Marker Lesion Research Articles

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

ABSTRACTIntroduction: Apaziquone (also known as EO9 and QapzolaTM) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells.Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date.Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers.

Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomised phase II trial (C2130/A12118).

11004 Background: ASPS is a rare disease (0.5-1% of soft tissue sarcomas) mainly affecting young people. It is unresponsive to conventional chemotherapy. Cediranib (C), an inhibitor of vascular endothelial growth factor receptors and other receptor tyrosine kinases, has shown significant activity in ASPS in single arm phase II trials. CASPS (NCT01337401) was designed to permit discrimination between the impact of cediranib and the often intrinsically indolent nature of the disease. Methods: CASPS compared C (30mg od) with placebo (P) in a 2:1 double blind randomisation in patients (pts) age ≥16 years with metastatic ASPS progressive in the previous 6 months. Pts were unblinded at week 24, or at progression if sooner, when those on P started C. The primary endpoint of percentage change in the sum of target marker lesions (TMLsum) between baseline and week 24 (or progression if sooner) was compared between groups by Mann-Whitney test. Secondary endpoints were progression-free survival (PFS), week 24 response rate and best response (RECIST v1.1), safety/tolerability and overall survival (OS). One-sided p-values and two-sided 90% confidence intervals are reported. Results: 48 pts were recruited between 07/2011 and 07/2016 from 12 centres (UK, Australia & Spain). 52% of pts were female, median age was 31. Most common grade ≥3 adverse events on C were hypertension (23%), diarrhoea (14%) and fatigue (9%). In the evaluable population (N = 44) median change in TMLsum on C was minus 8.3% (IQR minus 26.2% to +5.9%); versus P: +13.4% (IQR minus 0.6% to +21.3%), p = 0.0013. Best response by week 24 was partial response for 6/28 (21%) C pts compared with 0/16 on P (p = 0.053) and stable disease for an additional 19/28 (68%) on C and 12/16 (75%) on P. The PFS HR (C versus P) was 0.54 (90% CI 0.30-0.97, p = 0.041), median PFS: 10.8 mths on C versus 3.7 mths on P, OS at 12 mths was C: 96%; P: 64.3%. Conclusions: CASPS, the largest randomised trial to date in this disease, confirms the activity of C in ASPS, showing a significant reduction in tumour burden and improvement in PFS. Tumour tissue and serial blood samples will subsequently be investigated to identify potential predictive and prognostic biomarkers. Clinical trial information: NCT01337401.

The level of S100b protein in blood serum of patients with hiv/tb co-infectoin as a neurospecific biomarker of neurotoxicity

There was studied the influence of antiretroviral and antimycobacterial chemotherapy on releasing from the glia<br />cell marker lesions – S100b protein in the context of possible iatrogenic. It was established that a slight increase in<br />the concentration of S100b protein in blood serum of patients with co-infection of HIV /TB after starting HAART was<br />not associated with the occurrence of symptoms of the central nervous system.

Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer

Introduction/BackgroundNon-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. Patients and MethodsA multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. ResultsThe effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. ConclusionToll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.

Abstract 2575: Results from the first-in-human phase I trials of recombinant human Interleukin 15 (rhIL-15) administered as a daily 30 minute intravenous infusion (IVB) for 12 consecutive days or as continuous intravenous infusion (CIV) for 240 hours in patients with refractory metastatic cancers

