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Valosin containing protein ( VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis ( ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype-phenotype correlations in this unique disease. [ABSTRACT FROM AUTHOR]

Rationale: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming standard of care for the sampling of mediastinal adenopathy. The need for a safe, effective, accurate procedure makes EBUS-TBNA ideal for mastery training and testing. Objectives: The Endobronchial Ultrasound Skills and Tasks Assessment Tool (EBUS-STAT) was created as an objective competency-oriented assessment tool of EBUS-TBNA skills and knowledge. This study demonstrates the reliability and validity evidence of this tool. Methods: The EBUS-STAT objectively scores the EBUS-TBNA operator's skills, including atraumatic airway introduction and navigation, ultrasound image acquisition and optimization, identification of mediastinal nodal and vascular structures, EBUS-TBNA sampling, and recognition of EBUS/computed tomography images of mediastinal structures. It can be administered at the bedside or using combination of low- and high-fidelity simulation platforms. Two independent testers administered the EBUS-STAT to 24 operators at three levels of EBUS-TBNA experience (8 beginners, 8 intermediates, and 8 experienced) at three institutions; operators were also asked to self-assess their skills. Scores were analyzed for intertester reliability, correlation with prior EBUS-TBNA experience, and association with self-assessments. Measurements and Main Results: Intertester reliability between testers was very high (r = 0.9991, P < 0.00005). Mean EBUS-STAT scores for beginner, intermediate, and experienced groups, respectively, were 31.1, 74.9, and 93.6 out of 100 (F(2,21) = 118.6, P < 0.0001). Groups were nonoverlapping: post hoc tests showed each group differed significantly from the others (P < 0.001). Self-assessments corresponded closely to actual EBUS-STAT scores (r(2) = 0.81, P < 0.001). Conclusions: The EBUS-STAT can be used to reliably and objectively score and classify EBUS-TBNA operators from novice to expert. Its use to assess and document the acquisition of knowledge and skill is a step toward the goal of mastery training in EBUS-TBNA. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC)., Methods: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses., Results: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16])., Conclusions: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

The purpose of this study is twofold: (1) to determine the feasibility of optical coherence tomography (OCT) to differentiate normal and diseased tissue of the neck region intraoperatively and (2) to evaluate how accurately a cohort of test subjects can identify various tissue types when shown a sample set of OCT images. In this in vivo, prospective, single institutional study, an OCT imaging system (Niris, Imalux, Cleveland, OH) was used to image parathyroid, thyroid, lymph node, and fat tissue in 76 patients during neck surgery. Biopsies were performed for comparison of OCT images with histology in select cases (n = 20). Finally, a group of either surgeons or scientists familiar with OCT (n = 17) were shown a sample of OCT images and asked to identify the tissue. A total of 437 OCT images were analyzed, and characteristic features of each tissue type were identified. OCT demonstrated distinct differences in structural architecture and signal intensity that allows differentiation between thyroid and parathyroid tissues, lymph nodes, and fat. OCT images were also compared with histology with good correlation. There was no difference in correctly identifying OCT-imaged tissue type between surgeons and scientists. This study is the first in vivo OCT imaging study to evaluate both normal and diseased tissues that may be encountered during neck surgery. OCT has the potential to become a valuable intraoperative tool to differentiate diseased and normal thyroid tissue intraoperatively to obtain an "optical biopsy" in real time without fixation, staining, or tissue resection.

Prader-Willi syndrome (PWS) is a complex multisystemic condition caused by a lack of paternal expression of imprinted genes from the 15q11.2-q13 region. Limited literature exists on the association between molecular classes, growth hormone use, and the prevalence of psychiatric phenotypes in PWS. In this study, we analyzed nine psychiatric phenotypes (depressed mood, anxiety, skin picking, nail picking, compulsive counting, compulsive ordering, plays with strings, visual hallucinations, and delusions) recognized in PWS and investigated associations with growth hormone treatment (GHT), deletions (DEL) and uniparental disomy (UPD) in a cohort of 172 individuals with PWS who met the criteria for analysis. Associations were explored using Pearson chi-square tests and univariable and multivariable logistic regression analyses to control for confounding exposures. This observational study of the largest dataset of patients with PWS to date suggested the following genetic subtype and phenotype correlations in psychiatric behaviors: (1) skin picking was more frequent in those with DEL vs. UPD; (2) anxiety was more common in those with UPD vs. DEL; and (3) an increased frequency of anxiety was noted in the UPD group treated with GHT compared to the DEL group. No other significant associations were found between the genetic subtype or GHT including for depressed mood, nail picking, compulsive counting, compulsive ordering, playing with strings, and visual hallucinations. Further studies will be required before any conclusions can be reached.

Aims: In this two-part study, we sought to define how long sacral neuromodulation users with overactive bladder should trial a new setting before attributing symptoms to that setting. Subsequently, we evaluated patient preferences of variable stimulation regimens., Methods: In the initial phase of this prospective pilot study, participants' devices were turned off and later reactivated; time to symptom recurrence and resolution were recorded. In phase two, participants trialed four settings in a masked fashion with random order. After unmasking, participants chose their preferred setting and were followed 1 year., Results: Twelve subjects completed phase one. With the device off, the mean time to symptom recurrence was 11.25 days. Mean time to symptom regression following reactivation was 6.42 days. Combined, the 90th percentile was 15 days for symptoms to reflect the device's new setting. Among 23 women completing part two, the most popular setting at the time of unmasking was a 1-hr on, 2-hr off cycled setting chosen by 7 (30%) participants. According to published estimates of battery longevity, 14 (61%) participants chose a more energy-conserving setting at the time of unmasking. The mean difference in estimated battery longevity between the chosen and baseline regimens was 14.5 months. These gains diminished in the following year with clinical changes in device settings by patients and providers., Conclusions: Sacral neuromodulation patients should allow a 2-week trial before attributing symptoms to a new setting. With additional information, many opt for energy-conserving settings. A 1-hr on, 2-hr off regimen warrants further study. Neurourol. Urodynam. 36:486-489, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives/hypothesis: Current imaging modalities lack the necessary resolution to diagnose subglottic stenosis. The aim of this study was to use optical coherence tomography (OCT) to evaluate nascent subglottic mucosal injury and characterize mucosal thickness and structural changes using texture analysis in a simulated intubation rabbit model., Study Design: Prospective animal study in rabbits., Methods: Three-centimeter-long sections of endotracheal tubes (ETT) were endoscopically placed in the subglottis and proximal trachea of New Zealand White rabbits (n = 10) and secured via suture. OCT imaging and conventional endoscopic video was performed just prior to ETT segment placement (day 0), immediately after tube removal (day 7), and 1 week later (day 14). OCT images were analyzed for airway wall thickness and textural properties., Results: Endoscopy and histology of intubated rabbits showed a range of normal to edematous tissue, which correlated with OCT images. The mean airway mucosal wall thickness measured using OCT was 336.4 μm (day 0), 391.3 μm (day 7), and 420.4 μm (day 14), with significant differences between day 0 and day 14 (P = .002). Significance was found for correlation and homogeneity texture features across all time points (P < .05)., Conclusions: OCT is a minimally invasive endoscopic imaging modality capable of monitoring progression of subglottic mucosal injury. This study is the first to evaluate mucosal injury during simulated intubation using serial OCT imaging and texture analysis. OCT and texture analysis have the potential for early detection of subglottic mucosal injury, which could lead to better management of the neonatal airway and limit the progression to stenosis., Level of Evidence: NA Laryngoscope, 127:64-69, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Rationale: Rigid bronchoscopy is increasingly used by pulmonologists for the management of central airway disorders. However, an assessment tool to evaluate the competency of operators in the performance of this technique has not been developed. We created the Rigid Bronchoscopy Tool for Assessment of Skills and Competence (RIGID-TASC) to serve as an objective, competency-oriented assessment tool of basic rigid bronchoscopic skills, including rigid bronchoscopic intubation and central airway navigation., Objectives: To assess whether RIGID-TASC scores accurately distinguish the basic rigid bronchoscopy skills of novice, intermediate, and expert operators, and to determine whether RIGID-TASC has adequate interrater reliability when used by different independent testers., Methods: At two academic medical centers in the United States, 30 physician volunteers were selected in three categories: 10 novices at rigid bronchoscopy (performed at least 50 flexible, but no rigid, bronchoscopies), 10 operators with intermediate experience (performed 5-20 rigid bronchoscopies), and 10 experts (performed ≥100 rigid bronchoscopies). Participants included pulmonary and critical care fellows, interventional pulmonology fellows, and faculty interventional pulmonologists. Each subject then performed rigid bronchoscopic intubation and navigation on a manikin, while being scored independently by two testers, using RIGID-TASC., Measurements and Main Results: Mean scores for three categories (novice, intermediate, and expert) were 58.10 (±4.6 [SE]), 78.15 (±3.8), and 94.40 (±1.1), respectively. There was significant difference between novice and intermediate (20.05, 95% confidence interval [CI] = 7.77-32.33, P = 0.001), and intermediate and expert (16.25, 95% CI = 3.97-28.53, P = 0.008) operators. The interrater reliability (intraclass correlation coefficient) between the two testers was high (r = 0.95, 95% CI = 0.90-0.98)., Conclusions: RIGID-TASC showed evidence of construct validity and interrater reliability in this setting and group of subjects. It can be used to reliably and objectively score and classify operators from novice to expert in basic rigid bronchoscopic intubation and navigation.

