Remarkable application of serum EBV EBER-1 in monitoring response of nasopharyngeal cancer patients to salvage chemotherapy.

Nineteen consecutive patients with metastatic or recurrent nasopharyngeal cancer (NPC) receiving combination chemotherapy were monitored for EBV DNA in their serum. EBV DNA (EBER-1) concentration in serum was measured before, during, and after chemotherapy. Thirteen patients had additional multiple prechemotherapy readings. There was a significant lead time from first detection of serum EBER-1 to clinical recurrence in 62% of patients by a mean of 17.4 weeks (range: 8-74.5 weeks; mean = 28.2 weeks if confined to the 8 patients with significant lead time). The median EBER-1 concentration was significantly higher in those with distant metastasis as compared to those with loco-regional recurrence only (17,468 vs. 684 pg/mL serum; p = 0.046, Mann-Whitney U test). Among the 13 patients who responded to chemotherapy, 4 exhibited clinical complete remission (CR) who were only found in the group with EBER-1 DNA drop to background level, while the magnitude of EBER-1 drop did not discriminate partial remission (PR) and stable disease (SD) patients clearly. Subsequent profile of EBER-1 DNA showed concordance with clinical course of either continuous remission or later progression. EBER-1 DNA in serum can become a useful adjunctive surrogate marker to monitor chemotherapeutic response in NPC patients with distant metastasis or advanced local recurrence.

Urethral pressure profiles in the female canine implanted with sacral anterior nerve root electrodes.

The purpose of this work was to study the pressure distribution along the urethra in female canines with and without electrical stimulation of the sacral anterior roots innervating the bladder and urethra. Urethral pressure profiles were recorded in two orientations, dorsal and ventral, with microtransducer catheters. Two pulse types were applied at 1 Hz, 500 micros quasitrapezoidal pulses to selectively activate the small axons and 100 micros rectangular pulses. Four parameters were measured from each profile; maximum urethral pressure (MUP), bladder pressure (Pv), functional urethral length (FUL), and the position of the maximum peak from the bladder neck (PMP). Two derived measures, the estimated maximum urethral closing pressure (UCP) and the position of the maximum as a percentage of the FUL (PM%) were calculated. There were highly significant differences (P<0.01) in the value and position of the estimated UCP in the two orientations of the transducers. The highest pressures were recorded in the ventral orientation near the terminal portions of the urethra. Principal sphincter activity during electrical stimulation of the ventral sacral roots was also confined to this part. Selective small fiber activation did not result in any significant increase in this peak pressure from passive values.

Efficacy of sacral nerve stimulation for urinary retention: results 18 months after implantation.

PURPOSE: We investigate the efficacy of sacral neurostimulation in patients with idiopathic urinary retention in a prospective, randomized multicenter trial. MATERIALS AND METHODS: A total of 177 patients with urinary retention refractory to standard therapy were enrolled in the study. Greater than 50% improvement in baseline voiding symptoms during a 3 to 7-day percutaneous test stimulation qualified a patient for surgical implantation of an InterStim parallel system. Of the patients who qualified for implantation 37 were randomly assigned to a treatment and 31 to a control group. Patients in the treatment group underwent early surgical implantation of the sacral nerve stimulation system, while implantation was delayed in the control group for 6 months. Followup evaluations, including voiding diary analysis and temporary deactivation of the stimulator at 6 months, were conducted at 1, 3, 6, 12 and 18 months after implantation in the treatment group, and after 3 and 6 months in the control group. RESULTS: Compared to the control group, patients implanted with the InterStim system had statistically and clinically significant reductions in the catheter volume per catheterization (p <0.0001). Of the patients treated with implants 69% eliminated catheterization at 6 months and an additional 14% had a 50% or greater reduction in catheter volume per catheterization. Therefore, successful results were achieved in 83% of the implant group with retention compared to 9% of the control group at 6 months. Temporary inactivation of sacral nerve stimulation therapy resulted in a significant increase in residual volumes (p <0.0001) but effectiveness of sacral nerve stimulation was sustained through 18 months after implant. CONCLUSIONS: Results of this prospective, randomized clinical study demonstrate that sacral nerve stimulation is effective for restoring voiding in patients with retention who are refractory to other forms of treatment.

Trospium chloride--an effective drug in the treatment of overactive bladder and detrusor hyperreflexia.

