An immediate,single intravesical instillation of mitomycin C is of benefit in patients with non–muscle-invasive bladder cancer irrespective of prognostic risk groups

Background

In a recent meta-analysis, subgroups of patients were defined that may not benefit from a single, immediate instillation with chemotherapy. This led to a change in the European Association of Urology bladder cancer guidelines. In a previous paper, our group confirmed the efficacy of an immediate instillation of mitomycin C (MMC). However, prognostic groups in that study differ from those in the meta-analysis. Therefore, we performed a reanalysis using contemporary risk groups.

Conditional analyses of recurrence and progression in patients with TaG1 non–muscle-invasive bladder cancer

Objective

To determine conditional recurrence-free survival (RFS) and progression-free survival (PFS) and improve decision-making toward surveillance protocols and scheduling. Furthermore, evaluating the evolution of predictors for disease recurrence over time, because TaG1 non–muscle-invasive bladder cancer harbors a risk of disease recurrence and progression.

Impact of bladder neck involvement on progression in patients with primary non–muscle invasive bladder cancer: A prospective validation study

PurposeOur previous retrospective study reported that bladder neck involvement (BNI), as well as tumor grade and stage, was a significant risk factor for progression in primary non–muscle invasive bladder cancer (NMIBC). We prospectively validated BNI as a significant predictor for progression using a new cohort of patients with primary NMIBC.Patients and methodsA total of 297 new Japanese patients who underwent transurethral resection and were pathologically diagnosed with Ta or T1 urothelial carcinoma were enrolled in this prospective study. Clinicopathologic data were collected at study entry. Multivariate Cox proportional hazards regression models were performed to identify the independent predictors for progression. A predictive scoring model for progression was developed using the regression coefficients (RCs) from the final multivariate model. The predictive ability of the model was assessed using Harrell's c-index.ResultsWith a median follow-up of 37 months, 16 patients (5.4%) progressed. Progression probability at 1 and 5 years were 1.5% and 8.0%, respectively. Multivariate analysis revealed that histologic grade 3 (hazard ratio [HR] 9.45, P = 0.0004, RC 2.25), pathologic T1 stage (HR 6.91, P = 0.0014, RC 1.93), and BNI (HR 11.75, P = 0.0009, RC 2.46) were all independent predictors of progression. When all 3 variables were scored as 1 point and the patients were divided into 3 groups, progression rates were clearly discriminated (P<0.0001). The c-index was 0.80.ConclusionsThis prospective validation study has shown that BNI is a significant prognostic factor for progression in primary NMIBC. The scoring model including BNI enables the physician to classify patients with primary NMIBC into 3 groups with clearly different progression rates.     

Assessment of diagnostic gain with hexaminolevulinate (HAL) in the setting of newly diagnosed non–muscle-invasive bladder cancer with positive results on urine cytology

ObjectiveIn accordance with the European Association of Urology guidelines, a second transurethral resection of the bladder (TURB) is recommended for high-grade or T1-category tumors. This practice brings into question the benefit of photodynamic diagnosis (PDD) in reducing the residual disease after TURB in patients with positive results on urine cytology showing high-grade cancer cells.Methods and materialsA prospective, bicentric, randomized study comparing white light cystoscopy (WLC)+PDD with hexaminolevulinate arm with WLC alone (control arm) during the first TURB in patients with primary non–muscle-invasive bladder cancer and with positive results on urine cytology showing high-grade cancer cells. Patients underwent a first TURB with WLC and PDD or WLC alone, and then a second TURB with WLC and PDD, after 4 to 6 weeks. The number of tumors visualized in WLC and PDD and histology of the TURB specimen was recorded to perform a statistical analysis comparing both the 2 arms.ResultsA total of 151 patients were enrolled (hexaminolevulinate, n = 72; control, n = 79). The number of visualized tumors did not increase with PDD in the first or second TURB. During the second TURB, the residual tumor rate was not reduced in patients who had PDD during the first TURB. No significant difference was observed regarding the pattern of category and grade, the size, and the recurrence and progression risks during either the first or the second TURB.ConclusionsIn the setting of primary non–muscle-invasive bladder cancer with positive results on urine cytology, performing a second TURB allows to diagnose residual tumor in approximately half of the cases. This rate was not significantly reduced by the use of the PDD during the first TURB.     

Dose–response efficacy and safety of PA21 in Japanese hemodialysis patients with hyperphosphatemia: a randomized,placebo-controlled,double-blind,Phase II study

Background

Hyperphosphatemia is common in chronic kidney disease (CKD) and associated with mortality and morbidity. We aimed to evaluate the dose-dependent efficacy and safety of PA21 (sucroferric oxyhydroxide), an iron-based phosphate binder, in Japanese hemodialysis patients with hyperphosphatemia.

