Evaluation of intensity modulated radiation therapy dose painting for localized prostate cancer using 68 Ga-HBED-CC PSMA-PET/CT: A planning study based on histopathology reference

AbstractPurposeTo demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of IMRT dose painting using 68Ga-HBED-CC PSMA PET/CT for target delineation in prostate cancer (PCa).Methods and materials10 patients had PSMA PET/CT scans prior to prostatectomy. GTV-PET was generated on the basis of an intraprostatic SUVmax of 30%. Two IMRT plans were generated for each patient: Plan77 which consisted of whole-prostate IMRT to 77Gy, and Plan95 which consisted of whole-prostate IMRT to 77Gy and a simultaneous integrated boost to the GTV-PET up to 95Gy (35 fractions). The feasibility of these plans was judged by their ability to adhere to the FLAME trial protocol. TCP-histo/-PET were calculated on co-registered histology (GTV-histo) and GTV-PET, respectively. NTCPs for rectum and bladder were calculated.ResultsAll plans reached prescription doses whilst adhering to dose constraints. In Plan77 and Plan95 mean doses in GTV-histo were 75.8±0.3Gy and 96.9±1Gy, respectively. Average TCP-histo values for Plan77 and Plan95 were 70% (range: 15–97%), and 96% (range: 78–100%, p77 and Plan95 were 55% (range: 27–82%), and 100% (range: 99–100%, p95 (p=0.25). There were no significant differences in rectal (p=0.563) and bladder (p=0.3) NTCPs.ConclusionsIMRT dose painting using PSMA PET/CT was technically feasible and resulted in significantly higher TCPs without higher NTCPs

Results from extended lymphadenectomies with [111In]PSMA-617 for intraoperative detection of PSMA-PET/CT-positive nodal metastatic prostate cancer

CITATION: Jilg, C. A., et al. 2020. Results from extended lymphadenectomies with [111In]PSMA-617 for intraoperative detection of PSMA-PET/CT-positive nodal metastatic prostate cancer. EJNMMI Research, 10:17, doi:10.1186/s13550-020-0598-2.The original publication is available at https://ejnmmires.springeropen.comPurpose: Identification of suspicious PSMA-PET/CT-positive lymph node (LN) metastases (LNM) from prostate cancer (PCa) during lymphadenectomy (LA) is challenging. We evaluated an 111In-labelled PSMA ligand (DKFZ-617, referred to as [111In]PSMA-617) as a γ-emitting tracer for intraoperative γ-probe application for resected tissue samples in PCa patients. Forty-eight hours prior to LA, [111In]PSMA-617 was administered intravenously in 23 patients with suspected LNM on PSMA-PET/CT (n = 21 with biochemical relapse, n = 2 at primary therapy). Resected tissue samples (LN, LNM and fibrofatty tissue) were measured ex situ by a γ-probe expressed as counts per second (CPSnorm). [111In]PSMA-617 tissue sample uptake was measured by a germanium detector for verification and calculated as %IAlbm (percent injected activity per kilogram lean body mass at time of surgery). Based on a clinical requirement for a specificity > 95%, thresholds for both ex situ measurements were chosen accordingly. Correlation of the results from PET/CT, γ-probe and germanium detector with histopathology was done. Results: Eight hundred sixty-four LNs (197 LNM) were removed from 275 subregions in 23 patients, on average 8.6 ± 14.9 LNM per patient. One hundred four of 275 tissue samples showed cancer. Median γ-probe and germanium detector results were significantly different between tumour-affected (33.5 CPSnorm, 0.71 %IAlbm) and tumour-free subregions (3.0 CPSnorm, 0.03 %IAlbm) (each p value 23) and germanium detector cut-off (%IAlbm > 0.27), 64 and 74 true-positive and 158 true-negative samples for both measurements were identified. Thirty-nine and 30 false-negative and 6 and 5 false-positive tissue samples were identified by γ-probe and germanium detector measurements. Conclusion: [111In]PSMA-617 application for LA is feasible in terms of an intraoperative real-time measurement with a γ-probe for detection of tumour-affected tissue samples. γ-probe results can be confirmed by precise germanium detector measurements and were significantly different between tumour-affected and tumour-free samples.https://ejnmmires.springeropen.com/articles/10.1186/s13550-020-0598-2Publisher's versio

