Assessing Response to [177Lu]PSMA Radioligand Therapy using modified PSMA PET Progression Criteria.

Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate specific membrane antigen (PSMA) plays a key role in staging of patients with prostate cancer (PCa). Moreover, it is not only used for the assessment of adequate PSMA expression of PCa cells before PSMA-targeting radioligand therapy (PSMA RLT) but also for re-staging during the course of therapy to evaluate response to treatment. Whereas no established criteria exist for systematic response evaluation so far, recently proposed PSMA PET Progression (PPP) criteria might fill this gap. The aim of this study was to assess the feasibility of PPP criteria in patients undergoing PSMA RLT and their prognostic implications. Methods: In this retrospective analysis, PSMA PET/CT scans of 46 patients acquired before and after completion of PSMA RLT were analyzed separately by two readers using modified PPP criteria. After interobserver agreement assessment, consensus results (progressive vs. non-progressive disease) were compared in a multivariate cox regression model (endpoint overall survival, OS). Results: Interobserver agreement on modified PPP criteria was substantial (Cohens κ = 0.73) with a concordance in 87% of patients. Median OS of all patients after PSMA RLT (n = 46) was 9.0 [95% confidence interval (CI) 7.8 - 10.2] months. Progression according to modified PPP criteria was found in 32 patients and was a significant (p ≤0.001) prognostic marker for OS with a hazard ratio of 15.5 [95% CI 3.4 - 70.2]. Conclusion: Response assessment in patients undergoing PSMA RLT using modified PPP criteria are reproducible and highly prognostic for OS. Modified PPP criteria should be validated in future prospective trials.

Growth characteristics and therapeutic decision markers in von Hippel-Lindau disease patients with renal cell carcinoma.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a multi-systemic hereditary disease associated with several benign and malignant tumor entities, including clear cell renal cell carcinoma (ccRCC). Since ccRCCs grow slowly, nephron sparing surgery is typically performed at a tumor diameter of 3-4 cm before the tumor metastasizes. However, in the case of recurrent disease, repeated surgical intervention can impair renal function. Therefore, it is crucial to optimize the timing for surgical interventions through a better understanding of the growth kinetics of ccRCCs in VHL. We investigated tumor growth kinetics and modern volumetric assessment to guide future therapeutic decisions. RESULTS: The prevalence of ccRCC was 28% in a cohort of 510 VHL patients. Of 144 patients with ccRCC, 41 were followed with serial imaging which identified 102 renal tumors, which exhibited heterogeneous growth kinetics. ccRCCs grew at an average absolute growth rate of 0.287 cm/year, an average relative growth rate [(lnV1-lnV0)/(t1-t0)] of 0.42% and an average volume doubling time of 27.15 months. Women had a faster relative growth rate than men. Age and specific mutations did not influence tumor growth. Because of the tumor heterogeneity, we developed an additional cut-off volume of 40 cm3 for surgical intervention. CONCLUSIONS: Tumor heterogeneity and differences in growth kinetics is suggestive of a state of transient tumor dormancy in ccRCCs of VHL patients. The relative growth rate has not been previously described in other studies. Volumetric assessment as an additional parameter for surgical intervention could be a useful clinical tool and needs further investigation.

Peripheral zone lesions of intermediary risk in multiparametric prostate MRI: Frequency and validation of the PI-RADSv2 risk stratification algorithm based on focal contrast enhancement.

PURPOSE: To validate the risk stratification algorithm of the Prostate Imaging Reporting and Data System (PI-RADSv2) for intermediary risk lesions (PI-RADSv2 category 3) in the peripheral zone based on focal contrast enhancement and to compare cancer rates in category 3, upgraded category 4 and category 4 based on markedly low ADC value. MATERIALS AND METHODS: We retrospectively analyze 172 consecutive patients undergoing prostate MRI with 315 histopathologically verified lesions. We select all lesions either assigned category 3 or category 4 in the peripheral zone for further analysis. We compare cancer rates with the two-sided chi-squared test. To determine inter-observer agreement about contrast enhancement two blinded radiologists evaluate the subset of category 3 lesions based on the diffusion weighted sequence. RESULTS: The frequency of peripheral PI-RADS 3, upgraded PI-RADS 4 and PI-RADS 4 lesions based on markedly low ADC value is 10.8%, 10.8% and 20.3%, respectively. Cancer rates (significant cancer only) in these subgroups are 8.8% (3/34), 23.5% (8/34) and 40.6% (26/64), P < 0.01. Inter-observer agreement is moderate for evaluation of contrast enhancement with kappa values between 0.46 and 0.5. CONCLUSION: We demonstrate a trend of increasing cancer rate from PI-RADSv2 category 3 to upgraded category 4 to category 4 based on markedly low ADC value. Peripheral lesions of intermediary risk in the diffusion weighted sequence account for 21.6% of all prostate lesions encountered. Since it is likely that patient management recommendations will be linked to assessment categories in future versions of PI-RADS, cancer rates in upgraded category 4 and category 4 based on markedly low ADC values should be in a similar range. We conclude that in future studies of PI-RADSv2 upgraded category 4 and category 4 based on markedly low ADC value should be reported separately to generate a database for meta-analysis of cancer rates.

