Trends and outcomes of hospitalized patients with priapism in Germany: results from the GRAND study.

We aimed to provide evidence on the trends and in-hospital outcomes of patients with low- and high-flow priapism through the largest study in the field. We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal Bureau of Statistics (2008-2021), and performed multiple patient-level analyses. We included 6,588 men with low-flow and 729 with high-flow priapism. Among patients with low-flow priapism, 156 (2.4%) suffered from sickle cell disease, and 1,477 (22.4%) patients required shunt surgery. Of them, only 37 (2.5%) received a concomitant penile prosthesis implantation (30 inflatable and 7 semi-rigid prosthesis). In Germany, the total number of patients with low-flow priapism requiring hospital stay has steadily increased, while the number of patients with high-flow priapism requiring hospital stay has decreased in the last years. Among patients with high-flow priapism, 136 (18.7%) required selective artery embolization. In men with low-flow priapism, sickle cell disease was associated with high rates of exchange transfusion (OR: 21, 95% CI: 14-31, p < 0.001). The length of hospital stay (p = 0.06) and the intensive care unit admissions (p = 0.9) did not differ between patients with low-flow priapism due to sickle cell disease versus other causes of low-flow priapism. Accordingly, in men with high-flow priapism, embolization was not associated with worse outcomes in terms of length of hospital stay (p > 0.9), transfusion (p = 0.8), and intensive care unit admission (p = 0.5). Low-flow priapism is an absolute emergency that requires shunt surgery in more than one-fifth of all patients requiring hospital stay. On the contrary, high-flow priapism is still managed, in most cases, conservatively.

mpMRI-targeted biopsy of the prostate in men ≥ 75 years. 7-year report from a high-volume referral center.

OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) -Ultrasound- fusion guided biopsy of the prostate (FBx) is the new gold standard for the detection of prostate cancer. Hallmark studies showing superior detection rates of FBx over randomized biopsies routinely excluded patients≥75 years and information on outcome of FBx on this patient cohort is sparse. As a large referral center, we have performed FBx on a substantial number of patients this age. By evaluating outcome of FBx of patients over the age of 75 years we wanted to close the gap of knowledge on this patient cohort. MATERIALS AND METHODS: Between 2015 -2022, 1577 patients underwent FBx at our department and were considered for analysis. Clinical and histopathological parameters were recorded. Clinical data comprised age at FBx, serum level of Prostate-specific antigen (PSA), prostate volume, PSA-density, history of previous biopsies of the prostate, result of the digital rectal examination (DRE) and assessment of the indexlesion of mpMRI according to the Prostate Imaging and Reporting Data System (PI-RADS). Univariate analysis and multivariable logistic regression was used to identify age barrier of 75 years as a potential risk factor of detection of clinically significant prostate cancer by FBx. RESULTS: 379/1577 patients (24%) were≥75 years and 1198/1577 (76%) patients were < 75 years, respectively. Preoperative PSA was significantly higher in patients≥75 years compared to patients < 75 years (9.54 vs. 7.8, p < 0.001). Patients≥75 years presented significantly more often with mpMRI target lesions classified as PI-RADS 5 compared to patients < 75 years (45% vs. 29%, p < 0.001). Detection rate of clinically significant prostate cancer was significantly higher in patients≥75 years compared to patients < 75 years (63% vs. 43%, p < 0.001). Aggressive prostate cancer grade ISUP 5 was significantly more often detected in patients≥75 years compared to patients < 75 years (13% vs. 8%, p = 0.03). On multivariable logistic regression model adjusted for PSA and PI-RADS score, age barrier of 75 years was identified as a significant risk factor for the detection of clinically significant prostate cancer by FBx (OR: 1.77, 95% CI: 1.36 -2.31, p < 0.001). CONCLUSION: After evaluation of a large patient cohort, we show that age≥75 years represents a significant risk factor for the detection of clinically significant prostate cancer. Further studies on mid- and long term outcome are necessary to draw conclusions for clinical decision making in this patient cohort.

Reliability and practicability of PSMA-RADS 1.0 for structured reporting of PSMA-PET/CT scans in prostate cancer patients.

