Background: Extended pelvic nodal dissection (ePLND) represents the gold standard for nodal staging in prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS)... Show moreBackground: Extended pelvic nodal dissection (ePLND) represents the gold standard for nodal staging in prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS) could identify lymph node invasion (LNI) during robotassisted radical prostatectomy (RARP).Objective: To report the planned interim analyses of a phase 2 prospective study (NCT04832958) aimed at describing PSMA-RGS during RARP.Design, setting, and participants: A phase 2 trial aimed at enrolling 100 patients with intermediate- or high-risk cN0cM0 PCa at conventional imaging with a risk of LNI of >5% was conducted. Overall, 18 patients were enrolled between June 2021 and March 2022. Among them, 12 patients underwent PSMA-RGS and represented the study cohort.Surgical procedure: All patients received Ga-68-PSMA positron emission tomography (PET)/magnetic resonance imaging; Tc-99m-PSMA-I&S was synthesised and administered intravenously the day before surgery, followed by single-photon emission computed tomography/computed tomography. A Drop-In gamma probe was used for in vivo measurements. All positive lesions (count rate >= 2 compared with background) were excised and ePLND was performed.Measurements: Side effects, perioperative outcomes, and performance characteristics of robot-assisted PSMA-RGS for LNI were measured.Results and limitations: Overall, four (33%), six (50%), and two (17%) patients had intermediate-risk, high-risk, and locally advanced PCa. Overall, two (17%) patients had pathologic nodal uptake at PSMA PET. The median operative time, blood loss, and length of stay were 230 min, 100 ml, and 5 d, respectively. No adverse events and intraoperative complications were recorded. One patient experienced a 30-d complication (ClavienDindo 2; 8.3%). Overall, three (25%) patients had LNI at ePLND. At per-region analyses on 96 nodal areas, sensitivity, specificity, positive predictive value, and negative predictive value of PSMA-RGS were 63%, 99%, 83%, and 96%, respectively. On a per-patient level, sensitivity, specificity, positive predictive value, and negative predictive values of PSMA-RGS were 67%, 100%, 100%, and 90%, respectively.Conclusions: Robot-assisted PSMA-RGS in primary staging is a safe and feasible procedure characterised by acceptable specificity but suboptimal sensitivity, missing micrometastatic nodal disease.Patient summary: Prostate-specific membrane antigen radioguided robot-assisted surgery is a safe and feasible procedure for the intraoperative identification of nodal metastases in cN0cM0 prostate cancer patients undergoing robot-assisted radical prostatectomy with extended pelvic lymph node dissection. However, this approach might still miss micrometastatic nodal dissemination. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. Show less
Background: It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open... Show moreBackground: It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open surgery. Rapid extension of robot-assisted, minimally invasive surgery has increased the need to make PSMA-radioguided surgery (RGS) robot-compliant.Objective: To evaluate whether the miniaturized DROP-IN gamma probe facilitates translation of PSMA-RGS to robotic surgery in men with recurrent PCa.Design, setting, and participants: This prospective feasibility study included 20 patients with up to three pelvic PCa recurrences (nodal or local) on staging PSMA positron emission tomography (PET) after previous curative-intent therapy.Surgical procedure: Robot-assisted PSMA-RGS using the DROP-IN gamma probe was carried out 19-23 h after intravenous injection of (99m)technetium PSMA-Investigation & Surgery (Tc-99m-PSMA-I&S).Measurements: The primary endpoint was the feasibility of robot-assisted PSMA-RGS. Secondary endpoints were a comparison of the radioactive status (positive or negative) of resected specimens and final histopathology results, prostate-specific antigen (PSA) response following PSMA-RGS, and complications according to the Clavien-Dindo classification.Results and limitations: Using the DROP-IN probe, 19/21 (90%) PSMA-avid lesions could be resected robotically. On a per-lesion basis, the sensitivity and specificity of robot-assisted PSMA-RGS was 86% and 100%, respectively. A prostate-specific antigen (PSA) reduction of >50% and a complete biochemical response (PSA <0.2 ng/ml) were seen in 12/18 (67%) and 4/18 (22%) patients, respectively. During follow-up of up to 15 mo,* Corresponding author. Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands. Tel. +31 205126988. E-mail address: h.d.barros@nki.nl (H.A. de Barros) Show less
