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Objectives: To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset. Patients and methods: Patients with biopsy‐confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014–2018; six centres), and from the high‐intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK‐based registries (2006–2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post‐salvage with discrimination (concordance index [C‐index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically‐reasonable risk threshold ranges of 0.14–0.52 and 0.26–0.36 were considered, corresponding to previously published pooled 2‐year recurrence‐free survival rates for salvage local treatments. Results: A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow‐ups, and 72/168 (43%) within 2 years. The C‐index was 0.65 (95% confidence interval 0.58–0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14–0.52 risk threshold range, and all of the 0.26–0.36 range. Conclusion: In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow‐up is recommended. [ABSTRACT FROM AUTHOR]

Introduction: High-resolution micro-ultrasound (micro-US) is a novel precise imaging modality that allows targeted prostate biopsies and multiparametric magnet resonance imaging (mpMRI) fusion. Its high resolution relying on a 29 MHz transducer allows real-time visualisation of prostate cancer lesions; this might overcome the inaccuracy of conventional MRI-US fusion biopsy strategies. We compared cancer detection rates in patients who underwent transrectal (TR-B) versus transperineal (TP-B) MR-micro-US fusion biopsy. Materials and methods: 1:2 propensity score matching was performed in 322 consecutive procedures: 56 TR-B and 266 TP-B. All prostate biopsies were performed using ExactVuTM micro-US system with mpMRI image fusion. Clinically significant disease was defined as grade group ≥2. The primary objective was to evaluate the detection of clinically significant disease according to access route. The secondary outcomes were to compare the respective detection rates of random and targeted biopsies stratified per access route and to evaluate micro-US for its potential added value. Results: 47 men undergoing TR-B and 88 undergoing TP-B were matched for age, PSA, clinical stage, prostate volume, PIRADS score, number of mpMRI-visible lesions and indication to biopsy. The detection rates of clinically significant and of any prostate cancer did not differ between the two groups (45% TR-B vs 42% TP-B; p = 0.8, and 57% TR-B vs 59% TP-B; p = 0.9, respectively). Detection rates also did not differ significantly between random (p = 0.4) and targeted biopsies (p = 0.7) stratified per access route. Micro-US targeted biopsy detected 36 MRI-invisible lesions in 33 patients; 19% of these lesions were positive for clinically significant disease. Overall, micro-US targeted biopsies upgraded 2% of patients to clinically significant disease that would have been missed otherwise. Conclusions: MR-micro-US-fusion TR-B and TP-B have similar diagnostic yields in terms of detection rates of clinically significant prostate cancer. Micro-US targeted biopsy appears to have an additional diagnostic value over systematic and MRI-targeted biopsies. [ABSTRACT FROM AUTHOR]

Objectives: To develop a nomogram that could predict spontaneous stone passage (SSP) in patients presenting with acute ureteric colic who are suitable for conservative management. Patients and Methods: A 2517 patient dataset was utilised from an international multicentre cohort study (MIMIC, A Multi‐centre Cohort Study Evaluating the role of Inflammatory Markers In Patients Presenting with Acute Ureteric Colic) of patients presenting with acute ureteric colic across 71 secondary care hospitals in the UK, Ireland, Australia, and New Zealand. Inclusion criteria mandated a non‐contrast computed tomography of the kidneys, ureters, and bladder. SSP was defined as the 'absence of the need for intervention'. The model was developed using logistic regression and backwards selection (to achieve lowest Akaike's information criterion) in a subset from 2009–2015 (n = 1728) and temporally validated on a subset from 2016–2017 (n = 789). Results: Of the 2517 patients, 1874 had SSP (74.5%). The mean (SD) age was 47 (14.7) years and 1892 were male (75.2%). At the end of the modelling process, gender: male (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.64–1.01, P = 0.07), neutrophil count (OR 1.03, 95% CI 1.00–1.06, P = 0.08), hydronephrosis (OR 0.79, 95% CI 0.59–1.05, P = 0.1), hydroureter (OR 1.3, 95% CI 0.97–1.75, P = 0.08), stone size >5–7 mm (OR 0.2, 95% CI 0.16–0.25, P < 0.001), stone size >7 mm (OR 0.11, 95% CI 0.08–0.15, P < 0.001), middle ureter stone position (OR 0.59, 95% CI 0.43–0.81, P = 0.001), upper ureter stone position (OR 0.31, 95% CI 0.25–0.39, P < 0.001), medical expulsive therapy use (OR 1.36, 95% CI 1.1–1.67, P = 0.001), oral nonsteroidal anti‐inflammatory drug (NSAID) use (OR 1.3, 95% CI 0.99–1.71, P = 0.06), and rectal NSAID use (OR 1.17, 95% CI 0.9–1.53, P = 0.24) remained. The concordance‐statistic (C‐statistic) was 0.77 (95% CI 0.75–0.80) and a nomogram was developed based on these. Conclusion: The presented nomogram is available to use as an on‐line calculator via www.BURSTurology.com and could allow clinicians and patients to make a more informed decision on pursuing conservative management vs early intervention. [ABSTRACT FROM AUTHOR]

The five-item Imperial Rapid Access to Prostate Imaging and Diagnosis risk score using age, prostate-specific antigen density, prior negative biopsy, prostate volume, and highest magnetic resonance imaging (MRI) score provides a standardised tool for the prediction of clinically significant prostate cancer in patients with an MRI-detected Prostate Imaging Reporting and Data System/Likert ≥3 lesion and can support the decision for prostate biopsy. Although multiparametric magnetic resonance imaging (MRI) has high sensitivity, its lower specificity leads to a high prevalence of false-positive lesions requiring biopsy. To develop and externally validate a scoring system for MRI-detected Prostate Imaging Reporting and Data System (PIRADS)/Likert ≥3 lesions containing clinically significant prostate cancer (csPCa). The multicentre Rapid Access to Prostate Imaging and Diagnosis (RAPID) pathway included 1189 patients referred to urology due to elevated age-specific prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE); April 27, 2017 to October 25, 2019. Visual-registration or image-fusion targeted and systematic transperineal biopsies for an MRI score of ≥4 or 3 + PSA density ≥0.12 ng/ml/ml. Fourteen variables were used in multivariable logistic regression for Gleason ≥3 + 4 (primary) and Gleason ≥4 + 3, and PROMIS definition 1 (any ≥4 + 3 or ≥6 mm any grade; secondary). Nomograms were created and a decision curve analysis (DCA) was performed. Models with varying complexity were externally validated in 2374 patients from six international cohorts. The five-item Imperial RAPID risk score used age, PSA density, prior negative biopsy, prostate volume, and highest MRI score (corrected c-index for Gleason ≥3 + 4 of 0.82 and 0.80–0.86 externally). Incorporating family history, DRE, and Black ethnicity within the eight-item Imperial RAPID risk score provided similar outcomes. The DCA showed similar superiority of all models, with net benefit differences increasing in higher threshold probabilities. At 20%, 30%, and 40% of predicted Gleason ≥3 + 4 prostate cancer, the RAPID risk score was able to reduce, respectively, 11%, 21%, and 31% of biopsies against 1.8%, 6.2%, and 14% of missed csPCa (or 9.6%, 17%, and 26% of foregone biopsies, respectively). The Imperial RAPID risk score provides a standardised tool for the prediction of csPCa in patients with an MRI-detected PIRADS/Likert ≥3 lesion and can support the decision for prostate biopsy. In this multinational study, we developed a scoring system incorporating clinical and magnetic resonance imaging characteristics to predict which patients have prostate cancer requiring treatment and which patients can safely forego an invasive prostate biopsy. This model was validated in several other countries. [ABSTRACT FROM AUTHOR]

Focal high-intensity focused ultrasound is a safe alternative treatment option for patients with intermediate- to high-risk localised prostate cancer, which confers good medium-term cancer control. Focal therapy aims to treat areas of cancer to confer oncological control whilst reducing treatment-related functional detriment. To report oncological outcomes and adverse events following focal high-intensity focused ultrasound (HIFU) for treating nonmetastatic prostate cancer. An analysis of 1379 patients with ≥6 mo of follow-up prospectively recorded in the HIFU Evaluation and Assessment of Treatment (HEAT) registry from 13 UK centres (2005–2020) was conducted. Five or more years of follow-up was available for 325 (24%) patients. Focal HIFU therapy used a transrectal ultrasound-guided device (Sonablate; Sonacare Inc., Charlotte, NC, USA). Failure-free survival (FFS) was primarily defined as avoidance of no evidence of disease to require salvage whole-gland or systemic treatment, or metastases or prostate cancer–specific mortality. Differences in FFS between D'Amico risk groups were determined using a log-rank analysis. Adverse events were reported using Clavien-Dindo classification. The median (interquartile range) age was 66 (60–71) yr and prostate-specific antigen was 6.9 (4.9–9.4) ng/ml with D'Amico intermediate risk in 65% (896/1379) and high risk in 28% (386/1379). The overall median follow-up was 32 (17–58) mo; for those with ≥5 yr of follow-up, it was 82 (72–94). A total of 252 patients had repeat focal treatment due to residual or recurrent cancer; overall 92 patients required salvage whole-gland treatment. Kaplan-Meier 7-yr FFS was 69% (64–74%). Seven-year FFS in intermediate- and high-risk cancers was 68% (95% confidence interval [CI] 62–75%) and 65% (95% CI 56–74%; p = 0.3). Clavien-Dindo >2 adverse events occurred in 0.5% (7/1379). The median 10-yr follow-up is lacking. Focal HIFU in carefully selected patients with clinically significant prostate cancer, with six and three of ten patients having, respectively, intermediate- and high-risk cancer, has good cancer control in the medium term. Focal high-intensity focused ultrasound treatment to areas of prostate with cancer can provide an alternative to treating the whole prostate. This treatment modality has good medium-term cancer control over 7 yr, although 10-yr data are not yet available. [ABSTRACT FROM AUTHOR]

