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PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1).METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs).RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., similar to 30% of the c.769-784C>T allele alone).CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.

Background and aim Since individuals in the early stages of liver cirrhosis are typically asymptomatic, the prevalence of liver cirrhosis may be underestimated. Liver cirrhosis has a significant morbidity and mortality rate, with 1.03 million deaths worldwide each year. For end-stage liver disease, liver transplantation is a potential therapeutic option. The goal of our research was to examine the current trend in liver transplants using data from a national database. Methods Using the International Classification of Diseases (ICD)-9 codes, we identified individuals who had a liver transplant during the index hospital admission in the Nationwide Inpatient Sample from 2007 to 2011. This national sample of patients is from the United States. We looked at the yearly trend in liver transplants and related outcomes, such as duration of hospitalization (DOH), hospital expenses, and mortality in the hospital. In order to find determinants of mortality, we used a multivariate analysis. Results There were 25,331 patients hospitalized (weighted for national estimate). Between 2007 and 2011, the number of transplants grew by 1.2%. The majority of transplant recipients were Caucasian (57%), with an average age of 54 years, had a private healthcare plan (53%), and had average earnings in the upper quartile by zip code (26%). Patients with a higher Charlson Comorbidity Index (79% had a score of four) were more likely to be admitted to a southern hospital (33%), an academic hospital (>99%), and a large capacity hospital (90%). Seventy percent of liver transplant recipients received cadaver donors. Hepatitis C was the most prevalent reason for transplant (30%), followed by hepatocellular carcinoma (HCC) (29%) and alcoholic liver disease (25%). In 2011, compared to 2007, there was an upward rise in fatality (from 3.8% to 5.1%), average hospital expenditures (from $335,504 to $498,369), and DOH (from 17.4 to 22.7 days). The cost of hospitalization was two billion dollars per year. The independent variables related to an increased mortality on multivariate analysis were African American race (OR: 2.0, 95%, CI: 1.2-3.2; p=0.005) and large capacity hospitals (OR: 2.5, 95% CI: 1.6-4.1; p=0.0002). Predictors linked to lower mortality included private healthcare coverage (vs. Medicare: OR: 0.7, 95%, CI: 0.51-0.97; p=0.03), academic hospital (OR: 0.6, 95% CI: 0.4-0.8; p=0.005), cadaver donor (OR: 0.6, 95% CI: 0.5-0.8; p=0.002), HCC (OR: 0.6, 95% CI: 0.4-0.9; p=0.01), and non-alcoholic steatohepatitis (NASH) cirrhosis (OR: 0.4, 95% CI: 0.2-0.9; p=0.02). Conclusion Our study found an increasing trend in worse outcomes (increased mortality, average hospital costs, and average DOH) after a liver transplant. Patients of the African American race and large capacity hospitals were associated with a higher risk of death, whereas private healthcare plans, academic hospitals, cadaver donors, HCC, and NASH cirrhosis were associated with a lower risk.

PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders. ispartof: GENETICS IN MEDICINE vol:21 issue:8 pages:1761-1771 ispartof: location:United States status: published

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

Purpose of review Hepatitis C (HCV) is the most common cause of viral hepatitis in elderly individuals. This patient population previously experienced suboptimal outcomes with interferon-based regimens. Unfortunately, patients aged 65 years and older were underrepresented in phase 2 and 3 clinical trials with newer direct acting antiviral (DAA) therapies. Since the advent of second-generation DAA in 2013, numerous robust real-world experiences highlighting the efficacy and safety of DAA in the elderly have been published. This review article summarizes the cascade of care for hepatitis C from diagnosis to cure from an evidence-based perspective of the aging population. Recent finding In a large study from the Veterans Affairs Healthcare System, the overall sustained virologic response (SVR) of 15,884 patients treated with DAA regimens was 91.2%. These newer therapies remained highly effective in the subset of patients aged 65 years and older with SVR rates above 90%. A Spanish National Registry reported outcomes in patients ≥ 65 years old treated for HCV with oral DAA regimens over a 2-year period. The overall SVR was 94% in the study of 1252 subjects. Summary Current real-world data imply DAA treatment regimens remain highly effective and safe in elderly patients when compared to the general population.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases. Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Whelan, Laura. Trinity College; Estados Unidos Fil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países Bajos Fil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: De Baere, Elfride. University of Ghent; Bélgica Fil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; Italia Fil: Banin, Eyal. The Hebrew University of Jerusalem; Israel Fil: Bauwens, Miriam. University of Ghent; Bélgica Fil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; Israel Fil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países Bajos Fil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países Bajos Fil: Defoort, Sabine. Universite Lille; Francia Fil: Devos, Aurore. Universite Lille; Francia Fil: Dockery, Adrian. Trinity College; Estados Unidos Fil: Dudakova, Lubica. Charles University and General University Hospital; República Checa Fil: Fakin, Ana. Charles University and General University Hospital; República Checa Fil: Farrar, G. Jane. Trinity College; Estados Unidos Fil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; Brasil Fil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino Unido Fil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Glavac, Damjan. University of Ljubljana; Eslovenia Fil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Greenberg, Jacquie. University of Cape Town; Sudáfrica Fil: Hayashi, Takaaki. The Jikei University School of Medicine; Japón Fil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países Bajos Fil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; Alemania Fil: Jägle, Herbert. University Regensburg; Alemania Fil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; Grecia Fil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; Italia Fil: Kellner, Ulrich. No especifíca; Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Kousal, Bohdan. Charles University and General University Hospital; República Checa Fil: Lamey, Tina M.. University of Western Australia; Australia Fil: MacDonald, Ian M.. University of Alberta; Canadá Fil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: McLaren, Terri L.. University of Western Australia; Australia Fil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Meunier, Isabelle. Université Montpellier II; Francia Fil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Newman, Hadas. Universitat Tel Aviv; Israel Fil: Ntozini, Buhle. University of Cape Town; Sudáfrica Fil: Oldak, Monika. No especifíca; Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Puech, Bernard. Universite Lille; Francia Fil: Ramesar, Raj. University of Cape Town; Sudáfrica Fil: Rüther, Klaus. No especifíca; Fil: Salameh, Manar. No especifíca; Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; Brasil Fil: Sharon, Dror. The Hebrew University of Jerusalem; Israel Fil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; Italia Fil: Spital, Georg. No especifíca; Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Szaflik, Jacek P.. No especifíca; Fil: Thompson, Jennifer A.. No especifíca; Fil: Thuillier, Caroline. Universite Lille; Francia Fil: Tracewska, Anna M.. No especifíca; Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Vincent, Andrea L.. University of Auckland; Nueva Zelanda Fil: Zanlonghi, Xavier. No especifíca; Fil: Liskova, Petra. Charles University and General University Hospital; República Checa Fil: Stöhr, Heidi. Universitat Regensburg; Alemania Fil: De Roach, John N.. University of Western Australia; Australia Fil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; España Fil: Roberts, Lisa. University of Cape Town; Sudáfrica Fil: Weber, Bernhard H. F.. Universitat Regensburg; Alemania Fil: Dhaenens, Claire Marie. Universite Lille; Francia Fil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajos

Autosomal recessive Stargardt disease (STGD1) is associated with variants in the ABCA4 gene. The phenotypes range from early-onset STGD1, that clinically resembles severe cone-rod dystrophy, to intermediate STGD1 and late-onset STGD1. These different phenotypes can be correlated with different combinations of ABCA4 variants which can be classified according to their degree of severity. A significant fraction of STGD1 cases, particularly late-onset STGD1 cases, were shown to carry only a single ABCA4 variant. A frequent coding variant (p.Asn1868Ile) was recently identified which – in combination with a severe ABCA4 variant – is generally associated with late-onset STGD1. In addition, an increasing number of rare deep-intronic variants have been found and some of these are also associated with late-onset STGD1. The effect of these and other variants on ABCA4 RNA was tested using in vitro assays in human kidney cells using specially designed midigenes. With stem cells and photoreceptor progenitor cells derived from patient skin or blood cells, retina-specific splice defects can be assessed. With expert clinical examination to distinguish STGD1 cases from other maculopathies, as well as in-depth genomics and transcriptomics data, it is now possible to identify both mutant ABCA4 alleles in > 95% of cases.

Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease., Graphical Abstract, Khan et al. report on the clinical characterization of patients harboring a recurrent deep-intronic variant in ABCA4 underlying retinal disease and demonstrate that this, and other variants close by, lead to splicing defects that can be rescued by antisense oligonucleotides.

Missing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions that were accompanied by flanking exon deletions. Structural variant analysis revealed 11 distinct deletions, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Integrated complete gene sequencing combined with transcript analysis, identified pathogenic deep-intronic and structural variants in 26% of bi-allelic cases not solved previously by sequencing of coding regions. This strategy serves as a model study that can be applied to other inherited diseases in which only one or a few genes are involved in the majority of cases.

BACKGROUND Risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD) is well established; however, there is paucity of data on the potential added risk of VTE in patients with IBD with Clostridium difficile infection (CDI). We sought to study the difference in VTE rates in hospitalized patients with IBD with CDI compared to those without CDI. METHODS We queried Nationwide Inpatient Sample from year 2011 to identify patients ≥18 years of age with a discharge diagnosis of IBD (i.e., Crohn's disease and ulcerative colitis) based on ICD-9-CM codes 555.xx and 556.xx, respectively. Patients were further divided into 2 groups: those with and without CDI. To adjust and control for potential baseline differences between groups, 1:1 propensity matching was performed. Multivariate regression analysis was used to evaluate the difference in VTE rates in 2 groups. RESULTS Of 312,147 patients with the discharge diagnosis of IBD, 12,560 (4%) had CDI. VTE was present 6% in group with CDI versus 3% in group without CDI (P < 0.001). On performing multivariate analysis after propensity-score matching, CDI was significantly associated with VTE (adjusted odds ratio 1.7, 95% confidence interval 1.4-2.2, P < 0.001). On subgroup analysis, Crohn's disease with CDI had a higher association with VTE compared with Crohn's disease only. Similarly, ulcerative colitis with CDI had a higher association with VTE compared with ulcerative colitis only. CONCLUSIONS Rate of VTE was higher in hospitalized patients with IBD with CDI compared with those without CDI, necessitating extra vigilance in this patient population.

