Circulating microRNAs predict biochemical recurrence in prostate cancer patients.

BACKGROUND: Circulating microRNAs (miRNAs) are emerging as promising biomarkers for prostate cancer. Here, we investigated the potential of these molecules to assist in prognosis and treatment decision-making. METHODS: MicroRNAs in the serum of patients who had experienced rapid biochemical recurrence (BCR) (n=8) or no recurrence (n=8) following radical prostatectomy (RP) were profiled using high-throughput qRT-PCR. Recurrence-associated miRNAs were subsequently quantitated by qRT-PCR in a validation cohort comprised of 70 patients with Gleason 7 cancers treated by RP, 31 of whom had undergone disease progression following surgery. The expression of recurrence-associated miRNAs was also examined in tumour tissue cohorts. RESULTS: Three miRNAs - miR-141, miR-146b-3p and miR-194 - were elevated in patients who subsequently experienced BCR in the screening study. MiR-146b-3p and miR-194 were also associated with disease progression in the validation cohort, as determined by log-rank tests and Cox proportional hazards regression. Multivariate analysis revealed that miR-146b-3p possessed prognostic information beyond standard clinicopathological parameters. Analysis of tissue cohorts revealed that miR-194 was robustly expressed in the prostate, elevated in metastases, and its expression in primary tumours was associated with a poor prognosis. CONCLUSION: Our study suggests that circulating miRNAs, measured at the time of RP, could be combined with current prognostic tools to predict future disease progression in men with intermediate risk prostate cancers.

Elevated levels of peritumoral chondroitin sulfate are predictive of poor prognosis in patients treated by radical prostatectomy for early-stage prostate cancer.

The disease course of localized prostate cancer is highly variable, and patients potentially curable by aggressive management are not readily identified by current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a candidate biomarker as elevated levels of CS in peritumoral stroma of prostate cancer have been associated with prostate-specific antigen (PSA) failure. Immunoreactive CS was measured using image analysis of archived radical prostatectomy tissues, obtained from 157 men with a median of 47 months (range, 16-111 months) clinical follow-up. CS level, Gleason score, and preoperative serum PSA levels were independent predictors of PSA failure by Cox's multivariate analysis. Patients with low CS levels had significantly fewer PSA failures after radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot; 32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in discriminating retrospectively those patients most suited for surgery (Kaplan-Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that measurements of CS level can assist in predicting patient outcome after surgery. Additionally, our data suggest that the combination of CS and PSA measurements may improve outcome prediction for patients with intermediate Gleason scores.

Pregnancies after ultrasound-guided fallopian insemination with cryostored donor semen.

Twenty-nine patients, previously treated unsuccessfully with a median 9.5 cycles of conventional intracervical donor insemination, were offered fallopian catheterization on the side of the dominant follicle and direct insemination at the presumed site of fertilization, the ampullary-isthmic junction. Forty-five of 50 cycles were associated with successful tubal catheterization and 6 of these cycles were conceptional. Five viable intrauterine pregnancies resulted. We conclude: (1) that direct sperm transfer to the fallopian tubes is possible without the need for anesthesia or operation; and (2) that at the time of ovulation, the fallopian tube isthmus can be catheterized without later interfering with ovum or embryo transport to the uterus. Optimum timing for fallopian catheterization in relation to ovulation and the risk of side effects both remain to be established.

Nellcor Stat Cap differentiates oesophageal from tracheal intubation.

A trial of the Nellcor Stat Cap, which detects exhaled carbon dioxide, as an aid to determining whether endotracheal tubes are placed in the oesophagus or the trachea, was carried out in the neonatal unit of this hospital. Twenty five neonates, with a mean (range) gestational age of 33 (24-42) weeks and a mean (range) birthweight of 2.17 (0.54-4.1) kg were studied over two months. These babies underwent a total of 58 intubations and 20 suspected self-extubations. The Nellcor Stat Cap was easy to use. It confirmed clinical findings on 20/20 occasions when the endotracheal tube was in the oesophagus and on 57/58 (98%) occasions when it was in the trachea. On 14/78 (19%) occasions the machine provided helpful additional information in reaching a decision on the adequacy of tube placement. Failure to detect rapidly accidental oesophageal intubation or unintentional tracheal extubation can result in rapid deterioration of the condition of ventilated newborns. The machine is a valuable aid to intubation and rapid diagnosis of self-extubation.

Obstetric anaesthesia training in the Wessex region before and after introduction of Calman training.

