MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Penile cancer in Ireland - A national review.

OBJECTIVE: Penile cancer is a rare malignancy, with a reported incidence of 1.5/100,000 males in the Republic of Ireland in 2015. The aim of this study was to perform the first national review and to evaluate clinicopathological factors affecting survival. SUBJECTS AND METHODS: All cases of penile cancer in Ireland between 1995 and 2010 were identified through the National Cancer Registry Ireland (NCRI) and analysed to identify factors affecting survival. RESULTS: 360 cases of penile cancer were identified, with a mean age at diagnosis of 65.5 years and 88% (n = 315) of cases occurred in those over 50. 91% (n = 328) of cases were squamous cell carcinomas (SCC). The majority of patients were treated surgically (n = 289), with 57% (n = 206) and 24% (n = 87) undergoing partial penectomy and total penectomy respectively. Only 18% (n = 65) received radiotherapy, and 8% (n = 27) received chemotherapy. Mean overall survival (OS) was 113 months, and five year disease specific survival (DSS) was 70% (95%CI: 59.1-77.8%). Age at diagnosis, nodal status and presence of metastatic disease were independent prognostic markers on multivariate analysis. CONCLUSION: This study represents the first national review of penile cancer in Ireland. The annual incidence and survival rates are comparable to European figures, though superior DSS has previously been reported from our institution, highlighting the role for centralisation of care in Ireland. LEVEL OF EVIDENCE: 2b.

HFD-induced energy states-dependent bidirectional control of anxiety levels in mice.

BACKGROUND: The association between the development of obesity and its metabolic comorbidities, and chronic consumption of high-fat diet (HFD) has been well-demonstrated. Interestingly, emerging evidence indicates that obesity is also associated with an increased risk for psychiatric disorders including anxiety and depression. Although HFD feeding is associated with anxiety-related behaviors, previous studies have reported inconsistent findings on the direction of this relationship. Therefore, in this study we sought to investigate the link between HFD feeding, body weight, energy states and anxiety levels in mice and specifically to determine if the duration of HFD exposure has distinct effects on anxiety-related behaviors. METHODS: To disentangle the temporal dynamic effects of HFD feeding on anxiety-related behaviors, mice were fed a HFD or regular chow (RC) diet and were assayed periodically for anxiety-related behaviors by using behavioral tests (open field test; OFT) and the elevated plus maze. To determine if obesity phenotypes correlate with anxiety-related behaviors, changes in anxiety-related behaviors in OFTs were correlated with changes in both body weight and glucose sensitivity following various levels of HFD and RC exposure. RESULTS: Our results demonstrate a time-dependent biphasic effect of HFD feeding on anxiety-related behaviors. At 5 weeks, mice fed HFD show a reduction in anxiety-related behaviors when compared to pair-fed RC mice. At 8 weeks of HFD or RC feeding, anxiety levels were the same in both groups. Following 15 weeks of HFD and RC feeding, however, mice displaying metabolic symptoms of obesity showed increased anxiety-related behaviors relative to mice resilient to obesity phenotypes, independent of feeding conditions. CONCLUSIONS: Taken together our findings suggest that HFD bi-directionally effects anxiety-related behaviors such that short-term exposure to a HFD reduces anxiety levels, while longer exposure to a HFD promotes anxiety levels selectively in mice that display metabolic symptoms of obesity. Regardless of diet (HFD or RC), heavier animals display increased anxiety-like behaviors. These findings indicate diverse overlapping roles for HFD and body weight in modulating anxiety-related behaviors, and may partly resolve previous inconsistencies in studies examining the relationship between HFD feeding and anxiety.

Post-Chemotherapy Retroperitoneal Lymph Node Dissection in Patients with Non-Seminomatous Germ Cell Tumour (NSGCT).