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.

Diagnostic performance and reproducibility of T2w based and diffusion weighted imaging (DWI) based PI-RADSv2 lexicon descriptors for prostate MRI.

PURPOSE: To examine the diagnostic performance of PI-RADSv2 T2w and diffusion weighted imaging (DWI) based lexicon descriptors, inter-observer agreement for descriptor assignment and diagnostic accuracy of the PI-RADSv2 assessment categories for multiparametric prostate MRI. MATERIALS AND METHODS: 176 lesions in 79 consecutive patients are analyzed, lesions are histopathologically verified by MRI-ultrasound fusion biopsy. All lesions are rated according to the PI-RADSv2 lexicon, descriptors for T2w and DWI sequences and resulting assessment categories are assigned by two independent blinded radiologists. We perform receiver-operating-characteristic analysis using the assessment categories. To analyze inter-observer agreement, we calculate weighted kappa values for assessment category assignment and unweighted kappa values for descriptor assignment. RESULTS: PI-RADSv2 assessment categories yield an area under the curve of 0.76/0.74 (radiologist 1/radiologist 2), P >0.05. Weighted kappa for agreement is 0.601 in the peripheral zone and 0.580 in the transition zone. We detect a difference in the cancer rate for PI-RADSv2 category 3 between peripheral zone (32%) and transition zone (12%), P <0.05. We obtain moderate agreement at most for descriptor assignment with kappa values ranging from 0.082 (T2w shape in the transition zone) to 0.407 (T2w signal intensity in the peripheral zone) and 0.493 (ADC pattern in the peripheral zone). Our analysis corroborates typical descriptors for benign/malignant lesions, but also reveals insights into potential pitfalls - T2w wedge shaped lesions in the peripheral zone have a considerable cancer rate, despite being labelled category 2 in the lexicon. CONCLUSION: Agreement for descriptor assignment in the PI-RADSv2 lexicon is at most moderate in our study. Typical descriptors for benign and malignant lesions are validated, whereas the discriminatory power of some descriptors is challenged. The difference in the cancer rate for PI-RADSv2 category 3 between peripheral zone and transition zone should be considered when management recommendations are linked to assessment categories in the future.

Diagnosis of recurrent prostate cancer with PET/CT imaging using the gastrin-releasing peptide receptor antagonist 68Ga-RM2: Preliminary results in patients with negative or inconclusive [18F]Fluoroethylcholine-PET/CT.