Abstract Preclinical laboratory experiments with Interleukin 15 (IL-15) have demonstrated significant immunotherapeutic potential for recombinant human IL-15 (rhIL-15) in cancer patients. We have completed a first-in-human (FIH), phase I dose escalation trial of E. coli produced rhIL-15 administered as a 30 minute intravenous bolus (IVB) infusion given daily for 12 consecutive days to patients with metastatic melanoma (MM) or renal cell carcinoma (mRCC). rhIL-15 treatment produced up to an 8-fold expansion of circulating NK cells, approximately 2 fold expansion of CD8+ CD45RO+ memory T-cells and up to 50 fold increases in serum level for multiple cytokines. Characteristic toxicities associated with cytokine treatment such as fever, rigors or chills, capillary leak, myalgias and blood pressure changes occurred at frequency and severity proportional to the dose of rhIL-15. Laboratory results showed early course transient leukopenia, lymphopenia, modest neutropenia, occasional thrombocytopenia and significant elevations of alanine and asparagine transaminase (ALT, AST) in a number of patients. Antibodies to rhIL-15 antibodies were not detected in any patient. The maximum tolerated dose for this schedule was 0.3 μg/kg/day with dose-limiting toxicities (DLTs) of grade 3 hypotension, thrombocytopenia, grade 3 or 4 ALT and AST elevation. There were no documented objective responses by RECIST criteria, but decreases in the sum of diameters for the marker lesions between 10 and 30% and improvement or clearance of parenchymal lung metastases were observed in several patients suggesting some antitumor activity. A phase I dose escalation trial evaluating a 10 day (240 hour) continuous intravenous infusion (CIV) of rhIL-15 which is expected to produce greater expansion of CD8 effector cells and immune activation has been initiated. Patients treated at the first two dose levels have demonstrated improved clinical tolerability, immune activation; fewer laboratory abnormalities and no DLTs. Patient accrual and dose escalation to the third dose level are ongoing. Citation Format: Kevin C. Conlon, Enrico Lugli, Steven A. Rosenberg, John C. Morris, Thomas Fleisher, Hugh Welles, Sigrid Dubois, Liyanage Perera, Carolyn Goldman, Bonita Bryant, Jean Decker, Joanna Shih, Tat'Yana Worthy, William Figg, Cody Peer, Michael Sneller, H. Clifford Lane, Jason Yovandich, Stephen Creekmore, Mario Roederer, Thomas A. Waldmann. Results from the first-in-human phase I trials of recombinant human Interleukin 15 (rhIL-15) administered as a daily 30 minute intravenous infusion (IVB) for 12 consecutive days or as continuous intravenous infusion (CIV) for 240 hours in patients with refractory metastatic cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2014-2575

Abstract 257: Smooth Muscle Cell--Derived COL15A1 Increases Indices of Plaque Stability and Mediates Plaque Cellular Content

Introduction: Current dogma states that under conditions that promote atherosclerosis quiescent vascular smooth muscle cells (SMC) phenotypically modulate into migratory, proliferative cells that move into the arterial intima, form a fibrous cap, and secrete extracellular matrix components (ECM) that promote plaque stabilization. However, there is no direct evidence that SMC derived ECM is critical in promoting changes to plaque stability. We identified collagen, type XV, alpha 1 (COL15A1) as a vascular SMC derived ECM protein present in both human and mouse atherosclerotic aortas. COL15A1 links large fibrillar collagens as well as promotes basement membrane cell adhesion and collagen maturation. We have shown in humans that Col15a1 is associated with atherosclerosis and is epigenetically regulated. However, the role for COL15A1 in atherosclerosis had not been explored. To assess the role of SMC derived collagen and COL15A1 in atherosclerosis we developed unique, conditional, tamoxifen inducible SMC specific Col15a1 knockout mice. We hypothesized that SMC production of COL15A1 is essential to promote indices of plaque stability. Methods and Results: At five weeks of age, SMC specific Col15a1fl/flApoE-/-MYH11-CreERT2+/- mice (n=15) and their Col15a1+/+ counterparts (n=12) were injected for 7 days with 1mg tamoxifen to induce SMC specific Col15a1 knockout and were placed on a Western diet (21% milk fat, 0.15% cholesterol) for 18 weeks. We find that SMC specific Col15a1 knockout induces marked detrimental changes in indices of plaque stability including increased necrotic core area (p=0.002), increased lesion size (p=0.03), and decreased plaque collagen maturation (p=0.017). Moreover, these mice showed a decrease in LGALS3+ macrophage content (p=0.008) but no change in SMC marker (ACTA2+) lesion staining. Conclusion: These data provide the first evidence that a SMC derived collagen (COL15A1) can positively affect indices of plaque stability and mediate plaque cellular content as well as identify COL15A1 as a novel player in atherosclerosis.