Background: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence... Show moreBackground: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence guidance is growing. While proven very effective for radiotracers, microdosing approaches the detection limit for fluorescence imaging. Thus, utility will be highly dependent on the tracer performance, the sensitivity of the fluorescence camera used, and the degree of background signal. Using a porcine model the ability to perform robot-assisted radical prostatectomy under fluorescence guidance using the bimodal or rather hybrid PSMA tracer (Tc-99m-EuK-(SO3)Cy5-mas(3)) was studied, while employing the tracer in a microdosing regime. This was followed by ex vivo evaluation in surgical specimens obtained from prostate cancer patients. Results: T-50% blood and T-50% urine were reached at 85 min and 390 min, in, respectively, blood and urine. Surgical fluorescence imaging allowed visualization of the prostate gland based on the basal PSMA-expression in porcine prostate. Together, in vivo visualization of the prostate and urinary excretion suggests at least an interval of > 7 h between tracer administration and surgery. Confocal microscopy of excised tissues confirmed tracer uptake in kidney and prostate, which was confirmed with PSMA IHC. No fluorescence was detected in other excised tissues. Tumor identification based on ex vivo fluorescence imaging of human prostate cancer specimens correlated with PSMA IHC. Conclusion: Intraoperative PSMA-mediated fluorescence imaging with a microdosing approach was shown to be feasible. Furthermore, EuK-(SO3)Cy5-mas(3) allowed tumor identification in human prostate samples, underlining the translational potential of this novel tracer. Trial registration Approval for use of biological material for research purposes was provided by the Translational Research Board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital (NKI-AvL) under reference IRBm19-273 (22/10/2019). Show less
Moschovas, M.C.; Chew, C.; Bhat, S.; Sandri, M.; Rogers, T.; Dell'Oglio, P.; ... ; Patel, V. 2022
Background: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors.... Show moreBackground: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors. The test is performed on prostate tissue collected during biopsy. There is a lack of data on the association between the GPS and tumor pathology after radical prostatectomy (RP). Objective: To investigate the association between GPS and final pathology, including extra prostatic extension (EPE), positive surgical margin (PSM), and seminal vesicle invasion (SVI). Design, setting, and participants: Data for the 749 patients who underwent Oncotype DX assay and RP at a referral prostate cancer center between 2015 and 2019 were retrospectively assessed to evaluate the association between GPS and unfavorable pathology parameters. Intervention: After a GPS genetic test, patients underwent robotic RP performed by the same surgeon. Outcome measurement and statistical analysis: Multivariable logistic regression analyses were performed to assess the association between GPS and EPE, PSM, and SVI. The models were adjusted for age, clinical stage, prostate-specific antigen (PSA) level, Gleason score, and time between the genomic assay and surgery. The median time between Oncotype DX assay and surgery was 176 d (interquartile range [IQR] 141-226). The median age was 63 yr (IQR 58-68), median GPS was 29 (IQR 21-39), and median PSA was 5.7 ng/ml (IQR 4.6-7.7). In multivariable analyses assessing the odds ratio (OR) per 20-point change in GPS, GPS was an independent predictor of EPE (OR 1.8, 95% confidence interval [CI] 1.4-2.3) and SVI (OR 2.1, 95% CI 1.3-3.4). In addition, when patients were grouped by GPS quartile, the percentage of cases with EPE and SVI increased with the GPS quartile. Conclusions: We provide evidence that the Oncotype DX GPS is significantly associated with adverse pathology after RP. Specifically, the risk of EPE and SVI increases with the GPS. Therefore, use of the Oncotype DX GPS may help clinicians to improve preoperative patient counseling and develop surgical strategies for patients with a higher chance of EPE or unfavorable pathological features. Patient summary: We studied whether the score for a prostate genetic test was associated with prostate cancer pathology findings for patients who had their prostate removed. We found that the risk of prostate cancer spread outside the gland and to the seminal vesicle increases with higher test scores. These findings may help surgeons in counseling patients on surgical options for prostate cancer. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Groen, V.H.; Schie, M. van; Zuithoff, N.P.A.; Monninkhof, E.M.; Kunze-Busch, M.; Boer, J.C.J. de; ... ; Kerkmeijer, L.G.W. 2022
