Modified Citrus Pectin Treatment in Non-Metastatic Biochemically Relapsed Prostate Cancer: Long-Term Results of a Prospective Phase II Study.

The optimal therapy for patients with non-metastatic biochemically relapsed prostate cancer (BRPC-M0) after local therapy is elusive. Thus, the evaluation of new non-toxic compounds in BRPC-M0 patients is warranted. PectaSol®-Modified citrus pectin (P-MCP) is a food supplement categorized as GRAS (Generally Recognized As Safe) by the FDA. It is a competitive inhibitor of the galectin-3 protein, which is involved in cancer pathogenesis. In an early report of the present phase 2 study, P-MCP treatment for 6 months led to prostate-specific antigen doubling time (PSADT) improvement in 75% of patients with BRPC-M0. Herein, we report the second long-term treatment phase of an additional 12 months of P-MCP therapy (4.8 g × 3/day orally) in patients without disease progression after the initial 6 months of therapy. Of the 46 patients that entered the second treatment phase, 7 patients withdrew consent and decided to continue therapy out of pocket, and 39 initiated the second treatment phase. After a total of 18 months of P-MCP treatment, 85% (n = 33) had a durable long-term response, with 62% (n = 24) showing decreased/stable PSA, 90% (n = 35) PSADT improvement, and all with negative scans. No patient had grade 3/4 toxicity. In conclusion, P-MCP may have long-term durable efficacy and is safe in BRPC-M0.

A Novel Modality Enables New Evidence-Based Individual Risk Stratification That Can Potentially Lead to Decisive Management and Treatment Decisions in Prostate Cancer.

A key step in providing management/treatment options to men with suspected prostate cancer (PCa) is categorizing the risk in terms of the presence of benign, low-risk, intermediate-risk, or high-risk disease. Our novel modality brings new evidence, based on the long-known hallmark characteristic of PCa-decreased zinc (Zn), which is the most direct metabolic sign of malignancy and its aggressiveness. To date, this approach has not been adopted for clinical use for a number of reasons that are described in this article, and which have been addressed by our approach. Zn has to be measured on fresh samples, prior to fixating in formalin; therefore, samples have to be scanned during the biopsy session. As Zn depletion occurs in the glands where the tumors develop, estimation of the glands' levels in the scanned tissue, along with their compactness, are essential for accurate diagnosis. Combined with the Zn depletion, this facilitates a reliable assessment of disease aggressiveness. Data gathered in the clinical study described here indicate that, in addition to improving the biopsy quality by real-time interactive guidance, a malignancy score can now be established for the entire prostate, allowing higher granularity personalized risk stratification and more decisive treatment decisions for all PCa patients.

Modified Citrus Pectin Treatment in Non-Metastatic Biochemically Relapsed Prostate Cancer: Results of a Prospective Phase II Study.

Optimal therapy of biochemically relapsed prostate cancer (BRPC) after local treatment is elusive. An established modified citrus pectin (PectaSol®, P-MCP), a dietary polysaccharide, is an established antagonist of galectin-3, a carbohydrate-binding protein involved in cancer pathogenesis. Based on PSA dynamics, we report on the safety and the primary outcome analysis of a prospective phase II study of P-MCP in non-metastatic BRPC based. Sixty patients were enrolled, and one patient withdrew after a month. Patients (n = 59) were given P-MCP, 4.8 grams X 3/day, for six months. The primary endpoint was the rate without PSA progression and improved PSA doubling time (PSADT). Secondary endpoints were the rate without radiologic progression and toxicity. Patients that did not progress by PSA and radiologically at six months continued for an additional twelve months. After six months, 78% (n = 46) responded to therapy, with a decreased/stable PSA in 58% (n = 34), or improvement of PSADT in 75% (n = 44), and with negative scans, and entered the second twelve months treatment phase. Median PSADT improved significantly (p = 0.003). Disease progression during the first 6 months was noted in only 22% (n = 13), with PSA progression in 17% (n = 10), and PSA and radiologic progression in 5% (n = 3). No patients developed grade 3 or 4 toxicity.

In Utero Programming of Testicular Cancer.