Trospium chloride (TCL), a quaternary ammonium derivative of nortropanol, has been evaluated in a number of clinical and pharmacological studies. Selected pharmacological and clinical pharmacokinetic data are discussed as providing a basis for a better interpretation and understanding of the clinical trial results. An overview of the results of 20 clinical trials and post-marketing surveillance studies including more than 10000 patients is presented.

Historical aspects of the treatment of urinary incontinence.

Ancient reports on urinary incontinence are rather rare and mainly address cases of extraurethral incontinence, e.g. due to a fistula acquired during childbirth or overflow incontinence, e.g. in males with urinary retention or after spinal cord injury. In modern times several authors dealt with the problem of postoperative incontinence after perineal lithotomy. Surgical techniques for the cure of urinary incontinence were not introduced before the 19th century. First this was limited to fistula repair but at the turn of the century new procedures for stress incontinence were introduced and became standard clinical procedures. Other modern techniques, e.g. artificial sphincters or electrostimulation, were alternatives developed in urology during the second half of our century. This article from the history of medicine outlines early reports on urinary incontinence and reveals a more detailed review of the different treatment options including conservative therapies, incontinence devices, electrotherapy and surgical procedures, including injection therapies and artificial sphincters.

[Therapy for kidney cell carcinoma with cava thrombus. Importance of extracorporeal circulation and prognostic value of cranial tumor extension]. / Therapie des Nierenzellkarzinoms mit Kavathrombus. Stellenwert der extrakorporalen Zirkulathion (EKZ) und prognostische Bedeutung der kranialen tumorextension.

In approximately 4-10 % of patients presenting with renal cell cancer the transluminal propagation of a tumor thrombus into the vena cava inferior or the right atrium comes to diagnosis. Recent investigations have indicated that the presence of neoplastic extension into the venous system does not reveal independent prognostic value regarding the clinical course of the disease. Although the complete surgical removal of vena cava thrombosis in patients without simultaneously occurring regional lymph node or distant metastases has become a well established treatment modality, several questions concerning this surgical strategy still remain the subject of ongoing discussions. In the present investigation that included 92 patients with renal cell cancer and intracaval neoplastic extension it was clearly demonstrated that the use of cardiopulmonary bypass, deep hypothermia and circulatory arrest preferably during the removal of intracaval thrombosis extending into the right atrium does not result in a substantially increased treatment-related intra- or postoperative mortality. However, in contrast to a previously reported observation this treatment option did not reveal any substantial impact on the long-term survival of the patients following surgical therapy. Accordingly, the cranial extension of intracaval thrombosis was not identified as a biological variable of any prognostic importance for renal cell cancer patients.

Detection of Epstein-Barr virus in invasive breast cancers.

BACKGROUND: Epstein-Barr virus (EBV) may be a cofactor in the development of different malignancies, including several types of carcinomas. In this study, we investigated the presence of EBV in human breast cancers. METHODS: We used tissues from 100 consecutive primary invasive breast carcinomas, as well as 30 healthy tissues adjacent to a subset of the tumors. DNA was amplified by use of the polymerase chain reaction (PCR), with the primers covering three different regions of the EBV genome. Southern blot analysis was performed by use of a labeled EBV BamHI W restriction fragment as the probe. Infected cells were identified by means of immunohistochemical staining, using monoclonal antibodies directed against the EBV nuclear protein EBNA-1. RESULTS: We were able to detect the EBV genome by PCR in 51% of the tumors, whereas, in 90% of the cases studied, the virus was not detected in healthy tissue adjacent to the tumor (P<.001). The presence of the EBV genome in breast tumors was confirmed by Southern blot analysis. The observed EBNA-1 expression was restricted to a fraction (5%-30%) of tumor epithelial cells. Moreover, no immunohistochemical staining was observed in tumors that were negative for EBV by PCR. EBV was detected more frequently in breast tumors that were hormone-receptor negative (P =.01) and those of high histologic grade (P =.03). EBV detection in primary tumors varied by nodal status (P =.01), largely because of the difference between subjects with more than three lymph nodes versus less than or equal to three lymph nodes involved (72% versus 44%). CONCLUSIONS: Our results demonstrated the presence of the EBV genome in a large subset of breast cancers. The virus was restricted to tumor cells and was more frequently associated with the most aggressive tumors. EBV may be a cofactor in the development of some breast cancers.

Urodynamics in the anatomical work of Leonardo da Vinci (1452-1519).