OBJECTIVES: As structured reporting is increasingly used in the evaluation of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) for prostate cancer, there is a need to assess the reliability of these frameworks. This study aimed to evaluate the intra- and interreader agreement among readers with varying levels of experience using PSMA-RADS 1.0 for interpreting PSMA-PET/CT scans, even when blinded to clinical data, and therefore to determine the feasibility of implementing this reporting system in clinical practice. METHODS: PSMA-PET/CT scans of 103 patients were independently evaluated by 4 readers with different levels of experience according to the reporting and data system (RADS) for PSMA-PET/CT imaging PSMA-RADS 1.0 at 2 time points within 6 weeks. For each scan, a maximum of five target lesions were freely chosen and stratified according to PSMA-RADS 1.0. Overall scan score and compartment-based scores were assessed. Intra- and interreader agreement was determined using the intraclass correlation coefficient (ICC). RESULTS: PSMA-RADS 1.0 demonstrated excellent interreader agreement for both overall scan scores (ICC ≥ 0.91) and compartment-based scores (ICC ≥ 0.93) across all four readers. The framework showed excellent intrareader agreement for overall scan scores (ICC ≥ 0.86) and compartment-based scores (ICC ≥ 0.95), even among readers with varying levels of experience. CONCLUSIONS: PSMA-RADS 1.0 is a reliable method for assessing PSMA-PET/CT with strong consistency and agreement among readers. It shows great potential for establishing a standard approach to diagnosing and planning treatment for prostate cancer patients, and can be used confidently even by readers with less experience. CLINICAL RELEVANCE STATEMENT: This study underlines that PSMA-RADS 1.0 is a valuable and highly reliable scoring system for PSMA-PET/CT scans of prostate cancer patients and can be used confidently by radiologists with different levels of experience in routine clinical practice. KEY POINTS: PSMA-RADS version 1.0 is a scoring system for PSMA-PET/CT scans. Its reproducibility needs to be analyzed in order to make it applicable to clinical practice. Excellent interreader and intrareader agreement for overall scan scores and compartment-based scores using PSMA-RADS 1.0 were seen in readers with varying levels of experience. PSMA-RADS 1.0 is a reliable tool for accurately diagnosing and planning treatment for prostate cancer patients, and can be used confidently in clinical routine.

Added value of randomised biopsy to multiparametric magnetic resonance imaging-targeted biopsy of the prostate in a contemporary cohort.

OBJECTIVE: To assess the added value of concurrent systematic randomised ultrasonography-guided biopsy (SBx) to multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy and the additional rate of overdiagnosis of clinically insignificant prostate cancer (ciPCa) by SBx in a large contemporary, real-world cohort. PATIENTS AND METHODS: A total of 1552 patients with positive mpMRI and consecutive mpMRI-targeted biopsy and SBx were enrolled. Added value and the rate of overdiagnosis by SBx was evaluated. PRIMARY OUTCOME: added value of SBx, defined as detection rate of clinically significant PCa (csPCa; International Society of Urological Pathology [ISUP] Grade ≥2) by SBx, while mpMRI-targeted biopsy was negative or showed ciPCa (ISUP Grade 1). SECONDARY OUTCOME: rate of overdiagnosis by SBx, defined as detection of ciPCa in patients with negative mpMRI-targeted biopsy and PSA level of <10 ng/mL. RESULTS: Detection rate of csPCa by mpMRI-targeted biopsy and/or SBx was 753/1552 (49%). Added value of SBx was 145/944 (15%). Rate of overdiagnosis by SBx was 146/656 (22%). Added value of SBx did not change when comparing patients with previous prostate biopsy and biopsy naïve patients. In multivariable analysis, a Prostate Imaging-Reporting and Data System (PI-RADS) 4 index lesion (odds ratio [OR] 3.19, 95% confidence interval [CI] 1.66-6.78; P = 0.001), a PI-RADS 5 index lesion (OR 2.89, 95% CI 1.39-6.46; P = 0.006) and age (OR 1.05, 95% CI 1.03-1.08; P < 0.001) were independently associated with added value of SBx. CONCLUSIONS: In our real-world analysis, we saw a significant impact on added value and added rate of overdiagnosis by SBx. Subgroup analysis showed no significant decrease of added value in any evaluated risk group. Therefore, we do not endorse omitting concurrent SBx to mpMRI-guided biopsy of the prostate.

Perioperative outcomes of penile prosthesis implantation in Germany: results from the GRAND study.

