Comparison of PET/CT and whole-mount histopathology sections of the human prostate: a new strategy for voxel-wise evaluation.

BACKGROUND: Implementation of PET/CT in diagnosis of primary prostate cancer (PCa) requires a profound knowledge about the tracer, preferably from a quantitative evaluation. Direct visual comparison of PET/CT slices to whole prostate sections is hampered by considerable uncertainties from imperfect coregistration and fundamentally different image modalities. In the current study, we present a novel method for advanced voxel-wise comparison of histopathology from excised prostates to pre-surgical PET. Resected prostates from eight patients who underwent PSMA-PET/CT were scanned (ex vivo CT) and thoroughly pathologically prepared. In vivo and ex vivo CT including histopathology were coregistered with three different methods (manual, semi-/automatic). Spatial overlap after CT-based registration was evaluated with dice similarity (DSC). Furthermore, we constructed 3D cancer distribution models from histopathologic information in various slices. Subsequent smoothing reflected the intrinsically limited spatial resolution of PSMA-PET. The resulting histoPET models were used for quantitative analysis of spatial histopathology-PET pattern agreement focusing on p values and coefficients of determination (R 2). We examined additional rigid mutual information (MI) coregistration directly based on PSMA-PET and histoPET. RESULTS: Mean DSC for the three different methods (ManReg, ScalFactReg, and DefReg) were 0.79 ± 0.06, 0.82 ± 0.04, and 0.90 ± 0.02, respectively, while quantification of PET-histopathology pattern agreement after CT-based registration revealed R 2 45.7, 43.2, and 41.3% on average with p < 10-5. Subsequent PET-based MI coregistration yielded R 2 61.3, 55.9, and 55.6%, respectively, while implying anatomically plausible transformations. CONCLUSIONS: Creating 3D histoPET models based on thorough histopathological preparation allowed sophisticated quantitative analyses showing highly significant correlations between histopathology and (PSMA-)PET. We recommend manual CT-based coregistration followed by a PET-based MI algorithm to overcome limitations of purely CT-based coregistrations for meaningful voxel-wise comparisons between PET and histopathology.

[PSMA-radioguided surgery in localized recurrent prostate cancer : Current and future aspects]. / "PSMA-radioguided surgery" beim lokal begrenzten Prostatakarzinomrezidiv : Aktueller Stand und zukünftige Entwicklungen.

Recently, PSMA-radioguided surgery (PSMA-RGS) was introduced for targeted resection of localized prostate cancer recurrence. Prerequisite for preoperative patient selection and localization of tumor recurrence is a positive 68Ga-HBED-CC PSMA positron emission tomography (PET) scan with preferably only singular soft tissue or lymph node recurrence. After injection of In-PSMA I&T or Tc-PSMA-I&S single photon emission computer tomography (SPECT)/computer tomography (CT) examination is performed in every patient to verify radiotracer uptake in tumor lesions. In a preliminary study, 111In-PSMA I&T SPECT/CT could detect about half of the 68Ga-HBED-CC PSMA PET-positive lesions, while nearly all PET-positive lesions could be detected using PSMA-RGS and also five additional lesions compared to 68Ga-HBED-CC-PSMA PET. Follow-up data from 55 patients show a PSA reduction >50% and >90% in 44 (80%) and 29 (53%) patients, respectively. In 34 (62%) patients, a PSA drop to <0.2 ng/ml was observed. In all, 15 (27%) patients received further PC-specific treatment; the remaining 40 (73%) patients did not undergo further treatment. In 33% of patients, surgery-related complications were noted; however, most were regarded as minor. Thus, PSMA-RGS seems to be of high value in patients with localized prostate cancer recurrence with exact localization and resection of metastatic tissue. However, patient selection based on 68Ga-PSMA PET imaging and clinical parameters is crucial to obtain satisfactory oncological results.

High Rates of Thromboembolic Events in Patients with Germ Cell Cancer Undergoing Cisplatin-Based Polychemotherapy.