We canvassed the opinions of anaesthetic trainees by questionnaire in 1995 and 1998, before and after the introduction of Calman training in which the registrar and senior registrar grades were replaced by the specialist registrar grade. We received replies from 106 trainees in 1995 (90%) and 115 (92%) in 1998. The survey results demonstrate that the total experience in obstetric anaesthesia gained by trainees has not decreased. Experience of regional techniques (epidural, spinal and combined spinal-epidural) increased, but the proportion of senior trainees who had performed fewer than 20 general anaesthetics for caesarean section rose from 0/23 in 1995 to 4/33 (12%). In 1998, the majority of senior trainees had experience of general anaesthesia for fetal distress, severe preeclampsia, eclampsia and massive obstetric haemorrhage. Only a minority had experienced failed intubation or a total spinal. In 1995, 5/21 (24%) of senior house officers agreed or strongly agreed that they were on call before they felt confident about dealing with common problems. The proportion was still 4/23 (17%) in 1998.

The use of thromboembolic deterrent stockings and a sequential compression device to prevent spinal hypotension during caesarean section.

Hypotension is a common side effect of spinal anaesthesia for caesarean section. We have performed a randomised, controlled study to determine the efficacy of a sequential compression device (SCD) (Kendall) in combination with thromboembolic deterrent (TED) stockings (Kendall) to reduce the incidence of hypotension in this setting. Within 20 min of spinal injection, there was no statistically significant difference in the incidence of hypotension (defined as less than 100 mmHg and less than 80% of baseline blood pressure) (TED/SCD group 65%, control 80%, P = 0.12). However, there was a trend for those receiving TED/SCD prophylaxis to require less ephedrine to maintain normotension than the control group (median TED/SCD 3 mg, control 6 mg, P = 0.08). The administration of ephedrine deviated from protocol on a total of 46 occasions (2.3% of recordings). To try to reduce the influence of this, we reinspected our data using time to first episode of hypotension with a Kaplan-Meier survival analysis. This showed that the instantaneous risk (hazard) of developing hypotension was 1.8 (95% CI: 1.1-2.9) times higher in controls than those receiving TED/SCD prophylaxis (P = 0.02). Despite demonstrating some benefit of TED/SCD prophylaxis to prevent hypotension, we do not consider that the magnitude of this benefit warrants their routine use.

A 6-month study of the efficacy and safety of tadalafil in the treatment of erectile dysfunction: a randomised, double-blind, parallel-group, placebo-controlled study in Australian men.

The efficacy and safety of tadalafil for the treatment of erectile dysfunction (ED) were assessed in a 6-month, randomised, double-blind, placebo-controlled study. Australian men with mild, moderate or severe ED of organic, psychogenic or mixed aetiology were randomised to tadalafil 20 mg as needed (n = 93) or placebo (n = 47). Efficacy assessments included the international index of erectile function (IIEF) and the sexual encounter profile (SEP) diary. Tadalafil significantly improved erectile function compared with placebo (p < 0.001, all measures). At the end of the study, the mean per-patient proportion of successful sexual intercourse attempts (SEP question three) was 73.5% for patients treated with tadalafil and 26.8% for placebo-treated patients. Improved erections were reported by 78% of tadalafil-treated patients compared to 12.8% of placebo-treated patients. The most common treatment-emergent adverse events--headache and dyspepsia--were generally mild or moderate. Tadalafil was effective and well tolerated in Australian men with mild to severe ED.

Laparoscopic exploration for a presumed intra-abdominal testicle.

Removal of intra-abdominal testes in patients over the age of 10 years is recommended because of the small risk of subsequent malignant change. We report an experience in a 35-year-old male with no testicle in his left scrotum in whom an ultrasound scan demonstrated a 3 x 4 cm mass at the left internal ring. At laparoscopy, by delineating the landmarks of the left vas and the left testicular vessels, it was possible to confirm the presence of a testicle at the internal ring; atrophic epididymal material was confirmed histologically. Laparoscopic exploration in this patient permitted a thorough examination of the abdominal cavity for an undescended left testicle and required admission for less than 24 hours. We conclude this procedure is the approach of choice in patients with suspected intra-abdominal testes.

Association between infertility following reversal of vasectomy and the presence of sperm agglutinating activity in semen.

A statistically significant association between infertility, following reversal of vasectomy, and the presence of sperm agglutinating activity in post-operative semen samples has been demonstrated in a retrospective study. Sperm agglutinating activity was measured using a microtitration assay, and the number of positive samples rose from 3/78 (4%) pre-operatively, to 34/134 (25%) post-operatively. High titres (greater than or equal to 1:32) of agglutinating activity were observed only when viable sperm were present in the ejaculate. Positive semen titres were obtained only when parallel serum samples were positive at titres of greater than or equal to 1:256. Conception only occurred in the partner of one man whose seminal plasma contained agglutinating activity, but 22/34 (65%) of the men whose semen lacked such activity were fertile.

A comparative treatment trial of endometriosis using the gonadotrophin-releasing hormone agonist, nafarelin, and the synthetic steroid, danazol.