Purpose Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation-scanning methods. We aimed to develop a cost-effective sequencing method for ABCA4 exons and regions carrying known causal deep-intronic variants. Methods Fifty exons and 12 regions containing 14 deep-intronic variants of ABCA4 were sequenced using double-tiled single molecule Molecular Inversion Probe (smMIP)-based next-generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays. Results Thirty-four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep-intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep-intronic variant (c.4539+2065C>G) resulted in a 170-nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]). Conclusions smMIPs-based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost-effective mutation detection in STGD1 cases in previously unsolved cases.

Facial vascular malformations can cause dental emergencies that result in fatal or life-threatening and disfiguring situations. A knowledge of vascular malformation, its clinical presentation and its complications can prevent iatrogenically related accidents and minimize potential spontaneous crisis for the patient in the dental clinic. A vascular malformation (VM) is a morphogenetic abnormality of blood and/or lymphatic vessels with normal ultra-structural characteristics and endothelial hyperplasia. It results from a developmental arrest after the endothelial stage of embryologic vascular development contrary to hemangiomas, which appear to be a failure of differentiation at the endothelial stage. VM has a normal endothelial cell growth cycle that affects the veins, the capillaries and lymphatics and they do not involute. Intramuscular vascular malformations are uncommon tumors in the head and neck, although masseter muscle is the most common site, accounting for approximately 5% of all intramuscular vascular malformations in the head and neck region. Because of the rarity of these tumors, their deep location and unfamiliar presentation, inaccurate preoperative diagnosis and inappropriate treatment planning are common problems. The present report describes intramuscular arteriovenous malformation of masseter are presented highlighting the typical clinical presentation with MRI which should alert the dental physician to the possibility of such a lesion.

Introduction: Chronic renal failure (CRF) is an important health problem worldwide with a tendency of annual progression. Renal failure could alter the balance of the stomatognathic system, thus conditioning the prevalence of oral diseases at its different stages. Researchers estimate that up to 90% of renal patients show oral manifestations and a wide range of bony anomalies accounting for 92% of the patients. Aims and Objectives: The aim and objective of this study was to evaluate radiographic manifestations in CRF patients and compare the findings between the stages of CRF. Materials and Methods: A longitudinal study on fifty CRF patients was conducted. Patients were divided into three stages depending on the severity of renal failure. Orthopantomograph was taken for all the subjects. Results: The study showed that 88% of the study group had positive radiographic findings. Stage IV renal failure patients had more severe manifestations as compared to Stages II and III. Conclusion: Majority of the patients had positive radiographic findings which can be one of the diagnostic markers in CRF patients.

Gorlin-Goltz syndrome (GGS) is a rare genetic disease that is transmitted as an autosomal-dominant trait showing high level of penetrance and varying expressivity affecting multiple systems of the body. Characteristic clinical manifestations include the presence of multiple basal cell carcinomas, odontogenic keratocysts of the jaws, palmar/plantar pits and calcification of falx cerebri. Early diagnosis of GGS is of great importance due to susceptibility of affected individuals to multiple neoplasms of skin and brain (medulloblastoma) in an early age; life expectancy in GGS is not significantly altered, but morbidity from complications can be substantial. Dentist plays a crucial role in early diagnosis, which prevents recurrence and provides better survival rates from the existent diseases. We are reporting a rare case of GGS in a 14-year-old girl who visited our institution with characteristic clinical, radiological and histological features.

BACKGROUND: An estimated 22 million adults use marijuana in the USA. The role of marijuana in the progression of hepatic fibrosis remains unclear. AIMS: We carried out a systematic review and meta-analysis to evaluate the impact of marijuana on prevalence and progression of hepatic fibrosis in chronic liver disease. PATIENTS AND METHODS: We searched several databases from inception through 10 November 2017 to identify studies evaluating the role of marijuana in chronic liver disease. Our main outcome of interest was prevalence/progression of hepatic fibrosis. Adjusted odds ratios (ORs) and hazards ratios (HRs) were pooled and analyzed using random-effects model. RESULTS: Nine studies with 5 976 026 patients were included in this meta-analysis. Prevalence of hepatic fibrosis was evaluated in nonalcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis C and HIV coinfection by two, four, and one studies. Progression of hepatic fibrosis was evaluated by two studies. Pooled OR for prevalence of fibrosis was 0.91 (0.72–1.15), I(2) = 75%. On subgroup analysis, pooled OR among NAFLD patients was 0.80 (0.75–0.86), I(2) = 0% and pooled OR among HCV patients was 1.96 (0.78–4.92), I(2) = 77%. Among studies evaluating HR, pooled HR for progression of fibrosis in HCV–HIV coinfected patients was 1.03 (0.96–1.11), I(2) = 0%. CONCLUSION: Marijuana use did not increase the prevalence or progression of hepatic fibrosis in HCV and HCV–HIV-coinfected patients. On the contrary, we noted a reduction in the prevalence of NAFLD in marijuana users. Future studies are needed to further understand the therapeutic impact of cannabidiol-based formulations in the management of NAFLD.

