Tomohiko Koyanagi

Use of an implanted marker and real-time tracking of the marker for the positioning of prostate and bladder cancers

PURPOSE A real-time tracking radiotherapy was investigated to assess its usefulness in precise localization and verification of prostate and bladder cancers. METHODS AND MATERIALS The real-time tracking radiation therapy (RTRT) system consists of implantation of a 2.0-mm gold marker into a clinical target volume (CTV), three-dimensional radiation treatment planning (3DRTP) system, and the use of two sets of diagnostic x-ray television systems in the linear accelerator room, image processing units, and an image display unit. The position of the patient can be corrected by adjusting the actual marker position to the planned marker position, which has been transferred from the 3DRTP and superimposed on the fluoroscopic image on the display unit of the RTRT system. The position of the markers can be visualized during irradiation and after treatment delivery to verify the accuracy of the localization. Ten patients with prostate cancer and 5 patients with bladder cancer were examined using this system for the treatment setup on 91 occasions. RESULTS After manual setup using skin markers, the median of absolute value of discrepancies between the actual position of the marker and the planned position of the marker for prostate cancer was 3.4 (0.1-8.9) mm, 4.1 (0.2-18.1) mm, and 2.3 (0.0-10.6) mm for the lateral, anteroposterior, and craniocaudal directions, respectively. The 3D median distance between the actual and planned positions of the marker was 6.9 (1.1-18.2) mm for prostate cancer and 6.9 (1.7-18.6) mm for bladder cancer. After relocation using RTRT, the 3D distance between the actual and planned position of the marker was 0.9 +/- 0.9 mm. Median 3D distances between actual positions after treatment delivery and planned positions were 1.6 (0.0-6.3) mm and 2.0 (0.5-8.0) mm during daily radiotherapy for the marker in patients with prostate cancer and bladder cancer, respectively. CONCLUSION We believe the new positioning system can reduce uncertainty due to setup error and internal organ motion, although further improvement is needed for the system to account for the rotational and elastic changes of the affected tissues.

Human Brain Region Response to Distention or Cold Stimulation of the Bladder: A Positron Emission Tomography Study

PURPOSE Several kinds of perceptions, including distention and coldness, arise from the bladder. Information on bladder fullness conveyed by mechanoreceptors within the bladder wall contributes to the basic micturition reflex via the bulbospinal reflex pathway, whereas cold stimulation of the bladder is processed differently. To elucidate the human brain mechanisms of voluntary urine storage and bladder cold perception we performed positron emission tomography scanning to examine brain regions activated by bladder distention or cold stimulation. MATERIALS AND METHODS A total of 17 right-handed healthy male volunteers were catheterized via the urethra for bladder infusion. Subjects were divided into 2 groups for 2 types of positron emission tomography, namely the bladder distention group-11 who were 24 to 41 years old and the intravesical ice water group-6 who were 24 to 38 years old. Data were analyzed by the statistical parametric mapping procedure. RESULTS Significant brain activation during maximum urine storage (bladder distention) were found in the pons, midbrain periaqueductal gray, anterior insula, putamen, thalamus and anterior cingulate gyrus. On the other hand, intravesical ice water instillation significantly activated several regions in frontal and parietal lobes, amygdala-hippocampus area and crus cerebri ventral border. Distribution of the activated regions after intravesical instillation of ice water overlapped none of those observed after bladder distention. CONCLUSIONS Our data show that the brainstem as well as more rostral regions are involved in voluntary urine storage and these regions are functionally separated from those associated with bladder cold perception in healthy individuals.

Is suprapubic cystostomy an optimal urinary management in high quadriplegics?. A comparative study of suprapubic cystostomy and clean intermittent catheterization.

Introduction: Long–term outcome of spinal cord injury (SCI) patients was compared between those managed by suprapubic cystostomy (SPC) and clean intermittent catheterization (CIC) with particular emphasis on an incidence of urinary tract complications and patients perception for urinary management.Materials and Methods: The study comprised 61 SCI patients; 34 patients managed with SPC (group A), while 27 with CIC (group B). After stabilization of their condition, all were followed annually on an outpatient basis with clinical history, urinalysis, urinary imaging and renal function studies. Mean follow–up periods were 8.6 and 9.9 years for groups A and B, respectively. Between groups, a comparative study was performed on the incidence of urinary complications such as renal dysfunction, hydronephrosis, vesicoureteral reflux, symptomatic genitourinary infection and urinary stone. Satisfaction with urinary management was also estimated using the questionnaires during follow–up.Results: Renal dysfunction, hydronephrosis and vesicoureteral reflux were not found in either group. Symptomatic genitourinary infection was seen in 4 (12%) of group A and 7 (26%) of group B, respectively. The incidence of renal stone was 3 (9%) in group A and 1 (4%) in group B. A significant difference was not found between two groups in these urinary complications. On the contrary, bladder stone was seen more frequently in group A (65%) than in group B (30%) with a significant difference (p<0.001). The degrees of incontinence, bother score of daily activities, and overall satisfaction showed no significant difference between the two groups.Conclusion: Except for bladder stones, SPC is a valuable option of urinary management for quadriplegic patients, the results of which were comparable to paraplegic SCI patients managed with CIC.

An improved intravesical model using human bladder cancer cell lines to optimize gene and other therapies

Orthotopic implantation of human bladder cancer cells into immunodeficient mice is an important tool for studying the biology and effects of therapy. Nevertheless, the incidence of tumor implantation and growth by transurethral instillation of the human bladder cancer cells into murine bladders has been low or not reproducible. However, using a modified intravesical technique and the human bladder cancer cell lines, KU-7 and UM-UC-2, we have been able to obtain a high and reproducible incidence of superficial bladder tumors. Furthermore, intravesical administration of the LacZ adenovirus vector resulted in significant β-galactosidase expression in these bladder tumors as well as the normal urothelium, which was associated with the removal of the glycosoaminoglycan layer. Because this modified technique produces a high incidence of superficial human tumor growth and allows the efficacy of gene transfer to be evaluated, it should be a useful model for the study of intravesical gene therapy for human bladder cancer. Cancer Gene Therapy (2000) 7, 1575–1580.

Structural Changes of Collagen Components and Diminution of Nerves in Congenital Ureteropelvic Junction Obstruction

PURPOSE Three-dimensional arrangements of smooth muscle cells, collagenous component and peripheral nerves of congenital ureteropelvic junction (UPJ) obstruction were studied in order to clarify the pathogenetic mechanism of interaction among these neuro-myo-stromal components. MATERIALS AND METHODS The UPJ and upper ureters were obtained from 14 patients with congenital hydronephrosis (7 intrinsic and 4 extrinsic obstruction) and 7 normal controls. Three-dimensional arrangement of each structural component was observed by scanning electron microscopy, and the nerve distribution was analyzed with immunohistochemistry for protein gene product 9.5. RESULTS The UPJ of intrinsic obstruction had structural features as follows. Muscle fascicles were sparse and thin. Each muscle cell was thin in diameter. Intercellular spaces were six to seven times wider than controls. Collagen fibrillar sheaths of smooth muscle cells (pericellular collagen fibrils attached to the basement membrane) were interwoven to form a dense felt-like structure against thin lace-like sheaths in controls. Interstitial collagenous component showed dense and compact structure against loose network of wavy collagen bundles in controls. In the muscular layer, nerve distribution was decreased to about one-third of controls. In contrast, non-stenotic portion of intrinsic UPJ obstruction as well as materials from extrinsic UPJ obstruction showed no structural difference as compared with controls. CONCLUSIONS In the intrinsic obstruction, nerve fibers were depleted in the muscular layers in the ureteric walls, resulting in dysfunction and atrophy of muscle fibers and an increase of collagen fibers in the muscle layers with abnormal accumulation of intercellular and interstitial collagen. These changes may disrupt the mobility of UPJ and lead to both mechanical and functional obstruction.