• Nodal disease, tumour width and local failure are risk factors for NF post-treatment for LACC. • Any CI nodes without PAO nodes' and 'any PAO nodes' are stronger risk factors than 'small pelvis' nodes. • Elective PAO-irradiation was associated with significantly less NF PAO. To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. Data for pelvic NF and para-aortic (PAO) NF (NF PAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). 1338 patients with 152 NF and 104 NF PAO events were analysed with a median follow-up of 34.2 months (IQR 16.4–52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NF PAO (HR 0.53, 95%-CI 0.28–1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NF PAO (HR 0.38, 95%-CI 0.17–0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NF PAO , particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the oncological and functional outcomes of salvage cryosurgery (SCS) for radiorecurrent prostate cancer (rrPCa). Patients and Methods: A total of 169 consecutive patients with biopsy confirmed rrPCa were retrospectively analysed. All patients underwent SCS in a single referral centre between 2006 and 2018. The primary outcome was biochemical recurrence‐free survival (BRFS) according to the Phoenix definition (prostate‐specific antigen [PSA] nadir +2 ng/mL). The secondary outcomes were overall survival, BRFS defined as a PSA level of >0.5 ng/mL, metastasis‐free survival, androgen‐deprivation therapy (ADT)‐free survival, and functional outcomes. Complications were classified according to the Clavien–Dindo system. PSA was measured every 3–6 months postoperatively. Functional outcomes were scored as reported by patients at outpatient visits. Kaplan–Meier survival analysis and uni‐ and multivariable Cox regression were performed. Results: The median (interquartile range) follow‐up was 36 (18–66) months. The BRFS after 5 and 8 years was 52% (95% confidence interval [CI] 43–62%) and 45% (95% CI 35–57%), respectively. At multivariable analysis PSA level at initial diagnosis, initial treatment, interval between primary treatment and SCS, age at SCS, and post‐SCS PSA nadir were significant factors for BRFS. The 5‐year ADT‐free survival was 70% (95% CI 62–79%). Clavien–Dindo Grade ≥III complications occurred in 1.2% (two/169) of patients. In all, 19% (29/156) of patients had new‐onset urinary incontinence defined as >1 pad/24 h and 92% (57/62) of patients had new‐onset erectile dysfunction. Persistent urinary fistula occurred in 6.5% (11/169) of patients. Conclusions: The present study shows acceptable oncological outcomes of SCS considering the salvage character of the treatment. The occurrence of serious complications such as urinary incontinence and fistula should not be underestimated. [ABSTRACT FROM AUTHOR]

Objectives: To assess change in functional outcomes after a second focal high‐intensity focused ultrasonography (HIFU) treatment compared with outcomes after one focal HIFU treatment. Patients and Methods: In this multicentre study (2005–2016), 821 men underwent focal HIFU for localized non‐metastatic prostate cancer. The patient‐reported outcome measures of International Prostate Symptom Score (IPSS), pad usage and erectile function (EF) score were prospectively collected for up to 3 years. To be included in the study, completion of at least one follow‐up questionnaire was required. The primary outcome was comparison of change in functional outcomes between baseline and follow‐up after one focal HIFU procedure vs after a second focal HIFU procedure, using IPSS, Expanded Prostate Cancer Index Composite (EPIC) and International Index of Erectile Function (IIEF) questionnaires. Results: Of 821 men, 654 underwent one focal HIFU procedure and 167 underwent a second focal HIFU procedure. A total of 355 (54.3%) men undergoing one focal HIFU procedure and 65 (38.9%) with a second focal HIFU procedure returned follow‐up questionnaires, respectively. The mean age and prostate‐specific antigen level were 66.4 and 65.6 years, and 7.9 and 8.4 ng/mL, respectively. After one focal HIFU treatment, the mean change in IPSS was −0.03 (P = 0.02) and in IIEF (EF score) it was −0.4 (P = 0.02) at 1–2 years, with no subsequent decline. Absolute rates of erectile dysfunction increased from 9.9% to 20.8% (P = 0.08), leak‐free continence decreased from 77.9% to 72.8% (P = 0.06) and pad‐free continence from 98.6% to 94.8% (P = 0.07) at 1–2 years, respectively. IPSS prior to second focal HIFU treatment compared to baseline IPSS prior to first focal HIFU treatment was lower by −1.3 (P = 0.02), but mean IPSS change was +1.4 at 1–2 years (P = 0.03) and +1.2 at 2–3 years (P = 0.003) after the second focal HIFU treatment. The mean change in EF score after the second focal HIFU treatment was −0.2 at 1–2 years (P = 0.60) and −0.5 at 2–3 years (P = 0.10), with 17.8% and 6.2% of men with new erectile dysfunction. The rate of new pad use was 1.8% at 1–2 years and 2.6% at 2–3 years. Conclusion: A second focal HIFU procedure causes minor detrimental effects on urinary function and EF. These data can be used to counsel patients with non‐metastatic prostate cancer prior to considering HIFU therapy. [ABSTRACT FROM AUTHOR]

Purpose: Most patients with local prostate cancer recurrence after radiation therapy undergo palliative androgen deprivation therapy because whole-gland salvage treatments have a high risk of severe toxicity. Focal treatment reduces this risk while offering a second opportunity for cure. We report updated outcomes of ultrafocal salvage high-dose-rate brachytherapy (HDR-BT).Methods and Materials: Prospectively collected data from the first 50 treated patients were analyzed. Disease status was assessed by 3T multiparametric magnetic resonance imaging (MRI), 18F-Choline or 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography, and systematic or tumor-targeted biopsies. Ultrafocal salvage HDR-BT (1 × 19 Gy) was performed by implanting the clinical target volume (CTV: gross tumor volume + 5 mm margin) under fused transrectal ultrasound/MRI guidance. Follow-up included toxicity grading (using Common Terminology Criteria for Adverse Events 4.0), quality of life assessment, and prostate-specific antigen (PSA) testing.Results: Median follow-up was 31 months. Median CTV D95% was 18.8 Gy. We observed 2% grade 3 genitourinary toxicity, no grade 3 gastrointestinal toxicity, and 22% newly developed grade 3 erectile dysfunction. Five of 13 patients (38%) with self-reported pretreatment potency (International Index of Erectile Function >17) remained potent. Clinically relevant quality of life deterioration was reported for only 6 of 31 items and was not statistically significant. Biochemical failure (nadir + 2) occurred in 26 patients. Among intraprostatic recurrences, 73% were in field. After 2.5 years, biochemical disease-free survival was 51% (95% confidence interval, 37%-69%), metastases-free survival was 75% (64%-89%), androgen deprivation therapy-free survival was 90% (82%-99%), and overall survival was 98% (94%-100%). Presalvage PSA, CTV size, and stage ≥T3 were significantly associated with biochemical failure. Higher-risk patients (stage ≥T3, PSA ≥10, or PSA double time ≤9 months) had 25% biochemical disease-free survival at 2.5 years versus 71% for lower-risk patients.Conclusions: At this early stage, MRI-guided ultrafocal HDR-BT seems to be a safe salvage treatment option, with acceptable biochemical control in a well-selected group of patients and potential for effectively postponing androgen deprivation therapy. [ABSTRACT FROM AUTHOR]

Purpose: For the treatment of localized prostate cancer, focal therapy has the potential to cure with fewer side effects than traditional whole-gland treatments. We report an update on toxicity, quality of life (QoL), and tumor control in our magnetic resonance imaging (MRI)-guided ultrafocal high-dose-rate brachytherapy cohort.Methods and Materials: Disease status was evaluated by systematic biopsies and 3T multiparametric MRI. The brachytherapy implant procedure under fused transrectal ultrasound/MRI guidance was followed by a 1.5 T MRI for contour adjustments and catheter position verification. A single dose of 19 Gy was delivered to the tumor with a margin of 5 mm. Genitourinary (GU) toxicity, gastrointestinal (GI) toxicity, and erectile dysfunction (ED) were graded with the Common Terminology Criteria for Adverse Events version 4.0. QoL was measured with RAND-36, European Organisation for Research and Treatment of Cancer QLQ-C30 and PR25. International Prostate Symptom Scores and International Index of Erectile Function scores were obtained. Prostate-specific antigen level was monitored, with biochemical recurrence defined as nadir + 2 ng/mL (Phoenix).Results: Thirty patients with National Comprehensive Cancer Network low- (13%) to intermediate-risk (87%) prostate cancer were treated between May 2013 and April 2016. Median follow-up was 4 years. Median age was 71 years (interquartile range, 68-73) and median initial prostate-specific antigen level was 7.3 ng/mL (5.2-8.1). Maximum Gleason score was 4 + 3 = 7 (in 2 patients). All tumors were radiologic (MRI) stage T2. No grade >2 GU or >1 GI toxicity occurred. International Prostate Symptom Scores only deteriorated temporarily. Mild pretreatment ED deteriorated to moderate/severe ED in 50% of patients. Long-term clinically relevant QoL deterioration was seen in sexual activity and tiredness, whereas emotional and cognitive functioning improved. At 4 years, biochemical disease-free survival was 70% (95% confidence interval, 52%-93%), metastases-free survival was 93% (85%-100%), and overall survival was 100%. Of intraprostatic recurrences, 7 of 9 were out of field.Conclusions: Ultrafocal high-dose-rate brachytherapy conveys minimal GU or GI toxicity and has a marginal effect on QoL. An early decline in erectile function was seen. Tumor control outcomes are poor (biochemical disease-free survival of 70% [52%-93%] at 4 years), most likely as a result of poor patient selection. [ABSTRACT FROM AUTHOR]