It is well established that the intrauterine biological environment plays important roles in fetal development. In this review, we re-visit the hypothesis that testicular germ cell cancer (TGCC), especially in adolescents and young adults, has been programmed in utero. The origin for extreme in utero environments is mostly maternal driven and may be due to nutritional, physical and psychological stressful conditions that alter the optimal molecular and biophysical in utero environments. Moreover, precursors for TGCC may originate as early as during fertilization or implantation of the blastocyst. Further investigations of human developmental biology, both in vivo and in vitro, are needed in order to establish better understanding of in utero programming of future wellbeing or diseases.

A comparison between 68Ga-labeled prostate-specific membrane antigen-PET/CT and multiparametric MRI for excluding regional metastases prior to radical prostatectomy.

OBJECTIVES: To compare the ability of 68Ga -PSMA PET/CT (PSMA PET/CT) and multiparametric MRI (mpMRI) to exclude lymph node invasion (LNI) in patients who undergo radical prostatectomy (RP). MATERIALS AND METHODS: A multicenter cohort of patients who underwent PSMA PET/CT and pelvic mpMRI prior to RP with pelvic lymph node dissection (PLND) was analyzed. Increased Ga68-PSMA uptake on PET/CT and enlarged (> 10 mm) or abnormal lymph nodes on mpMRI were considered positive findings. The final surgical pathology served as the standard of reference. The negative predictive value (NPV) was calculated for each modality separately, as well as the combined value. RESULTS: Included were 89 patients with D'Amico intermediate (45%) or high-risk (55%) prostate cancer. The median number of extracted LN was 9 (IQR 6-14). LNI was found in 12 (13.5%) patients. The NPV of mpMRI, PSMA PET/CT, and the two tests combined were 87%, 89%, and 90%, in the entire cohort, 95%, 97%, and 97% in patients with intermediate-risk disease, and 80%, 82%, and 83% in patients with high-risk disease, respectively. The median diameter of LN missed by both imaging and the median intranodal tumor diameter was 5.5 (IQR 3-10) mm and 1 (IQR 1-3) mm, respectively. CONCLUSIONS: PSMA PET/CT and mpMRI demonstrated similar performance in excluding pelvic LNI with NPV of approximately 90%. The combination of both tests does not improve NPV significantly. Therefore, even in the era of advanced imaging, PLND is still recommended for accurate staging, especially in the high-risk population.

First-in-man Safety and Efficacy of the ClearRing Implant for the Treatment of Benign Prostatic Hyperplasia.

BACKGROUND: Although effective for benign prostatic hyperplasia (BPH), transurethral resection of the prostate (TURP) can be associated with side effects including prolonged recovery, storage and voiding symptoms, and a risk of acute urinary retention. OBJECTIVE: To test a new minimally invasive device for the treatment of lower urinary tract symptoms (LUTS) due to BPH, involving implantation of a C-shaped nitinol ring (ClearRing) in a circular incision in the prostatic tissue using an electrocuting blade over a dilatation balloon. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter single-arm clinical trial involving 29 men with severe symptomatic BPH. INTERVENTION: Implantation of a ClearRing device under regional anesthesia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Effectiveness in alleviating LUTS was assessed in terms of International Prostate Symptom Score (IPSS) at baseline and 3, 6, and 12 mo after the procedure. To evaluate changes from baseline, a general estimating equation model was fitted to IPSS, the Quality of Life (QOL) scale, Benign Prostatic Hyperplasia Impact Index, maximum flow rate (Qmax), and postvoid residual volume. Statistical significance was defined as p<0.05. RESULTS AND LIMITATIONS: The average age was 71.4 yr, prostate size was 35-50cm3, and IPSS was 21.6. All procedures were successfully completed with one implant in 28 patients and two implants in one patient. No serious complications occurred. Patients experienced symptom relief by 3 mo that was sustained to 12 mo. Mean IPSS, QOL, and Qmax improved by 45%, 41%, and 40% by 3 mo, and 53%, 52%, and 49% by 12 mo, respectively (p<0.05). Adverse events were mild and transient. There were no reports of loss of antegrade ejaculation or any effects on erectile function. Implantation positioning failed in 11/29 patients, who then underwent uneventful TURP. After modification of the delivery device, the success rate for implant positioning improved from 5/13 patients to 13/16 patients. Study limitations include the single-arm nature and the low patient number. CONCLUSIONS: We demonstrated preliminary feasibility of the ClearRing device for minimally invasive treatment of BPH in men. Further studies are needed to confirm the safety and efficacy of this approach. PATIENT SUMMARY: In this study we tested outcomes after implantation of a ClearRing device in patients with benign prostatic hyperplasia. We found that the device was safe and effective. However, there was a high rate of implantation failure due to malpositioning, which was significantly improved following modification of the delivery device.

