Alexander Karl

An angiogenic role for the human peptide antibiotic LL-37/hCAP-18

Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor-like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.

Hexaminolevulinate Guided Fluorescence Cystoscopy Reduces Recurrence in Patients With Nonmuscle Invasive Bladder Cancer

PURPOSE We assessed the impact that improved detection of nonmuscle invasive bladder cancer with hexaminolevulinate fluorescence cystoscopy may have on early recurrence rates. MATERIALS AND METHODS This prospective, randomized study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence. All patients underwent white light cystoscopy and mapping of lesions, followed by transurethral resection of the bladder when indicated. Patients in the fluorescence group also received intravesical hexaminolevulinate solution at least 1 hour before cystoscopy to induce fluorescence of cancerous lesions, and underwent additional inspection with blue light before and after transurethral resection of the bladder. Adjuvant intravesical therapy was based on risk. Followup cystoscopy at 3, 6 and 9 months was conducted with white light. RESULTS Detection was performed as a within patient comparison in the fluorescence group. In this group 286 patients had at least 1 Ta or T1 tumor (intent to treat). In 47 patients (16%) at least 1 of the tumors was seen only with fluorescence (p = 0.001). During the 9-month followup (intent to treat) there was tumor recurrence in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the white light group (p = 0.026). The relative reduction in recurrence rate was 16%. CONCLUSIONS Hexaminolevulinate fluorescence cystoscopy significantly improves the detection of Ta and T1 lesions and significantly reduces the rate of tumor recurrence at 9 months.

Photodynamic Diagnosis of Non–muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data

BACKGROUND Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Lairds random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

The impact of lymphadenectomy and lymph node metastasis on the outcomes of radical cystectomy for bladder cancer.

CONTEXT The presence of lymph node metastases and the extent of lymphadenectomy have both been shown to influence the outcome of patients with muscle-invasive bladder cancer. OBJECTIVE Current standards for detection of lymph node metastases, lymph-node mapping studies, histopathologic techniques, and risk factors in relation to lymph node involvement are discussed. The impact of lymph node metastases and the extent of lymphadenectomy on the outcome of patients treated with radical cystectomy are analyzed. EVIDENCE ACQUISITION A systematic literature review of bladder cancer and lymph nodes was performed searching the electronic databases Pubmed/Medline, Cochrane, and Embase. Articles were selected based on title, abstract, study format, and content by a consensus of all participating authors. EVIDENCE SYNTHESIS Lymph node status is highly consequential in bladder cancer patients because the presence of lymph node metastases is predictive of poor outcome. Knowledge of primary landing sites of lymph node metastases is important for optimum therapeutic management. Accurate pathologic work-ups of resected lymph node tissue are mandatory. Molecular markers could potentially guide therapeutic decisions in the future because they may enable the detection of micrometastatic disease. In current series, radical cystectomy with an extended lymphadenectomy seems to provide a clinically meaningful therapeutic benefit compared with a limited approach. However, the anatomic boundaries of lymph node dissection are still under debate. Therefore, large prospective multicenter trials are needed to validate the influence of extended lymph node dissection on disease-specific survival. CONCLUSIONS An extended pelvic lymph node dissection (encompassing the external iliac vessels, the obturator fossa, the lateral and medial aspects of the internal iliac vessels, and at least the distal half of the common iliac vessels together with its bifurcation) can be curative in patients with metastasis or micrometastasis to a few nodes. Therefore, the procedure may be offered to all patients undergoing radical cystectomy for invasive bladder cancer.

Prostate Cancer Managed with Active Surveillance: Role of Anatomic MR Imaging and MR Spectroscopic Imaging

