Four-year Prostate-specific Antigen Response Rate as a Predictive Measure in Intermediate-risk Prostate Cancer Treated With Ablative Therapies: The SPRAT Analysis.

AIMS: There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure. MATERIALS AND METHODS: Individual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA <0.4 ng/ml or ≥0.4 ng/ml and compared using the Log-rank test. A multivariable competing risk analysis was carried out to predict for biochemical failure and the development of metastases. RESULTS: Six hundred and thirty-seven patients were included, including 424 (67%) with favourable and 213 (33%) with unfavourable intermediate-risk disease. The median follow-up was 6.2 years (interquartile range 4.9-7.9). The cumulative incidence of biochemical failure and metastasis was 7 and 0.6%, respectively; overall survival at 6 years was 97%. The cumulative incidence of biochemical failure at 6 years if 4yPSARR <0.4 ng/ml was 1.7% compared with 27% if 4yPSARR ≥0.4 ng/ml (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (subdistribution hazard ratio 15.3, 95% confidence interval 7.5-31.3, P < 0.001) and metastasis-free survival (subdistribution hazard ratio 31.2, 95% confidence interval 3.1-311.6, P = 0.003). CONCLUSION: 4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.

Advancements in AAV-mediated Gene Therapy for Pompe Disease.

Pompe disease (glycogen storage disease type II) is caused by mutations in acid α-glucosidase (GAA) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient's immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy.

Intraspinal transplantation of subventricular zone-derived neural progenitor cells improves phrenic motor output after high cervical spinal cord injury.

Following spinal cord injury (SCI), intraspinal transplantation of neural progenitor cells (NPCs) harvested from the forebrain sub-ventricular zone (SVZ) can improve locomotor outcomes. Cervical SCI often results in respiratory-related impairments, and here we used an established model cervical SCI (C2 hemisection, C2Hx) to confirm the feasibility of mid-cervical transplantation of SVZ-derived NPCs and the hypothesis that that this procedure would improve spontaneous respiratory motor recovery. NPCs were isolated from the SVZ of enhanced green fluorescent protein (GFP) expressing neonatal rats, and then intraspinally delivered immediately caudal to an acute C2Hx lesion in adult non-GFP rats. Whole body plethysmography conducted at 4 and 8wks post-transplant demonstrated increased inspiratory tidal volume in SVZ vs. sham transplants during hypoxic (P=0.003) or hypercapnic respiratory challenge (P=0.019). Phrenic nerve output was assessed at 8wks post-transplant; burst amplitude recorded ipsilateral to C2Hx was greater in SVZ vs. sham rats across a wide range of conditions (e.g., quiet breathing through maximal chemoreceptor stimulation; P<0.001). Stereological analyses at 8wks post-injury indicated survival of ~50% of transplanted NPCs with ~90% of cells distributed in ipsilateral white matter at or near the injection site. Peak inspiratory phrenic bursting after NPC transplant was positively correlated with the total number of surviving cells (P<0.001). Immunohistochemistry confirmed an astrocytic phenotype in a subset of the transplanted cells with no evidence for neuronal differentiation. We conclude that intraspinal transplantation of SVZ-derived NPCs can improve respiratory recovery following high cervical SCI.

Breathing patterns after mid-cervical spinal contusion in rats.

Respiratory failure is the leading cause of death after cervical spinal injury. We hypothesized that incomplete cervical spinal injuries would alter respiratory pattern and initiate plasticity in the neural control of breathing. Further, we hypothesized that the severity of cervical spinal contusion would correlate with changes in breathing pattern. Fourteen days after C4-C5 contusions, respiratory frequency and tidal volume were measured in unanesthetized Sprague Dawley rats in a whole body plethysmograph. Phrenic motor output was monitored in the same rats which were anesthetized, vagotomized, paralyzed and ventilated to eliminate and/or control sensory feedback that could alter breathing patterns. The extent of spinal injury was approximated histologically by measurements of the injury-induced cyst area in transverse sections; cysts ranged from 2 to 28% of spinal cross-sectional area, and had a unilateral bias. In unanesthetized rats, the severity of spinal injury correlated negatively with tidal volume (R(2)=0.85; p<0.001) and positively with breathing frequency (R(2)=0.65; p<0.05). Thus, the severity of C4-C5 spinal contusion dictates post-injury breathing pattern. In anesthetized rats, phrenic burst amplitude was decreased on the side of injury, and burst frequency correlated negatively with contusion size (R(2)=0.51; p<0.05). A strong correlation between unanesthetized breathing pattern and the pattern of phrenic bursts in anesthetized, vagotomized and ventilated rats suggests that changes in respiratory motor output after spinal injury reflect, at least in part, intrinsic neural mechanisms of CNS plasticity initiated by injury.