Focal cryotherapy can be used to treat patients with clinically significant nonmetastatic prostate cancer to reduce side effects. Early-medium-term cancer control and functional outcomes. A prospective registry-based case series of 122 consecutive patients undergoing focal cryotherapy between October 1, 2013, and November 30, 2016, in five UK centres. Median follow-up was 27.8 mo [interquartile range (IQR) 19.5–36.7]. A total of 35 patients (28.7%) had National Comprehensive Cancer Network (NCCN) high risk and 87 (71.3%) had intermediate risk disease. Risk and zonal stratification included multiparametric magnetic resonance imaging (mpMRI) with targeted and systematic biopsies, or transperineal mapping biopsies. Focal cryoablation of MR-visible tumours. Follow-up involved prostate-specific antigen (PSA) monitoring, mpMRI, and for-cause biopsies. Primary outcome was failure-free survival (FFS), defined as transition to radical, whole-gland, or systemic therapy, or metastases/death. Secondary outcomes included adverse events and functional outcomes. A total of 80 (65.6%) had anterior ablation, 23 (19.7%) combined posterior and anterior ablation, and two (1.6%) posterior ablation alone (SeedNet or Visual-ICE, BTG plc). Median age was 68.7 yr (IQR 64.9–73.8) and preoperative PSA 10.8 ng/ml (IQR 7.8–15.6). Overall FFS at 3 yr was 90.5% [95% confidence interval (CI) 84.2–97.3]. When stratified for the NCCN risk group, 3-yr outcomes were 84.7% (95% CI 71.4–100) in high risk and 93.3% (95% CI 86.8–100) in intermediate risk. At last follow-up, incontinence defined as any pad use was 0/69 (0%) and erectile dysfunction (defined as erections insufficient for penetration) was 5/31 (16.1%). Limitations include lack of long-term outcomes. Focal cryotherapy primarily for anterior intermediate and high-risk prostate cancer results in good rates of cancer control and low rates of treatment-related side effects. In this multicentre study of 122 patients undergoing focal cryotherapy for medium- to high-risk prostate cancer, at 3 yr, no patient died from their cancer whilst failure-free survival, was approximately 90%. None of the patients needed pads for managing urine leakage, although 16% had erection problems. Focal cryotherapy used primarily for anterior intermediate and high-risk prostate cancer results in good rates of cancer control and low rates of treatment-related side effects in the medium term. [ABSTRACT FROM AUTHOR]

Abstract Purpose To describe toxicity, biochemical outcome and quality of life after MRI guided focal high dose rate brachytherapy (HDR-BT) in a single fraction of 19 Gy for localized prostate cancer. Materials and methods Between May 2013 and April 2016, 30 patients were treated by MRI-guided focal HDR-BT. Patients with visible tumour on MRI were included. All patients were ≥65 years, T-stage

Abstract Background Clinically significant nonmetastatic prostate cancer (PCa) is currently treated using whole-gland therapy. This approach is effective but can have urinary, sexual, and rectal side effects. Objective To report on 5-yr PCa control following focal high-intensity focused ultrasound (HIFU) therapy to treat individual areas of cancer within the prostate. Design, setting, and participants This was a prospective study of 625 consecutive patients with nonmetastatic clinically significant PCa undergoing focal HIFU therapy (Sonablate) in secondary care centres between January 1, 2006 and December 31, 2015. A minimum of 6-mo follow-up was available for599 patients. Intermediate- or high-risk PCa was found in 505 patients (84%). Intervention Disease was localised using multiparametric magnetic resonance imaging (mpMRI) combined with targeted and systematic biopsies, or transperineal mapping biopsies. Areas of significant disease were treated. Follow-up included prostate-specific antigen (PSA) measurement, mpMRI, and biopsies. Outcome measurements and statistical analysis The primary endpoint, failure-free survival (FFS), was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality. Results and limitations The median follow-up was 56 mo (interquartile range [IQR] 35–70). The median age was 65 yr (IQR 61–71) and median preoperative PSA was 7.2 ng/ml (IQR 5.2–10.0). FFS was 99% (95% confidence interval [CI] 98–100%) at 1 yr, 92% (95% CI 90–95%) at 3 yr, and 88% (95% 85–91%) at 5 yr. For the whole patient cohort, metastasis-free, cancer-specific, and overall survival at 5 yr was 98% (95% CI 97–99%), 100%, and 99% (95% CI 97–100%), respectively. Among patients who returned validated questionnaires, 241/247 (98%) achieved complete pad-free urinary continence and none required more than 1 pad/d. Limitations include the lack of long-term follow-up. Conclusions Focal therapy for select patients with clinically significant nonmetastatic prostate cancer is effective in the medium term and has a low probability of side effects. Patient summary In this multicentre study of 625 patients undergoing focal therapy using high-intensity focused ultrasound (HIFU), failure-free survival, metastasis-free survival, cancer-specific survival, and overall survival were 88%, 98%, 100%, and 99%, respectively. Urinary incontinence (any pad use) was 2%. Focal HIFU therapy for patients with clinically significant prostate cancer that has not spread has a low probability of side effects and is effective at 5 yr. Take Home Message Our study shows that at median follow-up of approximately 5 yr after focal high-intensity focused ultrasound, nine out of ten patients with predominantly intermediate- or high-risk prostate cancer are able to avoid surgery, radiotherapy, and systemic therapy. Prostate cancer–specific survival was 100%. There was a low probability of urinary incontinence (2%), erectile dysfunction (15%), and rectal side effects (rare). [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship between patient and tumor characteristics and pain response in patients with metastatic bone disease, and construct and internally validate a clinical prediction model for pain response to guide individualized treatment decision making.Material and Methods: A total of 965 patients with painful bone metastases undergoing palliative radiation therapy at a tertiary referral center between 1999 and 2007 were identified. Pain scores were measured at 1, 2, and 3 months after radiation therapy. Pain response was defined as at least a 2-point decrease on a pain score scale of 0-10, without increase in analgesics, or an analgesic decrease of at least 25% without an increase in pain score. Thirteen candidate predictors were identified from the literature and expert experience. After multiple imputation, final predictors were selected using stepwise regression and collapsed into a prediction model. Model performance was evaluated by calibration and discrimination and corrected for optimism.Results: Overall 462 patients (47.9%) showed a response. Primary tumor site, performance status, and baseline pain score were predictive for pain response, with a corrected c-statistic of 0.63. The predicted response rates after radiation therapy increased from 37.5% for patients with the highest risk score to 79.8% for patients with the lowest risk score and were in good agreement with the observed response rates.Conclusions: A prediction score for pain response after palliative radiation therapy was developed. The model performance was moderate, showing that prediction of pain response is difficult. New biomarkers and predictors may lead to improved identification of the large group of patients who are unlikely to respond and who may benefit from other or innovative treatment options. [ABSTRACT FROM AUTHOR]

The article focuses on a quarter-century review of whole-gland salvage ablation therapies for radio-recurrent prostate cancer at Western University, emphasizing cryoablation, high-intensity focused ultrasound (HIFU), and interstitial laser photodynamic therapy (PDT). Topics discussed include long-term outcomes, complications, comparisons with salvage prostatectomy, and the potential role of next-generation functional imaging for prostate cancer and salvage ablation.

Objective To assess short- to medium-term cancer control rates and side effects of focal salvage high- intensity focused ultrasound ( HIFU). Materials and Methods A retrospective registry analysis identified 150 men who underwent focal salvage HIFU (FS-HIFU) (Sonablate 500) between November 2006 and August 2015. Metastatic disease was excluded by nodal assessment on the pelvic MRI, a radioisotope bone scan and positron-emission tomography ( PET) imaging (choline-18F-fluorodeoxyglucose PET or choline PET- CT). In our current clinical practice, metastatic disease must be excluded by both choline PET and bone scan. Localization of cancer was carried out using multiparametric MRI of the prostate (T2-weighted, diffusion-weighted and dynamic contrast-enhanced imaging) with systematic or template prostate mapping biopsies. The primary outcome was a composite failure incorporating biochemical failure ( BCF) and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer-specific death. The secondary outcome was BCF using the Phoenix- ASTRO definition (prostate-specific antigen [ PSA] nadir + 2 ng/mL). We used Kaplan-Meier analysis and Cox proportional hazards regression to quantify the effect of the determinants on the endpoints. Results The mean (standard deviation [ sd]) patient age at focal salvage HIFU was 69.8 (6.1) years and the median (interquartile range [ IQR]) PSA pre-focal salvage HIFU was 5.5 (3.6-7.9) ng/ mL. The median ( IQR) follow-up was 35 (22-52) months. Patients were classified as having low- 2.7% (4/150), intermediate- 39.3% (59/150) and high-risk disease 41.3% (62/150) according to D'Amico classification, prior to focal salvage HIFU. Composite failure occurred in 61% of patients (91/150) and BCF occurred in 51.3% (77/150). The Kaplan-Meier composite endpoint-free survival ( CEFS) rate at 3 years was 40% (95% confidence interval [ CI] 31-50) for the entire group. Kaplan-Meier estimates of CEFS were 100%, 49% and 24% at 3 years in the low-, intermediate- and high-risk groups pre-salvage HIFU, respectively. The Kaplan-Meier biochemical disease-free survival ( BDFS) rate at 3 years was 48% (95% CI 39-59) for the entire group. Kaplan-Meier estimates of BDFS were 100%, 61% and 32% at 3 years in the low-, intermediate- and high-risk groups pre-salvage HIFU, respectively. Complications included urinary tract infection (11.3%; 17/150), bladder neck stricture (8%; 12/150), recto-urethral fistula after one HIFU procedure (2%; 3/150) and osteitis pubis (0.7%; 1/150). Conclusion Focal salvage HIFU conferred a relatively low complication and side effect rate. CEFS and biochemical control in the short to medium term were reasonable, especially in this relatively high-risk cohort, but still low compared with current whole-gland salvage therapies. Focal salvage therapy may offer disease control in men at high risk whilst minimizing additional treatment morbidities. [ABSTRACT FROM AUTHOR]