DNA Based Therapy with Diphtheria Toxin-A BC-819: A Phase 2b Marker Lesion Trial in Patients with Intermediate Risk Nonmuscle Invasive Bladder Cancer

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. 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. All patients were evaluable for adverse effects and 39 were evaluable forefficacy. 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 11.3months in all cases but significantly longer (22.1 months) when analyzed byresponse status at 3 months. Adverse events were mild. The study was limited by the small number of patients. 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.

Suture marker lesion detection in the colon by self-stabilizing and unmodified capsule endoscopes: pilot study in acute canine models

Capsule endoscopy is a noninvasive method for examining the small intestine. Recently, this method has been used to visualize the colon. However, the capsule often tumbles in the wider colon lumen, resulting in potentially missed pathology. In addition, the capsule does not have the ability to distend collapsed segments of the organ. Self-stabilizing capsule endoscopy is a new method of visualizing the colon without tumbling and with the ability to passively distend colon walls. To quantitatively compare the detection rate of intraluminal suture marker lesions for colonoscopy by using a custom-modified, self-stabilizing capsule endoscope (SCE); an unmodified capsule endoscope (CE) of the same brand; and a standard colonoscope. Four mongrel dogs underwent laparotomy and the implantation of 5 to 8 suture markers to approximate colon lesions. Each dog had both capsule endoscopy and self-stabilizing capsule endoscopy, administered consecutively in random order. In each case, the capsule was inserted endoscopically into the proximal lumen of the colon followed by pharmacologically induced colon peristalsis to propel it distally through the colon. Blinded standard colonoscopy was performed by an experienced gastroenterologist after the capsule endoscopies. Experimental study in a live canine model. Four dogs. Laparotomy, capsule endoscopy, colonoscopy. Comparison of the marker detection rate of the SCE to that of the unmodified MiroCam CE and a colonoscope. The average percentages of the marker detection rate for unmodified capsule endoscopy, self-stabilizing capsule endoscopy, and colonoscopy, respectively, were 31.1%, 86%, and 100% (P < .01), with both self-stabilizing capsule endoscopy and colonoscopy performing significantly better than the unmodified capsule endoscopy. Acute canine model, suture markings poorly representative of epithelial polyps, limited number of animals. The proposed self-stabilizing capsule endoscope delivered a significant improvement in detection rates of colon suture markings when compared with the unmodified capsule endoscope.

EO9 (Apaziquone): from the clinic to the laboratory and back again

EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered i.v. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue were the major factors responsible for EO9's poor efficacy. Based upon an understanding of why EO9 failed, a further clinical trial against patients with superficial transitional cell carcinoma of the bladder was conducted. The rationale for this was that intravesical administration directly into the bladder would circumvent the drug delivery problem, and any drug reaching the blood supply would be rapidly cleared thereby reducing the risk of systemic exposure. EO9 was well tolerated, and clinical activity against marker lesions was recorded in both phase I and II clinical trials. This article charts the pharmacological history of EO9 and discusses the potential implications that 'the EO9 story' has for the development of other loco-regional therapies.

Outcome of high-risk acute myeloid leukemia after allogeneic hematopoietic cell transplantation: negative impact of abnl(17p) and −5/5q−

AbstractThe European LeukemiaNet classification combines a heterogeneous group of aberrations as adverse-risk abnormalities. Our goal was to investigate the outcomes associated with distinct high-risk chromosomal abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). We performed a retrospective cohort analysis in patients with high-risk AML who received first, HLA-compatible, allogeneic HSCT between January 2005 and December 2008. Data from 236 patients with a median age of 55 years were included. Because complex karyotype (CK), −5/5q−, and abnl(17p) are overlapping categories, a hierarchical classification system based on the presence or absence of abnl(17p) and −5/5q− was developed. Patients with abnl(17p) had a 2-year event-free survival (EFS) of 11% (95% confidence interval [CI], 0%-25%), patients with −5/5q− but no abnl(17p) a 2-year EFS of 29% (95% CI, 14%-44%), and patients with adverse-risk AML but neither of the 2 marker lesions a 2-year EFS of 49% (95% CI, 39%-59%). Notably, complex and monosomal karyotypes lost their prognostic value when these marker lesions were excluded. In conclusion, hierarchical classification of adverse-risk karyotypes by 2 marker lesions, abnl(17p) and −5/5q−, is effective in prognostication of the outcome of allogeneic HSCT in AML.

Advanced Ovarian Cancer: Multiparametric MR Imaging Demonstrates Response- and Metastasis-specific Effects

To investigate the role of multiparametric magnetic resonance (MR) imaging in the evaluation of response to platinum-based neoadjuvant chemotherapy in advanced ovarian cancer and to compare imaging parameters between primary ovarian mass and metastatic disease. Evaluable patients suspected of having advanced ovarian carcinoma were enrolled in a prospective protocol-driven study. Research ethics committee approval and written informed consent were obtained. Multiparametric MR imaging (diffusion-weighted MR imaging, dynamic contrast material-enhanced [DCE] MR imaging, and hydrogen 1 MR spectroscopy) was performed with a 3.0-T wholebody MR imaging system. Three marker lesions-primary ovarian mass, omental cake, and peritoneal deposit-were outlined by a radiologist on apparent diffusion coefficient (ADC) and vascular signal fraction (VSF) maps and on DCE MR images. Comparisons of mean ADC, mean VSF, DCE MR imaging parameters, and choline concentration between responders and nonresponders were based on Response Evaluation Criteria in Solid Tumors and CA-125 criteria. Twenty-two patients were evaluable. The mean ADC for peritoneal metastases was lower than that for ovarian (P = .015) and omental (P = .006) sites. There were no differences in pretreatment DCE MR imaging parameters between tumor sites. After treatment, responders showed a significantly larger increase in ADC (P = .021) and fractional volume of the extravascular extracellular space (v(e)) (P = .025) of ovarian lesions compared with nonresponders, but there was no change in ADC at other sites. Pre- and posttreatment values of choline concentration of ovarian lesions were lower in responders (P = .025) than in nonresponders (P = .010). The significant differences in baseline ADCs among primary ovarian cancer, omental cake, and peritoneal deposits indicate that diffusivity profiles may be tumor-site dependent, suggesting biologic heterogeneity of disease. ADC and v(e) parameters correlated with the cytotoxic effects of platinum-based therapy and may be useful response markers, while choline concentration predicted but did not reflect response.

Intravesical gemcitabine therapy for non‐muscle invasive bladder cancer (NMIBC): a systematic review

• Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well-established treatment for preventing or delaying tumour recurrence after tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer. • To systematically review the literature on the effectiveness and toxicity of intravesical gemcitabine for non-muscle invasive bladder cancer (NMIBC). • MEDLINE, EMBASE, CINAHL, the Cochrane database of systematic reviews, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS were searched to identify trials of intravesical gemcitabine for the treatment of NMIBC. Also searched were meeting proceedings, international guidelines and trial registries. Data on authors, study design, patient characteristics, interventions and outcome data relating to tumour recurrence, disease progression, survival and adverse events were extracted from relevant studies. • Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes. • The first was a marker lesion study which reported greater tumour response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared with a single dose (9%). • One study compared a single postoperative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% vs 39%, respectively) or recurrence-free survival (hazard ratio 0.95, 95% confidence interval 0.64-1.39, P= 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% vs 0.8%). • A further trial compared gemcitabine with intravesical mitomycin C (MMC) and reported that the rates of recurrence (28% vs 39%) and progression (11% vs 18%) were lower with gemcitabine but did not reach statistical significance. The overall incidence of adverse events was significantly less with gemcitabine (38.8% vs 72.2%, P= 0.02). • Three trials compared gemcitabine with intravesical bacille Calmette-Guérin (BCG) but a meta-analysis was not possible due to clinical heterogeneity. • In untreated patients at intermediate risk of recurrence (primary Ta-T1, no carcinoma in situ) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P= 0.92) and overall progression equal. Dysuria (12.5% vs 45%, P < 0.05) and frequency (10% vs 45%, P < 0.001) were significantly less with gemcitabine. • In a second trial of high-risk patients the recurrence rate was significantly greater with gemcitabine compared with BCG (53.1% vs 28.1%, P= 0.04%) and the time to recurrence significantly shorter with gemcitabine (25.5 vs 39.4 months, P= 0.042). • Finally, in a third trial of high-risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% vs 87.5%, P= 0.002) and a longer time to recurrence (3.9 vs 3.1 months, P= 0.9) compared with BCG. Progression rates were similar in both groups (33% vs 37.5%, P= 0.12) with no significant differences in grade 2 or 3 toxicities. • The data from several observational studies confirm the pharmacology of gemcitabine as an intravesical agent whilst others report the activity of gemcitabine in terms of tumour recurrence. However, these studies are inherently biased and these data should be interpreted appropriately. • In conclusion a single study suggests that in NMIBC multiple doses of intravesical gemcitabine reduce tumour recurrences to a greater extent than a single dose. • In contrast, a single dose immediately after surgery is ineffective based on one study. Gemcitabine may be more active than MMC with a lower toxicity profile. • Compared with intravesical BCG therapy, gemcitabine had similar effects in intermediate-risk patients, less effective in high-risk patients and superior in BCG-refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. • Intravesical gemcitabine is a promising drug that may add to the urologist's options in treating patients with NMIBC.

Intravesical gemcitabine for non-muscle invasive bladder cancer

Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well established treatment for preventing or delaying tumour recurrence following tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer. To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer (NMIBC). A search strategy was developed for MEDLINE to identify randomised trials of intravesical gemcitabine for the treatment of non-muscle invasive bladder cancer. The searches were from 1947 to May 2011. Other databases searched included EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS. Handsearching of meeting proceedings, international guidelines and trial registries was also carried out. The titles and abstracts of the combined electronic and handsearching were manually screened by three authors independently to determine if they met the inclusion criteria for this review. Studies were selected if they were randomised, controlled trials or quasi-randomised clinical trials that included intravesical gemcitabine in at least one arm of a comparative study. Data extraction was carried out by three reviewers. The information retrieved included the author's details, the study design, the characteristics of the recruited patients, details of the interventions and data relating to the primary, and secondary outcome measures. Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes. One study compared a single post-operative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% versus 39%, respectively) or recurrence-free survival (HR (hazard ratio) 0.95, 95% CI 0.64 to1.39, P = 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% versus 0.8%). A further trial compared gemcitabine with intravesical mitomycin C and demonstrated that the rates of recurrence (28% versus 39%) and progression (11% versus 18%) were lower with gemcitabine but did not reach statistical significance. The global incidence of adverse events was significantly less with gemcitabine (38.8% versus 72.2%, P = 0.02).Three trials compared gemcitabine with intravesical BCG but a meta-analysis was not possible due to clinical heterogeneity. In untreated patients at intermediate risk of recurrence (primary Ta-T1 no CIS) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P = 0.92) and overall progression equal (P = 1.0). Dysuria (12.5% versus 45%, P < 0.05) and frequency (10% versus 45%, P < 0.001) were significantly less with gemcitabine. In a second trial of high risk patients the recurrence rate was significantly greater with gemcitabine compared to BCG (53.1% and 28.1%, P = 0.04) and the time to recurrence significantly shorter with gemcitabine (25.5 versus 39.4 months, P = 0.042). Finally in a third trial of high risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% versus 87.5%, P = 0.002) and a longer time to recurrence (3.9 versus 3.1 months, P = 0.9) compared to BCG. Progression rates were similar in both groups (33% versus 37.5%, P = 0.12) with no significant differences in grade 2 or 3 toxicities.The final trial was a marker lesion study which reported greater response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared to a single dose (9%). A single dose immediately following surgery is ineffective based on one study. Gemcitabine may be more active than mitomycin C with a lower toxicity profile. Compared to intravesical BCG therapy, gemcitabine had similar effects in intermediate risk patients, less effective in high risk patient and superior in BCG refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy. Intravesical gemcitabine is a promising drug that may add to the urologist's options in achieving this goal.