PURPOSE/BACKGROUND: [18F]fluoroethylcholine (18FECH) has been shown to be a valuable PET-tracer in recurrent prostate cancer (PCa), but still has limited accuracy. RM2 is a gastrin-releasing peptide receptor (GRPr) antagonist that binds to GRPr on PCa cells. Recent studies suggest that GRPr imaging with PET/CT is a promising technique for staging and restaging of PCa. We explore the value of GRPr-PET using the 68Ga-labeled GRPr antagonist RM2 in a selected population of patients with biochemically recurrent PCa and a negative/inconclusive 18FECH-PET/CT. MATERIAL AND METHODS: In this retrospective study 16 men with biochemical PCa relapse and negative (n = 14) or inconclusive (n = 2) 18FECH-PET/CT underwent whole-body 68Ga-RM2-PET/CT. Mean time from 18FECH-PET/CT to 68Ga-RM2-PET/CT was 6.1 ± 6.8 months. Primary therapies in these patients were radical prostatectomy (n = 13; 81.3%) or radiotherapy (n = 3; 18.7%). 14/16 patients (87.5%) had already undergone salvage therapies because of biochemical relapse prior to 68Ga-RM2-PET/CT imaging. Mean ± SD PSA at 68Ga-RM2-PET/CT was 19.4 ± 53.5 ng/ml (range 1.06-226.4 ng/ml). RESULTS: 68Ga-RM2-PET/CT showed at least one region with focal pathological uptake in 10/16 patients (62.5%), being suggestive of local relapse (n = 4), lymph node metastases (LNM; n = 4), bone metastases (n = 1) and lung metastasis with hilar LNM (n = 1). Seven of ten positive 68Ga-RM2 scans were positively confirmed by surgical resection and histology of the lesions (n = 2), by response to site-directed therapies (n = 2) or by further imaging (n = 3). Patients with a positive 68Ga-RM2-scan showed a significantly higher median PSA (6.8 ng/ml, IQR 10.2 ng/ml) value than those with a negative scan (1.5 ng/ml, IQR 3.1 ng/ml; p = 0.016). Gleason scores or concomitant antihormonal therapy had no apparent impact on the detection of recurrent disease. CONCLUSION: Even in this highly selected population of patients with known biochemical recurrence but negative or inconclusive 18FECH-PET/CT, a 68Ga-RM2-PET/CT was helpful to localize PCa recurrence in the majority of the cases. Thus, 68Ga-RM2-PET/CT deserves further investigation as a promising imaging modality for imaging PCa recurrence.

Diabetes and beta-adrenergic blockage are risk factors for metastatic prostate cancer.

BACKGROUND: We evaluated the influence of comorbidity inferred risks for lymph node metastasis (pN1) and positive surgical margins (R1) after radical prostatectomy in order to optimize pretherapeutic risk classification. We analyzed 454 patients after radical prostatectomy (RP) between 2009 and 2014. Comorbidities were defined by patients' medication from our electronic patient chart and stratified according to the ATC WHO code. Endpoints were lymph node metastasis (pN1) and positive surgical margins (R1). RESULTS: Rates for pN1 and R1 were 21.4% (97/454) and 29.3% (133/454), respectively. In addition to CAPRA and Gleason score, we identified diabetes as a significant medication inferred risk factor for pN1 (OR 2.9, p = 0.004/OR 3.2, p = 0.001/OR 3.5, p = 0.001) and beta-blockers for R1 (OR 1.9, p = 0.020/OR 2.9, p = 0.004). Patients with diabetes showed no statistically significant difference in Gleason score, CAPRA Score, PSA, and age compared to non-diabetic patients. CONCLUSIONS: We identified diabetes and beta1 adrenergic blockage as significant risk factors for lymph node metastasis and positive surgical margins in prostate cancer (PCa). Patients at risk will need intensive pretherapeutic staging for optimal therapeutic stratification.

Single fraction multimodal image guided focal salvage high-dose-rate brachytherapy for recurrent prostate cancer.

PURPOSE: We present a novel method for treatment of locally recurrent prostate cancer (PCa) following radiation therapy: focal, multimodal image guided high-dose-rate (HDR) brachytherapy. MATERIAL AND METHODS: We treated two patients with recurrent PCa after primary (#1) or adjuvant (#2) external beam radiation therapy. Multiparametric magnetic resonance imaging (mpMRI), choline, positron emission tomography combined with computed tomography (PET/CT), or prostate-specific membrane antigen (PSMA)-PET combined with CT identified a single intraprostatic lesion. Positron emission tomography or magnetic resonance imaging - transrectal ultrasound (MRI-TRUS) fusion guided transperineal biopsy confirmed PCa within each target lesion. We defined a PET and mpMRI based gross tumor volume (GTV). A 5 mm isotropic margin was applied additionally to each lesion to generate a planning target volume (PTV), which accounts for technical fusion inaccuracies. A D90 of 18 Gy was intended in one fraction to each PTV using ultrasound guided HDR brachytherapy. RESULTS: Six month follow-up showed adequate prostate specific antygen (PSA) decline in both patients (ΔPSA 83% in patient 1 and ΔPSA 59.3% in patient 2). Follow-up 3-tesla MRI revealed regressive disease in both patients and PSMA-PET/CT showed no evidence of active disease in patient #1. No acute or late toxicities occurred. CONCLUSIONS: Single fraction, focal, multimodal image guided salvage HDR brachytherapy for recurrent prostate cancer is a feasible therapy for selected patients with single lesions. This approach has to be evaluated in larger clinical trials.