Prenatal nicotine exposure alters respiratory long-term facilitation in neonatal rats.

Intermittent hypoxia can evoke persistent increases in ventilation (V (E)) in neonates (i.e. long-term facilitation, LTF) (Julien et al., 2008). Since prenatal nicotine (PN) exposure alters neonatal respiratory control (Fregosi and Pilarski, 2008), we hypothesized that PN would influence LTF of ventilation (V (E)) in neonatal rats. An osmotic minipump delivered nicotine 6 mg/kg per day or saline to pregnant dams. V (E) was assessed in unanesthetized pups via whole body plethysmography at post-natal (P) days 9-11 or 15-17 during baseline (BL, 21% O(2)), hypoxia (10 x 5 min, 5% O(2)) and 30 min post-hypoxia. PN pups had reduced BL V (E) (p<0.05) but greater increases in V (E) during hypoxia (p<0.05). Post-hypoxia V (E) (i.e. LTF) showed an agex treatment interaction (p<0.01) with similar values at P9-11 but enhanced LTF in saline (30+/-8%BL) vs. PN pups (6+/-5%BL; p=0.01) at P15-17. We conclude that the post-natal developmental time course of hypoxia-induced LTF is influenced by PN.

Multicenter evaluation of the Cepheid Xpert methicillin-resistant Staphylococcus aureus (MRSA) test as a rapid screening method for detection of MRSA in nares.

The first U.S. multicenter clinical trial to assess the performance of the Cepheid Xpert MRSA assay (Xpert MRSA) was conducted. The assay is a qualitative test designed for the rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) directly from nares swabs. This novel test combines integrated nucleic acid extraction and automated real-time PCR for the detection of a MRSA-specific signature sequence. A total of 1,077 nares specimens were collected from seven geographically distinct health care sites across the United States with prevalence rates ranging from 5.2% to 44%. Nares specimens were tested by (i) the Xpert MRSA assay, (ii) direct culture on CHROMagar MRSA medium (direct CM culture), and (iii) broth-enriched culture (Trypticase soy broth with 6.5% sodium chloride) followed by plating onto CHROMagar MRSA medium (broth-enriched CM culture). When direct CM culture was designated the reference method, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Xpert MRSA assay were 94.3%, 93.2%, 73.0%, and 98.8%, respectively. When broth-enriched CM culture was used as the reference method, the clinical sensitivity, specificity, PPV, and NPV of the Xpert MRSA assay were 86.3%, 94.9%, 80.5%, and 96.6%, respectively. The BD GeneOhm MRSA (BDGO) assay was performed as a comparative molecular method. No statistical performance differences were observed between the Xpert MRSA and BDGO assays when they were compared to culture methods. From this large-scale, multicenter clinical comparison, we conclude that the Xpert MRSA assay is a simple, rapid, and accurate method for performing active surveillance for MRSA in a variety of health care populations.

Ventilation and phrenic output following high cervical spinal hemisection in male vs. female rats.

Female sex hormones influence the neural control of breathing and may impact neurologic recovery from spinal cord injury. We hypothesized that respiratory recovery after C2 spinal hemisection (C2HS) differs between males and females and is blunted by prior ovariectomy (OVX) in females. Inspiratory tidal volume (VT), frequency (fR), and ventilation (VE) were quantified during quiet breathing (baseline) and 7% CO2 challenge before and after C2HS in unanesthetized adult rats via plethysmography. Baseline breathing was similarly altered in all rats (reduced VT, elevated fR) but during hypercapnia females had relatively higher VT (i.e. compared to pre-injury) than male or OVX rats (p<0.05). Phrenic neurograms recorded in anesthetized rats indicated that normalized burst amplitude recorded ipsilateral to C2HS (i.e. the crossed phrenic phenomenon) is greater in females during respiratory challenge (p<0.05 vs. male and OVX). We conclude that sex differences in recovery of VT and phrenic output are present at 2 weeks post-C2HS. These differences are consistent with the hypothesis that ovarian sex hormones influence respiratory recovery after cervical spinal cord injury.

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.

Robotic radiosurgery vs. brachytherapy as a boost to intensity modulated radiotherapy for tonsillar fossa and soft palate tumors: the clinical and economic impact of an emerging technology.

As a basis for making decisions regarding optimal treatment for patients with tonsillar fossa and soft palate tumors, we conducted a preliminary investigation of costs and quality of life (QoL) for two modalities [brachytherapy (BT) and robotic radiosurgery] used to boost radiation to the primary tumors following external beam radiotherapy. BT was well established in our center; a boost by robotic radiosurgery was begun more recently in patients for whom BT was not technically feasible. Robotic radiosurgery boost treatment has the advantage of being non-invasive and is able to reach tumors in cases where there is deep parapharyngeal tumor extension. A neck dissection was performed for patients with nodal-positive disease. Quality of life (pain and difficulty swallowing) was established in long-term follow-up for patients undergoing BT and over a one-year follow-up in robotic radiosurgery patients. Total hospital costs for both groups were computed. Our results show that efficacy and quality of life at one year are comparable for BT and robotic radiosurgery. Total cost for robotic radiosurgery was found to be less than BT primarily due to the elimination of hospital admission and operating room expenses. Confirmation of robotic radiosurgery treatment efficacy and reduced morbidity in the long term requires further study. Quality of life and cost analyses are critical to Health Technology Assessments (HTA). The present study shows how a preliminary HTA of a new medical technology such as robotic radiosurgery with its typical hypofractionation characteristics might be based on short-term clinical outcomes and assumptions of equivalence.

Carpal canal pressures after volar plating of distal radius fractures.

Elevated pressures within the carpal canal are known to occur after distal radius fractures. Controversy exists regarding prophylactic carpal tunnel release after open reduction with internal fixation of distal radius fractures. The purpose of this study was to determine the tissue pressures within the carpal canal after volar plating of distal radius fractures. This study was a prospective, observational, IRB approved research study. Ten consecutive patients undergoing volar plating of distal radius fractures were enrolled. After the distal radius fractures were reduced and fixed with volar plates, slit catheters were inserted into the carpal canals for continuous postoperative pressure monitoring for 24 hours. The maximum recorded pressure was 65 mmHg, which occurred in the only patient with fracture blisters. Peak pressures remained at 40 mmHg or less (range 16-40, mean 29) in all patients without fracture blisters. At the conclusion of data collection, all pressures were at 31 mmHg or less. No patient complained of median nerve dysfunction during the study period. Routine prophylactic carpal tunnel release is not recommended after volar plating of distal radius fractures based on these pressure recordings.

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.

I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients.

A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45-16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for children < or =4 years old and 0.8 mg/kg for patients >4 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV=9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.

Multicenter study assessing effects of heat and moisture exchanger use on respiratory symptoms and voice quality in laryngectomized individuals.

OBJECTIVE: A multicenter study based in the United States assessed the heat-moisture exchanger effect on respiratory symptoms and "voice quality" of laryngectomees. PATIENTS AND MEASURES: The study group consisted of 81 consecutive laryngectomees (62 men and 19 women; mean age, 66 years; age range, 45 to 89 years), with a median follow-up of 3.5 years (range, 0.5 to 24 years). A structured questionnaire was used to assess 3-month results, and tally sheets recorded the frequency of cough-expectoration during first and last trial weeks. RESULTS: Compliance was 73% (n = 59); decrease in coughing, 68%; sputum production, 73%; forced expectoration, 60%; and need for stoma cleaning, 52% of these 59 patients. Regarding daily cough-expectoration frequency, a statistically significant decrease (P < 0.0001) was found between the first and last trial weeks. Regarding influence on voice quality, 46% of regular users reported improvement in intelligibility, 30% in loudness, 37% in fluency, and 40% in telephone intelligibility. Fourteen patients (19%) reported skin irritation, with discontinuation of 7 patients. CONCLUSION: The observed decrease in pulmonary symptoms and improvement in voice quality confirm earlier reports from the Netherlands, United Kingdom, and Spain indicating improvement in postlaryngectomy quality of life.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients