Evaluation of the international Ki67 working group cut point recommendations for early breast cancer: comparison with 21-gene assay results in a large integrated health care system.

PURPOSE: The International Ki67 Working Group (IKWG) has developed training for immunohistochemistry (IHC) scoring reproducibility and recommends cut points of ≤ 5% and ≥ 30% for prognosis in ER+, HER2-, stage I/II breast cancer. We examined scoring reproducibility following IKWG training and evaluated these cut points for selecting patients for further testing with the 21-gene Recurrence Score (RS) assay. METHODS: We included 307 women aged 50+ years with node-negative, ER+PR+HER2- breast cancer and with available RS results. Slides from the diagnostic biopsy were stained for Ki67 and scored using digital image analysis (IA). Two IHC pathologists underwent IKWG training and visually scored slides, blinded to each other and IA readings. Interobserver reproducibility was examined using intraclass correlation (ICC) and Kappa statistics. RESULTS: Depending on reader, 8.8-16.0% of our cohort had Ki67 ≤ 5% and 11.4-22.5% had scores ≥ 30%. The ICC for Ki67 scores by the two pathologists was 0.82 (95% CI 0.78-0.85); it was 0.79 (95% CI 0.74-0.83) for pathologist 1 and IA and 0.76 (95% CI 0.71-0.80) for pathologist 2 and IA. For Ki67 scores ≤ 5%, the percentages with RS < 26 were 92.6%, 91.8%, and 90.9% for pathologist 1, pathologist 2, and IA, respectively. For Ki67 scores ≥ 30%, the percentages with RS ≥ 26 were 41.5%, 51.4%, and 27.5%, respectively. CONCLUSION: The IKWG's Ki67 training resulted in moderate to strong reproducibility across readers but cut points had only moderate overlap with RS cut points, especially for Ki67 ≥ 30% and RS ≥ 26; thus, their clinical utility for a 21-gene assay testing pathway remains unclear.

Topography of choriocapillaris flow deficit predicts development of neovascularization or atrophy in age-related macular degeneration.

PURPOSE: To evaluate the relationship between choriocapillaris (CC), flow deficits (FD), and structural optical coherence tomography (OCT) biomarkers, and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy (cRORA) or macular neovascularization (MNV). METHODS: Consecutive patients with iAMD were sequentially reviewed to define three equal sized groups: progressed to MNV, progressed to cRORA, or remained stable over 12 months of follow-up. Odds ratios for progression to cRORA and MNV were estimated by logistic regression for intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDDs), high central drusen volume, fellow eye with late AMD, and peripheral and central CC FD. RESULTS: Thirty iAMD eyes from 30 patients were enrolled into each group. The CC FD was greater in the peripheral sectors of the macula of eyes which progressed to cRORA compared to the other two groups (P < 0.0001). The central CC FD was also significantly impaired in eyes that progressed to cRORA or MNV compared to eyes that did not progress (P = 0.001 and P = 0.02, respectively). CC FD in the peripheral macula was significantly and independently associated with the development of cRORA, while CC FD in the center was significantly and independently associated with the development of MNV. CONCLUSIONS: While the CC is diffusely impaired throughout the macula in iAMD eyes that progress to cRORA, it is relatively spared in the more peripheral macula among eyes which progress to MNV. These differential findings may have implications for the pathophysiology of the different late-stage manifestations of AMD.

CHORIOCAPILLARIS FLOW DEFICITS AS A RISK FACTOR FOR PROGRESSION OF AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the association between choriocapillaris (CC) flow deficits and structural optical coherence tomography biomarkers and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy. METHODS: Retrospective analysis of consecutive patients with iAMD with a minimum follow-up of 12 months. Odds ratios of intraretinal hyperreflective foci, hyporeflective drusen cores, subretinal drusenoid deposits, the presence of drusen volume ≥0.03 mm3 within a central 3-mm circle, fellow eye with late stage of AMD, and CC flow deficits at baseline and months of follow-up were estimated from logistic regression. RESULTS: A total of 112 eyes with iAMD were included. Eyes that progressed were significantly more likely to show intraretinal hyperreflective foci, hyporeflective drusen cores, and drusen volume ≥0.03 mm3. The CC flow deficit was also significantly greater in eyes that developed complete retinal pigment epithelial and outer retinal atrophy. Intraretinal hyperreflective foci, hyporeflective drusen cores, drusen volume ≥0.03 mm3, and higher CC flow deficits were significantly and independently associated with the development of complete retinal pigment epithelial and outer retinal atrophy. CONCLUSION: The CC flow deficit was significantly greater in iAMD eyes that progressed to complete retinal pigment epithelial and outer retinal atrophy and remained an independent risk factor when structural optical coherence tomography biomarkers were considered. CC flow deficits may be useful for enhancing risk stratification and prognostication of patients with iAMD.

Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.

BACKGROUND: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown. METHODS: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer. RESULTS: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells. CONCLUSION: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers.

BACKGROUND: Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. MATERIALS AND METHODS: We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. RESULTS: A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. CONCLUSIONS: Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. The Oncologist 2017;22:152-157Implications for Practice: Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.

Precise Characterization and 3-Dimensional Reconstruction of the Autonomic Nerve Distribution of the Human Ureter.

PURPOSE: We sought to characterize and 3-dimensionally reconstruct the distribution of the autonomic innervation of the human ureter. MATERIALS AND METHODS: Three male and 3 female pairs of ureters were evaluated at 2 mm serial transverse sections along the entire length of the ureter. The location of nerve tissue was immunohistochemically identified using the neuronal marker, S100 protein. ImageJ software was used to calculate nerve count and density in the adventitia and smooth muscle. Blender® graphics software was used to create a 3-dimensional reconstruction of autonomic nerve distribution. RESULTS: Within the adventitia nerve density was highest in the mid and distal ureter (females 2.87 and 2.71 nerves per mm2, and males 1.68 and 1.69 nerves per mm2) relative to the proximal ureter (females and males 1.94 and 1.22 nerves per mm2, respectively, p >0.0005). Females had significantly higher nerve density throughout the adventitia, especially in the distal ureter (2.87 vs 1.68 nerves per mm2, p <0.0005). In smooth muscle the nerve density progressively increased from the proximal to the distal ureter (p >0.0005). Smooth muscle nerve density was similar in the 2 genders (p = 0.928). However, in females nerve density was significantly higher in the first 2 cm of the distal ureter relative to the second 2 cm (3.6 vs 1.5 nerves per mm2, p <0.001) but not in males (3.0 vs 2.1 nerves per mm2, p = 0.126). CONCLUSIONS: Nerve density was highly concentrated at the distal ureter in the adventitia and smooth muscle of the male and female human ureters. The female ureter had greater nerve density in the adventitia, and in smooth muscle nerves were significantly concentrated at the ureteral orifice and the ureteral tunnel.

Pediatric venous thromboembolism in relation to adults.

OBJECTIVE: This review was performed to analyze the current knowledge and controversies in the pathophysiology, diagnosis, treatment, and outcomes of pediatric venous thromboembolism (VTE) compared with adults. METHODS: Searches of the MEDLINE database and manual searches of the references of selected articles were performed to select reports for their relevance and quality of information on the similarities and differences in pathophysiology, diagnosis, and treatment of VTE in children and adults. RESULTS: Symptomatic VTE incidence is reported at a rate of 0.07 in every 10,000 children, which is significantly lower than the rate in adults. Pulmonary emboli in adolescents are rarely fatal, unlike in adults. VTE recurrence is also much lower in children. Young age has been shown to be protective of VTE, whereas central venous catheters are very important in pediatric venous thrombosis. The incidence of postthrombotic syndrome varies from 20% to 65%, with mild symptoms in most children. Cerebral and visceral vein thrombosis may lead to severe morbidity and death. Some factors of thrombophilia have a significant effect in the pediatric population; however, its overall significance is controversial. Most data on VTE treatment are extrapolated from studies in adults. Children with acute VTE should be treated with anticoagulation therapy. Treatment duration depends on the nature of the thrombosis and previous VTE events. CONCLUSIONS: There is a paucity of prospective randomized studies with data determining not only the effect of VTE but also the treatment options in children. Thrombophilia is a risk factor for pediatric VTE, but its significance has not been thoroughly investigated. Guidelines specific to children for antithrombotic therapy, prophylaxis, and optimal duration need re-evaluation and support by strong evidence.

Effects of Fucoidan Powder Combined with Mineral Trioxide Aggregate as a Direct Pulp-Capping Material.

The development of direct pulp-capping materials with favorable biological and structural properties is an important goal in restorative dentistry. Fucoidan is a sulfated, fucose-containing polysaccharide obtained from brown seaweed, with a wide range of applications; however, its use as a direct pulp-capping material has not been examined. This study aimed to evaluate the mechanical, physical, and biological effects of fucoidan combined with conventional mineral trioxide aggregate (MTA) for direct pulp capping. The capping materials were created using Portland cement (80 wt%) and zirconium oxide (20 wt%) as base components, compared with base components plus 5 wt% fucoidan (PZF5) and base components plus 10 wt% fucoidan (PZF10). The initial and final setting time, compressive strength, chemical components, cell viability, adhesion, migration, osteogenesis, and gene expression were analyzed. Fucoidan significantly reduced the initial and final setting time, regardless of quantity. However, the compressive strength was lower for PZF5. Sulfur levels increased with fucoidan. The biological activity improved, especially in the PZF5 group. Cell migration, Alizarin Red S staining, and alkaline phosphatase activity were upregulated in the PZF5 group. Fucoidan is a useful regenerative additive for conventional pulp-capping materials because it reduces the setting time and improves cell migration and osteogenic ability.

Cytotoxicity and Genotoxicity of Epoxy Resin-Based Root Canal Sealers before and after Setting Procedures.

Epoxy resin-based sealers are commonly used for successful endodontic treatment. This study aimed to evaluate the cytotoxicity and genotoxicity of epoxy resin-based sealers under unset and set conditions. Three epoxy resin-based sealers were used: Adseal, AH Plus, and Dia-Proseal. To test cytotoxicity, an agar overlay test and a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay were performed using unset and set sealers on L929 mouse fibroblasts. The genotoxicity test of the comet assay was performed using the same cell line. Extract dilutions in the culture media were used as test materials for the MTT and comet assays. The comet tail produced by the damaged DNA was calculated by image analyses. Statistical analyses were performed using one-way analysis of variance and Tukey's post hoc test. Unset sealers did not show defined decolorized areas. Hardened specimens of resin-based sealers showed circular discolored zones in the agar overlay test. Dia-Proseal was the least cytotoxic after hardening. These results were confirmed in the MTT assay. Cell viability was significantly higher in cells treated with hardened sealers in both groups than that in cells treated with freshly mixed sealers in the MTT assay. Unset AH Plus® and Dia-Proseal™ significantly increased cell viability with decreasing dilution. Adseal™ was the least cytotoxic. Freshly mixed Adseal™ was more genotoxic when freshly mixed than when set. Unset epoxy resin-based sealers were generally more cytotoxic and genotoxic than set materials. Cytotoxicity does not always match the genotoxicity results; therefore, various test tools are required to test toxicity. It is necessary to properly evaluate the toxic effects to establish a biocompatibility test that mimics clinical conditions.

Mitotic counts in one high power field in breast core biopsies is equivalent to counts in 10 high power fields.

Mitotic rate is an important prognostic predictor in invasive breast carcinoma. Current guidelines recommend counting mitoses from 10 contiguous high power fields (HPFs) in the core biopsy. We propose a method to score mitotic activity in 1 HPF at the most mitotically active area of the tumour edge, or the interface between invasive tumour and benign breast tissue. We propose a score of 1, 2, or 3, corresponding to ≤1, 2, or ≥3 mitoses in 1 HPF, respectively. A total of 141 breast core biopsies with corresponding surgical excisions were blindly examined. We counted the number of mitotic figures in 1 HPF and in 10 contiguous HPFs in the core biopsy and compared with the mitotic count from 10 contiguous HPFs in the excision which is considered the gold standard. Concordance rates and interobserver agreement rates were calculated. The concordance rate was 82.3%, 78.7% and 82.3% between 1 HPF versus 10 HPFs in the core biopsy, 1 HPF in the core biopsy versus 10 HPFs in the excision and 10 HPFs in the core biopsy vs 10 HPFs in the excision, respectively. In the core biopsy, all three investigators agreed in 73.8% and 83.7% of the cases using the 1 HPF method and the 10 HPFs method, respectively; in the excision specimen, agreement was reached in 82.3% of the cases. The 1 HPF method showed similar concordance rate and interobserver agreement compared to the conventional method in the prediction of the mitotic score in the excision in all score groups. When stratified by mitotic score, the 1 HPF method predicted superior correlation with excision in the score 1 group than the 10 HPFs method, but not in the score 2 or 3 groups. From these findings we conclude that the proposed 1 HPF method can be used in clinical practice to grade invasive breast carcinomas in core biopsies, with the possibility of being utilised in small biopsies with less than 10 HPFs of invasive carcinoma.

Evaluation of Tensile Bond Strength between Self-Adhesive Resin Cement and Surface-Pretreated Zirconia.

The tensile bond strength between zirconia subjected to different surface-pretreatment methods and methacryloyloxydecyl-dihydrogen-phosphate (MDP)-containing self-adhesive resin cement was evaluated herein. Eighty-eight cylindrical zirconia specimens were randomly divided into the following four groups based on the pretreatment method: (1) no treatment, (2) air abrasion, (3) HNO3/HF etching, and (4) zirconia-nanoparticle coating. The tensile bond strength of the zirconia−resin-cement complexes was investigated. One-way ANOVA and post hoc tests were performed at a 95% significance level, and the Weibull modulus was calculated. Fracture patterns were visualized by SEM. The surface roughness of the specimens without resin bonding was evaluated by AFM. The tensile bond strength of the specimens decreased as follows: Groups 3 > 4 > 2 > 1 (28.2 ± 6.6, 26.1 ± 5.7, 16.6 ± 3.3, and 13.9 ± 3.0 MPa, respectively). Groups 3 and 4 had significantly higher tensile bond strengths (p < 0.05) and lower fracture probabilities than those of Groups 1 and 2. They also showed both mixed failure and resin-cement cohesive failure, whereas Groups 1 and 2 showed mixed failure exclusively. The zirconia−resin tensile bond was stronger after HNO3/HF etching or ZrO2-nanoparticle coating than after air abrasion or no treatment. The estimated surface roughness decreased as follows: Groups 3 > 4 > 2 > 1. The combination of zirconia pretreated with HNO3/HF etching or ZrO2-nanoparticle coating and an MDP-containing self-adhesive resin cement can increase the clinical longevity of zirconia restorations by preventing their decementation.

Visual and anatomical outcomes associated with treat-and-extend administration of intravitreal aflibercept for neovascular age-related macular degeneration.

PURPOSE: To investigate the visual and anatomical outcomes associated with treat-and-extend (TAE) regimen of intravitreal (IVT) aflibercept in eyes with treatment naïve neovascular age-related macular degeneration (nvAMD). METHODS: A retrospective chart review of eyes that underwent IVT aflibercept injections for nvAMD between May 2014 and March 2018 was performed. The primary outcome was the change in best corrected visual acuity (BCVA) at 12 months. Secondary outcomes included the change in central retinal thickness (CRT), subretinal fluid (SRF) and intraretinal fluid (IRF). RESULTS: Data from 213 eyes of 213 patients (138 female, 65%) met the inclusion criteria. The mean (SD) age of the patients was 80.4 (± 9.2) years. The mean baseline BCVA (0.92 ± 0.50 logMAR, improved by 0.20 (± 0.40) logMAR units at 12 months (p < 0.001). Seventy-two (34%) eyes gained ≥ 0.3 logMAR and 47 (22%) eyes achieved BCVA ≤ 0.3 logMAR at 12 months. Baseline BCVA, patient age, and the number of aflibercept injections received were predictors of the change in BCVA at 12 months. Mean CRT improved from 347 (± 117) µm at baseline to 246 (± 55) µm at 12 months (p < 0.001). The percentage of eyes with SRF and IRF on SD-OCT declined from 63 to 21% and from 60 to 26% at 12 months, respectively. CONCLUSION: A TAE regimen of IVT aflibercept in treatment naïve nvAMD is associated with good visual and anatomical outcomes in routine clinical practice. Resolution of exudation occurred in about half of nvAMD cases at 12 months. Individualized administration of IVT aflibercept may reduce injection burden.

