Association of PSA kinetics after testosterone recovery with subsequent recurrence: secondary analysis of a phase III randomized controlled trial.

PURPOSE: After cessation of androgen deprivation therapy (ADT), testosterone gradually recovers to supracastrate levels (> 50 ng/dL). After this, rises in prostate-specific antigen (PSA) are often seen. However, it remains unknown whether early PSA kinetics after testosterone recovery are associated with subsequent biochemical recurrence (BCR). METHODS: We performed a secondary analysis of a phase III randomized controlled trial in which newly diagnosed localized prostate cancer patients were randomly allocated to ADT for 6 months starting 4 months prior to or simultaneously with prostate RT. We calculated the PSA doubling time (PSADT) based on PSA values up to 18 months after supracastrate testosterone recovery. Competing risk regression was used to evaluate the association of PSADT with relative incidence of BCR, considering deaths as competing events. RESULTS: Overall, 313 patients were eligible. Median PSADT was 8 months. Cumulative incidence of BCR at 10 years from supracastrate testosterone recovery was 19% and 11% in patients with PSADT < 8 months and ≥ 8 months (p = 0.03). Compared to patients with PSADT of < 4 months, patients with higher PSADT (sHR for PSADT 4 to < 8 months: 0.36 [95% CI 0.16-0.82]; 8 to < 12 months: 0.26 [0.08-0.91]; ≥ 12 months: 0.20 [0.07-0.56]) had lower risk of relative incidence of BCR. CONCLUSIONS: Early PSA kinetics, within 18 months of recovery of testosterone to a supracastrate level, can predict for subsequent BCR. Taking account of early changes in PSA after testosterone recovery may allow for recognition of potential failures earlier in the disease course and thereby permit superior personalization of treatment.

Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

Ferumoxytol-Enhanced MR Lymphography for Detection of Metastatic Lymph Nodes in Genitourinary Malignancies: A Prospective Study.

OBJECTIVE. The objective of our study was to evaluate the utility of ferumoxytol-enhanced MR lymphography (MRL) in detection of metastatic lymph nodes (LNs) in patients with prostate, bladder, and kidney cancer. SUBJECTS AND METHODS. This phase 2 single-institution study enrolled patients with confirmed prostate (arm 1), bladder (arm 2), and kidney (arm 3) cancer and evidence of suspected LN involvement. Participants underwent ferumoxytol-enhanced MRL 24 and 48 hours after IV injection of 7.5 mg Fe/kg of ferumoxytol. A retrospective quantitative analysis was performed to determine the optimal timing for ferumoxytol-enhanced MRL using percentage change in normalized signal intensity (SI) from baseline to 24 and 48 hours after injection, which were estimated using the linear mixed-effects model in which time (24 vs 48 hours), diseases status, and time and disease status interaction were the fixed-effects independent variables. Differences in normalized SI values between subgroups of lesions were estimated by forming fixed-effects contrasts and tested by the Wald test. RESULTS. Thirty-nine patients (n = 30, arm 1; n = 6, arm 2; n = 3, arm 3) (median age, 65 years) with 145 LNs (metastatic, n = 100; benign, n = 45) were included. LN-based sensitivity, specificity, positive predictive value, and negative predictive value of ferumoxytol-enhanced MRL was 98.0%, 64.4%, 86.0%, and 93.5%, respectively. Sensitivity and specificity of ferumoxytol-enhanced MRL did not vary by LN size. Metastatic LNs showed a significantly higher percentage decrease of normalized SI on MRL at 24 hours after ferumoxytol injection than at 48 hours after ferumoxytol injection (p = 0.023), whereas the normalized SI values for nonmetastatic LNs were similar at both imaging time points (p = 0.260). CONCLUSION. Ferumoxytol-enhanced MRL shows high sensitivity in the detection of metastatic LNs in genitourinary cancers independent of LN size. The SI difference between benign and malignant LNs on ferumoxytol-enhanced MRL appears similar 24 and 48 hours after ferumoxytol injection, suggesting that imaging can be performed safely within 1 or 2 days of injection. Although ferumoxytol-enhanced MRL can be useful in settings without an available targeted PET agent, issues of iron overload and repeatability of ferumoxytol-enhanced MRL remain concerns for this method.

Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo.

Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4(+)T cells. Some of these CD4(+)T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4(+) T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1-infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4(+)T cells can be a reservoir of infectious HIV-1.

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction.

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

Thrombotic microangiopathy in metastatic melanoma patients treated with adoptive cell therapy and total body irradiation.

BACKGROUND: Thrombotic microangiopathy (TMA) is a complication that developed in some patients receiving 12 Gy total body irradiation (TBI) in addition to lymphodepleting preparative chemotherapy prior to infusion of autologous tumor-infiltrating lymphocytes (TIL) with high-dose aldesleukin (IL-2). This article describes the incidence, presentation, and course of radiation-associated TMA. METHODS: The data for patients with metastatic melanoma who received ACT with TIL plus aldesleukin following myeloablative chemotherapy and 12-Gy TBI was examined, in order to look at patient characteristics and the natural history of TMA. RESULTS: The median time to presentation was approximately 8 months after completing TBI. The estimated cumulative incidence of TMA was 31.2% (median follow-up of 24 months). Noninvasive criteria for diagnosis included newly elevated creatinine levels, new-onset hypertension, new-onset anemia, microscopic hematuria, thrombocytopenia, low haptoglobin, and elevated lactate dehydrogenase values. Once diagnosed, patients were managed with control of their hypertension with multiple agents and supportive red blood cell transfusions. TMA typically stabilized or improved and no patient progressed to dialysis. TMA was associated with a higher probability of an antitumor response. CONCLUSIONS: TMA occurs in approximately a third of patients treated with a lymphodepleting preparative chemotherapy regimen with TBI prior to autologous T cell therapy. The disease has a variable natural history, however, no patient developed end-stage renal failure. Successful management with supportive care and aggressive hypertension control is vital to the safe application of a systemic therapy that has shown curative potential for patients with disseminated melanoma.

Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation.

Exposure to ionizing radiation (IR) can result in the development of cutaneous fibrosis, for which few therapeutic options exist. We tested the hypothesis that bone marrow-derived mesenchymal stem cells (BMSC) would favorably alter the progression of IR-induced fibrosis. We found that a systemic infusion of BMSC from syngeneic or allogeneic donors reduced skin contracture, thickening, and collagen deposition in a murine model. Transcriptional profiling with a fibrosis-targeted assay demonstrated increased expression of interleukin-10 (IL-10) and decreased expression of IL-1ß in the irradiated skin of mice 14 days after receiving BMSC. Similarly, immunoassay studies demonstrated durable alteration of these and several additional inflammatory mediators. Immunohistochemical studies revealed a reduction in infiltration of proinflammatory classically activated CD80(+) macrophages and increased numbers of anti-inflammatory regulatory CD163(+) macrophages in irradiated skin of BMSC-treated mice. In vitro coculture experiments confirmed that BMSC induce expression of IL-10 by activated macrophages, suggesting polarization toward a regulatory phenotype. Furthermore, we demonstrated that tumor necrosis factor-receptor 2 (TNF-R2) mediates IL-10 production and transition toward a regulatory phenotype during coculture with BMSC. Taken together, these data demonstrate that systemic infusion of BMSC can durably alter the progression of radiation-induced fibrosis by altering macrophage phenotype and suppressing local inflammation in a TNF-R2-dependent fashion.

Target Volume Optimization for Localized Prostate Cancer.

PURPOSE: To provide a comprehensive review of the means by which to optimize target volume definition for the purposes of treatment planning for patients with intact prostate cancer with a specific emphasis on focal boost volume definition. METHODS: Here we conduct a narrative review of the available literature summarizing the current state of knowledge on optimizing target volume definition for the treatment of localized prostate cancer. RESULTS: Historically, the treatment of prostate cancer included a uniform prescription dose administered to the entire prostate with or without coverage of all or part of the seminal vesicles. The development of prostate magnetic resonance imaging (MRI) and positron emission tomography (PET) using prostate-specific radiotracers has ushered in an era in which radiation oncologists are able to localize and focally dose-escalate high-risk volumes in the prostate gland. Recent phase 3 data has demonstrated that incorporating focal dose escalation to high-risk subvolumes of the prostate improves biochemical control without significantly increasing toxicity. Still, several fundamental questions remain regarding the optimal target volume definition and prescription strategy to implement this technique. Given the remaining uncertainty, a knowledge of the pathological correlates of radiographic findings and the anatomic patterns of tumor spread may help inform clinical judgement for the definition of clinical target volumes. CONCLUSION: Advanced imaging has the ability to improve outcomes for patients with prostate cancer in multiple ways, including by enabling focal dose escalation to high-risk subvolumes. However, many questions remain regarding the optimal target volume definition and prescription strategy to implement this practice, and key knowledge gaps remain. A detailed understanding of the pathological correlates of radiographic findings and the patterns of local tumor spread may help inform clinical judgement for target volume definition given the current state of uncertainty.