Nonalcoholic steatohepatitis (NASH) is one of the top 3 indications for liver transplantation (LT) in Western countries. It is unknown whether renal dysfunction at the time of LT has any effect on post-LT outcomes in recipients with NASH. From the United Network for Organ Sharing-Standard Transplant Analysis and Research data set, we identified 4088 NASH recipients who received deceased donor LT. We divided our recipients a priori into 3 categories: group 1 with estimated glomerular filtration rate (eGFR)

Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep-intronic ABCA4 variants (c.4539+2001G>A and c.4539+2028C>T) result in a retina-specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs∗36), likely due to the creation of exonic enhancers. Administration of antisense oligonucleotides (AONs) targeting the 345-nt pseudoexon can significantly rescue the splicing defect observed in PPCs of two individuals with these mutations. Intriguingly, an AON that is complementary to c.4539+2001G>A rescued the splicing defect only in PPCs derived from an individual with STGD1 with this but not the other mutation, demonstrating the high specificity of AONs. In addition, a single AON molecule rescued splicing defects associated with different neighboring mutations, thereby providing new strategies for the treatment of persons with STGD1. As many genes associated with human genetic conditions are expressed in specific tissues and pre-mRNA splicing may also rely on organ-specific factors, our approach to investigate and treat splicing variants using differentiated cells derived from individuals with STGD1 can be applied to any tissue of interest.

BACKGROUND AND AIM Pancreatic cancer is one of the common cancers in US and is associated with high mortality and morbidity. The objectives of our study were to look at the recent trends in the number of hospitalizations with pancreatic cancer. METHODS We identified patients with a discharge diagnosis of pancreatic cancer in the National Inpatient Sample from 2007 to 2011 using International Classification of Diseases-Clinical Modification, 9th revision (ICD-9-CM) codes. We looked at the yearly trend in the hospitalizations with pancreatic cancer and the outcomes which included length of stay (LOS), hospital charges and in-hospital mortality. We also performed multivariate analysis to look for the predictors of mortality. RESULTS There were 450, 414 patients with discharge diagnosis of pancreatic cancer. There was 18% increase in hospitalizations with pancreatic cancer in 2011 compared to 2007. Most of the patients were Caucasian (63%) with the mean age of 68 ± 0.14 years, had Medicare (57%) as primary insurance, were from Southern region (35%) and had higher Charlson Comorbidity Index (CCI) (87% with CCI > = 5). 6% underwent Whipple's procedure in the index hospitalization. After the adjustment for inflation, the mean hospital charges increased from $ 47,331 in 20007 to $ 53, 854 in 2011 (p = 0.01). LOS decreased from 7.31 ± 0.11 days in 2007 to 6.70 ± 0.09 days in 2011 (

Context: The diagnosis of malignant and potentially malignant epithelial lesions of the oral mucosa cannot be based solely on clinical findings. The histologic evaluation of a representative biopsy specimen thus becomes necessary. The site for biopsy however is always a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for the selection of the most appropriate area for biopsy. Colposcopy is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns. Aims: This study was planned to assess the role of Colposcopic examination in the selection of biopsy site in patients with varying grades of oral epithelial dysplasia at various sites. Settings and Design: One hundred and eighty patients between the ages of 30 and 60 years clinically diagnosed with leukoplakia and carcinoma buccal mucosa were included in the study. Materials and Methods: For each of the subjects, a thorough clinical examination followed by Colposcopic assessment was carried out for the selection of biopsy site from the involved mucosa. The histopathological findings were then compared in the two cases and results analyzed. Statistical Analysis Used: The statistical analysis was performed using a paired t-test. Results: In our study, sensitivity and specificity for the selection of biopsy site by Colposcopic examination was found to be higher for leukoplakia than for carcinoma buccal mucosa. Conclusions: It was concluded that Colposcopic examination was found to be significant in the selection of biopsy site for leukoplakia while clinical criterion was found to be more appropriate for carcinoma buccal mucosa cases.

Background: Epilepsy is described as a chronic neurological disorder characterized by recurrent seizures of cerebral origin, presenting with episodes of sensory, motor or autonomic phenomenon with or, without loss of consciousness. A recent meta-analysis of published and unpublished studies puts an overall prevalence rate of epilepsy in India at 5.59 per 1,000 populations.There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the anti-epileptic therapy in the prevention of anti-epileptic drug induced gingival enlargement. However, studies conducted in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy so as to justify the use of folic acid as a routine adjuvant to the usual anti-epileptic therapy to prevent this inevitable adverse effect without destabilizing the ongoing regimen leading to the precipitation of seizures in an otherwise stable patient (breakthrough seizures). Materials and Methods: A total of 100 patients between the ages 18 and 50 years were clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was performed prior to the start of and after 1 year of phenytoin therapy. Statistical Analysis Used: The statistical analysis was carried out using t -test and the baseline serum folate levels and the serum folate levels obtained after 1 year of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula. Results: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin induced gingival enlargement. Conclusions: The results of the study suggest a higher incidence of gingival enlargement with an early onset and increased severity in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.

Context: The diagnosis of malignant and potentially malignant epithelial lesions of oral mucosa cannot be based solely on clinical findings. The histologic evaluation of a representative biopsy specimen thus becomes necessary. The site for biopsy, however, is always a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for the selection of the most appropriate area for biopsy. Colposcopy is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns. Aims: The study was planned to assess the role of colposcopic examination in the selection of biopsy site in patients with varying grades of oral epithelial dysplasia at various sites. Settings and Design: Fifty patients between the ages of 30-60 years clinically diagnosed with leukoplakia and carcinoma buccal mucosa were included in the study. Materials and Methods: For each of the subject, a thorough clinical examination followed by colposcopic assessment was carried out for the selection of biopsy site from the involved mucosa. The histopathological findings were then compared in the two cases and results analyzed. Statistical Analysis Used: The statistical analysis was done using paired t-test. Results: In our study, sensitivity and specificity for the selection of biopsy site by colposcopic examination came out to be higher for leukoplakia than carcinoma buccal mucosa patients. Conclusions: It was concluded that colposcopic examination was found more significant in the selection of biopsy site for leukoplakia patients while clinical criterion was found to be more appropriate for carcinoma buccal mucosa cases.

Hereditary sensory and autonomic neuropathies (HSANs) are a group of disorders characterized by insensitivity to noxious stimuli and autonomic dysfunction, associated with pathological abnormalities of the peripheral nerves. Five types of HSAN have been reported in literature, out of which Type V known as congenital insensitivity to pain (CIP) is a rare autosomal recessive condition. Self-mutilation is an invariable feature of this disorder, involving the teeth and orofacial structures. This case report describes a case of a 6-year-old girl with CIP brought by her parents for prostheses to replace her self-extracted primary teeth.

Severe aortic stenosis causes recurrent mucosal bleeds, mainly from angiodysplasias and acquired von Willebrand deficiency (vWD) which is corrected after aortic valve replacement, either transcatheter (TAVR) or surgical (SAVR). Studies have shown major GI bleeding post-TAVR as an independent

Objectives: To assess the alveolar bone density by fractal dimension (FD) analysis in radiovisiograph of postmenopausal women of mandibular posterior region and to correlate FD values with t-scores of quantitative ultrasound of the calcaneus bone. Materials and Methods: This study, approved by the institutional review board, included 40 participants, aged 45–60 years divided into two groups. Twenty postmenopausal women with osteoporosis comprised group 1, and 20 postmenopausal women without osteoporosis comprised group 2 based on bone mineral density assessment of ultrasound of the calcaneus bone. Digital dental radiograph of mandibular first molar were obtained and used for assessing alveolar bone density by FD analysis and were correlated with t-scores of ultrasound of calcaneus bone. Results: The mean FD values were evaluated using SPSS 14 version software, and were found to be 1.738 and 1.867 for group 1 and group 2, respectively, which was statistically significant (P < 0.001). However, correlation between t-scores and FD values within the study group was not found to be statistically significant (P > 0.05). Conclusion: FD analysis using direct digital periapical radiographs is a novel method, which can be used for early diagnosis of osteoporosis in the alveolar bone.

Severe aortic stenosis is associated with acquired Von Willebrand deficiency (vWD) manifesting with recurrent gastrointestinal bleed (GIB) if left untreated. Few small studies have shown decreased incidence of GIB after surgical aortic valve replacement (SAVR) but limited data are available with

Background: The importance of fungal allergens in the development of allergic diseases in a desert environment is uncertain. This study evaluated the prevalence of IgE sensitization to moulds among patients with allergic respiratory diseases in Kuwait – a desert country. Methods: A total of 810 patients (male:female ratio 1.4) with a mean age of 32.3 years (range 2–76 years) with extrinsic asthma or allergic rhinitis were studied. Sera from the patients were tested by the CAP-RAST method for specific IgE to 6 fungi (Penicillium, Cladosporium, Aspergillus, Candida, Alternaria and Helminthosporium). For comparison house dust mite and Bermuda grass were also assessed. Results: The overall positivity to at least one mould was 20.9%. Among 120 matched control subjects, the value was 5.8%. The value was much higher among patients with asthma alone (45.8%) or both asthma and rhinitis (28.3%) than those with rhinitis alone (11.8%; p < 0.001). Asthmatic children had the highest sensitization rate (66.0% in the 7- to 12-year age group), which declined sharply with age. Among asthmatics, Candida and Aspergillus had the highest sensitization rates (23.1 and 21.3%, respectively), followed by Helminthosporium (18.8%), Cladosporium (15.9%), Alternaria (14.6%) and Penicillium (13.9%). The values for mite and Bermuda grass were 41.2 and 54.6%, respectively. Among asthmatic children, severe asthma was significantly more frequent among mould-positive (51.6%) than mould-negative patients (17.5%; p < 0.0001). Conclusions: Even in this desert environment, sensitization to moulds is quite common among patients with allergic respiratory diseases, with a striking preponderance among children with asthma. Mould allergy could also be an important factor determining asthma severity in this environment.

The purpose of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 90% of females (ED90) undergoing elective Cesarean delivery (CD) under spinal anesthesia.We conducted a double-blind dose-finding study of carbetocin. Forty females undergoing elective CD received carbetocin intravenously upon delivery of the fetus. The dose of carbetocin for each patient was determined according to a biased-coin up-and-down sequential allocation scheme designed to cluster doses close to ED90. The initial dose was 10 μg, with increments/decrements of 5 μg. The anesthesiologist, obstetrician, and patient were blinded to the dose. The obstetrician assessed the uterine tone at one-minute intervals for five minutes after carbetocin administration. In case of unsatisfactory tone, additional uterotonics were administered. The primary outcome was requirement for additional intraoperative uterotonics. Secondary outcomes were postoperative requirement for additional uterotonics within 24 hr of delivery, estimated blood loss and side effects.The ED90 of carbetocin was 14.8 μg (95% confidence interval 13.7 to 15.8). Thirty-seven patients (92.5%) had adequate uterine tone with no requirement of additional intraoperative uterotonics. Two patients (5%) required postoperative uterotonics within 24 hr. The overall mean (SD) estimated blood loss was 786 (403) mL and the overall incidence of hypotension (decrease in systolic blood pressure ≥ 20% baseline) was 37.5%.Based on our study, the ED90 of carbetocin at elective CD is less than one-fifth the currently recommended dose of 100 μg. This study was registered at clinicaltrials.gov (NCT-01651130).

