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Sample records for low-risk variants fgfr2

  1. Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

    PubMed Central

    Huijts, Petra EA; Vreeswijk, Maaike PG; Kroeze-Jansema, Karin HG; Jacobi, Catharina E; Seynaeve, Caroline; Krol-Warmerdam, Elly MM; Wijers-Koster, Pauline M; Blom, Jannet C; Pooley, Karen A; Klijn, Jan GM; Tollenaar, Rob AEM; Devilee, Peter; van Asperen, Christi J

    2007-01-01

    Introduction Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer. Methods We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer. Results Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants. Conclusion Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles. PMID:17997823

  2. A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis.

    PubMed

    Eswarakumar, Veraragavan P; Horowitz, Mark C; Locklin, Rachel; Morriss-Kay, Gillian M; Lonai, Peter

    2004-08-24

    The b and c variants of fibroblast growth factor receptor 2 (FGFR2) differ in sequence, binding specificity, and localization. Fgfr2b, expressed in epithelia, is required for limb outgrowth and branching morphogenesis, whereas the mesenchymal Fgfr2c variant is required by the osteocyte lineage for normal skeletogenesis. Gain-of-function mutations in human FGFR2c are associated with craniosynostosis syndromes. To confirm and extend this evidence, we introduced a Cys342Tyr replacement into Fgfr2c to create a gain-of-function mutation equivalent to a mutation in human Crouzon and Pfeiffer syndromes. Fgfr2c(C342Y/)(+) heterozygote mice are viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 expression in the calvaria. Homozygous mutants display multiple joint fusions, cleft palate, and trachea and lung defects, and die shortly after birth. They show enhanced Cbfa1/Runx2 expression without significant change in chondrocyte-specific Ihh, PTHrP, Sox9, Col2a, or Col10a gene expression. Histomorphometric analysis and bone marrow stromal cell culture showed a significant increase of osteoblast progenitors with no change in osteoclastogenic cells. Chondrocyte proliferation was decreased in the skull base at embryonic day 14.5 but not later. These results suggest that long-term aspects of the mutant phenotype, including craniosynostosis, are related to the Fgfr2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of Fgfr2c with Fgfr3 in the formation of the cartilage model for endochondral bone.

  3. Genetic variants in FGFR2 and TNRC9 genes are associated with breast cancer risk in Pakistani women.

    PubMed

    Mazhar, Ayesha; Jamil, Farrukh; Bashir, Qamar; Ahmad, Munawar Saleem; Masood, Misbah; Tanvir, Imrana; Rashid, Naeem; Waheed, Abdul; Afzal, Muhammad Naveed; Tariq, Muhammad Akram

    2016-10-01

    Single nucleotide polymorphisms (SNPs) lead to genetic differences in breast cancer (BC) susceptibility among women from different ethnicities. The present study aimed at investigating the involvement of SNPs of three genes, including fibroblast growth factor receptor 2 (FGFR2), trinucleotide-repeat-containing 9 (TNRC9) and mitogen-activated protein kinase kinase kinase 1 (MAP3K1), as risk factors for the development of BC. A case‑control study (90‑100 cases; 90‑100 controls) was performed to evaluate five genetic variants of three genes, including FGFR2 (SNPs: rs1219648, rs2981582), TNRC9 (SNPs: rs8051542, rs3803662) and MAP3K1 (SNP: rs889312) as BC risk factors in Pakistani women. Significant associations were observed between BC risk and two SNPs of FGFR2 [rs2981582 (P=0.005), rs1219648 (P=9.08e‑006)] and one SNP of TNRC9 [rs3803662) (P=0.012)] in Pakistani women. On examining the different interactions of these SNPs with various clinicopathological characteristics, all three associated genetic variants, rs2981582 rs1219648 and rs3803662, exhibited a greater predisposition to sporadic, in comparison to familial, BC. Furthermore, there was an increased effect of BC risk between haplotype combinations of the two SNPs of FGFR2 (rs2981582 and rs1219648) in Pakistani women. The results of the present study suggest that variants of FGFR2 and TNRC9 may contribute to the genetic susceptibility of BC in Pakistani women.

  4. Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

    PubMed Central

    Meyer, Kerstin B.; O’Reilly, Martin; Michailidou, Kyriaki; Carlebur, Saskia; Edwards, Stacey L.; French, Juliet D.; Prathalingham, Radhika; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; de Santiago, Ines; Hopper, John L.; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Van ’t Veer, Laura J.; Hogervorst, Frans B.; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Lux, Michael P.; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Zamora, M. Pilar; Arias, Jose I.; Benitez, Javier; Neuhausen, Susan; Anton-Culver, Hoda; Ziogas, Argyrios; Dur, Christina C.; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Engel, Christoph; Ditsch, Nina; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Dörk, Thilo; Helbig, Sonja; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Thienpont, Bernard; Christiaens, Marie-Rose; Smeets, Ann; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Bernard, Loris; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Purrington, Kristen; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo-Hwang; Yip, Cheng-Har; Phuah, Sze-Yee; Kristensen, Vessela; Grenaker Alnæs, Grethe; Børresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline M.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Darabi, Hartef; Eriksson, Kimael; Hooning, Maartje J.; Martens, John W.M.; van den Ouweland, Ans M.W.; van Deurzen, Carolien H.M.; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Pharoah, Paul D.P.; Ghoussaini, Maya; Harrington, Patricia; Tyrer, Jonathan; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Hui, Miao; Lim, Wei-Yen; Buhari, Shaik A.; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans-Ulrich; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Vachon, Celine; Slager, Susan; Fostira, Florentia; Pilarski, Robert; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Ponder, Bruce A.J.; Dunning, Alison M.; Easton, Douglas F.

    2013-01-01

    The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. PMID:24290378

  5. Identification of Functional Variants for Cleft Lip with or without Cleft Palate in or near PAX7, FGFR2, and NOG by Targeted Sequencing of GWAS Loci

    PubMed Central

    Leslie, Elizabeth J.; Taub, Margaret A.; Liu, Huan; Steinberg, Karyn Meltz; Koboldt, Daniel C.; Zhang, Qunyuan; Carlson, Jenna C.; Hetmanski, Jacqueline B.; Wang, Hang; Larson, David E.; Fulton, Robert S.; Kousa, Youssef A.; Fakhouri, Walid D.; Naji, Ali; Ruczinski, Ingo; Begum, Ferdouse; Parker, Margaret M.; Busch, Tamara; Standley, Jennifer; Rigdon, Jennifer; Hecht, Jacqueline T.; Scott, Alan F.; Wehby, George L.; Christensen, Kaare; Czeizel, Andrew E.; Deleyiannis, Frederic W.-B.; Schutte, Brian C.; Wilson, Richard K.; Cornell, Robert A.; Lidral, Andrew C.; Weinstock, George M.; Beaty, Terri H.; Marazita, Mary L.; Murray, Jeffrey C.

    2015-01-01

    Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans. PMID:25704602

  6. Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci.

    PubMed

    Leslie, Elizabeth J; Taub, Margaret A; Liu, Huan; Steinberg, Karyn Meltz; Koboldt, Daniel C; Zhang, Qunyuan; Carlson, Jenna C; Hetmanski, Jacqueline B; Wang, Hang; Larson, David E; Fulton, Robert S; Kousa, Youssef A; Fakhouri, Walid D; Naji, Ali; Ruczinski, Ingo; Begum, Ferdouse; Parker, Margaret M; Busch, Tamara; Standley, Jennifer; Rigdon, Jennifer; Hecht, Jacqueline T; Scott, Alan F; Wehby, George L; Christensen, Kaare; Czeizel, Andrew E; Deleyiannis, Frederic W-B; Schutte, Brian C; Wilson, Richard K; Cornell, Robert A; Lidral, Andrew C; Weinstock, George M; Beaty, Terri H; Marazita, Mary L; Murray, Jeffrey C

    2015-03-05

    Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. A Study on Genetic Variants of Fibroblast Growth Factor Receptor 2 (FGFR2) and the Risk of Breast Cancer from North India

    PubMed Central

    Siddiqui, Sarah; Chattopadhyay, Shilpi; Akhtar, Md. Salman; Najm, Mohammad Zeeshan; Deo, S. V. S.; Shukla, N. K.; Husain, Syed Akhtar

    2014-01-01

    Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694), respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0–1 risk loci, those with 2–4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152–2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was

  8. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

    PubMed

    Campbell, Thomas M; Castro, Mauro A A; de Santiago, Ines; Fletcher, Michael N C; Halim, Silvia; Prathalingam, Radhika; Ponder, Bruce A J; Meyer, Kerstin B

    2016-08-01

    The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.

  9. FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis.

    PubMed

    Huang, Yuan-Ling; Chou, Wen-Cheng; Hsiung, Chia-Ni; Hu, Ling-Yueh; Chu, Hou-Wei; Shen, Chen-Yang

    2015-06-15

    The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand-break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR. Our results show that expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy. This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer.

  10. Activating Somatic FGFR2 Mutations in Breast Cancer

    PubMed Central

    Reintjes, Nadine; Li, Yun; Becker, Alexandra; Rohmann, Edyta; Schmutzler, Rita; Wollnik, Bernd

    2013-01-01

    It is known that FGFR2 gene variations confer a risk for breast cancer. FGFR2 and FGF10, the main ligand of FGFR2, are both overexpressed in 5–10% of breast tumors. In our study, we sequenced the most important coding regions of FGFR2 in somatic tumor tissue of 140 sporadic breast cancer patients and performed MLPA analysis to detect copy number variations in FGFR2 and FGF10. We identified one somatic heterozygous missense mutation, p.K660N (c.1980G>C), within the tyrosine kinase domain of FGFR2 in tumor tissue of a sporadic breast cancer patient, which is likely mediated by the FGFR2-IIIb isoform. The presence of wild type and mutated alleles in equal quantities suggests that the mutation has driven clonal amplification of mutant cells. We have analyzed the tyrosine kinase activity of p.K660N and another recently described somatic breast cancer mutation in FGFR2, p.R203C, after expression in HEK293 cells and demonstrated that the intrinsic tyrosine kinase activity of both mutant proteins is strongly increased resulting in elevated phosphorylation and activity of downstream effectors. To our knowledge, this is the first report of functional analysis of somatic breast cancer mutations in FGFR2 providing evidence for the activating nature of FGFR2-mediated signalling in the pathogenesis of breast cancer. PMID:23527311

  11. Role of FGFR2-signaling in the pathogenesis of acne

    PubMed Central

    2009-01-01

    It is the purpose of this review to extend our understanding of the fibroblast growth factor (FGF) receptor-2b-signaling network in the pathogenesis of acne. A new concept of the role of FGFR2b-signaling in dermal-epithelial interaction for skin appendage formation, pilosebaceous follicle homeostasis, comedogenesis, sebaceous gland proliferation and lipogenesis is presented. The FGFR2-gain-of-function mutations in Apert syndrome and unilateral acneiform nevus are most helpful model diseases pointing the way to androgen-dependent dermalepithelial FGFR2-signaling in acne. Androgen-mediated upregulation of FGFR2b-signaling in acne-prone skin appears to be involved in the pathogenesis of acne vulgaris. In organotypic skin cultures, keratinocyte-derived interleukin-1α stimulated fibroblasts to secrete FGF7 which stimulated FGFR2b-mediated keratinocyte proliferation. Postnatal deletion of FGFR2b in mice resulted in severe sebaceous gland atrophy. The importance of FGFR2b in sebaceous gland physiology is further supported by the mode of action of anti-acne agents which have been proposed to attenuate FGFR2b-signaling. Downregulation of FGFR2b-signaling by isotretinoin explains its therapeutic effect in acne. Downregulation of FGFR2b-signaling during the first trimester of pregnancy disturbs branched morphogenesis and explains retinoid embryotoxicity. Insulin-like growth factor-1 (IGF-1), the mediator of growth hormone during puberty, intracts with androgen-dependent FGFR2b-signaling and links androgen- and FGF-mediated signal transduction important in sebaceous gland homeostasis. The search for a follicular defect in the dermalepithelial regulation of growth factor-signaling in acne-prone skin appears to be a most promising approach to clarify the pathogenesis of acne. PMID:20436882

  12. Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer.

    PubMed

    Cerliani, Juan P; Vanzulli, Silvia I; Piñero, Cecilia Pérez; Bottino, María C; Sahores, Ana; Nuñez, Myriam; Varchetta, Romina; Martins, Rubén; Zeitlin, Eduardo; Hewitt, Stephen M; Molinolo, Alfredo A; Lanari, Claudia; Lamb, Caroline A

    2012-06-01

    Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-β-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.

  13. FGFR2 mutation in 46,XY sex reversal with craniosynostosis

    PubMed Central

    Bagheri-Fam, Stefan; Ono, Makoto; Li, Li; Zhao, Liang; Ryan, Janelle; Lai, Raymond; Katsura, Yukako; Rossello, Fernando J.; Koopman, Peter; Scherer, Gerd; Bartsch, Oliver; Eswarakumar, Jacob V.P.; Harley, Vincent R.

    2015-01-01

    Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the ‘knock-in’ Crouzon mouse model Fgfr2cC342Y/C342Y carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2cC342Y/− mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination. PMID:26362256

  14. FGFR2 mutation in 46,XY sex reversal with craniosynostosis.

    PubMed

    Bagheri-Fam, Stefan; Ono, Makoto; Li, Li; Zhao, Liang; Ryan, Janelle; Lai, Raymond; Katsura, Yukako; Rossello, Fernando J; Koopman, Peter; Scherer, Gerd; Bartsch, Oliver; Eswarakumar, Jacob V P; Harley, Vincent R

    2015-12-01

    Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.

  15. Pfeiffer syndrome caused by haploinsufficient mutation of FGFR2.

    PubMed

    Tsukuno, M; Suzuki, H; Eto, Y

    1999-01-01

    Mutations of the fibroblast growth factor receptors (FGFRs) cause several dominantly inherited congenital skeletal disorders and syndromes. Recently, these mutations have been suggested to cause either ligand-independent activation of the receptor or a dominant negative inactivation. The analysis of two Japanese patients with Pfeiffer syndrome and postaxial polydactyly of the hand now shows that both carried the same 1119-2A-to-G transition of the FGFR2 gene and this nonsense mutation caused skipping of exon 9(B) and haploinsufficiency of FGFR2.

  16. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma

    PubMed Central

    Goyal, Lipika; Saha, Supriya K.; Liu, Leah Y.; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G.; Lennerz, Jochen K.; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura; Sun, Jiaoyuan Elisabeth; Van Seventer, Emily E.; Gurski, Joseph M.; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P.; Stone, James R.; Iafrate, A. John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B.; Bardeesy, Nabeel; Zhu, Andrew X.

    2017-01-01

    Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide development of future therapeutic strategies. PMID:28034880

  17. Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.

    PubMed

    Goyal, Lipika; Saha, Supriya K; Liu, Leah Y; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G; Lennerz, Jochen K; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura; Sun, Jiaoyuan Elisabeth; Van Seventer, Emily E; Gurski, Joseph M; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P; Stone, James R; Iafrate, A John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B; Bardeesy, Nabeel; Zhu, Andrew X

    2017-03-01

    Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.

  18. Association of FGFR2 gene polymorphisms with the risk of breast cancer in population of West Siberia

    PubMed Central

    Boyarskikh, Uljana A; Zarubina, Natalja A; Biltueva, Julia A; Sinkina, Tatjana V; Voronina, Elena N; Lazarev, Aleksander F; Petrova, Valentina D; Aulchenko, Yurii S; Filipenko, Maxim L

    2009-01-01

    Polymorphisms within intron 2 of the FGFR2 gene have been associated with increased risk of breast cancer (BC) in European and Asian populations. The study by Easton et al reported two FGFR2 SNPs, rs2981582 and rs7895676, to be among those most strongly associated with BC risk. Statistical modeling suggested that rs7895676 was the variant responsible for the association observed in the region. In this work, we studied the association between seven FGFR2 SNPs, including rs2981582 and rs7895676, and BC risk in the Russian population of 766 case and 665 control women from Siberia, Russian Federation. In our population, allelic frequencies and the magnitude of linkage disequilibrium (LD) were different from those observed in European and Asian populations. The following three SNPs were significantly associated with BC in our study: rs7895676[C] (odds ratio (OR)=1.28 (1.12–1.43), P=1.7 × 10−3), rs2981582[T] (OR=1.46 (1.30–1.62), P=2 × 10−6) and rs3135718[G] (OR=1.43 (1.27–1.58), P=6 × 10−6). The latter two SNPs were in strong (r2=0.95) LD in our sample. Maximum likelihood analysis showed that the model, including rs7895676, only explains that the association is significantly (P<0.001) worse than any of the models, including either rs2981582 or rs3135718. Thus, in addition to the confirmation of association of FGFR2 with the BC risk in this new population, our study has suggested that rs7895676 is not likely to represent the causative variant. PMID:19536173

  19. Tissue-specific roles of Fgfr2 in development of the external genitalia

    PubMed Central

    Gredler, Marissa L.; Seifert, Ashley W.; Cohn, Martin J.