Topical pimecrolimus effect on Fas inducing apoptosis in oral lichen planus: a clinical immunohistochemical study

To investigate the effectiveness of pimecrolimus treatment in patients not responding to corticosteroid treatment and to investigate its effect on Fas expression on keratinocytes in oral lichen planus (OLP). Twenty patients with OLP were recruited from the Oral Medicine Clinic at the School of Dentistry, Ain Shams University, Egypt. Pimecrolimus 1% cream with a hydrophilic adhesive gel base was applied to the oral lesions, four times daily, for a total of 2 months. A marker lesion was identified and assessed by clinical scoring (CS). The symptomatology score was obtained using a visual analog scale (VAS). Pre-treatment and post-treatment specimens were immunohistochemically stained for detecting Fas. The results of clinical scores showed statistically high significant improvement (P = 0.0001). The mean VAS decreased significantly over time as well as the mean of Fas expression (P < 0.05). The overall percentage of reduction from baseline to week 8 was 87%, 93%, and 67% for clinical scores, visual analog score, and Fas expression, respectively. Topical pimecrolimus reduced Fas expression, and it appears to be a promising alternative treatment for OLP.

Can Gemcitabine Instillation Ablate Solitary Low-Risk Non-Muscle-Invasive Bladder Cancer? Results of a Phase II Marker Lesion Study

Purpose: The purpose of this phase II study was to evaluate whether low-risk non-muscle-invasive bladder cancer can be ablated with intravesical gemcitabine in a marker lesion study. Patients and Methods: The study had a Simon II-stage design. Thirteen patients were to be recruited for stage I. In the event of ≧4 responses, another 30 patients were to be recruited. Patients were given gemcitabine 2,000 mg intravesically once per week for 6 weeks and the response was assessed with endoscopic, histological, and urine cytological findings. Results: Fourteen patients evaluated for efficacy completed the study; complete responses were achieved by 2 patients (14.3%), both of these patients had lesions of <1 cm. Eleven patients (78.6%) were non-responders and 1 patient (7.1%) had progressive disease. Since the response rate in stage I was below the minimal pre-defined limit, the study was stopped. Conclusions: This study shows that intravesical gemcitabine does not merit further study in this patient population. A tumor size of >1 cm may be a critical factor in accounting for the low response rate.

UP-01.061 Ablative Efficacy of Sequential Intravesical Chemotherapy Using Gemcitabine and Mitomycin C for Superficial Bladder Carcinoma

Surgical resection followed by intravesical chemotherapy to prevent further recurrence is the current standard of care for intermediate risk superficial bladder cancer.Ablative efficacy and safety of various intravesical chemotherapeutic drugs are well studied with marker lesions. But their efficacy remains low (23 -72%). To study the ablative efficacy and safety of sequential gemcitabine (GC) and mitomycin C (MMC) intravesical chemotherapy (IC) in superficial bladder carcinoma (SBC).