Trophic factor-induced intracellular calcium oscillations are required for the expression of postsynaptic acetylcholine receptors during synapse formation between Lymnaea neurons.

Nervous system functions in all animals rely upon synaptic connectivity that is established during early development. Whereas cell-cell signaling plays a critical role in establishing synapse specificity, the involvement of extrinsic growth factors cannot, however, be undermined. We have previously demonstrated that trophic factors are required for excitatory but not inhibitory synapse formation between Lymnaea neurons. Moreover, in the absence of trophic factors, neurons from a number of species establish inappropriate inhibitory synapses, which can, however, be corrected by the addition of trophic factors. The precise site of trophic factor actions (presynaptic versus postsynaptic) and the underlying mechanisms remain, however, undefined. Here, we provide the first direct evidence that the trophic factor-mediated excitatory synapse formation involves activity-induced calcium (Ca(2+)) oscillations in the postsynaptic left pedal dorsal 1 (LPeD1) but not the presynaptic visceral dorsal 4 (VD4, cholinergic) neuron. These oscillations involved Ca(2+) influx through voltage-gated Ca(2+) channels and required receptor tyrosine kinase activity which was essential for the expression of excitatory, nicotinic acetylcholine receptors in the postsynaptic cell during synapse formation. We also demonstrate that selectively blocking the electrical activity presynaptically did not perturb trophic factor-induced synapse formation between the paired cells, whereas hyperpolarizing the postsynaptic cell prevented appropriate synaptogenesis between VD4 and LPeD1 cells. Together, our data underscore the importance of extrinsic trophic factors in regulating the electrical activity of the postsynaptic but not the presynaptic cell and that the resulting Ca(2+) oscillations are essential for the expression of postsynaptic receptors during specific synapse formation.

A novel approach reveals temporal patterns of synaptogenesis between the isolated growth cones of Lymnaea neurons.

All brain functions, ranging from motor behaviour to cognition, depend on precise developmental patterns of synapse formation between the growth cones of both pre- and postsynaptic neurons. While the molecular evidence for the presence of 'pre-assembled' elements of synaptic machinery prior to physical contact is beginning to emerge, the precise timing of functional synaptogenesis between the growth cones has not yet been defined. Moreover, it is unclear whether an initial assembly of various synaptic molecules located at the extrasomal regions (e.g. growth cones) can indeed result in fully mature and consolidated synapses in the absence of somata signalling. Such evidence is difficult to obtain both in vivo and in vitro because the extrasomal sites are often challenging, if not impossible, to access for electrophysiological analysis. Here we demonstrate a novel approach to precisely define various steps underlying synapse formation between the isolated growth cones of individually identifiable pre- and postsynaptic neurons from the mollusc Lymnaea stagnalis. We show for the first time that isolated growth cones transformed into 'growth balls' have an innate propensity to develop specific and multiple synapses within minutes of physical contact. We also demonstrate that a prior 'synaptic history' primes the presynaptic growth ball to form synapses quicker with subsequent partners. This is the first demonstration that isolated Lymnaea growth cones have the necessary machinery to form functional synapses.

Conventional prostatic adenocarcinoma arising in a multilocular prostatic cystadenoma.

Multilocular prostatic cystadenoma is a rare benign neoplasm located between the bladder and the rectum. These are prostatic tissue and have been shown to harbor high-grade intraepithelial neoplasia and likely susceptible to the same disease processes seen in the prostate gland. We report the first case of conventional prostatic adenocarcinoma involving a multilocular cystadenoma. Distinction from cystadenocarcinoma is also made.

Non-invasive papillary urothelial neoplasms: the 2004 WHO/ISUP classification system.