Juvenile polymyositis associated with ureteral necrosis: a diagnostic and therapeutic dilemma-case report and review of the literature.

We describe an 11-year-old girl, diagnosed with juvenile polymyositis (JPM), who developed right ureteral obstruction secondary to necrosis. We emphasize the dilemmas regarding optimal timing for surgical intervention and medical treatment. Vascular involvement, which could be a part of juvenile dermatomyositis, may also be a feature of JPM. We discuss the association between vasculopathy and ureteral necrosis and review the literature regarding similar conditions. Whether the ureteral necrosis is a specific feature of vasculopathy, or a result of visceral calcinosis, needs to be further explored.

Uroflowmetry Before and After Meatotomy in Boys with Symptomatic Meatal Stenosis Following Neonatal Circumcision - A Long-term Prospective Study.

OBJECTIVE: To assess uroflowmetry in the long-term follow-up of symptomatic meatal stenosis patients prior to and following meatotomy. Severity of symptoms and treatment success has been defined by patient history, physical examination, and witnessed voiding. Uroflowmetry might add objective parameters for the assessment, however long-term data are lacking. METHODS: A prospective study following 25 symptomatic toilet-trained boys before and after meatotomy was performed with short and long-term follow-up after surgery. Patient history, physical examination, and uroflowmetry variables were recorded. RESULTS: Fifteen patients were fully evaluable. Mean age at operation was 6.4 years (2.5-10.5) with an average follow-up of 43 months. All patients were symptomatic before surgery; complete symptomatic resolution was achieved in all patients at short-term follow-up, and in 12 at long-term follow-up. A stenotic meatus was seen in all patients before surgery, at long-term follow-up 12 of 15 (80%) had an open appearing meatus (P = .0001). Abnormal uroflowmetry pattern was present in 8 of 15 (53%) prior to surgery and 2 of 15 (13%) at long-term follow-up (P = .02). Normal maximal flow rate as defined by ICCS were seen in 5, 11, and 12 patients before, 1 month after and at long-term follow-up (P = .06 and 0.02, respectively). PVR improved significantly at long-term follow-up (P = .0012). CONCLUSION: Symptom evaluation and physical examination should be the hallmark assessing children with meatal stenosis. Clinical assessment one month after surgery suffices and long-term follow-up is unnecessary. Uroflowmetry provides objective assessment as well as surgical success; however, it is unnecessary since it does not change the management.

Assessing the Safety and Efficacy of the ClearRing™ Implant for the Treatment of Benign Prostatic Hyperplasia in a Canine Model.

BACKGROUND: Transurethral resection of the prostate is the most common procedure for the treatment of benign prostatic hyperplasia (BPH). Although effective, transurethral resection of the prostate can be associated with side effects including prolonged recovery, storage and voiding symptoms, risk of acute urinary retention. OBJECTIVES: In this study, we describe a new minimally invasive device for the treatment of lower urinary track symptoms due to BPH, implanting a nitinol C shape ring in a circular incision in the prostatic tissue, surrounding the urethra, done by electrocuting blade over a dilatation balloon. METHODS: Two groups of dogs (4/ group) were implanted with the device under anesthesia. Clinical observation, body weight and weekly blood and urinary tests were performed throughout the study period to evaluate safety. Fluoroscopy and cystoscopy were used throughout the study period to evaluate implant condition and urethral dilatation. At the end of 3 weeks (Group I) or 3 months (Group II), the animals were sacrificed. The implantation site was examined macroscopically and histologically to evaluate urethral dilatation and tissue response. RESULTS: The presence of the ClearRing™ implant in an animal's prostate was associated with significant dilatation of the prostatic urethra. Fever, pain, behavior disturbances or gross hematuria, when occurred, resolved within 72 hours post procedure and no severe adverse events were observed. There was no evidence of prostatic hyperplasia associated to ring implantation. Partial epithelial coverage of the implant surface was observed without evidence of encrustation. CONCLUSION: The ClearRing™ implant seems a feasible minimally invasive procedure for relieving lower urinary track symptoms due to BPH.