We aimed to assess the recommended annual hospital volume for inflatable penile prosthesis implantation (PPI) and to provide evidence on perioperative outcomes of semi-rigid and inflatable PPI in Germany. We used the GeRmAn Nationwide inpatient Data (GRAND) from 2005 to 2021 and report the largest study to date with 7,222 patients. 6,818 (94.4%) patients underwent inflatable and 404 (5.6%) semi-rigid PPI. Inflatable PPI was significantly associated with shorter length of hospital stay (difference of 2.2 days, 95%CI: 1.6-2.7, p < 0.001), lower odds of perioperative urinary tract infections (5.5% versus 9.2%; OR: 0.58, 95%CI: 0.41-0.84, p = 0.003) and surgical wound infections (1% versus 2.5%; OR: 0.42, 95%CI: 0.22-0.88, p = 0.012) compared to semi-rigid PPI. Overall, 4255 (62.4%) inflatable PPIs were undertaken in low- ( < 20 PPI/year) and 2563 (37.6%) in high-volume ( ≥ 20 PPI/year) centers. High-volume centers were significantly associated with shorter length of hospital stay (difference of 1.4 days, 95%CI: 1.2-1.7, p < 0.001) compared to low-volume centers. Our findings suggest that inflatable PPI leads to a shorter length of hospital stay and lower rates of perioperative urinary tract and surgical wound infections compared to semi-rigid PPI. Patients undergoing surgery in high-volume centers for inflatable PPI are discharged earlier from the hospital.

The Impact of Prostate Volume on the Prostate Imaging and Reporting Data System (PI-RADS) in a Real-World Setting.

Multiparametric magnetic resonance imaging (mpMRI) has emerged as a new cornerstone in the diagnostic pathway of prostate cancer. However, mpMRI is not devoid of factors influencing its detection rate of clinically significant prostate cancer (csPCa). Amongst others, prostate volume has been demonstrated to influence the detection rates of csPCa. Particularly, increasing volume has been linked to a reduced cancer detection rate. However, information about the linkage between PI-RADS, prostate volume and detection rate is relatively sparse. Therefore, the current study aims to assess the association between prostate volume, PI-RADS score and detection rate of csP-Ca, representing daily practice and contemporary mpMRI expertise. Thus, 1039 consecutive patients with 1151 PI-RADS targets, who underwent mpMRI-guided prostate biopsy at our tertiary referral center, were included. Prior mpMRI had been assessed by a plethora of 111 radiology offices, including academic centers and private practices. mpMRI was not secondarily reviewed in house before biopsy. mpMRI-targeted biopsy was performed by a small group of a total of ten urologists, who had performed at least 100 previous biopsies. Using ROC analysis, we defined cut-off values of prostate volume for each PI-RADS score, where the detection rate drops significantly. For PI-RADS 4 lesions, we found a volume > 61.5 ccm significantly reduced the cancer detection rate (OR 0.24; 95% CI 0.16-0.38; p < 0.001). For PI-RADS 5 lesions, we found a volume > 51.5 ccm to significantly reduce the cancer detection rate (OR 0.39; 95% CI 0.25-0.62; p < 0.001). For PI-RADS 3 lesions, none of the evaluated clinical parameters had a significant impact on the detection rate of csPCa. In conclusion, we show that enlarged prostate volume represents a major limitation in the daily practice of mpMRI-targeted biopsy. This study is the first to define exact cut-off values of prostate volume to significantly impair the validity of PI-RADS assessed in a real-world setting. Therefore, the results of mpMRI-targeted biopsy should be interpreted carefully, especially in patients with prostate volumes above our defined thresholds.

Prognostic Value of Pretreatment Inflammatory Markers in Patients Receiving Radical Cystectomy for Urothelial Bladder Cancer: Does Age Matter?

INTRODUCTION: Biomarkers are known predictors for survival after radical cystectomy (RC) and can improve patient stratification. Yet, it remains unclear how age influences their prognostic value. The current study aimed to assess the impact of age on standard prognostic biomarkers in different age-groups. MATERIALS AND METHODS: Overall, 1,014 patients undergoing RC for bladder cancer were included. Patients were divided into age-groups (I - <60, II - 60-69, III - 70-79, and IV - ≥80). C-reactive protein (CRP), hemoglobin (Hb), thrombocytes, and leucocytes prior to RC were used as biomarkers. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) and cancer-specific survival (CSS). For independent predictors of survival, multivariate models were applied. RESULTS: Absolute levels of biomarkers except CRP revealed a significant decrease with increasing age. We found low Hb to be associated with impaired CSS in groups II (2.05 [1.32-3.17]; p = 0.001), III (2.83 [2.01-4.00]; p < 0.001), and IV (1.79 [1.12-2.84]; p = 0.014). Thrombocytes above the cutoff were associated with impaired CSS and OS in groups II, III, and IV for CSS and OS. Leukocytes were associated with impaired CSS and OS in group II (2.11 [1.38-3.23]; p < 0.001 and 1.99 [1.36-2.90]; p < 0.001) and III (1.70 [1.08-2.67]; p = 0.021 and 1.80 [1.25-2.58]; p = 0.002). Elevated CRP was associated with impaired CSS and OS across all groups. CONCLUSION: Biomarkers are predictors for survival after RC. Yet, their impact on survival is less in the oldest patient group. Therefore, careful patient stratification and treatment administration should be considered in elderly patients. Further investigations are needed to fully understand the underlying mechanisms.