Background: There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the antiepileptic therapy in the prevention of antiepileptic drug-induced gingival enlargement. However, studies in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin-induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy. The statistical analysis was done using t-test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula. Methods: A total of 25 patients aged between 18 and 50 years, clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was done prior to the start of and after 6 months of phenytoin therapy. Results: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin-induced gingival enlargement. Conclusions: The results of the study suggest a higher incidence of gingival enlargement in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.

Schizophrenia is a psychiatric disorder requiring constant vigilance and lifelong intervention with psycho therapeutic counseling and administration of Antipsychotic drugs. Metabolic aberrations are documented to occur more frequently in subjects with Schizophrenia (SCH) prior to treatment and the prevalence of these metabolic alterations is significantly raised following administration of Antipsychotic drugs especially the newer ones. Adiposity in SCH prior to drug therapy is significantly increased in comparison to age matched healthy subjects (N) as documented by several indices. Body Mass Index, kg/m2 (26.7 for SCH vs. 22.8 for N, p

Lipomas are rare, benign tumours of mesenchymal origin, representing 1–5% of all benign oral tumors. Clinically, intraoral lipomas present as slow growing, soft, asymptomatic mass. Histopathologically, they are composed predominantly of mature adipocytes admixed with collagenous tissue and may be surrounded by a thin fibrous capsule. Their diagnostic importance lies in the distinction from other benign connective tissue lesions, salivary gland neoplasms and liposarcomas. Complete surgical excision is the treatment of choice and recurrence is rare. Here we report a case of intraoral lipoma in the buccal mucosa.

Background Alteration in gustatory function among patients with human immunodeficiency virus (HIV) infection is sparsely studied and provides contradictory findings. The objectives of the study were to evaluate taste perversion in HIV-infected subjects and compare taste acuity between patients with and without Highly active antiretroviral therapy (HAART). Materials and Methods Fifty HIV-infected subjects aged 25–55 years were selected and divided into two subgroups: patients with HAART and patients without HAART. Control group included 50 healthy, age-, sex-, gender-, and socioeconomic status-matched individuals. Taste complaints were recorded on a structured questionnaire, and formal taste testing was carried out with triadic forced choice whole-mouth, above-threshold taste test for four tastants – sweet, salt, sour, and bitter. Taste identification, detection threshold, and intensity of tastant were recorded. Results Twenty-four (48%) among study group complained of taste perversion when compared to none among the control group (P

Epilepsy is a common neurological disorder with recurrent seizures due to a chronic underlying process. Despite tremendous advances in the field of understanding the etio-pathogenesis of epilepsy, phenytoin still remains the drug of choice in its management. Chronic administration of phenytoin has been associated to have a number of adverse effects. Gingival enlargement is one such most often reported adverse drug sequela of long term phenytoin usage with exclusion of local factors contributing towards gingival enlargement. Hence, the study was planned to investigate the association of phenytoin and gingival enlargement seen in epileptic patients being treated with phenytoin. For this, 25 patients between the ages of 18-50 years clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of gingival status was done using the index originally described by Angelopoulos and Goaz and later modified by Miller and Damm [Go Index]. The results of the study confirmed a significant association between long term usage of phenytoin and the onset and severity of gingival enlargement in epileptic patients being treated with phenytoin. This is a baseline study; the results of the study suggest a higher incidence of gingival enlargement in phenytoin treated epileptic patients with local factors having a little role, if any, towards phenytoin induced gingival enlargement.

Objective: To study the clinical types and association of psychological factors in patients with Oral Lichen Planus (OLP). Materials and Methods: An analytical age- and sex-matched study involved 30 patients with oral lichen planus (group 1) and 30 control subjects (group 2). We applied the following psychometric tests to both groups: General Health Questionnaire (GHQ) and Hospital Anxiety and Depression Scale (HADS). Results: The patients with OLP were found to exhibit statistically significant higher anxiety, insomnia, and social dysfunction with the tests that were used (GHQ 24 and HADS) than the control group (P > 0.05). The study group likewise exhibited greater depression and somatic symptoms. The mean total of the GHQ and HAD scores were found to be higher in the study group than in the controls (P > 0.05). Among the various types of OLP, patients with the erosive type had higher mean scores for anxiety and insomnia, social dysfunction and depression. Conclusion: In most patients psychiatric morbidity was strongly associated with OLP, which could support its role in the etiopathogenesis of the disease. The higher scores of the General Health Questionnaire and Hospital Anxiety and Depression Scale gave an insight into the hypothesis that psychological factors are associated with the causation of OLP.

Background: There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the antiepileptic therapy in the prevention of antiepileptic drug-induced gingival enlargement. However, studies conducted in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin-induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy. Subjects and Methods: A total of 25 patients aged between 18 and 50 years clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was done prior to the start of and after 6 months of phenytoin therapy. The statistical analysis was done using t -test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula. Results: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin-induced gingival enlargement justifying the judicious use of folate supplementation to prevent this inadvertent side effect of phenytoin administration. Conclusions: The results of the study suggest a higher incidence of gingival enlargement in phenytoin-treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.

Abstract 750 Background: Treatment remains a challenge for systemic light chain amyloidosis (AL). Autologous stem cell transplant (AutoSCT) has been associated with long term survival. However, a recent multicenter randomized study failed to show survival benefit for AutoSCT perhaps due to high non-relapse mortality (NRM). Here we present a comparison of AutoSCT to other conventional therapies in AL patients treated at our institution with a 14-year follow up. Methods: A total of 2018 cases were identified upon pathology review from 1998–2012. AL was confirmed in 264 patients; primary amyloidosis (PA) in 147 pts and multiple myeloma with amyloidosis (AM) in 110 patients; solitary amyloidoma in 7 patients. AutoSCT was performed in 126 patients (PA=79 and AM=47). Results: The day 100 NRM was 5% and 1-year NRM was 8%. With a follow up of 14 years in surviving patients, the 10-year overall survival (OS) of AL patients was significantly better in those undergoing AutoSCT (41% vs. 17%; p10 % at the time of autoSCT did not have an impact on OS. Cardiac biomarkers including NT-ProBNP and Troponin-I and T levels were available in a limited number of patients and were not analyzed for survival outcomes. In multivariate analysis, superior OS was associated with: age Conclusions: AL patients should be evaluated for AutoSCT and selected patients should undergo induction therapy to decrease amyloid burden prior to AutoSCT. Disclosures: No relevant conflicts of interest to declare.

Context: The role of oxygen free radicals in the initiation, promotion and progression of carcinogenesis and the protective role of antioxidant defenses has been the subject of much speculation in the recent past, with conflicting reports in the literature. Aims: The aim of this study was to measure the concentration of serum total proteins and albumin and advanced oxidation protein products (AOPP) in the sera of patients diagnosed with speckled leukoplakia and well-differentiated oral squamous cell carcinoma. Materials and Methods: The study consisted of sera analysis of 30 new cases of histologically proven well-differentiated, oral squamous cell carcinoma and 10 patients with speckled leukoplakia aged between 40 and 60 years in addition to 25 healthy controls. Statistical Analysis Used: One-way analysis of variance (ANOVA) was used to test the difference between groups. To find out which of the two groups' mean was significantly different, post hoc test of Scheffe was used. Results: The study revealed variations in sera levels of albumin and advanced oxidation protein products to be statistically significant. Conclusions: The results obtained emphasize the need for more studies with larger sample sizes to be conducted before a conclusive role for sera levels of total protein, albumin and AOPP could be drawn as markers of transition of the various oral precancerous lesions and conditions to frank oral squamous cell carcinoma.

Context: The diagnosis of malignant and potentially malignant epithelial lesions of the oral mucosa is based on a careful histologic evaluation of a representative biopsy specimen. The site for the biopsy, however, is always a subjective choice that raises doubts about its representativeness. So far, no simple and reliable method is available for selecting the most appropriate area for biopsy. Colposcopy, a well-known gynecological diagnostic procedure, is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns. Aims: The present study aimed at assessing the vascular patterns by colposcopic findings and selecting the biopsy site in leukoplakia patients and compared the two methods, clinical criteria, and colposcopic examination, for selecting the biopsy site. Settings and Design: Sixty patients between the ages of 30-60 years clinically diagnosed with leukoplakia were included in the study. Materials and Methods: For each of the subject, a thorough clinical examination was carried out followed by colpospopic examination for the selection of biopsy site. The histopathological findings were then compared in the two cases. Statistical Analysis Used: The statistical analysis was done using paired t -test. Results: Based on clinical criteria, a sensitivity of 0.5714 (57%) and a specificity of 0.5000 (50%) and that guided by colposcopic examination to be 0.8571 (85%) and 0.6667 (66%), respectively, was found. Conclusions: From the study, it was concluded that colposcopic examination could prove to be a valuable diagnostic adjunct in the selection of biopsy site for leukoplakia patients.