Etanercept plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6 weeks

A substantial portion of patients with psoriasis does not achieve a satisfactory response under antitumour necrosis factor (TNF)-α biological therapies. We aimed to evaluate whether etanercept plus narrowband ultraviolet B (NB-UVB) phototherapy is superior to etanercept monotherapy in the management of psoriasis. In this prospective study, patients with psoriasis were treated with etanercept 25 mg twice weekly. Two marker lesions were selected for determination of the modified Psoriasis Area and Severity Index (M-PASI). NB-UVB was administered thrice weekly whereby one marker lesion was covered as nonirradiated control. Skin biopsies for histology and immunohistochemistry were performed in both marker lesions after a 6-week treatment course. After 6 weeks of therapy, the relative M-PASI reduction (mean ± SD) in etanercept-treated sites (53·7 ± 36·9%) was significantly lower than the reduction in etanercept plus NB-UVB-treated lesions (64 ± 27·8%; P = 0·011). At the end of treatment, histology scores of etanercept-treated psoriatic plaques were significantly higher than scores of etanercept plus NB-UVB-treated sites (4·6 ± 2·7 vs. 3·7 ± 2·4; P =0·045). Epidermal immunoreactivity for CD1a, CD4 and CD8 was significantly lower in etanercept plus NB-UVB-treated lesions when compared with etanercept monotherapy. Etanercept combined with NB-UVB is more effective than etanercept monotherapy at 6 weeks as demonstrated at a clinical, histological and immunohistological level. However, as there is an increased risk for malignancy by treatment with TNF-α blockers alone or in combination with phototherapy, we recommend to restrict this highly effective combination to short periods of time, for instance to obtain a quicker response, and to avoid long-term treatment.