Rationale: Subglottic edema and acquired subglottic stenosis are potentially airway-compromising sequelae in neonates following endotracheal intubation. At present, no imaging modality is capable of in vivo diagnosis of subepithelial airway wall pathology as signs of intubation-related injury., Objectives: To use Fourier domain long-range optical coherence tomography (LR-OCT) to acquire micrometer-resolution images of the airway wall of intubated neonates in a neonatal intensive care unit setting and to analyze images for histopathology and airway wall thickness., Methods: LR-OCT of the neonatal laryngotracheal airway was performed a total of 94 times on 72 subjects (age, 1-175 d; total intubation, 1-104 d). LR-OCT images of the airway wall were analyzed in MATLAB. Medical records were reviewed retrospectively for extubation outcome., Measurements and Main Results: Backward stepwise regression analysis demonstrated a statistically significant association between log(duration of intubation) and both laryngeal (P < 0.001; multiple r(2) = 0.44) and subglottic (P < 0.001; multiple r(2) = 0.55) airway wall thickness. Subjects with positive histopathology on LR-OCT images had a higher likelihood of extubation failure (odds ratio, 5.9; P = 0.007). Longer intubation time was found to be significantly associated with extubation failure., Conclusions: LR-OCT allows for high-resolution evaluation and measurement of the airway wall in intubated neonates. Our data demonstrate a positive correlation between laryngeal and subglottic wall thickness and duration of intubation, suggestive of progressive soft tissue injury. LR-OCT may ultimately aid in the early diagnosis of postintubation subglottic injury and help reduce the incidences of failed extubation caused by subglottic edema or acquired subglottic stenosis in neonates. Clinical trial registered with www.clinicaltrials.gov (NCT 00544427).

Background and Objective: Port-wine stain (PWS) birthmarks affect ∼22 million people worldwide. After several treatment sessions, complete disappearance of the PWS occurs in only ∼10% of treated patients. There is a need to develop a new strategy to improve the efficacy of each treatment session and the overall treatment outcome. The study objective was to determine how intraoperative measurements of blood flow correlate with treatment response assessed several weeks post treatment., Study Design/materials and Methods: We employed Laser Speckle Imaging (LSI) to measure intraoperative blood-flow dynamics. We collected data from 24 subjects undergoing laser therapy for facial PWS birthmarks. Photographs were taken before treatment and at a follow-up visit, and analyzed by two expert observers., Results: Intraoperative LSI enables real-time monitoring of blood-flow dynamics in response to laser treatment and can inform clinicians on the need for focused re-treatment. The degree of PWS blanching achieved is positively correlated with the log-transformed acute blood-flow reduction (P = 0.022)., Conclusion: LSI is a simple, intraoperative monitoring tool during laser therapy of PWS birthmarks. LSI provides a single value for blood flow that correlates well with the degree of blanching achieved with laser therapy., (© 2015 Wiley Periodicals, Inc.)

Self-concept is a critical indicator of quality of life but few studies have examined this subject in children with Down syndrome (DS). In this study, we propose a novel methodology to assess the self-concept of children with DS by analyzing their responses towards two dolls, one with a "typically developing" (TD) appearance and one with the phenotypic features of DS. Fifty-four children with DS participated in play sessions with both dolls and were then interviewed to assess doll preference, resemblance, and attribution of positive qualities. We observed that children with DS: (i) exhibited a preference for the TD doll regardless of age, gender, IQ or self-awareness; (ii) attributed more positive qualities to the TD doll than the DS doll; and (iii) believed that they resembled the TD doll, rather than the more phenotypically accurate representation of themselves. Older participants were more likely to exhibit self-recognition by this technique. These findings contribute to current understandings of how people with DS view themselves and their disability., (© 2014 Wiley Periodicals, Inc.)

Until recently, maternal serum analyte levels paired with sonographic fetal nuchal translucency measurement was the most accurate prenatal screen available for Trisomies 18 and 21, (91% and 94% detection and false positive rates of 0.31% and 4.5% respectively). Women with positive California Prenatal Screening Program (CPSP) results have the option of diagnostic testing to determine definitively if the fetus has a chromosomal abnormality. Cell-free fetal (cff-) DNA screening for Trisomies 13, 18, and 21 was first offered in 2012, allowing women with positive screens to choose additional screening before diagnostic testing. Cff-DNA sensitivity rates are as high as 99.9% and 99.1%, with false positive rates of 0.4% and 0.1%, for Trisomies 18 and 21, respectively. A retrospective chart review was performed in 2012 on 500 CPSP referrals at the University of California, San Diego Thornton Hospital. Data were collected prior to and after the introduction of cff-DNA. There was a significant increase in the number of participants who chose to pursue additional testing and a decrease in the number of invasive procedures performed after cff-DNA screening was available. We conclude that as fetal aneuploidy screening improves, the number of invasive procedures will continue to decrease.

Aims: To assess whether InterStim lead wire placement with the curved stylet achieves motor response at lower amplitudes compared to straight stylet use., Methods: This was a prospective, randomized, crossover study of patients scheduled for InterStim lead wire placement. All patients underwent lead wire testing with both the curved and straight stylets. Patients were randomized to determine stylet order, and then crossed-over to the alternate. Intra-operatively, the amplitude achieving motor response at each electrode was recorded. The stylet with lowest overall amplitudes was used for final placement. Primary outcome measure was amplitude requirement in the two deepest (0 and 1) electrodes. Secondary outcomes included amplitudes at the number 2 and 3 electrodes, combined amplitudes, stylet order, and adverse outcomes., Results: Forty-two patients were enrolled, 40 of whom were included in the final analysis. Mean age was 69 years (SD = 12.8) and mean BMI 27 (SD = 5.6). Indications for placement included: urge urinary incontinence (N = 26), urge/frequency (N = 25), non-obstructive urinary retention (N = 5), and fecal incontinence (N = 10). There were no significant differences between randomized groups. Regardless of order, the curved stylet achieved a motor response at lower amplitudes in the deepest electrodes (P < 0.001). Combined amplitudes of all electrodes were also significantly lower with the curved stylet (P < 0.001). Subsequently, 88% underwent final "optimal" placement with curved stylet (N = 35)., Conclusions: The curved stylet for InterStim lead wire placement consistently achieved motor response at lower amplitudes. A brief intra-operative exchange of stylets represents a minor procedural alteration that could maximize Implantable Pulse Generator battery life and facilitate programming., (© 2013 Wiley Periodicals, Inc.)

