Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer.

BACKGROUND: Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain. OBJECTIVE: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS. DATA SOURCES: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model. RESULTS: The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high. LIMITATIONS: The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. CONCLUSIONS: This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

BACKGROUND: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. METHODS: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. RESULTS: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. CONCLUSION: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.

FGF8 isoform b expression in human prostate cancer.

Overexpression of fibroblast growth factor 8 (FGF8) mRNA has been previously described in prostate cancer. Of its four isoforms, FGF8b is thought to be the most important in carcinogenesis. We hypothesised that immunodetection of FGF8b in archival prostate cancer specimens is of potential prognostic value. Using a selected cohort of prostate tumours from transurethral (n=30) and radical prostatectomies (n=59), an optimised protocol for FGF8b immunoreactivity was used to corroborate expression with clinical parameters. No expression was observed in benign prostates (n=10). In prostate cancer, immunoreactivity was localised to the malignant epithelium with weak signals in the adjacent stroma. Expression of FGF8b in stage T1 and T2 cancers were 40 and 67%, respectively. In contrast, FGF8b expression was present in 94% of T3 and 100% of T4 cancers. By histological grade, FGF8b was found in 41% of low-grade cancers (Gleason score 4-6), 60% of intermediate-grade cancers (Gleason score 7 and 92% of high-grade cancers (Gleason score 8-10). The intensity of expression was significantly associated with stage (P=0.0004) and grade (P<0.0001) of disease. We further hypothesised that FGF8b overexpression resulted from enhanced transcription and translation rather than from abnormalities involving the FGF8 gene locus. This was tested by means of fluorescent in situ hybridisation in 20 cancer specimens to map the FGF8 gene locus. FGF8 gene copy number in benign and malignant nuclei was found to be similar (2.33+/-0.57 and 2.0+/-0.81, respectively P=0.51). Based on these findings, we propose a multicentre study on cohorts of patients to further evaluate FGF8b as a potential prognostic marker in prostate cancer.

Combined p21WAF1/CIP1 and p53 overexpression predict improved survival in muscle-invasive bladder cancer treated by radical radiotherapy.

PURPOSE: The prognostic value of p21 and p53 expression was evaluated for patients with muscle-invasive bladder cancer treated by radical radiotherapy. METHODS AND MATERIALS: Sixty-eight paraffin-embedded sections from surgically resected tumors taken prior to irradiation were immunostained for p21 and p53. RESULTS: Nuclear staining for p21 and p53 was demonstrated in 32/68 (47%) and 46/68 (68%) tumors, respectively. There was no correlation between p21 and p53 immunopositivity in this group (r = 0.067, p = 0.56). Patients were stratified into four distinct groups depending on staining for p21 and p53: p21+p53+, p21+p53-, p21-p53+, and p21-p53-. Patients with p21+p53+ tumors had the best prognosis with a 3-year survival of 82% compared to 12% for p21-p53+ tumors (p = 0.0031), 29% for p21+p53- tumors (p = 0.0108); and 45% for p21-p53- tumors (p = 0.0375). The p21+p53+ group also demonstrated significantly improved survival when a combined analysis was performed of p21-p53+, p21-p53-, and p21+p53- tumors (3-year survival = 30%, p = 0.0062). In a multivariate model, p21+p53+ tumors (p = 0.0108, relative risk [RR] = 5.18) and complete/partial response (p = 0.0019, RR = 3.76) were the only independent predictors of improved survival. CONCLUSIONS: With muscle-invasive bladder tumors treated by radical radiotherapy, stratification for p21 and p53 identifies distinct prognostic groups, with p21+p53+ tumors being associated with the best survival and p21-p53+ the worst.

Caveolin-1 expression is associated with high-grade bladder cancer.