Proteomic Characterization of Prostate Cancer to Distinguish Nonmetastasizing and Metastasizing Primary Tumors and Lymph Node Metastases

Patients with metastatic prostate cancer (PCa) have a poorer prognosis than patients with organ-confined tumors. We strove to uncover the proteome signature of primary PCa and associated lymph node metastases (LNMs) in order to identify proteins that may indicate or potentially promote metastases formation. We performed a proteomic comparative profiling of PCa tissue from radical prostatectomy (RPE) of patients without nodal metastases or relapse at the time of surgical resection (n = 5) to PCa tissue from RPE of patients who suffered from nodal relapse (n = 5). For the latter group, we also included patient-matched tissue of the nodal metastases. All samples were formalin fixed and paraffin embedded. We identified and quantified more than 1200 proteins by liquid chromatography tandem mass spectrometry with subsequent label-free quantification. An increase of ribosomal or proteasomal proteins in LNM (compared to corresponding PCa) became apparent, while extracellular matrix components rather decreased. Immunohistochemistry (IHC) corroborated accumulation of poly-(ADP-ribose)-polymerase 1 and N-myc-downstream-regulated-gene 3, alpha/beta hydrolase domain-containing protein 11, and protein phosphatase slingshot homolog 3 in LNM. These findings strengthen the present interest in examining PARP inhibitors for the treatment of aggressive PCa. IHC also corroborated increased abundance of retinol dehydrogenase 11 in metastasized primary PCa compared to organ-confined PCa. Generally, metastasizing primary tumors were characterized by an enrichment of proteins involved in cellular lipid metabolic processes with concomitant decrease of cell adhesion proteins. This study highlights the usefulness of a combined proteomic-IHC approach to explore novel aspects in tumor biology. Our initial results open novel opportunities for follow-up studies

PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells

The major threat in prostate cancer is the occurrence of metastases in androgen-independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo. PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents metastases in mice, showing that the PRK1-pathway is a promising target to hamper prostate cancer metastases in vivo

Performance of 111In-labelled PSMA ligand in patients with nodal metastatic prostate cancer: correlation between tracer uptake and histopathology from lymphadenectomy

PURPOSE: Intraoperative identification of lymph node (LN) metastases (LNM) detected on preoperative PSMA PET/CT may be facilitated by PSMA radioguided surgery with the use of a gamma probe. We evaluated the uptake of 111In-labelled PSMA ligand DKFZ-617 (referred to as 111In-PSMA-617) in unaffected LN and LNM at the level of single LN. METHODS: Six patients with prostate cancer (PCa) with suspicion of LNM on preoperative PSMA PET/CT underwent 111In-PSMA-617-guided lymphadenectomy (LA; four salvage LA and two primary LA). 111In-PSMA-617 (109 ± 5 MBq). was injected Intravenously 48 h prior to surgery Template LAs were performed in small subregions: common, external, obturator and internal iliac vessels, and presacral and retroperitoneal subregions (n = 4). Samples from each subregion were isolated aiming at the level of single LN. Uptake was measured ex situ using a germanium detector. Receiver operating characteristic (ROC) analysis was performed based on 111In-PSMA-617 uptake expressed as standardized uptake values normalized to lean body mass (SUL). RESULTS: Overall 310 LN (mean 52 ± 19.7) were removed from 74 subregions (mean 12 ± 3.7). Of the 310 LN, 35 turned out to be LNM on histopathology. Separation of the samples from all subregions resulted in 318 single specimens: 182 PCa-negative LN samples with 275 LN, 35 single LNM samples, 3 non-nodal PCa tissue samples and 98 fibrofatty tissue samples. The median SULs of nonaffected LN (0.16) and affected LN (13.2) were significantly different (p < 0.0001). Based on 38 tumour-containing and 182 tumour-free specimens, ROC analysis revealed an area under the curve of 0.976 (95% CI 0.95-1.00, p < 0.0001). Using a SUL cut-off value of 1.136, sensitivity, specificity, positive predictive value, negative predictive value and accuracy in discriminating affected from nonaffected LN were 92.1% (35/38), 98.9% (180/182), 94.6% (35/37), 98.4% (180/183) and 97.7% (215/220), respectively. CONCLUSION: Ex situ analysis at the level of single LN showed that 111In-PSMA-617 had excellent ability to discriminate between affected and nonaffected LN in our patients with PCa. This tracer characteristic is a prerequisite for in vivo real-time measurements during surgery

