D.M. Schmid

BOTULINUM-A TOXIN FOR TREATING DETRUSOR HYPERREFLEXIA IN SPINAL CORD INJURED PATIENTS: A NEW ALTERNATIVE TO ANTICHOLINERGIC DRUGS? PRELIMINARY RESULTS

PURPOSE We evaluated the efficacy of botulinum-A toxin injections into the detrusor muscle in patients with spinal cord injury, detrusor hyperreflexia and urge incontinence resistant to anticholinergic drugs. The purpose of treatment was to suppress incontinence episodes and increase functional bladder capacity. MATERIALS AND METHODS Included in our prospective nonrandomized study done at 2 clinics were 31 patients with traumatic spinal cord injury who emptied the bladder by intermittent self-catheterization. These patients had severe detrusor hyperreflexia and incontinence despite a high dose of anticholinergic medication. Pretreatment evaluation included a clinical examination and complete urodynamic investigation. Under cystoscopic control a total of 200 to 300 units of botulinum-A toxin were injected into the detrusor muscle at 20 to 30 sites (10 units per ml. per site), sparing the trigone. Clinical and urodynamic followup was planned for 6, 16 and 36 weeks after treatment. Patients were asked to decrease their intake of anticholinergic drugs during week 1 after treatment. RESULTS Of the 21 patients 19 underwent a complete examination 6 weeks after the botulinum-A toxin injections, and 11 at 16 and 36 weeks. At the 6-week followup complete continence was restored in 17 of 19 cases in which anticholinergic medication was markedly decreased or withdrawn. Less satisfactory results in 2 cases were associated with an insufficient dose of 200 units botulinum-A toxin. After the injections overall mean reflex volume and mean maximum cystometric bladder capacity plus or minus standard deviation significantly increased from 215.8 +/- 90.4 ml. to 415.7 +/- 211.1 (p <0.016) and 296.3 +/- 145.2 to 480.5 +/- 134.1 (p <0.016), respectively. There was also a significant decrease after treatment in mean maximum detrusor voiding pressure from 65.6 +/- 29.2 cm. water to 35 +/- 32. 1 (p <0.016). Mean post-void residual urine volume catheterized at the end of the urodynamic examination increased significantly from a mean of 261.8 +/- 241.3 ml. to 490.5 +/- 204.8 (p <0.016). Moreover, autonomic dysreflexia associated with bladder emptying that manifested as a hypertensive crisis during voiding disappeared after treatment in the 3 patients with tetraplegia. Satisfaction was high in all successfully treated patients and no side effects were observed. Ongoing improvement in urodynamic parameters and incontinence was already present in all patients reevaluated at 16 and 36 weeks. CONCLUSIONS Botulinum-A toxin injections into the detrusor seem to be a safe and valuable therapeutic option in spinal cord injured patients with incontinence resistant to anticholinergic medication who perform clean intermittent self-catheterization. Successfully treated patients become continent again and may withdraw from or markedly decrease anticholinergic drug intake. A dose of 300 units botulinum-A toxin seems to be needed to counteract an overactive detrusor. The duration of bladder paresis induced by the toxin is at least 9 months, when repeat injections are required.

Experience With 100 Cases Treated With Botulinum-A Toxin Injections in the Detrusor Muscle for Idiopathic Overactive Bladder Syndrome Refractory to Anticholinergics

