Evaluation of the urinary bladder using three-dimensional CT cinematic rendering.

Three-dimensional (3D) visualizations of volumetric data from computed tomography (CT) acquisitions can be important adjuncts to interpretation of two-dimensional (2D) reconstructions. Recently, the 3D technique known as cinematic rendering (CR) was introduced, allowing photorealistic images to be created from standard CT acquisitions. CR methodology is under increasing investigation for use in the display of regions of complex anatomy and as a tool for education and preoperative planning. In this article, we will illustrate the potential utility of CR for evaluating the urinary bladder and associated pathology. The urinary bladder is susceptible to a multitude of neoplastic and inflammatory conditions and their sequelae. The intrinsic properties of CR may prove useful for the display of subtle mucosal/luminal irregularities, the simultaneous display of soft tissue detail with high-resolution maps of associated tumor neovasculature, and the improved display of spatial relationships to aid pre-procedural planning. Further refinement of presets for CR image creation and prospective evaluation of urinary bladder CR in real-world settings will be important for widespread clinical adoption.

Focal therapy for localized prostate cancer in the era of routine multi-parametric MRI.

BACKGROUND: Prostate cancer focal therapy aims to minimize the side-effects of whole gland treatments, such as radical prostatectomy and radiotherapy without compromising oncological efficacy. However, concerns exist regarding the multifocal nature of prostate cancer and the lack of long-term oncological data for this form of treatment. In recent years, the routine adoption of multi-parametric magnetic resonance imaging (mpMRI) of the prostate has improved our ability to select candidates for focal therapy and to accurately deliver this form of prostate cancer treatment. METHODS: We performed a review of the literature to provide a summary of the oncological and functional outcomes of men receiving primary prostate focal therapy. Furthermore, we discuss the impact of the routine implementation of mpMRI as part of the initial prostate cancer diagnostic pathway on the selection of candidates and delivery of focal therapy. Finally, we summarize knowledge gaps in the field and highlight active clinical trials in this arena. RESULTS: Primary focal therapy involves the application of one of a number of energies that ablate tissue, such as cryotherapy and high intensity focused ultrasound (HIFU). Success is principally dependent on highly accurate patient selection and disease localization underpinned in large part by the routine integration of pre-biopsy mpMRI. Prospective medium-term follow-up data for primary HIFU and cryotherapy for men with intermediate-risk disease have shown acceptable cancer control with low risk of side effects and complications. Additional research is needed to clearly define an appropriate follow-up approach and to guide the management of in- and out-of-field recurrences. Multiple comparative trials with randomization against standard care are currently underway in men with intermediate- and high-risk prostate cancer. CONCLUSION: The widespread adoption of prostate mpMRI has led to improved disease localization, enabling the performance of focal therapy as a viable treatment strategy for men with low volume intermediate-risk prostate cancer.

Retinal Structure in Pre-Clinical Age-Related Macular Degeneration.

PURPOSE: To determine, if there are identifiable retinal structural changes associated with genetic risk for age-related macular degeneration (AMD). MATERIALS AND METHODS: Seventy-three subjects (range 51.5 to 68.9 years) participated in this prospective study. Subjects were recruited based on the presence of a family history of AMD in one or both parents. All participants underwent a complete ophthalmic exam and imagery for staging of disease severity and genetic testing to assess genetic risk for AMD development. Optical coherence tomography (OCT) imaging was performed on all participants. Semi-automated retinal layer segmentation was performed to assess retinal structural changes. RESULTS: Of 73 subjects, 47 subjects had normal appearing retina with no evidence of drusen or other changes consistent with AMD, 16 subjects were classified as early AMD, and 13 were designated as intermediate AMD. Retinal volume measures of total retina, outer retina, outer nuclear layer and the retinal pigment epithelium, were not related to AMD classification, genetic risk scores, or age. The thickness of the outer retina showed statistically significant thickening in the foveal region in only the intermediate AMD group and a statistically significant thickening of the RPE in early and intermediate AMD groups in the central retina. CONCLUSION: No consistent changes were observed in retinal structure at multiple locations that are associated with pre-clinical AMD, based on AMD genetic risk or with aging within the age range of our cohort.

PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies. METHODS: A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa. RESULTS: Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease. CONCLUSIONS: However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients.

Active surveillance for low-risk prostate cancer: knowledge, acceptance and practice among urologists.

BACKGROUND: This study aimed to survey urologists regarding their knowledge, acceptance and practice of active surveillance (AS) for low-risk prostate cancer. METHODS: An email-based survey was distributed to 4987 urologists. Respondents were surveyed regarding their knowledge and acceptance of AS. Those who felt AS was a reasonable strategy were asked their opinions on the criteria for AS enrollment and the details of their practice of AS. Respondents who felt AS was not a reasonable alternative were queried as to the reasons why. RESULTS: A total of 425 (9%) urologists successfully completed the survey and 387 (91%) were both familiar with AS and aware that AS differed from watchful waiting. Of this latter group, 370 (96%) respondents felt AS was a reasonable management strategy, 95% of whom manage patients with this approach. A minority of respondents (6%) felt that patients with a PSA>10 ng ml(-1) were eligible for AS. Further, most participants (74%) felt that patients required a Gleason score ≤6. There was little agreement on the timing of follow-up biopsies. Respondents who objected to AS were most commonly concerned with missing an opportunity for curative treatment (76%) and the risk of tumor undergrading (65%). CONCLUSIONS: The majority of participants were knowledgeable and accepting of AS. Respondents were in relative agreement regarding the PSA and Gleason score criteria for AS enrollment. In contrast, there was a lack of agreement on the timing of follow-up biopsies. In the future, comparative studies are required to determine the optimal enrollment criteria and follow-up protocol for patients managed with AS.

Pelvis and total hip arthroplasty acetabular component orientations in sitting and standing positions: measurements reproductibility with EOS imaging system versus conventional radiographies.

INTRODUCTION: The literature has recently underlined the interest of pelvic and acetabular component orientation measurements in the standing and sitting position. Radiographic follow-up of total hip arthroplasty (THA) is based on standard AP and lateral X-rays. The use of EOS™ 2D imaging system reduces patient's radiation exposure compared to conventional X-rays. However, using this system, the validity and reproducibility of angular measurements, have not been studied yet for the measurement of pelvic and acetabular parameters in patients with THA. HYPOTHESIS: The EOS™ 2D imaging system offers similar advantages to conventional X-rays in the measurement of pelvic and acetabular orientation parameters which are commonly used. PATIENTS AND METHOD: Five angular parameters characterizing pelvic tilt and acetabular cup orientation were determined using the same digital measurement Imagika™ software based on two series of standard X-rays and EOS™ 2D images acquired in both standing and sitting positions. Radiographs from 50 patients with unilateral THA were measured three times by two observers. Intra- and interobserver reproducibility using each method was independently studied then paired comparison was performed. RESULTS: The ICC and Spearman rank correlation coefficient demonstrated an excellent EOS/conventional X-ray correlation. According to the parameters, the mean difference between these two imaging modalities ranged from 0.30° to 3.43° (P<0.05). The intra- and interobserver variability ranged from ± 2.97° to ± 6.46° using the EOS™ imaging system and from ± 4.26° to ± 10.22° using conventional X-rays (P<0.05). DISCUSSION: The EOS™ 2D imaging system may replace conventional X-rays in the assessment and monitoring of pelvic and acetabular cup orientation in THA. LEVEL OF EVIDENCE: Level III. Prospective diagnostic study.

Technical modification for laparoscopic donor nephrectomy to minimize testicular pain: a complication with significant morbidity.

The laparoscopic approach to donor nephrectomy is becoming increasingly common. While it is felt that the recovery from laparoscopic nephrectomy is quicker and less painful, a number of complications have been reported. A rarely reported on complication in the literature with significant morbidity is ipsilateral orchalgia. From 1998 to 2008, 257 hand-assisted laparoscopic donor nephrectomies were performed at our institution. Eight of 129 (6.2%) men complained of de novo ipsilateral orchalgia postoperatively. The average duration of pain was 402 days. Patients reported significant morbidity related to this complication. None, however, required further treatment. Three patients reported that they would reconsider organ donation as a result of testicular pain. Our technique originally included dissection and ligation of the gonadal vein en bloc with the ureter at the level of the left common iliac artery. Since recognizing this complication, we have adopted a gonadal vein sparing approach so as not to disturb the vessel below its point of ligation at the renal vein. To date, 50 patients have undergone the modified technique without experiencing orchalgia. In conclusion, ipsilateral testicular pan is a relatively frequent complication of laparoscopic donor nephrectomy and may be a source of significant morbidity. Using a modified surgical technique, this complication can be reduced or eradicated.

Analysis of autofluorescent retinal images and measurement of atrophic lesion growth in Stargardt disease.