    2015-01-01

    Congenital anomalies frequently occur in organs that undergo tubulogenesis. Hypospadias is a urethral tube defect defined by mislocalized, oversized, or multiple openings of the penile urethra. Deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis. In the genital tubercle, the embryonic precursor of the penis and clitoris, Fgfr2 is expressed in two epithelial populations: the endodermally derived urethral epithelium and the ectodermally derived surface epithelium. Here, we investigate the tissue-specific roles of Fgfr2 in external genital development by generating conditional deletions of Fgfr2 in each of these cell types. Conditional deletion of Fgfr2 results in two distinct phenotypes: endodermal Fgfr2 deletion causes mild hypospadias and inhibits maturation of a complex urethral epithelium, whereas loss of ectodermal Fgfr2 results in severe hypospadias and absence of the ventral prepuce. Although these cell type-specific mutants exhibit distinctive genital anomalies, cellular analysis reveals that Fgfr2 regulates epithelial maturation and cell cycle progression in the urethral endoderm and in the surface ectoderm. The unexpected finding that ectodermal deletion of Fgfr2 results in the most severe hypospadias highlights a major role for Fgfr2 in the developing genital surface epithelium, where epithelial maturation is required for maintenance of a closed urethral tube. These results demonstrate that urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra are controlled by discrete regions of Fgfr2 activity. PMID:26081573

  20. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

    PubMed Central

    Cox, David G.; Curtit, Elsa; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Hervé; Bachelot, Thomas; Soulié, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine; Darut-Jouve, Ariane; Ferrero, Jean-Marc; Tarpin, Carole; Lévy, Christelle; Delecroix, Valérie; Trillet-Lenoir, Véronique; Cojocarasu, Oana; Meunier, Jérôme; Pierga, Jean-Yves; Faure-Mercier, Céline; Blanché, Hélène; Sahbatou, Mourad; Boland, Anne; Bacq, Delphine; Besse, Céline; Deleuze, Jean-François; Pauporté, Iris; Thomas, Gilles; Pivot, Xavier

    2016-01-01

    Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10−12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10−11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors. PMID:27764800

  1. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients.

    PubMed

    Cox, David G; Curtit, Elsa; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Hervé; Bachelot, Thomas; Soulié, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine; Darut-Jouve, Ariane; Ferrero, Jean-Marc; Tarpin, Carole; Lévy, Christelle; Delecroix, Valérie; Trillet-Lenoir, Véronique; Cojocarasu, Oana; Meunier, Jérôme; Pierga, Jean-Yves; Faure-Mercier, Céline; Blanché, Hélène; Sahbatou, Mourad; Boland, Anne; Bacq, Delphine; Besse, Céline; Deleuze, Jean-François; Pauporté, Iris; Thomas, Gilles; Pivot, Xavier

    2016-11-22

    Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.

  2. Association between rs2981582 polymorphism in the FGFR2 gene and the risk of breast cancer in Mexican women

    PubMed Central

    Murillo-Zamora, Efrén; Moreno-Macías, Hortensia; Ziv, Elad; Romieu, Isabelle; Lazcano-Ponce, Eduardo; Ángeles-Llerenas, Angélica; Pérez-Rodríguez, Edelmiro; Vidal-Millán, Silvia; Fejerman, Laura; Torres-Mejía, Gabriela

    2014-01-01

    Background and Aims The rs2981582 single nucleotide polymorphism in the Fibroblast Growth Factor Receptor 2 gene has been consistently associated with an increased risk of breast cancer. We evaluated the effect of rs2981582 polymorphism in the FGFR2 gene on the risk of breast cancer and its interaction with non-genetic risk factors. Methods A population based case control study was conducted in Mexico. Data from 687 cases and 907 controls were analyzed. Results The T allele of the rs2981582 polymorphism was associated with an increased risk of breast cancer (OR per allele =1.24, 95% CI 1.06 – 1.46). There was also an interaction between this polymorphism and alcohol consumption (p = 0.043); the effect of alcohol consumption on the risk of breast cancer varied according to the allelic variants of the rs2981582 polymorphism in the FGFR2 gene: OR = 3.97 (95% CI 2.10 – 7.49), OR = 2.01 (95% CI 1.23 − 3.29) and OR = 1.21 (95% CI 0.48 − 3.05) for genotypes CC, CT and TT, respectively. Conclusions This is the first study exploring the association between rs2981582 polymorphism in the FGFR2 gene and breast cancer risk in Mexican women. The interaction found may be of great public health interest, since alcohol consumption is a modifiable breast cancer risk factor. Therefore, replication of this finding is of foremost importance. PMID:24054997

  3. Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome.

    PubMed

    Lajeunie, Elisabeth; Heuertz, Solange; El Ghouzzi, Vincent; Martinovic, Jelena; Renier, Dominique; Le Merrer, Martine; Bonaventure, Jacky

    2006-03-01

    Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

  4. S267P mutation in FGFR2: first report in a patient with Crouzon syndrome.

    PubMed

    Ke, Ronghu; Yang, Xianxian; Ge, Min; Cai, Tianyi; Lei, Jiaqi; Mu, Xiongzheng

    2015-03-01

    It has been known for several years that mutations in the fibroblast growth factor receptor (FGFR2) result in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Here, we report on a child with a clinically diagnosed Crouzon syndrome that shows the missense point mutation S267P in FGFR2 gene. The mutation is firstly identified in Crouzon syndrome. Our observations expand the molecular spectrum of FGFR2 mutations in the syndrome.

  5. Severe meningeal calcification in a Crouzon patient carrying a mutant C342W FGFR2.

    PubMed

    Ke, Ronghu; Lei, Jiaqi; Ge, Min; Cai, Tianyi; Yang, Junyi; Wu, Yingzhi; Mu, Xiongzheng

    2015-03-01

    Crouzon is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of mineralization. Here, we presented a 5-year-old girl with severe meningeal calcification. Subsequently, we analyzed FGFR2 mutation and identified a mutation of Cys342Tyr. The findings suggest that abnormal calcification was atypical phenotype of Crouzon patients with Cys342Tyr mutation in FGFR2.

  6. FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies.

    PubMed

    Katoh, Masaru

    2009-08-01

    Fibroblast growth factor receptor (FGFR)2 is regulated on the basis of the balance of FGFs, heparan-sulfate proteoglycans, FGFR2 isoforms, endogenous inhibitors, and microRNAs. FGFR2 signals cross-talk with hedgehog, bone morphogenetic protein, and other regulatory networks. Some cases of congenital skeletal disorders with an FGFR2 mutation show skin phenotypes, including acne, cutis gyrata, and acanthosis nigricans. Gain-of-function mutations or variations of human FGFR2 occur in estrogen receptor-positive breast cancer, diffuse-type gastric cancer, and endometrial uterine cancer. Oral administration of AZD2171 or Ki23057 inhibits in vivo proliferation of cancer cells with aberrant FGFR2 activation in rodent therapeutic models. However, loss-of-function mutations of FGFR2 are reported in human melanoma. Conditional Fgfr2b knockout in the rodent epidermis leads to increased macrophage infiltration to the dermis and adipose tissue, epidermal thickening accompanied by basal-layer dysplasia and parakeratosis, and the promotion of chemically induced squamous-cell carcinoma. Dysregulation of FGFR2 results in a spectrum of bone and skin pathologies and several types of cancer.

  7. The Fgfr2 W290R mouse model of Crouzon syndrome.

    PubMed

    Gong, S-G

    2012-09-01

    This study aimed to review and discuss the utility of the Fgfr2 (W290R) mouse mutant as a model of human Crouzon syndrome. A review of current and past scientific literature on Fibroblast Growth Factor Receptor-2 (FGFR2) protein domain structure, FGFR mutations associated with human Crouzon syndrome, and phenotypic and molecular changes combined with recent observations and experimental data of the Fgfr2 (W290R) mouse mutant was conducted. A comparison of the Fgfr2 (W290R) mouse mutant with another mouse model of Crouzon syndrome, Fgfr2 (C342R) mouse mutant, was also performed. Finally, possible future research directions using the Fgfr2 (W290R) mutant mice were discussed. The Fgfr2 (W290R) heterozygous mouse exhibits defects characteristic of human Crouzon syndrome. At the molecular level, the defects observed in the mouse mutant are due to the dysregulation of signaling of both the IIIb and IIIc isoforms of Fgfr2. The involvement of the IIIb isoform of FGFR2 in the etiopathology of Crouzon syndrome is a novel finding in the craniosynostosis literature field. Dysregulated signaling of both IIIb and IIIc isoforms causes a broad spectrum of changes that explain some of the defects observed clinically in humans. Several of the defects observed in the Fgfr2 (W290R) homozygous mouse mutant are attributable to a loss-of-function mechanism in contrast to the frequently reported gain-of-function receptor function associated with mutated FGF receptors in craniosynostosis. The Fgfr2 ( W290R ) mouse model can be used as a model system to further investigate the cellular, molecular, and biochemical mechanisms of Crouzon syndrome.

  8. Testis determination requires a specific FGFR2 isoform to repress FOXL2.

    PubMed

    Bagheri-Fam, Stefan; Bird, Anthony D; Zhao, Liang; Ryan, Janelle M; Yong, Meiyun; Wilhelm, Dagmar; Koopman, Peter; Eswarakumar, Jacob V; Harley, Vincent R

    2017-09-11

    Male sex determination in mammals relies on SRY-mediated up-regulation of SOX9 expression in XY gonads, whereas WNT/RSPO signalling and FOXL2 drive female sex determination in XX gonads. FGF9-signalling ensures sustained SOX9 expression through repression of one of the ovarian pathways (WNT signalling), while the significance of FGF-mediated repression of the FOXL2 pathway has not been studied. Previously, we demonstrated that FGFR2 is the receptor for FGF9 in the XY gonad. Whether a specific isoform (FGFR2b or FGFR2c) is required was puzzling. Here, we show that FGFR2c is required for male sex determination. Initially, in developing mouse embryos at 12.5-13.5 days post coitum (dpc), XY Fgfr2c-/- gonads appear ovotestes, with SOX9 and FOXL2 expression predominantly localised to the posterior and anterior gonadal poles, respectively. However by 15.5dpc, XY Fgfr2c-/- gonads show complete male-to-female sex reversal, evident by the lack of SOX9 and ectopic expression of FOXL2 throughout the gonads. Furthermore, ablation of the Foxl2 gene leads to partial or complete rescue of gonadal sex reversal in XY Fgfr2c-/- mice. Together with previous findings, our data suggest that testis determination involves FGFR2c-mediated repression of both the WNT4- and FOXL2-driven ovarian determining pathways. Copyright © 2017 Endocrine Society.

  9. Treatment with FGFR2-IIIc monoclonal antibody suppresses weight gain and adiposity in KKAy mice

    PubMed Central

    Nonogaki, K; Kaji, T; Yamazaki, T; Murakami, Mari

    2016-01-01

    Expression of β-Kotho, fibroblast growth factor receptor (FGFR)-1c and 2c, which bind FGF21, is decreased in the white adipose tissue of obese mice. The aim of the present study was to determine the role of FGFR2c in the development of obesity and diabetes in KKAy mice. Treatment with mouse monoclonal FGFR2-IIIc antibody (0.5 mg kg−1) significantly suppressed body weight gain and epididymal white adipose tissue weight in individually housed KKAy mice while having no effect on daily food intake. In addition, treatment with FGFR2-IIIc antibody significantly increased plasma-free fatty acid levels while having no effect on blood glucose or plasma FGF21 levels. Moreover, treatment with FGFR2-IIIc antibody had no significant effect on the expression of uncoupling protein-1, uncoupling protein-2 or peroxisome proliferator-activated receptor-γ coactivator 1α in the epididymal white adipose tissue. The treatment with FGFR2-IIIc antibody had no significant effects on daily food intake and body weight gain in individually housed KK mice. These findings suggest that FGFR2-IIIc upregulates the adiposity induced by social isolation in KKAy mice, and that decreased expression and/or function of FGFR2c might be a compensatory response to enhanced adiposity. Inhibition of FGFR2-IIIc function might be a novel therapeutic approach for obesity. PMID:27892934

  10. Activating FGFR2-RAS-BRAF mutations in ameloblastoma.

    PubMed

    Brown, Noah A; Rolland, Delphine; McHugh, Jonathan B; Weigelin, Helmut C; Zhao, Lili; Lim, Megan S; Elenitoba-Johnson, Kojo S J; Betz, Bryan L

    2014-11-01

    Ameloblastoma is an odontogenic neoplasm whose overall mutational landscape has not been well characterized. We sought to characterize pathogenic mutations in ameloblastoma and their clinical and functional significance with an emphasis on the mitogen-activated protein kinase (MAPK) pathway. A total of 84 ameloblastomas and 40 non-ameloblastoma odontogenic tumors were evaluated with a combination of BRAF V600E allele-specific PCR, VE1 immunohistochemistry, the Ion AmpliSeq Cancer Hotspot Panel, and Sanger sequencing. Efficacy of a BRAF inhibitor was evaluated in an ameloblastoma-derived cell line. Somatic, activating, and mutually exclusive RAS-BRAF and FGFR2 mutations were identified in 88% of cases. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 were also identified. BRAF V600E was the most common mutation, found in 62% of ameloblastomas and in ameloblastic fibromas/fibrodentinomas but not in other odontogenic tumors. This mutation was associated with a younger age of onset, whereas BRAF wild-type cases arose more frequently in the maxilla and showed earlier recurrences. One hundred percent concordance was observed between VE1 immunohistochemistry and molecular detection of BRAF V600E mutations. Ameloblastoma cells demonstrated constitutive MAPK pathway activation in vitro. Proliferation and MAPK activation were potently inhibited by the BRAF inhibitor vemurafenib. Our findings suggest that activating FGFR2-RAS-BRAF mutations play a critical role in the pathogenesis of most cases of ameloblastoma. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 may function as secondary mutations. BRAF V600E mutations have both diagnostic and prognostic implications. In vitro response of ameloblastoma to a BRAF inhibitor suggests a potential role for targeted therapy. ©2014 American Association for Cancer Research.

  11. Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations

    PubMed Central

    Kim, Do-Hee; Kwak, Yeonui; Kim, Nam Doo; Sim, Taebo

    2016-01-01

    ABSTRACT Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLCγ signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLCγ and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs. PMID:26574622

  12. Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations.

    PubMed

    Kim, Do-Hee; Kwak, Yeonui; Kim, Nam Doo; Sim, Taebo

    2016-01-01

    Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLCγ signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLCγ and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs.

  13. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    SciTech Connect

    Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

    2011-04-01

    Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  14. Binding of human recombinant mutant soluble ectodomain of FGFR2IIIc to c subtype of FGFRs: implications for anticancer activity

    PubMed Central

    Li, Jun; He, Yan-Qing; Zhang, Shu-Shu; Wang, Yi; He, Wei-Yi; Cheng, Guo-Hua; Yang, Xuesong; Xu, Jun; Wang, Ju

    2016-01-01

    FGFRs are considered essential targets for cancer therapy. We previously reported that msFGFR2c, a Ser252Trp mutant soluble ectodomain of FGFR2IIIc, inhibited tumor growth by blocking FGF signaling pathway. However, the underlying molecular mechanism is still obscure. In this study, we reported that msFGFR2c but not wild-type soluble ectodomain of FGFR2IIIc (wsFGFR2c) could selectively bind to c subtype of FGFRs in the presence of FGF-2. Thermodynamic analysis demonstrated that msFGFR2c bound to wsFGFR2c in the presence of FGF-2 with a K value of 6.61 × 105 M−1. Molecular dynamics simulations revealed that the mutated residue Trp252 of msFGFR2c preferred a π-π interaction with His254 of wsFGFR2c. Concomitantly, Arg255 of msFGFR2c and Glu250 of wsFGFR2c adjusted their conformations and formed three H-bonds. These two interactions therefore stabilized the final structure of wsFGFR2c and msFGFR2c heterocomplex. In FGFR2IIIc-positive/high FGF-2-secreted BT-549 cells, msFGFR2c significantly inhibited the proliferation and induced apoptosis by the blockage of FGF-2-activated FGFRs phosphorylation, also the growth and angiogenesis of its xenograft tumors implanted in chick embryo chorioallantoic membrane model. While weaker the above inhibitory effects of msFGFR2c were observed on FGFR2IIIc-negative/low FGF-2-secreted MCF-7 and MDA-MB-231 cell lines in vitro and in vivo. Moreover, msFGFR2c significantly inhibited the proliferation of FGFR1IIIc-positive NCI-H1299 lung cancer cells by the suppression of FGF-2-induced FGFR1 activation and suppressed the growth of NCI-H1299 transplanted tumors in nude mice. In sum, msFGFR2c is a potential anti-tumor agent targeting FGFR2c/FGFR1c-positive tumor cells. These findings also provide a molecular basis for msFGFR2c to disrupt the activation of FGF signaling. PMID:28049184

  15. A novel FGFR2 mutation in tyrosine kinase II domain, L617F, in Crouzon syndrome.

    PubMed

    Suh, Ye-Jin; Bae, Han-Sol; Choi, Jin-Young; Lee, Jong-Ho; Kim, Myung-Jin; Kim, Sukwha; Ryoo, Hyun-Mo; Baek, Seung-Hak

    2014-01-01

    The purposes of this study were to find a novel mutation of FGFR2 in Korean Crouzon syndrome patients and to identify the functional consequences of this mutation. The samples consisted of 16 Crouzon patients. Peripheral venous blood was collected from the patients. FGFR2 mutation screening was performed by direct PCR sequencing of all exons and part of the introns. Restriction fragment length polymorphism (RFLP) analysis was performed to confirm the novel mutation. For functional studies, we performed luciferase assay for Runx2 transcriptional activity, real-time PCR for the bone markers (osteocalcin and alkaline phosphatase), and Western blot for phosphorylated FGFR2 and ERK1/2-MAPK protein. Among 16 patients, 10 showed FGFR2 mutations that had already been reported elsewhere. A novel FGFR2 mutation associated with tyrosine kinase II (TK-II) domain, L617F, was found in one Crouzon syndrome patient by direct PCR sequencing. Presence of this mutation was confirmed using RFLP analysis. Runx2 transcriptional activity and expression of osteocalcin and alkaline phosphatase significantly increased in L617F-transfected cells compared to wild-type cells. FGFR2 autophosphorylation in L617F-transfected cells increased in 1% serum, but ERK1/2-MAPK protein was not activated. The FGFR2-L617F mutation associated with the TK domain is potentially related to premature suture closure in Crouzon syndrome patient. © 2013 Wiley Periodicals, Inc.