• Recurrences after focal salvage HDR brachytherapy are mostly local and in-field. • 3-yrs local recurrence-free survival was 51% after focal salvage HDR brachytherapy. • 3-yrs local ADT-free survival was 86% after focal salvage HDR brachytherapy. Radiorecurrent prostate cancer is often confined to the prostate, predominantly near the index lesion. The purpose of this study was to look at recurrence characteristics in patients treated with focal salvage high dose-rate (HDR) brachytherapy. Patients treated with MRI-guided HDR brachytherapy, with a single fraction of 19 Gy from July 2013 to October 2021 as focal salvage treatment, were prospectively included in the current study. Imaging data were collected regarding the occurrence of local, regional and distant recurrences, including location of local recurrences (LR) in relation to the HDR radiotherapy field. One hundred seventy-five patients were included after focal salvage HDR brachytherapy (median follow-up 36 months (IQR 23–50)). Three-years biochemical recurrence-free survival, LR-free survival, in-field LR-free survival, out-of-field LR-free survival, any-recurrence-free survival and ADT-free survival were 43% (95%CI 34%–52%), 51% (41%–61%), 70% (61%–80%), 92% (88%–97%), 42% (32%–52%) and 86% (80%–92%), respectively. Larger GTV-size and shorter PSA doubling time were associated with in-field LR in multivariable analysis. After focal salvage HDR brachytherapy with a dose of 1x19 Gy for local prostate cancer recurrence, subsequent recurrences are mostly local and in-field. [ABSTRACT FROM AUTHOR]

• Radiological staging of prostate cancer with mpMRI leads to a possible Will Rogers phenomenon. • Our modified EAU risk group model that incorporates mpMRI provides a more precise risk stratification. • Predictive models using both DRE and mpMRI have the best predictive value for PFS. We aimed to test whether the current practice of using mpMRI stage might lead to a Will Rogers phenomenon with a stage migration compared to DRE in men undergoing radical prostatectomy. A total of 572 consecutive patients who underwent radical prostatectomy at a single institution (2007–2017) were included. Clinical stage using digital rectal examination was determined on table by the operating surgeon; mpMRI and pathological stage were recorded after tumor board review. Progression-free survival (PFS) was defined as no rising PSA, no adjuvant/salvage treatment, and no metastases or mortality. PFS was compared between groups and a model incorporating mpMRI into the EAU risk groups was created. Median age was 63 years (IQR 58.5–67) and median PSA was 8.9 ng/ml (IQR 6.5–13.2). Using DRE stage, 20% were NCCN low risk, 43% were intermediate, and 37% high. Median follow-up was 48 months (IQR 22–73). Estimated PFS at 1, 3, and 5 years was 75%, 59%, and 54%, respectively. When comparing PFS between DRE and mpMRI stages, patients deemed T1 (P < 0.01) or T3 (P = 0.03) by mpMRI showed better outcomes than patients staged T1 or T3 by DRE. On univariable analysis lower risk for failure was seen for MRI T1 disease (HR 0.10 95%, CI 0.01–0.73, P = 0.02) or MRI T3 (HR 0.70, CI 0.51–0.97, P = 0.03). On multivariable analysis, only MRI T1 remained a significant predictor (HR 0.08, 95% CI 0.01–0.59, P = 0.01). The subsequent, modified EAU risk model using both DRE and mpMRI performed significantly better than the DRE model. PFS based on mpMRI is not the same as DRE staging. Current risk groups which use DRE should be used with caution in whom local stage is based on mpMRI. Our modified EAU-risk categories can provide greater accuracy. [ABSTRACT FROM AUTHOR]

Purpose: Focal salvage (FS) iodine 125 (125I) brachytherapy could be an effective treatment for locally radiorecurrent prostate cancer (PCa). Toxicity is often reduced compared to total salvage (TS) while cancer control can be maintained, which could increase cost-effectiveness. The current study estimates the incremental cost per quality-adjusted life year (QALY) of FS compared to TS. Material and methods: A decision analytic Markov model was developed, which compares costs and QALYs associated with FS and TS. A 3-year time horizon was adopted with six month cycles, with a hospital perspective on costs. Probabilities for genitourinary (GU) and gastrointestinal (GI) toxicity and their impact on health-related quality of life (SF-36) were derived from clinical studies in the University Medical Center Utrecht (UMCU). Probabilistic sensitivity analysis, using 10,000 Monte Carlo simulations, was performed to quantify the joint decision uncertainty up to the recommended maximum willingness-to-pay threshold of €80,000/QALY. Results: Focal salvage dominates TS as it results in less severe toxicity and lower treatment costs. Decision uncertainty is small, with a 97-100% probability for FS to be cost-effective compared to TS (€0-€80,000/QALY). Half of the difference in costs between FS and TS was explained by higher treatment costs of TS, the other half by higher incidence of severe toxicity. One-way sensitivity analyses show that model outcomes are most sensitive to utilities and probabilities for severe toxicity. Conclusions: Focal salvage 125I brachytherapy dominates TS, as it has lower treatment costs and leads to less toxicity in our center. Larger comparative studies with longer follow-up are necessary to assess the exact influence on (biochemical disease free) survival and toxicity. [ABSTRACT FROM AUTHOR]

We study pinch-and-swell structures in order to uncover the onset of strain localization and the change of deformation mechanisms in layered ductile rocks. To this end, boudinaged monomineralic veins embedded in an ultramylonitic matrix are analyzed quantitatively. The swells are built up by relatively undeformed original calcite grains, showing twinning and minor subgrain rotation recrystallization (SGR). Combined with progressive formation of high-angle misorientations between grains, indicative of SGR, severe grain size reduction defines the transition to the pinches. Accordingly, dynamically recrystallized grains have a strong crystallographic preferred orientation (CPO). Toward the necks, further grain size reduction, increasingly random misorientations, nucleation of new grains, and a loss of the CPO occur. We postulate that this microstructure marks the transition from dislocation to diffusion creep induced by strain localization. We confirm that the development of boudins is insensitive to original grain sizes and single-crystal orientations. In order to test these microstructural interpretations, a self-consistent numerical grain size evolution is implemented, based on thermo-mechanical principles, end-member flow laws and microphysical processes. Applying constant velocity and isothermal boundary conditions to a 3-layer finite element pure shear box, pinch-and-swell structures emerge out of the homogeneous layer through grain size softening at a critical state. Viscosity weakening due to elevated strain rates and dissipated heat from grain size reduction promotes strain rate weakening until a critical grain size is reached. At this point, a switch from dislocation to diffusion creep occurs. This state locks in at local steady states and is microstructurally expressed in pinches and swells, respectively. Thus, boudinage is identified as an energy attractor, identifying the high-energy steady state of an extending layered structure. We conclude from the similarity between natural observations and numerical results that critical deformation conditions of ductile creep can be derived for the surrounding highly-strained host rock matrix. [ABSTRACT FROM AUTHOR]

Background Whole-gland salvage Iodine-125-brachytherapy is a potentially curative treatment strategy for localised prostate cancer (PCa) recurrences after radiotherapy. Prognostic factors influencing PCa-specific and overall survival (PCaSS & OS) are not known. The objective of this study was to develop a multivariable, internally validated prognostic model for survival after whole-gland salvage I-125-brachytherapy. Materials and methods Whole-gland salvage I-125-brachytherapy patients treated in the Netherlands from 1993-2010 were included. Eligible patients had a transrectal ultrasound-guided biopsy-confirmed localised recurrence after biochemical failure (clinical judgement, ASTRO or Phoenix-definition). Recurrences were assessed clinically and with CT and/or MRI. Metastases were excluded using CT/MRI and technetium-99m scintigraphy. Multivariable Cox-regression was used to assess the predictive value of clinical characteristics in relation to PCa-specific and overall mortality. PCa-specific mortality was defined as patients dying with distant metastases present. Missing data were handled using multiple imputation (20 imputed sets). Internal validation was performed and the C-statistic calculated. Calibration plots were created to visually assess the goodness-of-fit of the final model. Optimism-corrected survival proportions were calculated. All analyses were performed according to the TRIPOD statement. Results Median total follow-up was 78 months (range 5–139). A total of 62 patients were treated, of which 28 (45%) died from PCa after mean (±SD) 82 (±36) months. Overall, 36 patients (58%) patients died after mean 84 (±40) months. PSA doubling time (PSADT) remained a predictive factor for both types of mortality (PCa-specific and overall): corrected hazard ratio’s (HR’s) 0.92 (95% CI: 0.86–0.98, p = 0.02) and 0.94 (95% CI: 0.90–0.99, p = 0.01), respectively (C-statistics 0.71 and 0.69, respectively). Calibration was accurate up to 96 month follow-up. Over 80% of patients can survive 8 years if PSADT > 24 months (PCaSS) and >33 months (OS). Only approximately 50% survival is achieved with a PSADT of 12 months. Conclusion A PSADT of respectively >24 months and >33 months can result in >80% probability of PCa- specific and overall survival 8 years after whole-gland salvage I-125-brachytherapy. Survival should be weighed against toxicity from a salvage procedure. Larger series and external validation are necessary. [ABSTRACT FROM AUTHOR]

