Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials

OBJECTIVES: To evaluate the prognostic factors of recurrence and progression after intravesical adjuvant bacillus Calmette-Guérin (BCG) immunotherapy in patients with non-muscle-invasive bladder tumors. METHODS: From February 1990 to May 1999, the Spanish Club Urológico Espa?ol de Tratamiento Oncológico (CUETO) group has performed four randomized phase 3 studies comparing different intravesical treatments in patients with noninvasive bladder cancer. Data from 1062 evaluable patients treated only with BCG were analyzed. Most patients received BCG once weekly for 6 consecutive weeks and a short-term BCG maintenance (once every 2 wk 6 times more). Associated tumor in situ (TIS) was found in 7.5% (n=80) of cases. There were 22.1% (n=235) patients with T1G3 tumors, 22.9% of whom (n=54) were associated with TIS. Stepwise multivariate Cox regression models with stratification by study and dose were used to assess the independent effect of predictive factors and hazard ratios (HRs) were estimated from the Cox model. RESULTS: Multivariate analysis demonstrated that female gender (HR=1.71) compared to male gender, recurrent tumors (HR=1.9) compared to primary tumors, multiplicity, and presence of associated TIS (HR=1.54) increased the risk of recurrence. Recurrent tumors (HR=1.62) compared to primary tumors, high-grade tumors (HR=5.64) compared to G1 tumors, T1 tumors (HR=2.15) compared to Ta tumors, and recurrence at 3-mo cystoscopy (HR=4.6) increased the risk of progression. CONCLUSION: Significant independent predictors for recurrence were female gender, history of recurrence, multiplicity, and presence of associated TIS. Age, history of recurrence, high grade, T1 stage, and recurrence at first cystoscopy were independent predictors of progression by multivariate Cox analysis.     

Robotic renal surgery: pyeloplasty

The treatment of ureteropyelic junction (UPJ) obstruction offers a perfect sketch of the parallel evolution of the availability of technology and changes in surgical proceedings. From the open Anderson-Hynes pyeloplasty, passing through percutaneous or retrograde endopyelothomy with various instruments, to the laparoscopic approach, technology and human talent have found a field for development in this reconstructive procedure. Robotic surgery is young and starts to define its role in urology surgery. There are established procedures such as radical prostatectomy; it remains to be established what operations will benefit from the robotic technology, so results are under continuous evaluation. The non stopping advance of computer technology guarantees future achievements of robotic technology. The objective is to achieve that surgeons could perform difficult surgical procedures with a level of accuracy and clinical results that would be difficult to achieve with conventional methods. We analyze the technical features, results and comparative studies of the robotic pyeloplasty from the medical literature. Robotic surgery has demonstrated its usefulness in the performance of pyeloplasties, with good results in primary and secondary UPJ stenosis in children and adults, in various aetiologies. Robotics enables to diminish the difficulties of intracorporeal suture and the learning curve for surgeons without laparoscopic experience. Nevertheless, although initial clinical experience with robotic pyeloplasty is favourable, continuous evaluation of results is necessary to determine if the surgical procedure is as effective in the long-term as laparoscopic and open pyeloplasty.     

Integrative analysis of a cancer somatic mutome

Background  

The consecutive acquisition of genetic alterations characterizes neoplastic processes. As a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. The recent identification of the collection of somatically mutated genes in breast tumors (breast cancer somatic "mutome") allows the comprehensive study of its function and organization in complex networks.     

Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development,Dose Selection for First Time in Children and PK Study Design

Purpose

Bilastine is an H₁ antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years).

Methods

A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions.

Results

PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation.

Conclusion

The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.

     

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block

Background and Purpose: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314.Experimental Approach: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed.Key Results: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine''s nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine''s blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314.Conclusions and Implications: Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.     

Pyelolithotomy in a patient with Glanzmann thrombasthenia and antiglycoprotein IIb/IIIa antibodies: the shortest possible duration of treatment with recombinant activated factor VII and platelet transfusions

Transfusion of platelet concentrates remains the first-line therapy for Glanzmann thrombasthenia in case of bleeding or preparation for surgery. However, development of antibodies to platelet glycoprotein (Gp) IIb/IIIa complex or human leukocyte antigens (HLA) is frequent and the main cause of platelet refractoriness. Recombinant activated factor VII (rFVIIa) is a potent alternative for patients with Glanzmann thrombasthenia with anti-platelet antibodies. We describe a case of Glanzmann thrombasthenia with alloantibodies to platelet Gp IIb/IIIa complex who underwent a successful pyelolithotomy operation under the coverage of recombinant activated factor VIIa and platelet transfusions.