  16. The C342R mutation in FGFR2 causes Crouzon syndrome with elbow deformity.

    PubMed

    Ke, Ronghu; Yang, Xianxian; Tianyi, Cai; Ge, Min; Lei, Jiaqi; Mu, Xiongzheng

    2015-03-01

    Crouzon syndrome is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor 2 (FGFR-2). Numerous findings from animal studies imply a critical role for FGFRs in the regulation of skeletal development. Here, we report 2 unrelated patients with Crouzon syndrome accompanied by elbow deformity. Subsequently, we analyzed the sequence of the FGFR2 gene and found that both of the patients carried the Cys342Arg mutation. The findings suggest that the C342R mutation in FGFR2 may cause Crouzon syndrome and elbow deformity in Chinese patients.

  17. FGFR1 and FGFR2 mutations in Pfeiffer syndrome.

    PubMed

    Chokdeemboon, Chayanin; Mahatumarat, Charan; Rojvachiranonda, Nond; Tongkobpetch, Siraprapa; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

    2013-01-01

    Pfeiffer syndrome (PS) (MIM 101600) is one of the most common syndromic forms of craniosynostosis. It is characterized by craniosysnostosis, midface hypoplasia, broad and medially deviated thumbs, and great toes with partial syndactyly of the digits. Here, we described clinical and genetic features of 12 unrelated Thai individuals with PS. All 12 patients were sporadic, and advanced paternal age was found in 50% of the cases. Polymerase chain reaction sequencing of FGFR1 exon 5 and FGFR2 exons 8, 10, 15, 16, and 17 was performed in all PS patients and revealed 9 recurrent mutations in all patients. Most of the mutations clustered in exons 8 and 10 (9/12) accounting for 75% of PS cases. The most frequently detected mutation, p.S351C, was associated with the severe form of PS in the Thai population. Less frequent mutations in exons 16 (p.K641R) and 17 (p.G663E) were also identified. In addition, the p.P252R mutation in FGFR1 was detected in 1 PS patient with unilateral coronal craniosynostosis expanding the phenotypic spectrum of PS with this particular mutation. Knowing the mutation spectrum of the responsible genes could lead to the most effective strategy in identifying mutations causing Pfeiffer syndrome in the Thai population.

  18. [Analysis of FGFR2 gene mutations in two Chinese families with Crouzon syndrome].

    PubMed

    Huang, Yanru; Mei, Libin; Su, Wei; Yang, Pu; Liang, Desheng; Wu, Lingqian; Pan, Qian

    2014-06-01

    To detect potential mutations of fibroblast growth factor receptor 2 gene (FGFR2) in two Chinese families with Crouzon syndrome. Genomic DNA was extracted from peripheral blood leukocytes of 20 members from two affected families. All of the 18 exons of the FGFR2 gene were amplified with polymerase chain reaction and sequenced after purification. A missense mutation c.868T>C (p.W290R) in exon 8 of the FGFR2 gene was found solely in 2 affected members from family 1. Another missense mutation c.833G>T (p.C278F) in exon 8 was found solely in 5 affected members of family 2. The missense mutations of the FGFR2 gene are responsible for the Crouzon syndrome in the two families. The c.868T>C missense mutation is reported for the first time in Chinese population.

  19. [FGFR2 gene mutation in a family with Crouzon syndrome and a sporadic Crouzon syndrome patient].

    PubMed

    Guo, Lu; Lai, Yan-ni; Li, Lian-xi

    2008-04-01

    To detect the gene mutation of fibroblast growth factor receptor (FGFR2)in a Crouzon syndrome family and a sporadic patient. The genomic DNA from 10 members in the Crouzon syndrome family, as well as a sporadic patient, was extracted. Then exons 8 and 10 of FGFR2 gene and their flanking sequences were amplified by polymerase chain reaction. Some of the family members were studied by only amplifying exon 8. Finally, the PCR products were purified and sequenced. The G to T transversion mutation (heterozygote) at nucleotide 833 in exon 8 of FGFR2 (C278F), was found both in the patients of the family and the sporadic patient. FGFR2 gene mutation is responsible for the pathogenesis of Crouzon syndrome in these patients.

  20. Generalized Comedones, Acne, and Hidradenitis Suppurativa in a Patient with an FGFR2 Missense Mutation

    PubMed Central

    Higgins, Rebecca; Pink, Andrew; Hunger, Robert; Yawalkar, Nikhil; Navarini, Alexander A.

    2017-01-01

    Mutations in the fibroblast growth factor-receptor gene 2 (FGFR2) gene have been implicated in numerous diseases, including nevus comedonicus (NC) and naevoid acne that have somatic missense mutations in FGFR2 in the affected tissue. A patient presented in our department with unusual, innumerable large comedones throughout his back reminiscient of NC, as well as multifocal hidradenitis suppurativa and acne. Topical and systemic treatments were unsuccessful. Whole exome sequencing of blood-derived DNA detected a germline mutation in FGFR2 that was predicted to be damaging. This could explain the multifocal and severe nature of the disease. We suggest screening other, phenotypically similar patients for FGFR2 mutations. Our findings, once confirmed independently, could indicate that therapeutic modulation of FGFR signaling in the acne tetrad could be effective. PMID:28293556

  1. Therapeutic Effect of Nanogel-Based Delivery of Soluble FGFR2 with S252W Mutation on Craniosynostosis

    PubMed Central

    Yokota, Masako; Kobayashi, Yukiho; Morita, Jumpei; Suzuki, Hiroyuki; Hashimoto, Yoshihide; Sasaki, Yoshihiro; Akiyoshi, Kazunari; Moriyama, Keiji

    2014-01-01

    Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder. PMID:25003957

  2. Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis.

    PubMed

    Yokota, Masako; Kobayashi, Yukiho; Morita, Jumpei; Suzuki, Hiroyuki; Hashimoto, Yoshihide; Sasaki, Yoshihiro; Akiyoshi, Kazunari; Moriyama, Keiji

    2014-01-01

    Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder.

  3. Twist1 correlates with poor differentiation and progression in gastric adenocarcinoma via elevation of FGFR2 expression

    PubMed Central

    Zhu, Dong-Yuan; Guo, Qi-Sen; Li, Yan-Liang; Cui, Bin; Guo, Jun; Liu, Ji-Xiao; Li, Peng

    2014-01-01

    AIM: To explore the correlation between Twist-related protein (Twist)1, fibroblast growth factor receptor (FGFR)2 and gastric adenocarcinoma differentiation and progression. METHODS: We evaluated Twist1 and FGFR2 in 52 gastric adenocarcinoma samples by immunohistochemistry and quantitative real time polymerase chain reaction, and analyzed the correlation between Twist1, FGFR2 and cancer differentiation. We also detected Twist1 and FGFR2 expression in gastric adenocarcinoma cell lines, and evaluated Twist1 influence on FGFR2 expression. In addition, we studied the role of FGFR2 in Twist1-promoted cancer progression, including proliferation, invasion and epithelial-mesenchymal transition (EMT). RESULTS: Twist1 and FGFR2 were detected in almost all the gastric adenocarcinoma samples. Twist1 (P = 0.0213) and FGFR2 (P = 0.0310) mRNA levels had a significant association with gastric adenocarcinoma differentiation. Moreover, Twist1 and FGFR2 expression in poorly differentiated cells (SNU-1 and SNU-16) was notably higher than in well-differentiated cells (MKN-7 and MKN-28). In poorly differentiated gastric adenocarcinomas, FGFR2 mRNA level was significantly positively correlated with Twist1 mRNA level (P = 0.004). Twist1 was proved to promote FGFR2 by regulating Twist1 expression by knockdown and overexpression. Additionally, Twist1 could induce proliferation, invasion and EMT in gastric cancer; of these, FGFR2 was required for invasion and EMT, rather than proliferation. CONCLUSION: Twist1 and FGFR2 are highly associated with differentiation of gastric adenocarcinoma; Twist1 can facilitate invasion and EMT in gastric adenocarcinoma via promotion of FGFR2 expression. PMID:25561797

  4. Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts.

    PubMed

    Suzuki, Hiroyuki; Suda, Naoto; Shiga, Momotoshi; Kobayashi, Yukiho; Nakamura, Masataka; Iseki, Sachiko; Moriyama, Keiji

    2012-09-01

    Apert syndrome is characterized by craniosynostosis and syndactyly, and is predominantly caused by mutation of either S252W or P253W in the fibroblast growth factor receptor (FGFR) 2 gene. In this study, we characterized the effects of one of the mutations (S252W) using primary calvarial osteoblasts derived from transgenic mice, Ap-Tg and sAp-Tg, that expressed an Apert-type mutant FGFR2 (FGFR2IIIc-S252W; FGFR2IIIc-Ap), and the soluble form (extracellular domain only) of the mutant FGFR2 (sFGFR2IIIc-Ap), respectively. Compared to WT-derived osteoblasts, osteoblasts from Ap-Tg mouse showed a higher proliferative activity and enhanced differentiation, while those from sAp-Tg mouse exhibited reduced potential for proliferation and osteogenic differentiation. When transplanted with β-tricalcium phosphate (β-TCP) granules into immunodeficient mice, Ap-Tg-derived osteoblasts showed a higher bone forming capacity, whereas sAp-Tg-derived osteoblasts were completely deficient for this phenotype. Phosphorylation of extracellular signal-regulated kinase (ERK), MEK, PLCγ, and p38 was increased in Ap-Tg-derived osteoblasts, whereas phosphorylation of these signaling molecules was reduced in sAp-Tg-derived osteoblasts. Interestingly, when these experiments were carried out using osteoblasts from the mice generated by crossing Ap-Tg and sAp-Tg (Ap/sAp-Tg), which co-expressed FGFR2IIIc-Ap and sFGFR2IIIc-Ap, the results were comparable to those obtained from WT-derived osteoblasts. Taken together, these results indicate that osteoblasts expressing FGFR2IIIc-Ap proliferate and differentiate via highly activated MEK, ERK, and p38 pathways, while these pathways are suppressed in osteoblasts expressing sFGFR2IIIc-Ap. Our findings also suggest that altered FGFR2IIIc signaling in osteoblasts is mostly responsible for the phenotypes seen in Apert syndrome, therefore these osteoblast cell lines are useful tools for investigating the pathogenesis of Apert syndrome. Copyright © 2011

  5. Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome.

    PubMed

    Torres, Lilian; Hernández, Gualberto; Barrera, Alejandro; Ospina, Sandra; Prada, Rolando

    2015-09-30

    Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.

  6. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome

    PubMed Central

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V.P.; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-01-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak-like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811-812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the

  7. Interaction between FGFR-2, STAT5, and progesterone receptors in breast cancer.

    PubMed

    Cerliani, Juan P; Guillardoy, Tomás; Giulianelli, Sebastián; Vaque, José P; Gutkind, J Silvio; Vanzulli, Silvia I; Martins, Rubén; Zeitlin, Eduardo; Lamb, Caroline A; Lanari, Claudia

    2011-05-15

    Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment.

  8. Novel mutation detection of fibroblast growth factor receptor 1 (FGFR1) gene, FGFR2IIIa, FGFR2IIIb, FGFR2IIIc, FGFR3, FGFR4 gene for craniosynostosis: A prospective study in Asian Indian patient

    PubMed Central

    Barik, Mayadhar; Bajpai, Minu; Malhotra, Arun; Samantaray, Jyotish Chandra; Dwivedi, Sadananda; Das, Sambhunath

    2015-01-01

    Background: Craniosynostosis (CS) syndrome is an autosomal dominant condition classically combining craniosynostosis and non-syndromic craniosynostosis with digital anomalies of the hands and feet. The majority of cases are caused by heterozygous mutations in the third immunoglobulin-like domain (IgIII) of FGFR2, whilst a larger number of cases can be attributed to mutations outside this region of the protein. Aims: To find out the FGFR1, FGFR2, FGFR3 and FGFR4 gene in craniosynostosis syndrome. Settings and Design: A hospital based prospective study. Materials and Methods: Prospective analysis of clinical records of patients registered in CS clinic from December 2007 to January 2015 was done in patients between 4 months to 13 years of age. We have performed genetic findings in a three generation Indian family with Craniosynostosis syndrome. Results: We report for the first time the clinical and genetic findings in a three generation Indian family with Craniosynostosis syndrome caused by a heterozygous missense mutation, Thr 392 Thr and ser 311 try, located in the IgII domain of FGFR2. FGFR 3 and 4 gene basis syndrome was eponymously named. Genetic analysis demonstrated that 51/56 families to be unrelated. In FGFR3 gene 10/TM location of 1172 the nucleotide changes C>A, Ala 391 Glu 19/56 and Exon-19, 5q35.2 at conserved linker region the changes occurred pro 246 Arg in 25/56 families. Conclusions: Independent genetic origins, but phenotypic similarities in the 51 families add to the evidence supporting the theory of selfish spermatogonial selective advantage for this rare gain-of-function FGFR2 mutation. PMID:26557159

  9. Soluble form of FGFR2 with S252W partially prevents craniosynostosis of the apert mouse model.

    PubMed

    Morita, Jumpei; Nakamura, Masataka; Kobayashi, Yukiho; Deng, Chu-Xia; Funato, Noriko; Moriyama, Keiji

    2014-04-01

    Apert syndrome (AS) is characterized by craniosynostosis, midfacial hypoplasia, and bony syndactyly. It is an autosomal dominantly inherited disease caused by point mutations (S252W or P253R) in fibroblast growth factor receptor (FGFR) 2. These mutations cause activation of FGFR2 depending on ligand binding. Recently, an AS mouse model, Fgfr2(+/) (S252W) , showed phenotypes similar to those of AS patients. We previously reported that the soluble form of FGFR2(S252W) (sFGFR2IIIc(S252W) ) efficiently inhibits enhanced osteoblastic differentiation caused by FGFR2 activation in AS in vitro, presumably because FGFs binding to FGFRs is interrupted. In this study, we developed Fgfr2(+/) (S252W) (Ap) mice expressing the sFGFR2IIIc(S252W) protein, and we investigated the effects of sFGFR2IIIc(S252W) on AS-like phenotypes. In Ap mice, the coronal suture (CS) was fused prematurely at P1. In addition, the mice exhibited a widened interfrontal suture (IFS) with ectopic bone and thickened cartilage formation. In Fgfr2(+/) (S252W) sFGFR2IIIc(S252W) (Ap/Sol) mice, the CS was similar to that of wild-type mice. Ap/Sol mice did not show any ectopic bone or cartilage formation in the IFS, but showed a wider IFS than that of the wild-type mice. sFGFR2IIIc(S252W) may partially prevent craniosynostosis in the Apert mouse model by affecting the CS and IFS in vivo. Copyright © 2013 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

  10. Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome

    PubMed Central

    2014-01-01

    Background Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. Case presentation Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. Conclusions These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations. PMID:25174698

  11. Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome.

    PubMed

    Fenwick, Aimee L; Goos, Jacqueline A C; Rankin, Julia; Lord, Helen; Lester, Tracy; Hoogeboom, A Jeannette M; van den Ouweland, Ans M W; Wall, Steven A; Mathijssen, Irene M J; Wilkie, Andrew O M

    2014-08-31

    Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations.

  12. FGFR2 molecular analysis and related clinical findings in one Chinese family with Crouzon syndrome.

    PubMed

    Lin, Ying; Liang, Xuanwei; Ai, Siming; Chen, Chuan; Liu, Xialin; Luo, Lixia; Ye, Shaobi; Li, Baoxin; Liu, Yizhi; Yang, Huasheng

    2012-01-01

    The purposed of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in one Chinese family with Crouzon syndrome and to characterize the related clinical features. One family underwent complete ophthalmic examinations, and two patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from the family and 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull. The two patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, and clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.866A>C (Gln289Pro) in exon 8 was identified in the affected individuals, but not in any of the unaffected family members and the normal controls. Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 mutation in Chinese patients with Crouzon syndrome.