Purpose or objectives: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical... Show morePurpose or objectives: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade >= 2 in the entire cohort.Material and methods: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade >= 2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade >= 1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated.Results: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm(3) and urethra D0.1 cm(3), with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed.Conclusion: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer. (C) 2021 The Author(s). Published by Elsevier B.V. Show less
Wit, E.M.K.; Beurden, F. van; Kleinjan, G.H.; Grivas, N.; Korne, C.M. de; Buckle, T.; ... ; Poel, H.G. van der 2021
Introduction Previous studies indicated that location and amount of detected sentinel lymph nodes (SLNs) in prostate cancer (PCa) are influenced where SLN-tracer is deposited within the prostate.... Show moreIntroduction Previous studies indicated that location and amount of detected sentinel lymph nodes (SLNs) in prostate cancer (PCa) are influenced where SLN-tracer is deposited within the prostate. To validate whether intratumoral (IT) tracer injection helps to increase identification of tumor-positive lymph nodes (LNs) better than intraprostatic (IP) tracer injection, a prospective randomized phase II trial was performed.Methods PCa patients with a > 5% risk of lymphatic involvement were randomized between ultrasound-guided transrectal injection of indocyanine green-[Tc-99m]Tc-nanocolloid in 2 depots of 1 mL in the tumor (n = 55, IT-group) or in 4 depots of 0.5 mL in the peripheral zone of the prostate (n = 58, IP-group). Preoperative lymphoscintigraphy and SPECT/CT were used to define the location of the SLNs. SLNs were dissected using combination of radio- and fluorescence-guidance, followed by extended pelvic LN dissection and robot-assisted radical prostatectomy. Outcome measurements were number of tumor-bearing SNs, tumor-bearing LNs, removed nodes, number of patients with nodal metastases, and metastasis-free survival (MFS) of 4-7-year follow-up data.Results IT-injection did not result in significant difference of removed SLNs (5.0 vs 6.0, p = 0.317) and histologically positive SLNs (28 vs 22, p = 0.571). However, in IT-group, the SLN-positive nodes were 73.7% of total positive nodes compared to 37.3% in IP-group (p = 0.015). Moreover, significantly more node-positive patients were found in IT-group (42% vs 24%, p = 0.045), which did not result in worse MFS. In two patients (3.6%) from whom the IT-tracer injection only partly covered intraprostatic tumor spread, nodal metastases in ePLND without tumor-positive SNs were yielded.Conclusions The percentage-positive SLNs found after IT-injection were significantly higher compared to IP-injection. Significantly more node-positive patients were found using IT-injection, which did not affect MFS. IT-injection failed to detect nodal metastases from non-index satellite lesions. Therefore, we suggest to combine IT- and IP-tracer injections in men with visible tumor on imaging. Show less
The relation between prostate-specific antigen (PSA) and other relevant prebiopsy information is often combined in a risk calculator (RC). If the setting for RC use differs from that in which it... Show moreThe relation between prostate-specific antigen (PSA) and other relevant prebiopsy information is often combined in a risk calculator (RC). If the setting for RC use differs from that in which it was developed, there is a risk of making clinical decisions based on incorrect estimates of the absolute risk. The ERSPC-MRI RC predicts clinically significant prostate cancer (csPC; Gleason >= 3 + 4) on targeted and systematic biopsy using information on PSA, digital rectal examination, prostate volume, age, previous negative biopsy, and Prostate Imaging-Recording and Data System score. This calculator was developed on a clinical cohort of 961 men (2012-2017) with a csPC prevalence of 36%. Discrimination was good (area under the