Listening to Music during Outpatient Cystoscopy Reduces Pain and Anxiety and Increases Satisfaction: Results from a Prospective Randomized Study.

BACKGROUND: This study investigates the effect of classical music, music of patients' own choice, or no music on pain reduction during elective cystoscopy. OBJECTIVES: The aim of the study was to describe the effect of listening to classical music, music of patients' own choice, or no music on patient's pain and satisfaction rates when carrying out an elective cystoscopy and the effect on the assessment capability of the performing urologist. DESIGN, SETTING, AND PARTICIPANTS: This randomized trial included 127 patients undergoing elective cystoscopy at the Urological Department of the University Clinic of Munich between June 2019 and March 2020. Outcome Measurements and Statistical Analysis: Patients were assigned randomly to 3 groups: group I: listening to standardized classical music (n = 35), group II: listening to music according to the patients' choice (n = 34), and control group III: no music (n = 44). Prior to cystoscopy, anxiety levels were assessed by the Beck Anxiety Inventory (BAI). The Visual Analog Scale (VAS, range 1-100) was used for a self-assessment of pain, discomfort, and satisfaction. Statistical analysis was done with Spearman's rank correlation and t-tests. RESULTS AND LIMITATIONS: The median age was 63 (range 27-91) years. The duration of cystoscopy was 5.7 (1-30) min. Patients had undergone a median of 2.3 cystoscopies in the past. Between giving informed consent and cystoscopy, patients had to wait for a median of 64 (0-260) min. The median VAS pain score was significantly lower in group I at 1.7 and group II at 2.3 versus 5.2 in the control group III (p < 0.001). The control group III had significantly worse pain and patient satisfaction rates compared with groups I and II. Group I had a significant lower VAS pain score than groups II and III (p < 0.001). Classical music also increased the assessment capability of the preforming urologist. CONCLUSIONS: Listening to music during elective cystoscopy significantly reduces pain and distress and leads to higher patient and surgeon satisfaction. We recommend listening to classical music or music chosen by the patients during outpatient flexible/rigid cystoscopy in daily clinical routine. Patient Summary: In this study, we found that patients who listened to classical music or music of their own choice while undergoing a cystoscopy showed significant reduction of pain and distress.

Salvage cystectomy and ileal conduit urinary diversion as a last-line option for benign diseases-perioperative safety and postoperative health-related quality of life.

AIMS: Radical cystectomy and urinary diversion impact various dimensions of patients' health-related-quality-of-life (HRQOL). Yet, less is known about salvage cystectomy as a last-line option for treatment-refractory benign diseases. Therefore, our aim is to provide HRQOL data from a contemporary cohort of open salvage cystectomies for benign conditions. METHODS: Fifty-four consecutive patients were enrolled in one single tertiary referral center. Analysis was limited to patients undergoing urinary diversion via ileal conduit (IC). Complications were assessed via Clavien-Dindo-scale. HRQOL was measured using the validated European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-BLM30 questionnaire. HRQOL QLQ-C30 domains were measured preoperatively and up to 3 years postoperatively. Longitudinal changes were analyzed using Friedman's rank test. Primary endpoint was good general HRQOL based on QLQ-C30 global health status (GHS). Multivariate analysis was performed using logistic regression models with a step-wise backward selection procedure. RESULTS: Longitudinal analysis of HRQOL subdomains revealed significantly improved pain (p = .005) and fatigue (p = .002) scores as well as improved social functioning (p = .038). Furthermore, general HRQOL (GHS scores) improved significantly during the follow-up period (28.0 vs. 50.6 [36 months], p = .045). In multivariate analysis, the indication for salvage cystectomy could not be identified as an independent predictor for good general HRQOL. We observed a total number of 10 (41.7%) high-grade (Clavien ≥III) 90 day-complications. Limitations include limited follow-up rates at respective time-points. CONCLUSION: Salvage cystectomy and IC can be safely performed as a last-line treatment for benign conditions and increases general HRQOL in the long-term follow-up. Thus, it can play a role in a holistic approach for a challenging clinical setting.

Radical cystectomy for locally advanced urothelial carcinoma of the urinary bladder: Health-related quality of life, oncological outcomes and predictors for survival.

