FISH mapping of de novo apparently balanced chromosome rearrangements identifies characteristics associated with phenotypic abnormality.

We report fluorescence in situ hybridization (FISH) mapping of 152, mostly de novo, apparently balanced chromosomal rearrangement (ABCR) breakpoints in 76 individuals, 30 of whom had no obvious phenotypic abnormality (control group) and 46 of whom had an associated disease (case group). The aim of this study was to identify breakpoint characteristics that could discriminate between these groups and which might be of predictive value in de novo ABCR (DN-ABCR) cases detected antenatally. We found no difference in the proportion of breakpoints that interrupted a gene, although in three cases, direct interruption or deletion of known autosomal-dominant or X-linked recessive Mendelian disease genes was diagnostic. The only significant predictor of phenotypic abnormality in the group as a whole was the localization of one or both breakpoints to an R-positive (G-negative) band with estimated predictive values of 0.69 (95% CL 0.54-0.81) and 0.90 (95% CL 0.60-0.98), respectively. R-positive bands are known to contain more genes and have a higher guanine-cytosine (GC) content than do G-positive (R-negative) bands; however, whether a gene was interrupted by the breakpoint or the GC content in the 200 kB around the breakpoint had no discriminant ability. Our results suggest that the large-scale genomic context of the breakpoint has prognostic utility and that the pathological mechanism of mapping to an R-band cannot be accounted for by direct gene inactivation.

Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases.

This study identifies multiple copies of the AML1 gene on a duplicated chromosome 21, dup(21), as a recurrent abnormality in acute lymphoblastic leukemia (ALL). Clusters of AML1 signals were visible at interphase by fluorescence in situ hybridization (FISH). In metaphase, they appeared tandemly duplicated on marker chromosomes of five distinct morphological types: large or small acrocentrics, metacentrics, submetacentrics or rings. The markers comprised only chromosome 21 material. Karyotypes were near-diploid and, besides dup(21), no other established chromosomal changes were observed. A total of 20 patients, 1.5 and <0.5% among consecutive series of childhood and adult ALL respectively, showed this phenomenon. Their median age was 9 years, white cell counts were low and all had a pre-B/common immunophenotype. Although this series is not the first report of this abnormality, it is the largest, permitting a detailed description of the variety of morphological forms that duplicated chromosome 21 can assume.

ETV6/AML1 fusion by FISH in adult acute lymphoblastic leukemia.

Dual-color interphase fluorescence in situ hybridization (FISH) with ETV6 and AML1 probes was used for the first time on a series of 159 adult patients with acute lymphoblastic leukemia (ALL), for detection of the t(12;21)(p13;q22) translocation. Seven patients (4.4%) were found, with 50-100% of positive cells, of whom one of two tested, proved negative for the fusion product by RT-PCR. Two of them, aged 43 and 50 years, are the oldest patients so far confirmed to have the translocation. Three who relapsed at 10, 11 and 24 months, suggest that adults may not enjoy the good short-term prognosis reported for t(12;21)-positive children. Thirty-one-negative cases had signal numbers differing from the two expected for each gene. In 15 cases these results were consistent with the karyotype. In nine cases with uninformative cytogenetics, the numbers were consistent with those for centromeres and indicated a hidden aneuploidy. Loss of ETV6 genes in two cases and AML1 amplification in three others were not suspected from the cytogenetics. In conclusion, FISH proved to be reliable in defining ETV6/AML1 positivity in this group of patients as well as providing valuable insights into negative cases.

A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects.

BACKGROUND: The development of prostate carcinoma is androgen-dependent. The coding sequence of the androgen receptor (AR) gene contains a CAG repeat polymorphism that has been shown to influence AR activity in vitro. Studies of this polymorphism as a prostate carcinoma risk factor have been conflicting. METHODS: A matched case-control design was used in a clinic-based multicenter study of Australian prostate carcinoma subjects. Cancer subjects were matched by age and locality with controls, all of whom had a serum prostate specific antigen (PSA) level of less than 4 mg/L. Conditional logistic regression was used to determine the relative risk of prostate carcinoma dependent on AR gene CAG number. The association of disease characteristics at diagnosis with the polymorphism also was assessed. RESULTS: Five hundred forty-five cases of prostate carcinoma and 456 matched case-control pairs were recruited. Association studies of disease characteristics at diagnosis showed age at diagnosis to be associated with AR CAG number by univariate (P = 0.004) and multivariate (adjusting for PSA, stage, and grade) linear regression (P = 0.018). No association was observed between the polymorphism and disease stage (TNM-based categories; P = 0.277), histologic grade (P = 0.41), or PSA level at diagnosis (P = 0.48). In the pairwise case-control analysis, the odds ratio of prostate carcinoma for a change of 5 CAG repeats gave an odds ratio of 0.9821 (95% confidence interval, 0.84-1.15). CONCLUSIONS: In this Australian study population, the AR CAG repeat polymorphism was not a risk factor for prostate carcinoma, but a shorter repeat sequence was associated with earlier age at diagnosis.

MR imaging of renal masses interpreted on CT to be suspicious.

OBJECTIVE: Prior studies have shown that renal MR contrast enhancement improves the efficacy of mass and proximal vascular evaluation. This study assessed the usefulness of different sequences for characterization of masses that appeared suspicious on CT and for prediction of their potential for malignancy. SUBJECTS AND METHODS: In a prospective manner 32 patients (age range, 26-78 years: average age, 54 years), each with at least one suspicious mass on CT, were examined with MR imaging. The following sequences were performed: conventional spin-echo with and without fat saturation, fast spin-echo, and dynamic gadopentetate dimeglumine-enhanced infusion using a 1.5-T superconducting magnet. Results were analyzed and compared with pathologic results after resection. RESULTS: A total of 65 renal masses of average size 2.6 cm (range, 1-10 cm) were detected with dynamic MR imaging. Seventeen of the 65 masses were malignant. Of the 17 malignant masses, three did not enhance on dynamic MR imaging (because of hemorrhage). Sixteen of the 17 malignant masses were heterogeneous on T2-weighted images. Three enhancing masses contained fat and all were angiomyolipomas. Thirty-five of the 65 masses (four with hemorrhage) did not show enhancement, all of which were homogeneous on T2-weighted images and were proven to be cysts. Five masses resulted from infections and had heterogeneous T2 appearance. The remaining masses were three hematomas with hemorrhage, one column of Bertin, and one aneurysm. CONCLUSION: Renal masses that are interpreted as suspicious on CT may lack MR enhancement because of hemorrhage effects; heterogeneity of their T2 appearance is thus critical in differentiating malignancy from benign disease. Odds-ratio calculations give an adjusted estimate of a 3.36-fold increase (95% confidence interval, 1.8-6.27) in the likelihood of malignancy when masses are heterogeneous on T2-weighted images and a 29-fold increase (95% confidence interval, 3.67-241.8) for predicting malignancy when enhancement is present.

Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis.

BACKGROUND & AIMS: Hepatic osteodystrophy is a complication of primary biliary cirrhosis (PBC). Allelic polymorphisms of the vitamin D receptor (VDR) gene are related to bone mineral density (BMD) in normal cohorts and those with primary osteoporosis. We sought to establish the prevalence of reduced bone mass in PBC, correlate BMD with VDR gene polymorphisms, and identify risk factors for the development of hepatic osteodystrophy. METHODS: Seventy-two female patients with PBC were evaluated prospectively. Clinical information, BMD assessment, disease severity, and osteoporosis risk factors were documented, and multivariate regression modeling was performed. RESULTS: Twenty-four percent of the patients were osteoporotic at the lumbar spine and 32% at the femur. Severe bone loss (z score <-2.0) occurs 4 times more frequently in patients with PBC compared with controls. Body weight (P = 0.003) and postmenopausal status (P = 0.012) correlated independently with BMD. VDR genotype (P = 0.01) correlated with lower BMD at the spine only. CONCLUSIONS: Osteoporosis is a common complication of PBC. VDR genotype predicts lower BMD in patients with PBC. Studies are warranted to investigate the mechanism(s) by which VDR as well as other candidate genes may contribute to the development of hepatic osteodystrophy in PBC.

Percutaneous management of caliceal diverticular calculi: technique and outcome.

OBJECTIVE: Symptomatic renal calculi found within caliceal diverticula are difficult to treat. We present a single-surgeon cohort of 21 consecutive patients undergoing percutaneous treatment of stones within caliceal diverticula over a 12-year period. PATIENTS AND METHODS: Each patient was managed by a one-stage percutaneous nephrolithotomy (PCNL). The majority of diverticula were situated at the upper pole. Access was gained via a direct target puncture, a Y puncture from a parallel calix, or through the diverticular stalk in the neighboring calix. The approach was commonly supracostal. A single-stage dilator was used to establish the track. Stones were removed intact or fragmented with ultrasonic lithotripsy, and the diverticular necks were treated with endoscopic division or dilation and splinted with a 22F nephrostomy tube for several days. RESULTS: Total stone clearance was obtained by PCNL alone in 95% of cases. The only case with incomplete clearance was cleared successfully with shockwave lithotripsy (SWL). Twenty patients were assessed with an intravenous urogram at 3 months and then annual plain films and clinical assessment. Further imaging was performed in selected cases. The diverticula were obliterated or had improved drainage in 85% of assessable cases. Three patients developed recurrent stones and were treated with SWL, laparoscopic diverticulectomy, on partial nephrectomy. One further patient required partial nephrectomy for poor drainage and ongoing pain. Of the 21 patients, 17 have remained stone, symptom, and infection free with clinical and radiologic follow-up ranging from 6 months to 12 years. CONCLUSIONS: This series demonstrates that percutaneous surgery can clear calculi from caliceal diverticula and, in most cases, correct or remove the underlying anatomic abnormality.

Retroperitoneal and pelvic extraperitoneal laparoscopy: an international perspective.

OBJECTIVES: To assess technical preferences and current practice trends of retroperitoneal and pelvic extraperitoneal laparoscopy. METHODS: A questionnaire survey of 36 selected urologic laparoscopic centers worldwide was performed. RESULTS: Twenty-four centers (67%) responded. Overall, 3988 laparoscopic procedures were reported: transperitoneal approach (n = 2945) and retroperitoneal/extraperitoneal approach (n = 1043). Retroperitoneoscopic/extraperitoneoscopic procedures included adrenalectomy (n = 74), nephrectomy (n = 299), ureteral procedures (n = 166), pelvic lymph node dissection (n = 197), bladder neck suspension (n = 210), varix ligation (n = 91), and lumbar sympathectomy (n = 6). Mean number of total laparoscopic procedures performed in 1995 per center was 41 (range 5 to 86). Major complications occurred in 49 (4.7%) patients and included visceral complications in 26 (2.5%) patients and vascular complications in 23 (2.2%). Open conversion was performed in 69 (6.6%) patients, electively in 41 and emergently in 28 (visceral injuries, n = 16; vascular injuries, n = 1 2). Retroperitoneoscopy/extraperitoneoscopy is gaining in acceptance worldwide: in 1993, the mean estimated ratio of transperitoneal laparoscopic cases versus retroperitoneoscopic/ extraperitoneoscopic cases per center was 74:26; however, in 1996 the ratio was 49:51. CONCLUSIONS: Retroperitoneoscopy and pelvic extraperitoneoscopy are important adjuncts to the laparoscopic armamentarium in urologic surgery. The overall major complication rate associated with retroperitoneoscopy/extraperitoneoscopy was 4.7%.

Extraperitoneal laparoscopic caliceal diverticulectomy.

Three women with symptomatic stone-containing caliceal diverticula in the right kidney were treated by extraperitoneal laparoscopic diverticulectomy. The diverticula measured 31 x 21 mm, 15 x 12 mm, and 12 x 9 mm, with the calculi measuring 10 x 8 mm, 5 x 4 mm, and 6 x 6 mm, respectively. The site of the diverticulum was identified by the presence of a depression on the surface of the kidney. The diverticulum was marsupialized, the lining fulgurated, and in the second and third patients, a flap of Gerota's fascia and perirenal fat inserted. The mean operating time was 127 minutes. The mean postoperative analgesic requirement was six doses of pethidine (meperidine). The median time to drainage tube removal was 3 days, and the median time to discharge after surgery was 4 days. Complications were minimal. On follow-up, all patients were stone free and asymptomatic. The first patient had a slight recurrence of the diverticulum, measuring 15 x 7 mm. Laparoscopic caliceal diverticulectomy has been successful in three patients.

A study of the efficacy and safety of transurethral needle ablation (TUNA) treatment for benign prostatic hyperplasia.

The objective of this early phase III study was to determine the efficacy and safety of transurethral needle ablation (TUNA) in patients presenting in acute urinary retention due to benign prostatic hyperplasia (BPH). Between September 1993 and August 1994, 20 patients of mean age 68.8 years were entered into a two-center study and treated with TUNA after presenting in acute urinary retention and having failed at least one trial of voiding. A mean of 5.4 lesions at shield temperatures of 54.6 degrees C were produced. Patients were reviewed at 1, 3, 6, and 12 months (mean, 6.2 months). In 17 of 20 patients, voiding was reestablished in a mean of 2.6 days. Three patients required TURP for persistent retention, and 2 patients had delayed TURP for bothersome symptoms. Two voiders died later of unrelated causes. Five patients were lost to follow-up at 6 months but were voiding when last reviewed. Symptom scores decreased from a mean of 19.0 (range 4-35) to 8.25 (range 1-20) at 12 months (p = 0.06). Mean peak flow rate was 11.4 ml/sec (range 6.6-16.8) at 12 months (p = 0.001). Mean prostatic volume at baseline was 65.8 cc and decreased to 56 cc at 12 months (p = 0.111). The treatment was well tolerated by all patients, and side effects were mild, including urinary tract infection and epididymo-orchitis. This study demonstrates the safety and effectiveness of TUNA procedure in patients with urinary retention due to benign prostatic hypertrophy.

Transurethral Needle Ablation of the prostate (TUNA): clinical results and ultrasound, endoscopic, and histologic findings in pilot study of patients in urinary retention.