OBJECTIVES: To assess the levels of caveolin-1 in a series of bladder tumor specimens of varying stage and grade and to identify possible links between caveolin-1 status and clinical behavior. Caveolae have emerged as sites of important regulatory events at the cell membrane in many different cell types. Caveolins are the main structural components of caveolae and belong to a family of highly conserved integral membrane proteins. The function of caveolin-1 appears to be intrinsically linked to cell signaling modulation by multiple pathways. Modification of CAV-1 gene expression appears to be a common feature of the oncogenically transformed phenotype. METHODS: Using a rabbit polyclonal antibody against caveolin-1 and immunohistochemistry, we assessed caveolin-1 protein expression in 89 formalin-fixed, paraffin-embedded bladder tumor sections. The patient group studied included 71 men and 18 women (mean age +/- SD 69.7 +/- 10.9 years). The stage was Ta-T1 in 68 and T2-T4 in 21 tumors in this series. The clinical follow-up was 1 to 38 months (mean 21.2 +/- 9.9). RESULTS: A statistically significant association was observed between caveolin-1 immunoreactivity and tumor grade (P = 0.0118, chi-square test), with 8 (21%) of 38 G3, 1 (3%) of 30 G2, and 0 of 21 G1 tumors positive for caveolin-1. When the clinical data were examined in conjunction with caveolin-1 status, no statistically significant relationship was seen between caveolin-1 expression and tumor multiplicity, tumor recurrence, tumor progression, or patient survival. CONCLUSIONS: The results of our study demonstrate that altered expression of caveolin-1 protein is a component of tumor dedifferentiation in a subset of high-grade bladder cancers. This pilot study provides a basis for further investigation of the role of caveolin-1 and the function of caveolae in the most aggressive forms of this tumor.

Localization and quantification of mRNA for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human benign and malignant prostatic tissue.

BACKGROUND: The family of matrix metalloproteinases (MMPs) has been shown to be involved in proteolytic degradation of the extracellular matrix, which is an essential step in tumor invasion and metastasis. MMPs are tightly regulated by the levels of active enzymes and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). MMP-2 and its ratio to TIMP-2 have been associated with tumor recurrence and progression in a number of human malignancies. METHODS: We examined the relationship between MMP-2 and TIMP-2 mRNA expression in 42 men with malignant (n = 32) and benign (n = 10) prostates using nonisotopic in situ hybridization and Northern blot analysis. RESULTS: mRNA for MMP-2 and TIMP-2 was localized to the malignant epithelial cells of both high- and low-grade tumors in the periphery of the glands and in areas of extracapsular involvement, and to the glandular epithelium in the benign prostates. Using Northern blot analysis, the mean MMP-2 to TIMP-2 ratio was approximately one in the benign prostates and low-grade and -stage cancers. The MMP-2 to TIMP-2 ratio increased to 3.3 in the high-grade and 2.8 in the high-stage tumors. CONCLUSIONS: The results suggest a close association between MMP-2/TIMP-2 expression and local tumor invasion, with a disruption in expression of the two genes leading to disease progression. Future studies should focus on the activity of these enzymes and on the ratio of enzyme/inhibitor expression, which may become a useful prognostic marker in prostate cancer.

TP53 accumulation predicts improved survival in patients resistant to systemic cisplatin-based chemotherapy for muscle-invasive bladder cancer.

To examine retrospectively the prognostic significance of TP53 immunoreactivity for both tumor response and patient survival in 83 patients with nonmetastatic muscle-invasive bladder cancer treated with a single transurethral resection (TUR) of tumor and combined cisplatin-based systemic chemotherapy followed by repeat TUR, paraffin-embedded sections of a bladder tumor obtained at TUR before chemotherapy (1 T2, 52 T3, and 30 T4) were immunostained for TP53 using monoclonal PAb1801 and DO-7 antibodies. For the entire cohort, TP53 immunopositivity (PAb1801 or DO-7) did not predict complete response (CR), complete or partial response (PR), progressive disease, or time to death from bladder cancer. There was a highly significant correlation between PAb1801 and DO-7 nuclear immunoreactivity (r = 0.8242; P<0.0001). In 76 patients in which complete clinical data were available, tumor stage (T2/T3; P = 0.0499), CR and PR (P = 0.0016) and CR (P<0.0001) were associated with patient survival. In a multivariate model, CR (P<0.0001) was the only independent predictor of improved survival. In complete responders, neither TP53 immunostaining nor clinicopathological factors stratified patients into prognostic groups. However, in the subset of patients (n = 38) who were chemoresistant (PR or progressive disease), improved survival was associated with > or =20% TP53 immunoreactivity (PAb1801; P = 0.0191) and tumor stage (T2/T3; P = 0.0358). TP53 immunopositivity (PAb1801 or DO-7) did not predict overall survival or response to systemic chemotherapy in patients with nonmetastatic but predominantly clinical stage > or =T3 bladder cancer, but it had prognostic significance within the chemoresistant subgroup.