Background and Purpose: Recent advances in distal sensor technologies have made distal sensor ureteroscopes both commercially and technically feasible. We evaluated performance characteristics and optics of a new generation distal sensor Flex-X(C) (X(C)) and a standard flexible fiberoptic ureteroscope Flex-X(2) (X(2)), both from Karl Storz, Tuttlingen, Germany., Materials and Methods: The ureteroscopes were compared for active deflection, irrigation flow, and optical characteristics. Each ureteroscope was evaluated with an empty working channel and with various accessories. Optical characteristics (resolution, grayscale imaging, and color representation) were measured using United States Air Force test targets. We digitally recorded a renal porcine ureteroscopy and laser ablation of a stone with the X(2) and with the X(C). Edited footage of the recorded procedure was shown to different expert surgeons (n=8) on a high-definition monitor for evaluation by questionnaire for image quality and performance., Results: The X(C) had a higher resolution than the X(2) at 20 and 10 mm 3.17 lines/mm vs 1.41 lines/mm, 10.1 vs 3.56, respectively (P=0.003, P=0.002). Color representation was better in the X(C). There was no difference in contrast quality between the two ureteroscopes. For each individual ureteroscope, the upward deflection was greater than the downward deflection both with and without accessories. When compared with the X(2), the X(C) manifested superior deflection and flow (P<0.0005, P<0.05) with and without accessory present in the working channel. Observers deemed the distal sensor ureteroscope superior in visualization in clear and bloody fields, as well as for illumination (P=0.0005, P=0.002, P=0.0125)., Conclusions: In this in vitro and porcine evaluation, the distal sensor ureteroscope provided significantly improved resolution, color representation, and visualization in the upper urinary tract compared with a standard fiberoptic ureteroscope. The overall deflection was also better in the X(C), and deflection as well as flow rate was less impaired by the various accessories.

Background and Purpose: Surgery is a high-stakes "performance." Yet, unlike athletes or musicians, surgeons do not engage in routine "warm-up" exercises before "performing" in the operating room. We study the impact of a preoperative warm-up exercise routine (POWER) on surgeon performance during laparoscopic surgery., Materials and Methods: Serving as their own controls, each subject performed two pairs of laparoscopic cases, each pair consisting of one case with POWER (+POWER) and one without (-POWER). Subjects were randomly assigned to +POWER or -POWER for the initial case of each pairing, and all cases were performed ≥ 1 week apart. POWER consisted of completing an electrocautery skill task on a virtual reality simulator and 15 minutes of laparoscopic suturing and knot tying in a pelvic box trainer. For each case, cognitive, psychomotor, and technical performance data were collected during two different tasks: mobilization of the colon (MC) and intracorporeal suturing and knot tying (iSKT). Statistical analysis was performed using SYSTAT v11.0., Results: A total of 28 study cases (14+POWER, 14-POWER) were performed by seven different subjects. Cognitive and psychomotor performance (attention, distraction, workload, spatial reasoning, movement smoothness, posture stability) were found to be significantly better in the +POWER group (P ≤ 0.05) and technical performance, as scored by two blinded laparoscopic experts, was found to be better in the +POWER group for MC (P=0.04) but not iSKT (P=0.92). Technical scores demonstrated excellent reliability using our assessment tool (Cronbach ∝=0.88). Subject performance during POWER was also found to correlate with intraoperative performance scores., Conclusions: Urologic trainees who perform a POWER approximately 1 hour before laparoscopic renal surgery demonstrate improved cognitive, psychomotor, and technical performance.

Objective: To investigate the relationship between multiple cryoprobes was investigated to determine whether they work in an additive or synergistic fashion in an in vivo animal model because 1.47 mm (17-gauge) cryoprobes have been introduced to the armamentarium for renal cryotherapy., Methods: Laparoscopic-guided percutaneous cryoablation was performed in both renal poles of 3 pigs using 3 IceRod cryoprobes. These 12 cryolesions were compared with 12 cryolesions using a single IceRod cryoprobe. Each cycle consisted of two 10-minute freeze cycles separated by a 5-minute thaw. The iceball volume was measured using intraoperative ultrasonography. The kidneys were harvested, and cryolesion surface area was calculated. The lesions were fixed and excised to obtain a volume measurement. Statistical analysis was used to compare the single probe results multiplied by 3 to the multiple probe group for iceball volume, cryolesion surface area, and cryolesion volume., Results: The iceball volume for the first freeze cycle for the single cryoprobe multiplied by 3 was 8.55 cm3 compared with 9.79 cm3 for the multiple cryoprobe group (P=.44) and 10.01 cm3 versus 16.58 cm3 for the second freeze (P=.03). The cryolesion volume for the single cryoprobe multiplied by 3 was 11.29 cm3 versus 14.75 cm3 for the multiple cyroprobe group (P=.06). The gross cryolesion surface area for the single cryoprobe multiplied by 3 was 13.14 cm2 versus 13.89 cm2 for the multiple probe group (P=.52)., Conclusion: The cryolesion created by 3 simultaneously activated 1.47-mm probes appears to be larger than that of an additive effect. The lesions were significantly larger as measured by ultrasonography and nearly so (P=.06) as measured by the gross cryolesion volume., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To our knowledge the optimal freeze cycle length in renal cryotherapy is unknown. Ten-minute time based freeze cycles were compared to temperature based freeze cycles to -20C., Materials and Methods: Laparoscopic renal cryotherapy was performed on 16 swine. Time based trials consisted of a double 10-minute freeze separated by a 5-minute thaw. Temperature based trials were double cycles of 1, 5 or 10-minute freeze initiated after 1 of 4 sensors indicated -20C. A 5-minute active thaw was used between freeze cycles. Control trials consisted of cryoneedle placement for 25 minutes without freeze or thaw. Viability staining and histological analysis were done., Results: There was no difference in cellular necrosis between any of the temperature based freeze cycles (p = 0.1). Time based freeze cycles showed more nuclear pyknosis, indicative of necrosis, than the 3 experimental freeze cycles for the renal cortex (p = 0.05) but not for the renal medulla (p = 0.61). Mean time to -20C for freeze cycle 1 was 19 minutes 10 seconds (range 9 to 46 minutes). In 4 of 21 trials (19%) -20C was never attained despite freezing for 25 to 63 minutes., Conclusions: There was no difference in immediate cellular necrosis among double 1, 5 or 10-minute freeze cycles. Cellular necrosis was evident on histological analysis for trials in which -20C was attained and in freeze cycles based on time alone. With a standard 10-minute cryoablation period most treated parenchyma 1 cm from the probe never attained -20C. Cell death appeared to occur at temperatures warmer than -20C during renal cryotherapy., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Health literacy and numeracy are necessary to understand health information and to make informed medical decisions. This study explored the relationships among health literacy, numeracy, and ability to accurately interpret graphical representations of breast cancer risk., Methods: Participants (N=120) were recruited from the Facing Our Risk of Cancer Empowered (FORCE) membership. Health literacy and numeracy were assessed. Participants interpreted graphs depicting breast cancer risk, made hypothetical treatment decisions, and rated preference of graphs., Results: Most participants were Caucasian (98%) and had completed at least one year of college (93%). Fifty-two percent had breast cancer, 86% had a family history of breast cancer, and 57% had a deleterious BRCA gene mutation. Mean health literacy score was 65/66; mean numeracy score was 4/6; and mean graphicacy score was 9/12. Education and numeracy were significantly associated with accurate graph interpretation (r=0.42, p<0.001 and r=0.65, p<0.001, respectively). However, after adjusting for numeracy in multivariate linear regression, education added little to the prediction of graphicacy (r(2)=0.41 versus 0.42, respectively)., Conclusion: In our highly health-literate population, numeracy was predictive of graphicacy., Practice Implications: Effective risk communication strategies should consider the impact of numeracy on graphicacy and patient understanding., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Despite a lack of evidence for survival benefit, the American College of Obstetrics and Gynecology has recommendations for referral to gynecologic oncologists for the treatment of endometrial cancer. Therefore, we propose to determine the influence of gynecologic oncologists on the treatment and survival of patients with endometrial cancer., Patients and Methods: Data were obtained from Medicare and Surveillance, Epidemiology, and End Results (SEER) databases from 1988 to 2005. Kaplan-Meier and Cox proportional hazard methods were used for analyses., Results: Of 18,338 women, 21.4% received care from gynecologic oncologists (group A) while 78.6% were treated by others (group B). Women in group A were older (age > 71 years: 49.6% v 44%; P < .001), had more lymph nodes (> 16) removed (22% v 17%; P < .001), presented with more advanced (stages III to IV) cancers (21.9% v 14.6%; P < .001), had higher-grade tumors (P < .001), and were more likely to receive chemotherapy for advanced disease (22.6% v 12.4%; P < .001). In those with stages II to IV disease, the 5-year disease-specific survival (DSS) of group A was 79% versus 73% in group B (P = .001). Moreover, in advanced-stage (III to IV) disease, group A had 5-year DSS of 72% versus 64% in group B (P < .001). However, no association with DSS was identified in stage I cancers. On multivariable analysis, younger age, early stage, lower grade, and treatment by gynecologic oncologists were independent prognostic factors for improved survival., Conclusion: Patients with endometrial cancer treated by gynecologic oncologists were more likely to undergo staging surgery and receive adjuvant chemotherapy for advanced disease. Care provided by gynecologic oncologists improved the survival of those with high-risk cancers.

Introduction and Objectives: Cryoablation is a viable minimally invasive strategy for the treatment of small renal masses. One of the most common postoperative complaints is pain or paresthesia at the cryoprobe insertion site. The use of a 14-gauge angiocatheter to insulate the flank during renal cryotherapy was investigated., Materials and Methods: Six Yorkshire swine underwent laparoscopy-guided percutaneous cryoablation of the upper and lower poles of both kidneys with a 1.47 mm (17 gauge) cryoneedle. Treatment consisted of a double 10-minute freeze separated by a 5-minute active thaw. Trials were randomized to placement of the cryoneedle directly through the flank or through a 14-gauge angiocatheter as an insulating sheath. Temperatures were recorded adjacent to the cryoneedle at two depths in the flank with a Multi-Point Thermal Sensor., Results: Twelve trials were completed each with a bare and sheathed cryoneedle. The coldest temperature observed was -26 degrees C for the bare cryoneedle and -21 degrees C for the sheathed cryoneedle. At the outer sensor, there was a 4.1 degrees C increase in mean temperature for freeze 1, and 6.2 degrees C increase in mean temperature for freeze 2 with sheath use. At the inner sensor, there was a 3.0 degrees C increase in mean temperature for freeze 1, and 9.4 degrees C increase in mean temperature for freeze 2 with sheath use. There was a trend toward statistical significance of sheath insulation at the outer (p = 0.07) and inner (p = 0.08) temperature sensors., Conclusions: A 14-gauge angiocatheter may provide some insulation and thereby might help protect against "ice burn" during renal cryotherapy.

Purpose: Preoperative planning for renal cryotherapy is based on isotherms established in gel. We replicated gel isotherms and correlated them with ex vivo and in vivo isotherms in a porcine model., Materials and Methods: PERC-17 CryoProbes (1.7 mm) and IceRods (1.47 mm) underwent trials in gel, ex vivo and in vivo porcine kidneys. Temperatures were recorded at 13 predetermined locations with multipoint thermal sensors., Results: At the cryoprobe temperatures were not significantly different along the probe in any medium for either system (p = 0.0947 to 0.9609). However, away from the probe ex vivo and in vivo trials showed warmer temperatures toward the cryoprobe tip for each system (p = 0.0003 to 0.2141). Mean +/- SE temperature 5 mm distal to the cryoprobe tip in vivo was 19.2C +/- 16.1C for CryoProbes and 27.3C +/- 11.2C for IceRods. Temperatures were consistently colder with CryoProbes than with IceRods in gel (p <0.00005), ex vivo (p <0.00005) and in vivo (p = 0.0014). At almost all sites temperatures were significantly colder in gel and in ex vivo kidney than in in vivo kidney for CryoProbes (p = 0.0107 and 0.0008, respectively) and for IceRods (each p <0.00005)., Conclusions: Gel and ex vivo isotherms do not predict the in vivo pattern of freezing. Thus, they should not be used for preoperative planning. The cryoprobe should be passed 5 mm beyond the tumor border to achieve suitably cold temperatures. Multipoint thermal sensor probes are recommended to record actual temperature during renal cryotherapy., (Copyright 2010 American Urological Association. Published by Elsevier Inc. All rights reserved.)

Aim: Whether or not sacrificing accessory pudendal arteries (APAs) during radical prostatectomy affects potency has been an ongoing source of concern. Herein, we present our potency results relative to sacrificing APAs in normally pre-potent men following robot-assisted radical prostatectomy (RARP)., Methods: The distribution of APAs and clinical characteristics were prospectively recorded in 200 consecutive patients undergoing RARP with a cautery-free technique. Sexual function was assessed using the International Index of Erectile Function 5-item questionnaire (IIEF-5). All APAs were sacrificed due to stapling the dorsal vein complex., Main Outcome Measures: Postoperatively, potency was defined by an affirmative answer to the following two questions: "Were erections adequate for penetration?" and "were the erections satisfactory?" Postoperative IIEF-5 scores and quality of erections (% of preoperative firmness: 0%, 25%, 50%, 75%, 100%) were also obtained. Subgroup analysis of patients age < or =65 years with IIEF-5 score of 22-25 was performed., Results: Eighty patients (40%) had APAs. Preoperatively, there was no association with having an APA and normal/abnormal sexual function. Preoperatively, 58/200 were < or =65 years with self-administered IIEF-5 scores of 22-25. Postoperatively, 53/58 (91%) were potent at 24 months follow-up. Nineteen of 58 patients had a sacrificed APA; 39 patients had no APA. Eighteen of 19 (95%) patients with sacrificed APAs were potent vs. 35/39 (90%) with no APA present (P = 0.53). Multivariate analysis showed no significant correlation between sacrificing an APA and time of potency recovery, quality of postoperative erections (94% vs. 90% P = 0.80) or mean IIEF-5 score (22.4 vs. 20.8, P = 0.13)., Conclusion: We found no correlation between the presence or absence of APAs and preoperative sexual function. Furthermore, after sacrificing all APAs, we found no correlation with potency return, time to return of potency, quality of erections, or mean IIEF-5 scores at 24 months.

Post-prostatectomy urinary incontinence is a major cause of morbidity from radical prostatectomy. Efforts have been made to develop techniques to hasten return of urinary control. Several authors have demonstrated improved early continence with anterior, posterior, or combined reconstruction of the urethral-pelvic attachments. In this study, we compare three-month urinary function and continence data for patients who underwent RALP with posterior reconstruction and anterior suspension with single anastomotic suture (PRASS). A prospective cohort of 50 patients underwent RALP with PRASS reconstruction and were compared to 50 control patients who underwent standard RALP. Continence was defined as use of 0-1 urinary pads and was evaluated at each follow-up visit using the EPIC-26 questionnaire. A weighted summary score was created and group differences were compared using a repeated measures analysis of variance model. After adjusting for age, baseline AUA symptom score, and SHIM scores, which were found to correlate with continence, patients who underwent the PRASS reconstruction had significantly improved urinary control at three months compared with the control group; 90.9% of the patients in the PRASS group wore 0-1 pads per day versus 48.2% in the control group (P = 0.014). Of the patients undergoing the standard prostatectomy 20.6% were totally pad-free compared with 42% of the patients undergoing the PRASS procedure (P = 0.042). In conclusion, the PRASS technique resulted in statistically significant improvement in urinary control three months post-operation. The PRASS reconstruction is technically straightforward, requires no additional sutures, and is a simple technique that is easily learned and adaptable to other robotic surgery.

Background: Pulsed dye laser (PDL) is a commonly utilized treatment for port wine stain birthmarks (PWS) in the United States; however, results are variable and few patients achieve complete removal. Photodynamic therapy (PDT) is commonly used in China, but treatment associated photosensitivity lasts several weeks and scarring may occur. We propose an alternative treatment option, combined PDT+PDL and performed a proof-of-concept preliminary clinical trial., Methods: Subjects with non-facial PWS were studied. Each subject had four test sites: control, PDL alone, PDT alone (benzoporphyrin derivative monoacid ring A photosensitizer with 576 nm light), and PDT+PDL. Radiant exposure time for PDT was increased in increments of 15 J/cm(2). Authors evaluated photographs and chromametric measurements before and 12 weeks post-treatment., Results: No serious adverse events were reported; epidermal changes were mild and self-limited. No clinical blanching was noted in control or PDT-alone sites. At PDT radiant exposures of 15 and 30 J/cm(2), equivalent purpura and blanching was observed at PDL and PDT+PDL sites. At PDT radiant exposures over 30 J/cm(2), greater purpura was noted at PDT+PDL sites as compared to PDL alone. Starting at 75 J/cm(2), improved blanching was noted at PDT+PDL sites., Conclusions: Preliminary results indicate that PDT+PDL is safe and may offer improved PWS treatment efficacy. Additional studies are warranted.

Purpose: Pneumoperitoneum is known to decrease blood flow to the kidney during laparoscopy. We investigated if this change in blood flow would increase the size of the cryolesion., Materials and Methods: Twelve Yorkshire swine underwent laparoscopy-guided percutaneous cryoablation of the upper and lower pole of each kidney at four randomized pneumoperitoneum pressures (10, 15, 20, and 25 mm Hg). Cryolesions were made with a 1.47-mm IceRod (Galil Medical, Plymouth Meeting, PA). Each site underwent two 10-minute freeze cycles separated by a 5-minute active thaw with pressurized helium gas. At the conclusion of each freeze cycle, the iceball volume was measured with intraoperative ultrasound. After completion of the four cryolesions, the kidneys were harvested, and the cryolesion surface area was calculated. The lesions were fixed in 10% buffered formalin and then excised with a 1-mm margin to obtain a volume measurement using fluid displacement., Results: Iceball volume was 3.41, 2.85, 3.44, and 2.36 cm(3) for freeze cycle 1 (p = 0.16) and 3.67, 3.34, 4.88, 3.95 cm(3) for freeze cycle 2 (p = 0.20) at 10, 15, 20, and 25 mm Hg, respectively. Cryolesion volume by fluid displacement was 4.06, 3.77, 3.97, and 3.93 cm(3) (p = 0.86) and cryolesion surface area was 4.55, 4.38, 4.39, and 4.20 cm(2) (p = 0.71) at 10, 15, 20, and 25 mm Hg, respectively., Conclusions: In this study, pneumoperitoneum pressure between 10 and 25 mm Hg did not affect iceball size as measured by intraoperative ultrasound, cryolesion volume by fluid displacement, or cryolesion surface.

Purpose: Repetitive practice of laparoscopic suturing and knot tying can facilitate surgeon proficiency in performing this reconstructive technique. We compared a silicone model and pelvic trainer to a virtual reality simulator in the learning of laparoscopic suturing and knot tying by laparoscopically naïve medical students, and evaluated the subsequent performance of porcine laparoscopic cystorrhaphy., Materials and Methods: A total of 20 medical students underwent a 1-hour didactic session with video demonstration of laparoscopic suturing and knot tying by an expert laparoscopic surgeon. The students were randomized to a pelvic trainer (10) or virtual reality simulator (10) for a minimum of 2 hours of laparoscopic suturing and knot tying training. Within 1 week of the training session the medical students performed laparoscopic closure of a 2 cm cystotomy in a porcine model. Objective structured assessment of technical skills for laparoscopic cystorrhaphy was performed at the procedure by laparoscopic surgeons blinded to the medical student training format. A video of the procedure was evaluated with an objective structured assessment of technical skills by an expert laparoscopic surgeon blinded to medical student identity and training format. The medical students completed an evaluation questionnaire regarding the training format after the laparoscopic cystorrhaphy., Results: All students were able to complete the laparoscopic cystorrhaphy. There was no difference between the pelvic trainer and virtual reality groups in mean +/- SD time to perform the porcine cystorrhaphy at 40 +/- 15 vs 41 +/- 10 minutes (p = 0.87) or the objective structured assessment of technical skills score of 8.8 +/- 2.3 vs 8.2 +/- 2.2 (p = 0.24), respectively. Bladder leak occurred in 3 (30%) of the pelvic trainer trained and 6 (60%) of the virtual reality trained medical student laparoscopic cystorrhaphy procedures (Fisher exact test p = 0.37). The only significant difference between the 2 groups was that 4 virtual reality trained medical students considered the training session too short compared to none of those trained on the pelvic trainer (p = 0.04)., Conclusions: There is no significant difference between the pelvic trainer and virtual reality trained medical students in proficiency to perform laparoscopic cystorrhaphy in a pig model, although both groups require considerably more training before performing this procedure clinically. The pelvic trainer training may be more user-friendly for the novice surgeon to begin learning these challenging laparoscopic skills.

The occurrence of other autoimmune diseases in celiac disease families has not been previously reported in a North American population. We investigated the familial aggregation of rheumatoid arthritis (RA), juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), hypothyroidism, insulin dependent diabetes mellitus (IDDM), and alopecia areata (AA) among individuals in families with celiac disease (CD). Family history information, obtained from questionnaires from the University of California Irvine Celiac Disease study, was reviewed for reports of RA, JRA/JIA, hypothyroidism, IDDM, and AA in celiac disease cases and their first-degree relatives. Reports of disease were compared with prevalence data from the literature and analyzed by calculating the standardized ratio (SR) with 95% confidence limits. We analyzed: (1) subjects with confirmed celiac disease or dermatitis herpetiformis (205 probands and 203 affected first-degree relatives) and (2) first-degree relatives of celiac disease cases (n=1272). We found a significantly increased number of cases, relative to the expected number, of IDDM in both groups and hypothyroidism among subjects with celiac disease. JRA/JIA was increased among first-degree relatives of celiacs. These results indicate that the presence of IDDM within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general.

Purpose: To characterize a rabbit model of Mycobacterium chelonae keratitis after lamellar keratectomy and assess the effectiveness of fluoroquinolone therapy., Setting: University Laboratory, University of California, Irvine, California, USA., Methods: Twenty-eight New Zealand white rabbits had unilateral lamellar keratectomy with placement of 2.5 x 10(5) colony-forming units of log-phase M chelonae under each flap. Eyes (7 per group) were randomized and treated with sterile balanced salt solution, gatifloxacin 0.3%, ciprofloxacin 0.3%, or levofloxacin 0.5% 4 times daily. Two masked observers examined all eyes on days 2, 5, and 7 and weekly for 4 weeks. Severity of disease and bacterial culture results were the main outcomes measured. The means and standard deviations were calculated, and differences between the groups were statistically analyzed., Results: All eyes developed clinical disease. At the time the rabbits were killed, eyes treated with balanced salt solution, ciprofloxacin, levofloxacin, and gatifloxacin were culture positive in 6 (85.7%), 7 (100%), 6 (85.7%), and 3 (42.9%) of 7 eyes per group, respectively. Frequency of positive culture and the severity of clinical disease in gatifloxacin-treated eyes were significantly less (P < .05) than in the other groups combined., Conclusions: The rabbit model of M chelonae keratitis was successfully developed in our study. A fourth-generation quinolone (gatifloxacin) showed the best performance among the fluoroquinolones tested in our experimental approach. The fourth-generation fluoroquinolone, gatifloxacin, could be effectively used for the treatment of mycobacterial keratitis.