  13. FGFR2 molecular analysis and related clinical findings in one Chinese family with Crouzon Syndrome

    PubMed Central

    Lin, Ying; Liang, Xuanwei; Ai, Siming; Chen, Chuan; Liu, Xialin; Luo, Lixia; Ye, Shaobi; Li, Baoxin; Yang, Huasheng

    2012-01-01

    Purpose The purposed of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in one Chinese family with Crouzon syndrome and to characterize the related clinical features. Methods One family underwent complete ophthalmic examinations, and two patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from the family and 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull. Results The two patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, and clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.866A>C (Gln289Pro) in exon 8 was identified in the affected individuals, but not in any of the unaffected family members and the normal controls. Conclusions Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 mutation in Chinese patients with Crouzon syndrome. PMID:22355256

  14. A novel exonic variant (221delT) in the LGALS13 gene encoding placental protein 13 (PP13) is associated with preterm labour in a low risk population.

    PubMed

    Gebhardt, S; Bruiners, N; Hillermann, R

    2009-11-01

    Predicting adverse pregnancy outcome in low risk patients in a community with poor socio-economic circumstances is difficult, yet about 5% of these pregnancies will result in preterm labour or severe pre-eclampsia. In this study we aimed to identify markers in pro- and anti-inflammatory genes that may contribute to disease and possibly disease prediction in a low risk community setting. A prospective study was undertaken on 450 consecutive low risk primigravid patients. Blood obtained at first booking was screened for known immunological gene variants (IL4 -590, IL1B +3953, IL1RN, IL10 -1082; -819; -592 and TNFA -308; -238; +488) as well as for novel variants in the LGALS13 gene coding for placental protein 13 (PP13). The incidence of preterm labour and pre-eclampsia was 7.1% and 6.8% respectively. A novel exonic variant (221delT) in the LGALS13 gene increased the risk for preterm labour in the total study group (relative risk RR 2.27). Maternal carriage of the interleukin-1 RN*2 allele was associated with an increased risk of hypertension in pregnancy in the Coloured subgroup of the study cohort (RR 2.53). There was an increased risk for preterm labour in the same subgroup with carriage of the TNFA -308 A-allele (TNF2) (RR 2.53). No significance was found for the other variants examined. We conclude that single nucleotide polymorphisms (SNPs) in certain genes regulating implantation and inflammation may contribute to the complex etiology of pre-eclampsia and preterm labour. The association between the 221delT deletion and adverse pregnancy outcome needs to be confirmed in different populations.

  15. Terminal end bud maintenance in mammary gland is dependent upon FGFR2b signaling.

    PubMed

    Parsa, Sara; Ramasamy, Suresh K; De Langhe, Stijn; Gupte, Varsha V; Haigh, Jody J; Medina, Daniel; Bellusci, Savério

    2008-05-01

    We previously demonstrated that Fibroblast Growth Factor 10 (FGF10) and its receptor FGFR2b play a key role in controlling the very early stages of mammary gland development during embryogenesis [Mailleux, A.A., Spencer-Dene, B., Dillon, C., Ndiaye, D., Savona-Baron, C., Itoh, N., Kato, S., Dickson, C., Thiery, J.P., and Bellusci, S. (2002). Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 129, 53-60. Veltmaat, J. M., Relaix, F., Le, L.T., Kratochwil, K., Sala, F.G., van Veelen, W., Rice, R., Spencer-Dene, B., Mailleux, A.A., Rice, D.P., Thiery, J.P., and Bellusci, S. (2006). Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 133, 2325-35.]. However, the role of FGFR2b signaling in postnatal mammary gland development is still elusive. We show that FGF10 is expressed at high level throughout the adipose tissue in the mammary gland of young virgin female mice whereas its main receptor FGFR2 is found mostly in the epithelium. Using a rtTA transactivator/tetracycline promoter approach allowing inducible and reversible attenuation of the FGFR2b signaling throughout the adult mouse, we are now reporting that FGFR2b signaling is also critical during postnatal mammary gland development. Ubiquitous attenuation of FGFR2b signaling in the postnatal mouse for 6 weeks starting immediately after birth is not lethal and leads to minor defects in the animal. Upon dissection of the mammary glands, a 40% reduction in size compared to the WT control is observed. Further examination shows a rudimentary mammary epithelial tree with completely absent terminal end buds (TEBs), compared to a well-branched structure observed in wild type. Transplantation of mammary gland explants into cleared fat pad of wild type mouse recipients indicates that the observed abnormal branching results from defective FGFR2b signaling in the epithelium. We

  16. Reciprocal interactions of Fgf10/Fgfr2b modulate the mouse tongue epithelial differentiation.

    PubMed

    Sohn, Wern-Joo; Jung, Hye-In; Choi, Min-A; Han, Jin-Hyun; Gwon, Gi-Jeong; Yamamoto, Hitoshi; Lee, Sanggyu; Ryoo, Zae Young; Park, Eui-Kyun; Shin, Hong-In; Jung, Han-Sung; Kim, Jae-Young

    2011-08-01

    The molecular mechanisms for epithelial differentiation have been studied by observing skin development in embryogenesis, but the early signaling modulations involved in tongue epithelial differentiation are not completely understood. Based on the gene expression patterns of the Fgf signaling molecules and previous results from Fgf10 and Fgfr2b knockout mice, it was hypothesized that there would be fundamental signaling interactions through the epithelial Fgfr2b and its mesenchymal ligand Fgf10 to regulate tongue epithelium differentiation. To elucidate these reciprocal interactions in tongue epithelial differentiation, this study employed an in vitro tongue organ culture system with antisense-oligodeoxynucleotides (AS-ODNs) and recombinant protein-soaked bead implantation for the loss-of-function and gain-of-function studies. Functional analysis of Fgf signaling revealed precise reciprocal interactions, which showed that mesenchymal Fgf10 rather than Fgf7 modulates tongue epithelial differentiation via Fgfr2b in a temporal- and spatial-specific manner.

  17. Functional characterization of a novel FGFR2 mutation, E731K, in craniosynostosis.

    PubMed

    Park, Jounghyen; Park, Ok-Jin; Yoon, Won-Joon; Kim, Hyun-Jung; Choi, Kang-Young; Cho, Tae-Joon; Ryoo, Hyun-Mo

    2012-02-01

    Craniosynostosis is a condition in which some or all of the sutures in the skull of an infant close prematurely. Fibroblast growth factor receptor 2 (FGFR2) mutations are a well-known cause of craniosynostosis. Many syndromes that comprise craniosynostosis, such as Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome, have one of the phenotypes that have been reported in FGFR2 mutant patients. FGFRs have been reported in four types (FGFR1-4), and upon binding with FGF ligands, signal transduction occurs inside of cells. Activated FGFR stimulates an osteogenic master transcription factor, Runx2, through the MAP kinase and PKC pathways. We obtained a genetic analysis of six Korean patients who have craniosynostosis as a phenotype. All of the patients had at least one mutation in the FGFR2 gene; five of those mutations have already been reported elsewhere, while one mutation is novel and was hypothesized to lead to Apert syndrome. In this study, we reported and functionally analyzed a novel mutation of the FGFR2 gene found in a craniosynostosis patient, E731K. The mutation is in the 2nd tyrosine kinase domain in the C-terminal cytoplasmic region of the molecule. The mutation caused an enhanced phosphorylation of the FGFR2(E731K) and ERK-MAP kinase, the stimulation of transcriptional activity of Runx2, and consequently, the enhancement of osteogenic marker gene expression. We conclude that the substitution of E731K in FGFR2 is a novel mutation that resulted in a constitutive activation of the receptor and ultimately resulted in premature suture obliteration. Copyright © 2011 Wiley Periodicals, Inc.

  18. A Novel Mouse Fgfr2 Mutant, Hobbyhorse (hob), Exhibits Complete XY Gonadal Sex Reversal

    PubMed Central

    Siggers, Pam; Carré, Gwenn-Aël; Bogani, Debora; Warr, Nick; Wells, Sara; Hilton, Helen; Esapa, Chris; Hajihosseini, Mohammad K.; Greenfield, Andy

    2014-01-01

    The secreted molecule fibroblast growth factor 9 (FGF9) plays a critical role in testis determination in the mouse. In embryonic gonadal somatic cells it is required for maintenance of SOX9 expression, a key determinant of Sertoli cell fate. Conditional gene targeting studies have identified FGFR2 as the main gonadal receptor for FGF9 during sex determination. However, such studies can be complicated by inefficient and variable deletion of floxed alleles, depending on the choice of Cre deleter strain. Here, we report a novel, constitutive allele of Fgfr2, hobbyhorse (hob), which was identified in an ENU-based forward genetic screen for novel testis-determining loci. Fgr2hob is caused by a C to T mutation in the invariant exon 7, resulting in a polypeptide with a mis-sense mutation at position 263 (Pro263Ser) in the third extracellular immunoglobulin-like domain of FGFR2. Mutant homozygous embryos show severe limb and lung defects and, when on the sensitised C57BL/6J (B6) genetic background, undergo complete XY gonadal sex reversal associated with failure to maintain expression of Sox9. Genetic crosses employing a null mutant of Fgfr2 suggest that Fgr2hob is a hypomorphic allele, affecting both the FGFR2b and FGFR2c splice isoforms of the receptor. We exploited the consistent phenotype of this constitutive mutant by analysing MAPK signalling at the sex-determining stage of gonad development, but no significant abnormalities in mutant embryos were detected. PMID:24956260

  19. Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors

    PubMed Central

    Parsa, Sara; Kuremoto, Koh-ichi; Seidel, Kerstin; Tabatabai, Reza; MacKenzie, BreAnne; Yamaza, Takayoshi; Akiyama, Kentaro; Branch, Jonathan; Koh, Chester J.; Alam, Denise Al; Klein, Ophir D.; Bellusci, Saverio

    2010-01-01

    Rodent incisors regenerate throughout the lifetime of the animal owing to the presence of epithelial and mesenchymal stem cells in the proximal region of the tooth. Enamel, the hardest component of the tooth, is continuously deposited by stem cell-derived ameloblasts exclusively on the labial, or outer, surface of the tooth. The epithelial stem cells that are the ameloblast progenitors reside in structures called cervical loops at the base of the incisors. Previous studies have suggested that FGF10, acting mainly through fibroblast growth factor receptor 2b (FGFR2b), is crucial for development of the epithelial stem cell population in mouse incisors. To explore the role of FGFR2b signaling during development and adult life, we used an rtTA transactivator/tetracycline promoter approach that allows inducible and reversible attenuation of FGFR2b signaling. Downregulation of FGFR2b signaling during embryonic stages led to abnormal development of the labial cervical loop and of the inner enamel epithelial layer. In addition, postnatal attenuation of signaling resulted in impaired incisor growth, characterized by failure of enamel formation and degradation of the incisors. At a cellular level, these changes were accompanied by decreased proliferation of the transit-amplifying cells that are progenitors of the ameloblasts. Upon release of the signaling blockade, the incisors resumed growth and reformed an enamel layer, demonstrating that survival of the stem cells was not compromised by transient postnatal attenuation of FGFR2b signaling. Taken together, our results demonstrate that FGFR2b signaling regulates both the establishment of the incisor stem cell niches in the embryo and the regenerative capacity of incisors in the adult. PMID:20978072

  20. Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome.

    PubMed

    Cornejo-Roldan, L R; Roessler, E; Muenke, M

    1999-05-01

    Pfeiffer syndrome (PS) is one of the classical craniosynostosis syndromes correlated with specific mutations in the human fibroblast growth factor receptor (FGFR) genes, FGFR1 and FGFR2. In this study, we set out to examine the exons in FGFR2 most commonly associated with mutations in PS, exons IIIa and IIIc, in a panel of 78 unrelated individuals with PS by the most sensitive method (direct DNA sequencing). We have identified a total of 18 different mutations among 40 patients; eight of these mutations have not been previously described. The mutational spectrum displays a non-random character with the frequent involvement of cysteine codons.

  1. Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome.

    PubMed

    Zankl, Andreas; Jaeger, Gudrun; Bonafé, Luisa; Boltshauser, Eugen; Superti-Furga, Andrea

    2004-12-15

    Mutations in the fibroblast growth factor receptor 2 (FGFR2) cause a variety of craniosynostosis syndromes. The mutational spectrum tends to be narrow with the majority of mutations occurring in either exon IIIa or IIIc or in the intronic sequence preceding exon IIIc. Mutations outside of this hotspot are uncommon and the few identified mutations have demonstrated wide clinical variability, making it difficult to establish a clear-cut genotype-phenotype correlation. To better delineate the clinical picture associated with these unusual mutations, we describe a severely affected patient with Pfeiffer syndrome and a missense mutation in the tyrosine kinase (TK) domain of FGFR2.

  2. Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues.

    PubMed Central

    Luqmani, Y. A.; Graham, M.; Coombes, R. C.

    1992-01-01

    The expression of basic fibroblast growth factor (bFGF) and two of its receptors, FGFR1 and FGFR2, was detected using the polymerase chain reaction, and quantified by comparison to the relative amount of product obtained following co-amplification of the ubiquitous glyceraldehyde phosphate dehydrogenase transcript. Varying levels were found in the vast majority of both cancer and non-malignant breast biopsies as well as in samples of several other normal human tissues. Significantly less bFGF was present in cancers (P less than 0.0001). Similarly, FGFR2 product was also much less in cancer tissues (P = 0.0078), as was FGFR1 (P = 0.002). FGFR1 levels in cancers tended to be higher in those which were oestrogen receptor positive (P less than 0.06). Amplification of different coding regions showed evidence of variant forms of FGFR1 RNA. Cancers appeared to have a significantly greater proportion of PCR product corresponding to the region between the third immunoglobulin like domain and the tyrosine kinase domain (P = 0.046). Differential expression was observed in breast cell lines, with bFGF in the normal derived HBL100, HBR SV1.6.1 and 184A1 but little or none in ZR-75-1, MCF-7, T47D and MDA-MB-231. FGFR1 was present in most of these but FGFR2 was absent from T47D, MDA-MB-231 and HBL100. ZR-75-1 cells had a marked preponderance of FGFR1 variants lacking part of the coding sequence. Aberrant receptor processing may provide clues concerning the role of FGF's and their potential involvement in malignancy. Images Figure 3 PMID:1380281

  3. Nuclear staining of fgfr-2/stat-5 and runx-2 in mucinous breast cancer.

    PubMed

    May, María; Mosto, Julián; Vazquez, Paula Martinez; Gonzalez, Pedro; Rojas, Paola; Gass, Hugo; Lanari, Claudia; Molinolo, Alfredo A

    2016-02-01

    Mucinous carcinoma (MBC) is a rare subtype of breast cancer characterized by the production of variable amounts of mucin, with a prognosis better than that of non-mucinous carcinomas (NMBC). The aim of this project was to evaluate the expression of STAT-5, RUNX-2, and FGFR-2 in a cohort of MBC and compare it with that of NMBC using standard immunohistochemistry. STAT-5 and RUNX-2 are two transcription factors with cytoplasmic and/or nuclear localization that have been related to FGFR-2, a tyrosine kinase growth factor receptor that can interact with STAT-5 and with PR in the nuclei of breast cancer cells. Membranous, cytoplasmic, and nuclear staining were evaluated and expressed as the percentage of stained cells (0-100%) multiplied by the staining intensity (0-3), thus obtaining an index ranging from 0 to 300. Nuclear and/or cytoplasmic immunoreactivity of the three proteins were detected in a high number of NMBC. Nuclear FGFR-2 staining correlated with nuclear STAT-5 (p<0.05) and nuclear RUNX-2 (p<0.01) in both tumor types; however MBC had a significant higher expression of nuclear FGFR-2 (p<0.01) and RUNX-2 (p<0.05) than that of NMBC, and displayed positive immunoreactivity of the 3 proteins in 70.8% of the cases. These results suggest that these proteins may have a role in the progression of the mucinous phenotype, in which nuclear STAT-5 may inhibit RUNX-2 prometastatic effect.

  4. FGFR2 mutations and associated clinical observations in two Chinese patients with Crouzon syndrome.

    PubMed

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V P; Zhu, Yi; Chen, Chuan; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Li, Yonghao; Wu, Qingxiu; Li, Haichun; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin

    2017-08-29

    The aim of the present study was to identify mutations in the fibroblast growth factor receptor 2 (FGFR2) gene in patients with Crouzon syndrome and characterize the associated clinical features. A total of two Chinese patients diagnosed with Crouzon syndrome underwent complete examinations, including best‑corrected visual acuity, slit‑lamp, examination, fundus examination, optical coherence tomography and computed tomography of the skull. Genomic DNA was extracted from peripheral blood samples collected from the patients, as well as their family members and 200 unrelated control subjects from the same population. Exons 8 and 10 in the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Patient #1 had a heterozygous missense mutation (c.1025G>A, p.C342Y) in exon 10 of FGFR2. Patient #2 had a heterozygous mutation (c.1084+1 G>T; IVS10+1G>T) in intron 10. The mutations were not present in any of the unaffected family members or unrelated control subjects. These findings expand the mutation spectrum of FGFR2, and are valuable for genetic counseling in addition to prenatal diagnosis in patients with Crouzon syndrome.

  5. Mutations in the FGFR2 gene in Mexican patients with Apert syndrome.

    PubMed

    Ibarra-Arce, A; Ortiz de Zárate-Alarcón, G; Flores-Peña, L G; Martínez-Hernández, F; Romero-Valdovinos, M; Olivo-Díaz, A

    2015-03-27

    Apert syndrome (AS) is a frequent acrocephalosyndactyly, with autosomal dominant inheritance. AS has been associated with mutations in fibroblast growth factor receptor 2 (FGFR2), and approximately 99% of cases show 2 of the frequent mutations located in exon IIIa (Ser252Trp or Pro253Arg). The purpose of the present study was to describe the mutations in exon IIIa of FGFR2 in Mexican AS patients and the relationships with clinical features. Exon IIIa of FGFR2 from 6 AS patients was amplified by polymerase chain reaction. Mutations in exon IIIa of the FGFR2 gene were identified by digestion with the restriction endonuclease Bstx1 and polyacrylamide gel electrophoresis. PCR fragments were cloned into the PCR 2.1 vector, and both DNA strands were sequenced using the T7 promoter and M13 universal cloning region oligonucleotides. Sequence alignment was performed using the MEGA software version 5. The patients' major clinical features included craniosynostosis, hypertelorism, proptosis, otitis media, midfacial hypoplasia, rhizomelic shortening, and hyperhidrosis. Mutation S252W was present in 4 patients, while the other 2 patients had P253R. In conclusion, either S252W or P253R mutations were present independently in AS patients; however, the 2 mutations were not found together. None of the clinical features were associated with any of the mutations, suggesting that other mutations may be involved in the development of this syndrome.

  6. Characterization of sequences and mechanisms through which ISE/ISS-3 regulates FGFR2 splicing.

    PubMed

    Hovhannisyan, Ruben H; Warzecha, Claude C; Carstens, Russ P

    2006-01-01

    Alternative splicing of fibroblast growth factor receptor-2 (FGFR2) mutually exclusive exons IIIb and IIIc results in highly cell-type-specific expression of functionally distinct receptors, FGFR2-IIIb and FGFR2-IIIc. We previously identified an RNA cis-element, ISE/ISS-3, that enhanced exon IIIb splicing and silenced exon IIIc splicing. Here, we have performed comprehensive mutational analysis to define critical sequence motifs within this element that independently either enhance splicing of upstream exons or repress splicing of downstream exons. Such analysis included use of a novel fluorescence-based splicing reporter assay that allowed quantitative determination of relative functional activity of ISE/ISS-3 mutants using flow cytometric analysis of live cells. We determined that specific sequences within this element that mediate splicing enhancement also mediate splicing repression, depending on their position relative to a regulated exon. Thus, factors that bind the element are likely to be coordinately involved in mediating both aspects of splicing regulation. Exon IIIc silencing is dependent upon a suboptimal branchpoint sequence containing a guanine branchpoint nucleotide. Previous studies of exon IIIc splicing in HeLa nuclear extracts demonstrated that this guanine branchsite primarily impaired the second step of splicing suggesting that ISE/ISS-3 may block exon IIIc inclusion at this step. However, results presented here that include use of newly developed in vitro splicing assays of FGFR2 using extracts from a cell line expressing FGFR2-IIIb strongly suggest that cell-type-specific silencing of exon IIIc occurs at or prior to the first step of splicing.

  7. Sporadic melanoma in South-Eastern Italy: the impact of melanocortin 1 receptor (MC1R) polymorphism analysis in low-risk people and report of three novel variants.

    PubMed

    Guida, S; Bartolomeo, N; Zanna, P T; Grieco, C; Maida, I; De Summa, S; Tommasi, S; Guida, M; Azzariti, A; Foti, C; Filotico, R; Guida, G

    2015-08-01

    Environmental and genetic risk factors are involved in the development of melanoma. The role of the melanocortin 1 receptor (MC1R) gene has been investigated and differences according to geographic areas have been described. To evaluate the role of some clinical and genetic risk factors in melanoma development, we performed a case-control study involving 101 melanoma patients and 103 controls coming from South-Eastern Italy (Puglia), after achieving informed consent. We confirmed the role of known clinical risk factors for melanoma. Furthermore, 42 MC1R polymorphisms were observed. Three of these variants (L26V, H232L, D294Y) were not previously reported in the literature. Their predicted impact on receptor function was evaluated using bioinformatic tools. We report an overall frequency of MC1R variants in our population higher than in Northern or Central Italy. The most common polymorphism found was V60L, that has been recently reported to spread among South Mediterranean population. This variant influenced phenotypic characteristics of our population while it did not impinge on melanoma risk. An increased risk of melanoma was associated with two or more MC1R variants, when at least one was RHC, compared to people carrying the MC1R consensus sequence or a single MC1R polymorphism. Interestingly, we observed an increased risk of melanoma in subjects with darker skin and lower nevus count, usually considered at low risk, when carrying MC1R polymorphisms.

  8. Craniosynostosis with tracheal sleeve: a patient with Pfeiffer syndrome, tracheal sleeve and additional malformations in whom an FGFR2 mutation was found.

    PubMed

    Zackai, Elaine H; McDonald-McGinn, Donna M; Stolle, Catherine; Huff, Dale S

    2003-07-01

    We discuss a patient with Pfeiffer syndrome who had a tracheal sleeve and an FGFR2 mutation. In the light of our findings, and previous reports of patients with craniosynostosis that also reported similar mutations, we suggest that genomic screening for FGFR2 may be useful in cases with negative FGFR2 mutation testing.

  9. Further Analysis of the Crouzon Mouse, Effects of the FGFR2C342Y Mutation are Cranial Bone Dependent

    PubMed Central

    Liu, Jin; Nam, Hwa Kyung; Wang, Estee; Hatch, Nan E.

    2013-01-01

    Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in Fibroblast Growth Factor Receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate biologic mechanisms by which the Crouzon syndrome associated FGFR2C342Y mutation leads to abnormal craniofacial skeletal development we created congenic BALB/c FGFR2C342Y/+ mice. Here we show that BALB/c FGFR2C342Y/+ mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2C342Y/+ mice on the BALB/c genetic background differ significantly in form and shape from their wild type littermates, and that in this genetic background the FGFR2C342Y mutation preferentially effects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2C342Y mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2C342Y/+ frontal but not parietal bones exhibit significantly diminished bone volume and density compared to wild type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients. PMID:23358860

  10. Investigation of G-quadruplex formation in the FGFR2 promoter region and its transcriptional regulation by liensinine.

    PubMed

    Zhang, Lulu; Tan, Wei; Zhou, Jiang; Xu, Ming; Yuan, Gu

    2017-04-01

    Fibroblast growth factor receptor 2 (FGFR2) is overexpressed in breast cancer tissues and cells, and has been shown to be a susceptibility factor for breast cancer. In this study, we found that the G-rich sequences in the FGFR2 promoter region can form G-quadruplexes, which could be the target and inhibitor of the FGFR2 gene. Initially, the formation of G-quadruplexes was confirmed by ESI-MS and CD, and DMS footprinting experiments gave the folding pattern of the G-quadruplexes. After luciferase reporter assays revealed that the G-quadruplex could inhibit the activity of the FGFR2 promoter, MS and SPR showed binding affinity and selectivity of the ligand. Then cell culture experiments and ChIP assay showed the bioactivity of the ligand. We found that three G-rich sequences (S1-S3) in the FGFR2 promoter region can form G-quadruplex structures. And a natural alkaloid, liensinine, was found to bind to the S1 G-quadruplex with relative high affinity and selectivity. Cell culture experiments showed that liensinine inhibits FGFR2 activity at both the transcriptional and translational levels. Moreover, chromatin immunoprecipitation assay (ChIP) results showed that liensinine blocks the binding of E2F1 at the transcription factor binding site (TFBS) in the S1 sequence, which is the mechanism through which liensinine inhibits the FGFR2 gene. A natural alkaloid was discovered to selectively bind to the S1 G-quadruplex with relative high affinity, and therefore inhibited FGFR2 transcription and translation. Our discovery offers a useful strategy to inhibit FGFR2 transcription, i.e., targeting the G-quadruplex with a natural alkaloid. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent.

    PubMed

    Liu, Jin; Nam, Hwa Kyung; Wang, Estee; Hatch, Nan E

    2013-05-01

    Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in fibroblast growth factor receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate the biologic mechanisms by which the Crouzon syndrome-associated FGFR2(C342Y) mutation leads to abnormal craniofacial skeletal development, we created congenic BALB/c FGFR2(C342Y/+) mice. Here, we show that BALB/c FGFR2(C342Y/+) mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis, and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2(C342Y/+) mice on the BALB/c genetic background differ significantly in form and shape from their wild-type littermates and that in this genetic background the FGFR2(C342Y) mutation preferentially affects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2(C342Y) mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2(C342Y/+) frontal, but not parietal, bones exhibit significantly diminished bone volume and density compared to wild-type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients.

  12. Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice

    PubMed Central

    2010-01-01

    Background Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. Results We generated inbred Fgfr2+/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2+/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKCα were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Conclusions Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the

  13. Activated FGFR2 as a Viable Therapeutic Target in a Subset of Ovarian Cancers

    DTIC Science & Technology

    2009-07-01

    endom etrioid ovarian 70 carcinomas [3], whereas PTEN, PIK3CA, and CTNNB-1 (β-catenin) mutations are more common 71 in low-grade endom etrioid ovarian...100 high-grade advanced stage serous ovarian tumors [16]. FGF9 has also been implicated as playing 101 a key role in ovarian endom etrioid ade...mutations in FGFR2 in endom etrial cancer, 111 predominantly in the endom etrioid histologic subtype [20, 21]. Interestin gly, ovarian cancer and 112

  14. A new case of Pfeiffer syndrome with mutation in FGFR2.

    PubMed

    Addor, M C; Gudinchet, F; Laurini, R N; Pescia, G; Schorderet, D F

    1997-01-01

    We report on a sporadic case of Pfeiffer syndrome in a male newborn with complex craniosynostosis, broad thumbs and great toes and early demise. SSCP and direct sequencing revealed a missense mutation at position 1037 of the exon B (or IIIc) of the FGFR2 gene (codon 342) resulting in a cysteine to serine modification (TGC-TCC). Genotype-phenotype correlations between the FGFRs mutations and the different craniosynostotic syndromes are discussed.

  15. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome.

    PubMed

    Glaser, R L; Jiang, W; Boyadjiev, S A; Tran, A K; Zachary, A A; Van Maldergem, L; Johnson, D; Walsh, S; Oldridge, M; Wall, S A; Wilkie, A O; Jabs, E W

    2000-03-01

    Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2. 4x10-7; 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34. 50+/-7.65 years vs. 30.45+/-1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.

  16. Paternal Origin of FGFR2 Mutations in Sporadic Cases of Crouzon Syndrome and Pfeiffer Syndrome

    PubMed Central

    Glaser, Rivka L.; Jiang, Wen; Boyadjiev, Simeon A.; Tran, Alissa K.; Zachary, Andrea A.; Van Maldergem, Lionel; Johnson, David; Walsh, Sinead; Oldridge, Michael; Wall, Steven A.; Wilkie, Andrew O. M.; Jabs, Ethylin Wang

    2000-01-01

    Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2.4×10-7; 95% confidence limits 87%–100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34.50±7.65 years vs. 30.45±1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations. PMID:10712195

  17. FGFR2 is amplified in the NCI-H716 colorectal cancer cell line and is required for growth and survival.

    PubMed

    Mathur, Anjili; Ware, Christopher; Davis, Lenora; Gazdar, Adi; Pan, Bo-Sheng; Lutterbach, Bart

    2014-01-01

    Aberrant kinase activation resulting from mutation, amplification, or translocation can drive growth and survival in a subset of human cancer. FGFR2 is amplified in breast and gastric cancer, and we report here the first characterization of FGFR2 gene amplification in colorectal cancer in the NCI-H716 colorectal cancer cell line. FGFR2 is highly expressed and activated in NCI-H716 cells, and FGFR selective small molecule inhibitors or FGFR2 shRNA strongly inhibited cell viability in vitro, indicating "addiction" of NCI-H716 cells to FGFR2. NCI-H716 growth in a xenograft model was also inhibited by an FGFR small molecule inhibitor. FGFR2 was required for activation of multiple downstream signaling proteins including AKT, ERK, S6RP and NFKB. Inhibition of downstream kinases such as AKT or ERK alone had modest effects on proliferation, whereas combined inhibition of AKT and ERK signaling resulted in a loss of viability similar to FGFR2 inhibition. We identified elevated FGFR2 expression in a small subset of primary colorectal cancer, however FGFR2 amplification was not observed. Although FGFR2 amplification is not common in primary colon cancer or lymph node and liver metastases, other subsets of colorectal cancer such as ascites, from which the NCI-H716 cell line was derived, have yet to be tested. These results suggest that emerging FGFR inhibitor therapeutics may have efficacy in a subset of colon cancer driven by FGFR2 amplification.

  18. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome.

    PubMed

    Schell, U; Hehr, A; Feldman, G J; Robin, N H; Zackai, E H; de Die-Smulders, C; Viskochil, D H; Stewart, J M; Wolff, G; Ohashi, H

    1995-03-01

    Pfeiffer syndrome (PS) is an autosomal dominant skeletal disorder which affects the bones of the skull, hands and feet. Previously, we have mapped PS in a subset of families to chromosome 8cen by linkage analysis and demonstrated a common mutation in the fibroblast growth factor receptor-1 (FGFR1) gene in the linked families. Here we report a second locus for PS on chromosome 10q25, and present evidence that mutations in the fibroblast growth factor receptor-2 (FGFR2) gene on 10q25 cause PS in an additional subset of familial and sporadic cases. Three different point mutations in FGFR2, which alter the same acceptor splice site of exon B, were observed in both sporadic and familial PS. In addition, a T to C transition in exon B predicting a cysteine to arginine substitution was identified in three sporadic PS individuals. Interestingly, this T to C change is identical to a mutation in FGFR2 previously reported in Crouzon syndrome, a phenotypically similar disorder but one lacking the hand and foot anomalies seen in PS. Our results highlight the genetic heterogeneity in PS and suggest that the molecular data will be an important complement to the clinical phenotype in defining craniosynostosis syndromes.

  19. FGFR2 mutation in a Chinese family with unusual Crouzon syndrome

    PubMed Central

    Li, Zi-Li; Chen, Xue; Zhuang, Wen-Juan; Zhao, Wei; Liu, Ya-Ni; Zhang, Fang-Xia; Ha, Ruo-Shui; Wu, Jin-Hua; Zhao, Chen; Sheng, Xun-Lun

    2016-01-01

    AIM To describe the clinical characteristics with genetic lesions in a Chinese family with Crouzon syndrome. METHODS All five patients from this family were included and received comprehensive ophthalmic and systemic examinations. Direct sequencing of the FGFR2 gene was employed for mutation identification. Crystal structure analysis was applied to analyze the structural changes associated with the substitution. RESULTS All patients presented typical Crouzon features, including short stature, craniosynostosis, mandibular prognathism, shallow orbits with proptosis, and exotropia. Intrafamilial phenotypic diversities were observed. Atrophic optic nerves were exclusively detected in the proband and her son. Cranial magnetic resonance imaging (MRI) implied a cystic lesion in her sellar and third ventricular regions. A missense mutation, FGFR2 p.Cys342Trp, was found as disease causative. This substitution would generate conformational changes in the extracellular Ig-III domain of the FGFR-2 protein, thus altering its physical and biological properties. CONCLUSION We describe the clinical presentations and genotypic lesions in a Chinese family with Crouzon syndrome. The intrafamilial phenotypic varieties in this family suggest that other genetic modifiers may also play a role in the pathogenesis of Crouzon syndrome. PMID:27803855

  20. FGFR2 mutation in a Chinese family with unusual Crouzon syndrome.

    PubMed

    Li, Zi-Li; Chen, Xue; Zhuang, Wen-Juan; Zhao, Wei; Liu, Ya-Ni; Zhang, Fang-Xia; Ha, Ruo-Shui; Wu, Jin-Hua; Zhao, Chen; Sheng, Xun-Lun

    2016-01-01

    To describe the clinical characteristics with genetic lesions in a Chinese family with Crouzon syndrome. All five patients from this family were included and received comprehensive ophthalmic and systemic examinations. Direct sequencing of the FGFR2 gene was employed for mutation identification. Crystal structure analysis was applied to analyze the structural changes associated with the substitution. All patients presented typical Crouzon features, including short stature, craniosynostosis, mandibular prognathism, shallow orbits with proptosis, and exotropia. Intrafamilial phenotypic diversities were observed. Atrophic optic nerves were exclusively detected in the proband and her son. Cranial magnetic resonance imaging (MRI) implied a cystic lesion in her sellar and third ventricular regions. A missense mutation, FGFR2 p.Cys342Trp, was found as disease causative. This substitution would generate conformational changes in the extracellular Ig-III domain of the FGFR-2 protein, thus altering its physical and biological properties. We describe the clinical presentations and genotypic lesions in a Chinese family with Crouzon syndrome. The intrafamilial phenotypic varieties in this family suggest that other genetic modifiers may also play a role in the pathogenesis of Crouzon syndrome.