PURPOSE In this prospective, nonrandomized, ongoing study we evaluated the efficacy and safety of botulinum-A toxin injections in the detrusor muscle to treat patients with idiopathic overactive bladder resistant to conventional treatment, such as anticholinergic drugs. MATERIALS AND METHODS A total of 23 men and 77 women with a mean age of 63 years (range 24 to 89) with nonneurogenic overactive bladder, including urgency-frequency syndrome, and incontinence despite the administration of maximal doses of anticholinergics were consecutively treated with injections of 100 U botulinum-A toxin in the detrusor muscle at 30 sites under cystoscopic guidance. Micturition diary, full urodynamics, neurological status and urine probes were performed in all participants before treatment. Bladder biopsies were done only in cases of suspected bladder fibrosis or unclear findings. Special attention was given to reflex volume, maximal bladder capacity, detrusor compliance, post-void residual urine, urgency and frequency/nocturia. Clinical, urodynamic and quality of life assessments were performed at baseline, and 4, 12 and 36 weeks after botulinum-A toxin treatment. RESULTS Overall after 4 and 12 weeks 88% of our patients showed significant improvement in bladder function in regard to subjective symptoms, quality of life and urodynamic parameters (p <0.001). Urgency disappeared in 82% of the patients and incontinence resolved in 86% within 1 to 2 weeks after botulinum-A toxin injections. Mean frequency decreased from 14 to 7 micturitions daily (-50%) and nocturia decreased from 4 to 1.5 micturitions. Mean maximal bladder capacity increased 56% from 246 to 381 ml, mean detrusor compliance increased from 24 to 41 ml/cm H(2)O and pretreatment detrusor instability (mean reflex volume 169 ml) resolved in 74% of patients. Mean volume at first desire to void increased from 126 to 212 ml and mean urge volume increased from 214 to 309 ml. There were no severe side effects except temporary urine retention in 4 cases. Only in 8 patients was the clinical benefit poor and analysis revealed preoperative low detrusor compliance. Mean efficacy duration +/- SD was at least approximately 6 +/- 2 months and then symptoms began to increase. CONCLUSIONS Our results show that intradetrusor botulinum-A toxin injections may be an efficient and safe treatment option in patients with severe overactive bladder resistant to all conventional treatments.

Sildenafil in the Treatment of Sexual Dysfunction in Spinal Cord–Injured Male Patients

Objectives: The aim of this study was to evaluate the efficacy and safety of sildenafil in the treatment of erectile dysfunction (ED) in spinal cord–injury (SCI) patients. Moreover, we looked for neurological conditions permitting therapeutic success and for the ideal dose needed to achieve sufficient erections.Methods: 41 SCI patients were prospectively examined. Sexual dysfunction was assessed by means of anamnesis, the International Index of Erectile Function (IIEF) questionnaire, and neurological examination. Psychogenic erection capacity was tested by audiovisual stimulation and reflexive erection using a vibrator device. Neurophysiological recordings and cystomanometry were performed in parallel to clinical examinations. Neurophysiological recordings included sympathetic skin responses (SSR), pudendus somatosensory evoked potentials (pSSEP), and bulbocavernous reflex (BCR). Urodynamics aimed at classifying the neurogenic bladder dysfunction (upper motoneuron lesion versus lower motoneuron lesion). Intracavernous injection tests with PGE1 were performed in all patients to exclude major organic disease. 50 mg sildenafil was first given 3 times. Thereafter, the doses were adapted according to patients’ reports.Results: Clinically, 28 subjects preserved either reflexive erections (24) or psychogenic erections (4), 11 had both types and only 2 presented with a complete loss of erection. 38 patients (93%) had a positive response to sildenafil and reached a penile rigidity sufficient to permit sexual intercourse. 3 patients dropped out because of non–response despite having increased the dosis up to 100 mg. 22 patients (58%) showed functional erections 1 h after 50 mg sildenafil, whereas 14 (37%) required higher doses of 75–100 mg. By comparing the IIEF questionnaire scores before and after therapy, there was a significant improvement in erectile function and intercourse satisfaction from 9.2±4.4 SD) and 4.5 (±2.5 SD) to 25.5 (±4.2 SD) and 10.5 (±2.1 SD) points, respectively (p<0.05). Nearly 10% (4/41) suffered from side effects such as headache or dizziness. Two of them stopped therapy because of the side effects. At least 36 patients (88%) continue treatment with sildenafil. Absence of both psychogenic (nonsomesthetic supraspinally elicited) and reflexive (somesthetic spinally elicited) erections, confirmed by urodynamical and electrophysiological findings (SSR perineum, BCR and pSSEP), seems to exclude a successful treatment. In contrast, SCI male patients with preserved function of at least one component of the erection phenomenon (psychogenic/reflexive) responded well to sildenafil and the dose required to achieve erections sufficient for sexual intercourse did not differ between the two groups.Conclusions: Sildenafil proves to be a valuable and safe therapeutic management in ED of SCI patients. Therefore, patient acceptance and satisfaction are high. The most common dose required to achieve a satisfying erection is 50 mg. The efficacy of sildenafil depends on sparing of either sacral (S2–S4) or thoracolumbar (T10–L2) spinal segments which, in this study, have been shown to be of relevance in mediating psychogenic erections in male SCI patients. Complete disturbance of any neurogenic impulses excludes successful treatment.