Abstract 333 Impact of Non High-Risk Chromosomal Abnormalities on the Outcome of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Background: Despite novel therapeutic agents and high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HCT), most patients eventually progress and die of their disease. Recent advances in cytogenetic, molecular and genomic studies have led to identification of several chromosomal and molecular abnormalities. These abnormalities are important predictors of response to therapy, progression-free survival (PFS) and overall survival (OS). On conventional cytogenetic (CC) analyses, del 13, t(4;14), t(14;16) and del 17p are considered high-risk (HR). On Fluorescence in situ hybridization (FISH) analysis, all except del 13 are considered HR (Munshi, N et al. Blood 2011 117: 4696–4700). However there are a number of chromosomal abnormalities whose significance is not clearly identified (non-HR). In this study we report the impact of these non-HR chromosomal abnormalities on the outcome of patients who received high-dose chemotherapy and auto-HCT. Methods: We performed a retrospective review of patients with multiple myeloma who underwent high dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center. Between 10/1991 and 12/2010, 1570 patients received auto-HCT. The results of CC studies were available for 1329 patients, either at diagnosis or at relapse, but before auto-HCT. The primary objective was to study the impact of non-HR chromosomal abnormalities on PFS and OS, and to compare them to patients without chromosomal abnormalities. Results: Patient characteristics and major outcomes are summarized in the attached Table. In 1329 patients with available CC analyses before auto-HCT, chromosomal abnormalities were identified in 405 (30%) patients. One-hundred and seven (7%) patients had known HR chromosomal abnormalities, while 298 (23%) patients had non-HR chromosomal abnormalities. Fifty (17%) patients with non-HR chromosomal abnormalities and 296 patients (32%) with normal CC achieved complete or stringent complete responses (CR + sCR) (p=0.0001). Median follow up in surviving patients was 36 months. Median PFS in patients with non-HR chromosomal abnormalities and normal CC were 18.2 months (95%CI: 16–22.7) and 32.7 months (95% CI: 27.8–36.3), respectively (p= Figure 1 ). The OS in patients with non-HR chromosomal abnormalities and with normal CC were 56.5 months (95% CI: 43.2–66.9) and 87.2 months (95%CI: 80.1–102.4), respectively (p= Figure 2 ). Download : Download high-res image (40KB) Download : Download full-size image FIGURE 1 . Download : Download high-res image (42KB) Download : Download full-size image FIGURE 2 . Conclusions: In this large single center study with a long follow up, we demonstrated that non-HR chromosomal abnormalities in myeloma are associated with a lower CR rate and shorter PFS and OS after auto-HCT. Further studies are needed to better define these non-HR abnormalities and their impact on prognosis. TABLE 1 . Normal (n= 924) Non-High Risk (n= 298) Median age at auto-HCT 57 59 Age >65 at auto-HCT 137/924 (14.8%) 70/298 (23.4%) Race White = 605 (65%) Black = 148 (16%) Other = 171 (19%) W = 202 (67%) B = 44 (14%) O = 52 (19%) Gender Female = 391 (42%) Male = 533 (58%) F = 104 (34%) M = 194 (66%) Disease status at transplant First Remission = 799 (86%) Relapsed: 110 (12%) Unknown = 15 (2%) First Remission = 224 (75%) Relapsed = 72 (24%) Unknown = 2 (1%) Conditioning Regimen Melphalan or non melphalan = 198 (79%) Melphalan alone = 726 (21%) Melphalan or non melphalan = 57 (81%) Melphalan alone = 241 (19%) Final Response PD = 17 (1.8%) PD = 20 (6.7%) Progressed 447/924 (48%) 172/298 (57%) Died 278/924 (30%) 123/298 (41%) PD: Progressive Disease PR: Partial Remission CR: Complete Response VGPR: Very Good Partial Response sCR: Stringent Complete Response Disclosures: No relevant conflicts of interest to declare.

Abstract 2400 Background: Approximately 10% of patients with multiple myeloma (MM) have clinically overt primary systemic light-chain (AL) amyloidosis, and about 30% have concurrent occult AL amyloidosis. The impact of concurrent AL amyloidosis on the prognosis of myeloma is not well known. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) has shown significant activity in both MM and AL amyloidosis. Methods: We performed a retrospective analysis of patients who had concurrent MM and AL amyloidosis and underwent auto HSCT with high dose Melphalan at MDACC between 01/1998 to 05/2010. We identified 41 patients with concurrent MM and AL amyloidosis. Patient characteristics are summarized in Table 1. Twenty -six patients had occult AL amyloid, while 15 had clinically overt disease. Results: Median age at auto HSCT was 56 years (39-77), 58.5% being male with median follow up of 58.7 months from the time of diagnosis and 42.5 months from auto HCT. The median time from diagnosis to auto HCT was 8.9 mos (2.7-102.4 mos). 39% had Salmon Durie Stage III disease and 36.6% had more than one involved site at the time of transplant.Cytogenetic abnormalities were detected in 24.4% of patients. Post transplant hematologic responses were as follows: ≥CR=10 (24%), ≥VGPR=16 (39%), >PR=33 (80.5%), ≥stable disease= 40 (97.6%). Among the patients with overt organ involvement, one had early death. Of the 15 evaluable patients, organ responses were scored using the published consensus guidelines for amyloidosis and were as follows: PR=5 (33.3%), ≥SD=7 (46.7%). No correlation was seen between organ response and hematologic response. The 100-day treatment related mortality (TRM) was 0 and 1-year TRM of 2.4% which is comparable to patients transplanted for MM alone at our center. The median progression-free (PFS) and overall survival (OS) from auto HCT were 33.8 and 58.3 months, respectively.The median PFS and OS from diagnosis were 49.8 and 96 mos, respectively. In multivariate analysis, creatinine ≥ 2mg/dl was associated with a shorter PFS (p=0.043) and hemoglobin 60yrs, Creatinine≥2mg/dl, B2M >3.5mg/l, BM plasma cells>30%) emerged as significant predictors of OS. There was no significant difference in outcome between patients with occult or symptomatic AL amyloidosis for OS (p=0.24) or PFS (P=0.9) Conclusion: In this analysis the outcome of patients with concurrent MM and AL amyloidosis was comparable to patients with MM alone. We believe these patients are acceptable candidates for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.