Leonardo da Vinci (1452-1519) incorporates the symbiosis of art and medicine and can be addressed as the founder of medical illustration in the time of the Renaissance. His anatomy studies were not published in his time, which explains why Leonardo's outstanding knowledge of anatomy, physiology, and medicine had no impact on his scientific contemporaries and is therefore primarily of retrospective importance in the history of medicine. The collection of anatomical illustrations remained unknown until their rediscovery in the eighteenth century and their wide publication at the beginning of our century. This article systematically reviews Leonardo's genitourinary drawings with regard to urodynamic aspects of the upper and lower urinary tract, highlighting topics such as vesicoureteral reflux and urinary sphincter mechanisms.

Sacral electrical neuromodulation as an alternative treatment option for lower urinary tract dysfunction.

Temporary electrical stimulation using anal or vaginal electrodes and an external pulse generator has been a treatment modality for urinary urge incontinence for nearly three decades. In 1981 Tanagho and Schmidt introduced chronic electrical stimulation of the sacral spinal nerves using a permanently implanted sacral foramen electrode and a battery powered pulse generator for treatment of different kinds of lower urinary tract dysfunction, refractory to conservative treatment. At our department chronic unilateral electrical stimulation of the S3 sacral spinal nerve has been used for treatment of vesi-courethral dysfunction in 43 patients with a mean postoperative follow up of 43,6 months. Lasting symptomatic improvement by more than 50 % could be achieved in 13 of 18 patients with motor urge incontinence (72,2 %) and in 18 of the 21 patients with urinary retention (85,7 %). Implants offer a sustained therapeutic effect to treatment responders, which is not achieved by temporary neuromodulation. Chronic neuromodulation should be predominantly considered in patients with urinary retention. Furthermore in patients with motor urge incontinence, refusing temporary techniques or in those requiring too much effort to achieve a sustained clinical effect. Despite high initial costs chronic sacral neuromodulation is an economically reasonable treatment option in the long run, when comparing it to the more invasive remaining therapeutic alternatives.

Functional conditions of micturition induced by selective sacral anterior root stimulation: experimental results in a canine animal model.

Electrical stimulation of the sacral anterior roots using conventional rectangular current pulses results in a simultaneous contraction of the urinary bladder and the striated urethral sphincter. Using a tripolar nerve cuff electrode with quasitrapezoidal current pulses and appropriate stimulation parameters, hyperpolarization of the nerve-fiber cell membrane under the anode of the stimulating electrode can reversibly arrest action potential propagation in large myelinated nerve fibers, innervating the striated urethral sphincter, while leaving action potential propagation unaffected in small nonmyelinated nerve fibers innervating the urinary bladder smooth muscle (anodal arrest). Using this technique in 19 female mongrel dogs, we studied the effect of bladder filling, level of anesthesia, and sacral deafferentation on bladder pressure, urethral pressure, and urinary flow. Effective micturition could be induced only after complete dorsal rhizotomy, abolishing reflex contraction of the striated urethral sphincter, when blocking quasitrapezoidal current pulses were used for stimulation. Stimulation with rectangular current pulses directly induced a rise in distal urethral pressure, preventing micturition during stimulation.

A questionnaire-based outcome analysis of the Stamey bladder neck suspension procedure for the treatment of urinary stress incontinence: the Hannover experience.

OBJECTIVES: To evaluate the long-term continence rate, including subjective satisfaction and therapy-associated morbidity, of patients undergoing Stamey bladder neck suspension. PATIENTS AND METHODS: Eighty-five women (median age 55 years, range 30-85) with urinary stress incontinence treated by Stamey bladder neck suspension at our institution between 1987 and 1995 were evaluated using an anonymous questionnaire over a mean (range) follow-up of 61 (13-93) months. RESULTS: Of the 85 patients, 44 (52%) reported an improvement in clinical symptoms at the evaluation and 29 (34%) were completely continent after the Stamey procedure. However, 53 (62%) patients reported subjective satisfaction with the result, because they had a durable improvement in continence for a mean (range) of 44 (10-79) months. There was no correlation between the number of previous urogynaecological operations undergone by the patients and the success of the Stamey procedure. However, the frequency of complications other than urinary retention was significant during and after surgery, at 27%, and in accord with the complication rate reported in earlier studies. CONCLUSIONS: Compared with other bladder neck suspension procedures, e.g. Burch colposuspension, the Stamey procedure appears to be associated with a higher frequency of postoperative recurrent urinary stress incontinence. Therefore, the Stamey procedure should only be used if the patient demands a minimally invasive surgical procedure for bladder neck suspension. Although approximately equal to 60% of patients were satisfied with the durable improvement in clinical symptoms, it is appropriate to inform patients before surgery of the high recurrence rate after Stamey bladder neck suspension.