  1. Preclinical Efficacy of the Auristatin-Based Antibody-Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors.

    PubMed

    Sommer, Anette; Kopitz, Charlotte; Schatz, Christoph A; Nising, Carl F; Mahlert, Christoph; Lerchen, Hans-Georg; Stelte-Ludwig, Beatrix; Hammer, Stefanie; Greven, Simone; Schuhmacher, Joachim; Braun, Manuela; Zierz, Ruprecht; Wittemer-Rump, Sabine; Harrenga, Axel; Dittmer, Frank; Reetz, Frank; Apeler, Heiner; Jautelat, Rolf; Huynh, Hung; Ziegelbauer, Karl; Kreft, Bertolt

    2016-11-01

    The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody-drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line-based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair.

    PubMed

    MacKenzie, BreAnne; Henneke, Ingrid; Hezel, Stefanie; Al Alam, Denise; El Agha, Elie; Chao, Cho-Ming; Quantius, Jennifer; Wilhelm, Jochen; Jones, Matthew; Goth, Kerstin; Li, Xiaokun; Seeger, Werner; Königshoff, Melanie; Herold, Susanne; Rizvanov, Albert A; Günther, Andreas; Bellusci, Saverio

    2015-05-15

    Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0-28) or during later stages (days 6-28 and 14-28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice.

  3. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair

    PubMed Central

    MacKenzie, BreAnne; Henneke, Ingrid; Hezel, Stefanie; Al Alam, Denise; El Agha, Elie; Chao, Cho-Ming; Quantius, Jennifer; Wilhelm, Jochen; Jones, Matthew; Goth, Kerstin; Li, Xiaokun; Seeger, Werner; Königshoff, Melanie; Herold, Susanne; Rizvanov, Albert A.; Günther, Andreas

    2015-01-01

    Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26rtTA/+;tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0–11; days 0–28) or during later stages (days 6–28 and 14–28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice. PMID:25820524

  4. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity

    SciTech Connect

    Wu, Zong-Sian; Liu, Che Fu; Fu, Brian; Chou, Ruey-Hwang; Yu, Chin

    2016-09-02

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. - Highlights: • The interfacial residues on hFGF1-FGFR2 D2 and hFGF1-Suramin contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • hFGF1-FGFR2 D2 and hFGF1-Suramin complex models were generated from NMR restraints by using HADDOCK program. • We analyzed hFGF1-Suramin complex models and found the interaction between hFGF1-Suramin is hydrophobic. • The bioactivity of the hFGF1-FGFR2 D2 and hFGF1-Suramin complex was studied by using WST1 assay.

  5. FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

    PubMed

    Jeske, Yvette W; Ali, Shamshad; Byron, Sara A; Gao, Feng; Mannel, Robert S; Ghebre, Rahel G; DiSilvestro, Paul A; Lele, Shashikant B; Pearl, Michael L; Schmidt, Amy P; Lankes, Heather A; Ramirez, Nilsa C; Rasty, Golnar; Powell, Matthew; Goodfellow, Paul J; Pollock, Pamela M

    2017-05-01

    Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. Tumors were collected as part of the GOG 210 clinical trial "Molecular Staging of Endometrial Cancer" where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p=0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p<0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p<0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177-3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096-3.696). In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. FGF/FGFR2 signaling regulates the generation and correct positioning of Bergmann glia cells in the developing mouse cerebellum.

    PubMed

    Meier, Florian; Giesert, Florian; Delic, Sabit; Faus-Kessler, Theresa; Matheus, Friederike; Simeone, Antonio; Hölter, Sabine M; Kühn, Ralf; Weisenhorn, Daniela M Vogt; Wurst, Wolfgang; Prakash, Nilima

    2014-01-01

    The normal cellular organization and layering of the vertebrate cerebellum is established during embryonic and early postnatal development by the interplay of a complex array of genetic and signaling pathways. Disruption of these processes and of the proper layering of the cerebellum usually leads to ataxic behaviors. Here, we analyzed the relative contribution of Fibroblast growth factor receptor 2 (FGFR2)-mediated signaling to cerebellar development in conditional Fgfr2 single mutant mice. We show that during embryonic mouse development, Fgfr2 expression is higher in the anterior cerebellar primordium and excluded from the proliferative ventricular neuroepithelium. Consistent with this finding, conditional Fgfr2 single mutant mice display the most prominent defects in the anterior lobules of the adult cerebellum. In this context, FGFR2-mediated signaling is required for the proper generation of Bergmann glia cells and the correct positioning of these cells within the Purkinje cell layer, and for cell survival in the developing cerebellar primordium. Using cerebellar microexplant cultures treated with an FGFR agonist (FGF9) or antagonist (SU5402), we also show that FGF9/FGFR-mediated signaling inhibits the outward migration of radial glia and Bergmann glia precursors and cells, and might thus act as a positioning cue for these cells. Altogether, our findings reveal the specific functions of the FGFR2-mediated signaling pathway in the generation and positioning of Bergmann glia cells during cerebellar development in the mouse.

  7. The role of fibroblast growth factor receptor 2 (FGFR2) in differentiation of bovine spermatogonial stem cells (SCC)

    PubMed Central

    Akbarinejad, Vahid; Tajik, Parviz; Movahedin, Mansoureh; Youssefi, Reza

    2016-01-01

    The receptors 1 and 2 of fibroblast growth factor (FGFR1 and FGFR2, respectively) have been observed in all types of testicular cells. Culture on extracellular matrix (ECM) has been observed to lead to initiation of differentiation in spermatogonial stem cells (SSCs). The present study was carried out to investigate whether FGFR1 and FGFR2 play a role in SSCs differentiation. Following isolation, bovine testicular cells were cultured on ECM-coated or uncoated (control) plates for 12 days. The gene expression of THY1, cKIT, FGFR1 and FGFR2 was evaluated using quantitative real-time polymerase chain reaction (PCR). Results related to the gene expression of markers of with undifferentiated (THY1) and differentiated (cKIT) spermatogonia implicated stimulation of self-renewal and differentiation in cells cultured on ECM-coated and uncoated plates, respectively (p < 0.05). Concomitantly, the expression of FGFR2 increased during culture in the ECM group (p < 0.05), whereas it did not change in the control group (p > 0.05). As a result, the gene expression of FGFR2 was greater in the ECM than control group (p < 0.05). Nevertheless, FGFR1 expression did not change during culture in the control and ECM groups (p > 0.05). In conclusion, the present study revealed the potential role of FGFR2 in differentiation of SSCs during culture on ECM. PMID:27482360

  8. FGF/FGFR2 Signaling Regulates the Generation and Correct Positioning of Bergmann Glia Cells in the Developing Mouse Cerebellum

    PubMed Central

    Faus-Kessler, Theresa; Matheus, Friederike; Simeone, Antonio; Hölter, Sabine M.; Kühn, Ralf; Weisenhorn, Daniela M. Vogt.; Wurst, Wolfgang; Prakash, Nilima

    2014-01-01

    The normal cellular organization and layering of the vertebrate cerebellum is established during embryonic and early postnatal development by the interplay of a complex array of genetic and signaling pathways. Disruption of these processes and of the proper layering of the cerebellum usually leads to ataxic behaviors. Here, we analyzed the relative contribution of Fibroblast growth factor receptor 2 (FGFR2)-mediated signaling to cerebellar development in conditional Fgfr2 single mutant mice. We show that during embryonic mouse development, Fgfr2 expression is higher in the anterior cerebellar primordium and excluded from the proliferative ventricular neuroepithelium. Consistent with this finding, conditional Fgfr2 single mutant mice display the most prominent defects in the anterior lobules of the adult cerebellum. In this context, FGFR2-mediated signaling is required for the proper generation of Bergmann glia cells and the correct positioning of these cells within the Purkinje cell layer, and for cell survival in the developing cerebellar primordium. Using cerebellar microexplant cultures treated with an FGFR agonist (FGF9) or antagonist (SU5402), we also show that FGF9/FGFR-mediated signaling inhibits the outward migration of radial glia and Bergmann glia precursors and cells, and might thus act as a positioning cue for these cells. Altogether, our findings reveal the specific functions of the FGFR2-mediated signaling pathway in the generation and positioning of Bergmann glia cells during cerebellar development in the mouse. PMID:24983448

  9. Quantification of alternatively spliced FGFR2 RNAs using the RNA invasive cleavage assay

    PubMed Central

    WAGNER, ERIC J.; CURTIS, MICHELLE L.; ROBSON, NICOLE D.; BARANIAK, ANDREW P.; EIS, PEGGY S.; GARCIA-BLANCO, MARIANO A.

    2003-01-01

    The regulated splicing of fibroblast growth factor receptor-2 (FGFR2) transcripts leads to tissue-specific expression of distinct receptor isoforms. These isoforms contain two different versions of the ligand binding Ig-like domain III, which are encoded by exon IIIb or exon IIIc. The mutually exclusive use of exon IIIb and exon IIIc can be recapitulated in tissue culture using DT3 and AT3 rat prostate carcinoma cells. We used this well-characterized system to evaluate the precision and accuracy of the RNA invasive cleavage assay to specifically measure FGFR2 alternative splicing outcomes. Experiments presented here demonstrated that the RNA invasive cleavage assay could specifically detect isoforms with discrimination levels that ranged from 1 in 5 × 103 to 1 in 105. Moreover the assay could detect close to 0.01 amole of FGFR2 RNAs. The assay detected the expected levels of transcripts containing either exon IIIb or IIIc, but, surprisingly, it detected high levels of IIIb-IIIc double inclusion transcripts. This finding, which has important implications for the role of exon silencing and of mRNA surveillance mechanisms, had been missed by RT-PCR. Additionally, we used the RNA invasive cleavage assay to demonstrate a novel function for the regulatory element IAS2 in repressing exon IIIc inclusion. We also show here that purification of RNA is not necessary for the invasive cleavage assay, because crude cell lysates could be used to accurately measure alternative transcripts. The data presented here indicate that the RNA invasive cleavage assay is an important addition to the repertoire of techniques available for the study of alternative splicing. PMID:14624010

  10. C278F mutation in FGFR2 gene causes two different types of syndromic craniosynostosis in two Chinese patients.

    PubMed

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V P; Chen, Chuan; Zhu, Yi; Li, Tao; Liu, Bingqian; Liu, Xialin; Luo, Lixia; Jiang, Hongye; Li, Yonghao; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin

    2017-08-14

    The current study was performed with aim to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in two Chinese families with two different forms of syndromic craniosynostosis, and to characterize their associated clinical features. Two families underwent complete ophthalmic examinations, and two patients from each family were diagnosed with craniosynostosis. Genomic DNA was extracted from leukocytes of peripheral blood collected from these two families and from 200 unrelated subjects within the same population as controls. Exons 8 and 10 of the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Ophthalmic examinations of the two patients revealed shallow orbits and ocular proptosis, accompanied by midface hypoplasia and craniosynostosis. Case 1 had retinal detachment, abnormal limbs and hands, while case 2 exhibited normal hands and feet upon clinical examination. A heterozygous FGFR2 missense mutation c.833G>T (C278F) in exon 8 was identified in these two patients, but not in unaffected family members or the normal controls. Although FGFR2 gene mutations and polymorphisms have been studied in various ethnic groups, we report a mutation of FGFR2 in two different Chinese patients with two different types of syndromic craniosynostosis.

  11. Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.

    PubMed

    Teebi, Ahmad S; Kennedy, Shelley; Chun, Kathy; Ray, Peter N

    2002-01-01

    Pfeiffer syndrome is clinically and genetically heterogeneous. Three clinical subtypes have been delineated based on the severity of acrocephalysyndactyly and associated manifestations. Severe cases are usually sporadic and caused by a number of different mutations in exons IIIa and IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. Mild cases are either sporadic or familial and are caused by mutations in FGFR2 or FGFR1, respectively. We report on two individuals with different novel de novo mutations in FGFR2. The first is a 17-year-old male who has a severe phenotype, within the spectrum of subtype 1 including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. This patient was found to have a novel complex mutation at the 3' acceptor site of exon IIIc of FGFR2, denoted as C952-3 del10insACC. The other patient, a 2-year-old female, has a mild phenotype, typical of the classic subtype 1 including brachycephaly with coronal synostosis and hypertelorism. She was also found to have a mutation at the 3' acceptor site (the same splice site) of exon IIIc of FGFR2, a point mutation designated as 952-1G-->A. Speculation on the molecular mechanisms that cause severe and mild phenotypes is presented in relation to these two cases.

  12. Ala344Pro mutation in the FGFR2 gene and related clinical findings in one Chinese family with Crouzon syndrome.

    PubMed

    Lin, Ying; Ai, Siming; Chen, Chuan; Liu, Xialin; Luo, Lixia; Ye, Shaobi; Liang, Xuanwei; Zhu, Yi; Yang, Huasheng; Liu, Yizhi

    2012-01-01

    The purpose of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in three Chinese patients with Crouzon syndrome and to characterize the related clinical features. A single family underwent complete ophthalmic examinations, and three patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from members of the family as well as from 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR 2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull. The three patients were affected with shallow orbits and ocular proptosis, accompanied by mid-face hypoplasia and craniosynostosis, but had clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.1030G>C (Ala344Pro) in exon 10 was identified in the affected individuals, but not in any of the unaffected family members or the normal controls. The mutation we identified has not previously been reported, either in China or abroad. Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 gene mutation in Chinese patients with Crouzon syndrome.

  13. Ala344Pro mutation in the FGFR2 gene and related clinical findings in one Chinese family with Crouzon syndrome

    PubMed Central

    Lin, Ying; Ai, Siming; Chen, Chuan; Liu, Xialin; Luo, Lixia; Ye, Shaobi; Liang, Xuanwei; Zhu, Yi; Yang, Huasheng

    2012-01-01

    Purpose The purpose of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in three Chinese patients with Crouzon syndrome and to characterize the related clinical features. Methods A single family underwent complete ophthalmic examinations, and three patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from members of the family as well as from 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR 2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull. Results The three patients were affected with shallow orbits and ocular proptosis, accompanied by mid-face hypoplasia and craniosynostosis, but had clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.1030G>C (Ala344Pro) in exon 10 was identified in the affected individuals, but not in any of the unaffected family members or the normal controls. The mutation we identified has not previously been reported, either in China or abroad. Conclusions Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 gene mutation in Chinese patients with Crouzon syndrome. PMID:22665975

  14. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome

    SciTech Connect

    Slaney, S.F.; Oldridge, M.; Wilkie, A.O.M.

    1996-05-01

    Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel SfiI and BstUI restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2. 54 refs., 5 figs., 3 tabs.

  15. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.

    PubMed Central

    Park, W J; Theda, C; Maestri, N E; Meyers, G A; Fryburg, J S; Dufresne, C; Cohen, M M; Jabs, E W

    1995-01-01

    A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26%, for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences. Images Figure 2 Figure 3 Figure 4 PMID:7668257

  16. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome

    SciTech Connect

    Park, Woo-Jin; Theda, C.; Maestri, N.E.

    1995-08-01

    A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26% for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences. 34 refs., 4 figs., 1 tab.

  17. A case of Pfeiffer syndrome type 1 with an A344P mutation in the FGFR2 gene.

    PubMed

    Shotelersuk, V; Srivuthana, S; Ittiwut, C; Theamboonlers, A; Mahatumarat, C; Poovorawan, Y

    2001-06-01

    Pfeiffer syndrome, an autosomal dominant disorder, consists of craniosynostosis, broadening of the thumbs and great toes, and partial soft tissue syndactyly of the hands and feet. Three clinical subtypes have been classified mainly for the purpose of genetic counseling. Mutations in FGFR1 and FGFR2 are known to be associated with the syndrome. However, the correlation between genotype and phenotype is not well defined. Only one patient with Pfeiffer syndrome with no other clinical information has been reported to have had an A344P mutation of the FGFR2. Here we report a Thai male patient with sporadic Pfeiffer syndrome type 1 with impaired intelligence (IQ = 77). Mutation analysis revealed A344P in FGFR2. Identification of the clinical features and molecular defects in more patients is required to better correlate the genotype and phenotype of this complex syndrome.

  18. Biochemical Analysis of Pathogenic Ligand-Dependent FGFR2 Mutations Suggests Distinct Pathophysiological Mechanisms for Craniofacial and Limb Abnormalities in Human Skeletal Disorders

    SciTech Connect

    Ibrahimi,O.; Zhang, F.; Eliseenkova, A.; Itoh, N.; Linhardt, R.; Mohammadi, M.

