Disease Control With Delayed Salvage Radiotherapy for Macroscopic Local Recurrence Following Radical Prostatectomy

Purpose: To retrospectively assess clinical outcomes and toxicity profile of prostate cancer patients treated with delayed dose-escalated image-guided salvage radiotherapy (SRT) for macroscopic local recurrence after radical prostatectomy (RP).Material and Methods: We report on a cohort of 69 consecutive patients with local recurrence after RP and no evidence of regional or distant metastasis who were referred for salvage radiotherapy between 2007 and 2016. SRT consisted of 64–66 Gy (2 Gy/fraction) to the prostatic bed followed by dose escalation to 72–74 Gy (2Gy/fraction) to the macroscopic disease. All patients received concurrent short-term androgen deprivation therapy (ADT). Biochemical recurrence-free survival (bRFS) and clinical progression-free-survival (cPFS) were depicted using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predictors of survival outcomes. Baseline, acute, and late urinary and gastrointestinal (GI) toxicity rates were reported using CTCAE v4.03.Results: Median time from RP to SRT was 66 months (IQR: 32–124). Median pre-SRT prostate-specific antigen (PSA) was 2.7 ng/ml (IQR: 0.9–6.5). Median follow-up after SRT was 38 months (IQR: 24–66). The 3- and 5-year bRFS were 58 and 44%, respectively. The 3- and 5-year cPFS were 91 and 76%, respectively. Median time from SRT to clinical disease progression was 102 months (IQR 77.5–165). At baseline, 3 patients (4%) had grade 3 urinary symptoms. Six patients (9%) developed acute and six patients (9%) developed late grade 3 urinary toxicity. Five patients (7%) had acute grade 2 GI toxicity. No acute grade 3 GI toxicity was reported. Late grade 3 GI toxicity was reported in one patient (1.5%).Conclusions: Delayed dose-escalated SRT combined with short-course ADT for macroscopic LR after RP was associated with 44% bRFS and 76% cPFS at 5 years. Albeit improved patient stratification is warranted, these data suggest that delayed SRT provides inferior tumor control compared to early intervention

an analysis of the ClinicalTrials.gov database

Background To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. Methods The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database. Results In total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p < 0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %). Conclusion Most clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future

Portfolio of prospective clinical trials including brachytherapy: an analysis of the ClinicalTrials.gov database

Background: To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. Methods: The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database. Results: In total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p<0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %). Conclusion: Most clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future

A semi-coherent generalization of the 5-vector method to search for continuous gravitational waves

The emission of continuous gravitational waves (CWs), with duration much longer than the typical data taking runs, is expected from several sources, notably spinning neutron stars, asymmetric with respect to their rotation axis and more exotic sources, like ultra-light scalar boson clouds formed around Kerr black holes and sub-solar mass primordial binary black holes. Unless the signal time evolution is well predicted and its relevant parameters accurately known, the search for CWs is typically based on semi-coherent methods, where the full data set is divided in shorter chunks of given duration, which are properly processed, and then incoherently combined. In this paper we present a semi-coherent method, in which the so-called \textit{5-vector} statistics is computed for the various data segments and then summed after the removal of the Earth Doppler modulation and signal intrinsic spin-down. The method can work with segment duration of several days, thanks to a double stage procedure in which an initial rough correction of the Doppler and spin-down is followed by a refined step in which the residual variations are removed. This method can be efficiently applied for directed searches, where the source position is known to a good level of accuracy, and in the candidate follow-up stage of wide-parameter space searches.Comment: 16 pages, 12 figure

Validación del índice compuesto DAPSA (Disease Activity for Psoriatic Arthritis) en una cohorte de pacientes con artritis psoriásica en Argentina y determinación de sus valores de corte

Objetivos: Validar el índice DAPSA en pacientes con Artritis Psoriásica (APs) en Argentina, comparar su rendimiento con índices compuestos y con la ultrasonografía (US) y establecer valores de corte

Validation of the Decipher Genomic Classifier in Patients receiving Salvage Radiotherapy without Hormone Therapy after Radical Prostatectomy - An Ancillary Study of the SAKK 09/10 Randomized Clinical Trial.

BACKGROUND The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase 3 trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS A clinical grade whole-transcriptome assay was performed on RP samples obtained from patients enrolled in SAKK 09/10, a phase 3 trial of 350 men with biochemical recurrence post-radical prostatectomy randomized to 64Gy vs. 70Gy without concurrent hormonal therapy or pelvic nodal radiotherapy (RT). A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, post-radical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS The analytic cohort of 226 patients was representative of the overall trial, with median follow-up of 6.3 years (IQR 6.1-7.2). GC (high vs. low-intermediate) was independently associated with biochemical progression (subdistribution hazard ratio [sHR] 2.26 [95% CI 1.42-3.60], p<0.001), clinical progression (HR 2.29 [95% CI 1.32-3.98], p=0.003), and use of hormone therapy (sHR 2.99 [95% CI 1.55-5.76], p=0.001). GC high patients had 5-year freedom from biochemical progression of 45% vs. 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower vs. higher GC scores. CONCLUSIONS This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. This data confirms the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting

Binding between Crossveinless-2 and Chordin Von Willebrand Factor Type C Domains Promotes BMP Signaling by Blocking Chordin Activity

BACKGROUND: Crossveinless-2 (CV2) is an extracellular BMP modulator protein of the Chordin family, which can either enhance or inhibit BMP activity. CV2 binds to BMP2 via subdomain 1 of the first of its five N-terminal von Willebrand factor type C domains (VWC1). Previous studies showed that this BMP binding is required for the anti-, but not for the pro-BMP effect of CV2. More recently, it was shown that CV2 can also bind to the BMP inhibitor Chordin. However, it remained unclear which domains mediate this binding, and whether it accounts for an anti- or pro-BMP effect. PRINCIPAL FINDINGS: Here we report that a composite interface of CV2 consisting of subdomain 2 of VWC1 and of VWC2-4, which are dispensable for BMP binding, binds to the VWC2 domain of Chordin. Functional data obtained in zebrafish embryos indicate that this binding of Chordin is required for CV2's pro-BMP effect, which actually is an anti-Chordin effect and, at least to a large extent, independent of Tolloid-mediated Chordin degradation. We further demonstrate that CV2 mutant versions that per se are incapable of BMP binding can attenuate the Chordin/BMP interaction. CONCLUSIONS: We have physically dissected the anti- and pro-BMP effects of CV2. Its anti-BMP effect is obtained by binding to BMP via subdomain1 of the VWC1 domain, a binding that occurs in competition with Chordin. In contrast, its pro-BMP effect is achieved by direct binding to Chordin via subdomain 2 of VWC1 and VWC2-4. This binding seems to induce conformational changes within the Chordin protein that weaken Chordin's affinity to BMP. We propose that in ternary Chordin-CV2-BMP complexes, both BMP and Chordin are directly associated with CV2, whereas Chordin is pushed away from BMP, ensuring that BMPs can be more easily delivered to their receptors