Does bone anchor fixation improve the outcome of percutaneous bladder neck suspension in female stress urinary incontinence?

OBJECTIVE: To evaluate the outcome of a new modification of percutaneous needle suspension, using a bone anchor system for fixing the suture at the public bone, and to compare the results with those published previously. PATIENTS AND METHODS: From March 1996, 37 patients with stress urinary incontinence (> 2 years) were treated using a bone anchor system. On each side the suture was attached to the pubocervical fascia and the vaginal wall via a broad 'Z'-stitch. A urodynamic investigation performed preoperatively in all patients confirmed stress incontinence and excluded detrusor instability. The outcome was assessed by either by a clinical follow-up investigation or using a standardized questionnaire, over a mean follow-up of 11 months (range 6-18). RESULTS: In the 37 patients, the procedure was successful in 25 (68%), with 16 (43%) of the patients completely dry and nine (24%) significantly improved. Removal of the bone anchor and suture was necessary in two patients, because of unilateral bacterial infection in one and a bilateral soft tissue granuloma in the other. One bone anchor became dislocated in a third patient. In two cases where the treatment failed, new detrusor instability was documented urodynamically. Minor complications were prolonged wound pain in 10 (26%) and transient urinary retention or residual urine in 12 patients (32%). CONCLUSION: The poor success rate in the study corresponds with the long-term results of conventional or modified needle suspension procedures and does not reinforce the optimistic results of bone anchoring published recently. Because of the poorer long-term results from percutaneous needle suspension than from other techniques of open retropubic bladder neck suspension, it remains questionable whether percutaneous needle suspension should be considered a first-line procedure for the treatment of female stress urinary incontinence.

[Percutaneous bladder neck suspension with osseous fixation. Surgical technique and initial results in 26 patients]. / Perkutane Blasenhalssuspension mit ossärer Verankerung. OP-Technik und erste Ergebnisse bei 26 Patientinnen.

A modification of percutaneous needle suspension using a bone anchor system for fixation of the suture to the pubic bone is presented. After a follow-up of 3-11 months (mean 6,8) the postoperative success-rate in 26 patients is 73.1% (n = 19). A removal of bone anchor and suture was necessary in 2 patients because of bacterial infection or soft tissue granuloma. We can not reinforce the very optimistic results of the first reports published in the recent years. Therefore it is still questionable whether percutaneous needle bladder neck suspension should be a first line procedure for the treatment of female urinary stress incontinence.

Amino-acid change in the Epstein-Barr-virus ZEBRA protein in undifferentiated nasopharyngeal carcinomas from Europe and North Africa.

Different Epstein-Barr-virus(EBV) variants were found to be associated with nasopharyngeal carcinoma (NPC). The type-C variant lacks the BamHI site between the BamHI W1* and I* regions and the type-f variant has an extra BamHI site in the BamHI F fragment. The BNLF1 gene (which encodes the LMP1 protein) from a nude-mouse-passaged CAO strain and from NPC biopsies from Taiwanese patients also exhibits variations resulting in structural and functional differences in the protein. The BZLF1 gene encodes the ZEBRA protein which triggers the EBV lytic cycle. A difference has been observed in 8 amino acids in the ZEBRA sequence in B95-8 (Z95) and P3HR1 (ZP3) cell lines. EBV found in NPC biopsies and peripheral-blood cells from Asians was predominantly of the ZP3 type (72%), while 81% of samples from different EBV-associated diseases and peripheral-blood cells from North Africa or Europe were of the Z95 type. We found that an alanine 206 had been replaced by a serine in the Z95 sequence in 72% of the NPC biopsies from European and North African patients. The Zser206 variant is found in a significantly lower percentage (p < 0.001) of other EBV-positive tissues from individuals in the same region (10-33%). In contrast, a 30-bp deletion is observed near the 3' end of the LMP1 gene in the majority of EBV (86%) from NPC and peripheral-blood cells from Asians, whereas a significantly lower percentage (p < 0.001) of NPC biopsies from European and North African patients (56%) have this deletion, as do lymphocytes from control individuals from the same region (36 and 55% respectively).

The MXI1 tumor suppressor gene is not mutated in primary prostate cancer.

