Molecular screening of multifocal transitional cell carcinoma of the bladder using p53 mutations as biomarkers.

Thirteen of 28 patients (46%) with grade 2-3 multifocal transitional cell carcinoma (TCC) of the bladder were found to have p53 mutations using DNA sequence analysis. These were subsequently utilized as tumor-specific biomarkers. Analysis of 17 episodes of recurrence from five of the patients revealed that all but one carried the identical mutation to the primary tumor. Thirty urine samples were collected, at initial diagnosis and during follow-up screening, from eight patients with mutations over a period of 24 months. Sequence analysis of PCR products generated from DNA extracted from the urine sediments was carried out. The p53 mutation seen in the primary tumors was detectable in 24 of 30 urine samples. The remaining six cases coincided with a negative cystoscopic examination. Interestingly, 6 of the 24 urine samples in which mutations were detectable also coincided with negative cystoscopy. The results are consistent with: (a) monoclonality of multifocal TCC; (b) the spread of TCC through a seeding mechanism; and (c) the long-term persistence of tumor cell clones (up to 97 months) within the bladder, even in the absence of obvious tumor growth.

The role of percutaneous nephrostomy in malignant ureteric obstruction.

OBJECTIVES: Uraemia as a result of malignant ureteric obstruction is a recognised event in those with advanced malignancy, usually of pelvic origin, which, if left untreated, is quickly a terminal event. Palliative decompression of the obstructed urinary system, either by percutaneous nephrostomy (PCN), ureteric stent or a combination of both is a recognised method of improving renal function, with presumed low morbidity. The aims of the study were to assess whether PCN placement in malignant ureteric obstruction provided any additional survival benefit or patient morbidity. PATIENTS AND METHODS: The case notes of 32 patients with a mean age of 68.1 years (16 male, 16 female) who underwent PCN drainage for malignant ureteric obstruction were retrospectively analysed. Data on the site of primary malignancy, mode of presentation, improvement in renal function, median survival, conversion to internal ureteric stents and intervention-related complications were collected for analysis. RESULTS: The median survival following PCN insertion was 87 days and was unrelated to the patient's age and renal function. Those patients with primary underlying gynaecological malignancies appeared to survive almost 4 times as long as those with underlying primary bladder cancer. Renal function took a mean of 16.8 days to reach a nadir. Almost 79% of patients were able to be discharged from hospital--each patient, however, being re-admitted back to hospital on average 1.6 times prior to their death through PCN or internal ureteric stent related events. Retrospective "useful quality of life" was seen in less than half of the patient cohort. CONCLUSIONS: In the presence of malignant ureteric obstruction, palliative percutaneous urinary diversion may be performed and is effective in improving renal function. However, long-term survival is limited and should, therefore, be performed only when the views and wishes of the patient and carers are taken into account and if there is a definitive treatment plan available for the patient as quality of life can be suboptimal.

A hot spot for p53 mutation in transitional cell carcinoma of the bladder: clues to the etiology of bladder cancer.

Twenty-eight transitional cell carcinomas of the bladder, grade 2 or 3, were analyzed for the presence of p53 mutations. Thirteen tumors were found to contain 14 mutations. These were all base substitution mutations, of which nine were GC-->AT transitions (three at CpG sites). The remaining five mutations were transversions (three GC-->CG, one GC-->TA, and one AT-->TA). Four of the mutations were found at codon 280. A comparison with other studies of bladder tumors reveals that a region encompassing codons 280 and 285 represents a hot spot for p53 mutation in bladder cancer. The 280/285 hot spot lies within two purine-rich sequences that may provide some clues to the identity of potential bladder carcinogens. A comparison of mutations from bladder tumors of smokers and nonsmokers reveals no significant differences.

Bacteriuria and bacteraemia in patients with long-term indwelling catheters--a domiciliary study.

Men with indwelling catheters and men and women with suprapubic catheters were studied in their homes. Urine and blood were cultured and body temperature recorded after every catheter change. Nearly all patients had infected urine after 4 weeks of catheterisation, and all had bacteriuria after longer periods, usually with a mixture of organisms. Culture on selective media revealed a wider range of organisms than was detected on routine C.L.E.D. and blood agar with antibiotic sensitivity disks, but routine culture gave adequate information for clinical purposes. Bacteraemia was demonstrated after 20 of 197 changes of urethral catheter and after one of 19 changes of suprapubic catheter; but no patient had pyrexia or other symptoms. However, two had rigors on other occasions. When assessing "risk factors" for blood-stream infection in catheterised patients, it is important to record the total incidence of bacteraemia, asymptomatic as well as symptomatic.

Urethral closure in management of urinary incontinence.

Urethral closure with suprapubic catheterization has been used in 50 patients with urethral destruction due to an indwelling catheter. Thirty-seven of the patients were dry after the initial operation. Long-term complications were seen in 33 patients. Those that did occur were not life threatening. This relatively minor procedure offers a good alternative to formal diversion in this group of severely disabled patients.

Quantification of prostatic cancer metastatic disease using prostate-specific antigen.

The serum prostate-specific antigen (PSA) of 58 men with benign prostatic hypertrophy (BPH) and 17 men with carcinoma of the prostate (CaP) was correlated with the weight of prostatic tissue resected at transurethral prostatectomy (TURP). A significant correlation was identified between the weight of resected BPH tissue and the serum PSA (p less than or equal to 0.001; r = 0.54). No such correlation was seen in the CaP patients. By arbitrarily dividing the serum PSA by the prostate weight, it was possible to devise an index. This index corrected PSA in relation to prostatic size and unlike PSA in isolation did not differ significantly between normal controls and those with BPH. The index in CaP was significantly greater than that of either controls or BPH (p less than or equal to 0.001). Furthermore the index of metastatic CaP (M1) was significantly higher than that of nonmetastatic disease (MO) (p = 0.05). The higher index found in CaP would seem to be related to the bulk metastatic tumor, either manifest or occult. Comparing the index of CaPs to that found in normal and benign disease (a constant) offers a possible means of estimating the extent of local and metastatic tumor mass.

The results of 1115 patients with colorectal cancer treated over an 8-year period in a single hospital.

The results of treatment of 1115 patients with colorectal cancer, from one hospital, are presented. The mean age of the patients was 67.24 (+/- 0.35 SEM) years and there were the same number of male and female patients. Forty per cent of patients were admitted as an emergency, and 67% of the tumours were in the rectum or sigmoid colon. 46.7% of the patients were considered to have undergone a 'curative' resection. Six per cent of the tumours were Dukes' Stage A lesions; 37% were Stage B and 57% Stage C. Twenty-six per cent had liver metastases. The overall hospital mortality was 21.5% and the operative mortality 14%. One-third of the patients admitted as an emergency died during their first admission. The overall 5-year survival was 25.8%; those with Dukes' Stage A tumours had a 5-year survival of 82.1%, Stage B 53.6% and Stage C 12.8%. The sex, site of tumour or duration of symptoms had no effect on prognosis.

Ambulatory esophageal pH monitoring in children as an indicator for surgery.

Twenty-four-hour esophageal pH monitoring was performed in 59 children with symptoms of gastroesophageal reflux using a miniature pH electrode and a portable recording system to establish the diagnosis. Significant reflux was seen in 26 (44%) of the patients and these were treated for six weeks with cimetidine, Gaviscon, and Nestargel. Five children who did not improve either symptomatically or on repeat pH monitoring while on treatment underwent antireflux surgery. The pretreatment reflux index in this group was 26.5 compared with a pretreatment reflux index of 11.2 in the 21 patients who improved on therapy (P less than 0.01). Esophageal pH monitoring has enabled selection of children for surgery and may be used as an early indicator of those who will not benefit from long-term medical therapy. Ambulatory and home monitoring techniques are more convenient and cost-effective and allow studies to be performed in the normal home environment.

The incidence and pattern of hand fractures in children.

The incidence and pattern of hand fractures occurring in children living in Nottingham has been reviewed. The hand is the second commonest site of fracture in children. The incidence is low in infants, but rises steeply after the age of eight, especially in boys. The most common site is the proximal phalanx. The little finger/fifth metacarpal is the most vulnerable area, especially around the metacarpophalangeal joint. Greenstick fractures are more common in metacarpals, while epiphyseal injuries predominate in the phalanges. Over 45% of fractures occurred either at sport or in a fight. Aetiological factors are discussed in relation to the fracture patterns described.

Surgical emergencies and manpower.

The emergency surgical admissions to one firm during the year 1979 have been reviewed. Emergency cases constituted half the workload of this and other units in the hospital. Male and female admissions were equal. The under twenty year old was the largest age group admitted. The commonest diagnosis, non specific abdominal pain, was made in 22.9% of all the patients and acute appendicitis accounted for 11.1%, whilst the remainder fell into a large number of diagnostic categories with only a few patients in each. Only 30.2% of all the patients had an operation within 48 of admission. These figures suggest that surgical trainees may no longer gain the experience in managing acute admissions which was once possible and that any future training programmes must ensure wider exposure to surgical emergencies.

The changing practice of transurethral prostatectomy: a comparison of cases performed in 1990 and 2000.

OBJECTIVES: Transurethral resection of the prostate (TURP) is considered by many to be the 'gold standard' treatment for benign prostatic enlargement. However, with the relatively recent introduction of pharmacological and other surgical treatment modalities, the performance of TURP appears to be in decline. METHODS: A retrospective casenote analysis of 200 patients who underwent TURP in 1990 and the year 2000 with the aim of identifying changes in the incidence and practice of TURP. RESULTS: There was a decline in the number of TURPs performed of 31.6% over the 10-year period, with more being carried out because of urinary retention. In 2000, the patient was older and the operative procedure took statistically longer than 10-years earlier, but the weight of prostate tissue resected, patient satisfaction and complication rates were similar. CONCLUSIONS: At present, TURP is in decline, with urinary retention being the commonest indication. The population at present is older but this does not carry additional co-morbidity. The weight of resection has not altered, although surgery currently takes longer to perform.

Evaluation of the plain abdominal X-ray in the acute abdomen.

The prognostic value of an erect and supine abdominal X-ray was studied prospectively in 97 patients with an acute abdomen. Although 64 (66%) of the radiographs showed an abnormality, the surgical registrar altered his clinical diagnosis on only seven occasions and changed his management on four. A consultant radiologist was the most accurate at reporting the X-rays even without seeing the patient, whilst junior surgical and radiological staff were as accurate as each other. A surgical registrar, however, was more accurate than junior radiologists in making a diagnosis. The investigation was of immediate clinical value in only 4% of the patients, and its use could probably be limited without detriment to patients.

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation.

Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers. For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion. We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.

Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN.

The mouse haematopoietic stem cell (SC) regulator Latexin (LXN) is the only known homologue of the retinoic acid receptor responder 1 (RARRES1) gene. Both genes lie adjacent on chromosome 3 and differ mostly by the presence of a transmembrane domain in RARRES1. Despite their homology, it is not known whether they possess similar regulatory mechanisms, cellular localization and function. Here, we identified RARRES1 and LXN as highly significantly downregulated genes in human prostate SCs, whose expression was induced by the pro-differentiation agent all-trans retinoic acid (atRA). AtRA induced expression in the most differentiated cells compared with the SC fraction, suggesting that this subpopulation was less responsive to atRA. Small interfering RNA suppression of RARRES1 and LXN enhanced the SC properties of primary prostate cultures, as shown by a significant increase in their colony-forming ability. Expression of both RARRES1 and LXN was co-ordinately repressed by DNA methylation in prostate cancer cell lines and inhibition of RARRES1 and LXN increased the invasive capacity of primary prostate cultures, which also fully rescued an inhibitory effect induced by atRA. Moreover, we showed that RARRES1 and LXN reside within different sub-cellular compartments, providing evidence that RARRES1 is not a plasma membrane protein as previously supposed but is located primarily in the endoplasmic reticulum; whereas LXN was detected in the nucleus of prostate epithelial cells. Thus, LXN and RARRES1 are potential tumour suppressor genes, which are co-ordinately regulated, SC-silenced genes functioning to suppress invasion and colony-forming ability of prostate cancer cells; yet the proteins reside within different sub-cellular compartments.