Methods

In this double-blind, multicenter, Phase II study, 183 patients were randomized to placebo or PA21 at doses of 250, 500, 750, or 1000 mg (based on iron content) three times/day for 6 weeks. The primary efficacy endpoint was the mean change in serum phosphorus levels from baseline to end of treatment in each group. Adverse reactions were evaluated.

Results

The change in serum phosphorus level was significantly greater in each PA21 group than in the placebo group (analysis of covariance: P < 0.001 for all groups). A dose-dependent change in serum phosphorus levels was observed in the PA21 groups. A notable decrease in mean serum phosphorus levels to the target level of ≤6 mg/dL was shown starting at Week 1 in all PA21 groups. The cumulative achievement rates for target serum phosphorus level at the end of treatment were generally >80 % in all PA21 groups. The major adverse reaction reported was diarrhea; however, most cases were mild.

Conclusions

PA21 was an effective and safe treatment that decreased serum phosphorus levels starting at 1 week of treatment when administered as one 250-mg tablet three times/day. PA21 demonstrated a dose-dependent phosphorus lowering effect up to 3000 mg/day. PA21 may be a new treatment alternative with relatively low pill burden for Japanese hemodialysis patients with hyperphosphatemia.

     

Prognostic role of pretreatment neutrophil-to-lymphocyte ratio (NLR) in patients with non–muscle-invasive bladder cancer (NMIBC): A systematic review and meta-analysis

Objective

The aim of this study was to summarize and analyze the current evidence regarding the prognostic and predictive value of preoperative neutrophil-to-lymphocyte ratio (NLR) in patients undergoing transurethral resection of bladder tumors (TURBT) for non–muscle-invasive bladder cancer (NMIBC).

Validation of the ezrin,CK20, and Ki-67 as potential predictive markers for BCG instillation therapy of non–muscle-invasive bladder cancer

Objective

The aim of our study was to try to validate 3 promising predictive biomarkers in a database based on prospective trials comparing bacillus Calmette-Guerin (BCG) with mitomycin-C and a combination of epirubicin and interferon, respectively.

A multicenter phase I study of cabazitaxel,mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study

Background

Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile.

Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer

BackgroundBoth bacillus Calmette-Guérin (BCG) and interferon-alpha (IFN-α) express activity against superficial bladder cancer. The results of a national multicenter phase II trial of a combination of these 2 agents used in a wide range of patients are reported.Materials and MethodsPatients previously having BCG failure received IFN-α (50 million units) plus reduced dose BCG, while patients naïve to BCG received the same IFN-α dose with standard dose BCG. All patients who were relapse free received an additional 3 series of 3-week reduced dose BCG plus IFN-α treatments at 3, 9, and 15 months after completing induction. Any relapse during the 3-month evaluation was counted as a failure of therapy for Kaplan-Meier analysis. Multivariate analysis was performed to identify factors associated with recurrence.ResultsOf 1,007 valuable patients, 59% and 45% of patients naïve to BCG and those having BCG failure, respectively, remained disease free at 24-month median follow-up. Stage T1, tumor size >5 cm, prior BCG failure more than once, and multifocality were all statistically significant risk factors for recurrence.ConclusionsAlthough BCG plus IFN-α can be effectively applied to both patients naïve to BCG and those having BCG failure, certain patient and tumor characteristics influence durable response.     

A multicenter phase I–II study of docetaxel plus epirubicin plus bevacizumab as first-line treatment in women with HER2-negative metastatic breast cancer

PurposeTo assess the efficacy and toxicity of docetaxel (D) plus epirubicin (E) in combination with bevacizumab (B) [DEB regimen] as front-line treatment in patients with metastatic breast cancer (MBC).Patients and methodsWomen with previously untreated HER2-negative MBC received B (15 mg/kg), E (75 mg/m²) and D (75 mg/m²) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles followed by B (15 mg/kg q3w) until disease progression. Primary endpoint was the overall response rate (ORR). Circulating tumor cells (CTCs) were evaluated using the CellSearch system at different time points during therapy.ResultsEighty-three women were enrolled with median age 62 years, performance status 0–1 in 93%, triple negative disease in 12% and liver metastases in 47%. In an intention to treat analysis, complete response was achieved in 13 (15.7%) and partial response in 42 (50.6%) (overall response rate 66.3%; 95% CI 56.09–76.44%). The median time to progression was 20.1 months and the 1-year overall survival rate 82.3%. Grade 3–4 neutropenia occurred in 37%, febrile neutropenia in 10%, anemia in 4%, thrombocytopenia in 2% and diarrhea in 2% of patients. There were two deaths possibly related to study treatment (sigmoid perforation n = 1; sudden death n = 1). Moreover, one patient developed pulmonary embolism and another one myocardial infarction while on treatment. Although DEB administration significantly reduced the proportion of patients presenting CTCs, the detection of ≥5 or ≥1 CTCs before treatment initiation was significantly associated with worse progression-free survival (p = 0.001 and p = 0.004) and overall survival (p = 0.001 and p = 0.027), respectively.ConclusionsThe DEB regimen is a very active but also potentially toxic combination in MBC. Detection of CTCs before treatment is associated with worse outcome.Clinicaltrials.govNCT00705315     