BACKGROUND: We examined whether or not extended prophylaxis with low molecular weight heparin (LMWH) would significantly reduce thromboembolic event (TEE) rates in germ cell cancer patients undergoing cisplatin-based chemotherapy. PATIENTS AND METHODS: LMWH prophylaxis was given from the first day of chemotherapy until 21 days after completing the last chemotherapy cycle to 45 out of 93 (48.4%) patients (extended), and to 48 out of 93 (51.6%) patients during their hospitalization only (limited) between January 2008 and December 2013. Patients were analyzed retrospectively for TEEs such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) or peripheral arterial thrombosis. RESULTS: A total of 22/93 (23.7%) patients experienced 30 TEE during chemotherapy: 12 out of 30 (40%) deep vein thrombosis, 4 out of 30 (13.3%) MI, 10 out of 30 (33.3%) PE and 4 out of 30 peripheral arterial thrombosis (13.3%). TEE rates in both groups did not differ significantly (extended: 26.7 vs. limited: 20.8%). CONCLUSIONS: The introduction of extended LMWH prophylaxis did not significantly reduce TEE rates in our patient cohort.

[Salvage lymphadenectomy in patients with prostate cancer recurrence: A review]. / Salvagelymphadenektomie beim Rezidiv eines Prostatakarzinoms : Eine Übersicht.

BACKGROUND: Salvage extended pelvic lymph node dissection (salvage ePLND) in patients with prostate cancer (PCa) biochemical recurrence is an alternative to the commonly used androgen deprivation therapy (ADT) and/or chemotherapy. Small patient number, insufficient accuracy of contemporary imaging methods for lymph node relapse diagnostics, and the lack of prospective data present limiting factors for a wider application of salvage ePLND. The purpose of this publication is to review German and European data and studies on the subject of salvage ePLND and to discuss future perspectives. MATERIALS AND METHODS: We analyzed available studies up to October 2014 from Medline with the keywords "salvage lymph node dissection prostate cancer". RESULTS: A total of 51 publications since 1984 (up to October 2014) meeting the search criteria were found. Ten of these were studies that analyzed the results of salvage ePLND. Of these 10 studies, 6 originated from German clinics. Furthermore, among these 51 publications, there were 2 clinical case reports (1 from Germany) and 3 reviews (none from Germany). CONCLUSIONS: The available data show insufficient evidence-based validity. There have been no prospective studies and just one multicenter study. However, single-center retrospective studies have shown promising results. Salvage ePLND leads to biochemical remission, freedom from clinical recurrence, and probably also to renewed response to ADT in patients with castration-resistant PCa. Multicenter prospective studies should be conducted in Germany (where most of the available studies have been performed). The selection of patients should be analyzed in order to identify clear selection criteria for salvage ePLND.

Quantitative proteomic analysis of formalin-fixed, paraffin-embedded clear cell renal cell carcinoma tissue using stable isotopic dimethylation of primary amines.

BACKGROUND: Formalin-fixed, paraffin-embedded (FFPE) tissues represent the most abundant resource of archived human specimens in pathology. Such tissue specimens are emerging as a highly valuable resource for translational proteomic studies. In quantitative proteomic analysis, reductive di-methylation of primary amines using stable isotopic formaldehyde variants is increasingly used due to its robustness and cost-effectiveness. RESULTS: In the present study we show for the first time that isotopic amine dimethylation can be used in a straightforward manner for the quantitative proteomic analysis of FFPE specimens without interference from formalin employed in the FFPE process. Isotopic amine dimethylation of FFPE specimens showed equal labeling efficiency as for cryopreserved specimens. For both FFPE and cryopreserved specimens, differential labeling of identical samples yielded highly similar ratio distributions within the expected range for dimethyl labeling. In an initial application, we profiled proteome changes in clear cell renal cell carcinoma (ccRCC) FFPE tissue specimens compared to adjacent non-malignant renal tissue. Our findings highlight increased levels of glyocolytic enzymes, annexins as well as ribosomal and proteasomal proteins. CONCLUSION: Our study establishes isotopic amine dimethylation as a versatile tool for quantitative proteomic analysis of FFPE specimens and underlines proteome alterations in ccRCC.

LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6.

Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.

Salvage lymph node dissection with adjuvant radiotherapy for nodal recurrence of prostate cancer.

PURPOSE: We evaluated the impact of salvage lymph node dissection with adjuvant radiotherapy in patients with nodal recurrence of prostate cancer. By default, nodal recurrence of prostate cancer is treated with palliative antihormonal therapy, which causes serious side effects and invariably leads to the development of hormone refractory disease. MATERIALS AND METHODS: A total of 47 patients with nodal recurrence of prostate cancer based on evidence of (11)C-choline/(18)F-choline ((18)F-fluorethylcholine) positron emission tomography-computerized tomography underwent primary (2 of 52), secondary (45 of 52), tertiary (4 of 52) and quaternary (1 of 52) salvage lymph node dissection with histological confirmation. Of 52 salvage lymph node dissections 27 were followed by radiotherapy. Biochemical response was defined as a prostate specific antigen less than 0.2 ng/ml after salvage therapy. The Kaplan-Meier method, binary logistic regression and Cox regression were used to analyze survival as well as predictors of biochemical response and clinical progression. RESULTS: Mean prostate specific antigen at salvage lymph node dissection was 11.1 ng/ml. A mean of 23.3 lymph nodes were removed per salvage lymph node dissection. Median followup was 35.5 months. Of 52 salvage lymph node dissections 24 resulted in complete biochemical response followed by 1-year biochemical recurrence-free survival of 71.8%. Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b (OR 5.91, p = 0.042) and N0 status at primary therapy (OR 8.01, p = 0.011) were identified as independent predictors of biochemical response. Gleason 8-10 (HR 3.5, p = 0.039) as a preoperative variable, retroperitoneal positive lymph nodes (HR 3.76, p = 0.021) and incomplete biochemical response (HR 4.0, p = 0.031) were identified as postoperative predictors of clinical progression. Clinical progression-free survival was 25.6% and cancer specific survival was 77.7% at 5 years. CONCLUSIONS: Based on (11)C/(18)F-choline positron emission tomography-computerized tomography as a diagnostic tool, salvage lymph node dissection is feasible for the treatment of nodal recurrence of prostate cancer. Most patients experience biochemical recurrence after salvage lymph node dissection. However, a specific population has a lasting complete prostate specific antigen response.

Nephron sparing surgery in von Hippel-Lindau associated renal cell carcinoma; clinicopathological long-term follow-up.

We evaluated the clinicopathological outcome of von Hippel-Lindau (VHL)-patients who had mainly undergone nephron sparing surgery (NSS) for renal cell carcinoma (RCC) when the tumour diameter has reached 4.0 cm. Multiple, bilateral RCC with high recurrence rates and subsequent repeated interventions, followed by increasing risk for end-stage renal failure and metastases is characteristic for VHL. NSS is widely used for VHL-associated RCC at 3.0 cm cut-off. 54 VHL patients underwent NSS, nephrectomy or thermal ablation for RCC. We analysed time to second treatment, overall and cancer specific survival, intra- and post-operative data as well as tumour characteristics. We also examined the effects of delaying removal of RCC to 4.0 cm cut-off. Median follow-up was 67 months. 54 patients underwent 97 kidney treatments. 96 % of first and 67 % of second interventions comprised of NSS. 0 % metastases were observed in the group with largest tumour size ≤4 cm. The probability for second surgery was 21 %, at 5 years and 42 % at 10 years. Median time to second NSS was 149.6 months. The overall and cancer specific survival rate was 96.5 and 100 % at 5-year follow-up, and 82.5 and 90.5 % respectively at 10-year follow-up. Median delay to second NSS at 4.0 cm cut-off versus 3.0 cm was 27.8 months. NSS was both successfully used in first and second surgery and to some extent even in third surgery. By following a strict surveillance protocol it is possible to support a 4.0 cm-threshold strategy for NSS, based on the assumption that delaying time to second NSS prevents patients from premature renal failure.

Growth kinetics in von Hippel-Lindau-associated renal cell carcinoma.

OBJECTIVE: To evaluate the growth kinetics of renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease in a large trial by CT/MRI scan. VHL disease is a multisystemic disorder predisposing to renal cysts and cancer. There is a general assumption that VHL-associated RCC presents slower growth rates than sporadic RCC. PATIENTS AND METHODS: We describe growth kinetics of 96 renal tumours in 64 VHL patients with analysed germline mutation (54/64 treated, 10/64 active surveillance) over a mean follow-up of 54.9 months. We calculated tumour volume, growth rate, multiplication of tumour volume per year and overall, as well as tumour volume doubling time. RESULTS: The mean growth rate of 96 tumours was 4.4 mm/year (SD 3.2, median 4.1 mm/year), mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). We saw a median 1.4-fold increase in tumour volume per year. At treatment time point, VHL kidneys comprised 39% tumour and 15.7% cyst volume fraction. We saw no correlation between tumour size and growth parameters. CONCLUSION: VHL-associated RCC show large variances in tumour growth behaviour. Compared to the literature, in our study the growth rates (mm/year) of RCC in VHL disease did not differ from those of sporadic RCC. Fast tumour growth increases the risk for metastases.