Staging of prostate cancer using 3-dimensional transrectal ultrasound images: a pilot study.

PURPOSE: We used conventional transrectal ultrasound images for 3-dimensional (D) reconstruction of the prostate, and determined its value in staging clinically localized prostate cancer. MATERIALS AND METHODS: A total of 36 patients with newly diagnosed clinically localized prostate cancer were studied. All patients underwent conventional transrectal ultrasonography with 3-D reconstruction. Images were examined and analyzed blindly, and findings were compared to histopathological staging following radical prostatectomy. RESULTS: Pathological staging of specimens revealed 15 sites of extracapsular extension in 10 patients, of whom 8 had positive margins and 2 had seminal vesicle invasion. The 3-D imaging identified 12 sites of extracapsular extension in 9 patients with 80% sensitivity, 96% specificity and 90% positive predictive value. Of the 2 patients with seminal vesicle invasion 1 was identified correctly on 3-D images. Overall staging accuracy of 3-D imaging was 94%. CONCLUSIONS: The 3-D reconstruction of conventional transrectal ultrasonography imaging is superior to 2-D imaging for staging localized prostate cancer. However, this advantage relies entirely on the visibility of prostate cancer lesions on conventional ultrasonography. Further studies are warranted to evaluate this technology for the management of prostate cancer.

FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease.

Identification of prostate cancers at high risk of progression is difficult and a better understanding of how peptide growth factors influence cellular function might be useful. Fibroblast growth factors (FGFs) have been implicated in prostate cancer development. FGF8 was identified in the Shionogi mouse mammary carcinoma SC-3 cell line as an androgen-induced mitogen. We tested if FGF8 was over-expressed in human prostate cancer and if its expression correlated with clinical data and outcome. One hundred and six cases of prostate cancer and ten cases of BPH were examined. In situ hybridization was employed to detect FGF8 mRNA expression, which was identified within the malignant prostatic epithelium in 85/106 (80.2%) cases. Increased expression of FGF8 correlated significantly with higher Gleason scores (P=0.0004) and advanced tumour stage (P=0.0016). Using immunohistochemistry, we confirmed over-expression of the FGF8b isoform. Men with tumours which expressed high levels of FGF8 had worse survival (P=0.034), although FGF8 mRNA was not able to provide additional prognostic information in a multivariate analysis. Additionally, FGF8 expression was shown to persist in androgen independent prostate cancer. Using a range of normal adult tissues, FGF8 expression was restricted to neurones and the germinal epithelium in addition to the prostate. In vitro studies demonstrated that in the presence of neutralizing antibody to FGF8b there was significant inhibition of prostate cancer cell growth, confirming the biological significance of FGF8 in prostate carcinogenesis.

aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8.

Fibroblast growth factors (FGFs) have been implicated in the development of numerous malignancies including prostate cancer. In a pilot study it has been shown that FGF8 mRNA is up-regulated in prostate cancer. The aim of the present study was to determine whether aFGF and bFGF were co-expressed with FGF8 in human prostate cancer. Twenty-nine cases of prostate cancer of different histological grades were examined. Immunohistochemical analysis was employed to study aFGF and bFGF expression. In the light of the results, aFGF immunoreactivity was studied in a further 43 cases. aFGF and bFGF immunoreactivity was identified in the cytoplasm of the malignant prostatic epithelium. aFGF was overexpressed in 62/72 (86.1 per cent) cases and bFGF in 19/29 (65.5 per cent). High levels of aFGF immunoreactivity were noted in areas of high-grade prostatic intraepithelial neoplasia (PIN). In this series, aFGF immunoreactivity was most commonly observed and correlated closely with Gleason score and tumour stage ( p=0.007 and 0.007, respectively). Co-localization of aFGF, bFGF, and FGF8 was detected in 9/29 (31.0 per cent) cases. There was a significant correlation between aFGF and FGF8 expression. In conclusion, aFGF, bFGF, and FGF8 are co-localized in human prostate cancer; they may have a synergistic effect in prostate cancer growth and progression.