Prostate cancer stem cells: a target for new therapies.

Prostate cancer is now a common disease in men over 50 years of age. Medical therapies for prostate cancer are based on discoveries from the mid-twentieth century, and in the long term are rarely curative. Most treatments are directed towards an androgen receptor-expressing, highly proliferative target cell, which does indeed form the vast majority of cells in a prostate tumour. However, by invoking the existence of a cancer stem cell which, like normal epithelial stem cells in the prostate, does not express androgen receptor and is relatively quiescent, the observed resistance to most medical therapies can be explained. The phenotype of the prostate cancer stem cells is that of a basal cell and cultures derived from cancers, but not benign tissues, express a range of prostate cancer-associated RNAs. Furthermore, stem cells purified on the basis of alpha2beta1 high integrin and CD133 cell surface antigen expression, from an established culture of Gleason 4 (2+2) prostate cancer (P4E6), were able to form multiple intraprostatic tumours in nude mice when grafted orthotopically in a matrigel plug containing human prostatic stroma. The final tumours reexpressed androgen receptor and displayed a histology similar to that of a Gleason 4 cancer.

Life with urostomy.

The quality of life of urostomy patients was assessed by direct interview. Specific problems, such as urine leakage, were documented and the size, site and quality of the stoma were assessed. The study included 41 patients; 83% noted an improvement in the quality of life since their urinary diversion and 90% were still able to work or continue to perform household duties. Urine leakage was the commonest problem and this was unrelated to the length of the stoma or the build of the patient. More important factors were the correct siting of the stoma and the avoidance of parastomal herniation. All patients emphasised the importance of the stoma therapist.

The action of glucagon and commonly used antispasmodics and analgesics on the canine ureter.

Ureteric peristalsis has been studied using extraluminal bipolar electrodes and metal foil strain gauges in both the unanaesthetized and anaesthetized dog. Electrical activity of the ureter was characterized by bipolar action potentials, which always preceded mechanical activity. In the acute studies glucagon 44 micrograms/kg i.v. was given during the unstimulated phase and again during a forced diuresis. Complete inhibition of ureteric activity was seen for 19 . 50 (+/- 3 . 76 s.e.) and 16 . 25 (+/- 1 . 59 s.e.) min respectively. During this period there was no change in the rate of urine flow. In the conscious dog glucagon was given as a bolus of 22 micrograms/kg followed by an infusion for 45 min. An infusion of 88 micrograms/kg h produced complete inhibition for 39 . 2 (+/- 2 . 41 s.e.) min. Propantheline, hyoscine, morphine, pethidine and buprenorphine were given in equivalent therapeutic human doses, but no consistent effect on ureteric peristalsis was seen. Glucagon may have a role to play in the management of ureteric colic.

Urethral strictures in childhood.

Thirty-six children have been treated for a non-hypospadiac urethral stricture. Of 12 patients with meatal or submeatal stenosis, 10 had undergone circumcision for balanitis xerotica obliterans. The strictures were successfully treated by meatoplasty or meatal dilatation. Twenty-four children had a more proximal urethral stricture: 16 were caused by urethral catheterisation, 4 were post-traumatic, 2 were congenital and 2 were idiopathic. Sixteen children were treated by visual urethrotomy; this was successful in 12 after a maximum of 2 urethrotomies. Two children required 4 or more urethrotomies and 2 required urethroplasty for restricturing. Seven children were treated by a formal urethroplasty. There were no complications. Two patients died of unrelated medical conditions. Follow-up was for a mean of 2 years.