PURPOSE To determine the role that magnetic resonance (MR) imaging and MR spectroscopic imaging findings obtained at the time of diagnosis play in the progression of disease in patients whose prostate cancer is being managed with active surveillance and to compare the role of these findings with the role of transrectal ultrasonography (US) findings. MATERIALS AND METHODS The institutional review board approved this HIPAA-compliant retrospective study, and informed consent was obtained from all patients whose records were to be entered into the research database. All patients who had prostate cancer managed with active surveillance and who had undergone both MR imaging and MR spectroscopic imaging of the prostate and transrectal US at time of diagnosis were identified. Two urologists blinded to the clinical outcome in these patients independently reviewed and dichotomized the MR imaging report and the MR spectroscopic imaging report as normal or suggestive of malignancy. One experienced urologist performed all US examinations that were then dichotomized similarly. Uni- and multivariate (with use of standard clinical variables) Cox models were fitted to assess time to cancer progression, defined as Gleason score upgrading, prostate-specific antigen velocity of more than 0.75 (microg x L(-1))/y, or initiation of treatment more than 6 months after diagnosis. RESULTS The final cohort included 114 patients with a median follow-up of 59 months. Patients with a lesion that was suggestive of cancer at MR imaging had a greater risk of the Gleason score being upgraded at subsequent biopsy (hazard ratio, 4.0; 95% confidence interval: 1.1, 14.9) than did patients without such a lesion. Neither MR spectroscopic imaging nor transrectal US could be used to predict cancer progression. CONCLUSION Abnormal prostate MR imaging results suggestive of cancer may confer an increased risk of Gleason score upgrade at subsequent biopsy. Although expensive, prostate MR imaging may help in counseling potential candidates about active surveillance.

Diagnosis of urothelial carcinoma of the bladder using fluorescence endoscopy

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of superficial bladder cancer are now well established, significant challenges remain, which influences patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity, and increase quality of life and survival. Fluorescence endoscopy, often referred to as ‘photodynamic diagnosis’ (PDD), with intravesical application of photosensitizing agents, has been developed to enhance the early detection of bladder cancer. There is growing evidence that PDD using 5‐aminolaevulinic acid (ALA), hexyl‐ALA ester or hypericin enhances the detection of bladder cancer, particularly of high‐grade flat lesions. Furthermore, transurethral resection of bladder tumour under fluorescence guidance reduces the risk of recurrent tumours. However, the impact on the progression of disease remains unclear and must be investigated in prospective randomized trials.

A New Concept for Early Recovery after Surgery for Patients Undergoing Radical Cystectomy for Bladder Cancer: Results of a Prospective Randomized Study

PURPOSE Early recovery after surgery concepts have gained wide acceptance in various surgical specialties. However, limited data are available for radical cystectomy. A new early recovery after surgery concept was compared to a more conservative regimen in patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS A total of 101 consecutive patients were prospectively randomized to early recovery after surgery (62) or a conservative regimen (39) (intended randomization ratio was 2 early recovery after surgery-to-1 conservative regimen). Primary end points were differences in quality of life, and secondary end points included postoperative morbidity, demand for analgesics, time spent in the intermediate care unit, mobility and number of gastrointestinal events during hospital stay. RESULTS Quality of life parameters, as measured by the EORTC (European Organization for the Research and Treatment of Cancer) Quality of Life questionnaire QLQ-30 did not change significantly between postoperative days 3 and 7 and at discharge from hospital in the conservative regimen group, whereas a significant improvement was observed in the early recovery after surgery group. Postoperative morbidity was lower in the early recovery after surgery group in terms of wound healing disorders (p = 0.006), fever (p = 0.004) and thrombosis (p = 0.027). The demand for analgesics was significantly lower in the early recovery after surgery group. The amount of food consumed in relation to the amount of food offered was significantly higher for the early recovery after surgery group as early as day 3 (p = 0.02). Time spent in the intermediate care unit was significantly shorter for the early recovery after surgery group (p <0.001). There were no significant differences between the groups with respect to gastrointestinal events. The main limitations of this study were the lack of long-term data as well as the single center approach. CONCLUSIONS Early recovery after surgery of patients who underwent radical cystectomy appears to have significant benefits compared to a conservative regimen in terms of postoperative morbidity, quality of life, use of analgesics and time spent in the intermediate care unit.

Mid-term results for the retroluminar transobturator sling suspension for stress urinary incontinence after prostatectomy

Study Type – Therapy (case series) 
Level of Evidence 4

Quality of life and perioperative outcomes after retroperitoneoscopic radical nephrectomy (RN), open RN and nephron-sparing surgery in patients with renal cell carcinoma

To prospectively evaluate health‐related quality of life (HRQoL) and perioperative outcomes in patients with T1 and T2 renal cell carcinoma (RCC) after retroperitoneoscopic radical nephrectomy (RRN), open RN (ORN) or open nephron‐sparing surgery (NSS).

Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma

Study Type – Therapy (case series)