978 PHARMACOKINETICS AND TOXICITY OF INTRAVESICAL TMX-101: A PRECLINICAL STUDY IN PIGS

You have accessJournal of UrologyBladder Cancer: Basic Research II1 Apr 2010978 PHARMACOKINETICS AND TOXICITY OF INTRAVESICAL TMX-101: A PRECLINICAL STUDY IN PIGS Harm Arentsen, Christina Hulsbergen-van de Kaa, Kees Jansen, Roberto Maj, Lorenzo Leoni, Egbert Oosterwijk, and Fred Witjes Harm ArentsenHarm Arentsen Nijmegen, Netherlands More articles by this author , Christina Hulsbergen-van de KaaChristina Hulsbergen-van de Kaa Nijmegen, Netherlands More articles by this author , Kees JansenKees Jansen Nijmegen, Netherlands More articles by this author , Roberto MajRoberto Maj Bioggio, Switzerland More articles by this author , Lorenzo LeoniLorenzo Leoni Bioggio, Switzerland More articles by this author , Egbert OosterwijkEgbert Oosterwijk Nijmegen, Netherlands More articles by this author , and Fred WitjesFred Witjes Nijmegen, Netherlands More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1925AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES TMX-101 is an optimized intravesical formulation containing R-837, a synthetic Toll-like receptor (TLR)-7 agonist. R-837 acts as immune modulating agent and is effective as a topical agent for the treatment of various benign and malignant skin lesions. In recent bladder cancer studies R-837 has shown in vitro and in vivo antitumor effects. In the current study, the pharmacokinetic and toxicity profile of intravesically administered R-837 was examined in a pig model. METHODS TLR-7 expression was determined by immunohistochemistry in human and pig bladder tissue. For pharmacokinetic and toxicity studies, 24 female pigs were divided into four groups. Animals received a one-hour intravesical instillation with R-837 0.5% in 0.1M lactic acid (group 1); R-837 0.5% in 0.1M lactic acid, poloxamer 407 16% and hydroxypropyl-β-cyclodextrin (HPBCD) 15% (group 2); R-837 0.5% in 0.1M lactic acid, poloxamer 407 16% and HPBCD 5% (group 3) and a vehicle control (0.1M lactic acid) (group 4). The pharmacokinetic analysis was performed on plasma. Toxicity evaluation included: monitoring the well-being of the animals, peripheral blood cell counts, IL-6 and creatinine measurements. Urine was collected for R-837 measurement and dipstick analysis. Three pigs per group were sacrificed 24 hours after treatment, the remaining three animals per group were sacrificed after one week. Histopathological examination of the bladder wall was performed. RESULTS TLR-7 was homogeneously expressed in human and pig urothelium. TMX-101 and vehicle were well tolerated without deterioration in animal well-being. The mean R-837 level in post-treatment collected urine of animals in group 1 was almost 2-fold higher than that of animals in group 2 and 3. After 24 hours urinary R-837 levels were close to the detection limit. Systemic R-837 absorption, as measured by serum levels, was low. Mean maximum plasma concentration of R-837 of group 1 animals was 3-fold higher than that of group 2 and 3 animals. Twenty-four hours post-treatment R-837 plasma levels were negligible. Histopathological examination of the bladders did not reveal significant abnormalities, apart from the intended inflammatory reaction in the TMX-101 treated groups. CONCLUSIONS Intravesically administered TMX-101 in pigs, which demonstrated a similar TLR-7 distribution in bladder tissue as humans, is well tolerated, causes no bladder wall toxicity and formulations with poloxamer and HPBCD stay longer in the bladder with less systemic absorption. A phase I/IIa marker lesion study will be initiated. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e380 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Harm Arentsen Nijmegen, Netherlands More articles by this author Christina Hulsbergen-van de Kaa Nijmegen, Netherlands More articles by this author Kees Jansen Nijmegen, Netherlands More articles by this author Roberto Maj Bioggio, Switzerland More articles by this author Lorenzo Leoni Bioggio, Switzerland More articles by this author Egbert Oosterwijk Nijmegen, Netherlands More articles by this author Fred Witjes Nijmegen, Netherlands More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Dynamic contrast-enhanced MRI in ovarian cancer: Initial experience at 3 tesla in primary and metastatic disease

The aim of this study was to develop and demonstrate a methodology for dynamic contrast-enhanced MRI at 3 T in patients with advanced ovarian cancer and to report the results from pharmacokinetic modeling of the data. Nineteen patients with suspected advanced ovarian carcinoma (FIGO stage 3 or higher) were enrolled in this prospective study. Up to three marker lesions were identified: primary ovarian mass, omental ''cake'', and peritoneal deposits. Dynamic contrast-enhanced MRI was performed using a three-dimensional T(1)-weighted gradient-echo acquisition with a temporal resolution of 1.6 sec, following intravenous administration of 0.1 mmol/kg gadobutrol. Precontrast T(1) mapping, using an inversion-recovery fast gradient-echo sequence, was also performed. Imaging was completed in 18/19 patients, although two were subsequently excluded based on pathology results. Pharmacokinetic modeling of the data was performed according to the extended Kety model, using an arterial input function formed by concatenation of the Fritz-Hansen and Weinmann curves. No statistically significant differences were found between the results for the three marker lesions. In the future, this work will allow kinetic modeling results from ovarian dynamic contrast-enhanced MRI to be correlated with response to treatment. The high temporal resolution allows good characterization of the rapid contrast agent uptake in these vascular tumors.

Synophrys

Introduction Meeting of the medial eyebrows in the midline (synophrys) may serve as a cutaneous marker lesion for syndromal disorders (e.g. Cornelia de Lange syndrome). Case presentation A 31-year-old man showed supercilia forming a single band of terminal hairs between left and right lateral orbital rim. Medical examination of the patient revealed coldness-inducable urticaria, xanthelasma formation and long eyelashes without any signs of a syndromal disorder. Conclusion Synophrys can be found in some syndromal disorders, but are not pathognomonic for any illness per se.