MOESM2 of Proteomic distinction of renal oncocytomas and chromophobe renal cell carcinomas

Additional file 2: Table S2. Overview of the > 2400 proteins were identified (false-discovery rate < 1%) and quantified in at least four RO and four chRCC samples

Diagnostic Accuracy of Robot-Guided, Software Based Transperineal MRI/TRUS Fusion Biopsy of the Prostate in a High Risk Population of Previously Biopsy Negative Men

Objective. In this study, we compared prostate cancer detection rates between MRI-TRUS fusion targeted and systematic biopsies using a robot-guided, software based transperineal approach. Methods and Patients. 52 patients received a MRIT/TRUS fusion followed by a systematic volume adapted biopsy using the same robot-guided transperineal approach. The primary outcome was the detection rate of clinically significant disease (Gleason grade ≥ 4). Secondary outcomes were detection rate of all cancers, sampling efficiency and utility, and serious adverse event rate. Patients received no antibiotic prophylaxis. Results. From 52 patients, 519 targeted biopsies from 135 lesions and 1561 random biopsies were generated (total = 2080). Overall detection rate of clinically significant PCa was 44.2% (23/52) and 50.0% (26/52) for target and random biopsy, respectively. Sampling efficiency as the median number of cores needed to detect clinically significant prostate cancer was 9 for target (IQR: 6-14.0) and 32 (IQR: 24-32) for random biopsy. The utility as the number of additionally detected clinically significant PCa cases by either strategy was 0% (0/52) for target and 3.9% (2/52) for random biopsy. Conclusions. MRI/TRUS fusion based target biopsy did not show an advantage in the overall detection rate of clinically significant prostate cancer

Diagnostic Accuracy of Robot-Guided, Software Based Transperineal MRI/TRUS Fusion Biopsy of the Prostate in a High Risk Population of Previously Biopsy Negative Men

Objective. In this study, we compared prostate cancer detection rates between MRI-TRUS fusion targeted and systematic biopsies using a robot-guided, software based transperineal approach. Methods and Patients. 52 patients received a MRIT/TRUS fusion followed by a systematic volume adapted biopsy using the same robot-guided transperineal approach. The primary outcome was the detection rate of clinically significant disease (Gleason grade ≥ 4). Secondary outcomes were detection rate of all cancers, sampling efficiency and utility, and serious adverse event rate. Patients received no antibiotic prophylaxis. Results. From 52 patients, 519 targeted biopsies from 135 lesions and 1561 random biopsies were generated (total n=2080). Overall detection rate of clinically significant PCa was 44.2% (23/52) and 50.0% (26/52) for target and random biopsy, respectively. Sampling efficiency as the median number of cores needed to detect clinically significant prostate cancer was 9 for target (IQR: 6–14.0) and 32 (IQR: 24–32) for random biopsy. The utility as the number of additionally detected clinically significant PCa cases by either strategy was 0% (0/52) for target and 3.9% (2/52) for random biopsy. Conclusions. MRI/TRUS fusion based target biopsy did not show an advantage in the overall detection rate of clinically significant prostate cancer

Additional file 1: of Diabetes and beta-adrenergic blockage are risk factors for metastatic prostate cancer

Medication characteristics (n=157). (DOCX 20 kb