    2004-01-01

    Gain-of-function missense mutations in FGF receptor 2 (FGFR2) are responsible for a variety of craniosynostosis syndromes including Apert syndrome (AS), Pfeiffer syndrome (PS) and Crouzon syndrome (CS). Unlike the majority of FGFR2 mutations, S252W and P253R AS mutations and a D321A PS mutation retain ligand-dependency and are also associated with severe limb pathology. In addition, a recently identified ligand-dependent S252L/A315S double mutation in FGFR2 was shown to cause syndactyly in the absence of craniosynostosis. Here, we analyze the effect of the canonical AS mutations, the D321A PS mutation and the S252L/A315S double mutation on FGFR2 ligand binding affinity and specificity using surface plasmon resonance. Both AS mutations and the D321A PS mutation, but not the S252L/A315S double mutation, increase the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. Additionally, all four pathogenic mutations also violate FGFR2c ligand binding specificity and enable this receptor to bind FGF10. Based on our data, we propose that an increase in mutant FGFR2c binding to multiple FGFs results in craniosynostosis, whereas binding of mutant FGFR2c to FGF10 results in severe limb pathology. Structural and biophysical analysis shows that AS mutations in FGFR2b also enhance and violate FGFR2b ligand binding affinity and specificity, respectively. We suggest that elevated AS mutant FGFR2b signaling may account for the dermatological manifestations of AS.

  19. PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells.

    PubMed

    Plantamura, Ilaria; Casalini, Patrizia; Dugnani, Erica; Sasso, Marianna; D'Ippolito, Elvira; Tortoreto, Monica; Cacciatore, Matilde; Guarnotta, Carla; Ghirelli, Cristina; Barajon, Isabella; Bianchi, Francesca; Triulzi, Tiziana; Agresti, Roberto; Balsari, Andrea; Campiglio, Manuela; Tripodo, Claudio; Iorio, Marilena V; Tagliabue, Elda

    2014-07-01

    Triple negative breast cancer (TNBC) is a very aggressive subgroup of breast carcinoma, still lacking specific markers for an effective targeted therapy and with a poorer prognosis compared to other breast cancer subtypes. In this study we investigated the possibility that TNBC cells contribute to the establishment of tumor vascular network by the process known as vasculogenic mimicry, through endothelial cell differentiation. Vascular-like functional properties of breast cancer cell lines were investigated in vitro by tube formation assay and in vivo by confocal microscopy, immunofluorescence or immunohistochemistry on frozen tumor sections. TNBCs express endothelial markers and acquire the ability to form vascular-like channels in vitro and in vivo, both in xenograft models and in human specimens, generating blood lacunae surrounded by tumor cells. Notably this feature is significantly associated with reduced disease free survival. The impairment of the main pathways involved in vessel formation, by treatment with inhibitors (i.e. Sunitinib and Bevacizumab) or by siRNA-mediating silencing, allowed the identification of PDGFRβ and FGFR2 as relevant players in this phenomenon. Inhibition of these tyrosine kinase receptors negatively affects vascular lacunae formation and significantly inhibits TNBC growth in vivo. In summary, we demonstrated that TNBCs have the ability to form vascular-like channels in vitro and to generate blood lacunae lined by tumor cells in vivo. Moreover, this feature is associated with poor outcome, probably contributing to the aggressiveness of this breast cancer subgroup. Finally, PDGFRβ and FGFR2-mediated pathways, identified as relevant in mediating this characteristic, potentially represent valid targets for a specific therapy of this breast cancer subgroup.

  20. Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation.

    PubMed

    Chen, C-P; Lin, S-P; Su, Y-N; Chien, S-C; Tsai, F-J; Wang, W

    2008-01-01

    Pfeiffer syndrome (OMIM 101600) is an autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, ocular proptosis and digital malformations. We report on a type II Pfeiffer female infant with craniosynostosis, hydrocephalus, and characteristic craniofacial and digital abnormalities. The patient had a history of airway difficulty. Bronchoscopy at age four months revealed low tracheal stenosis and fibrous cartilaginous rings. She underwent tracheostomy for the treatment of cyanotic episodes. Molecular analysis revealed a de novo missense mutation c.870 G>T (TGG>TGT) in the FGFR2 gene that predicts a substitution of cysteine for tryptophan at the codon 290, (W290C). There is phenotypic heterogeneity of tracheal anomalies due to FGFR2 mutations. A review of the literature shows that Pfeiffer patients with the similar tracheal abnormalities can be caused by different FGFR2 mutations and, likewise, the patients with the same FGFR2 mutation may manifest different kinds of tracheal anomalies. Tracheal anomalies may occur in Pfeiffer patients and cause morbidity and mortality because of airway obstruction. Recognition and detailed evaluation of tracheal anomalies should be included in the early diagnostic workup for severe Pfeiffer patients.

  1. Functional analysis of a breast cancer-associated FGFR2 single nucleotide polymorphism using zinc finger mediated genome editing.

    PubMed

    Robbez-Masson, Luisa J; Bödör, Csaba; Jones, J Louise; Hurst, Helen C; Fitzgibbon, Jude; Hart, Ian R; Grose, Richard P

    2013-01-01

    Genome wide association studies have identified single nucleotide polymorphisms (SNP) within fibroblast growth factor receptor 2 (FGFR2) as one of the highest ranking risk alleles in terms of development of breast cancer. The potential effect of these SNPs, in intron two, was postulated to be due to the differential binding of cis-regulatory elements, such as transcription factors, since all the SNPs in linkage disequilibrium were located in a regulatory DNA region. A Runx2 binding site was reported to be functional only in the minor, disease associated allele of rs2981578, resulting in increased expression of FGFR2 in cancers from patients homozygous for that allele. Moreover, the increased risk conferred by the minor FGFR2 allele associates most strongly in oestrogen receptor alpha positive (ERα) breast tumours, suggesting a potential interaction between ERα and FGFR signalling. Here, we have developed a human cell line model system to study the effect of the putative functional SNP, rs2981578, on cell behaviour. MCF7 cells, an ERα positive breast cancer cell line homozygous for the wild-type allele were edited using a Zinc Finger Nuclease approach. Unexpectedly, the acquisition of a single risk allele in MCF7 clones failed to affect proliferation or cell cycle progression. Binding of Runx2 to the risk allele was not observed. However FOXA1 binding, an important ERα partner, appeared decreased at the rs2981578 locus in the risk allele cells. Differences in allele specific expression (ASE) of FGFR2 were not observed in a panel of 72 ERα positive breast cancer samples. Thus, the apparent increased risk of developing ERα positive breast cancer seems not to be caused by rs2981578 alone. Rather, the observed increased risk of developing breast cancer might be the result of a coordinated effect of multiple SNPs forming a risk haplotype in the second intron of FGFR2.

  2. Craniosynostosis-Associated Fgfr2C342Y Mutant Bone Marrow Stromal Cells Exhibit Cell Autonomous Abnormalities in Osteoblast Differentiation and Bone Formation

    PubMed Central

    Liu, J.; Kwon, T.-G.; Nam, H. K.; Hatch, N. E.

    2013-01-01

    We recently reported that cranial bones of Fgfr2C342Y/+ craniosynostotic mice are diminished in density when compared to those of wild type mice, and that cranial bone cells isolated from the mutant mice exhibit inhibited late stage osteoblast differentiation. To provide further support for the idea that craniosynostosis-associated Fgfr mutations lead to cell autonomous defects in osteoblast differentiation and mineralized tissue formation, here we tested bone marrow stromal cells isolated from Fgfr2C342Y/+ mice for their ability to differentiate into osteoblasts. Additionally, to determine if the low bone mass phenotype of Crouzon syndrome includes the appendicular skeleton, long bones were assessed by micro CT. Fgfr2C342Y/+ cells showed increased osteoblastic gene expression during early osteoblastic differentiation but decreased expression of alkaline phosphatase mRNA and enzyme activity, and decreased mineralization during later stages of differentiation, when cultured under 2D in vitro conditions. Cells isolated from Fgfr2C342Y/+ mice also formed less bone when allowed to differentiate in a 3D matrix in vivo. Cortical bone parameters were diminished in long bones of Fgfr2C342Y/+ mice. These results demonstrate that marrow stromal cells of Fgfr2C342Y/+ mice have an autonomous defect in osteoblast differentiation and bone mineralization, and that the Fgfr2C342Y mutation influences both the axial and appendicular skeletons. PMID:23762837

  3. Effects of FGFR2 kinase activation loop dynamics on catalytic activity

    PubMed Central

    2017-01-01

    The structural mechanisms by which receptor tyrosine kinases (RTKs) regulate catalytic activity are diverse and often based on subtle changes in conformational dynamics. The regulatory mechanism of one such RTK, fibroblast growth factor receptor 2 (FGFR2) kinase, is still unknown, as the numerous crystal structures of the unphosphorylated and phosphorylated forms of the kinase domains show no apparent structural change that could explain how phosphorylation could enable catalytic activity. In this study, we use several enhanced sampling molecular dynamics (MD) methods to elucidate the structural changes to the kinase’s activation loop that occur upon phosphorylation. We show that phosphorylation favors inward motion of Arg664, while simultaneously favoring outward motion of Leu665 and Pro666. The latter structural change enables the substrate to bind leading to its resultant phosphorylation. Inward motion of Arg664 allows it to interact with the γ-phosphate of ATP as well as the substrate tyrosine. We show that this stabilizes the tyrosine and primes it for the catalytic phosphotransfer, and it may lower the activation barrier of the phosphotransfer reaction. Our work demonstrates the value of including dynamic information gleaned from computer simulation in deciphering RTK regulatory function. PMID:28151998

  4. Effects of FGFR2 kinase activation loop dynamics on catalytic activity.

    PubMed

    Karp, Jerome M; Sparks, Samuel; Cowburn, David

    2017-02-01

    The structural mechanisms by which receptor tyrosine kinases (RTKs) regulate catalytic activity are diverse and often based on subtle changes in conformational dynamics. The regulatory mechanism of one such RTK, fibroblast growth factor receptor 2 (FGFR2) kinase, is still unknown, as the numerous crystal structures of the unphosphorylated and phosphorylated forms of the kinase domains show no apparent structural change that could explain how phosphorylation could enable catalytic activity. In this study, we use several enhanced sampling molecular dynamics (MD) methods to elucidate the structural changes to the kinase's activation loop that occur upon phosphorylation. We show that phosphorylation favors inward motion of Arg664, while simultaneously favoring outward motion of Leu665 and Pro666. The latter structural change enables the substrate to bind leading to its resultant phosphorylation. Inward motion of Arg664 allows it to interact with the γ-phosphate of ATP as well as the substrate tyrosine. We show that this stabilizes the tyrosine and primes it for the catalytic phosphotransfer, and it may lower the activation barrier of the phosphotransfer reaction. Our work demonstrates the value of including dynamic information gleaned from computer simulation in deciphering RTK regulatory function.

  5. Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development.

    PubMed

    Mukhopadhyay, Anandaroop; Krishnaswami, Suguna Rani; Cowing-Zitron, Christopher; Hung, Nai-Jung; Reilly-Rhoten, Heather; Burns, Julianne; Yu, Benjamin D

    2013-01-15

    Activating mutations in the KRAS oncogene are associated with three related human syndromes, which vary in hair and skin phenotypes depending on the involved allele. How variations in RAS signals are interpreted during hair and skin development is unknown. In this study, we investigated the developmental and transcriptional response of skin and hair to changes in RAS activity, using mouse genetic models and microarray analysis. While activation of Kras (Kras(G12D)) in the skin had strong effects on hair growth and hair shape, steady state changes in downstream RAS/MAPK effectors were subtle and detected only by transcriptional responses. To model the transcriptional response of multiple developmental pathways to active RAS, the effects of growth factor stimulation were studied in skin explants. Here FGF acutely suppressed Shh transcription within 90 min but had significantly less effect on Eda, WNT, Notch or BMP pathways. Furthermore, in vivo Fgfr2 loss-of-function in the ectoderm caused derepression of Shh, revealing a role for FGF in Shh regulation in the hair follicle. These studies define both dosage sensitive effects of RAS signaling on hair morphogenesis and reveal acute mechanisms for fine-tuning Shh levels in the hair follicle. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Apert syndrome with S252W FGFR2 mutation and characterization using Phenomizer: An Indian case report.

    PubMed

    Kunwar, Fulesh; Tewari, Shikha; Bakshi, Sonal R

    2017-01-01

    Human genetic disease needs differential diagnosis to optimize clinical management, enable prenatal detection, and genetic counselling. The current methods of robust DNA sequencing also require next generation phenotyping to match with for better interpretation of genotypic and phenotypic heterogeneity commonly observed. We report use of human ontology based phenotypic characterization with Phenomizer that gives statistical score for possible diagnoses based on which, the gene mutation was studied. A case of craniosynostosis which refers to a group of syndromes characterized by a premature fusion of skull was studied. The phenotypic features viz, dental crowding and dental malocclusion, bulbous nose, downslanted palpebral fissures, radial deviation of thumb, syndactyly of fingers, macrocephaly, and oxycephaly were entered to query the web-based tool Phenomizer which indicated high probability of mutation in FGFR2 gene. The proband, a 13-year-old male born to non-consanguineous parents showed mutation on FGFR2 gene at c.755C>G indicative of Apert syndrome. Apert syndrome is one of the most severe craniosynostosis syndromes with two possible mutations in the exon IIIa of FGFR2 gene reported in majority of the cases. This case study shows the importance of Phenomizer and molecular genetic analysis in differential diagnosis of genetic diseases.

  7. The IgLON Family Member Negr1 Promotes Neuronal Arborization Acting as Soluble Factor via FGFR2

    PubMed Central

    Pischedda, Francesca; Piccoli, Giovanni

    2016-01-01

    IgLON proteins are GPI anchored adhesion molecules that control neurite outgrowth. In particular, Negr1 down-regulation negatively influences neuronal arborization in vitro and in vivo. In the present study, we found that the metalloprotease ADAM10 releases Negr1 from neuronal membrane. Ectodomain shedding influences several neuronal mechanisms, including survival, synaptogenesis, and the formation of neurite trees. By combining morphological analysis and virus-mediated selective protein silencing in primary murine cortical neurons, we found that pharmacologically inhibition of ADAM10 results in an impairment of neurite tree maturation that can be rescued upon treatment with soluble Negr1. Furthermore, we report that released Negr1 influences neurite outgrowth in a P-ERK1/2 and FGFR2 dependent manner. Together our findings suggest a role for Negr1 in regulating neurite outgrowth through the modulation of FGFR2 signaling pathway. Given the physiological and pathological role of ADAM10, Negr1, and FGFR2, the regulation of Negr1 shedding may play a crucial role in sustaining brain function and development. PMID:26793057

  8. FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro

    PubMed Central

    Künstlinger, Helen; Fassunke, Jana; Schildhaus, Hans-Ulrich; Brors, Benedikt; Heydt, Carina; Ihle, Michaela Angelika; Mechtersheimer, Gunhild; Wardelmann, Eva; Büttner, Reinhard; Merkelbach-Bruse, Sabine

    2015-01-01

    Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R-DDIT3. The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro, our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors. PMID:26036639

  9. FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro.

    PubMed

    Künstlinger, Helen; Fassunke, Jana; Schildhaus, Hans-Ulrich; Brors, Benedikt; Heydt, Carina; Ihle, Michaela Angelika; Mechtersheimer, Gunhild; Wardelmann, Eva; Büttner, Reinhard; Merkelbach-Bruse, Sabine

    2015-08-21

    Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R-DDIT3. The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro, our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors.

  10. A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2

    PubMed Central

    Wu, Ying; Gao, He; Li, Huaixing; Tabara, Yasuharu; Nakatochi, Masahiro; Chiu, Yen-Feng; Park, Eun Jung; Wen, Wanqing; Adair, Linda S.; Borja, Judith B.; Cai, Qiuyin; Chang, Yi-Cheng; Chen, Peng; Croteau-Chonka, Damien C.; Fogarty, Marie P.; Gan, Wei; He, Chih-Tsueng; Hsiung, Chao A.; Hwu, Chii-Min; Ichihara, Sahoko; Igase, Michiya; Jo, Jaeseong; Kato, Norihiro; Kawamoto, Ryuichi; Kuzawa, Christophor W.; Lee, Jeannette J.M.; Liu, Jianjun; Lu, Ling; Mcdade, Thomas W.; Osawa, Haruhiko; Sheu, Wayne H-H.; Teo, Yvonne; Vadlamudi, Swarooparani; Van Dam, Rob M.; Wang, Yiqin; Xiang, Yong-Bing; Yamamoto, Ken; Ye, Xingwang; Young, Terri L.; Zheng, Wei; Zhu, Jingwen; Shu, Xiao-Ou; Shin, Chol; Jee, Sun Ha; Chuang, Lee-Ming; Miki, Tetsuro; Yokota, Mitsuhiro; Lin, Xu; Mohlke, Karen L; Tai, E Shyong

    2014-01-01

    Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms. PMID:24105470

  11. Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC.

    PubMed

    Tchaicha, Jeremy H; Akbay, Esra A; Altabef, Abigail; Mikse, Oliver R; Kikuchi, Eiki; Rhee, Kevin; Liao, Rachel G; Bronson, Roderick T; Sholl, Lynette M; Meyerson, Matthew; Hammerman, Peter S; Wong, Kwok-Kin

    2014-09-01

    Somatic mutations in FGFR2 are present in 4% to 5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLCs, and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma, although mouse models of FGFR-driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade 3/4 adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting.

  12. Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme

    PubMed Central

    Peskett, Emma; Kumar, Samin; Baird, William; Jaiswal, Janhvi; Li, Ming; Patel, Priyanca; Britto, Jonathan A.

