MRI-guided Focused Ultrasound Focal Therapy for Intermediate-Risk Prostate Cancer: Final Results from a 2-year Phase II Clinical Trial.

Background MRI-guided focal therapy (FT) allows for accurate targeting of localized clinically significant prostate cancer (csPCa) while preserving healthy prostate tissue, but the long-term outcomes of this approach require more study. Purpose To assess the 2-year oncological and functional outcomes of men with intermediate-risk prostate cancer (PCa) treated with targeted FT. Materials and Methods In this single-center prospective phase II trial, men with localized unifocal intermediate-risk PCa underwent transrectal MRI-guided focused ultrasound between July 2016 and July 2019. Planned ablation volumes included 10-mm margins when possible. Data regarding adverse events were collected and quality-of-life questionnaires were completed by participants at 6 weeks and at 5, 12, 18, and 24 months after treatment. Multiparametric MRI and targeted and systematic biopsies were performed at 24 months. Ablation volumes were determined by manual contouring of nonperfused volumes on immediate contrast-enhanced images. Generalized estimating equations were used to model trends in quality-of-life measures. Results Treatment was successfully completed in the 44 participants (median age, 67 years; IQR, 62-70 years; 36 patients with grade group [GG] 2; eight patients with GG 3). No major adverse events from treatment were recorded. One participant refused biopsy at 24 months. After 2 years, 39 of 43 participants (91%) had no csPCa at the treatment site and 36 of 43 (84%) had no cancer in the entire gland. No changes in International Index of Erectile Function-15 score or International Prostate Symptom Score were observed during 2-year follow-up (P = .73 and .39, respectively). Conclusion The majority of men treated with MRI-guided focused ultrasound for intermediate risk PCa had negative results for csPCa at biopsy 2 years after treatment. Additionally, there was no significant decline in quality of life per the validated questionnaires. Clinical trial registration no. NCT02968784 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Woodrum in this issue.

MRI-guided Focused Ultrasound Ablation for Localized Intermediate-Risk Prostate Cancer: Early Results of a Phase II Trial.

Background To reduce adverse effects of whole-gland therapy, participants with localized clinically significant prostate cancer can undergo MRI-guided focal therapy. Purpose To explore safety and early oncologic and functional outcomes of targeted focal high-intensity focused ultrasound performed under MRI-guided focused ultrasound for intermediate-risk clinically significant prostate cancer. Materials and Methods In this prospective phase II trial, between February 2016 and July 2019, men with unifocal clinically significant prostate cancer visible at MRI were treated with transrectal MRI-guided focused ultrasound. The primary end point was the 5-month biopsy (last recorded in December 2019) with continuation to the 24-month follow-up projected to December 2021. Real-time ablation monitoring was performed with MR thermography. Nonperfused volume was measured at treatment completion. Periprocedural complications were recorded. Follow-up included International Prostate Symptom Score (IPSS) and International Index of Erectile Function-15 (IIEF-15) score at 6 weeks and 5 months, and multiparametric MRI and targeted biopsy of the treated area at 5 months. The generalized estimating equation model was used for statistical analysis, and the Holm method was used to adjust P value. Results Treatment was successfully completed in all 44 men, 36 with grade group (GG) 2 and eight with GG 3 disease (median age, 67 years; interquartile range [IQR], 62-70 years). No major treatment-related adverse events occurred. Forty-one of 44 participants (93%; 95% CI: 82, 98) were free of clinically significant prostate cancer (≥6 mm GG 1 disease or any volume ≥GG 2 disease) at the treatment site at 5-month biopsy (median, seven cores). Median IIEF-15 and IPSS scores were similar at baseline and at 5 months (IIEF-15 score at baseline, 61 [IQR, 34-67] and at 5 months, 53 [IQR, 24-65.5], P = .18; IPSS score at baseline, 3.5 [IQR, 1.8-7] and at 5 months, 6 [IQR, 2-7.3], P = .43). Larger ablations (≥15 cm3) compared with smaller ones were associated with a decline in IIEF-15 scores at 6 weeks (adjusted P < .01) and at 5 months (adjusted P = .07). Conclusion Targeted focal therapy of intermediate-risk prostate cancer performed with MRI-guided focused ultrasound ablation was safe and had encouraging early oncologic and functional outcomes. © RSNA, 2021 Online supplemental material is available for this article See also the editorial by Tempany-Afdhal in this issue.

Deep learning for whole-body medical image generation.

BACKGROUND: Artificial intelligence (AI) algorithms based on deep convolutional networks have demonstrated remarkable success for image transformation tasks. State-of-the-art results have been achieved by generative adversarial networks (GANs) and training approaches which do not require paired data. Recently, these techniques have been applied in the medical field for cross-domain image translation. PURPOSE: This study investigated deep learning transformation in medical imaging. It was motivated to identify generalizable methods which would satisfy the simultaneous requirements of quality and anatomical accuracy across the entire human body. Specifically, whole-body MR patient data acquired on a PET/MR system were used to generate synthetic CT image volumes. The capacity of these synthetic CT data for use in PET attenuation correction (AC) was evaluated and compared to current MR-based attenuation correction (MR-AC) methods, which typically use multiphase Dixon sequences to segment various tissue types. MATERIALS AND METHODS: This work aimed to investigate the technical performance of a GAN system for general MR-to-CT volumetric transformation and to evaluate the performance of the generated images for PET AC. A dataset comprising matched, same-day PET/MR and PET/CT patient scans was used for validation. RESULTS: A combination of training techniques was used to produce synthetic images which were of high-quality and anatomically accurate. Higher correlation was found between the values of mu maps calculated directly from CT data and those derived from the synthetic CT images than those from the default segmented Dixon approach. Over the entire body, the total amounts of reconstructed PET activities were similar between the two MR-AC methods, but the synthetic CT method yielded higher accuracy for quantifying the tracer uptake in specific regions. CONCLUSION: The findings reported here demonstrate the feasibility of this technique and its potential to improve certain aspects of attenuation correction for PET/MR systems. Moreover, this work may have larger implications for establishing generalized methods for inter-modality, whole-body transformation in medical imaging. Unsupervised deep learning techniques can produce high-quality synthetic images, but additional constraints may be needed to maintain medical integrity in the generated data.

Detection of clinically significant prostate cancer with 18F-DCFPyL PET/multiparametric MR.

PURPOSE: To assess whether 18F-DCFPyL PET/multiparametric (mp)MR contributes to the diagnosis of clinically significant (cs) prostate cancer (PCa) compared to mpMR in patients with suspicion of PCa, or patients being considered for focal ablative therapies (FT). PATIENTS AND METHODS: This ethics review board-approved, prospective study included 55 men with suspicion of PCa and negative systematic biopsies or clinically discordant low-risk PCa (n = 21) or those being considered for FT (n = 34) who received 18F-DCFPyL PET/mpMR. Each modality, PET, mpMR, and PET/MR (using the PROMISE classification), was assessed independently. All suspicious lesions underwent PET/MR-ultrasound fusion biopsies. RESULTS: There were 45/55 patients (81.8%) that had histologically proven PCa and 41/55 (74.5%) were diagnosed with csPCa. Overall, 61/114 lesions (53.5%) identified on any modality were malignant; 49/61 lesions (80.3%) were csPCa. On lesion-level analysis, for detection of csPCa, the sensitivity of PET was higher than that of mpMR and PET/MR (86% vs 67% and 69% [p = 0.027 and 0.041, respectively]), but at a lower specificity (32% vs 85% and 86%, respectively [p < 0.001]). The performance of MR and PET/MR was comparable. For identification of csPCa in PI-RADS ≥ 3 lesions, the AUC (95% CI) for PET, mpMR, and PET/MR was 0.75 (0.65-0.86), 0.69 (0.56-0.82), and 0.78 (0.67-0.89), respectively. The AUC for PET/MR was significantly larger than that of mpMR (p = 0.04). CONCLUSION: PSMA PET detects more csPCa than mpMR, but at low specificity. The performance PET/MR is better than mpMR for detection of csPCa in PI-RADS ≥ 3 lesions. CLINICAL REGISTRATION: NCT03149861.

Internet of Things (IoT)-Enhanced Applied Behavior Analysis (ABA) for Special Education Needs.

Applied behavior analysis (ABA) has become a popular behavioral therapy in the special education needs (SEN) community. ABA is used to manage SEN students' behaviors by solving problems in socially important settings, and puts emphasis on having precise measurements on physical and observable events. In this work, we present how Internet of Things (IoT) technologies can be applied to enhance ABA therapy in normal SEN classroom settings. We measured (1) learning performance data, (2) learners' physiological data, and (3) learning environment sensors' data. Upon preliminary analysis, we have found that learners' physiological data is highly diverse, while learner performance seems to be related to learners' electrodermal activity. Our preliminary findings suggest the possibility of enhancing ABA for SEN with IoT technologies.

Comparison of MRI Sequences in Whole-Body PET/MRI for Staging of Patients With High-Risk Prostate Cancer.

OBJECTIVE: The purpose of this study is to investigate the diagnostic value of various MRI sequences used for whole-body (WB) 18F-fluorocholine (FCH) PET/MRI staging of patients with high-risk prostate cancer (PCa). SUBJECTS AND METHODS: This analysis is based on data from a prospective study that included 58 patients with untreated high-risk PCa who underwent integrated WB FCH PET/MRI (n = 10) or FCH PET/CT and WB MRI (n = 48). Metastatic sites were recorded. The standard of reference was histopathologic findings or clinical and imaging follow-up, or both. For each MRI sequence (Dixon T1-weighted, turbo inversion recovery magnitude, WB DWI, and gadolinium-enhanced T1-weighted volumetric interpolated breath-hold examination [VIBE]), acquisition time was recorded, and conspicuity of metastatic lesions was qualitatively assessed by two radiologists using a 4-point ordinal scale (0-3). RESULTS: Total WB acquisition times were 1 minute 25 seconds for Dixon T1-weighted, 15 minutes 7 seconds for turbo inversion recovery magnitude, 16 minutes 33 seconds for WB DWI, and 1 minute 28 seconds for gadolinium-enhanced T1-weighted VIBE. The lesion detection rates were 88.3% (68/77) for Dixon T1-weighted, 94.8% (73/77) for turbo inversion recovery magnitude, 95.2% (40/42) for WB DWI, and 97.4% (75/77) for gadolinium-enhanced T1-weighted VIBE sequences. Moderate or high conspicuity scores were assigned to 62.3% (48/77) of lesions for Dixon T1-weighted, 88.3% (68/77) of lesions for turbo inversion recovery magnitude, 90.5% (38/42) of lesions for WB DWI, and 92.2% (71/77) of lesions for gadolinium-enhanced T1-weighted VIBE sequences. Conspicuity of metastases on gadolinium-enhanced T1-weighted VIBE and WB DWI sequences was higher than that on Dixon T1-weighted sequences (p < 0.0001 and p = 0.0011, respectively). CONCLUSION: Metastases from prostate cancer are best detected at DWI or gadolinium-enhanced T1-weighted VIBE sequences. The most time-efficient sequence with the highest lesion detection rate and conspicuity is gadolinium-enhanced T1-weighted VIBE.

In vivo comparison of a polymer-free Biolimus A9-eluting stent with a biodegradable polymer-based Biolimus A9 eluting stent and a bare metal stent in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.

OBJECTIVES: To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries. METHODS: Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry. RESULTS: The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both). CONCLUSION: This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Combined Cardiac Fluorodeoxyglucose-Positron Emission Tomography/Magnetic Resonance Imaging Assessment of Myocardial Injury in Patients Who Recently Recovered From COVID-19.

IMPORTANCE: Although myocardial injury can occur with acute COVID-19, there is limited understanding of changes with myocardial metabolism in recovered patients. OBJECTIVE: To examine myocardial metabolic changes early after recovery from COVID-19 using fluorodeoxyglucose-positron emission tomography (PET) and associate these changes to abnormalities in cardiac magnetic resonance imaging (MRI)-based function and tissue characterization measures and inflammatory blood markers. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study took place at a single-center tertiary referral hospital system. A volunteer sample of adult patients within 3 months of a diagnosis of COVID-19 who responded to a mail invitation were recruited for cardiac PET/MRI and blood biomarker evaluation between November 2020 and June 2021. EXPOSURES: Myocardial inflammation as determined by focal fluorodeoxyglucose (FDG) uptake on PET. MAIN OUTCOMES AND MEASURES: Demographic characteristics, cardiac and inflammatory blood markers, and fasting combined cardiac 18F-FDG PET/MRI imaging were obtained. All patients with focal FDG uptake at baseline returned for repeated PET/MRI and blood marker assessment 2 months later. RESULTS: Of 47 included patients, 24 (51%) were female, and the mean (SD) age was 43 (13) years. The mean (SD) interval between COVID-19 diagnosis and PET/MRI was 67 (16) days. Most patients recovered at home during the acute infection (40 [85%]). Eight patients (17%) had focal FDG uptake on PET consistent with myocardial inflammation. Compared with those without FDG uptake, patients with focal FDG uptake had higher regional T2, T1, and extracellular volume (colocalizing with focal FDG uptake), higher prevalence of late gadolinium enhancement (6 of 8 [75%] vs 9 of 39 [23%], P = .009), lower left ventricular ejection fraction (mean [SD], 55% [4%] vs 62% [5%], P < .001), worse global longitudinal and circumferential strain (mean [SD], -16% [2%] vs -17% [2%], P = .02 and -18% [2%] vs -20% [2%], P = .047, respectively), and higher systemic inflammatory blood markers including interleukin 6, interleukin 8, and high-sensitivity C-reactive protein. Among patients with focal FDG uptake, PET/MRI, and inflammatory blood markers resolved or improved at follow-up performed a mean (SD) of 52 (17) days after baseline PET/MRI. CONCLUSIONS AND RELEVANCE: In this study of patients recently recovered from COVID-19, myocardial inflammation was identified on PET in a small proportion of patients, was associated with cardiac MRI abnormalities and elevated inflammatory blood markers at baseline, and improved at follow-up.

A Combined Echocardiography Approach for the Diagnosis of Cancer Therapy-Related Cardiac Dysfunction in Women With Early-Stage Breast Cancer.

IMPORTANCE: Diagnosis of cancer therapy-related cardiac dysfunction (CTRCD) remains a challenge. Cardiovascular magnetic resonance (CMR) provides accurate measurement of left ventricular ejection fraction (LVEF), but access to repeated scans is limited. OBJECTIVE: To develop a diagnostic model for CTRCD using echocardiographic LVEF and strain and biomarkers, with CMR as the reference standard. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, patients were recruited from University of Toronto-affiliated hospitals from November 2013 to January 2019 with all cardiac imaging performed at a single tertiary care center. Women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were included. The main exclusion criterion was contraindication to CMR. A total of 160 patients were recruited, 136 of whom completed the study. EXPOSURES: Sequential therapy with anthracyclines and trastuzumab. MAIN OUTCOMES AND MEASURES: Patients underwent echocardiography, high-sensitivity troponin I (hsTnI), B-type natriuretic peptide (BNP), and CMR studies preanthracycline and postanthracycline every 3 months during and after trastuzumab therapy. Echocardiographic measures included 2-dimensional (2-D) LVEF, 3-D LVEF, peak systolic global longitudinal strain (GLS), and global circumferential strain (GCS). LVEF CTRCD was defined using the Cardiac Review and Evaluation Committee Criteria, GLS or GCS CTRCD as a greater than 15% relative change, and abnormal hsTnI and BNP as greater than 26 pg/mL and ≥ 35 pg/mL, respectively, at any follow-up point. Combinations of echocardiographic measures and biomarkers were examined to diagnose CMR CTRCD using conditional inference tree models. RESULTS: Among 136 women (mean [SD] age, 51.1 [9.2] years), CMR-identified CTRCD occurred in 37 (27%), and among those with analyzable images, in 30 of 131 (23%) by 2-D LVEF, 27 of 124 (22%) by 3-D LVEF, 53 of 126 (42%) by GLS, 61 of 123 (50%) by GCS, 32 of 136 (24%) by BNP, and 14 of 136 (10%) by hsTnI. In isolation, 3-D LVEF had greater sensitivity and specificity than 2-D LVEF for CMR CTRCD while GLS had greater sensitivity than 2-D or 3-D LVEF. Regression tree analysis identified a sequential algorithm using 3-D LVEF, GLS, and GCS for the optimal diagnosis of CTRCD (area under the receiver operating characteristic curve, 89.3%). The probability of CTRCD when results for all 3 tests were negative was 1.0%. When 3-D LVEF was replaced by 2-D LVEF in the model, the algorithm still performed well; however, its primary value was to rule out CTRCD. Biomarkers did not improve the ability to diagnose CTRCD. CONCLUSIONS AND RELEVANCE: Using CMR CTRCD as the reference standard, these data suggest that a sequential approach combining echocardiographic 3-D LVEF with 2-D GLS and 2-D GCS may provide a timely diagnosis of CTRCD during routine CTRCD surveillance with greater accuracy than using these measures individually. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02306538.

Extended Results and Independent Validation of a Phase 2 Trial of Metastasis-Directed Therapy for Molecularly Defined Oligometastatic Prostate Cancer.

PURPOSE: The role of metastasis-directed therapy (MDT) in molecularly defined oligorecurrent prostate cancer (PCa) remains irresolute. We present extended follow-up and an independent validation cohort of a prospective trial. METHODS AND MATERIALS: This study consists of 2 sequential single-arm phase-2 trials of patients with biochemical recurrence (prostate specific antigen [PSA] 0.4-3.0 ng/mL) and negative conventional imaging after radical prostatectomy and postoperative radiation therapy. All patients underwent [18F]DCFPyL positron emission tomography/computed tomography. Patients with molecularly defined oligorecurrent prostate cancer underwent MDT with stereotactic body radiation therapy or surgery, without androgen deprivation therapy (ADT). The primary end point was biochemical response (≥50% PSA decline from baseline). Secondary end points included PSA progression-free survival and ADT-free survival. The sample size of 37 MDT patients was determined based on a Simon's 2-stage design with biochemical response rate >20%, and this design was also applied for the subsequent independent validation cohort. RESULTS: Seventy-four patients underwent MDT: 37 each in the initial and validation cohorts. Both cohorts met the prespecified biochemical response rate and completed the planned 2-stages of accrual. For the pooled cohort, the median number of prostate specific membrane antigen positron emission tomography avid lesions was 2 and most (87%) recurrences were nodal. Sixty-four (87%) had stereotactic body radiation therapy and 10 (13%) had surgery. Median follow-up (interquartile range [IQR]) for the initial, validation and combined cohorts were 41 (35-46) months, 14 months (7-21), and 24 months (14-41), respectively. The biochemical response rates for the initial, validation and combined cohorts were 59%, 43%, and 51%, respectively. For the combined cohort, median biochemical progression-free survival was 21 months (95% confidence interval, 13-not reached), and median ADT-free survival was 45 months (95% confidence interval, 31-not reached). CONCLUSIONS: Half of patients treated with MDT for molecularly defined-only oligorecurrent prostate cancer exhibited a biochemical response. This study provides necessary and validated evidence to support randomized trials aiming to determine whether MDT (alone or with systemic therapy) can affect clinically meaningful end points.

Sensitivity to Communication Partners During Naturalistic AAC Conversations in Cantonese Chinese.

Previous studies have shown that graphic-based augmentative and alternative communication (AAC) output tend to be short and simple in structure with non-canonical word order, and that AAC users may show differences when communicating with peers compared to professionals such as speech therapists (STs). However, there was a lack of report for graphic-based AAC in the Chinese context, and the effect of communication partners had not been investigated systematically. In this study with 34 AAC users and 10 STs, we reported common and distinct features of free conversations in Cantonese graphic-based AAC, relative to AAC in other languages. We also found that AAC users were sensitive to different types of communication partners. In particular, when conversing with peers, AAC users produced long messages with equal proportion of questions and responses, which suggested active and bi-directional exchanges. In conversations with STs, AAC users showed high diversity in expressive vocabulary, indicating access to more semantic concepts. Results suggested that the base language and the communication partner are both influential factors that should be considered in studies of graphic-based AAC. The mobile AAC system facilitated free conversations in users with complex communication needs, affording an additional channel for social participation.

18F-DCFPyL (PSMA) PET in the Management of Men with Biochemical Failure after Primary Therapy: Initial Clinical Experience of an Academic Cancer Center.

PURPOSE: To describe the initial experience of an academic center using 18F-DCFPyL PET in managing men with recurrent prostate cancer. MATERIALS & METHODS: This prospective, single-arm IRB-approved study included men with biochemical failure after primary therapy for prostate cancer and negative/equivocal CT and bone scintigraphy who were candidates for salvage therapy, as determined by a multidisciplinary panel of experts. 18F-DCFPyL PET was assessed for the presence and extent of recurrence: local, oligometastatic (≤4), or extensive. Post-PET management and clinical outcome, including PSA response, was documented. For patients who received PET-directed ablative therapies, response was categorized as "complete" if PSA became undetectable or "favorable" if PSA decreased ≥50%. RESULTS: Forty-seven men with biochemical failure after radical prostatectomy (n = 29), primary radiotherapy (n = 15) or focal tumor ablation (n = 3) were included. PET was positive in (43/47) 91.5%, including local recurrence in (9/47) 19.2%; oligometastatic disease in (16/47) 34%; and extensive metastatic disease in (18/47) 38.3%. PET-directed focal ablative therapies without systemic therapy were given to (13/29) 44.8% of patients without extensive metastases on PET with a mean PSA response of 69% (median, 74.5%; range: 35-100). Favorable biochemical response was observed in (10/13) 76.9% of patients with limited recurrence on PET, and in 23.1% (3/13), there was complete response. CONCLUSION: 18F-DCFPyL PET was positive in >90% of patients with biochemical failure. For those with limited recurrence, PSMA PET-directed local ablative therapies resulted in favorable outcome in more than 3 in 4 patients, and in nearly a quarter of them, there was complete biochemical response.

Salvage interstitial laser thermal therapy under MRI guidance (MRgFLA) for high-intensity focal ultrasound (HIFU) recurrences: feasibility study.

While focal therapy (FT) is increasingly endorsed for treating localized prostate cancer in the appropriately selected patient, management of recurrences following FT is not well-established in the literature. This case series describes three patients who received high-intensity focal ultrasound (HIFU) for primary treatment followed by focal laser interstitial thermal therapy (FLTT) for salvage therapy treated in the context of an ongoing clinical trial. Evaluation of these reported patients demonstrates that FLTT is feasible in the salvage setting with promising short-term oncologic outcomes and with the potential to preserve functional outcomes. Repeat focal therapy for previous failures is feasible however, it requires sophisticated imaging modalities for the accurate identification of recurrence and treatment of the tumor.

Combined simultaneous FDG-PET/MRI with T1 and T2 mapping as an imaging biomarker for the diagnosis and prognosis of suspected cardiac sarcoidosis.

PURPOSE: To evaluate the diagnostic and prognostic significance of combined cardiac 18F-fluorodeoxyglucose (FDG) PET/MRI with T1/T2 mapping in the evaluation of suspected cardiac sarcoidosis. METHODS: Patients with suspected cardiac sarcoidosis were prospectively enrolled for cardiac 18F-FDG PET/MRI, including late gadolinium enhancement (LGE) and T1/T2 mapping with calculation of extracellular volume (ECV). The final diagnosis of cardiac sarcoidosis was established using modified JMHW guidelines. Major adverse cardiac events (MACE) were assessed as a composite of cardiovascular death, ventricular tachyarrhythmia, bradyarrhythmia, cardiac transplantation or heart failure. Statistical analysis included Cox proportional hazard models. RESULTS: Forty-two patients (53 ± 13 years, 67% male) were evaluated, 13 (31%) with a final diagnosis of cardiac sarcoidosis. Among patients with cardiac sarcoidosis, 100% of patients had at least one abnormality on PET/MRI: FDG uptake in 69%, LGE in 100%, elevated T1 and ECV in 100%, and elevated T2 in 46%. FDG uptake co-localized with LGE in 69% of patients with cardiac sarcoidosis compared to 24% of those without, p = 0.014. Diagnostic specificity for cardiac sarcoidosis was highest for FDG uptake (69%), elevated T2 (79%), and FDG uptake co-localizing with LGE (76%). Diagnostic sensitivity was highest for LGE, elevated T1 and ECV (100%). After median follow-up duration of 634 days, 13 patients experienced MACE. All patients who experienced MACE had LGE, elevated T1 and elevated ECV. FDG uptake (HR 14.7, p = 0.002), elevated T2 (HR 9.0, p = 0.002) and native T1 (HR 1.1 per 10 ms increase, p = 0.044) were significant predictors of MACE even after adjusting for left ventricular ejection fraction and immune suppression treatment. The presence of FDG uptake co-localizing with LGE had the highest diagnostic performance overall (AUC 0.73) and was the best predictor of MACE based on model goodness of fit (HR 14.9, p = 0.001). CONCLUSIONS: Combined cardiac FDG-PET/MRI with T1/T2 mapping provides complementary diagnostic information and predicts MACE in patients with suspected cardiac sarcoidosis.

Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

BACKGROUND: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches. OBJECTIVE: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT). DESIGN/SETTING/PARTICIPANTS: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible. INTERVENTIONS: All patients underwent [18F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT. OUTCOME MEASUREMENTS/STATISTICAL ANALYSIS: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and ß of 0.1. RESULTS: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed. CONCLUSIONS: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa. PATIENT SUMMARY: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.

The Genetic Basis of Natural Variation in Drosophila melanogaster Immune Defense against Enterococcus faecalis.

Dissecting the genetic basis of natural variation in disease response in hosts provides insights into the coevolutionary dynamics of host-pathogen interactions. Here, a genome-wide association study of Drosophila melanogaster survival after infection with the Gram-positive entomopathogenic bacterium Enterococcus faecalis is reported. There was considerable variation in defense against E. faecalis infection among inbred lines of the Drosophila Genetics Reference Panel. We identified single nucleotide polymorphisms associated with six genes with a significant (p < 10-08, corresponding to a false discovery rate of 2.4%) association with survival, none of which were canonical immune genes. To validate the role of these genes in immune defense, their expression was knocked-down using RNAi and survival of infected hosts was followed, which confirmed a role for the genes krishah and S6k in immune defense. We further identified a putative role for the Bomanin gene BomBc1 (also known as IM23), in E. faecalis infection response. This study adds to the growing set of association studies for infection in Drosophila melanogaster and suggests that the genetic causes of variation in immune defense differ for different pathogens.

Combined Vascular Brachytherapy and Stenting for the Treatment of In-Stent Restenosis.

In-stent restenosis (ISR) remains a therapeutic challenge in the current drug-eluting stent (DES) era. Vascular brachytherapy (VBT) is a therapeutic option for ISR, but data about the outcomes of combination therapy with VBT and stenting for ISR lesions are sparse. We retrospectively analyzed patients who presented with ISR at our institution from 2003 through 2017. Three treatment arms were compared: VBT alone, VBT plus bare-metal stent (BMS), and VBT plus DES. Clinical, procedural, and 1-year outcome data were collected. Follow-up was obtained by phone calls and clinic visits. The patient cohort included 461 patients (764 ISR lesions). Of these, 333 patients (533 lesions) were treated with VBT alone, 89 patients (158 lesions) with VBT plus BMS, and 39 patients (73 lesions) with VBT plus DES. There were no significant differences in baseline characteristics among the 3 groups except for more patients with a remote smoking history in the VBT plus BMS (43.8%) and VBT plus DES groups (56.4%), and more patients with history of peripheral vascular disease (39.5%) and congestive heart failure (27%) in the VBT plus DES group. The most common clinical presentation was unstable angina (64.6%). In the VBT plus DES group, 10.3% of patients presented with MI, versus 5.5% in the VBT alone group and 2.2% in the VBT plus BMS group. At 1-year follow-up, the VBT plus DES group had higher rates of target vessel revascularization-major adverse cardiovascular events (38.5%) than the VBT plus BMS (21.3%) and VBT alone (15.6%) groups (p = 0.002). In conclusion, in patients with ISR, combination therapy with VBT and stenting at the same setup is associated with worse outcomes at 12 months and, if possible, should be avoided.