A randomized and double-blind trial was carried out comparing intranasal nafarelin acetate (400 micrograms daily) and oral danazol (600 mg daily), given over 6 months, in the treatment of 49 patients with laparoscopically proven endometriosis. Both drugs produced a highly significant and similar reduction (of 60 to 70%) in objective American Fertility Society scoring, even in severe disease. No effect was seen on adhesions. Both drugs suppressed oestradiol levels to a similar extent, although nafarelin caused a substantial rise in the first 2 weeks after the initiation of therapy. Nafarelin suppressed LH substantially and FSH, testosterone and prolactin to a small degree, whereas FSH and LH increased slightly during danazol. Pregnancies occurred in 12 of 22 infertile women in the 12 months following nafarelin, and in 6 of 14 in the danazol group. Side-effects were reported at a similar rate with both drugs, but the pattern was different. Hot flushes were the predominant side effect with nafarelin, although oestradiol levels were not suppressed to the extent expected. Small amounts of spotting or light bleeding were experienced with both drugs, but these tended to decrease with time with nafarelin and increase with danazol.

Urethral stricture after cardiac surgery.

During January and February 1980 there was an epidemic of urethral strictures at the Royal Adelaide Hospital. These strictures all occurred in men undergoing coronary artery bypass surgery. The strictures were inflammatory in nature and the patients were assessed to determine if a common aetiological factor could be identified. Follow-up has reaffirmed that inflammatory strictures are difficult to treat. Only half of the patients responded to conservative treatment; the only factor which appeared to influence the outcome of treatment was the time taken for a patient to present because of his symptoms.

Clinical evaluation of the heterologous oocyte penetration (HOP) test.

The heterologous oocyte penetration (HOP) test, using zona-free hamster oocytes, was used to assess the fertilising capacity of human spermatozoa. There was good correlation between the ability of ejaculated spermatozoa to penetrate the zona-free hamster oocytes and intact human oocytes. Using epididymal spermatozoa, the HOP test results showed that the ability to penetrate oocytes was acquired during their passage through the epididymis. Applied clinically, the HOP test enables a group of infertile men to be identified with a functional defect of their spermatozoa; these men may not be identified at routine seminal fluid analysis. Men with two negative HOP test results were confirmed as being infertile since their wives, if normal, conceived rapidly when donor spermatozoa were artificially inseminated.

Outpatient gamete intrafallopian transfer: a clinical analysis of 710 cases.

From February 1986 to June 1989 445 infertile couples were treated with a total of 710 treatment cycles involving laparoscopic gamete intrafallopian transfer (GIFT). The median age of the female partner was 33.5 years (range, 24 to 49 years) and the median duration of infertility was 4 years (range, 2 to 20 years). The final outcome of all 217 clinical pregnancies is known. There were 150 live births among which all but one baby survived, comprising 112 singleton births, 28 twin births, nine triplet births and one quadruplet birth. There were no still births, but there were two premature, multiple live births (one triplet, one quadruplet) among which no babies survived the neonatal period. Overall, 40 of the 152 potentially viable pregnancies were multiple (26.3%). Three of 206 potentially viable babies were born with congenital anomalies (1.5%). There were 50 clinical spontaneous abortions (24.8% of uterine pregnancies), one termination of pregnancy for Down's syndrome, and 14 ectopic pregnancies rate was 30.6% per laparoscopy and, among 740 initiated cycles, a live and surviving birth-per-initiated-cycle rate of 20.2%, or 33.7% to date per couple entering the programme. The 710 laparscopies resulted in two serious complications (0.3%), one of which required laparotomy. Eight other patients were admitted to hospital for rest and observation because of painful ovarian enlargement in the luteal phase. The total inpatient admission rate was 1.4%. Outpatient laparoscopic GIFT under general anaesthesia is a safe and effective procedure when conventional treatment for infertility has been unsuccessful.

Maturity of fetal lungs tested by production of stable microbubbles in amniotic fluid.

Lung surfactant in amniotic fluid, and hence the maturity of the fetal lungs, can be assessed by observation of stable microbubbles (less than 15 micron diameter). Bubbles are formed by agitation with a Pasteur pipette and examined in hanging drops under the 10 x power of a microscope. Either after a count of bubbles, or after a general survey of hanging drops, the fluid is given a stable microbubble rating. A 'strong' rating indicates that the idiopathic respiratory distress syndrome will not occur after delivery, and that the lecithin/sphingomyelin ratio will indicate maturity. Complete absence of stable microbubbles suggests a high risk of respiratory trouble for the newborn infant, as does a weak or lower rating in the 30 to 37 week gestational age group. The test takes 5 to 10 minutes to perform, is cheap and easy, is not affected by blood, but may be affected by meconium. If a 'strong' rating is found, measurement of the L/S ratio can safely be omitted.