Comparative Evaluation of LLMs in Clinical Oncology.

BACKGROUND: As artificial intelligence (AI) tools become widely accessible, more patients and medical professionals will turn to them for medical information. Large language models (LLMs), a subset of AI, excel in natural language processing tasks and hold considerable promise for clinical use. Fields such as oncology, in which clinical decisions are highly dependent on a continuous influx of new clinical trial data and evolving guidelines, stand to gain immensely from such advancements. It is therefore of critical importance to benchmark these models and describe their performance characteristics to guide their safe application to clinical oncology. Accordingly, the primary objectives of this work were to conduct comprehensive evaluations of LLMs in the field of oncology and to identify and characterize strategies that medical professionals can use to bolster their confidence in a model's response. METHODS: This study tested five publicly available LLMs (LLaMA 1, PaLM 2, Claude-v1, generative pretrained transformer 3.5 [GPT-3.5], and GPT-4) on a comprehensive battery of 2044 oncology questions, including topics from medical oncology, surgical oncology, radiation oncology, medical statistics, medical physics, and cancer biology. Model prompts were presented independently of each other, and each prompt was repeated three times to assess output consistency. For each response, models were instructed to provide a self-appraised confidence score (from 1 to 4). Model performance was also evaluated against a novel validation set comprising 50 oncology questions curated to eliminate any risk of overlap with the data used to train the LLMs. RESULTS: There was significant heterogeneity in performance between models (analysis of variance, P<0.001). Relative to a human benchmark (2013 and 2014 examination results), GPT-4 was the only model to perform above the 50th percentile. Overall, model performance varied as a function of subject area across all models, with worse performance observed in clinical oncology subcategories compared with foundational topics (medical statistics, medical physics, and cancer biology). Within the clinical oncology subdomain, worse performance was observed in female-predominant malignancies. A combination of model selection, prompt repetition, and confidence self-appraisal allowed for the identification of high-performing subgroups of questions with observed accuracies of 81.7 and 81.1% in the Claude-v1 and GPT-4 models, respectively. Evaluation of the novel validation question set produced similar trends in model performance while also highlighting improved performance in newer, centrally hosted models (GPT-4 Turbo and Gemini 1.0 Ultra) and local models (Mixtral 8×7B and LLaMA 2). CONCLUSIONS: Of the models tested on a standardized set of oncology questions, GPT-4 was observed to have the highest performance. Although this performance is impressive, all LLMs continue to have clinically significant error rates, including examples of overconfidence and consistent inaccuracies. Given the enthusiasm to integrate these new implementations of AI into clinical practice, continued standardized evaluations of the strengths and limitations of these products will be critical to guide both patients and medical professionals. (Funded by the National Institutes of Health Clinical Center for Research and the Intramural Research Program of the National Institutes of Health; Z99 CA999999.).

The clinical manifestations and molecular pathogenesis of radiation fibrosis.

Advances in radiation techniques have enabled the precise delivery of higher doses of radiotherapy to tumours, while sparing surrounding healthy tissues. Consequently, the incidence of radiation toxicities has declined, and will likely continue to improve as radiotherapy further evolves. Nonetheless, ionizing radiation elicits tissue-specific toxicities that gradually develop into radiation-induced fibrosis, a common long-term side-effect of radiotherapy. Radiation fibrosis is characterized by an aberrant wound repair process, which promotes the deposition of extensive scar tissue, clinically manifesting as a loss of elasticity, tissue thickening, and organ-specific functional consequences. In addition to improving the existing technologies and guidelines directing the administration of radiotherapy, understanding the pathogenesis underlying radiation fibrosis is essential for the success of cancer treatments. This review integrates the principles for radiotherapy dosimetry to minimize off-target effects, the tissue-specific clinical manifestations, the key cellular and molecular drivers of radiation fibrosis, and emerging therapeutic opportunities for both prevention and treatment.