For prostate cancer, allelic deletions from the long arm of chromosome 10 (#10q23-25), the locus of the putative tumor suppressor gene MXI1 (#10q24-25), have been identified as a frequently occurring genetic event. During the development of several human malignancies, the c-myc proto-oncogene has been identified to enhance cellular transformation, mitogenesis and cell proliferation. The MXI1 gene, belonging to the helix-loop-helix (bHLH) gene family, was demonstrated to display tumor suppressor function by antagonizing c-myc induced transcriptional activities. Due to the detection of point mutations in the retained alleles of four primary adenocarcinomas of the prostate, MXI1 gene alterations have been suggested to be involved in the development and/or the progression of prostate cancer. To evaluate the role of MXI1 gene alterations for the development of adenocarcinoma of the prostate, 42 primary prostate cancers of different stage (T1-4) and histological grade (G1-3) were investigated for alterations within exons 4 and 5 of the MXI1 gene (spanning 6 exons in total), encoding for the functional HLH-Zip domain, by RNA-SSCP analysis and direct PCR-DNA-sequencing following the microscopically guided tumor cell dissection from 5 microm fresh-frozen buffer-soaked tissue sections. Even by application of this highly elaborated technical approach, MXI1 gene alterations could not be deleted in any of the tumor specimens investigated. Therefore, a substantial involvement of MXI1 gene alterations in the development of prostate cancer appears unlikely. The newly identified putative tumor suppressor gene PTEN, located at #10q23, might be responsible for the frequently observed allelic deletions from #10q23-25 in prostate cancer.

Urodynamics and transurethral microwave thermotherapy.

In this paper the role and value of urodynamic measurements in symptomatic benign prostatic hyperplasia (BPH) patients selected for transurethral microwave thermotherapy (TUMT) reviewed. Although pressure-flow studies alone can diagnose benign prostatic obstruction, the level of acceptance of urodynamic investigations in BPH remains low, reportedly due to their cost and to their invasive and time-consuming nature. Furthermore, the observation that extremely different treatment modalities in BPH have nearly the same symptomatic outcome, independently of their influence on obstruction, has played a part in raising doubt as to the value of baseline urodynamics as a predictor of clinical success. Pre- and posttherapy urodynamic investigations in TUMT-treated patients have shown that urodynamic algorithms must be capable of distinguishing between compressive and constrictive types of obstruction to document the limited effects of low-energy TUMT on obstruction. Furthermore, it has been shown that urodynamics evaluated in this way seems to be the only predictor of the clinical success of TUMT when improvements in the objective parameters Qmax (peak uroflow) and residual urine are included in the definition of outcome.

Qualitative analysis of the expression of Epstein-Barr virus lytic genes in nasopharyngeal carcinoma biopsies.

We recently showed that BZLF1, the gene encoding the Epstein-Barr virus (EBV) ZEBRA protein, was expressed in all eight nasopharyngeal carcinoma (NPC) specimens studied. We present here studies on the expression of EBV lytic cycle genes in the same eight NPC biopsies to determine if production of the ZEBRA transactivator could lead to a complete productive cycle. The tumour lesions exhibit a number of different patterns of limited lytic gene expression. In three out of eight tumours neither BRLF1 nor BMLF1 expression could be detected. Otherwise BMLF1 mRNA was expressed in all the other specimens. Three specimens also expressed BRLF1. Two specimens not only exhibited BZLF1, BMLF1 and BRLF1 transcripts, but also expressed the late gene BLLF1 which encodes the membrane protein gp220. The early gene product BBLF2 could not be detected in any of the eight NPC. However, expression of the late gene encoding the lytic truncated form of LMP1 (D1LMP) was found in seven of the eight NPC biopsies. Thus, it could be suggested that the EBV abortive lytic cycle occurred in most of the NPC studied.

Expression of the Epstein-Barr virus immediate early gene, BZLF1, in nasopharyngeal carcinoma tumor cells.

The Epstein-Barr virus has been shown to be associated with nasopharyngeal carcinoma (NPC). We have shown that anti-ZEBRA transactivator antibodies were present in sera of most NPC patients. We investigated the expression of the BZLF1 gene in fresh NPC tumor biopsies. RNA transcripts of this gene could be detected by in situ hybridization. This expression is restricted to tumor cells and is not present in infiltrating lymphocytes. ZEBRA protein could also be visualized in a fraction of these cells. A cDNA library made from polyadenylated mRNA of an NPC tumor biopsy was constructed and analyzed by PCR. Transcripts of the BZLF1 gene were unspliced, incompletely spliced, or fully processed. A transcript lacking the middle exon was also observed. Fully processed BZLF1 mRNA was also detected in six more NPC tumor biopsies.