Robotic-Assisted Laparoscopic Extended Pelvic Lymph Node Dissection for Prostate Cancer: Surgical Technique and Experience with the First 99 Cases

BACKGROUND To date, there is still a paucity of data in the literature on robotic-assisted laparoscopic extended pelvic lymph node dissection (RALEPLND) in patients with prostate cancer. OBJECTIVE To assess the technical feasibility of RALEPLND and to present our surgical technique. DESIGN, SETTING, AND PARTICIPANTS From April 2006 to March 2008, we performed RALEPLND in 99 patients prior to robotic-assisted laparoscopic radical prostatectomy. Indications for RALEPLND were a prostate-specific antigen (PSA) > or = 10 ng/ml or a preoperative Gleason score > or = 7. The data were evaluated retrospectively. SURGICAL PROCEDURE The transperitoneal approach was used in all cases. In order to gain optimal access to the common iliac bifurcation, the five trocars were placed in a more cephalad position than in patients undergoing radical prostatectomy without RALEPLND. After identification of important landmarks, the lymphatics covering the external iliac vein, the obturator lymphatic packet, and the lymphatics overlying the internal iliac artery were removed on both sides. MEASUREMENTS The total lymph node yield, the frequency of lymph node metastases, and the complication rate. RESULTS AND LIMITATIONS The median patient age was 64 yr (range: 45-78). The median preoperative PSA level was 7.7 ng/ml (range: 1.5-84.6). The median number of lymph nodes harvested was 19 (range: 8-53). In 16 patients (16%), we found lymph node metastasis. Complications occurred in seven patients (7%). CONCLUSIONS RALEPLND is feasible, and its lymph node yield is well in the range of open series. The robotic-assisted laparoscopic approach in itself does not seem to limit a surgeons ability to perform a complete extended pelvic lymph node dissection.

Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses

Renal proximal tubular epithelial cells, a target of infiltrating T cells during renal allograft rejection, may be protected from this injury by the cell surface protein CD274 (also termed PD-L1 for programmed death ligand 1). The co-inhibitory molecules PD-L1 (CD274) and PD-L2 (CD273) are ligands of PD-1 (programmed death 1; CD279). Here we determine the functional role of PD-1/PD-L pathways in human renal allograft rejection. Treatment of human primary tubular epithelial cells with interferon-beta and -gamma caused a dose-dependent and synergistic increase of PD-L1 and PD-L2 expression. Blockade of surface PD-L1, but not PD-L2, on interferon-treated tubular epithelial cells resulted in a significant increase in CD4+ T-cell proliferation and cytokine production by CD4+ and CD8+ T cells. The expression of PD-L1, PD-L2, and PD-1 mRNA and protein was upregulated in biopsies of patients with renal allograft rejection compared to the respective levels found in the pre-transplant biopsies. Induction of PD-L1 was significantly associated with acute vascular rejection. Our study suggests that the renal epithelial PD-1/PD-L1 pathway exerts an inhibitory effect of on alloreactive T-cell responses. The upregulation of PD-L1 on proximal tubular epithelial cells in patients with acute allograft rejection may reduce T-cell-mediated injury.

Sympathetic sudomotor skin activity in human after complete spinal cord injury

Spinal cord injury (SCI) causes serious disturbances in autonomic innervation and malfunction of the sympathetic nervous system that controls the pelvic organs, blood pressure, skin temperature and sweating. We studied sympathetic sudomotor pathways in 6 healthy subjects and 14 patients with sensory and motor complete SCI on cervical, thoracic and lumbar level. Sympathetic skin responses (SSRs) were provoked by auditory bursts and electrical stimulation of median, pudendal and tibial nerve and recorded from the palmar and plantar skin. The SSRs in healthy subjects occurred generally with the same pattern and with similar latencies suggesting a common sudomotor pathway mediating the SSR. Appearance or absence of the SSRs in SCI following stimulation above the lesion depend on the spinal level of lesion and on the location of stimulation. Lesions below T3 show palmar and lesions below T12 palmar and plantar SSR. Pudendal nerve stimulation evoked plantar SSRs in patients with complete cervical and thoracic SCI. No SSRs were obtained in patients with lesions at L1 and more caudal. SSRs following pudendal nerve stimulation in complete SCI above the level L1 are mediated by sacral somatic afferents and a sympathetic pathway originating at the upper lumbar level. The underlying sacro-lumbar reflex circuit is organized on spinal level and requires intact lumbar segments. Tibial nerve stimulation was not found to elicit SSRs below a SCI lesion and we suppose that this type of electrical stimulation cannot activate the spinal sudomotor reflex circuit.

Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer

The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long‐term follow‐up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E‐cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1‐MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome.

Immunoscintigraphy of patients with head and neck carcinomas, with an anti-angiogenetic antibody fragment

Objective In a phase I/II clinical study, we investigated tumor targeting in patients with head and neck squamous cell carcinomas (SCC), using an antibody directed against the extra-domain-B of fibronectin (EDB), a marker of angiogenesis and tissue remodeling. Study Design And Setting Five patients with SCC were injected with the 123-iodine-radiolabeled L19(scFv)2 antibody and underwent scintigraphic detection with single photon emission tomography with computerized tomography (SPECT/CT). In addition, 18 F-fluorodeoxyglucose ( 18 FDG) positron emission tomography with computerized tomography (PET/CT) was performed. Results Successful targeting of the primary tumor could be achieved in 4 of 5 patients and was comparable to PET imaging. No side effects were observed. Conclusions Tumor targeting with the L19(scFv)2 antibody is also feasible for head and neck SCC. Significance These results may serve as a base for future therapeutical applications in human beings, with modified versions of the L19(scFv)2 antibody, designed to selectively deliver bioactive molecules into malignant tumors.

3D-Segmentation of the 18F-choline PET Signal for Target Volume Definition in Radiation Therapy of the Prostate

Volumetric assessment of PET signals becomes increasingly relevant for radiotherapy (RT) planning. Here, we investigate the utility of 18F-choline PET signals to serve as a structure for semi-automatic segmentation for forward treatment planning of prostate cancer. 18F-choline PET and CT scans of ten patients with histologically proven prostate cancer without extracapsular growth were acquired using a combined PET/CT scanner. Target volumes were manually delineated on CT images using standard software. Volumes were also obtained from 18F-choline PET images using an asymmetrical segmentation algorithm. PTVs were derived from CT 18F-choline PET based clinical target volumes (CTVs) by automatic expansion and comparative planning was performed. As a read-out for dose given to non-target structures, dose to the rectal wall was assessed. Planning target volumes (PTVs) derived from CT and 18F-choline PET yielded comparable results. Optimal matching of CT and 18F-choline PET derived volumes in the lateral and cranial-caudal directions was obtained using a background-subtracted signal thresholds of 23.0+/-2.6%. In antero-posterior direction, where adaptation compensating for rectal signal overflow was required, optimal matching was achieved with a threshold of 49.5+/-4.6%. 3D-conformal planning with CT or 18F-choline PET resulted in comparable doses to the rectal wall. Choline PET signals of the prostate provide adequate spatial information amendable to standardized asymmetrical region growing algorithms for PET-based target volume definition for external beam RT.

Electrophysiological Assessment of Sensations Arising from the Bladder: Are there Objective Criteria for Subjective Perceptions?

PURPOSE Initial bladder filling sensation, first and strong desire to void are subjective perceptions that occur periodically during the urine storage mode of bladder function, representing sensory input from the lower urinary tract. To our knowledge methods for evaluating sensory bladder function are not available. We studied a simple electrophysiological procedure for the objective assessment of bladder sensations using sympathetic skin responses and surface pelvic floor electromyography. MATERIALS AND METHODS Informed consent was provided by 8 healthy male subjects, who were administered 20 mg. furosemide and 1 l. fluid to drink. Palmar and plantar sympathetic skin responses, and surface pelvic floor electromyogram were continuously recorded during bladder filling, voluntary pelvic floor contraction and voiding. RESULTS First desire to void evoked simultaneous sympathetic skin responses and pelvic floor contractions. This pattern appeared periodically with the desire to void sensation as well as with strong desire to void at maximum bladder capacity and it correlated well with the subjective sensation of the subjects. Voluntary pelvic floor contraction decreased the subjective intensity of the desire to void sensation as well as sympathetic skin response activity for the same short period. During voiding sympathetic skin responses almost complete absence of sympathetic skin responses was observed. CONCLUSIONS Sensations arising from the bladder induce combined activation of sympathetic skin responses and pelvic floor activity. This coherence indicates synchronized activation and inactivation of the autonomic and somatic pathways necessary for appropriate urine storage and coordinated voiding. Our observations may introduce a new approach for objectively assessing subjective sensations arising from the urinary tract.