(68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.

PURPOSE: We performed a voxel-wise comparison of (68)Ga-HBED-CC-PSMA PET/CT with prostate histopathology to evaluate the performance of (68)Ga-HBED-CC-PSMA for the detection and delineation of primary prostate cancer (PCa). METHODOLOGY: Nine patients with histopathological proven primary PCa underwent (68)Ga-HBED-CC-PSMA PET/CT followed by radical prostatectomy. Resected prostates were scanned by ex-vivo CT in a special localizer and histopathologically prepared. Histopathological information was matched to ex-vivo CT. PCa volume (PCa-histo) and non-PCa tissue in the prostate (NPCa-histo) were processed to obtain a PCa-model, which was adjusted to PET-resolution (histo-PET). Each histo-PET was coregistered to in-vivo PSMA-PET/CT data. RESULTS: Analysis of spatial overlap between histo-PET and PSMA PET revealed highly significant correlations (p < 10(-5)) in nine patients and moderate to high coefficients of determination (R²) from 42 to 82 % with an average of 60 ± 14 % in eight patients (in one patient R(2) = 7 %). Mean SUVmean in PCa-histo and NPCa-histo was 5.6 ± 6.1 and 3.3 ± 2.5 (p = 0.012). Voxel-wise receiver-operating characteristic (ROC) analyses comparing the prediction by PSMA-PET with the non-smoothed tumor distribution from histopathology yielded an average area under the curve of 0.83 ± 0.12. Absolute and relative SUV (normalized to SUVmax) thresholds for achieving at least 90 % sensitivity were 3.19 ± 3.35 and 0.28 ± 0.09, respectively. CONCLUSIONS: Voxel-wise analyses revealed good correlations of (68)Ga-HBED-CC-PSMA PET/CT and histopathology in eight out of nine patients. Thus, PSMA-PET allows a reliable detection and delineation of PCa as basis for PET-guided focal therapies.

The histone code reader SPIN1 controls RET signaling in liposarcoma.

The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ. Accordingly, knockdown of SPIN1 or MAZ results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, activated RET, and MAZ are increased in human liposarcoma compared to normal adipose tissue or lipoma. Importantly, a mutation of SPIN1 within the reader domain interfering with chromatin binding reduces liposarcoma cell proliferation and survival. Together, our data describe a molecular mechanism for SPIN1 function in liposarcoma and suggest that targeting SPIN1 chromatin association with small molecule inhibitors may represent a novel therapeutic strategy.

Adjuvant radiotherapy after salvage lymph node dissection because of nodal relapse of prostate cancer versus salvage lymph node dissection only.

BACKGROUND: Nodal pelvic/retroperitoneal recurrent prostate cancer (PCa) after primary therapy can be treated with salvage lymph node dissection (salvage-LND) in order to delay disease progression and offer cure for a subset of patients. Whether adjuvant radiotherapy (ART) in affected regions improves the outcome by elimination of residual tumour burden remains unclear. METHODS: A total of 93 patients with exclusively nodal PCa relapse underwent choline-positron-emission tomography-computed-tomography-directed pelvic/retroperitoneal salvage-LND; 46 patients had surgery only and 47 patients received ART in regions with proven lymph node metastases. In case of subsequent prostate specific antigen (PSA) progression, different imaging modalities were performed to confirm next relapse within or outside the treated region (TR). Mean follow-up was 3.2 years. RESULTS: Lymphatic tumour burden was balanced between the two groups. Additional ART resulted in delayed relapse within TR (5-year relapse-free rate 70.7 %) versus surgery only (5-year relapse-free rate 26.3 %, p < 0.0001). In both treatment arms, time to next relapse outside the TR was almost equal (median 27 months versus 29.6 months, p = 0.359). With respect to the detection of the first new lesion, regardless if present within or outside the TR, 5 years after the treatment 34.3 % of patients in the group with additional ART were free of relapse, versus 15.4 % in the surgery only group (p = 0.0122). ART had no influence on the extent of PSA reduction at latest follow-up compared to treatment with surgery only. CONCLUSION: ART after salvage-LND provides stable local control in TR and results in overall significant improved next-relapse-free survival, compared to patients who received surgery only in case of nodal PCa-relapse.