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.

Effect of Pelvic External Beam Radiation Therapy on Bone Mineral Density: A Secondary Analysis of a Phase 3 Randomized Controlled Trial.

PURPOSE: Pelvic radiation therapy may lead to decreased bone mineral density (BMD) and increased risk of fracture that could be of particular concern in patients with prostate cancer who also receive androgen deprivation therapy (ADT). We performed an exploratory analysis of a randomized, double-masked, placebo-controlled trial to determine whether exposure to prior pelvic external beam radiation therapy (XRT) affects BMD and risk of fracture in patients with prostate cancer treated with ADT. METHODS AND MATERIALS: Patients with nonmetastatic prostate cancer aged ≥70 years or <70 years with low BMD (T-score < -1) or osteoporotic fracture who had been receiving ADT for ≥12 months were randomly assigned to receive densoumab or placebo every 6 months for 3 years. BMD was measured at baseline and at months 1, 3, 6, 12, 24, and 36. We applied multivariable linear mixed-effects models with an interaction term between the treatment arm and exposure to prior pelvic XRT to evaluate differential XRT effect on percent BMD change between the 2 treatment arms. RESULTS: Among 1407 eligible patients, 31% (n = 447) received prior pelvic XRT. There was no significant difference in any clinical fractures among patients with (5.8%, 26 of 447) or without (5.2%, 50 of 960) prior pelvic XRT (P = .42). Prior pelvic XRT was associated with a significant (0.54%) improvement in BMD (95% CI, 0.05-1.02) in the placebo group and a nonsignificant (0.04%) decline in BMD (95% CI, -0.47 to -0.35) in the denosumab group (interaction P = .007). There was no significant difference in pelvic XRT effect on percent BMD change in the lumbar spine (P = .65) or total hip (P = .39) between the 2 treatment groups. CONCLUSIONS: We did not find sufficient evidence to suggest any detrimental effect of pelvic XRT on the treatment effect from denosumab on percent BMD change, with only an approximately 5% incidence of clinical fractures.

AI-ADC: Channel and Spatial Attention-Based Contrastive Learning to Generate ADC Maps from T2W MRI for Prostate Cancer Detection.

BACKGROUND/OBJECTIVES: Apparent Diffusion Coefficient (ADC) maps in prostate MRI can reveal tumor characteristics, but their accuracy can be compromised by artifacts related with patient motion or rectal gas associated distortions. To address these challenges, we propose a novel approach that utilizes a Generative Adversarial Network to synthesize ADC maps from T2-weighted magnetic resonance images (T2W MRI). METHODS: By leveraging contrastive learning, our model accurately maps axial T2W MRI to ADC maps within the cropped region of the prostate organ boundary, capturing subtle variations and intricate structural details by learning similar and dissimilar pairs from two imaging modalities. We trained our model on a comprehensive dataset of unpaired T2-weighted images and ADC maps from 506 patients. In evaluating our model, named AI-ADC, we compared it against three state-of-the-art methods: CycleGAN, CUT, and StyTr2. RESULTS: Our model demonstrated a higher mean Structural Similarity Index (SSIM) of 0.863 on a test dataset of 3240 2D MRI slices from 195 patients, compared to values of 0.855, 0.797, and 0.824 for CycleGAN, CUT, and StyTr2, respectively. Similarly, our model achieved a significantly lower Fréchet Inception Distance (FID) value of 31.992, compared to values of 43.458, 179.983, and 58.784 for the other three models, indicating its superior performance in generating ADC maps. Furthermore, we evaluated our model on 147 patients from the publicly available ProstateX dataset, where it demonstrated a higher SSIM of 0.647 and a lower FID of 113.876 compared to the other three models. CONCLUSIONS: These results highlight the efficacy of our proposed model in generating ADC maps from T2W MRI, showcasing its potential for enhancing clinical diagnostics and radiological workflows.

A Phase 1 Trial of Image Guided Risk Volume-Adapted Postprostatectomy Radiation Therapy.