Diabetic retinopathy is a significant complication of diabetes, and the most common cause of blindness in people under the age of 65. The National Diabetic Retinal Screening Programme (Diabetic RetinaScreen) was established to detect sight threatening retinopathies. The purpose of this cross-sectional study is to determine the barriers to the uptake of Diabetic RetinaScreen, to investigate discrepancies in attendance, if any, between patients whose diabetes care is delivered in a large tertiary referral hospital out-patient setting or in general practice, and to evaluate general practitioner's satisfaction with the service. Older age (OR 1.023, 95% CI 1.001 to 1.046) and complications of diabetes, excluding ocular complications, (OR 2.741, 95% CI 1.158 to 6.489) were associated with increased attendance at Diabetic RetinaScreen. Online referral is now available and the preferred method of referral. Efforts to encourage younger patients who do not yet have complications of diabetes may be beneficial.

Is there a role for the development of a supra-regional network for the management of penile cancer in the Republic of Ireland?

INTRODUCTION: There is an average of 25 cases of penile cancer in the Republic of Ireland each year. Due to the low volume of cases, the National Institute for Clinical Excellence recommends that treatment is centralised to allow the best standardised treatment for primary tumours and nodal disease. OBJECTIVES: To determine whether outcomes for patients with penile cancer differed significantly between secondary and tertiary referral centres in the Republic of Ireland. METHODS: Between 2001 and 2014, 36 patients were treated in the Mercy University Hospital (MUH) with penile cancer. Twenty patients were treated primarily in MUH and 16 patients underwent initial management in a secondary referral centre (SRC) with subsequent referral to the MUH. A retrospective matched case-control study was performed on this patient cohort. RESULTS: There were no significant differences in length of follow-up or risk factors for the development of penile cancer between both groups (p = 0.6 and p = 0.5 respectively) Ultimately, the incidence of high risk disease, nodal metasases, high grade disease and pelvic lymph node dissection were significantly greater in patients that were initially managed in a SRC (p = 0.02, p = 0.03, p = 0.004 and p = 0.028 respectively). Patients undergoing initial treatment in a SRC had a non-significantly reduced rate of cancer specific survival (88 Vs 66%, MUH Vs SRCs, p = 0.495) and recurrence free survival (85 Vs 46%, MUH Vs SRCs, p = 0.24). CONCLUSION: Our findings suggest that managing penile cancer in special interest centres may improve oncological outcome.

Penile cancer--Guideline adherence produces optimum results.

OBJECTIVE: To audit the management and outcome of penile cancer in a tertiary university teaching hospital, comparing our results to international best practice and published guidelines. METHODS: The Hospital Inpatient Enquiry database of the Mercy University Hospital was interrogated for penile cancer patients treated between 2001 and 2012. Data relating to presentation, local treatment, histology, lymph-node management, outcome and survival was recorded. Data were analysed using the Log Rank test, with significance defined as P ≤ 0.05. RESULTS: Twenty-five patients were identified with a median age of 61 years. The majority of cases at presentation were ≥ T2 (54%) and intermediate to high grade (76%). The median follow-up of patients was 3.75 years (range 9 months-10 years). Overall survival was 76% (n = 19), these patients are all disease free to date. Disease-specific survival was 85% at 10 years. Penile cancer related mortality was 8% (n = 2), 4 patients (16%) died of non-penile cancer related causes. Twenty-two patients (88%) had surgery and 3 patients (12%) had radiotherapy. Based on EAU guidelines inguinal lymph node dissection (ILND) was performed in 64% (n = 16) of cases with 44% (n = 7) of these patients requiring concurrent bilateral pelvic lymph node dissection. Fifty percent (n = 8) of ILNDs showed metastatic disease. Ten year disease-specific survival for node negative versus node positive disease is 100% versus 57%. Thirty-two percent (n = 8) of patients received chemotherapy. CONCLUSIONS: Penile cancer is a rare oncological condition that often requires bilateral inguinal ± pelvic lymph node dissection and should be managed according to published guidelines, in specialist centres in order to maximize outcomes.

Characteristics of modern Gleason 9/10 prostate adenocarcinoma: a single tertiary centre experience within the Republic of Ireland.

INTRODUCTION: The 2005 international society of urological pathology consensus statement on Gleason grading in prostate cancer revised Gleason scoring in clinical practice. The potential for grade migration with this refinement poses difficulties in interpreting historical series. We report the characteristics of a recent cohort of consecutive Gleason score 9 or 10 prostate cancers in our institution. The purpose of this study was to define the clinicopathologic variables and staging information for this high-risk population, and to identify whether traditional prostate staging techniques are adequate for this subcohort of men. MATERIALS AND METHODS: A computational review of our pathology database was performed. Between May 2010 and September 2012, 1,295 consecutive biopsies were undertaken, 168 of which were high-grade tumours (12.97 %). This group were divided into two cohorts of which 84 (12.05 %) had a highest reported Gleason score of 9 (N = 79) or 10 (N = 5) and 84 were reported as Gleason 8. All biopsies were double-reported by pathologists with a special interest in uropathology. RESULTS: Men diagnosed with a Gleason pattern 5 tumour were statistically far more likely to have advanced disease on direct rectal examination of the prostate compared with Gleason sum 8 tumours (p < 0.001) and a positive first-degree family history of prostate cancer (p < 0.001). Overall, Gleason sum 9/10 prostate cancers were also found to be statistically more aggressive than Gleason sum 8 tumours on TRUS core biopsy analysis with significantly higher levels of perineural invasion (p < 0.0001) and extracapsular extension (p = 0.001) as well as a higher levels of tumour found within the core biopsy sample. Those men diagnosed with Gleason pattern 5 prostate cancer also had radiological indicators of increased tumour aggressiveness compared with Gleason sum 8 cancer with respect to bone (p = 0.0002) and visceral (p = 0.044) metastases at presentation. CONCLUSIONS: This series of Gleason score 9/10 prostate cancers serves to highlight the large disease burden, adverse pathologic features, and locally advanced nature of this aggressive subtype, which has previously been under-described in the literature, and differs from historical series in having a large high-grade cohort demonstrating high rates of metastatic disease. A history of prostate cancer amongst first-degree relatives was particularly prevalent in this population raising the issue of screening in a high-risk population. The high incidence of visceral metastatic disease at presentation supports upfront staging with CT thorax, abdomen, and pelvis in patients with Gleason 9 or 10 prostate cancers.

Long-term persistence of crop alleles in weedy populations of wild radish (Raphanus raphanistrum).

*Hybridization allows transgenes and other crop alleles to spread to wild/weedy populations of related taxa. Researchers have debated whether such alleles will persist because low hybrid fitness and linkage to domestication traits could severely impede introgression. *To examine variation in the fates of three unlinked crop alleles, we monitored four experimental, self-seeding, hybrid populations of Raphanus raphanistrum x Raphanus sativus (radish) in Michigan, USA, over a decade. We also compared the fecundity of advanced-generation hybrid plants with wild plants in a common garden experiment. *Initially, F(1) hybrids had reduced fitness, but the populations quickly evolved wild-type pollen fertility. In Year 10, the fecundity of plants from the experimental populations was similar to that of wild genotypes. Crop-specific alleles at the three loci persisted for 10 yr in all populations, and their frequencies varied among loci, populations and years. *This research provides a unique case study of substantial variation in the rates and patterns of crop allele introgression after a single hybridization event. Our findings demonstrate that certain crop alleles can introgress easily while others remain rare, supporting the assumption that neutral or beneficial transgenes that are not linked to maladaptive traits can persist in the wild.

Salivary gland dysfunction ('dry mouth') in patients with cancer: a consensus statement.

A group of interested professionals was convened to develop some evidence-based recommendations on the management of salivary gland dysfunction (SGD) in oncology patients. A Medline search was performed to identify the literature on SGD. The abstracts of all identified papers were read, and the full texts of all relevant papers were reviewed. The evidence was graded according to the Scottish Intercollegiate Guidelines Network grading system for recommendations in evidence-based guidelines. The summary of the main recommendations are: (1) patients with cancer should be regularly assessed for SGD (grade of recommendation - D); (2) the management of SGD should be individualised (D); (3) consideration should be given to strategies to prevent the development of radiation-induced SGD (C); (4) consideration should be given to treatment of the cause(s) of the SGD (C); (5) the treatment of choice for the symptomatic management of SGD is use of an appropriate saliva stimulant (C); (6) consideration should be given to prevention of the complications of the SGD (D); (7) consideration should be given to treatment of the complications of the SGD (D); and (8) patients with SGD should be regularly reassessed (D).

Impact of pharmacotherapy on the incidence of transurethral prostatectomy for benign prostatic hyperplasia and the implications for surgical training.

Medical therapy has become first line treatment for Benign Prostatic Hypertrophy (BPH) and in many cases TURP may no longer be required. Proof and quantification of this evolution in practice has been somewhat elusive and provided the principle impetus for this study. This is a retrospective study of BPH management in Republic of Ireland from 1995 to 2008. National treatment databases were sourced for numbers undergoing TURP and pharmacotherapy prescribing data was obtained from individual pharmaceutical companies. A total of 28,240 TURP's were performed nationally between 1995 and 2008. TURP's performed annually, decreased by 1,494 (51%), alpha-blocker prescriptions increased from 8,710 to 302,159 units and the number of urology trainees increased by 10 (60%). Clear association between decreases in TURP's and increases in pharmacotherapy for BPH is demonstrated. Implications on training likely exist and will require proper evaluation in order to maintain future standards in this surgical practice.

The natural history of Leydig cell testicular tumours: an analysis of the National Cancer Registry.

BACKGROUND: Leydig cell tumour (LCT) of the testis is a rare histological subtype of stromal tumours, accounting for 1 to 3% of testicular neoplasms. The natural history of LCT is poorly understood. AIMS: The aim of this study was to assess the incidence and natural history of Leydig cell tumours (LCT) of the testes. METHODS: A search of the National Cancer Registry of Ireland database was performed regarding Leydig cell testicular tumours. Recurrence free survival (RFS) and disease-specific survival (DSS) were analysed. RESULTS: Between 1994 and 2013, 2755 new cases of testicular cancer were diagnosed in Ireland. Of these, 22 (0.79%) were Leydig cell tumours. Nineteen were invasive (stage T1) and three were in situ (stage Tis). One patient developed a local recurrence following an organ preserving procedure and underwent a completion orchidectomy 107 days after initial diagnosis. No further treatment was required. There have been no disease-specific deaths. The 1-, 3- and 5-year overall survival (OS) rates were 95.5, 88.2 and 73.3%, respectively. The 5-year disease-specific survival (DSS) was 100% and the 5-year recurrence free survival (RFS) was 93.3%. CONCLUSION: From the National Cancer Registry, LCT has been shown to be a rare subtype of testicular tumour. Due to the relatively favourable natural history, it may be possible to tailor less aggressive surveillance regimens in these patients.

Flavoxate in the symptomatic treatment of overactive bladder: a meta-analysis.

OBJECTIVE: Overactive bladder is a syndrome of urinary frequency and urgency, with or without urge incontinence, in the absence of local pathological factors. Since multiple causes are responsible for OAB, it requires proper diagnosis and comprehensive management. For decades, flavoxate is a globally used and accepted molecule by the urologists and the general physicians for the symptomatic treatment of OAB. In spite of its extensive use in OAB, a meta-analysis of the available publications for efficacy, safety and tolerability of flavoxate has not been conducted. This paper evaluates the strength of evidence of clinical effectiveness of safety and tolerability of flavoxate in the symptomatic treatment of OAB. METHODS: Review articles, original studies and case reports on MEDLINE, the Cochrane Library, Google Scholar, Scirus, internal repository, etc. were searched using the keyword "flavoxate". For the primary outcome, the comparative data of flavoxate versus comparator was extracted for following parameters - overall efficacy and its side effect profile. Similarly as for secondary outcome, data were extracted for flavoxate per se for overall efficacy, frequency, urinary incontinence, mixed incontinence, nocturia, unpleasant urination, stranguria and its side effect profile and were analyzed using Comprehensive Meta-Analysis (CMA) software version 2.0. RESULTS: In the current meta-analysis, 43 relevant published studies were considered which clearly demonstrated that flavoxate had improved clinical efficacy than placebo, emepronium, propantheline, and phenazopyridine. CONCLUSIONS: Amongst all the interventions studied, flavoxate was effective and well-tolerated, with almost negligible side effects, making it worthy of consideration for the treatment of OAB.

A novel rapid access testicular cancer clinic: prospective evaluation after one year.

BACKGROUND: Our institution has recently developed a rapid access outpatient clinic to investigate men with testicular lumps and/or pain suspicious for testicular cancer (TCa). AIMS: To present our experience after 12 months. METHODS: All referrals to the rapid access testicular clinic (RATC) clinic were prospectively analysed from 01/01/2013 to 01/01/2014. The primary outcome variable was incidence of TCa in the referred patient cohort. Secondary outcome variables were waiting times prior to clinical review and waiting times prior to radical orchidectomy in patients diagnosed with TCa. RESULTS: Seventy-four new patients were referred to the RATC during the 1-year period and the mean age was 34 (range 15-81 years). TCa was the most common diagnosis and was found in 18 (25 %) patients. Patients diagnosed with TCa underwent radical orchidectomy, a median of 3 (range 1-5) days after their initial GP referral. Patients requiring surgical intervention for benign scrotal pathology underwent their procedure a median of 32 (range 3-61) days after their initial referral. Of the 18 patients diagnosed with TCa, 9 (50 %) were diagnosed with a seminomatous germ cell tumour on histopathology. CONCLUSION: The RATC is a new initiative in Ireland that provides expedient and definitive treatment of patients with newly diagnosed TCa. Early treatment will ultimately improve long-term prognosis in this patient cohort.

Six-core versus twelve-core prostate biopsy: a retrospective study comparing accuracy, oncological outcomes and safety.

AIMS: To compare sextant and 12 core transrectal ultrasound-guided (TRUS) prostate biopsies for detecting prostate cancer (PCa) and to determine whether 12-core prostate biopsies are associated with a higher incidence of insignificant prostate cancer and complications. METHODS: A retrospective study was performed on all patients with a positive TRUS biopsy for prostate cancer between January 2011 and December 2013. Group A underwent a sextant core prostate biopsy and group B underwent a 12-core prostate biopsy. Outcome variables were cancer detection rates, oncological outcomes, incidence of clinically insignificant PCa and incidence of biopsy associated complications. Exclusion criteria included a negative TRUS biopsy and metastatic prostate cancer. RESULT: In total 718 prostate biopsies were performed and 286 patients met inclusion criteria (143 patients in each group). The overall cancer detection rate was 43 % in group A compared to 53 % in group B (p = 0.03). In group A, 31 (21.7 %) patients proceeded to open retropubic radical prostatectomy (RRP) compared to 36 (25.2 %) in group B (p = 0.7). Sextant biopsies were associated with a significantly higher rate of upgrading compared to 12-core biopsies in RRP specimens (51.6 versus 25 % respectively, p < 0.01). The incidence of clinically insignificant PCa was 10.5 % in group A versus 14.7 % in group B (p = 0.2). The incidence of urosepsis post biopsy was 0.7 % in both groups (n = 1). CONCLUSION: Twelve-core biopsies were associated with higher PCa cancer detection rates, greater accuracy for Gleason grading and no differences for detecting clinically insignificant PCa or urosepsis compared to sextant biopsies.

Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC.

PURPOSE: We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging. PATIENTS AND METHODS: A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy. RESULTS: There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured. CONCLUSION: These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort.

Gene therapy of human bladder cancer with adenovirus-mediated antisense basic fibroblast growth factor.

We previously investigated the role of basic fibroblast growth factor (bFGF) as a mediator of angiogenesis, tumorigenicity, and metastasis of transitional cell carcinoma (TCC) of the bladder. In the present study, we determined whether adenoviral-mediated antisense bFGF gene transfer therapy (Ad bFGF-AS) would inhibit TCCs growing in the subcutis of nude mice. In vitro, Ad bFGF-AS inhibited endothelial cell proliferation and enhanced apoptosis. The highly metastatic human TCC cell line 253J-BV(R) was implanted ectopically in the subcutis of athymic nude mice, and therapy was begun when the tumors reached a diameter between 5 and 7 mm. Intralesional therapy with Ad bFGF-AS decreased the in vivo expression of bFGF and matrix metalloproteinase type 9 mRNA and protein, and reduced microvessel density and enhanced endothelial cell apoptosis. Tumor growth was significantly inhibited by Ad bFGF-AS (mean, 58 mg) compared with controls [saline (mean, 562 mg), beta-galactosidase adenovirus (mean, 586 mg), and sense bFGF adenoviral therapy (Ad bFGF-S; mean, 3012 mg)]. These results suggest that Ad bFGF-AS therapy affects endothelial cells directly and tumor cells indirectly through down-regulation of bFGF and matrix metalloproteinase type 9, resulting in endothelial cell apoptosis and significant tumor growth inhibition. Furthermore, these studies confirm that bFGF expression is a valid target for the therapy of bladder cancer.

The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy.

To determine the prognostic value of angiogenesis factor expression for patients with muscle-invasive transitional cell carcinoma (TCC) of the bladder treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy and radical cystectomy, we evaluated the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8) by in situ hybridization, and we determined microvessel density (MVD) by immunohistochemistry. These factors were evaluated in 55 biopsy specimens prior to therapy and in the cystectomy specimens of 51 patients after completion of therapy. By univariate analysis, VEGF expression and MVD in the biopsy specimens were significant predictors of disease recurrence. By multivariate analysis, only VEGF expression was an independent prognostic factor. Pathological stage, bFGF expression, and MVD in the cystectomy specimens after therapy were all independent prognostic factors for disease recurrence. The results of this exploratory study indicate that the expression levels of VEGF and bFGF as indicated by in situ hybridization and MVD as indicated by immunohistochemistry identify patients with muscle-invasive TCC who are at high risk of developing metastasis after aggressive therapy with systemic M-VAC chemotherapy and radical cystectomy.

Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma.

Previously we reported that when cells from the human transitional cell carcinoma cell line 253J B-V growing orthotopically within the bladder of athymic nude mice were treated with the anti-epidermal growth factor receptor monoclonal antibody C225, angiogenesis was inhibited, resulting in regression of the primary tumor and inhibition of metastasis. In this study, we evaluated whether paclitaxel enhanced this therapeutic effect of C225. In vitro, the proliferation of 253J B-V cells was inhibited more by the combination of C225 and paclitaxel than with either agent alone. In vivo therapy with C225 and paclitaxel resulted in significantly greater regression of tumors compared with either agent alone. Median bladder tumor weight was 85 mg (range, 69-133 mg) compared with 168 mg (range, 72-288 mg) after C225 alone (P < 0.05), and 273 mg (range, 83-563 mg) after paclitaxel alone (P < 0.005). The incidence of spontaneous lymph node metastasis was also reduced by the combination of C225 with paclitaxel, although this result did not significantly differ from results after the use of C225 alone. Treatment with paclitaxel and C225 down-regulated the expression of basic fibroblast growth factor, vascular endothelial cell growth factor, interleukin-8, and matrix metalloproteinase type 9 and inhibited tumor-induced neovascularity compared with untreated controls (P < 0.005). Moreover, the combination of C225 and paclitaxel enhanced apoptosis in tumor and endothelial cells compared with either agent alone (P < 0.005). These studies indicate that therapy with paclitaxel increases the ability of C225 to inhibit tumorigenicity and metastasis. This effect is mediated by inhibition of angiogenesis and induction of apoptosis.