First-in-man results of a novel vascular graft coated with resorbable polymer for aortic reconstructions—a multicenter,non-randomized safety study

Objectives

The purpose of this “first-in-man” study was to investigate the safety of a novel vascular polyester prosthesis coated with a resorbable polymer and free of any animal-based coating agents such as gelatin or collagen.

Methods

In a nonrandomized first-in-man multicenter safety study, the frequency of perigraft seroma (PGS) as the primary endpoint was studied in consecutive patients undergoing aortic reconstructions. The follow-up control to study the primary endpoint was intended at 3 months under routine clinical conditions. Pre- and postoperative white blood cell counts (WBC), C-reactive protein (CRP), and liver enzyme levels to characterize the systemic inflammation response and possible metabolic consequences were determined at different postoperative time points (secondary endpoints). Additionally, the primary unassisted patency rate, perioperative complications and serious adverse events, as well as intraoperative handling properties of the graft based on a semiquantitative scale were assessed. Magnetic resonance angiography (MRA) follow-up investigations were scheduled postoperatively at 3 months to determine graft tissue integration and the presence of PGS.

Results

A total of 24 patients with comorbidities such as coronary artery disease (8.3 %, 2/24), chronic occlusive pulmonary disease (COPD, 8.3 %, 2/24), Fontaine III/IV (20.8 %, 5/24), and diabetes (20.8 %, 5/24) were enrolled from June 2011 to September 2012. Due to two early nongraft-related deaths, there were 22 patients that had a follow-up. In these 22 patients, the freedom from PGS was 90.9 % (20/22) suggesting that the graft/tissue integration was comparable to other vascular grafts described in the relevant literature. WBC counts were not significantly different (pre (8.67?±?2.98 1/nl) vs. follow-up (7.97?±?2.24 1/nlI, p?=?0.203). Likewise, preoperative CRP serum levels (6.47?±?11.59 mg/l) were not different from those at follow-up (7.87?±?12.81 mg/l, p?=?0.769). There were two patients with a documented coagulation disorder and two premature deaths (cardiac failure, cerebral bleeding). The primary unassisted patency at follow-up was 77.3 % (17/22) in all patients who reached the follow-up (85.0 % or 17/20 if two cases with documented coagulation disorders are excluded). The reasons for occlusions were technical/surgical difficulties (2/5) and documented coagulation disorders (2/5). In one occlusion, the cause was unknown. There were no graft infections. Intraoperative graft handling properties were evaluated less favorable as compared to the routinely used gelatin- or collagen-coated polyester grafts in each investigator’s clinical practice.

Conclusions

Our results suggest that Uni-Graft® Synthetic is a promising prosthetic vascular graft to reduce PGS. Our findings should be interpreted with caution noting the limitation of the lack of a control group.     

An exploratory, placebo-controlled, dose–response study of the efficacy and safety of onabotulinumtoxinA in spinal cord injury patients with urinary incontinence due to neurogenic detrusor overactivity

Purpose

To explore the dose response to onabotulinumtoxinA 50, 100, and 200 U in patients with spinal cord injury (SCI) with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).

Methods

Patients (N = 73) with SCI (level T1 or lower) with NDO and UI (≥14 UI episodes/week) received 30 intradetrusor injections of onabotulinumtoxinA (50 U [n = 19], 100 U [n = 21], or 200 U [n = 17]) or placebo (n = 16) via cystoscopy, avoiding the trigone. Changes from baseline in UI episodes/week, volume voided/micturition, maximum cystometric capacity, and maximum detrusor pressure (MDP) during first involuntary detrusor contraction (IDC) were evaluated. Adverse events (AEs) were assessed.

Results

A significant linear dose response for UI episodes/week was identified at weeks 18, 30, 36, 42, and 54 (P < 0.05) with a similar trend (P = 0.092) at week 6 (primary time point). A significant linear dose response was observed in volume/void at all post-treatment time points up to week 54 (P < 0.05) and in MDP during first IDC at week 6 (P = 0.034). The proportion of patients who achieved continence at week 6 was highest in the 200 U group. Duration of effect was longest with the 200 U dose, compared with other treatment groups. The AEs were comparable across groups; urinary tract infection was the most common AE across all treatment groups.

Conclusions

In this exploratory dose–response study of SCI patients with UI due to NDO, onabotulinumtoxinA 200 U was the most effective dose. The AE profile was comparable across all groups.     

Efficacy,safety, and tolerability of mirabegron in patients aged ≥65 yr with overactive bladder wet: a phase IV,double-blind,randomised, placebo-controlled study (PILLAR)

BackgroundThe majority of patients with overactive bladder (OAB) are aged >65 yr. There has been no prospectively designed study assessing treatment efficacy with the β3-adrenoreceptor agonist, mirabegron, specifically in this age group.ObjectiveA phase IV study comparing flexibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence.Design, setting, and participantsCommunity-dwelling patients aged ≥65 yr with OAB for ≥3 mo.InterventionFollowing a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/24 h were randomised 1:1 to double-blind 25 mg/d mirabegron or matched placebo, for 12 wk. After week 4 or 8, the dose could be increased to 50 mg/d mirabegron/matched placebo based on patient and investigator discretion.Outcome measurements and statistical analysisCoprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h. Stratified rank ANCOVA was used for the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h.Results and limitationsStatistically significant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24 h, mean number of incontinence episodes/24 h, mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Safety and tolerability were consistent with the known mirabegron safety profile.ConclusionsMirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged ≥65 yr with OAB and incontinence.Patient summaryWe examined the effect of mirabegron compared with placebo in people aged 65 yr or older with overactive bladder and incontinence. Mirabegron improved the symptoms of overactive bladder compared with placebo. Side effects were similar to those already known for mirabegron.     

Erratum to: A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of Phase I—a short report

Neurosurgical Review -     

Effectiveness and safety of anakinra in gout patients with stage 4–5 chronic kidney disease or kidney transplantation: A multicentre,retrospective study

Objectives

Interleukin (IL)-1β blocking is effective for the treatment of gout flares and is recommended in patients with contraindications to the standard of care, such as stage 4–5 chronic kidney disease (CKD) patients. However, efficacy and safety data regarding these agents are lacking in this population. We aimed to investigate the efficacy and safety of anakinra for the treatment of gout flares in patients with stage 4–5 CKD or renal transplantation.

A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Jatoi A,Ellison N,Burch PA,Sloan JA,Dakhil SR,Novotny P,Tan W,Fitch TR,Rowland KM,Young CY,Flynn PJ,Mayo Clinic and Mayo Foundation,Rochester, MN: Cancer 2003;97:1442–1446

BackgroundRecent laboratory and epidemiologic studies have suggested that green tea has antitumor effects in patients with prostate carcinoma. This Phase II trial explored green tea’s antineoplastic effects in patients with androgen-independent prostate carcinoma.MethodsThis study, which was conducted by the North Central Cancer Treatment Group, evaluated 42 patients who were asymptomatic and had manifested, progressive prostate specific antigen (PSA) elevation with hormone therapy. Continued use of luteinizing hormone-releasing hormone agonist was permitted; however, patients were ineligible if they had received other treatments for their disease in the preceding 4 weeks or if they had received a long-acting antiandrogen therapy in the preceding 6 weeks. Patients were instructed to take 6 g of green tea per day orally in 6 divided doses. Each dose contained 100 calories and 46 mg of caffeine. Patients were monitored monthly for response and toxicity.ResultsTumor response, defined as a decline ≥ 50% in the baseline PSA value, occurred in a single patient, or 2% of the cohort (95% confidence interval, 1–14%). This one response was not sustained beyond 2 months. At the end of the first month, the median change in the PSA value from baseline for the cohort increased by 43%. Green tea toxicity, usually Grade 1 or 2, occurred in 69% of patients and included nausea, emesis, insomnia, fatigue, diarrhea, abdominal pain, and confusion. However, six episodes of Grade 3 toxicity and one episode of Grade 4 toxicity also occurred, with the latter manifesting as severe confusion.ConclusionsGreen tea carries limited antineoplastic activity, as defined by a decline in PSA levels, among patients with androgen-independent prostate carcinoma. Copyright 2003 American Cancer Society.