Local treatment failure after globe-conserving therapy for choroidal melanoma.

Local treatment failure after globe-conserving therapy for choroidal melanoma is a surgical complication with significant morbidity to the vision and eye. Few reports in the literature have addressed this complication exclusively. A review of the published literature with reference to local treatment failure in the management of choroidal melanoma was performed to make known the potential differences in failure rates between treatment modalities and methods. A search of the literature regarding local treatment failure was performed to identify relevant studies using combinations of the following keywords on PubMed: uveal melanoma, choroidal melanoma, local recurrence, local failure, endoresection, gamma knife, radiotherapy, helium, iodine, proton, palladium, ruthenium, trans-scleral resection, transpupillary thermotherapy. Further studies were found by searching the text and references of previously identified studies for articles reporting local treatment failure rates in choroidal melanoma. Among the 49 studies identified, the local treatment failure rate ranged from 0% to 55.6%, with follow-up ranging from 10 to 150 months. The two most widely used forms of radiation therapy, iodine-125 and ruthenium-106 brachytherapy, were both associated with a local recurrence rate of 9.6%. The weighted-average of treatment failure in all radiation therapies was 6.15% compared with 18.6% in surgical and 20.8% in laser therapies. Rates of local treatment failure for globe-conserving therapy of choroidal melanoma varied widely between modalities and between centres using similar modalities. Radiation therapy overall resulted in lower local treatment failures compared with surgical or transpupillary thermotherapy

Heterogeneity of monosomy 3 in fine needle aspiration biopsy of choroidal melanoma.

PurposeTo report on the heterogeneity of monosomy 3 in a fine needle aspiration biopsy obtained transsclerally from choroidal melanoma for prognosis.MethodsAll clinical records for patients who had been diagnosed with choroidal melanoma and underwent iodine-125 plaque brachytherapy with intraoperative transscleral fine needle aspiration biopsy from January 2005 to August 20, 2011, and who had a positive result for monosomy 3 according to fluorescence in situ hybridization as reported by clinical cytogenetics testing were collected. Patient age and sex, total number of cells evaluated and number of cells positive for monosomy 3, tumor size, and metastatic outcome were recorded for each patient.ResultsA positive result for monosomy 3 was reported in 93 patients who underwent transscleral fine needle aspiration biopsy. Two patients were lost to follow-up immediately post-operatively, and the remaining 91 patients were included in this study. The mean number of cells evaluated in the biopsy was 273 (range 28 to 520). The mean percentage of cells positive for monosomy 3 was 62.9% (range 4.7%-100%). The mean tumor height was 5.91 mm (range 1.99 to 10.85 mm). Larger tumors were associated with a higher percentage of cells positive for monosomy 3. During the average follow-up interval of 28.9 months (range 3-76 months), choroidal melanoma metastasis developed in 18 (20%) patients. Patients whose tumors had 1%-33% of cells positive for monosomy 3 had a significantly lower risk of metastasis-related death compared to patients whose tumors harbored a higher percentage of monosomy 3 (p = 0.04).ConclusionsCytogenetic heterogeneity of fluorescent in situ hybridization for monosomy 3 exists in a biopsy sample. Larger tumors were more likely to have a higher percentage of monosomy 3 positive cells in the sample. Furthermore, patients whose tumors had more than 33% of cells positive for monosomy 3 had a poorer prognosis than patients whose tumors had lower percentages of monosomy 3

Vaginal delivery of siRNA using a novel PEGylated lipoplex-entrapped alginate scaffold system

Sustained vaginal delivery of siRNA has been precluded by the mucosal barrier lining the vaginal tract. In contrast to prior reports, we showed that conventional lipoplexes administered intravaginally are unable to reach the vaginal epithelium under normal physiological conditions. Here we have developed a novel alginate scaffold system containing muco-inert PEGylated lipoplexes to provide a sustained vaginal presence of lipoplexes in vivo and to facilitate the delivery of siRNA/oligonucleotides into the vaginal epithelium. These PEGylated lipoplex-entrapped alginate scaffolds (PLAS) were fabricated using a freeze-drying method and the entrapment efficiency, release rate, and efficacy were characterized. We demonstrated that the PLAS system had an entrapment efficiency of ~ 50%, which released PEGylated lipoplexes gradually both in vitro and in vivo. While the presence of alginate diminished the cell uptake efficiency of PEGylated lipoplexes in vitro, as expected, we showed a six-fold increase their uptake into the vaginal epithelium compared to existing transfection systems following intravaginal administration in mice. A significant knockdown of Lamin A/C level was also observed in vaginal tissues using siLamin A/C-containing PLAS system in vivo. Overall, our results indicated the potential of the biodegradable PLAS system for the sustained delivery of siRNA/oligonucleotides to vaginal epithelium

Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia

[[abstract]]Background: Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes. Methods: We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002. Results: We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL. Conclusions: These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications