Regulation of receptor for activated C kinase 1 protein by the von Hippel-Lindau tumor suppressor in IGF-I-induced renal carcinoma cell invasiveness.

von Hippel-Lindau (VHL) tumor suppressor loss is associated with renal cell carcinoma (RCC) pathogenesis. Meanwhile, aberrant activation of the insulin-like growth factor-I (IGF-I) signaling has been implicated in the development of highly invasive metastatic RCC. However, the link between VHL inactivation and RCC invasiveness is still unexplored. Here, we show that the receptor for activated C kinase 1 (RACK1) is a novel pVHL-interacting protein. pVHL competes with IGF-I receptor (IGF-IR) for binding to RACK1 thus potentially modulating the downstream IGF-I signal pathway. Upon IGF-I stimulation, pVHL-deficient RCC cells exhibit increased RACK1/IGF-IR binding and increased IGF-IR tyrosine kinase activity. pVHL-deficient RCC cells also demonstrate elevated PI3K/Akt signaling and matrix metalloproteinase-2 activity that culminates in enhanced cellular invasiveness, which can be partially suppressed by RACK1 small interfering RNA. Domain mapping analysis showed that the pVHL α-domain and the RACK1 WD 6-7 domains are critical for the interaction. Additionally, the RACK1 expression level is not regulated by pVHL expression status, suggesting that pVHL modifies RACK1 functions independent of the VHL/elongin E3 ubiquitin ligase complex. Our data indicate that RACK1 serves as a direct mediator between loss of pVHL function and enhanced IGF-IR signaling pathway in RCC.

A real-time prostate cancer detection technique using needle insertion force and patient-specific criteria during percutaneous intervention.

In this article, the authors present a novel real-time cancer detection technique by using needle insertion forces in conjunction with patient-specific criteria during percutaneous interventions. Needle insertion experiments and pathological analysis were performed for developing a computer-aided detection (CAD) model. Backward stepwise regression method was performed to identify the statistically significant patient-specific factors. A baseline force model was then developed using these significant factors. The threshold force model that estimated the lower bound of the cancerous tissue forces was formulated by adding an adjustable classifier to the baseline force model. Tradeoff between sensitivity and specificity was obtained by varying the threshold value of the classifier, from which the receiver-operating characteristic (ROC) curve was generated. Sequential quadratic programming was used to optimize the CAD model by maximizing the area under the ROC curve (AUC) using a set of model-training patient data. When the CAD model was evaluated using an independent set of model-validation patient data, an AUC of 0.90 was achieved. The feasibility of cancer detection in real time during percutaneous interventions was established.

A real-time prostate cancer detection technique using needle insertion force and patient-specific criteria during percutaneous intervention.

In this article, the authors present a novel real-time cancer detection technique by using needle insertion forces in conjunction with patient-specific criteria during percutaneous interventions. Needle insertion experiments and pathological analysis were performed for developing a computer-aided detection (CAD) model. Backward stepwise regression method was performed to identify the statistically significant patient-specific factors. A baseline force model was then developed using these significant factors. The threshold force model that estimated the lower bound of the cancerous tissue forces was formulated by adding an adjustable classifier to the baseline force model. Trade-off between sensitivity and specificity was obtained by varying the threshold value of the classifier, from which the receiver-operating characteristic (ROC) curve was generated. Sequential quadratic programming was used to optimize the CAD model by maximizing the area under the ROC curve (AUC) using a set of model-training patient data. When the CAD model was evaluated using an independent set of model-validation patient data, an AUC of 0.90 was achieved. The feasibility of cancer detection in real time during percutaneous interventions was established.

Robotic system for prostate brachytherapy.

In contemporary brachytherapy procedures, needle placement at the desired target is challenging for a variety of reasons. A robot-assisted brachytherapy system can potentially improve needle placement and seed delivery, resulting in enhanced therapeutic outcome. In this paper we present a robotic system with 16 degrees of freedom (DOF) (9 DOF for the positioning module and 7 DOF for the surgery module) that has been developed and fabricated for prostate brachytherapy. Strategies to reduce needle deflection and target movement were incorporated after extensive experimental validation. Provision for needle motion and force feedback was included in the system to improve robot control and seed delivery. Preliminary experimental results reveal that the prototype system is sufficiently accurate in placing brachytherapy needles.

Efficacy of prostate stabilizing techniques during brachytherapy procedure.

During the prostate brachytherapy procedure, multiple needles are inserted into the prostate and radioactive seeds are deposited. Stabilizing needles are first inserted to provide some rigidity and support to the prostate, ideally this will provide better seed placement and an overall improved treatment. However, there is much speculation regarding the effectiveness of using regular brachytherapy needles as stabilizers. In this study, we explored the efficacy of (1) two types of needles--18 gauge brachytherapy needle vs. 18 gauge hooked needle; and (2) parallel vs. angulated needle configurations to stabilize the prostate. Prostate phantom movement and needle insertion progression were imaged using ultrasound (US). The recorded images were analyzed and prostate displacement was computed from images using implanted artifacts. Experimentation allowed us to further understand the mechanics behind prostate stabilization. We observed superior stabilization by the hooked needles compared to the regular brachytherapy needles (more than 40% for parallel stabilization). Prostate movement was also reduced significantly when regular brachytherapy needles were in an angulated configuration as compared to the parallel configuration (approximately 40%). When the hooked needles were angled for stabilization, further improvement in decreased displacement was observed. In general, for convenience of dosimetric planning, all needles are desired to be in parallel and in this case, hooked needles are better suited to improve stabilization of the prostate. On the other hand, both regular and hooked needles appear to be equally effective in reducing prostate movement when they are in angulated configurations, which will be useful in robotic permanent seed implantation (PSI).

Needle insertion force estimation model using procedure-specific and patient-specific criteria.

Placement accuracy of different types of surgical needles in soft biological tissues depends on a variety of factors. The needles used for prostate brachytherapy procedures are typically about 200 mm in length and 1.27-1.47 mm in diameter. These needles are prone to deflection and thereby depositing the seeds at a location other than the planned one. Thus tumorous tissues may not receive the planned dose whereas the critical organs may be over-dosed. A significant amount of needle deflection and target movement is related to some procedure-specific criteria and some patient-specific criteria. In this paper we have developed needle insertion force models taking both procedure-specific criteria and patient-specific criteria. These statistical models can be used to estimate the force that the needle will experience during insertion and thereby control the needle to reduce the needle deflection and enhance seed delivery accuracy.

In-vivo measurement of surgical needle intervention parameters: a pilot study.

Percutaneous intervention is essential in numerous medical diagnostic and therapeutic procedures. In these procedures, accurate insertion of the surgical needle is very important. But precise interstitial intervention is quite challenging. Robot-assisted needle intervention can significantly improve accuracy and consistency of various medical procedures. To design and control any robotic system, the design and control engineers must know the forces that will be encountered by the system and the motion trajectories that the needling mechanism will have to follow. Several researchers have reported needle insertion forces encountered while steering through soft tissue and soft material phantoms, but hardly any in-vivo force measurement data is available in the literature. In this paper, we present needle insertion forces and motion trajectories measured during actual brachytherapy needle insertion while implanting radioactive seeds in the prostate glands of twenty five patients.

Effects of velocity modulation during surgical needle insertion.

Precise interstitial intervention is essential for many medical diagnostic and therapeutic procedures. But accurate insertion and placement of surgical needle in soft tissue is quite challenging. The understanding of the interaction between surgical needle and soft tissue is very important to develop new devices and systems to achieve better accuracy and to deliver quality treatment. In this paper we present the effects of velocity (linear, rotational, and oscillatory) modulation on needle force and target deflection. We have experimentally verified our hypothesis that needle insertion with continuous rotation reduces target movement and needle force significantly. We have observed little changes in force and target deflection in rotational oscillation (at least at lower frequency) of the needle.

A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis.

PURPOSE: This pilot study was designed to evaluate the feasibility of a multicenter, randomized, clinical trial in interstitial cystitis (IC). Secondary objectives were to evaluate the safety and efficacy of oral pentosan polysulfate sodium (PPS), hydroxyzine, and the combination to consider their use in a larger randomized clinical trial. MATERIALS AND METHODS: A 2 x 2 factorial study design was used to evaluate PPS and hydroxyzine. Participants met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC and reported at least moderate pain and frequency for a minimum of 6 months before study entry. The primary end point was a patient reported global response assessment. Secondary end points included validated symptom indexes and patient reports of pain, urgency and frequency. The target sample size was 136 participants recruited during 10 months. RESULTS: A total of 121 (89% of goal) participants were randomized over 18 months and 79% provided complete followup data. The response rate for hydroxyzine was 31% for those treated and 20% for those not treated (p = 0.26). A nonsignificant trend was seen in the PPS treatment groups (34%) as compared to no PPS (18%, p = 0.064). There were no treatment differences for any of the secondary end points. Adverse events were mostly minor and similar to those in previous reports. CONCLUSIONS: The low global response rates for PPS and hydroxyzine suggest that neither provided benefit for the majority of patients with IC. This trial demonstrated the feasibility of conducting a multicenter randomized clinical trial in IC using uniform procedures and outcomes. However, slow recruitment underscored the difficulties of evaluating commonly available IC drugs.

Real-time US versus CT determination of pubic arch interference for brachytherapy.

PURPOSE: Part 1, to determine whether transrectal ultrasonography (US) enables accurate determination of pubic arch interference (PAI) for prostate brachytherapy (PBT); part 2, to compare the accuracy of transrectal US with that of computed tomography (CT) for PAI determination; and part 3, to determine the cost savings of PAI determination with transrectal US versus that with CT. MATERIALS AND METHODS: Part 1: The pubic arch was identified intraoperatively with transrectal US and compared with attempted needle passage (14 patients). Part 2: Planning CT with the patient supine was compared with planning transrectal US with patients in the dorsal lithotomy position (nine patients). Part 3: Cost savings were calculated for PAI determination with transrectal US versus that with CT (32 patients per group). RESULTS: Part 1: Transrectal US accurately showed the pubic arch relative to the prostate. Part 2: CT resulted in PAI overestimation by 11.8 mm. Part 3: Cost savings with transrectal US were $1,465 per patient. CONCLUSION: Transrectal US PAI determination is easily performed, intraoperatively useful, and accurate. CT can result in PAI overestimation. Reducing direct CT costs and the indirect costs of unnecessary hormonal therapy for false-positive PAI will reduce expense and improve patient care. Transrectal US should replace CT for PAI determination.

Localization of androgen receptor expression in human bone marrow.

Androgens have been shown to modulate the haematopoietic and immune systems and have been used clinically for stimulating haematopoiesis in bone marrow failure conditions. To identify the bone marrow cell types as potential targets of androgens, an androgen receptor (AR)-specific antibody was used to localize the AR in normal human bone marrow biopsies. The results show that AR was ubiquitously expressed in the bone marrow of both males and females. Furthermore, the AR expression pattern did not change with age. Stromal cells, macrophages, endothelial cells, myeloblasts, myelocytes, neutrophils, and megakaryocytes expressed AR. In contrast, AR was not detected in the lymphoid and erythroid cells, or in eosinophils. These results indicate that androgens may exert direct modulating effects on a wide spectrum of bone marrow cell types via AR-mediated responses.

Automated noninvasive measurement of cyclophosphamide-induced changes in murine voiding frequency and volume.

PURPOSE: We developed an automated noninvasive method for studying bladder function in mice. Changes in voided volume and frequency accompanying cyclophosphamide-induced cystitis were measured using computerized digital balances. MATERIALS AND METHODS: Eight CRL CD-1 mice were given a solution of glucose and saccharin to increase urine output and studied during the dark cycle, when most voiding occurs. Urine fell directly onto electronic balance pans. The time and weight of each void was recorded. Computer programs adjusted for evaporative loss analyzed voiding data within and across sessions. After establishing stable voiding patterns 300 mg./kg. cyclophosphamide were administered intraperitoneally. The Wilcoxon signed rank test was done to compare median voided volumes, frequency and gm. per hour of urine produced before and after cyclophosphamide. RESULTS: We implemented an automated method for voiding studies in mice. After cyclophosphamide administration the number of voids per hour increased and voided volume decreased. Some mice had as much as a 70% decrease in bladder volume and a tripling of urinary frequency. Mice responded by a sustained elevation in frequency and decreased voided volume as early as 24 hours after cyclophosphamide administration or by a pattern of delayed toxicity. CONCLUSIONS: This noninvasive technique measures changes in mouse voiding patterns with great sensitivity and minimal effort. The method is applicable to murine models of interstitial cystitis, detrusor instability and other abnormal voiding states. It may be used for evaluating potential therapies for such conditions.

Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer.

BACKGROUND: Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. METHODS: Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually. RESULTS: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome. CONCLUSIONS: Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.

Chromosome 9 monosomy by fluorescence in situ hybridization of bladder irrigation specimens is predictive of tumor recurrence.

PURPOSE: Bladder irrigation specimens are effective for sampling the urothelium for detection of recurrent bladder cancer. These specimens can be evaluated by cytology or quantitative techniques. Proliferation and ploidy changes are readily detected using deoxyribonucleic acid (DNA) cytometry. Tumor associated chromosomal aberrations can be assayed using fluorescence in situ hybridization (FISH). The prognostic values of DNA cytometry, and chromosome 9 and 9p21 FISH on exfoliated cells from bladder irrigation specimens from 61 bladder cancer patients were evaluated. MATERIALS AND METHODS: A total of 61 consecutive bladder irrigation specimens were obtained during cystoscopy. DNA cytometry was performed by image analysis. FISH was performed using a centromeric chromosome 9 probe and a cosmid contig (COSp16) probe to the CDKN2A/p16 tumor suppressor region of 9p21. Proportional hazards regression analysis was performed with statistical software to test the predictor variables of initial patient status (presence of tumor), COSp16 fraction (the proportion of COSp16 signals relative to centromeric probe signals), monosomic and hyperdisomic fractions of the chromosome 9 probe, and hyperdiploid fraction from DNA cytometry. Median time to recurrence was calculated using statistical software survival analysis. RESULTS: Initial patient status and monosomy of chromosome 9 were predictive of bladder cancer recurrence (p <0.0001 and p = 0.0073, respectively). The 11 patients with chromosome 9 monosomy fractions greater than 15% and a visible tumor had a median time to recurrence of 105 days. In contrast, only 8 of the 25 patients with chromosome 9 monosomy fractions less than 15% and no visible tumor had recurrence within 560 days. Median time to recurrence was 185 days for 6 patients with chromosome 9 monosomy fractions greater than 15% and no visible tumor, and 225 for 19 with chromosome 9 monosomy fractions less than 15% and a visible tumor. Hyperdiploid fraction was suggestive but not predictive of bladder cancer recurrence (p = 0.078). COSp16 and hyperdisomic fractions were not predictive of bladder tumor recurrence (p = 0.11 and p = 0.30, respectively). CONCLUSIONS: Chromosome 9 monosomy by FISH was predictive of bladder tumor recurrence. Furthermore, our findings support the hypothesis that losses of tumor suppressor genes on chromosome 9 are critical, perhaps initiating genetic events in bladder cancer.

Intraoperative optimized inverse planning for prostate brachytherapy: early experience.

PURPOSE: To demonstrate the feasibility of an intraoperative inverse planning technique with advanced optimization for prostate seed implantation. METHODS AND MATERIALS: We have implemented a method for optimized inverse planning of prostate seed implantation in the operating room (OR), based on the genetic algorithm (GA) driven Prostate Implant Planning Engine for Radiotherapy (PIPER). An integrated treatment planning system was deployed, which includes real-time ultrasound image acquisition, treatment volume segmentation, GA optimization, real-time decision making and sensitivity analysis, isodose and DVH evaluation, and virtual reality navigation and surgical guidance. Ten consecutive patients previously scheduled for implantation were included in the series. RESULTS: The feasibility of the technique was established by careful monitoring of each step in the OR and comparison with conventional preplanned implants. The median elapsed time for complete image capture, segmentation, GA optimization, and plan evaluation was 4, 10, 2.2, and 2 min, respectively. The dosimetric quality of the OR-based plan was shown to be equivalent to the corresponding preplan. CONCLUSION: An intraoperative optimized inverse planning technique was developed for prostate brachytherapy. The feasibility of the method was demonstrated through an early clinical experience.