Blood RNA Integrity is a Direct and Simple Reporter of Radiation Exposure and Prognosis: A Pilot Study.

In the event of a mass casualty radiation scenario, rapid assessment of patients' health and triage is required for optimal resource utilization. Identifying the level and extent of exposure as well as prioritization of care is extremely challenging under such disaster conditions. Blood-based biomarkers, such as RNA integrity numbers (RIN), could help healthcare personnel quickly and efficiently determine the extent and effect of multiple injuries on patients' health. Evaluation of the effect of different radiation doses, alone or in combination with burn injury, on total RNA integrity over multiple time points was performed. Total RNA integrity was tallied in blood samples for potential application as a marker of radiation exposure and survival. Groups of aged mice (3-6 mice/group, 13-18 months old) received 0.5, 1, 5, 10 or 20 Gy ionizing radiation. Two additional mouse groups received low-dose irradiation (0.5 or 1 Gy) with a 15% total body surface area (TBSA) burn injury. Animals were euthanized at 2 or 12 h and at day 1, 2, 3, 7 or 14 postirradiation, or when injury-mediated mortality occurred. Total RNA was isolated from blood. The quality of RNA was evaluated and RNA RIN were obtained. Analysis of RIN indicated that blood showed the clearest radiation effect. There was a time- and radiation-dose-dependent reduction in RIN that was first detectable at 12 h postirradiation for all doses in animals receiving irradiation alone. This effect was reversible in lower-dose groups (i.e., 0.5, 1 and 5 Gy) that survived to the end of the study (14 days). In contrast, the effect persisted for 10 and 20 Gy groups, which showed suppression of RIN values <4.5 with high mortalities. Radiation doses of 20 Gy were lethal and required euthanasia by day 6. A low RIN (<2.5) at any time point was associated with 100% mortality. Combined radiation-burn injury produced significantly increased mortality such that no dually-injured animals survived beyond day 3, and no radiation dose >1 Gy resulted in survival past day 1. More modest suppression of RIN was observed in the surviving dually challenged mice, and no statistically significant changes were identified in RIN values of burn-only mice at any time point. In this study of an animal model, a proof of concept is presented for a simple and accurate method of assessing radiation dose exposure in blood which potentially predicts lethality. RIN assessment of blood-derived RNA could form the basis for a clinical decision-support tool to guide healthcare providers under the strenuous conditions of a radiation-based mass casualty event.

Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts.

BACKGROUND: Intracoronary radiation therapy is effective in reducing the recurrence of in-stent stenosis in native coronary arteries. We examined the effects of intravascular gamma radiation in patients with in-stent restenosis of saphenous-vein bypass grafts. METHODS: A total of 120 patients with in-stent restenosis in saphenous-vein grafts, the majority of whom had diffuse lesions, underwent balloon angioplasty, atherectomy, additional stenting, or a combination of these procedures. If the intervention was successful, the patients were randomly assigned in a double-blind fashion to intravascular treatment with a ribbon containing either iridium-192 or nonradioactive seeds. The prescribed dose, delivered at a distance of 2 mm from the source, was 14 to 15 Gy in vessels that were 2.5 to 4.0 mm in diameter and 18 Gy in vessels with a diameter that exceeded 4.0 mm. The primary end points were death from cardiac causes, Q-wave myocardial infarction, revascularization of the target vessel, and a composite of these events at 12 months. RESULTS: Revascularization and radiation therapy were successfully accomplished in all patients. At six months, the restenosis rate was lower in the 60 patients assigned to the iridium-192 group than in the 60 assigned to the placebo group (21 percent vs. 44 percent, P=0.005). At 12 months, the rate of revascularization of the target lesion was 70 percent lower in the iridium-192 group than in the placebo group (17 percent vs. 57 percent, P<0.001), and the rate of major cardiac events was 49 percent lower (32 percent vs. 63 percent, P<0.001). CONCLUSIONS: The results of our study support the use of gamma-radiation therapy for the treatment of in-stent restenosis in patients with bypass grafts.