Jørgen Bjerggaard Jensen

Efficacy of a multiprofessional rehabilitation programme in radical cystectomy pathways: A prospective randomized controlled trial

Abstract Introduction. Radical cystectomy with lymph-node dissection is a complex procedure and often followed by high postoperative morbidity and physical impairments leading to prolonged length of stay (LOS). Fast-track principles are standard procedure in radical cystectomy. Additional preoperative and postoperative physical exercises and enhanced mobilization may reduce LOS and early complications. Materials and methods. In total, 107 patients were included in a prospective randomized controlled design, 50 in the intervention group (nI = 50) and 57 in the standard group (ns = 57). The standard regimen comprised regular fast-track principles. The intervention included standardized preoperative and postoperative strength and endurance exercises and progressive postoperative mobilization. The programme was initiated 2 weeks before surgery. Efficacy was expressed as a reduction in postoperative LOS. Early complications were defined as events occurring at most 90 days postoperatively and graded using the Clavien–Dindo classification system. Results. Adherence to prehabilitation, i.e. patients who accomplished at least 75% of the programme, was 59%. Postoperative mobilization was significantly improved by walking distance (p ≤ 0.001). The ability to perform personal activities of daily living was improved by 1 day (p ≤ 0.05). The median LOS was 8 days in both treatment groups (p = 0.68). There was no significant difference between treatment groups in severity of complications (p = 0.64). Conclusions. There was no reduction in LOS due to the preoperative and postoperative rehabilitation programme, although enhanced mobilization was achieved. The optimized minimal surgical procedure may have affected the ability to reduce LOS further with available techniques and procedures. Alternative parameters for recovery may offer more precise and relevant information.

Monitoring Treatment Response and Metastatic Relapse in Advanced Bladder Cancer by Liquid Biopsy Analysis

Of the patients undergoing radical cystectomy, 20-80% experience relapse. Minimally invasive methods for early detection of metastatic relapse after cystectomy and for monitoring ongoing therapy are urgently needed to improve individualised follow-up and treatment. Therefore, we evaluated the use of circulating tumour DNA (ctDNA) in plasma and urine to detect metastatic relapse after cystectomy and measure treatment efficacy. We exome sequenced tumour and germline DNA from patients with muscle-invasive bladder cancer and monitored ctDNA in 370 liquid biopsies throughout the disease courses by 84 personalised digital droplet polymerase chain reaction assays targeting 61 genes. Patients were prospectively recruited between 2013 and 2017. Patients with metastatic relapse had significantly higher ctDNA levels compared with disease-free patients (p<0.001). The median positive lead time between ctDNA detection in plasma and diagnosis of relapse was 101 d after cystectomy (range 0-932 d). Early detection of metastatic relapse and treatment response using liquid biopsies represents a novel, highly sensitive tool for monitoring patients, supporting clinicians, and guiding treatment decisions.nnnPATIENT SUMMARYnMeasurement of tumour-specific mutations in plasma and urine may be a powerful tool to monitor response during treatment and identify early signs of metastatic disease.

Optimized targeted sequencing of cell-free plasma DNA from bladder cancer patients

Analysis of plasma cell-free DNA (cfDNA) may provide important information in cancer research, though the often small fraction of DNA originating from tumor cells makes the analysis technically challenging. Digital droplet PCR (ddPCR) has been utilized extensively as sufficient technical performance is easily achieved, but analysis is restricted to few mutations. Next generation sequencing (NGS) approaches have been optimized to provide comparable technical performance, especially with the introduction of unique identifiers (UIDs). However, the parameters influencing data quality when utilizing UIDs are not fully understood. In this study, we applied a targeted NGS approach to 65 plasma samples from bladder cancer patients. Laboratory and bioinformatics parameters were found to influence data quality when using UIDs. We successfully sequenced 249 unique DNA fragments on average per genomic position of interest using a 225u2009kb genexa0panel. Validation identified 24 of 38 mutations originally identified using ddPCR across several plasma samples. In addition, four mutations detected in associated tumor samples were detected using NGS, but not using ddPCR. CfDNA analysis of consecutively collected plasma samples from a bladder cancer patient indicated earlier detection of recurrence compared to radiographic imaging. The insights presented here may further the technical advancement of NGS mediated cfDNA analysis.

Prospective comparison of 68Ga-PSMA PET/CT, 18F-sodium fluoride PET/CT and diffusion weighted-MRI at for the detection of bone metastases in biochemically recurrent prostate cancer