Transurethral Needle Ablation of the prostate (TUNA) is a new thermal ablation treatment for benign prostatic hyperplasia (BPH) utilizing radiofrequency electric current delivered by needles into the depth of the prostate to produce an area of coagulative necrosis. A pilot study of 10 patients in urinary retention was undertaken to assess the procedure. After treatment, nine patients voided at a median time of 3 days, although a further two required transurethral resection because of chronic infection in one and chronic urinary retention in the other. At 3 months' follow-up, the mean Qmax was 13.0 mL/sec, the mean AUA Symptom Score was 9.1, and the mean quality of life score was 1.6. The mean Pdet fell from 73.3 to 39.0 cm H2O. On transrectal ultrasound at 3 months, cystic lesions were seen in two patients, with a third having large cavities. A 10.2% reduction in mean prostatic volume, from 48.8 cc to 43.8 cc, was noted but considered to be not significant. On endoscopy at 3 months, mucosal retraction was seen in seven patients, with cavities in two patients. Histologic study in patients undergoing transurethral resection 4 to 6 months after TUNA showed necrosis and fibrosis. It is considered that an area of coagulative necrosis is produced by TUNA that resolves either by scar formation with retraction or by liquefaction with cyst formation. If the lesion communicates with the urethra, a cavity may form, which is undesirable. Our early experience is encouraging. The TUNA treatment is effective, can be given without anesthesia, and should be either a day case or an office procedure. It should prove to have a significant place in the treatment of BPH.

Laparoscopic ureterolithotomy: the results of an initial series, and an evaluation of its role in the management of ureteric calculi.

OBJECTIVE: To evaluate the place of laparoscopic ureterolithotomy in the management of ureteric calculi for which extracorporeal shockwave lithotripsy (ESWL) and endourological techniques are unsuitable. PATIENTS AND METHODS: Laparoscopic ureterolithotomy was attempted in nine patients (eight men, one woman) with an age range of 26-81 years (mean 55.5) who had large, long standing and impacted calculi in the upper and mid ureter. The stone size ranged from 5 to 28 mm (mean 13.2) and stone duration ranged from one to 24 months (mean 8.2). The transperitoneal route was used in six patients and the extraperitoneal route in three but was converted to a transperitoneal approach in two. RESULTS: The stone was successfully removed in all nine patients. The operative time ranged from 80 to 260 minutes (mean 158). No intra-operative complication was encountered and no patient required a blood transfusion. Post-operative complications included urinary leak and fever. The post-operative stay ranged from 2 to 13 days (mean 5.2). CONCLUSIONS: Laparoscopic ureterolithotomy has definite advantages over open ureterolithotomy. Furthermore, the more difficult a stone is for treatment by ESWL and endourological techniques, the more suitable it is for laparoscopic removal. For large, hard, long-standing and impacted ureteric calculi, one laparoscopic ureterolithotomy as initial therapy may be preferable to multiple endourological and ESWL procedures.

Laparoscopic needle colposuspension for genuine stress incontinence.

Laparoscopic needle colposuspension offers a minimally invasive endosurgical treatment of genuine stress incontinence. With the patient in the low lithotomy position, three lower abdominal ports are inserted. Bilateral incisions are made in the peritoneum, and the retropubic space is dissected, leaving the urachus intact. A suprapubic incision is made down to rectus fascia only and a Stamey needle inserted into the retropubic space and passed into the vagina under vision. Using No. 1 Ethibond, a double bite of the vaginal wall is taken and the suture pulled into the suprapubic incision. The suture is tied over a silicone button with no slack and no tension. Seven women have been treated by this method, with all having control of their stress incontinence in the short term. The mean operative time was 112 minutes. The catheter was removed on the first postoperative day in six women and on the second day in one woman, with no voiding difficulties. The mean time to discharge was 3.3 days for all except one woman, who had a perforation of the bladder and remained for 12 days. The advantages of the laparoscopic approach are that it allows dissection of the retropubic space, direct examination of the bladder, and observation of the bladder neck during tying of the sutures, allowing them to be tied with no slack and no tension. As a consequence, there is a minimization of the duration of catheterization, voiding difficulties, hospital stay, and postoperative discomfort, with avoidance of scarring of the vaginal wall and urethra.

Extraperitoneal laparoscopy: early experience and evaluation.

This paper evaluates the use of various balloon dilators in the flank, iliac fossa and retro-pubic regions to create extraperitoneal spaces for subsequent extraperitoneal laparoscopy. Eight patients were investigated, three undergoing pelvic surgery, four renal surgery (two nephrectomies) and one laparoscopic ureterolithotomy. Extraperitoneal balloon dilatation was simple, safe and easy and provided large tamponaded bloodless cavities and excellent vision. Port access was slightly restricted by the lateral peritoneal reflections and bony prominences of the thorax and pelvis. This approach for laparoscopy is safe, simple and deserving of further evaluation.