Current retinal imaging techniques using scanning laser ophthalmoscopy (SLO) provide a powerful mechanism for characterizing the topographical distribution of lipofuscin fluorophores and atrophic lesions (ALs) in retinal disease. In this paper we describe a novel Edge-Flow-Driven Variational Image Segmentation analysis to measure and evaluate progressive change in the area of ALs as well as regions of hyperfluorescence (HF). The algorithm is embedded in a series of almost completely automated image processing steps that allow rapid comparison of serial images. The sensitivity of the methodology to detect change was evaluated by measuring progression of AF lesion size in a cohort of Stargardt Macular Dystrophy (STGD) patients. Fifty-two STGD subjects (mean age = 41.0 +/- 16.6 years, range 9-78 yrs) at varying stages of disease participated in this prospective study. Twenty-four of the 52 subjects presented with atrophic lesions in one or both eyes on first evaluation. For this subgroup of subjects, the mean (+/-1 sd) follow-up time was 2.92 (+0.26) years (range 0.57-3.26 years) and the mean (+/-1 sd) rate of change was found to be approximately 0.94 (+/-0.87) mm(2)/year (range 0.2-2.13 mm(2)/yr). With this methodology, progressive enlargement of AL area was detectable in as little as one year, while regions of HF generally decreased, although there was considerable variability in the appearnce of HF, presumably reflecting the combined effects of the creation or expansion of lipofuscin deposits and resorption and loss associated with retinal cell death. Our findings suggest that this methodology is sufficiently sensitive to detect change and provides a clinically relevant tool to monitor progression not only with regards to natural history, but also to evaluate the efficacy of potential therapeutic interventions in STGD. Finally, we evaluated the association between AL area and measures of rod- and cone-mediated retinal function, as assessed with electroretinography (ERG). In general, the larger the AL, the poorer the ERG response, with a greater impact of lesion size on cone- rather than rod-mediated retinal function, a finding that was expected on the basis of the location and size of the AL and the distribution of rod- and cone-photoreceptors.

Hip spine relationships: application to total hip arthroplasty.

Lumbo-sacral orientation in the sagittal plane is of utmost importance, as it plays a critical role in the function of the spine and the hip joints. Equilibrium of the trunk influences the tridimensional orientation of the acetabulum and the functional range of motion of the hips. Each patient is characterized by a "morphological" parameter named incidence angle; its sagittal balance is the consequence of a postural adaptation for other functional parameters (pelvic tilt, sacral slope, lumbar lordosis, acetabular sagittal tilt, functional anteversion). Understanding variations of the sacral slope on lateral pelvic X-rays is essential for planning total hip arthroplasty and identifying patients at risk of impingement, as lumbosacral posture influences functional anteversion of the acetabulum. Posterior pelvic version as in sitting position (sacral slope decrease) is linked to the increase of the functional acetabular anteversion. Anterior pelvic version as in standing position (sacral slope increase) is linked to the decrease of the functional acetabular anteversion.

Variations of caudal, central, and cranial acetabular anteversion according to the tilt of the pelvis.

Variations of acetabular anteversion measured at the level of the diameter of the acetabulum according to the tilt of the pelvis are known. But the values of this anteversion at other levels of the acetabulum, near the roof or near the obturator foramen, are unknown. Attracted by the very changeable morphology of the acetabular cover, we studied the caudal, central, and cranial acetabular anteversion of 12 pelvises in four positions of dorsal-ventral inclination. The caudal, central, and cranial acetabular anteversion diminished with the ventral tilt of the pelvis. The anteversions also diminished from the caudal part of the acetabulum to the cranial part, whatever the inclination of the pelvis. These notions represent a reference that, once completed with clinical studies of healthy volunteers and patients presenting an anomaly of the acetabulum cover, will enable researchers to define threshold values of normal and pathological conditions.

Hip-spine relationship: a radio-anatomical study for optimization in acetabular cup positioning.

The criteria for acetabular cup positioning during total hip replacement are a matter of considerable discussion, particularly with regards to the optimal degree of anteversion. "Anatomical anteversion" is defined in the transverse plane, and "surgical anteversion" in the sagittal plane. Computed tomography measurements of anteversion are characteristic of a given transverse section plane and fail to take into account the position of the pelvis. We suggest a simple method for evaluating acetabular cup position in both the transverse and sagittal planes during standing and sitting. By shedding new light on the relationships between the pelvis and the spine, this method may help to understand some cases of impingement, instability or abnormal wear.

A new genetic locus for X linked progressive cone-rod dystrophy.

X linked progressive cone-rod dystrophy (COD) is a retinal disease primarily affecting the cone photoreceptors. The disease is genetically heterogeneous and two loci, COD1 (Xp21.1-11.4) and COD2 (Xq27.2-28), have been previously identified. COD1 was recently shown to be caused by mutations in RPGR exon ORF15 (Xp21.1), the gene that is also responsible for RP3 type retinitis pigmentosa. In this study, we performed a linkage study to map the disease gene in a large Finnish family with X linked cone-rod dystrophy, using a panel of 39 X chromosomal markers. Several recombinations between the disease gene and markers in the Xp21.1-p11.4 region have excluded COD1 as a candidate locus in this family. Consistent with the linkage results, no mutation was detected by direct PCR sequencing of the coding region of RPGR, including exon ORF15. The COD2 locus has been also excluded as the site of the gene on the basis of negative lod score values obtained for COD2 linked markers. The disease causing gene of the studied COD family has been localised between the markers DXS10042 and DXS8060 on Xp11.4-q13.1. Positive pairwise lod scores >3 were obtained for markers DXS993, MAOB, DXS1055, and DXS1194. Since this locus is distinct from the previously identified two loci, COD1 and COD2, our results establish a new third genetic locus for X linked progressive cone-rod dystrophy and further expands our knowledge about the genetic heterogeneity underlying this disease entity.

Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions.

PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (S(all) statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or S(all) scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

Identification, genomic structure, and screening of the vacuolar proton-ATPase membrane sector-associated protein M8-9 gene within the COD1 critical region (Xp11.4).

PURPOSE: Our goal is to identify the gene responsible for X-linked cone-rod dystrophy (COD1) that has been localized to a limited region of Xp11.4. METHODS: A complete physical contig of the COD1 region was partially sequenced and subjected to BLAST searches to identify homologies with GenBank ESTs. ESTs were analyzed for overlapping or related cDNA sequences and retinal expression by PCR screening of multiple human retina cDNA libraries. RACE was performed to complete the missing 5' end of the transcripts. Transcripts were compared with genomic sequences to specify intron-exon boundaries. Genomic DNAs from COD1-affected males from 3 families were screened for mutations using direct PCR sequencing of the exons. RESULTS: The vacuolar proton-ATPase membrane sector-associated protein M8-9 (APT6M8-9) gene was identified within our critical region. We confirmed its retinal expression and its genomic location in our physical contig. Eight exons (with flanking intronic sequences) were characterized from partial cDNA sequence and genomic sequence data. An additional 5' end exon was identified using RACE. No mutations were found in the COD1-affected males. CONCLUSIONS: The combination of disease mapping and information from the Human Genome project has enabled us to identify candidate genes within the COD1 region, including APT6M8-9 gene. We found no evidence that this gene is responsible for COD1 in our families, but it may be an important candidate for other diseases that have been mapped to this region of the X chromosome.

Concentric retinitis pigmentosa: clinicopathologic correlations.

Progressive concentric (centripetal) loss of vision is one pattern of visual field loss in retinitis pigmentosa. This study provides the first clinicopathologic correlations for this form of retinitis pigmentosa. A family with autosomal dominant concentric retinitis pigmentosa was examined clinically and with visual function tests. A post-mortem eye of an affected 94 year old family member was processed for histopathology and immunocytochemistry with retinal cell specific antibodies. Unrelated simplex/multiplex patients with concentric retinitis pigmentosa were also examined. Affected family members of the eye donor and patients from the other families had prominent peripheral pigmentary retinopathy with more normal appearing central retina, good visual acuity, concentric field loss, normal or near normal rod and cone sensitivity within the preserved visual field, and reduced rod and cone electroretinograms. The eye donor, at age 90, had good acuity and function in a central island. Grossly, the central region of the donor retina appeared thinned but otherwise normal, while the far periphery contained heavy bone spicule pigment. Microscopically the central retina showed photoreceptor outer segment shortening and some photoreceptor cell loss. The mid periphery had a sharp line of demarcation where more central photoreceptors were near normal except for very short outer segments and peripheral photoreceptors were absent. Rods and cones showed abrupt loss of outer segments and cell death at this interface. It is concluded that concentric retinitis pigmentosa is a rare but recognizable phenotype with slowly progressive photoreceptor death from the far periphery toward the central retina. The disease is retina-wide but shows regional variation in severity of degeneration; photoreceptor death is severe in the peripheral retina with an abrupt edge between viable and degenerate photoreceptors. Peripheral to central gradients of unknown retinal molecule(s) may be defective or modify photoreceptor degeneration in concentric retinitis pigmentosa.

Genomic structure of the mouse Ap3b1 gene in normal and pearl mice.

The mouse hypopigmentation mutant pearl is an established model for Hermansky-Pudlak syndrome (HPS), a genetically heterogenous disease with misregulation of the biogenesis/function of melanosomes, lysosomes, and platelet dense granules. The pearl (Ap3b1) gene encodes the beta3A subunit of the AP-3 adaptor complex, which regulates vesicular trafficking. The genomic structure of the normal Ap3b1 gene includes 25 introns and a putative promoter sequence. The original pearl (pe) mutation, which has an unusually high reversion rate on certain strain backgrounds, has been postulated to be caused by insertion of a transposable element. Indeed, the mutation contains a 215-bp partial mouse transposon at the junction point of a large tandem genomic duplication of 6 exons and associated introns. At the cDNA level, three pearl mutations (pearl, pearl-8J, and pearl-9J) are caused by deletions or duplications of a complete exon(s).

Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I.

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.