A Novel Urine-Based Assay for Bladder Cancer Diagnosis: Multi-Institutional Validation Study.

BACKGROUND: CellDetect is a unique histochemical stain enabling color and morphological discrimination between malignant and benign cells based on differences in metabolic signature. OBJECTIVE: The objective of the present study was to validate the performance of this assay in a controlled, blinded, multicenter study. DESIGN, SETTING, AND PARTICIPANTS: The study, conducted in nine hospitals, included patients with documented history of bladder cancer, monitored for urothelial carcinoma (UCC) or scheduled for bladder cancer surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cystoscopy and/or biopsy were used as a reference standard to determine sensitivity and specificity. Smears were stained by CellDetect and interpreted by two cytologists blinded to the patient's final diagnosis. The findings were compared with those of standard urine cytology and BTA stat. RESULTS AND LIMITATIONS: Two hundred and seventeen voided urine specimens were included. Ninety-six (44%) were positive by histology and 121 (56%) were negative by either cystoscopy or histology. The overall sensitivity of CellDetect was 84%. Notably, the sensitivity for detecting low-grade nonmuscle-invasive bladder cancer tumors was greater than this of BTA stat (78% vs 54%) and more than two-fold higher compared with standard cytology (33%, p ≤ 0.05). The specificity was 84% in patients undergoing routine surveillance by cystoscopy. At a median follow-up of 9 mo, 21% of the patients with positive CellDetect and negative reference standard developed UCC, which was significantly higher compared with the 5% of the true negative cases. Limitations include the lack of instrumental urine samples and the lack of patients with nongenitourinary cancers in the study population. CONCLUSIONS: This study validates the performance of CellDetect as a urine-based assay to identify UCC in patients with history of bladder cancer. The high sensitivity was maintained across all cancer grades and stages without compromising the assay specificity. Further studies are required to test whether this novel stain can be incorporated in routine bladder cancer surveillance as a noninvasive alternative to cystoscopy. PATIENT SUMMARY: Surveillance of bladder cancer requires frequent invasive procedures. In the present study, we validate the ability of a novel biomarker to accurately identify early-stage tumors in urine specimens for the noninvasive monitoring of patients with history of bladder cancer.

Performance of the Bladder EpiCheck™ Methylation Test for Patients Under Surveillance for Non-muscle-invasive Bladder Cancer: Results of a Multicenter, Prospective, Blinded Clinical Trial.

BACKGROUND: The highly frequent strategy of surveillance for non-muscle-invasive bladder cancer (NMIBC) involves cystoscopy and cytology. Urine assays currently available have not shown performance sufficient to replace the current gold standard for follow-up, which would require a very high negative predictive value (NPV), especially for high-grade tumors. Bladder EpiCheck (BE) is a novel urine assay that uses 15 proprietary DNA methylation biomarkers to assess the presence of bladder cancer. OBJECTIVE: To assess the performance of BE for NMIBC recurrence. DESIGN, SETTING, AND PARTICIPANTS: This was a blinded, single-arm, prospective multicenter study. The inclusion criteria were age ≥22 yr, urothelial carcinoma (UC) being monitored cystoscopically at 3-mo intervals, all UC resected within 12 mo, able to produce 10ml of urine, and able to consent. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The BE test characteristics were calculated and compared to cytology and cystoscopy results confirmed by pathology. RESULTS AND LIMITATIONS: Out of 440 patients recruited, 353 were eligible for the performance analysis. Overall sensitivity, specificity, NPV, and positive predictive value were 68.2%, 88.0%, 95.1%, and 44.8%, respectively. Excluding low-grade (LG) Ta recurrences, the sensitivity was 91.7% and NPV was 99.3%. The area under receiver operating characteristic (ROC) curves with and without LG Ta lesions was 0.82 and 0.94, respectively. CONCLUSIONS: In follow-up of NMIBC patients, the BE test showed an overall high NPV of 95.1%, and 99.3% when excluding LG Ta recurrences. With high specificity of 88.0%, the test could be incorporated in NMIBC follow-up since high-grade recurrences would be instantly detected with high confidence. Thus, the current burden of repeat cystoscopies and cytology tests could be reduced. PATIENT SUMMARY: The Bladder EpiCheck urine test has a clinically relevant and high negative predictive value. Its use in clinical routine could reduce the number of follow-up cystoscopies, and thus associated patient and financial burdens.