Purpose: To determine the efficacy of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in inhibiting corneal neovascularization., Methods: Twenty-six adult male Sprague-Dawley rats were randomly divided into three groups. Each group received intrastromal polymer micropellets containing one of the following: Group 1, no active ingredient (n=10); Group 2, vascular endothelial growth factor (VEGF) (n=7); Group 3, VEGF and pioglitazone (n=9). Neovascularization was evaluated 7 days after pellet implantation. After systemic India ink injection, digital photographs of the eyes were taken. The area and density of neovascularization were measured using imaging software., Results: Mean area of neovascularization was 0.43+/-0.18 mm2 for Group 1, 2.87+/-0.48 mm2 for Group 2 and 2.10+/-0.22 mm2 for Group 3. Statistical analysis showed significant differences between Groups 1 and 2 and Groups 1 and 3. There was no significant difference between Groups 2 and 3. Mean density of neovascularization was 2.16+/-0.66 for Group 1, 27.14+/-2.93 for Group 2 and 12.02+/-2.24 for Group 3. All comparisons between groups were statistically significant (P<0.01)., Conclusions: Pioglitazone is effective in decreasing the density of angiogenesis in a VEGF-induced neovascular rat cornea model. There is possibility of even greater effect with higher doses of the drug. Pioglitazone is a promising drug for the treatment of ocular neovascularization.

Objective: To determine the viability in cold eye bank storage of different layers of central and limbal corneal epithelium, including the limbal basal stem cell population, on days 0, 3, 6, and 9 after harvest using a large diameter microkeratome system., Methods: Twenty-two human whole globes not suitable for transplantation were obtained from an eye bank (San Diego Eye Bank, San Diego, California) and used for study. Large-diameter anterior corneal discs were prepared using a large diameter microkeratome and stained with calcein AM and an ethidium homodimer to differentiate live from dead cells, respectively. A laser confocal microscope and digital imaging were used to distinguish live (green) from dead (red) cells. Central and limbal epithelial regions were isolated and the middle and basal epithelial sections were cell counted by 3 independent observers. These sections were stored up to 9 days at 4 degrees C in an eye bank corneal storage medium. Differences were tested using nonparametric methods., Main Outcome Measures: The percentage of live cells in each of these epithelial layers was determined for up to 9 days in cold eye bank corneal storage medium., Results: At all time points studied, the better protected basal epithelial layers displayed greater mean viability than the overlying middle epithelial layers. However, the difference was not statistically significant on all days. When comparing the basal epithelial viability of the limbal and central regions, after day 0 in 4 degrees C cold organ culture, the observed viability of the limbal basal epithelium, the purported location of the limbal epithelial stem cell region, was significantly greater than that of the central epithelium. On day 0, median limbal basal versus central basal epithelial viability were 100% (range, 71.7-100%) versus 98.4% (range, 88.9-100%) (P>0.05); on day 3, 100% (range, 64.3-100%) versus 63.4% (range, 13.6-95.5%) (P<0.0005); on day 6, 95.0% (range, 35.0-100%) versus 28.0% (range, 0-92.0%) (P<0.0005); and on day 9, 95.0% (range, 3.7-100%) versus 68.6% (range, 0-100%) (P<0.0005)., Conclusions: After microkeratome harvesting, the limbal basal epithelium is significantly longer lived in cold eye bank storage than central basal epithelium and the middle layers of limbal and central epithelium. This longevity not only bodes well for organ storage of limbal grafts, but also confirms the hardiness of the stem cell region.

We report somatic mutations in three genes (CSNK1 epsilon, encoding the Ser/Thr kinase casein kinase I epsilon; DLG1, encoding a membrane-associated putative scaffolding protein; and EDD/hHYD, encoding a progestin induced putative ubiquitin-protein ligase) in mammary ductal carcinoma. These genes were suspected of playing a role in cancer because loss-of-function mutations in their Drosophila homologues cause excess tissue growth. Using DNA from 82 laser-microdissected tumor samples, followed by microsatellite analysis, denaturing HPLC and direct sequencing, we found multiple somatic point mutations in all three genes, and these mutations showed significant association with loss of heterozygosity of closely linked polymorphic microsatellite markers. For CSNK1 epsilon and DLG1, most of the mutations affected highly conserved residues, some were found repetitively in different patients, and no synonymous mutations were found, indicating that the observed mutations were selected in tumors and may be functionally significant. Immunohistochemical reactivity of each protein was reduced in poorly differentiated tumors, and there was a positive association between altered protein reactivity, loss of heterozygosity, and somatic mutations. There was a statistically significant association of hDlg staining with p53 and Ki67 reactivity, whereas CSK1 epsilon and EDD/hHYD staining levels were associated with progesterone receptor status. The results provide strong indications for a role of all three genes in mammary ductal carcinoma. They also justify additional studies of the functional significance of the changes, as well as a search for additional changes in these and other genes identified from studies on model systems.

Objective: To examine the association between the size and number of promyelocyte protein-containing nuclear bodies, their colocalization with the small ubiquitin-like modifier protein, and existing histopathologic staging of cervical neoplasia progressing toward squamous cell carcinoma., Methods: Fluorescence-based immunodetection of the promyelocyte protein and the small ubiquitin-like modifier protein was performed on paraffin-embedded and histopathologically graded human uterine cervical tissues. Quantitative measurements of the size and number of the promyelocyte protein-containing nuclear bodies were made and statistically analyzed., Results: We found that promyelocyte protein-containing nuclear bodies exhibit changes in both size and number throughout the continuum of cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma. An increase in number and size of the bodies occurs with progression from normal to CIN I/CIN II. In CIN III, two new subcategories of nuclear body are present with distinctly different promyelocyte protein patterns, with the type B CIN III losing the small ubiquitin-like modifier protein partnership. In squamous cell carcinoma, we see the loss of this colocalization in both well and poorly differentiated tumors, with a distinctly different promyelocyte protein pattern. Well-differentiated tumors have bigger nuclear bodies that are more numerous than those of the poorly differentiated tumors., Conclusion: These data support the use of promyelocyte and small ubiquitin-like modifier proteins as a cytodiagnostic marker that parallels cervical cancer progression.

Purpose: To evaluate the safety and accuracy of a manual microkeratome and an artificial anterior chamber used at high intrachamber pressure to harvest corneal lenticules for lamellar keratoplasty., Setting: Department of Ophthalmology, University of California, Irvine, California, USA., Methods: Forty-seven human eye-bank corneoscleral rims were mounted on an artificial anterior chamber. A manual microkeratome was used to perform lamellar keratectomy at a mean intrachamber pressure of 95.8 mm hg +/- 4.8 (sd). Two thicknesses (300 microm and 360 microm microkeratome heads) and diameters (8.0 mm and 9.0 mm) were attempted, and the resultant lenticules were analyzed by pachymetry and digital photography., Results: In the 9.0 mm/360 microm group, corneal perforation occurred in 12 of 17 lenticules (71.2%). Except for this group, 24 of 30 corneas (80.0%) showed a less than 0.5 mm deviation from the expected diameter. Neither the horizontal nor the vertical diameter differences were statistically significant (P >.05). The difference between the horizontal and vertical diameters was within +/-0.2 mm in 23 corneas (76.7%). Three (10.0%) corneal beds contained a slightly uneven keratectomy margin., Conclusions: This system provided accurate and smooth lenticules for lamellar keratoplasty. The precision and accuracy of the obtained corneal lenticules were better than those in previous reports. However, the 9.0 mm diameter/360 microm thickness head with high intrachamber pressure should not be applied in the clinical setting without further testing. In this laboratory study, a minimal corneal thickness of 588 microm was required to avoid perforation.

We have earlier shown that VP-16 combined with Cyclosporin A (CsA) produces tumor specific immunity to L1210 leukemia in BDF/1 mice [Slater LM, Sweet P, Stupecky M, Reynolds JT. Cyclosporin A/VP-16 produced immunity to L1210 leukemia: the participation of cytotoxic CD(8) T-lymphocytes, Clin Immunol Immunopathol 1995;75:239-45]. Our current studies, designed to determine the role of VP-16 independently of CsA in this effect show that increased dose intensity of VP-16, in the absence of CsA, improves the frequency of 60 day survival of treated mice but impairs the ability of 60 day surviving mice to reject L1210 leukemia challenge. This impairment is associated with progressive diminution of mitogen responses by spleen cells harvested from tumor free VP-16 treated mice.

Objective: To describe the epithelial healing rates observed in freshly cultured rabbit corneas chemically burned with high-concentration hydrochloric acid (HCl) and sodium hydroxide (NaOH) and subsequently treated with phototherapeutic keratectomy (PTK)., Methods: We obtained 126 fresh corneoscleral rims from cadaveric New Zealand white rabbits. Each cornea was exposed to 4-mm cellulose sponges soaked in a solution of topical 0.9% isotonic sodium chloride solution, 2M HCl, or 0.5M NaOH. A transepithelial PTK (6-mm zone; 100-microm ablation depth) was then performed using the excimer laser (150-mJ/cm(2) energy pulse; 20 nanosecond duration; and 10-Hz frequency). Corneas were placed in tissue culture, and 1 cornea from each group was taken out of culture each day after treatment. Re-epithelialization was monitored by means of fluorescein staining, slitlamp photography, and histopathological analysis., Results: Corneas treated with HCl and NaOH exhibited immediate epithelial defects that slowly healed over time. In PTK-treated corneas, the re-epithelialization rate was accelerated compared with that of controls (P =.003 for the HCl group, and P<.001 for the NaOH group). The new epithelial layers were smoother in PTK-treated corneas, as confirmed by results of histopathological analysis., Conclusion: Corneal damage caused by HCl and NaOH may be modulated in vitro by PTK in this rabbit model., Clinical Relevance: After corneal chemical damage, 193-nm excimer laser PTK accelerates epithelial wound healing.

DAB(389)IL-2 (denileukin diftitox, ONTAK) is a cytokine-targeted fusion protein that delivers the catalytic domain of diphtheria toxin to lymphoma cells expressing the interleukin-2 receptor (IL-2R). In phase I and phase III studies of DAB(389)IL-2 in patients with cutaneous T-cell lymphoma (CTCL), non-Hodgkin's lymphoma, and Hodgkin's disease in which premedications were limited to diphenhydramine and acetaminophen, acute infusion-related hypersensitivity reactions occurred in 70% of patients and vascular leak syndrome (VLS) in 27%, resulting in discontinuation of therapy in 29% of patients. There was no correlation between the dose or half-life of DAB(389)IL-2 and the occurrence of hypersensitivity events or VLS. To explore whether steroid premedication would improve the tolerability of DAB(389)IL-2, we treated 15 patients with CTCL with either dexamethasone or prednisone prior to each dose of DAB(389)IL-2. The incidence of acute infusion events was significantly decreased, with only three patients experiencing acute infusion events (one grade 4) and only two patients developing clinically apparent VLS. Grade 3 skin rash occurred in two patients and moderately severe asthenia in nine patients. A significantly improved response rate of 60% was noted with the use of steroid premedication compared to prior studies in which steroids were prohibited. We conclude that steroid premedication significantly improves the tolerability of DAB(389)IL-2 without compromising the clinical response.

Background and Objective: Most of the in vitro work to characterize the effects of clinical laser surgery on corneal tissues has concentrated on the effects on stromal keratocytes and endothelium with little attention being paid to corneal epithelium. Our purpose is to describe the epithelial healing rates observed in freshly cultured rabbit corneas treated with phototherapeutic keratectomy (PTK)., Study Design/materials and Methods: Corneas were placed in a simple organ culture system, with media change every 2 days. A clinical excimer laser was used to perform a 6 mm diameter, 100 microm depth transepithelial PTK on 24 cultured rabbit corneas, 1 day after culture initiation. For each post-treatment day, one experimental and one control cornea were removed from culture and stained with fluorescein, photographed, and fixed for histology. Epithelial defect area was measured with digital imaging software and analyzed statistically to assess the re-epithelialization rate., Results: Control corneas, maintained in culture for 1-4 days, had no epithelial defects. Those corneas treated with PTK exhibited an immediate epithelial defect that slowly healed over 3 days. This was confirmed on histopathological analysis. A significant linear trend in re-epithelialization across the time points studied was found (F = 80.48, P = 0.0029). The slope of the linear regression model showed an estimate rate of re-epithelialization of -6.70 over the 3 days., Conclusion: We have described the development of a simple, whole organ, rabbit cornea culture model for re-epithelialization after PTK. Our rates of epithelial healing resemble those found in the literature in live rabbit models. Therefore, this model may possibly be used to monitor epithelial wound healing in different corneal diseases or injuries., (Copyright 2001 Wiley-Liss, Inc.)

Small cell carcinoma of the lung (SCLC) occurs most frequently in heavy smokers, yet exhibits a lesser predominance among men than other smoking-associated lung cancers. Incidence rates have increased more rapidly in women than men and at a faster rate among women than other cell types. To investigate the importance of smoking and other risk factors, a case-control study of SCLC in women was conducted. A total of 98 women with primary SCLC and 204 healthy controls, identified by random-digit dialing and frequency matched for age, completed telephone interviews. Data collected include demographics, medical history, family cancer history, residence history, and lifetime smoking habits. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated using logistic regression analysis. Risk for small cell carcinoma in women is strongly associated with current use of cigarettes. Ninety-seven of 98 cases had smoked cigarettes; 79% of cases were current smokers and 20% were former smokers at the time of diagnosis compared to 13% current and 34% former smokers among controls. The ORs associated with smoking are 108.7 (95% CI 14.8-801) for ever-use of cigarettes, 278.9 (95% CI 37.0-2102) for current smoking, and 31.5 (95% CI 4. 1-241) for former smoking. Risk increases steeply with pack-years of smoking and decreases with duration of smoking cessation. After adjusting for age, education, and lifetime smoking history, medical history of physician-diagnosed respiratory disease including chronic bronchitis, emphysema, pneumonia, tuberculosis, asthma, and hay fever is not associated with a significant increase in lung cancer risk. Employment in blue collar, service, or other high risk occupations is associated with a two to three-fold non-significant increase in risk for small cell carcinoma after adjusting for smoking.

Objective: Bilateral staple lung volume reduction surgery (LVRS) immediately improves pulmonary function and dyspnea symptoms in patients with advanced heterogeneous emphysema to a greater degree than do unilateral procedures. However, the long-term outcome after these surgical procedures needs to be critically evaluated. We compare 2-year survival of patients who underwent unilateral versus bilateral video-assisted LVRS in a large cohort treated by a single surgical group., Methods: The cases of all 260 patients who underwent video-assisted thoracoscopic stapled LVRS from April 1994 to March 1996 were analyzed to compare results after unilateral versus bilateral procedures. Overall survival was calculated by Kaplan-Meier methods; Cox proportional hazard methods were used to adjust for patient heterogeneity and baseline differences between groups., Results: Overall survival at 2 years was 86.4% (95% CI 80. 9%-91.8%) after bilateral LVRS versus 72.6% (95% CI 64.2%-81.2%) after unilateral LVRS (P =.001 for overall survival comparison). Improved survival after bilateral LVRS was seen among high- and low-risk subgroups as well. Average follow-up time was 28.5 months (range, 6 days to 46.6 months) for the bilateral LVRS group and 29.3 months (range, 6 days to 45.0 months) for the unilateral LVRS patients., Conclusions: Comparison of unilateral versus bilateral thoracoscopic LVRS procedures for the treatment of emphysema reveals that bilateral LVRS by video-assisted thoracoscopy resulted in better overall survival at 2-year follow-up than did unilateral LVRS. This survival study, together with other studies demonstrating improved lung function after bilateral LVRS, suggests that bilateral surgery appears to be the procedure of choice for patients undergoing LVRS for most eligible patients with severe heterogeneous emphysema.

Lung cancer incidence is now decreasing in US men. Although rates continue to increase in women, the rate of increase is declining. Most lung cancer in men and women is attributable to cigarette smoking. Histologic patterns are consistent with smoking trends for gender, race, and age. Trends in adenocarcinoma may be related to an increase in exposure to tobacco-specific nitrosamines from low-tar cigarettes. Other risk factors, including exposure to residential radon, occupational exposures, diet, and family history, have been shown to increase risk of lung cancer independent of cigarette smoking. Recent research in molecular epidemiology has greatly increased our understanding of the mechanism of lung carcinogenesis and the interactions between exposure to lung carcinogens (smoking, occupational exposures, radon), diet, and heritable variations in susceptibility.

Objective: Our intent was to refine the patient selection criteria for lung volume reduction surgery because various centers have different criteria and not all patients benefit from the procedure., Methods: Patient information, x-ray results, arterial blood gases, and plethysmographic pulmonary function tests in 154 consecutive patients who underwent bilateral thoracoscopic staple lung volume reduction surgery were compared with clinical outcome (change in forced expiratory volume in 1 second and dyspnea scale) with t tests and analysis of variance., Results: Three hundred thirty-three of 487 (69%) patients evaluated for lung volume reduction surgery were rejected for lack of heterogeneous emphysema (n = 212), medical contraindications (n = 88), hypercapnia (n = 20), uncontrolled anxiety or depression (n = 10), or pulmonary hypertension (n = 1). Two patients died during the evaluation process. When tested by analysis of variance, there was no difference in clinical outcome associated with preoperative forced expiratory volume in 1 second, residual volume, total lung capacity, single-breath diffusing, and arterial oxygen or carbon dioxide tension. All patients selected for the operation had a heterogeneous pattern of emphysema. The upper lobe heterogeneous pattern of emphysema on chest computed tomography and lung perfusion scan was strongly associated with improved outcome with a mean (95% confidence interval) improvement in forced expiratory volume in 1 second of 73.2% (63.3 to 83.1) for the upper lobe compared with a mean (95% confidence interval) improvement of 37.9% (22.9 to 53.0) for the lower lobe or diffuse pattern of emphysema., Conclusion: The most important selection criteria for lung volume reduction surgery is the presence of a bilateral upper lobe heterogeneous pattern of emphysema on chest computed tomography and lung perfusion scan. After patients have been selected on the basis of a heterogeneous pattern of emphysema, clinical factors and physiology are not associated with clinical outcome well enough to further refine patient selection criteria. These results do not support the arbitrary patient selection criteria for lung volume reduction surgery reported in the literature.

Background: Bronchioloalveolar lung carcinoma (BAC) is a unique type of lung cancer with distinguishing pathologic, biologic, epidemiologic, demographic, and perhaps etiologic features., Methods: The authors investigated and analyzed all of the cases of pathologically confirmed BAC seen at our institution in the hope of discovering new or confirming known features of this disease., Results: When cases of BAC expressed as a percentage of total lung cancers were analyzed in successive 5-year periods from 1955 to 1990, BAC rose from less than 5% to 24.0% (P < 0.001). Much of the increase in BAC occurred in women, as evidenced by a male-to-female ratio that wavered around unity. The mean age of BAC adenocarcinoma patients was 59.2 +/- 11.5 years, compared to 64.1 +/- 13.5 years for non-BAC adenocarcinoma (P < 0.05). BAC also contrasted with other forms of lung cancer by exhibiting a relatively high incidence of multifocality (25% versus 5%) (P < 0.001). There was an association between histologic subtype of BAC and pattern of pulmonic involvement. The mucinous subtype was more strongly associated with diffuse pulmonic involvement, and the sclerotic subtype was more strongly associated with multifocal involvement (P < 0.001). Furthermore, BAC cases exhibited a 20% incidence of dedifferentiation into patterns of poorly differentiated adenocarcinoma, a feature that was more associated with the mucinous and sclerotic subtypes (P < 0.05)., Conclusions: The emergence of BAC as a prominent type of lung cancer should stimulate new basic laboratory and case-control studies to elucidate further the natural history and etiology of this unique disease.

The importance of cigarette smoking as a risk factor for specific histologic types of lung cancer in men and women has been examined in a case-control analysis of data from the Cancer Surveillance Program of Orange County, a population-based registry. Smoking habits were abstracted from medical records for 1153 men and 833 women diagnosed with primary lung cancer in 1984-1986 and 1851 men and 1656 women aged 30 or older diagnosed with cancers not associated with smoking. Ninety-six percent of men and 89% of women with lung cancer were current or former cigarette smokers, as compared with 55% of men and 34% of women with other cancers. The age and ethnicity-adjusted odds ratios (OR) for ever-smoking were 19.7 for men and 15.0 for women. Men and women who smoked 2 or more packs per day experienced nearly equal risks. Comparison of the most common cell types showed that women smokers had equal or lower ORs for squamous-cell carcinoma and adenocarcinoma, but higher OR for small-cell carcinoma, as compared with men smokers. While the smoking-associated OR were equal for small-cell and squamous-cell carcinomas in men, the OR for women were significantly higher for small-cell carcinoma than for squamous-cell carcinoma.

The importance of smoking and other factors for lung cancer in women was investigated in a case-control study of women who had previously received a multiphasic health checkup at Northern California Kaiser Hospitals. Smoking and medical histories for 217 cases and matched controls were obtained from the multiphasic questionnaire. Odds ratios (ORs) and confidence intervals (CIs) associated with cigarette smoking were 35.1 (95% CI 4.8-256) for squamous and small cell and large cell carcinomas combined and 2.5 (95% CI 1.3-5.1) for adenocarcinoma. After adjusting for smoking, risk was increased in women with a family history of lung cancer (OR 1.9, 95% CI 0.7-5.6) and family history of any cancer (OR 1.8, 95% CI 1.0-3.2). A significant interaction existed between smoking and family history. Women with a history of bronchitis, pneumonia, or emphysema were at increased risk, whereas women with a history of asthma or hay fever experienced a significantly lower risk for lung cancer.

Using data from a population-based registry, the Cancer Surveillance Program of Orange County, we examined patterns in lung cancer incidence by histological type for 1984 in Orange County, CA. Age-adjusted incidence rates per 100,000 population are 66.4 for men and 34.1 for women. Compared to 1983 rates for whites from all SEER areas combined, Orange County incidence rates are lower for men but equal for women. Squamous cell carcinoma incidence shows a strong male predominance [male/female 3.4; 95% confidence interval = (2.6, 4.4)], whereas the male/female incidence ratios for adenocarcinoma [male/female 1.4; 95% confidence interval = (1.1, 1.8)] and small cell carcinoma [male/female = 1.8; 95% confidence interval = 1.3, 2.4)] are closer to unity. Smoking habits were abstracted from medical records for 79% of cases. Only 8% of lung cancer cases (5% of men and 12% of women) with known smoking habits are nonsmokers. Adenocarcinoma is the most common cell type among women smokers and nonsmokers, while squamous cell carcinoma predominates in both male smokers and nonsmokers. Cases who smoked were younger at diagnosis than nonsmokers (P less than 0.001) for each cell type. Despite a greater proportion of nonsmokers, cases with adenocarcinoma were younger at diagnosis compared to small cell carcinoma (P less than 0.01) and squamous cell carcinoma (P less than 0.05). The observed patterns of incidence rates by histological type are not entirely explained by current knowledge of the relationship between smoking and cell type.