The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice.

Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGFxxxb, where xxx is the amino acid number. The most studied isoforms, VEGF165 and VEGF165b have been shown to be present in tumour and normal tissues respectively. VEGF165b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF165b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF165b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF165b can inhibit growth of multiple tumour types in vivo indicating that VEGF165b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF165b expression by regulation of splicing, overexpression of VEGF165b, or therapeutic delivery of VEGF165b to tumours.

Do tumor volume, tumor volume ratio, type of nerve sparing and surgical experience affect prostate specific antigen recurrence after laparoscopic radical prostatectomy? A matched pair analysis.

PURPOSE: We assessed the impact of tumor volume, tumor volume ratio (tumor volume-to-prostate volume), surgical experience and type of nerve sparing procedure on biochemical recurrence after laparoscopic radical prostatectomy. MATERIALS AND METHODS: Of 1,600 laparoscopic radical prostatectomies performed between March 1999 and May 2006 we evaluated 555 patients who had at least 24 months of followup and received neither neoadjuvant nor adjuvant therapy. Of 555 patients 81 had biochemical recurrence and were match paired in 3 groups with those without recurrence. Matching decisions were based on factors such as age, preoperative prostate specific antigen, pathological stage, Gleason score, surgical margin status with localization, tumor volume, type of nerve sparing procedure, surgeon and date of operation that are related to surgical experience. We evaluated the impact of tumor volume and tumor volume ratio, type of nerve sparing procedure and surgeon on biochemical recurrence, and excluded the factor being investigated in each matched pair. RESULTS: Tumor volumes were 3.58 vs 3.3 cc and tumor volume ratios were 0.081 vs 0.071 in the biochemical recurrence and no biochemical recurrence groups, respectively (p=0.026 and p=0.040). At the second match pair the numbers of nonnerve sparing, unilateral and bilateral nerve sparing procedures were 65, 12 and 4 vs 62, 13 and 6, respectively, without statistical significance. At the last match pair the volume of cases for the first generation and the other generations were 56 and 25 vs 59 and 22, respectively, also without statistical significance. CONCLUSIONS: Although surgical experience based on an adequate training program and type of nerve sparing procedure do not have a significant impact on biochemical recurrence, tumor volume and tumor volume ratio do.

Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study.

OBJECTIVE: To evaluate the efficacy of bicalutamide vs cyproterone acetate in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing hormone-releasing hormone (LHRH) analogue therapy for prostate cancer. PATIENTS AND METHODS: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to goserelin acetate and continued for 21 days thereafter. PSA, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone pain were secondary end points. RESULTS: Both groups were equally matched apart from serum creatinine and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period. CONCLUSION: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study.

Contemporary update of cancer control after radical prostatectomy in the UK.

Despite a significant increase of the number of radical prostatectomies (RPs) to treat organ-confined prostate cancer, there is very limited documentation of its oncological outcome in the UK. Pathological stage distribution and changes of outcome have not been audited on a consistent basis. We present the results of a multicentre review of postoperative predictive variables and prostatic-specific antigen (PSA) recurrence after RP for clinically organ-confined disease. In all, 854 patient's notes were audited for staging parameters and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment as well as patients with incomplete data and follow-up were excluded. Median follow-up was 52 months for the remaining 705 patients. The median PSA was 10 ng ml(-1). A large migration towards lower PSA and stage was seen. This translated into improved PSA survival rates. Overall Kaplan-Meier PSA recurrence-free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. The 5-year PSA recurrence-free survival probability for PSA ranges <4, 4.1-10, 10.1-20 and >20 ng ml(-1) was 0.82, 0.73, 0.59 and 0.20, respectively (log rank, P<0.0001). PSA recurrence-free survival probabilities for pathological Gleason grade 2-4, 5 and 6, 7 and 8-10 at 5 years were 0.84, 0.66, 0.55 and 0.21, respectively (log rank, P<0.0001). Similarly, 5-year PSA recurrence-free survival probabilities for pathological stages T2a, T2b, T3a, T3b and T4 were 0.82, 0.78, 0.48, 0.23 and 0.12, respectively (log rank, P=0.0012). Oncological outcome after RP has improved over time in the UK. PSA recurrence-free survival estimates are less optimistic compared to quoted survival figures in the literature. Survival figures based on pathological stage and Gleason grade may serve to counsel patients postoperatively and to stratify patients better for adjuvant treatment.

Case selection for radical prostatectomy in the UK.

INTRODUCTION: Radical prostatectomy is an increasingly popular treatment option for clinically localised prostate cancer, yet PSA outcome figures are rare in the UK. This makes it difficult to establish appropriate criteria for case selection. We conducted an audit of PSA recurrence of 5 large centres in the south of England and investigated the use of pre-operative PSA to improve case selection and outcome. METHOD: 854 patients notes were audited for pre-operative staging parameters and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment as well as patients with incomplete data and follow-up were excluded. RESULT: Median follow-up was 52 months for the remaining 663 patients. Median PSA was 10 ng/ml. A large improvement of PSA recurrence free survival rates was observed from 1988 to 1998 as a result of change in case selection and stage migration. Overall Kaplan-Meier PSA recurrence free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. Five-year PSA recurrence free survival probability for PSA ranges <4 ng/ml, 4.1-10 ng/ml, 10.1-20 ng/ml and >20 ng/ml was 0.82, 0.73, 0.59 and 0.20, respectively (Wilcoxon, p < 0.0001). A simulation of biochemical recurrence free survival for patient cohorts with stepwise reduced inclusion PSAs suggests an improved outcome for patients with a pre-operative inclusion PSA of <12 ng/ml. Further reduction of the inclusion PSA does not improve outcome. CONCLUSION: Intermediate PSA recurrence free survival has improved over time in England. PSA recurrence free survival estimates are less optimistic compared to frequently quoted American figures. A reduced pre-operative PSA cut-off for case selection may be used to improve outcome.