PURPOSE: This was a phase 1 trial with the primary objective of identifying the most compressed dose schedule (DS) tolerable using risk volume-adapted, hypofractionated, postoperative radiation therapy (PORT) for biochemically recurrent prostate cancer. Secondary endpoints included biochemical progression-free survival and quality of life (QOL). METHODS AND MATERIALS: Patients were treated with 1 of 3 isoeffective DSs (DS1: 20 fractions, DS2: 15 fractions, and DS3: 10 fractions) that escalated the dose to the imaging-defined local recurrence (73 Gy3 equivalent dose in 2Gy fractions) and de-escalated the dose to the remainder of the prostate bed (48 Gy3 equivalent dose in 2Gy fractions). Escalation followed a standard 3 + 3 design with a 6-patient expansion at the maximally tolerated hypofractionated DS. Dose-limiting toxicity was defined as Common Terminology Criteria for Adverse Events v.4.0 grade (G) 3 toxicity lasting >4 days within 21 days of PORT completion or G4 gastrointestinal (GI) or genitourinary toxicities thereafter. QOL was assessed longitudinally through 24 months with the Expanded Prostate Cancer Index Composite short form. RESULTS: Between January 2018 and December 2023, 15 patients were treated (3 with DS1, 3 with DS2, and 9 with DS3). The median follow-up was 48 months. No dose-limiting toxicities were observed on any DS, and thus, expansion occurred at DS3. The cumulative incidence of G3 GI and genitourinary toxicity was 7% and 9% at 24 months, respectively, with no G4 events observed. Transient, acute G2+ GI toxicity was the most common. QOL worsened transiently during study follow-up in urinary incontinence, GI, and sexual subdomains but was similar to baseline by 24 months. The biochemical progression-free survival was 91% at both 24 and 60 months. CONCLUSIONS: The maximally tolerated hypofractionated DS for hypofractionated, risk volume-adapted PORT was determined to be DS3 (36.4 Gy to the prostate bed and 47.1 Gy to the imaging-defined recurrence in 10 daily fractions). No >G3 events were observed. Transient declines in QOL did not persist through 24 months.

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.

Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.

PURPOSE: Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans. METHODS: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images. 18F-DCFPyL PSMA PET-CT studies from 302 prostate cancer patients, split into training, validation, and testing cohorts (n = 183, 60, 59, respectively). Models were trained with two normalization strategies: Standard Uptake Value (SUV)-based and SUV-Nyul-based. Scan-level performance was evaluated by normalized mean square error (NMSE), mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR). Lesion-level analysis was performed in regions-of-interest prospectively from nuclear medicine physicians. SUV metrics were evaluated using intraclass correlation coefficient (ICC), repeatability coefficient (RC), and linear mixed-effects modeling. RESULTS: Median NMSE, MAE, SSIM, and PSNR were 13.26%, 3.59%, 0.891, and 26.82, respectively, in the independent test cohort. ICC for SUVmax and SUVmean were 0.88 and 0.89, which indicated a high correlation between original and AI-generated quantitative imaging markers. Lesion location, density (Hounsfield units), and lesion uptake were all shown to impact relative error in generated SUV metrics (all p < 0.05). CONCLUSION: The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.

Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926.

PURPOSE: To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG). PATIENTS AND METHODS: Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety. RESULTS: This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia. CONCLUSION: Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.

A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins.

Proteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13Pru by degradation of its UCHL5/Uch37-binding DEUBAD domain and retention of an intact proteasome- and ubiquitin-binding Pru domain. By using structure-guided virtual screening, we identify an hRpn13 binder (XL44) and solve its structure ligated to hRpn13 Pru by integrated X-ray crystallography and NMR to reveal its targeting mechanism. Surprisingly, hRpn13Pru is depleted in myeloma cells following treatment with XL44. TMT-MS experiments reveal a select group of off-targets, including PCNA clamp-associated factor PCLAF and ribonucleoside-diphosphate reductase subunit M2 (RRM2), that are similarly depleted by XL44 treatment. XL44 induces hRpn13-dependent apoptosis and also restricts cell viability by a PCLAF-dependent mechanism. A KEN box, but not ubiquitination, is required for XL44-induced depletion of PCLAF. Here, we show that XL44 induces ubiquitin-dependent loss of hRpn13Pru and ubiquitin-independent loss of select KEN box containing proteins.