The Association between Age-Related Macular Degeneration and Renal Cell Carcinoma: A Nested Case-Control Study.

Background: Overexpression of VEGF is implicated in the pathogenesis of both renal cell carcinoma (RCC) and age-related macular degeneration (AMD). We evaluated the association between AMD and RCC risk.Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of RCC. For every case, four eligible controls were matched on age, sex, practice site, calendar time, and duration of follow-up. Exposure of interest was diagnosis of AMD prior to cancer diagnosis. Adjusted ORs and 95% confidence intervals (CI) for RCC were estimated using conditional logistic regression. In a secondary analysis, we evaluated the association between other retinopathies and RCC and AMD and the hypovascular pancreatic cancer.Results: The study population included 1,547 patients with RCC and 6,066 matched controls. Median follow-up time was 6 years (IQR, 3-9). AMD diagnosis was associated with a significantly increased RCC risk (OR, 1.89; 95% CI, 1.09-3.29). In contrast, there was no association between other retinopathies and RCC risk (OR, 0.8; 95% CI, 0.56-1.15). AMD was associated with a lower risk for pancreatic cancer (OR, 0.47; 95% CI, 0.35-0.64).Conclusions: Patients with AMD may be at higher risk for RCC. Providers should be aware of this potential link and consider screening for RCC within this population.Impact: Providers should be aware of the potential link between AMD and RCC. Cancer Epidemiol Biomarkers Prev; 26(5); 743-7. ©2017 AACR.

[InoPro trial: collaboration between urologists and primary care physicians in the treatment of osteoporosis in prostate cancer patients].

INTRODUCTION: Osteoporosis is more common in elderly men than previously suspected. Prostate cancer patients may have an increased rate of osteopenia and osteoporosis independent of therapy. Osteopenia and fracture risk are accelerated in men receiving androgen deprivation therapy. Nevertheless, little is done by primary care physicians and urologists to diagnose and treat osteoporosis in men. AIMS: (1) Assess prostate cancer patients' compliance and adherence to bisphosphonate therapy; (2) Increase awareness for osteoporosis in men diagnosed with prostate cancer among urologists and primary care physicians and to evaluate collaboration between the two disciplines. METHODS: We included patients with confirmed diagnosis of prostate cancer who fulfilled one or more of the following criteria: (1) age 70 and above; (2) age 60 and above with androgen deprivation therapy or (3) prior diagnosis of osteopenia and osteoporosis. Qualified patients were referred to DXA bone density test. Patients with osteopenia or osteoporosis, who were naïve to bisphosphonates, received recommendations for oral bisphosphonates. Follow-up lasted 6 months and included 2 office visits to ensure patients' compliance and adherence to recommended therapy. RESULTS: A total of 28 community-based urologists recruited 180 patients. Of the 180 prostate cancer patients, 87 (48%) had osteoporosis and 93 (52%) osteopenia, all were naïve to bisphosphonates. Of the 180 patients, 153 (85%) patients started treatment with bisphosphonates after inclusion; 147/180 (82%) and 136/180 (76%) patients stayed on bisphosphonates for 3 and 6 months respectively. Primary care physicians adopted recommendations for bisphosphonate in 123/180 (68%). CONCLUSIONS: This study showed high compliance and adherence of prostate cancer patients for bisphosphonate recommendation.

Attenuation of encrustation by self-assembled inorganic fullerene-like nanoparticles.

Ureteral stents and urethral catheters are commonly used medical devices for maintaining urinary flow. However, long-term placement (>30 days) of these devices in the urinary tracts is limited by the development of encrustation, a phenomenon that holds a prevalence of 50% within this patient population, resulting in a great deal of morbidity to the patients. Here we report the influence of surface coating of an all-silicone catheter with rhenium-doped fullerene-like molybdenum disulfide (Re:IF-MoS2) nanoparticles on the growth and attachment of in vitro encrustation stones. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (XRD) analyses indicated a remarkable attenuation in encrustation occupation on the Re:IF-MoS2-coated catheter surfaces compared to neat catheters. The doped nanoparticles displayed a unique tendency to self-assemble into mosaic-like arrangements, modifying the surface to be encrustation-repellent. The mechanism of encrustation retardation on the surface coated catheters is discussed in some detail. The ramification of these results for the clogging of other body indwelling devices is briefly discussed.