PurposeTo prospectively compare diagnostic accuracies for detection of bone metastases by 68Ga-PSMA PET/CT, 18F-NaF PET/CT and diffusion-weighted MRI (DW600-MRI) in prostate cancer (PCa) patients with biochemical recurrence (BCR).MethodsSixty-eight PCa patients with BCR participated in this prospective study. The patients underwent 68Ga-PSMA PET/CT, a 18F-NaF PET/CT and a DW600-MRI (performed in accordance with European Society of Urogenital Radiology guidelines, with b values of 0 and 600xa0s/mm2). Bone lesions were categorized using a three-point scale (benign, malignant or equivocal for metastases) and a dichotomous scale (benign or metastatic) for each imaging modality by at least two experienced observers. A best valuable comparator was defined for each patient based on study-specific imaging, at least 12xa0months of clinical follow-up and any imaging prior to the study and during follow-up. Diagnostic performance was assessed using a sensitivity analysis where equivocal lesions were handled as non-metastatic and then as metastatic.ResultsTen of the 68 patients were diagnosed with bone metastases. On a patient level, sensitivity, specificity and the area under the curve (AUC) by receiver operating characteristic analysis were, respectively, 0.80, 0.98–1.00 and 0.89–0.90 for 68Ga-PSMA PET/CT (nu2009=u200968 patients); 0.90, 0.90–0.98 and 0.90–0.94 for 18NaF PET/CT (nu2009=u200967 patients); and 0.25–0.38, 0.87–0.92 and 0.59–0.62 for DW600-MRI (nu2009=u200960 patients). The diagnostic performance of DW600-MRI was significantly lower than that of 68Ga-PSMA PET/CT and 18NaF PET/CT for diagnosing bone metastases (pu2009<u20090.01), and no significant difference in the AUC was seen between 68Ga-PSMA PET/CT and 18NaF PET/CT (pu2009=u20090.65).Conclusion68Ga-PSMA PET/CT and 18F-NaF PET/CT showed comparable and high diagnostic accuracies for detecting bone metastases in PCa patients with BCR. Both methods performed significantly better than DW600-MRI, which was inadequate for diagnosing bone metastases when conducted in accordance with European Society of Urogenital Radiology guidelines.

Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion vs. open mini-laparotomy cystectomy: evaluation of surgical inflammatory response and immunosuppressive ability of CO2-pneumoperitoneum in an experimental porcine study

Abstract Objects: To compare surgical inflammatory response (SIR) after radical cystectomy (RC) in a porcine model using minimal invasive techniques. Additionally we aimed to investigate the potential immunosuppressive ability of preoperative CO2-pneumoperitoneum (CO2P). Materials and Methods: Forty female landrace pigs were randomized to five groups: Three intervention groups all having a cystectomy and an ileal conduit either done by robot-assisted laparoscopic technique with intracorporeal urinary diversion (RALC) or an open mini-laparotomy with or without prior CO2P (OMCu2009±u2009CO2P). Two control sham groups with or without prior CO2P (Su2009±u2009CO2P). Serum samples were obtained preoperatively, immediately postoperative, 24, 48 and 72u2009hours postoperatively, and the inflammatory mediators CRP, Haptoglobin, Ceruloplasmin, Albumin, Cortisol, IL-4, IL-6, IL-12 and IFN-α were measured. Results: Operative time was significantly longer in RALC compared to open groups (OMCu2009±u2009CO2P) (p’su2009<u2009.0001). CRP and Haptoglobin levels were significantly higher for surgical intervention groups (SIG) compared to controls 24, 48 and 72u2009hours postoperatively (p’su2009<u2009.001). At 48u2009hours, CRP was higher for RALC vs OMCu2009+u2009CO2P (pu2009=u2009.029). At 72u2009hours, Haptoglobin was higher for RALC vs open groups (p’s < .024). Ceruloplasmin, cortisol, albumin, IL-4, IL-6, IL-12 and IFN-α, revealed no significant differences between SIG. Conclusions: No major differences were found between RALC and OMC regarding the degree of tissue trauma quantified by inflammatory markers. Thirty minutes of CO2-insufflation preoperative appears to have a transient immunosuppressive effect of the innate postoperative SIR, whereas prolonged CO2P apparently diminishes this effect.

Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients

Background We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.

Efficacy of commercialised extracorporeal shock wave lithotripsy service: a review of 589 renal stones

BackgroundExtracorporeal shockwave lithotripsy (ESWL) is the management of choice for renal stones 20 mm or smaller, with a stone clearance rate of up to 89%. The purpose of the present is to investigate the efficacy of a commercialised ESWL service, being performed as an outsourced treatment using a mobile lithotripsy system on an outpatient basis. Furthermore, the study aims to evaluate the risk of needing treatment with an internal ureteral double-J stent (JJ) after ESWL treatment.MethodsDuring an eight-year period, 461 patients with a total of 589 renal stones were treated using a mobile lithotripsy system at a single Danish institution. A commercial company performed all treatments using a Storz Modulith SLK® system. Each stone was prospectively registered according to size, intra renal location and the presence of a JJ at the time of treatment. The number of required ESWL treatments and auxiliary procedures were retrospectively evaluated.ResultsThe success rate after the initial ESWL procedure was 69%, which increased to an overall success rate of 93% after repeated treatment. A negative correlation was found between stone size and the overall success rate (rxa0=xa0−0.2, pxa0<xa00.01). The upper calyx was associated with a significantly better success rate, but otherwise intra renal stone location was not predictive for treatment success. A total of 17 patients (2.9%) required treatment with a JJ after the ESWL procedure. No significant difference was observed between the stone size or intra renal location and the risk of needing treatment with JJ after ESWL.ConclusionsCommercialised ESWL treatment can achieve an overall success rate of more than 90% using a mobile lithotripsy system. As expected, an inverse relation between stone size and success rate was found. Patients who do not require treatment with a JJ prior to ESWL will only rarely need treatment with a JJ after ESWL, irrespective of stone size and intra renal stone location.