Three-Dimensional Arrangement of Collagen and Elastin Fibers in the Human Urinary Bladder: A Scanning Electron Microscopic Study*

To clarify the arrangements of collagen and elastin fibers of the urinary bladder, we examined 9 human (male, aged 42 to 72) urinary bladders by scanning electron microscopy with chemical digestion methods. The mucosal layer was divided into 3 portions according to the collagen arrangement: the superficial portion interwoven densely by collagen fibrils, the middle portion layered by flat bundles of collagen fibrils and the deep portion made of a loose network of twisted collagen bundles. In the muscular layer, the smooth muscle fascicles were firmly covered with collagen sheets, while each muscle cell in a fascicle was accommodated by a thin sheath of collagen fibrils. The serosal layer consists of wavy collagen bundles piled up in a sheet, which was intercalated by clusters of adipose cells. Elastic fibers were, on the other hand, sparse throughout the bladder wall, except for denser networks around the blood vessels and muscle fascicles and beneath the peritoneal mesothelium. The arrangements of these components were discussed in relation to the mechanical function and compliance of the urinary bladder.

Impact of nephron-sparing surgery on quality of life in patients with localized renal cell carcinoma

Objectives: The aim of the study is to evaluate the impact of nephron–sparing surgery on postoperative quality of life (QOL) in patients with localized renal cell carcinoma, compared with radical nephrectomy. Methods: From 1986 to 1996, a total of 66 patients with localized small renal cell carcinoma <4 cm in diameter and a functioning contralateral renal unit underwent radical nephrectomy (n = 51) or nephron–sparing surgery (n = 15). Of these, 50 patients evaluated various dimensions of QOL using standardized self–rating questionnaires, EORTC QLQ–C30. Results: There is no significant difference in 5–year overall survival between the nephron–sparing surgery group and the radical nephrectomy group. With regard to postoperative QOL, patients who underwent nephron–sparing surgery showed a significantly higher score on physical function than patients treated with radical nephrectomy (p<0.05). Nephron–sparing surgery was additionally superior to radical nephrectomy in terms of fatigue, sleep disturbance, pain and constipation. Conclusion: Selected patients with localized, small, unilateral renal cell carcinoma and a normal contralateral kidney will benefit from nephron–sparing surgery.

The Relevance of Preoperative Cystometrography in Patients with Benign Prostatic Hyperplasia: Correlating the Findings with Clinical Features and Outcome After Prostatectomy

Preoperative water cystometrograms in 437 patients with benign prostatic hyperplasia (BPH) were examined in a retrospective study. The cystometrographic results were analyzed regarding the preoperative clinical features: patient age, presence or absence of urinary incontinence, history of urinary retention and rate of residual urine. The prognostic value in improvement in voiding difficulty and postoperative urinary incontinence was also analyzed at 1 and 6 months after elective prostatectomy. Subjective symptoms of the patients were the primary reasons for prostatectomy, the majority of which were performed by a single competent resectionist (K. T.) who evaluated the outcome but was blinded to the cystometric findings. Of these patients 263 (60.2%) had detrusor instability (group 1), while 174 did not (group 2). Vesical denervation supersensitivity to bethanechol chloride was noted in 47 of 375 patients (12.5%). The difference in clinical features was significant between the 2 groups, with group 1 showing older patient age (p < 0.01), and a greater incidence of urinary incontinence (p < 0.001) and retention (p < 0.001). The difference between groups 1 and 2 in mean bladder capacity (p < 0.01), compliance (p < 0.01) and a greater positive rate of vesical denervation supersensitivity (p < 0.001) was also significant. The clinical and cystometrographic parameters studied worsened with advancing patient age. Although the majority of the patients (94.7%) were relieved of obstructive symptoms after transurethral prostatectomy (6 months later), 113 (25.9%) were not at 1 month. Compared to 324 patients with early improvement (74.1%), those without improvement at 1 month were characterized by older age (p < 0.01), greater prevalence of preoperative incontinence (p < 0.05), retention (p < 0.01), greater residual rate (p < 0.05), a less compliant bladder (p < 0.01) and a higher positive rate of vesical denervation supersensitivity (p < 0.05). Cystometrographic findings, however, had no relevance to late (6 months) outcome of voiding difficulty. On the other hand, postoperative incontinence was noted in 100 patients (22.9%) at 1 month after transurethral prostatectomy, with the majority having episodes similar to those experienced preoperatively (70.0%) as well as detrusor instability (87.0%). They also were older (p < 0.01), and had a less compliant bladder (p < 0.01) and a higher positive rate of vesical denervation supersensitivity (p < 0.01) than did continent patients. Only 18 elderly patients (4.1%) remained incontinent 6 months later, all with a less compliant (p < 0.01) and more unstable (p < 0.01) bladder initially. The genesis of this detrusor dysfunction was believed to be aging in male patients, in whom BPH evolves and progresses. In conclusion, preoperative cystometrography in patients with BPH is valuable in that it correlated well with the clinical features and it can predict to some extent the outcome of obstructive symptoms and urinary incontinence after transurethral prostatectomy.

Studies on the sphincteric system located distally in the urethra: the external urethral sphincter revisited.

Anatomical, physiological and clinical studies were done on the sphincteric system located distally in the male urethra. Results revealed that urinary continence after radical transurethral prostatectomy is attributed to the true external urethral sphincter, which is defined anatomically as intrinsic striated muscle of the urethra. Urodynamic and electrophysiologic data suggested that this external sphincter is influenced directly and more predominantly by the autonomic alpha-adrenergic system than by the somatic innervation system. Clinical experiences in the management of external sphincter disorder in neurogenic vesical dysfunction by pharmacologic manipulation of the alpha-adrenergic system were presented. A plea is made for consideration of this revised concept of the external sphincter in understanding various pathophysiology of the lower urinary tract.

Reduction in acute morbidity using hypofractionated intensity-modulated radiation therapy assisted with a fluoroscopic real-time tumor-tracking system for prostate cancer: preliminary results of a phase I/II study.

PURPOSEThe positioning of the prostate is improved with the use of the fluoroscopic real-time tumor-tracking radiation therapy system for prostate cancer. The acute radiation reaction and preliminary tumor response of prostate cancer to hypofractionated intensity-modulated radiation therapy assisted with real-time tumortracking radiation therapy were investigated in this study. METHODSPatients were classified into prognostic risk groups on the basis of the presence of the pretreatment prostate-specific antigen, clinical stage, and histologic differentiation. Neoadjuvant hormonal therapy was administered to patients in the high-risk group for 6 months before radiation therapy commenced. The intensity-modulated radiation therapy employed a segmental multileaf collimator, which generated a field made up of two or more shaped subfields using forward planning. Real-time tumor-tracking radiation therapy was used for the precise positioning of the prostate to minimize geometric uncertainties, while the dose was escalated in increments of 5 Gy from 65 Gy using a daily dose of 2.5 Gy (65 Gy/2.5 Gy), following the dose-escalation rules. Acute and late gastrointestinal and genitourinary morbidities due to radiation therapy were scored according to the toxicity criteria of Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer. RESULTSThirty-one patients were enrolled in this study between 1998 and 2001. Eighteen patients were classified as being members of the high-risk group. Total dose was escalated, with 65 Gy/2.5 Gy being administered to 12 patients and 70 Gy/2.5 Gy to 19 patients. The median follow-up period was 37 months (range, 30–43 months), and 19 months (range, 10–27 months), for the 65-Gy and 70-Gy arms, respectively. Patients experienced no acute toxicity and grade 1 late gastrointestinal toxicity (8.3%) in the 65-Gy/2.5-Gy arm. Patients in the 70-Gy/2.5-Gy arm experienced grade 1 acute gastrointestinal toxicity (5.3%) and grade 1 and 2 acute genitourinary toxicities (15.8%). No patients experienced dose-limiting toxicity (defined as a grade 3 or higher acute toxicity) or a grade 2 or higher late complication in this study period. One and two prostate-specific antigen relapses were observed in the 65-Gy and 70-Gy arms, respectively. CONCLUSIONUp to 70 Gy/2.5 Gy, equivalent to 80 Gy with a daily dose of 2.0 Gy, assuming α/β ratio of 1.5, intensity-modulated radiation therapy assisted with real-time tumor-tracking radiation therapy was administered safely with a reasonable biochemical control rate. A further dose-escalation study using this system is justifiable.