DNA based therapy with diphtheria toxin-A BC-819: a phase 2b marker lesion trial in patients with intermediate risk nonmuscle invasive bladder cancer.

PURPOSE: H19 is a paternally imprinted oncofetal gene expressed in various embryonic tissues and in 85% of bladder tumors but suppressed in the adult healthy bladder. BC-819 is a DNA plasmid that carries the gene for diphtheria toxin-A under regulation of the H19 promoter sequence. We assessed the efficacy and toxicity of intravesical BC-819 instillations to prevent tumor recurrence and ablate a marker lesion in a phase 2b trial. MATERIALS AND METHODS: A total of 47 patients with recurrent, multiple nonmuscle invasive bladder tumors in whom prior intravesical therapy had failed underwent transurethral resection of all except 1 marker tumor. Patients expressing H19 received a 6-week induction course of intravesical BC-819. Patients who achieved a complete response (absent new tumors at 3 months) were given 3 maintenance courses of 3-weekly instillations every 3 months. RESULTS: All patients were evaluable for adverse effects and 39 were evaluable for efficacy. Complete tumor ablation was achieved in 33% of patients and in 64% there were no new tumors at 3 months. Median time to recurrence was 11.3 months in all cases but significantly longer (22.1 months) when analyzed by response status at 3 months. Adverse events were mild. The study was limited by the small number of patients. CONCLUSIONS: BC-819 prevented new tumor growth in two-thirds of the patients and ablated a third of the marker lesions. Prolonged time to recurrence was observed in responding patients. These results along with the good safety profile make BC-819 a potential medication for bladder cancer.

The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review.

CONTEXT: Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings. OBJECTIVE: To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC. EVIDENCE ACQUISITION: The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate. EVIDENCE SYNTHESIS: A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant. CONCLUSIONS: Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated.

Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette-Guerin.

PURPOSE: Despite an initial adequate response many patients with nonmuscle invasive urothelial cell carcinoma of the bladder eventually have recurrence after intravesical bacillus Calmette-Guerin treatments. We evaluated the efficacy of combined bladder wall hyperthermia and intravesical mitomycin C instillation (thermo-chemotherapy) in cases of recurrence after bacillus Calmette-Guerin. MATERIALS AND METHODS: A total of 111 patients with recurrent papillary nonmuscle invasive urothelial cell carcinoma of the bladder after previous bacillus Calmette-Guerin treatment underwent complete bladder tumor resection and were referred for prophylactic adjuvant treatment with thermo-chemotherapy. Treatment was received on an outpatient basis weekly for 6 weeks, followed by 6 maintenance sessions at 4 to 6-week intervals. Each treatment included 2, 30-minute cycles of 20 mg mitomycin C and bladder wall hyperthermia to 42C +/- 2C. Cystoscopy and urine cytology were performed after the completion of induction treatment and every 3 months thereafter. RESULTS: The Kaplan-Meier estimated disease-free survival rate was 85% and 56% after 1 and 2 years, respectively. No maintenance treatment was associated with decreased efficacy, that is the recurrence rate was 61% at 2 years vs 39% in those with maintenance treatments (p = 0.01). The progression rate was 3%. CONCLUSIONS: Thermo-chemotherapy may be effective for papillary nonmuscle invasive urothelial cell carcinoma of the bladder that recurs after BCG treatment without increasing the risk of tumor progression. Maintenance therapy is important and improves the outcome.

Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin.

