (29.3%) applied to and matched into radiation oncology residencies. Alumni of both the research and the clinical track were 5.76 (P < .01) times more likely to enter a radiation oncology residency program than the average single-track alumnus. CONCLUSIONS: Mentorship in medical school is an important factor in the development of future radiation oncologists. These results demonstrate the positive impact mentorship has on specialty selection and research productivity.