receiver operating characteristic curve 0.84). With the increasing use of multiparametric magnetic resonance imaging, we foresee that this RC will also be used for men with a lower a priori likelihood of PC. We investigated the effect of such a scenario on individual risk predictions. A small update of the intercept for the calculator can restore the accuracy to support decision-making with locally valid risk estimates.Patient summary: Decisions on who to refer for a prostate biopsy with its risk of sepsis and overdiagnosis require more than a prostate-specific antigen test. A prediction tool may take other relevant prebiopsy information into account, but may need to be updated to contemporary center-specific settings to provide accurate estimates of the risk of having prostate cancer. (C) 2019 Published by Elsevier B.V. on behalf of European Association of Urology. Show less
Early detection of prostate cancer may lead to the overdiagnosis and overtreatment of patients as well as missing significant cancers. The current diagnostic approach uses elevated serum... Show moreEarly detection of prostate cancer may lead to the overdiagnosis and overtreatment of patients as well as missing significant cancers. The current diagnostic approach uses elevated serum concentrations of prostate-specific antigen (PSA) as an indicator of risk. However, this test has been widely criticized as it shows poor specificity and sensitivity. In order to improve early detection and diagnosis, several studies have investigated whether different PSA proteoforms are correlated to prostate cancer. Until now, studies and methodologies for the comprehensive characterization of PSA proteoforms from biofluids are scarce. For this purpose, we developed an intact protein assay to analyze PSA by capillary electrophoresis-electrospray ionization-mass spectrometry after affinity purification from patients? urine. Here, we determined six proteolytic cleavage variants. In regard to glycosylation, tri-, di-, mono- and non-sialylated complex-type N-glycans were found on non-cleaved PSA, as well as the non-glycosylated variant. The performance of the intact protein assay was assessed using a pooled sample, obtaining an inter-day variability of 15%. Furthermore, urinary patient samples were analyzed by intact protein analysis and a bottom-up approach (glycopeptide analysis). This combined approach revealed complimentary information on both levels, demonstrating the benefit of using two orthogonal techniques to provide a thorough profile of urinary PSA.Significance: The detection of clinically relevant prostate cancer requires a more specific and sensitive biomarker and, in this case, several PSA proteoforms may be able to aid or improve the current PSA test. However, a comprehensive analysis of the intact PSA proteoform profile is still lacking. This study investigated the PSA proteoforms present in urine and, in particular, determined the relative contribution of cleaved PSA and noncleaved PSA forms to the total glycosylation profile. Importantly, intact protein analysis did not require further sample treatment before being measured by CE-ESI-MS. Furthermore, its glycosylation was also assessed in a bottom-up approach to provide complementary information. Overall, these results represent an important basis for future characterization and biomarker studies. Show less
Background: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be... Show moreBackground: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately.Objective: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed.Design, setting, and participants: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020). All patients presented with biochemical recurrence (BCR) after RP with a singular local recurrence at PSMA PET imaging. Thirty-three (82.5%) patients received previous salvage radiation therapy.Surgical procedure: Open salvage surgery with PSMA radioguidance.Measurements: Prostate-specific antigen (PSA) nadir and percentage of patients with complete biochemical response (cBR) without further treatment (PSA < 0.2 ng/ml) after 6-16 wk were assessed. BCR-free survival and TFS were calculated using Kaplan-Meier estimates. Clavien-Dindo complications were evaluated.Results and limitations: Prior to salvage surgery, median PSA was 0.9 ng/ml (interquartile range [IQR]: 0.5-1.7 ng/ml). Postoperatively, median PSA nadir was 0.1 ng/ml (IQR: 0-0.4 ng/ml). In 31 (77.5%) patients, cBR was observed. During the median follow-up of 24.4 months, 22 (55.0%) patients experienced