PURPOSE: We studied the safety and preliminary efficacy (marker tumor ablation) of 5 doses of BC-819 given as 6 intravesical infusions in patients with superficial bladder cancer in whom intravesical therapy with bacillus Calmette-Guerin had failed. BC-819 is a DNA plasmid that contains H19 gene regulatory sequences that drive the expression of an intracellular toxin. MATERIALS AND METHODS: A total of 18 patients in 4 groups of 3 and 1 group of 6 received escalating doses of BC-819 intravesically during 7 weeks. Patients had low grade superficial bladder cancer, which expressed H19. The effect on a marker tumor was examined 12 weeks after starting treatment. The escalating doses were 2, 4, 6, 12 and 20 mg plasmid per intravesical treatment. Responders continued to receive BC-819 once monthly every month for 1 year. RESULTS: No dose limiting toxicity was observed. The most frequent adverse events were mild to moderate bladder discomfort, dysuria, micturition urgency, urinary tract infection, diarrhea, hypertension and asthenia. Intravesical administration of BC-819 resulted in complete ablation of the marker tumor without any new tumors in 4 of the 18 patients for a 22% overall complete response rate. Eight of the 18 patients (44%) had complete marker tumor ablation or a 50% reduction of the marker lesion. Nine patients received monthly maintenance, of whom 4 and 1 were disease-free at 35 and 49 weeks, respectively. CONCLUSIONS: Intravesical BC-819 causes tumor ablation following intravesical administration at doses that were well tolerated. It is worthy of continued clinical investigation.

Irradiation enhances the metastatic potential of prostatic small cell carcinoma xenografts.

BACKGROUND: Small cell carcinoma of the prostate (SCCP) is a rare subset of prostate cancer (0.5-2% of all prostatic carcinomas), predominantly composed of neuroendocrine (NE) cells, with a very poor prognosis. Irradiation is one of the mainstay options for SCCP local treatment, yet, little is known about the clinical response of these aggressive tumors to radiotherapy. METHODS: Using SCID mice, the response to fractionated ionizing radiation (IR) of two unique human NE xenografts of SCCP (WISH-PC2 and WM-4A) was investigated. RESULTS: Fractionated irradiation of WISH-PC2 xenografts using total doses of >24 Gy induced a delay in tumor growth, while total doses of >36 Gy led to local tumor eradication. However, most of the irradiated mice suffered from disseminated metastases. Similarly, in the WM-4A xenograft, a total dose of 20 Gy led to tumor growth delay and some of the mice also developed metastases. Non-irradiated local xenografts failed to disseminate, even following surgical excision of the main tumor mass; however, tumor cells administered intravenously did form metastases. Metastases of both xenografts were located in the adrenal/kidney and inter-scapular regions, areas rich in brown adipose tissue. A correlation was found between the appearance of irradiation-induced metastases and activation of the gelatinase activity of matrix metalloproteinase-9. CONCLUSIONS: Clinically, this study raises the possibility that radiation to SCCP may promote metastatic disease. For patients in whom prostate biopsy shows a predominance of small cell cancer, it may be necessary to deliver systemic therapy together with the radiotherapy in order to prevent the development of metastases.

Urological implications of concurrent bladder and lung cancer.

BACKGROUND: Multiple primary malignancies are increasingly being detected among cancer patients. OBJECTIVES: To investigate the co-occurrence of primary bladder cancer and primary lung cancer, two established smoking-related neoplasms characteristically associated with increased risk of secondary cancers. METHODS: A retrospective search of the patient registry in our institution identified 25 patients (23 men and 2 women) who were diagnosed with both bladder cancer and lung cancer during the period 1990-2005. Medical records were reviewed and clinical and pathological data were extracted. RESULTS: In 21 patients (84%) bladder cancer was the first primary tumor and in 4 (16%) the second primary tumor. More than 90% of the patients had a history of smoking. Mean smoking exposure was 62.1 pack years (range 30-120). All bladder cancers were transitional cell carcinomas with the majority being superficial at presentation. Most lung cancers were of the non-small cell type. Second primary lung cancers were significantly more advanced at diagnosis. Overall, mean follow-up was 105.8 months (range 6-288). Seven patients (28%) were alive at the time of evaluation; 68% died of lung cancer, while none died of bladder cancer. CONCLUSIONS: Second primary lung cancer may occur in patients with bladder carcinoma and vice versa. In view of the relatively frequent involvement of the genitourinary tract as a site of multiple primary tumors, urologists may have a key role in the detection of second primary tumors arising in the genitourinary tract, or second primary tumors that occur in patients with primary genitourinary tract malignancies.