Expression of Bcl-2, Bax, and p53 in high-grade prostatic intraepithelial neoplasia and localized prostate cancer: relationship with apoptosis and proliferation.

BACKGROUND: Apoptosis-regulating genes have been shown to be important in the biology of prostate cancer. The aim of this study was to examine and correlate the expression of the apoptosis-regulating genes bcl-2, bax, and p53 with the frequency of apoptosis and rate of proliferation in benign prostatic epithelium (BP), prostate cancer, and high-grade prostatic intraepithelial neoplasia (HGPIN), which is currently considered the most likely precursor of prostate cancer. METHODS: Forty-four patients with histologically proven prostate cancer were investigated. All the men underwent radical prostatectomy. Immunohistochemistry was performed to assess expression of bcl-2, bax, and p53, and proliferation rate, as measured by the Ki-67 index. The frequency of apoptotic bodies was assessed by morphological criteria. RESULTS: The apoptotic index (AI) was highest in prostate cancer, and was significantly greater in HGPIN compared to benign prostate. The Ki-67 index was greatest in cancer, intermediate in HGPIN, and lowest in BP. The AI was increased in areas of BP in patients treated with neoadjuvant androgen ablation. No change in AI was seen in treated cases of HGPIN or cancer. Accumulation of p53 protein was infrequent in prostate cancer (2/43: 4.6%), and was absent in HGPIN. Bcl-2 overexpression was present in 2.3% of cancers (1/43) and in 34.9% of cases of HGPIN (15/43). Bax expression was seen in all cases of cancer and HGPIN. There was no correlation between bcl-2 expression and the apoptotic and Ki-67 indices in HGPIN. CONCLUSIONS: p53 and bcl-2 expression is infrequent in clinically organ confined prostate cancer. Bcl-2 expression is significantly higher in HGPIN than in both the associated prostate cancer and BP. The AI and Ki-67 index appeared intermediate in the putative precursor lesion HGPIN compared to prostate cancer and BP.

The immunohistochemical detection of cripto-1 in benign and malignant human bladder.

The recently identified epidermal growth factor-related peptide cripto-1 has been previously implicated in the development of the malignant phenotype. The identification of gene products that can act as prognostic markers in bladder cancer would be value in determining the management of this heterogeneous group of patients. This study examines cripto-1 expression in benign and malignant bladder using immunohistochemical techniques. The expression of cripto-1 protein in benign and malignant bladder was examined in 45 bladder tumours (Ta/T1 n = 26, T2 n = 5, T3/T4 n = 14) and six benign controls. All 45 tumours showed positive cytoplasmic staining for cripto-1, including areas of carcinoma in situ. None of the six benign controls showed any evidence of positive cripto-1 staining. Twenty-three (60 per cent) bladder tumours had areas of papillary tumour that showed strong positive staining for cripto-1 as opposed to six (29 per cent) sections of histologically normal urothelium adjacent to tumour (P < 0.05). There was no association between cripto-1 staining and tumour grade, stage, or clinical outcome. Cripto-1 protein appears to be specifically expressed in malignant and benign adjacent urothelium of patients with bladder cancer. Its clinical significance, however, remains to be determined.

Neural network analysis of combined conventional and experimental prognostic markers in prostate cancer: a pilot study.