Time trends in case selection, stage and prostate-specific antigen recurrence after radical prostatectomy: a multicentre audit.

OBJECTIVES: To report an audit of preoperative staging variables, case selection, stage migration and prostate-specific antigen (PSA) recurrence at five large centres in the south of England. To establish PSA outcome values after radical prostatectomy for clinically localized prostate cancer in the UK, and enable appropriate patient counselling. PATIENTS AND METHODS: The notes of 854 patients were audited for preoperative staging variables and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment, and with incomplete data and follow-up, were excluded. RESULTS: The median follow-up was 52 months for the remaining 663 patients; the median PSA level was 10 ng/mL. There was a large migration towards lower PSA and stage; this translated into improved PSA survival rates. The overall Kaplan-Meier PSA recurrence-free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. The 5-year PSA recurrence-free survival probabilities for PSA levels of < 4, 4.1-10, 10.1-20 and > 20 ng/mL were 0.82, 0.73, 0.59 and 0.20, respectively (Wilcoxon, P < 0.001). The PSA recurrence-free survival probabilities for biopsy Gleason grade 2-4, 5 and 6, 7 and 8-10 at 5 years were 0.70, 0.61, 0.55 and 0.21, respectively (Wilcoxon, P < 0.001). Similarly, the 5-year PSA recurrence-free survival probabilities for clinical stages T1a and 1b, T1c, T2a and T2b were 0.79, 0.62, 0.57 and 0.44, respectively (Wilcoxon, P = 0.0012). CONCLUSION: With better case selection the intermediate oncological outcome has improved over time in the UK. PSA recurrence-free survival estimates are less optimistic than the frequently quoted American values. The present values may be used to help in counselling British patients before radical prostatectomy.

Is the conservative management of chronic retention in men ever justified?

OBJECTIVE: To assess the outcome of men presenting with lower urinary tract symptoms (LUTS) associated with large postvoid residual urine volumes (PVR). PATIENTS AND METHODS: The study included men presenting with LUTS and a PVR of > 250 mL who, because of significant comorbidity, a low symptom score or patient request, were managed conservatively and prospectively, and were followed with symptom assessment, serum creatinine levels, flow rates and renal ultrasonography. Patients were actively managed if there was a history of previous outflow tract surgery, prostate cancer, urethral strictures, neuropathy, elevated creatinine or hydronephrosis. In all, 93 men (mean age 70 years, range 40-84) with a median (range) PVR of 363 mL (250-700) were included in the study and followed for 5 (3-10) years. At presentation, the median maximum flow rate was 10.2 (3-30) mL/s and the voided volume 316 (89-714) mL. RESULTS: The measured PVR remained stable in 47 (51%), reduced in 27 (29%) and increased in 19 (20%) patients; 31 patients (33%) went on to transurethral resection of the prostate after a median of 30 (10-120) months, because of serum creatinine elevation (two), acute retention (seven), increasing PVR (eight) and worsening symptoms (14). Of 31 patients 25 were available for evaluation after surgery; their median PVR was 159 (0-1000) mL, flow rate 18.4 (4-37) mL/s and voided volume 321 (90-653) mL. Symptoms were improved in all but five men. There was no difference in initial flow rate, voided volume or PVR between those who developed complications or went on to surgery and those who did not. Urinary tract infections (UTIs) occurred in five patients and two developed bladder stones. CONCLUSIONS: Complications such as renal failure, acute retention and UTIs are uncommon in men with large, chronic PVRs. Conservative management for this group of patients is reasonable but outpatient review is prudent. There were no factors that could be used to predict those patients who eventually required surgery.

Long-term results following operation for diabetic foot problems: arterial disease confers a poor prognosis.

OBJECTIVES: to describe the long-term outcome of local amputations and debridements of diabetic feet, with special reference to the presence or absence of arterial disease. MATERIALS AND METHODS: a consecutive series of 75 diabetic patients having local foot surgery during 1987-92 was reviewed in 1998. A total of 136 operations had been done on 92 limbs, of which 52 (60%) had evidence of arterial disease. Survivors were interrogated in 1998, with follow-up intervals of 69-120 (median 92) months after their index operations. RESULTS: complete healing occurred in 48% feet, and 36% limbs required major amputation, after 1 day-7 years (median 24 days). Major amputation was more common in limbs with arterial disease (52% vs. 18%) -p;<0.001. At follow-up 20 (27%) patients were alive (five lost to long-term follow-up) - five of 44 (11%) arteriopaths, and 15 of 26 (58%) of those without arterial disease (p<0.001). No patient who had arterial reconstruction at the outset survived to follow-up. Among the survivors, 78% feet had remained healed, with no recurrent ulceration. CONCLUSIONS: among diabetics requiring local foot surgery, the presence of arterial disease confers a poor long-term prognosis for both life and limb. Those with neuropathy alone tend to do well with good foot care.