BCR and 12 (30.0%) received further therapy. At 1 yr of follow-up, BCR-free survival rate was 62.2% and TFS rate was 88.3%. Three (7.5%) Clavien-Dindo grade III complications were observed. The main limitations are the retrospective design, short follow-up, and lack of a control group.Conclusions: Salvage surgery of local recurrence within the seminal vesicle bed is feasible. It may present an opportunity in selected, locally recurrent patients to prolong BCR-free survival and increase TFS. Further studies are needed to confirm our findings.Patient summary: We looked at the outcomes from prostate cancer patients with locally recurrent disease after radical prostatectomy and radiotherapy. We found that surgery in well-selected patients may be an opportunity to prolong treatment-free survival. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Albers, L.F.; Tillier, C.N.; Muilekom, E. van; Werkhoven, E. van; Elzevier, H.W.; Rhijn, B.W.G. van; ... ; Hendricksen, K. 2021
Background: Preservation of erectile function is an important postoperative quality of life concern for patients after robot-assisted radical prostatectomy (RARP) for prostate cancer. Although... Show moreBackground: Preservation of erectile function is an important postoperative quality of life concern for patients after robot-assisted radical prostatectomy (RARP) for prostate cancer. Although erectile function may recover, many men continue to suffer from erectile dysfunction (ED).Aim: This study aims to determine whether satisfaction with sexual life improves in patients with ED after RARP and which factors are associated with satisfaction during follow-up.Methods: A review was carried out of a prospectively maintained database of patients with prostate cancer who underwent a RARP between 2006 and 2019. The 'International Index of Erectile Function' questionnaire was used to describe ED (range 5-25), overall satisfaction with sexual life and sexual desire (range for both: 2-10). Patients with ED due to RARP were compared with those without ED after RARP. Mixed effect model was used to test differences in satisfaction over time. Mann-Whitney U tests and multiple logistic regression were used to assess factors associated with being satisfied at 24 and 36 months.Outcomes: The main outcomes of this study are the overall satisfaction with sexual life score over time and factors which influence sexual satisfaction.Results: Data of 2808 patients were reviewed. Patients whose erectile function was not known (n = 643) or who had ED at the baseline (n = 1281) were excluded. About 884 patients were included for analysis. They had an overall satisfaction score of 8.4. Patients with ED due to RARP had mean overall satisfaction scores of 4.8, 4.8, 4.9, and 4.6 at 6 mo, 12 mo, 24 mo, and 36 mo. These scores were significantly lower than those of patients without ED at every time point. In multiple regression analysis, higher overall satisfaction score at the baseline and higher sexual desire at 24 and 36 months' follow-up were associated with satisfaction with sexual life at 24 and 36 months? follow-up. No association was found for erectile function.Clinical implications: Interventions focusing on adjustment to the changes in sexual functioning might improve sexual satisfaction; especially for those men who continue to suffer from ED.Strengths & Limitations: Strengths of this study are the large number of patients, time of follow-up, and use of multiple validated questionnaires. Our results must be interpreted within the limits of retrospectively collected, observational data.Conclusion: Satisfaction with sexual life in men with ED due to RARP may take a long time to improve. One could counsel patients that sexual satisfaction is based on individual baseline sexual satisfaction and the return of sexual desire after RARP. Copyright (C) 2020, The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine. Show less