Purpose Organ-confined prostate cancer recurrences after primary radiotherapy can be treated with salvage iodine-125 brachytherapy. Options include total salvage (TS) or focal salvage (FS). TS often leads to severe late gastrointestinal (GI) toxicity. Differences in rectal dosimetry between TS and FS are presented and dose constraints proposed to reduce late severe GI toxicity (>90 days). Methods and Materials Intraoperative dosimetry and 30-day CT-dosimetry of 20 FS and 28 TS patients were evaluated. GI toxicity was evaluated using the common terminology criteria for adverse events-4. With receiver operating characteristic analysis, dosimetry cutoff values to prevent severe late GI toxicity were assessed. Results FS reduces rectal dose significantly. Median D 0.1cc , D 1cc , D 2cc , and V 100 reductions were 38 Gy ( p = 0.002), 46 Gy ( p < 0.0001), 46 Gy ( p < 0.0001), and 0.41 cc ( p = 0.0001), respectively, compared with TS. FS patients had no late severe GI toxicity. TS patients with severe GI toxicity (41%, n = 11) showed significantly higher rectal doses than TS patients without GI toxicity (59%, n = 16). Median D 0.1cc , D 1cc , D 2cc , and V 100 differences were 29 Gy ( p < 0.001), 17 Gy ( p = 0.001), 28 Gy ( p < 0.001), and 0.45 cc ( p = 0.001). With receiver operating characteristic analysis, restrictions for the D 0.1cc , D 1cc , D 2cc , and V 100 are <160 Gy (area under the curve [AUC], 0.88; 95% confidence interval [CI] 0.76–1.00), <119 Gy (AUC, 0.87; 95% CI, 0.74–1.00), <102 Gy (AUC, 0.89; 95% CI, 0.77–1.00), and <0.38 cc (AUC, 0.88; 95% CI, 0.75–1.00), respectively. Thirty-day CT dosimetry showed minor overestimation of intraoperative D 2cc (median, 10 Gy [ p = 0.02]). Conclusions FS reduces rectal dose compared with TS. D 0.1cc , D 1cc , D 2cc , and V 100 restrictions were 160 Gy, 120 Gy, 100 Gy, and 0.35 cc. Taking correlation into account, the D 2cc <100 Gy might be sufficient for clinical practice. Larger series and multivariable models are necessary to further assess the found restrictions. [ABSTRACT FROM AUTHOR]

Introduction Salvage Iodine-125 brachytherapy (I-125-BT) constitutes a curative treatment approach for patients with organ-confined recurrent prostate cancer after primary radiotherapy. Currently, focal salvage (FS) instead of whole-gland or total salvage (TS) is being investigated, to reduce severe toxicity associated with cumulative radiation dose. Differences in urethral and bladder dosimetry and constraints to reduce late (>90 days) genitourinary (GU) toxicity are presented here. Materials and methods Dosimetry on intraoperative ultrasound (US) of 20 FS and 28 TS patients was compared. The prostate, bladder, urethra and bulbomembranous (BM) urethra were delineated. Toxicity was assessed using the CTCAE version 4.0. Dose constraints to reduce toxicity in TS patients were evaluated with receiver operating characteristic (ROC) analysis. Results FS I-125 BT significantly reduces bladder and urethral dose compared to TS. Grade 3 GU toxicity occurred once in the FS group. For TS patients late severe (⩾grade 3) GU toxicity was frequent (38% in the total 61 patients and 56% in the 27 analyzed patients). TS patients with ⩾grade 3 GU toxicity showed higher bladder D2 cc than TS patients without toxicity (median 43 Gy) ( p = 0.02). The urethral V100 was significantly higher in TS patients with several toxicity profiles: ⩾grade 3 urethral strictures, ⩾grade 2 urinary retention and multiple ⩾grade 2 GU toxicity events. Dose to the BM urethra did not show a relation with stricture formation. ROC-analysis indicated a bladder D2 cc <70 Gy to prevent ⩾grade 3 GU toxicity (AUC 0.76, 95%CI: 0.56–0.96, p = 0.02). A urethral V100 <0.40 cc (AUC from 0.73–0.91, p = 0.003–0.05) could prevent other late GU toxicity. Conclusion FS I-125 BT reduces urethral and bladder dose significantly compared to TS. With TS, there is an increased risk of cumulative dose and severe GU toxicity. Based on these findings, bladder D2 cc should be below 70 Gy and urethral V100 below 0.40 cc. [ABSTRACT FROM AUTHOR]

We present the design and synthesis of artificial specific nucleobases, each one recognizing a single base pair within the major groove of duplex DNA. Computational calculations indicate that PNAs modified with these nucleobases enable the formation of highly stable triple helices with no sequence restrictions through multiple hydrogen bonding and π⋅⋅⋅π stacking interactions, without significantly widening the DNA double helix. New synthetic routes were developed to the structures of these fused heterocycles which have rarely been described in the literature. NMR titration experiments indicate specific hydrogen bonding at the Hoogsteen sites. The new building blocks allow the construction of four PNA monomers for each canonic base pair and their covalent connection to PNA oligomers. These can be designed complementary to any given DNA sequence. With high efficiency and relative simplicity of operation, the described methodologies and strategies hence form the basis for a new supramolecular ligand system targeting double‐stranded DNA without strand invasion. [ABSTRACT FROM AUTHOR]

Pinch-and-swell structures are commonly interpreted to evolve out of viscosity contrasts, which are induced by geometric interactions and material imperfections. From materials science an additional localization phenomenon is well established, where localization emerges out of steady state for critical material parameters and/or loading rates. Here we investigate the conditions under which this second type of instabilities prevails and whether geological materials necessarily require a trigger by imperfections in order to generate instability. We focus on imperfections in terms of grain size variations embedded in a deformation environment controlled by thermo-mechanical feedbacks. We introduce a random distribution of grain sizes over two orders of magnitude in a central layer embedded in a matrix with a diffusion creep rheology. The rheology of the layer evolves with dislocation and diffusion creep as end-member deformation mechanisms. Applying pure shear extension, the 3-layer model is subjected to natural deformation conditions. The central layer quickly establishes a viscous steady state as a natural response of the system due to relaxation and energy optimization. Upon continued loading, localization then intriguingly arises out of a homogeneous state. We present an analysis which confirms that this type of instability is indeed physically admissible. Using vibration analysis, we verify the robustness of the numerical solution by first identifying the natural mode shapes and frequencies of the simulated structure and material parameters, including geometric imperfections. In a second step, the eigenmodes are perturbed and superposed to the initial conditions. We conclude that this pattern of perturbations guides the onset of strain localization. Boudinage can therefore be seen both as a geometric problem and/or a material bifurcation, which evolves out of homogeneous state. The latter class offers the great possibility of extracting fundamental material parameters out of localized structures directly from field observations. [ABSTRACT FROM AUTHOR]

Purpose: Current salvage treatments for recurrent prostate cancer after primary radiation therapy include radical prostatectomy, cryosurgery and brachytherapy. Because toxicity and failure rates are considerable, salvage treatments are not commonly performed. As most centers perform only one preferred salvage technique, the literature only describes single-center outcomes from a single salvage technique with a limited number of patients. In this overview, five high-volume Dutch centers describe their toxicity and outcome data using different salvage techniques. This provides a view on how salvage is performed in clinical practice in the Netherlands. Methods: A total of 129 patients from five different centers in the Netherlands were retrospectively analyzed. Biochemical failure (BF) was defined as PSA >0.1 ng/ml for the salvage prostatectomy group ( n = 44) and PSA nadir + 2.0 ng/ml (Phoenix definition) for the salvage cryosurgery ( n = 54) and salvage brachytherapy group ( n = 31). Toxicity was scored according to the Common Toxicity Criteria for Adverse events (CTCAE v3.0). Results: BF occurred in 25 (81 %) patients in the brachytherapy group (mean follow-up 29 ± 24 months), 29 (66 %) patients in the prostatectomy group (mean follow-up 22 ± 25 months) and 33 (61 %) patients in the cryosurgery group (mean follow-up 14 ± 11 months). Severe (grade >3) genitourinary and gastrointestinal toxicity was observed in up to 30 % of patients in all three groups. Conclusion: This overview shows clinical practice of prostate cancer salvage. Significant failure and toxicity rates are observed, regardless of salvage technique. Patients should be selected with great care before offering these salvage treatment strategies. [ABSTRACT FROM AUTHOR]

Prostate cancer oligometastatic disease can be treated using stereotactic body radiotherapy (SBRT) in order to postpone start of systemic treatments such as androgen deprivation therapy (ADT). 68Ga-PSMA-PET/CT imaging allows for diagnosis of oligometastases at lower PSA values. We analysed a cohort of patients with prostate cancer lymph node oligometastases detected on PSMA-PET/CT. Ninety patients with metachronous oligometastatic prostate cancer received SBRT for 1–3 lymph node metastases diagnosed on 68Ga-PSMA-PET/CT. The primary end point was progression free survival (PFS), with disease progression defined as occurrence of either target lesion progression, new metastatic lesion or biochemical progression. Secondary outcomes were biochemical PFS (BPFS), ADT-free survival (ADT-FS), toxicity and quality of life (QoL). Baseline patient characteristics were tested for association with PFS and a preliminary risk score was created. Median follow-up was 21 months (interquartile range 10–31 months). Median PFS and BPFS were 16 and 21 months, respectively. Median ADT-FS was not reached (73% (95%-CI 62–86%) at 24 months). In multivariable analysis, younger age, higher PSA prior to SBRT and extrapelvic location were associated with shorter PFS. Grade 1 fatigue was the most predominant acute toxicity (34%). Highest grade toxicity was grade 2 for acute and late events. QoL analysis showed mild, transient increase in fatigue at 1–4 weeks after SBRT. A median PFS of 16 months was attained after SBRT for patients with PSMA-PET positive oligometastatic lymph nodes from prostate cancer. Higher pre-SBRT PSA, younger age and extrapelvic location were found to be predictors of shorter PFS. [ABSTRACT FROM AUTHOR]

Over the last decades, primary prostate cancer radiotherapy saw improving developments, such as more conformal dose administration and hypofractionated treatment regimens. Still, prostate cancer recurrences after whole-gland radiotherapy remain common, especially in patients with intermediate- to high-risk disease. The vast majority of these patients are treated palliatively with androgen deprivation therapy (ADT), which exposes them to harmful side-effects and is only effective for a limited amount of time. For patients with a localized recurrent tumor and no signs of metastatic disease, local treatment with curative intent seems more rational. However, whole-gland salvage treatments such as salvage radiotherapy or salvage prostatectomy are associated with significant toxicity and are, therefore, uncommonly performed. Treatments that are solely aimed at the recurrent tumor itself, thereby better sparing the surrounding organs at risk, potentially provide a safer salvage treatment option in terms of toxicity. To achieve such tumor-targeted treatment, imaging developments have made it possible to better exclude metastatic disease and accurately discriminate the tumor. Currently, focal salvage treatment is being performed with different modalities, including brachytherapy, cryotherapy, high-intensity focused ultrasound (HIFU), and stereotactic body radiation therapy (SBRT). Oncologic outcomes seem comparable to whole-gland salvage series, but with much lower toxicity rates. In terms of oncologic control, these results will improve further with better understanding of patient selection. Other developments, such as high-field diagnostic MRI and live adaptive MRI-guided radiotherapy, will further improve precision of the treatment. [ABSTRACT FROM AUTHOR]

Purpose: Patient selection for focal salvage remains difficult. Therefore, we developed and internally validated prediction models for biochemical failure (BF) and a composite endpoint (CE) following focal salvage high intensity focused ultrasound (HIFU) for radiorecurrent prostate cancer.Materials and Methods: A prospective HIFU registry identified 150 cases (November 2006-August 2015). Recurrence was assessed with multiparametric magnetic resonance imaging (MRI) combined with template prostate mapping biopsies, targeted biopsies, or systematic transrectal ultrasound-guided biopsies. Metastatic disease was ruled out with a positron emission tomography-computed tomography and a bone scan. Focal salvage HIFU consisted of quadrant-ablation, hemi-ablation, or index-lesion ablation. Cox-regression was used for BF (Phoenix-definition) and CE (BF/MRI+/biopsies+/local or systemic treatment/metastases+/prostate cancer specific mortality+). Internal validation was performed using bootstrap resampling (500 datasets) after which C-statistic and hazard ratios were adjusted. Models were calibrated and risk scores created.Results: Median follow-up was 35 months (interquartile range: 22-52). Median biochemical disease-free survival (DFS) was 33 months (95% CI: 23-45). Median CE-free survival was 24 months (95% CI: 21-35). After multivariable analysis, DFS interval after primary radiotherapy, presalvage prostate-specific antigen (PSA), PSA-doubling time, prostatic volume, and T-stage (both MRI based) predicted BF. For the CE, PSA-doubling time was not predictive but additionally, primary Gleason score was. The adjusted C-statistics were 0.68 and 0.64 for BF and CE, respectively. Calibration was accurate until 48 months. The risk scores showed 3 groups, with biochemical DFS of 60%, 35%, and 7% and CE-free survival of 40%, 24%, and 0% at 4 years.Conclusion: Our model, once externally validated, could allow for better selection of patients for focal salvage HIFU. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical validity and utility of Likert assessment and the Prostate Imaging Reporting and Data System (PI‐RADS) v2 in the detection of clinically significant and insignificant prostate cancer. Patients and Methods: A total of 489 pre‐biopsy multiparametric magnetic resonance imaging (mpMRI) scans in consecutive patients were subject to prospective paired reporting using both Likert and PI‐RADS v2 by expert uro‐radiologists. Patients were offered biopsy for any Likert or PI‐RADS score ≥4 or a score of 3 with PSA density ≥0.12 ng/mL/mL. Utility was evaluated in terms of proportion biopsied, and proportion of clinically significant and insignificant cancer detected (both overall and on a 'per score' basis). In those patients biopsied, the overall accuracy of each system was assessed by calculating total and partial area under the receiver‐operating characteristic (ROC) curves. The primary threshold of significance was Gleason ≥3 + 4. Secondary thresholds of Gleason ≥4 + 3, Ahmed/UCL1 (Gleason ≥4 + 3 or maximum cancer core length [CCL] ≥6 or total CCL≥6) and Ahmed/UCL2 (Gleason ≥3 + 4 or maximum CCL ≥4 or total CCL ≥6) were also used. Results: The median (interquartile range [IQR]) age was 66 (60–72) years and the median (IQR) prostate‐specific antigen level was 7 (5–10) ng/mL. A similar proportion of men met the biopsy threshold and underwent biopsy in both groups (83.8% [Likert] vs 84.8% [PI‐RADS v2]; P = 0.704). The Likert system predicted more clinically significant cancers than PI‐RADS across all disease thresholds. Rates of insignificant cancers were comparable in each group. ROC analysis of biopsied patients showed that, although both scoring systems performed well as predictors of significant cancer, Likert scoring was superior to PI‐RADS v2, exhibiting higher total and partial areas under the ROC curve. Conclusions: Both scoring systems demonstrated good diagnostic performance, with similar rates of decision to biopsy. Overall, Likert was superior by all definitions of clinically significant prostate cancer. It has the advantages of being flexible, intuitive and allowing inclusion of clinical data. However, its use should only be considered once radiologists have developed sufficient experience in reporting prostate mpMRI. [ABSTRACT FROM AUTHOR]

Objectives: To assess the relationship of white blood cell count (WBC) and other routinely collected inflammatory and clinical markers including stone size, stone position, and medical expulsive therapy use (MET), with spontaneous stone passage (SSP) in a large contemporary cohort of patients with acute ureteric colic, as there are conflicting data on the role of WBC and other inflammatory markers in SSP in patients with acute ureteric colic. Patients and methods: Multicentre retrospective cohort study coordinated by the British Urology Researchers in Surgical Training (BURST) Research Collaborative at 71 secondary care hospitals across four countries (UK, Republic of Ireland, Australia, and New Zealand). In all, 4170 patients presented with acute ureteric colic and a computed tomography confirmed single ureteric stone. Our primary outcome measure was SSP, as defined by the absence of need for intervention to assist stone passage (SP). Multivariable mixed effects logistic regression was used to explore the relationship between key patient factors and SSP. Results: In all, 2518 patients were discharged with conservative management and had further follow‐up with a SSP rate of 74% (n = 1874/2518). Sepsis after discharge with conservative management was reported in 0.6% (n = 16/2518). On multivariable analysis neither WBC, neutrophils count, nor C‐reactive protein (CRP) predicted SSP, with an adjusted odds ratio (OR) of 0.97 (95% confidence interval [CI] 0.91–1.04, P = 0.38), 1.06 (95% CI 0.99–1.13, P = 0.1) and 1.00 (95% CI 0.99–1.00, P = 0.17), respectively. MET also did not predict SSP (adjusted OR 1.11, 95% CI 0.76–1.61). However, stone size and stone position were significant predictors. SSP for stones <5 mm was 89% (95% CI 87–90) compared to 49% (95% CI 44–53) for stones ≥5–7 mm, and 29% (95% CI 23–36) for stones >7 mm. For stones in the upper ureter the SSP rate was 52% (95% CI 48–56), middle ureter was 70% (95% CI 64–76), and lower ureter was 83% (95% CI 81–85). Conclusion: In contrast to the previously published literature, we found that in patients with acute ureteric colic who are discharged with initial conservative management neither WBC, neutrophil count, nor CRP, helps determine the likelihood of SSP. We also found no overall benefit from the use of MET. Stone size and position are important predictors and our present findings represent the most comprehensive SP rates for each millimetre increase in stone size from a large contemporary cohort adjusting for key potential confounders. We anticipate that these data will aid clinicians managing patients with acute ureteric colic and help guide management decisions and the need for intervention. [ABSTRACT FROM AUTHOR]

Purpose Mitral regurgitation (MR) grading by two-dimensional transthoracic echocardiography is challenging, but important to determine the best treatment strategy in patients with MR. Current guidelines advocate an integrative approach, although no recommendation is provided on how to do so. An easy-to-use index will be helpful for standardized and reproducible MR grading. Methods Eleven echocardiographic parameters were retrospectively evaluated in 145 patients with moderate or severe MR. Parameters were scored positive or negative for severe MR, where expert panel consensus reading was considered as the reference standard. Logistic regression was performed, and adjusted coefficients were used to create a risk score for severe MR per patient ( ROSE-index). The best cutoff with corresponding predictive values was determined. Results Eighty-two percent of all parameters could be determined. Multivariable analysis revealed five parameters that remained significant predictors for severe MR: morphology, jet characteristics, vena contracta, systolic reversal, and left ventricular dimensions. With different weighing, a total score of 8 could be obtained. Median total ROSE-index score for moderate (2.0) and severe MR (5.0) did significantly differ. The cutoff score (≥4) revealed sensitivity 0.84 and specificity 0.83 to diagnose severe MR. Negative predictive value was 100% for score 0 and 1; score 6-8 showed a 100% positive predictive value. Inter- and intra-observer agreements were excellent ( K-values >0.80). Conclusion Here, we propose an easy-to-use tool for integrated analysis of guideline parameters to assess MR severity. Using this so-called ROSE-index revealed reliable and reproducible assessment of severe MR (cutoff≥4) that may be helpful for clinical decision making. [ABSTRACT FROM AUTHOR]

Mid-crustal deformation is classically characterized by the transition from ductile to brittle deformation defining the frictional-to-viscous transition (FVT). Here we investigate an exhumed continental mid-crustal basement section in order to envisage the relationship between ductile and brittle deformation at the FVT. Our detailed study from km- to micro-scale shows that, under greenschist metamorphic conditions, deformation is accommodated by a dense network of highly-localized ductile shear zones. In the investigated case it is not quartz which defines the overall ductile deformation behavior but the viscous granular deformation in shear zones with an ultrafine-grained polymineralic matrix consisting of quartz, feldspar, sheet silicates and epidote. During viscous granular flow mass transfer processes under the presence of fluids promote a chemo-mechanical mixing, resulting in grain size reduction and reaction softening. Coeval with this ductile deformation, fluid-assisted embrittlement occurs, as indicated by biotite-coated fractures, cataclasites and injection of non-cohesive polymineralic gouge material into secondary fractures inside the host rock. The embrittlement during predominant ductile deformation occurs in cycles, i.e. prolonged periods of slow viscous granular flow are interrupted by rapid brittle deformation. We interpret this fluid–assisted cyclic embrittlement evidenced by injection of the fluidized material into off-fault fractures as an alternative equivalent to pseudotachylites and as a microstructural indicator for paleo-seismic activity. With exhumation and associated cooling, localized deformation persists in the ultrafine-grained polymineralic shear zones but progressively transitions to cataclastic flow and finally to pressure-dependent frictional flow; always showing cycles of slow interseismic flow and fast seismic injection events. Overall, in the granitic crust of the Aar-massif, brittle and ductile deformation coexist up to deformation temperatures of minimum 450 °C, indicating that the FVT has to be placed in a rather wide range from 8 km up to > 18–20 km in the granitoid crust. [ABSTRACT FROM AUTHOR]

Background: 'Trials-within-Cohorts' (TwiCs), previously known as 'cohort multiple randomized controlled trials' is a pragmatic trial design, supporting an efficient and representative recruitment of patients for (future) trials. To our knowledge, the 'COhort for Lung cancer Outcome Reporting and trial inclusion' (COLOR) is the first TwiCs in lung cancer patients. In this study we aimed to assess the feasibility and first year results of COLOR. Material and Methods: All patients diagnosed with lung cancer referred to the Radiotherapy department were eligible to participate in the ongoing prospective COLOR study. At inclusion, written informed consent was requested for use of patient data, participation in patient-reported outcomes (PROs), and willingness to participate in (future) trials. Feasibility was studied by assessing participation and comparing baseline PROs to EORTC reference values. First-year results of PROs at baseline and 3 months after inclusion were evaluated separately for stereotactic body radiotherapy (SBRT) and conventional radiotherapy patients. Results: Of the 338 eligible patients between July 2020 and July 2021, 169 (50%) participated. Among these, 127 (75%) gave informed consent to PROs participation and 110 (65%) were willing to participate in (future) trials. The inclusion percentage dropped from 77% to 33% when the information procedure was switched from in-person to by phone (due to COVID-19 pandemic measures). Baseline PROs for physical and cognitive functioning were comparable in COLOR patients compared to the EORTC reference values. No significant changes in PROs were observed 3 months after inclusion, except for a slight increase in pain scores in the SBRT group (n = 97). Conclusions: The TwiCs-design appears feasible in lung cancer patients with fair participation rates (although negatively impacted by the COVID-19 pandemic). With a planned expansion to other centers, the COLOR-study is expected to enable multiple (randomized) evaluations of experimental interventions with important advantages for recruitment, generalizability, and long-term outcome data collection. [ABSTRACT FROM AUTHOR]

Prior research underlined the importance of timely oncological care as longer waiting times from diagnosis to treatment may result in poorer survival outcomes. The aim of this study was to determine the impact of waiting time from diagnosis to treatment on overall survival (OS) in patients with cervical cancer treated with curative intent. Patients from a nationwide population-based cohort with newly diagnosed cervical cancer between 2010 and 2019 were studied. Patients who underwent surgery or (chemo)radiotherapy with curative intent were selected. Waiting time (i.e. interval between first pathologic confirmation and treatment) was modelled as continuous (i.e. linear per week), dichotomized (i.e. ≤8 versus >8 weeks), and polynomial (i.e. restricted cubic splines). The association with OS was examined using Cox regression analyses. Among 6895 patients with cervical cancer, 2755 treated with primary surgery and 1898 who received primary (chemo)radiotherapy were included. Mean waiting time was 8.5 (±4.2) weeks to surgery and 7.7 (±2.9) weeks to (chemo)radiotherapy. Adjusted for confounders, waiting time to surgery was not significantly associated with OS (continuous HR 0.97 [95%CI: 0.93–1.01], dichotomized HR 0.93 [95%CI: 0.68–1.27], polynomial HR not significant). Similarly, a longer waiting time to (chemo)radiotherapy was not significantly associated with poorer OS (continuous HR 0.97 [95%CI: 0.93–1.00], dichotomized HR 0.91 [95%CI: 0.75–1.09], polynomial HR not significant). This large population-based study demonstrates that a longer waiting time (of up to 12 weeks) from diagnosis to treatment in patients with cervical cancer treated with curatively intended surgery or (chemo)radiotherapy does not negatively impact survival. • Waiting times to cervical cancer treatment can vary (e.g. from varying logistical challenges or fertility preservation). • The impact of waiting time from diagnosis to treatment with curative intent on overall survival (OS) was studied. • This nationwide population-based study confirmed (and adjusted for) established prognostic factors impacting OS. • In 2755 patients treated with surgery, longer waiting time (of up to 12 weeks) was not significantly associated with OS. • In 1898 patients treated with (chemo)radiotherapy, longer waiting time was also not significantly associated with OS. [ABSTRACT FROM AUTHOR]

Accurate staging of para-aortic nodal status in cervical cancer is of great importance for individualizing treatment and impacting outcomes. Three-dimensional imaging (i.e. PET, CT, MRI) may miss para-aortic lymph node (PALN) metastases. The aim of this study was to systematically review and meta-analyze the proportion of upstaging by PALN dissection in patients with locally advanced cervical cancer without suspicious PALNs on imaging. PubMed/MEDLINE and Embase were systematically searched. The analysis included diagnostic studies that reported on 3D imaging and pre-therapeutic surgical assessment of PALN status in patients with cervical cancer. An overall pooled upstaging rate was calculated using a random-effects model. The search identified 16 eligible studies including 18 cohorts with a total of 1530 patients. Pooling of 12 cohorts demonstrated an upstaging rate of 12% (95% confidence interval [CI] 10–15%) by PALN dissection after negative PET or PET-CT. Pooling of 6 cohorts demonstrated a pooled upstaging rate of 11% (95% CI: 8–16%) by PALN dissection after negative MRI or CT. No significant heterogeneity in upstaging proportions across cohorts was observed (I2 = 0% and 27%, respectively). In 7 cohorts including only patients with pelvic nodal metastases on imaging (but no suspicion of PALN involvement) a pooled upstaging rate by PALN dissection of 21% (95% CI: 17–26%) was found (I2 = 0%). This meta-analysis demonstrates that in case of no suspicious PALN on PET-CT or MRI, PALN dissection still identifies lymph node metastases in a considerable amount of patients with locally advanced cervical cancer and especially in those patients with confirmed pelvic nodal metastases. • Para-aortic lymph node (PALN) status in locally advanced cervical cancer has therapeutic and prognostic implications. • Reported proportions in literature of upstaging by PALN dissection after negative PALN imaging were meta-analyzed. • After negative PET or PET-CT, PALN dissection yielded pathologic PALNs in 12% of all patients. • After negative MRI or CT, PALN dissection yielded pathologic PALNs in 11% of all patients. • After PET-CT showed pelvic nodal (but no PALN) involvement, PALN dissection yielded pathologic PALNs in 21% of patients. [ABSTRACT FROM AUTHOR]