Prostate cancer is the second most common malignancy in men in the UK. The disease is unpredictable in its behaviour and, at present, no single investigative method allows clinicians to differentiate between tumours that will progress and those that will remain quiescent. There is an increasing need for novel means to predict prognosis and outcome of the disease. The aim of this study was to assess the value of artificial neural networks in predicting outcome in prostate cancer in comparison with statistical methods, using a combination of conventional and experimental biological markers. Forty-one patients with different stages and grades of prostate cancer undergoing a variety of treatments were analysed. Artificial neural networks were used as follows: eight input neurons consisting of six conventional factors (age, stage, bone scan findings, grade, serum PSA, treatment) and two experimental markers (immunostaining for bcl-2 and p53, which are both apoptosis-regulating genes). Twenty-one patients were used for training and 20 for testing. A total of 80% of the patients were correctly classified regarding outcome using the combination of factors. When both bcl-2 and p53 immunoreactivity were excluded from the analysis, correct prediction of the outcome was achieved in only 60% of the patients (P = 0.0032). This study was able to demonstrate the value of artificial neural networks in the analysis of prognostic markers in prostate cancer. In addition, the potential for using this technology to evaluate novel markers is highlighted. Further large-scale analyses are required to incorporate this methodology into routine clinical practice.

Alterations of TP53 in microdissected transitional cell carcinoma of the human urinary bladder: high frequency of TP53 accumulation in the absence of detected mutations is associated with poor prognosis.

We have used microdissection of paraffin-embedded histological sections and polymerase chain reaction (PCR)-based direct DNA sequencing for 54 transitional cell carcinoma (TCC) of the bladder, to examine critically the association between TP53 nuclear accumulation determined by immunohistochemistry and the presence of TP53 mutations, and to examine their relationship to tumour stage and grade, as well as patient survival. There was a significant association between the presence of TP53-positive nuclei (> 10%) and a higher histological stage and grade (P = 0.0115, P = 0.0151 respectively; Fisher's exact). A significant association between TP53 gene mutations and TP53 nuclear reactivity in more than 10% of tumour cell nuclei was also observed (P = 0.0003; Fisher's exact). Mutations were detected in 18/54 (33%) cases together with the wild-type sequence when analysed from bulk frozen samples, with significant clustering of mutations in exons 7 and 8. The microdissection method distinguished more clearly between heterozygous and/or homozygous alterations of the TP53 tumour-suppressor gene, and clearly showed frequent accumulation of TP53 in the absence of mutations. When microdissecting immunonegative regions from the same paraffin sections, three out of ten samples showed the identical mutations detected in the immunopositive regions. There was a significant association between TP53 immunoreactivity in more than 50% of tumour cell nuclei and decreased survival among all patients (P = 0.0325; log-rank test). The patients with TP53 mutations showed a trend for a shorter survival period; however, the association was not statistically significant at the 95% confidence level (P = 0.132; log-rank test). In conclusion, our observations show that accumulation of TP53 occurs frequently in the absence of mutations, and that such accumulation is nevertheless associated with poor survival when it occurs in a high proportion (> 50%) of tumour cell nuclei.

Immunolocalization and messenger RNA expression of bone morphogenetic protein-6 in human benign and malignant prostatic tissue.

Skeletal metastases are common in advanced prostate cancer, causing considerable morbidity, and they are usually osteoblastic in nature with no clear explanation for this phenomenon. Bone morphogenetic proteins (BMPs) induce bone formation in vivo, and preliminary work showed a possible association between BMPs and prostatic skeletal metastases; differential expression favors BMP-6 as a potential new marker and mediator of osteosclerotic deposit formation. We investigated BMP-6 mRNA and protein expression by in situ hybridization and immunohistochemistry in malignant and benign prostates from 40 men. BMP-6 mRNA expression was detected exclusively in malignant epithelial cells in 20 of 21 patients (95%) with metastases and in 2 of 11 patients (18%) with localized cancer, and it was absent in 8 benign samples. Immunostaining for BMP-6 was predominantly cytoplasmic and was present in all primary tumors with established metastases and in 4 of 11 (36%) organ-confined cancers. In benign prostatic hyperplasia, basal cells and areas of basal cell hyperplasia were positive for BMP-6 by immunohistochemistry. The results suggest a close association between BMP-6 expression in primary malignant prostatic tissue and skeletal metastases. BMP-6 may be responsible, in part, for the osteoblastic changes in metastatic lesions secondary to prostate cancer.

Development of a minimally invasive technique for coronary revascularization in a porcine model.

BACKGROUND: This porcine model was designed to develop a minimally invasive method for internal mammary artery (IMA) grafting using an anterior mediastinal approach and without routine use of cardiopulmonary bypass. METHODS: Assessment was made of IMA mobilization through a small parasternal incision, the feasibility of coronary artery grafting with cardiopulmonary bypass using this approach, and conditions for off-pump bypass grafting. RESULTS: In group 1, 6 pigs underwent IMA mobilization through a 5-cm horizontal midparasternal incision. Of the 2 group 2 pigs, 1 underwent IMA grafting to the left anterior descending coronary artery and the other, bilateral IMA grafting to the left anterior descending and right coronary arteries using femoral-vessel cardiopulmonary bypass. In group 3, 4 of 10 pigs had successful off-pump grafting during retrograde regional coronary venous perfusion of arterial blood. Retrograde coronary venous perfusion could not be established in the other 6 pigs, and attempts at off-pump grafting failed. CONCLUSIONS: The study demonstrates that coronary artery grafting with the IMA by this minimally invasive off-pump method is feasible, although it draws attention to areas of concern and potential methods of correction. The model provides a realistic and important learning platform for the surgical issues involved with this minimally invasive technique.

Transient ventricular asystole using adenosine during minimally invasive and open sternotomy coronary artery bypass grafting.

BACKGROUND: The emergence of minimally invasive coronary artery bypass grafting and recent off-pump open sternotomy clinical reports have refocused attention on the technical aspects and outcome of grafting on the beating heart. METHODS: To optimize the surgical field we report a method using adenosine for induction of controlled intervals of ventricular asystole to produce a transiently still cardiac field that facilitates anastomotic accuracy. RESULTS: Adenosine was used in 57 patients, 31 included off-pump coronary artery bypass grafting (27 by minimally invasive technique, 4 by open sternotomy). In a further 26 patients adenosine pauses were used for suture placement to control anastomotic bleeding after cardiopulmonary bypass. Average adenosine boluses per anastomosis were 9 (6-14), mean dose of adenosine per bolus (mg/kg) was 0.24 (0.15-0.35), mean duration of pause (seconds) was 6 (3-19), and mean time for arterial blood pressure (mean) to return to baseline (seconds) was 35 (13-48). Presence of repolarization arrhythmias was noted in 1 patient. There were no deaths. Two patients had recurrent myocardial ischemia shown on angiography to be the result of technical problems. CONCLUSIONS: This report describes our experience with the emerging procedure of minimally invasive coronary operations and off-pump grafting with the adenosine technique. The method also includes mechanical devices and other pharmacological therapy to optimize the surgical field, and the technique has now become a standard component of our off-pump revascularization methods.

The expression of waf-1, p53 and bcl-2 in prostatic adenocarcinoma.

OBJECTIVE: To determine the associations between the expression of waf-1 (a cyclin-dependent kinase inhibitor regulated by p53), p53, bcl-2 and tumour progression in prostate cancer. PATIENTS AND METHODS: Samples of prostatic tissue were obtained by biopsy or at prostatectomy from 40 men (mean age 73 years, range 55-88) with histologically confirmed prostate cancer, examined using immunohistochemical staining for the three gene products, and the expression related to the stage, grade, disease progression and survival of the patients. RESULTS: Fifteen of 18 patients whose tumours were positive for waf-1, 10 of 12 positive for bcl-2 and 17 of 19 positive for p53 had disease progression. Fifteen of 19 patients positive for p53 had poorly differentiated tumours compared with 11 of 21 negative for p53 (P < 0.05). A significant number of patients positive for p53 progressed and had a shorter time to progression compared to those negative for p53 (P < 0.05). There was no correlation between either waf-1 and/or bcl-2 staining and clinical grade, stage or tumour progression. CONCLUSIONS: This study confirmed the association of p53 protein accumulation with aggressive behaviour in prostate cancer and identified waf-1 protein in prostatic tumours. There was no evidence that the upregulation of waf-1 was associated with a better outcome in patients with prostate cancer.