The classification and grading of papillary urothelial neoplasms has been a long-standing subject of controversy. Previously, numerous diverse grading schemes for bladder tumor, including the 1973 World Health Organization (WHO) classification, existed whereby one of the major limitations was poor inter-observer reproducibility among pathologists. The WHO/International Society of Urological Pathology (ISUP) consensus classification system of urothelial neoplasms of the urinary bladder was developed in 1998 and was revised most recently in 2003 (published in 2004). Importantly, the current classification system provides detailed histological criteria for papillary urothelial lesions and allows for designation of a lesion (papillary urothelial neoplasm of low malignant potential) with a negligible risk of progression. Thus, the latest system is designed to be a universally acceptable one for bladder tumors that not only could be effectively used by pathologists, urologists, and oncologists, but also stratifies the tumors into prognostically significant categories. This article outlines the 2004 WHO/ISUP classification system regarding the specific histological criteria for non-invasive papillary urothelial neoplasms and the clinical significance of each category.

Complementary angiographic and autofluorescence findings in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a systemic disease with characteristic findings on fundus examination. The fundus findings may be difficult to detect with ophthalmoscopy. A case report is described as follows. A PXE patient had subtle retinal findings on fundoscopy that were more prominently seen using a combination of both fundus autofluorescence (FAF) imaging and indocyanine green (ICG) angiography. The fundus features visualized using each of these two modalities appeared different from each other. FAF imaging and ICG angiography may be able to more prominently detect pathology at the level of the retinal pigment epithelium and Bruch's membrane, respectively. The use of these imaging modalities together may be complementary and useful in the evaluation of patients with PXE.

Radical prostatectomy findings in patients in whom active surveillance of prostate cancer fails.

PURPOSE: Little data are available on radical prostatectomy findings in men who experience disease progression following active surveillance. MATERIALS AND METHODS: A total of 470 men in our active surveillance program underwent annual repeat needle biopsies to look for progression defined as any Gleason pattern grade 4/5, more than 50% cancer on any core or cancer in more than 2 cores. Slides were available for review in 48 of 51 radical prostatectomies with progression. RESULTS: The average time between the first prostate biopsy and radical prostatectomy was 29.5 months (range 13 to 70), with 44% and 75% of the patients showing progression by the second and third biopsy, respectively. There were 31 (65%) organ confined cases, of which 25 (52%) were Gleason score 6. Of 48 cases 17 (35%) had extraprostatic extension, 3 had seminal vesicle/lymph node involvement and 7 (15%) had positive margins. Mean total tumor volume was 1.3 cm(3) (range 0.02 to 10.8). Of the 48 tumors 13 (27%) were potentially clinically insignificant (organ confined, dominant nodule less than 0.5 cm(3), no Gleason pattern 4/5) and 19% (5 of 26) of the radical prostatectomies with a dominant tumor nodule less than 0.5 cm(3) demonstrated extraprostatic extension, 4 with Gleason pattern 4. All 10 tumors with a dominant nodule greater than 1 cm(3) were located predominantly anteriorly. CONCLUSIONS: Most progression after active surveillance occurs 1 to 2 years after diagnosis suggesting undersampling of more aggressive tumor rather than progression of indolent tumor. Even with progression most tumors have favorable pathology (27% potentially insignificant). A small percentage of men have advanced stage disease (pT3b or N1). The anterior region should be sampled in men on active surveillance.

Genetics of age-related macular degeneration.

PURPOSE OF REVIEW: Age-related macular degeneration (AMD) was until recently viewed as a part of the normal aging process; however, we are increasingly aware that genetic factors play a much greater role than previously suspected. This review will provide an up-to-date snapshot of the genetics of AMD to help guide our thoughts about its causes and the risk for family members. RECENT FINDINGS: Epidemiological research and basic bench research have identified pathways of oxidative stress, lipid metabolism and inflammation as playing causative roles in the pathogenesis of AMD. Emerging research is focusing on the biology of the retinal pigment epithelium as secreting pro and anti-inflammatory mediators in the eye. Antivascular endothelial growth factor therapy has dramatically improved the prognosis for neovascular or wet AMD patients. Nutritional supplementation with antioxidants and omega-3 fatty acids has provided treatment options for patients with atrophic or dry AMD. We should expect that some of the response to therapy might be genetically determined. SUMMARY: First-degree relatives of patients with AMD tend to have a higher risk of AMD. Recognizing an inherent genetic risk of AMD in these patients will improve their management and potentially help prevent blindness.