PURPOSE: While survival outcomes of locally advanced bladder cancer patients undergoing radical cystectomy are known to be poor, less is known regarding patient-reported outcomes and predictive features for survival in this patient subgroup. METHODS: One hundred and eighteen consecutive patients with pT4a cM0 urothelial carcinoma of the bladder were included. Based on pathological review, patients were stratified into 3 subgroups based on existence of additional lesions and invasion depth of the respective lesions. Cancer-specific survival and overall survival (OS) was determined using Kaplan-Meier-analyses and multivariate Cox regression models (P <0.05). Health-related quality of life was assessed using the validated EORTC-QLQ-C30 questionnaire pre- and postoperatively. RESULTS: Seventy-two (61.0%) patients were ineligible for neoadjuvant chemotherapy. Median follow-up based on censored patients was 12 months. Twelve month OS rate was 56.1%, 24 months OS rate was 21.1%. A total of 44.4% of the patients stated good general health-related quality of life. In multivariate analysis, we found significantly adverse OS outcomes for female patients (hazard ratio 2.35, 95% confidence interval 1.09-5.08, P = 0.030). Patients with at least 1 additional locally advanced tumor had significantly worse OS outcomes compared to patients who had no additional lesions in multivariate Cox regression analysis (hazard Ratio 3.37, 95% confidence interval 1.29-8.78, P = 0.013). CONCLUSION: Existence of multiple locally advanced lesions and female gender is an independent predictor of worse survival outcomes in patients with pT4a urothelial carcinoma undergoing radical cystectomy.

Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation.

BACKGROUND: Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. METHODS: We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. RESULTS: We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. CONCLUSION: For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

Prognostic impact of perioperative blood transfusions on oncological outcomes of patients with bladder cancer undergoing radical cystectomy: A systematic review.

Objective: To conduct a systematic review of whether blood transfusions may be associated with worse outcomes for patients with bladder cancer treated with radical cystectomy (RC), as there has been a recent increase in studies addressing this clinically relevant topic. Methods: PubMed, Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), Google Scholar, and the ClinicalTrials.gov databases were searched with pre-specified search terms for studies published between January 2010 and May 2020. The systemic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 17 studies with 19 627 patients were included after 183 records were screened for eligibility. In all, 10 studies proposed perioperative blood transfusion to be associated with impaired prognosis regarding overall survival, nine studies regarding cancer-specific and four studies regarding recurrence-free survival. The timing of blood transfusion might affect patient outcomes. Notably, several studies did not find a significant correlation between blood transfusions and prognosis. As all studies to date are of retrospective design, the grade of evidence is still limited. Conclusions: Despite the lack of prospective trials, perioperative blood transfusion may lead to worse oncological outcomes. These results, as well as known non-oncological side-effects and associated costs, are important arguments to carefully consider the indication for blood transfusion. Abbreviations BCa: bladder cancer; CSS: cancer-specific survival; HR: hazard ratio; (N)MIBC: (non-) muscle-invasive BCa; OS: overall survival; PBT, perioperative blood transfusion; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RC: radical cystectomy; RFS: recurrence-free survival.

Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells.

Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.

Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia.

OBJECTIVE: The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. DESIGN: Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. RESULTS: Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%±5.25% of PanINs) and KC;sgp130(tg) (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6(-/-) mice: 5.9±0.9; and KC;sgp130(tg): 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. CONCLUSIONS: Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression.

Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion.

BACKGROUND: In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer. METHODS: Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75(NTR) receptor. The frequency and emergence of the Schwann cell markers Sox10, S100, ALDH1L1, and glial-fibrillary-acidic-protein (GFAP) around cancer precursor lesions were studied in human and conditional murine pancreatic and colon cancer specimens using multiple immunolabeling. RESULTS: Schwann cells migrated toward pancreatic and colon cancer cells, but not toward benign cells, before the onset of cancer migration toward peripheral neurons. This chemoattraction was inhibited after blockade of p75(NTR)-signaling on Schwann and pancreatic cancer cells. Schwann cells were specifically detected around murine and human pancreatic intraepithelial neoplasias (PanINs) (mean percent of murine PanINs surrounded by Schwann cells = 78.9%, 95% CI = 70.9 to 86.8%, and mean percent of human PanINs surrounded by Schwann cells = 52.5%, 95% CI = 14.7 to 90.4%; human: n = 44, murine: n = 14) and intestinal adenomas (mean percent of murine adenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of human adenomas surrounded by Schwann cells = 17.2%, 95% CI = -126.9 to 161.4; human: n = 36, murine: n = 12). The Schwann cell presence in this premalignant stage was associated with the frequency of NI in the malignant phase. CONCLUSIONS: Schwann cells have particular and specific affinity to cancer cells. Emergence of Schwann cells in the premalignant phase of pancreatic and colon cancer implies that, in contrast with the traditional assumption, nerves-and not cancer cells-migrate first during NI.