Objectives: Focal salvage HIFU is a feasible therapeutic option in some men who have recurrence after primary radiotherapy for prostate cancer. We aimed to determine if multi-parametric quantitative parameters, in addition to clinical factors, might have a role in independently predicting focal salvage HIFU outcomes.Methods: A retrospective registry analysis included 150 consecutive men who underwent focal salvage HIFU (Sonablate500) (2006-2015); 89 had mpMRI available. Metastatic disease was excluded by nodal assessment on pelvic MRI, a radioisotope bone-scan and/or choline or FDG PET/CT scan. All men had mpMRI and either transperineal template prostate mapping biopsy or targeted and systematic TRUS-biopsy. mpMRI included T2-weighted, diffusion-weighted and dynamic contrast-enhancement. Pre-HIFU quantitative mpMRI data was obtained using Horos DICOM Viewer v3.3.5 for general MRI parameters and IB DCE v2.0 plug-in. Progression-free survival (PFS) was defined by biochemical failure and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer-specific death. Potential predictors of PFS were analyzed by univariable and multivariable Cox-regression.Results: Median age at focal salvage HIFU was 71 years (interquartile range [IQR] 65-74.5) and median PSA pre-focal salvage treatment was 5.8ng/ml (3.8-8). Median follow-up was 35 months (23-47) and median time to failure was 15 months (7.8-24.3). D-Amico low, intermediate and high-risk disease was present in 1% (1/89), 40% (36/89) and 43% (38/89) prior to focal salvage HIFU (16% missing data). 56% (50/89) failed by the composite outcome. A total of 22 factors were evaluated on univariable and 8 factors on multivariable analysis. The following quantitative parameters were included: Ktrans, Kep, Ve, Vp, IS, rTTP and TTP. On univariable analysis, PSA, prostate volume at time of radiotherapy failure and Ve (median) value were predictors for failure. Ve represents extracellular fraction of the whole tissue volume. On multivariable analysis, only Ve (median) value remained as an independent predictor.Conclusions: One pharmacokinetic quantitative parameter based on DCE sequences seems to independently predict failure following focal salvage HIFU for radio-recurrent prostate cancer. This likely relates to the tumor microenvironment producing heat-sinks which counter the heating effect of HIFU. Further validation in larger datasets and evaluating mechanisms to reduce heat-sinks are required. [ABSTRACT FROM AUTHOR]

Purpose: Emerging evidence suggests a detrimental prognostic association between radiation-induced lymphopenia (RIL) and pathologic response, progression-free survival, and overall survival (OS) in patients who undergo radiation therapy for cancer. The aim of this study was to systematically review and meta-analyze the prognostic impact of RIL on OS in patients with solid tumors.Methods and Materials: PubMed/MEDLINE and Embase were systematically searched. The analysis included intervention and prognostic studies that reported on the prognostic relationship between RIL and survival in patients with solid tumors. An overall pooled adjusted hazard ratio (aHR) was calculated using a random-effects model. Subgroup analyses for different patient-, tumor-, treatment-, and study-related characteristics were performed using meta-regression.Results: Pooling of 21 cohorts within 20 eligible studies demonstrated a statistically significant association between OS and grade ≥3 versus grade 0-2 RIL (n = 16; pooled aHR, 1.65; 95% confidence interval [CI], 1.43-1.90) and grade 4 RIL versus grade 0-3 (n = 5; aHR, 1.53; 95% CI, 1.24-1.90). Moderate heterogeneity among aHRs was observed, mostly attributable to overestimated aHRs in 7 studies likely subject to model-overfitting. Subgroup analysis showed significant prognostic impact of grade ≥3 RIL in 4 brain tumor (aHR, 1.63; 95% CI, 1.06-2.51), 4 lung cancer (aHR, 1.52; 95% CI, 1.01-2.29), and 3 pancreatic cancer (aHR, 1.92; 95% CI, 1.10-3.36) cohorts.Conclusions: This meta-analysis demonstrates a significant detrimental prognostic association between grade ≥3 lymphopenia and OS in patients receiving radiation therapy for solid tumors. This finding appears consistent for tumors of the brain, thorax, and upper abdomen and provides an imperative to further elucidate the potential survival benefit of lymphopenia-mitigating strategies. [ABSTRACT FROM AUTHOR]

In this study functional and oncological outcomes of salvage cryosurgery (SCS) for radiorecurrent prostate cancer (rrPCa) were evaluated in 169 patients. Recurrence free survival (BRFS), overall survival, metastasis free survival, androgen deprivation therapy (ADT) free survival, functional outcomes and complications were retrospectively analyzed. Median follow-up was 36 months (IQR = 18–66). BRFS after five and eight years was 52% (95%-CI = 43–62) and 45% (95%-CI = 35–57), respectively. PSA at initial diagnosis, initial treatment, interval between primary treatment and SCS, age at SCS, and post-SCS PSA-nadir were significant factors for BRFS. Five-year ADT-free survival was 70% (95%-CI = 62–79). Grade III or more complications occurred in 1.2% of patients. 19% and 92% of patients had new-onset urinary incontinence respectively erectile dysfunction, 6.5% persistent urinary fistula and 12% needed desobstruction. SCS has acceptable oncological outcomes, but can be accompanied by serious complications (urinary incontinence, stenosis and fistula). [ABSTRACT FROM AUTHOR]

To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. • Surgery for locally advanced vulvar cancer is often extensive with stoma formation or need for reconstructive surgery. • Definitive capecitabine-based chemoradiation is feasible with acceptable acute and late toxicity. • Local clinical complete response of 62% after 12 weeks and persistent local control of 42% after 2 years • Need for subsequent stoma formation in only 17% of patients. • Definitive chemoradiation can serve as alternative for extensive surgery in locally advanced vulvar cancer. [ABSTRACT FROM AUTHOR]

• More grade 4 lymphopenia in extended-CROSS compared with CROSS CRT. • Grade 4 lymphopenia was associated with a reduced overall survival. • The pretreatment prediction model demonstrated good external performance. • The model identifies patients at high-risk for grade 4 lymphopenia. • The model could identify patients eligible for lymphopenia-mitigating strategies. The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia. Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy ("extended-CROSS") and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir < 0.2 µL). The secondary outcome measures were the prediction model's external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan–Meier analysis. A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (p < 0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70–0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (p = 0.045). The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia–mitigating strategies. [ABSTRACT FROM AUTHOR]

For patients with early stage or medically inoperable lung cancer, stereotactic body radiotherapy (SBRT) is a general accepted and effective treatment option. The role of SBRT in ultra-central tumors remains controversial. The aim of this single-center retrospective analysis was to evaluate the safety and efficacy of protracted SBRT with 60 Gy in 12 fractions (with a biological effective dose (BED10) of 90–150 Gy) for patients with ultra-central lung tumors. Patients with ultra-central lung tumors treated in our institution with 60 Gy in 12 fractions from January 2012 until April 2020 were included. Ultra-central tumors were defined as planning target volume (PTV) abutting or overlapping the main bronchi and/or trachea and/or esophagus. Data regarding patient-, tumor-, and treatment-related characteristics were evaluated. A total of 72 patients met the criteria for ultra-central tumor location. The PTV abutted the main bronchus, trachea or esophagus in 79%, 22% and 28% of cases, respectively. At a median follow-up of 19 months, 1- and 2-year local control rates were 98% and 85%, respectively. Overall survival rates at 1 and 2 years were 77% and 52%, respectively. Grade 3 or higher toxicity was observed in 21%, of which 10 patients (14% of total) died of bronchopulmonary hemorrhage. A significant difference between patients with or without grade ≥3 toxicity was found for the mean dose (Dmean) to the main bronchus (p = 0.003), where a Dmean BED3 of ≥91 Gy increased the risk of grade ≥3 toxicity significantly. A protracted SBRT regimen of 60 Gy in 12 fractions for ultra-central lung tumors leads to high local control rates with toxicity rates similar to previous series, but with substantial risk of fatal bronchopulmonary hemorrhage. Therefore, possible risk factors of bronchopulmonary hemorrhage such as dose to the main bronchus should be taken into account. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic body radiation therapy (SBRT) has become a widely adopted treatment for patients with oligometastatic disease, despite limited evidence of superiority. We compared pain response and quality of life (QoL) in patients with oligometastatic disease treated with conventionally fractionated 3-dimensional radiation therapy (3DCRT) or SBRT to bone metastases.Methods and Materials: We included patients with oligometastatic disease (≤5 lesions within ≤3 organs) treated within the prospective PRESENT cohort. Main outcomes were pain response, clinical local control, and QoL 2, 4, and 8 weeks and 3, 6, and 12 months after treatment. Pain response was assessed only in patients who reported pain at baseline and was defined according to international consensus criteria.Results: Of 131 patients with oligometastatic disease, 66 patients were treated with 3DCRT and 65 patients with SBRT. A pain response was achieved in 81% (3DCRT) versus 84% (SBRT) with a median duration of 23 weeks (range, 1-58) and 24 weeks (range, 0-50), respectively. Reirradiation was needed in 33% versus 5% of the patients, respectively. None of the QoL subscales were significantly different between both groups.Conclusions: In patients with oligometastatic disease, SBRT to bone metastases did not improve pain response or QoL compared with 3DCRT. Reirradiation was less often needed in the SBRT group. [ABSTRACT FROM AUTHOR]