Background: The DROP-IN gamma probe was introduced to overcome the restricted manoeuvrability of traditional laparoscopic gamma probes. Through enhanced manoeuvrability and surgical autonomy, the... Show moreBackground: The DROP-IN gamma probe was introduced to overcome the restricted manoeuvrability of traditional laparoscopic gamma probes. Through enhanced manoeuvrability and surgical autonomy, the DROP-IN promotes the implementation of radioguided surgery in the robotic setting.Objective: To confirm the utility and safety profile of the DROP-IN gamma probe and to perform a comparison with the traditional laparoscopic gamma probe and fluorescence guidance.Design, setting, and participants: Twenty-five prostate cancer patients were scheduled for a robot-assisted sentinel lymph node (SN) procedure, extended pelvic lymph node dissection, and prostatectomy at a single European centre.Surgical procedure: After intraprostatic injection of indocyanine green (ICG)-Tc-99m-nanocolloid (n = 12) or Tc-99m-nanocolloid + ICG (n = 13), SN locations were defined using preoperative imaging. Surgical excision of SNs was performed under image guidance using the DROP-IN gamma probe, the traditional laparoscopic gamma probe, and fluorescence imaging.Measurements: Intraoperative SN detection was assessed for the different modalities and related to anatomical locations. Patient follow-up was included (a median of 18 mo).Results and limitations: Overall, 47 SNs were pursued in vivo by the DROP-IN gamma probe, of which 100% were identified. No adverse events related to its use were observed. In vivo fluorescence imaging identified 91% of these SNs. The laparoscopic gamma probe identified only 76% of these SNs, where the detection inaccuracies appeared to be related to specific anatomical regions.Conclusions: Owing to improved manoeuvrability, the DROP-IN probe yielded improved SN detection rates compared with the traditional gamma probe and fluorescence imaging. These findings underline that the DROP-IN technology provides a valuable tool for radioguided surgery in the robotic setting.Patient summary: Radioguided robot-assisted surgery with the novel DROP-IN gamma probe is feasible and safe. It enables more efficient intraoperative identification of sentinel lymph nodes than can be achieved with a traditional laparoscopic gamma probe. The use of the DROP-IN probe in combination with fluorescence imaging allows for a complementary optical confirmation of node localisations. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. Show less
Collamati, F.; Oosterom, M.N. van; Simoni, M. de; Faccini, R.; Fischetti, M.; Terracciano, C.M.; ... ; Morganti, S. 2020
Background Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve... Show moreBackground Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET tracers during robot-assisted tumor-receptor-targeted. In this study, we have engineered and validated the performance of a novel DROP-IN beta particle (DROP-IN beta) detector. Methods Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of similar to 70 MBq(68)Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-IN(beta)probe prototype, which merged a scintillating detector with a housing optimized for a 12-mm trocar and prograsp instruments. Results After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-IN(beta)probe prototype was tested in a robotic setting. In the ex vivo setting, the probe-positioned by the robot-was able to identify(68)Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located < 1 mm below the specimen surface.Ga-68-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-IN(beta)probe (S/B > 3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta-tracing. Conclusions This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-IN(beta)detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes. Show less
Grivas, N.; Bergh, R.C.N. van den; Brouwer, O.R.; Kleinjan, G.H.; Ramirez-Backhaus, M.; Wilthagen, E.A.; Poel, H.G. van der 2020
Purpose To systematically review the relevant literature that evaluates the LN topographical distribution and propose a uniform template. Methods A bibliographic search of PubMed/Medline, Embase... Show morePurpose To systematically review the relevant literature that evaluates the LN topographical distribution and propose a uniform template. Methods A bibliographic search of PubMed/Medline, Embase and SCOPUS was performed for studies reporting data of LN imaging and/or nodal resection. Results 101 and 26 articles met the inclusion criteria for PCa and BCa, respectively. In PCa, the most common locations of positive LNs for surgical and imaging studies were external iliac (both 38 studies), followed by obturator (38 and 37, respectively). Similarly, in BCa, the most common location of positive nodes for surgical and imaging studies were external iliac (19 and 4, respectively), followed by obturator (15 and 3 studies, respectively). In PCa, median percentages of positive external iliac nodes/patient were 12.2% and 11.6% for surgical and imaging studies, respectively while corresponding rates for BCa were 3.9% and 17.6%. There were high risks of bias across studies as well as high heterogeneity in the definition of the anatomic boundaries of lymphadenectomy templates. ConclusionsThis review highlights the lack of detailed information on exact LN templates and metastases location, which in turn hinders generation of high-quality evidence on optimal lymphadenectomy templates. Our proposed template is applicable for both imaging and surgical description and could facilitate the translation of anatomical location from imaging to surgical resection. Show less
Page, E.C.; Bancroft, E.K.; Brook, M.N.; Assel, M.; Battat, M.H. al; Thomas, S.; ... ; IMPACT Study Collaborators 2019
Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in... Show moreBackground: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.Design, setting, and participants: Men aged 40-69 yr with a germline pathogenic BRCA1/ 2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA> 3.0 ng/ml, men were offered prostate biopsy.Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p= 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.Patient summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening. (C) 2019 The Authors. Published by Elsevier B.V. Show less
Korne, C.M. de; Wit, E.M.; Jong, J. de; Olmos, R.A.V.; Buckle, T.; Leeuwen, F.W.B. van; Poel, H.G. van der 2019
PurposeSystems for magnetic resonance (MR-) guided radiotherapy enable daily MR imaging of cancer patients during treatment, which is of interest for treatment response monitoring and biomarker... Show morePurposeSystems for magnetic resonance (MR-) guided radiotherapy enable daily MR imaging of cancer patients during treatment, which is of interest for treatment response monitoring and biomarker discovery using quantitative MRI (qMRI). Here, the performance of a 1.5 T MR-linac regarding qMRI was assessed on phantoms. Additionally, we show the feasibility of qMRI in a prostate cancer patient on this system for the first time.Materials and methodsFour 1.5 T MR-linac systems from four institutes were included in this study. T1 and T2 relaxation times, and apparent diffusion coefficient (ADC) maps, as well as dynamic contrast enhanced (DCE) images were acquired. Bland–Altman statistics were used, and accuracy, repeatability, and reproducibility were determined.ResultsMedian accuracy for T1 ranged over the four systems from 2.7 to 14.3%, for T2 from 10.4 to 14.1%, and for ADC from 1.9 to 2.7%. For DCE images, the accuracy ranged from 12.8 to 35.8% for a gadolinium concentration of 0.5 mM and deteriorated for higher concentrations. Median short-term repeatability for T1 ranged from 0.6 to 5.1%, for T2 from 0.4 to 1.2%, and for ADC from 1.3 to 2.2%. DCE acquisitions showed a coefficient of variation of 0.1–0.6% in the signal intensity. Long-term repeatability was 1.8% for T1, 1.4% for T2, 1.7% for ADC, and 17.9% for DCE. Reproducibility was 11.2% for T1, 2.9% for T2, 2.2% for ADC, and 18.4% for DCE.ConclusionThese results indicate that qMRI on the Unity MR-linac is feasible, accurate, and repeatable which is promising for treatment response monitoring and treatment plan adaptation based on daily qMRI. Show less
Background: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable... Show moreBackground: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging.Objective: To describe the technique, feasibility, and short-term outcomes of (99m)Technetium (Tc-99m)-based PSMA-radioguided surgery (Tc-99m-PSMA-RGS) for removal of recurrent PC lesions.Design, setting, and participants: Thirty-one consecutive patients with evidence of recurrent PC on Ga-68-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid (Ga-68-PSMA-11) PET after radical prostatectomy undergoing Tc-99m-PSMA-RGS were retrospectively analyzed.Surgical procedure: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of Tc-99m-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7 h).Measurements: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated.Results and limitations: In total,132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5-96.7%). With Tc-99m-PSMA-RGS, all lesions visualized on preoperative Ga-68-PSMA-11 PET could be removed. Moreover, Tc-99m-PSMA-RGS detected additional metastases as small as 3 mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6-18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo.Conclusions: As a new technique for surgical guidance, Tc-99m-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated.Patient summary: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo). (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less