    2017-01-01

    ABSTRACT Syndromic craniosynostosis caused by mutations in FGFR2 is characterised by developmental pathology in both endochondral and membranous skeletogenesis. Detailed phenotypic characterisation of features in the membranous calvarium, the endochondral cranial base and other structures in the axial and appendicular skeleton has not been performed at embryonic stages. We investigated bone development in the Crouzon mouse model (Fgfr2C342Y) at pre- and post-ossification stages to improve understanding of the underlying pathogenesis. Phenotypic analysis was performed by whole-mount skeletal staining (Alcian Blue/Alizarin Red) and histological staining of sections of CD1 wild-type (WT), Fgfr2C342Y/+ heterozygous (HET) and Fgfr2C342Y/C342Y homozygous (HOM) mouse embryos from embryonic day (E)12.5-E17.5 stages. Gene expression (Sox9, Shh, Fgf10 and Runx2) was studied by in situ hybridisation and protein expression (COL2A1) by immunohistochemistry. Our analysis has identified severely decreased osteogenesis in parts of the craniofacial skeleton together with increased chondrogenesis in parts of the endochondral and cartilaginous skeleton in HOM embryos. The Sox9 expression domain in tracheal and basi-cranial chondrocytic precursors at E13.5 in HOM embryos is increased and expanded, correlating with the phenotypic observations which suggest FGFR2 signalling regulates Sox9 expression. Combined with abnormal staining of type II collagen in pre-chondrocytic mesenchyme, this is indicative of a mesenchymal condensation defect. An expanded spectrum of phenotypic features observed in the Fgfr2C342Y/C342Y mouse embryo paves the way towards better understanding the clinical attributes of human Crouzon–Pfeiffer syndrome. FGFR2 mutation results in impaired skeletogenesis; however, our findings suggest that many phenotypic aberrations stem from a primary failure of pre-chondrogenic/osteogenic mesenchymal condensation and link FGFR2 to SOX9, a principal regulator of skeletogenesis

  13. Activating (P253R, C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation, differentiation, and mineralization.

    PubMed

    Ratisoontorn, Chootima; Fan, Gao-Feng; McEntee, Kerry; Nah, Hyun-Duck

    2003-01-01

    Various activating mutations of FgfR2 have been linked to a number of craniosynostosis syndromes, suggesting that FGFR2-mediated signaling plays significant roles in intramembranous bone formation. To define (i) the roles of FGFR2-mediated signaling in osteogenesis and (ii) bone cell functions affected by abnormal signaling induced by craniosynostosis mutations, chicken calvarial osteoblasts were infected with replication competent avian sarcoma viruses expressing FgfR2 with dominant negative (DN), P253R (Apert), or C278F (Pfeiffer and Crouzon) mutation. Analyses of the infected osteoblasts revealed that attenuated FGF/FGFR signaling by DN-FgfR2 resulted in a decrease in cell proliferation and accelerated mineralization. In contrast, the C278F mutation, which causes ligand-independent activation of the receptor, significantly stimulated cell proliferation and inhibited mineralization. Interestingly, the P253R mutation, which does not cause ligand-independent activation of the receptor, showed a weaker mitogenic effect than the C278F mutation and did not inhibit mineralization. Gene expression analysis also revealed diverse effects of C278F and P253R mutations on expression of several osteogenic genes. Based on these results, we conclude that one of the major functions of FGFR2 is to mediate mitogenic signals in osteoblasts and that distinctively different cellular mechanisms underlie the pathogenesis of craniosynostosis phenotypes resulting from P253R and C278F mutations of the FGFR2 gene.

  14. Virtual screening on an α-helix to β-strand switchable region of the FGFR2 extracellular domain revealed positive and negative modulators.

    PubMed

    Diaz, Constantino; Corentin, Herbert; Thierry, Vermat; Chantal, Alcouffe; Tanguy, Bozec; David, Sibrac; Jean-Marc, Herbert; Pascual, Ferrara; Françoise, Bono; Edgardo, Ferran

    2014-11-01

    The secondary structure of some protein segments may vary between α-helix and β-strand. To predict these switchable segments, we have developed an algorithm, Switch-P, based solely on the protein sequence. This algorithm was used on the extracellular parts of FGF receptors. For FGFR2, it predicted that β4 and β5 strands of the third Ig-like domain were highly switchable. These two strands possess a high number of somatic mutations associated with cancer. Analysis of PDB structures of FGF receptors confirmed the switchability prediction for β5. We thus evaluated if compound-driven α-helix/β-strand switching of β5 could modulate FGFR2 signaling. We performed the virtual screening of a library containing 1.4 million of chemical compounds with two models of the third Ig-like domain of FGFR2 showing different secondary structures for β5, and we selected 32 compounds. Experimental testing using proliferation assays with FGF7-stimulated SNU-16 cells and a FGFR2-dependent Erk1/2 phosphorylation assay with FGFR2-transfected L6 cells, revealed activators and inhibitors of FGFR2. Our method for the identification of switchable proteinic regions, associated with our virtual screening approach, provides an opportunity to discover new generation of drugs with under-explored mechanism of action.

  15. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome.

    PubMed

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V P; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-09-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak‑like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811‑812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of

  16. The primary site of the acrocephalic feature in Apert Syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling.

    PubMed

    Nagata, Masaki; Nuckolls, Glen H; Wang, Xibin; Shum, Lillian; Seki, Yukie; Kawase, Tomoyuki; Takahashi, Katsu; Nonaka, Kazuaki; Takahashi, Ichiro; Noman, Arhab A; Suzuki, Kenji; Slavkin, Harold C

    2011-04-01

    Activation of osteoblastic bone anabolism in the calvarial sutures is considered to be the essential pathologic condition underlying mutant FGFR2-related craniofacial dysostosis. However, early clinical investigations indicated that abnormal cartilage development in the cranial base was rather a primary site of abnormal feature in Apert Syndrome (AS). To examine the significance of cartilaginous growth of the cranial base in AS, we generated a transgenic mouse bearing AS-type mutant Fgfr2IIIc under the control of the Col2a1 promoter-enhancer (Fgfr2IIIc(P253R) mouse). Despite the lacking expression of Fgfr2IIIc(P253R) in osteoblasts, exclusive disruption of chondrocytic differentiation and growth reproduced AS-like acrocephaly accompanied by short anterior cranial base with fusion of the cranial base synchondroses, maxillary hypoplasia and synostosis of the calvarial sutures with no significant abnormalities in the trunk and extremities. Gene expression analyses demonstrated upregulation of p21, Ihh and Mmp-13 accompanied by modest increase in expression of Sox9 and Runx2, indicating acceleration of chondrocytic maturation and hypertrophy in the cranial base of the Fgfr2IIIc(P253R) mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIc(P253R) receptor with FGF2 and FGF10 is suggested as a mechanism of activation of FGFR2 signaling selectively in the cranial base. In this report, we strongly suggest that the acrocephalic feature of AS is not alone a result of the coronal suture synostosis, but is a result of the primary disturbance in growth of the cranial base with precocious endochondral ossification. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women.

    PubMed

    Barnholtz-Sloan, Jill S; Shetty, Priya B; Guan, Xiaowei; Nyante, Sarah J; Luo, Jingchun; Brennan, Donal J; Millikan, Robert C

    2010-08-01

    Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry [odds ratios (OR) range 1.17-1.81]. Associations were observed for SNPs in FGFR2, LSP1, H19, TLR1/TLR6 and RELN for AA; FGFR2, TNRC9, H19 and MAP3K1 for Whites; FGFR2, TNRC9, Msc5A1 and chromosome 8q for women > or =50 years old and FGFR2 and TNRC9 for women <50 years old. FGFR2 haplotypes based upon rs11200014, rs2981579, rs1219648 and rs2420946 were associated with increased risk of breast cancer, including the GTGT haplotype in AAs [OR = 1.27, 95% confidence interval (CI) 1.04-1.56] and younger women of either race [OR = 1.35, 95% CI 1.02-1.78) and the ATGT haplotype in Whites (OR = 1.30, 95% CI 1.15-1.46). Recent GWAS hits for breast cancer in Europeans and Whites (i.e. women of European descent) thus showed evidence of replication among AAs and Whites in the CBCS. Several new haplotypes were associated with breast cancer in AA and younger women, particularly the FGFR2 GTGT haplotype. These results highlight the need to conduct GWAS among younger women and in a variety of racial-ethnic populations.

  18. Variation in the FGFR2 Gene and the Effects of Postmenopausal Hormone Therapy on Invasive Breast Cancer

    PubMed Central

    Prentice, Ross L.; Huang, Ying; Hinds, David A.; Peters, Ulrike; Pettinger, Mary; Cox, David R.; Beilharz, Erica; Chlebowski, Rowan T.; Rossouw, Jacques E.; Caan, Bette; Ballinger, Dennis G.

    2009-01-01

    Background Breast cancer concern is a major reason for the recent marked reduction in use of postmenopausal hormone therapy, though equally effective means of controlling menopausal symptoms are lacking. Single nucleotide polymorphisms (SNPs) in the fibroblast growth factor receptor two (FGFR2) gene are substantially associated with postmenopausal breast cancer risk, and could influence hormone therapy effects. Participants and Methods We interrogated eight SNPs in intron 2 of the FGFR2 gene for 2166 invasive breast cancer cases from the Women's Health Initiative clinical trial and one-to-one matched controls, to confirm an association with breast cancer risk. We used case-only analyses to examine the dependence of estrogen plus progestin and estrogen-alone odds ratios on SNP genotype. Results Seven FGFR2 SNPs, including six in a single linkage disequilibrium region, were found to associate strongly (p<10−7) with breast cancer risk. SNP rs3750817 (minor allele T with frequency 0.37) had an estimated `per minor allele' odds ratio of 0.78, and was not in such strong linkage disequilibrium with the other SNPs. The genotype of this SNP related significantly (p<0.05) to hormone therapy odds ratios. For estrogen plus progestin, the odds ratios (95% confidence intervals) at 0, 1, and 2 minor SNP alleles were 1.52 (1.14, 2.02), 1.33 (1.01, 1.75), and 0.69 (0.41, 1.17), while corresponding values for estrogen-alone were 0.74 (0.51, 1.09), 0.99 (0.68, 1.44), and 0.34 (0.15, 0.76). Conclusions Postmenopausal women having TT genotype for SNP rs3750817 have a reduced breast cancer risk, and appear to experience comparatively favorable effects of postmenopausal hormone therapy. PMID:19861516

  19. Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome.

    PubMed

    Tartaglia, M; Valeri, S; Velardi, F; Di Rocco, C; Battaglia, P A

    1997-05-01

    Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.

  20. Beyond the closed suture in Apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth

    PubMed Central

    Martínez-Abadías, Neus; Percival, Christopher; Aldridge, Kristina; Hill, Cheryl A; Ryan, Timothy; Sirivunnabood, Satama; Wang, Yingli; Jabs, Ethylin Wang; Richtsmeier, Joan T

    2010-01-01

    Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2+/S252W and Fgfr2+/P253R, to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial skeleton is the most affected region of the cranium. Coronal suture patency shows marked variation that is not strongly correlated with skull dysmorphology. The craniofacial effects of the FGFR2 mutations are similar, but Fgfr2+/S252W mutant mice display significantly more severe dysmorphology localized to the posterior palate. Our results demonstrate that coronal suture closure is neither the primary nor the sole locus of skull dysmorphology in these mouse models for Apert syndrome, but that the face is also primarily affected. PMID:20842696

  1. Transient Inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular β-catenin organization and signaling in AER during mouse limb development.

    PubMed

    Danopoulos, Soula; Parsa, Sara; Al Alam, Denise; Tabatabai, Reza; Baptista, Sheryl; Tiozzo, Caterina; Carraro, Gianni; Wheeler, Matthew; Barreto, Guillermo; Braun, Thomas; Li, Xiaokun; Hajihosseini, Mohammad K; Bellusci, Saverio

    2013-01-01

    The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (≤ 24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, β1-integrin and E-cadherin, and a permanent loss of cellular β-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development.

  2. Fgf receptors Fgfr1a and Fgfr2 control the function of pharyngeal endoderm in late cranial cartilage development.

    PubMed

    Larbuisson, Arnaud; Dalcq, Julia; Martial, Joseph A; Muller, Marc

    2013-01-01

    Cranial cartilage derives mainly from cranial neural crest cells and its formation requires fibroblast growth factor (Fgf) signaling for early differentiation and survival of developing chondrocytes as well as patterning of the endodermal pouches. Here, we investigate the role of Fgf receptors in chondrocyte maturation at later stages, beyond 24 hpf. Using inducible expression of a dominant-negative Fgf receptor, we show that Fgf signaling is required around 30 hpf for correct cartilage formation. The receptor genes fgfr1a and fgr2 are expressed in pharyngeal endodermal pouches after 24 hpf or 26 hpf, respectively. Depletion of any of these two receptors by microinjection of antisense morpholinos results in severe defects in cartilage formation at 4 dpf and a decrease in expression of the late chondrocyte markers barx1 and runx2b. Although endodermal pouches are correctly formed and patterned, receptor knock down leads to decreased expression of runx3, egr1 and sox9b in this tissue, while expression of fsta, coding for a secreted BMP/Tgfß inhibitor, is clearly increased. Rescue experiments revealed that each Fgfr1a or Fgfr2 receptor is able to compensate for the loss of the other. Thus, we show that minimal amounts of Fgfr1a or Fgfr2 are required to initiate a regulatory cascade in pharyngeal endoderm reducing expression of fsta, thereby allowing correct BMP signaling to the maturing chondrocytes of the head cartilage.

  3. BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

    PubMed Central

    Zhang, Zong Xin; Jin, Wen Jun; Yang, Sheng; Ji, Cun Li

    2016-01-01

    Most anti-angiogenic therapies currently being evaluated in clinical trials targetvascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified BRAF kinase inhibitor, vemurafenibas an agent with potential anti-angiogenic and anti-breast cancer activities. Vemurafenib demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor (bFGF). In ex vivo and in vivo angiogenesis assays, vemurafenib suppressed bFGF-induced microvessel sprouting of rat aortic rings and angiogenesis in vivo. To understand the underlying molecular basis, we examined the effects of vemurafenib on different molecular components in treated endothelial cell, and found that vemurafenib suppressed bFGF-triggered activation of FGFR2 and protein kinase B (AKT). Moreover, vemurafenib directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer cells MDA-MB-231, vemurafenib showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Taken together, our results indicate that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. PMID:27293997

  4. Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate.

    PubMed

    Snyder-Warwick, Alison K; Perlyn, Chad A; Pan, Jing; Yu, Kai; Zhang, Lijuan; Ornitz, David M

    2010-02-09

    Cleft palate is a common birth defect in humans and is a common phenotype associated with syndromic mutations in fibroblast growth factor receptor 2 (Fgfr2). Cleft palate occurred in nearly all mice homozygous for the Crouzon syndrome mutation C342Y in the mesenchymal splice form of Fgfr2. Mutant embryos showed delayed palate elevation, stage-specific biphasic changes in palate mesenchymal proliferation, and reduced levels of mesenchymal glycosaminoglycans (GAGs). Reduced levels of feedback regulators of FGF signaling suggest that this gain-of-function mutation in FGFR2 ultimately resembles loss of FGF function in palate mesenchyme. Knowledge of how mesenchymal FGF signaling regulates palatal shelf development may ultimately lead to pharmacological approaches to reduce cleft palate incidence in genetically predisposed humans.

  5. Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

    PubMed Central

    Snyder-Warwick, Alison K.; Perlyn, Chad A.; Pan, Jing; Yu, Kai; Zhang, Lijuan; Ornitz, David M.

    2010-01-01

    Cleft palate is a common birth defect in humans and is a common phenotype associated with syndromic mutations in fibroblast growth factor receptor 2 (Fgfr2). Cleft palate occurred in nearly all mice homozygous for the Crouzon syndrome mutation C342Y in the mesenchymal splice form of Fgfr2. Mutant embryos showed delayed palate elevation, stage-specific biphasic changes in palate mesenchymal proliferation, and reduced levels of mesenchymal glycosaminoglycans (GAGs). Reduced levels of feedback regulators of FGF signaling suggest that this gain-of-function mutation in FGFR2 ultimately resembles loss of FGF function in palate mesenchyme. Knowledge of how mesenchymal FGF signaling regulates palatal shelf development may ultimately lead to pharmacological approaches to reduce cleft palate incidence in genetically predisposed humans. PMID:20133659

  6. A case of Pfeiffer syndrome with c833_834GC>TG (Cys278Leu) mutation in the FGFR2 gene.

    PubMed

    Lee, Min Young; Jeon, Ga Won; Jung, Ji Mi; Sin, Jong Beom

    2010-07-01

    Pfeiffer syndrome is a rare autosomal dominant disorder characterized by coronal craniosynostosis, brachycephaly, mid-facial hypoplasia, and broad and deviated thumbs and great toes. Pfeiffer syndrome occurs in approximately 1:100,000 live births. Clinical manifestations and molecular genetic testing are important to confirm the diagnosis. Mutations of the fibroblast growth factor receptor 1 (FGFR1) gene or FGFR2 gene can cause Pfeiffer syndrome. Here, we describe a case of Pfeiffer syndrome with a novel c833_834GC>TG mutation (encoding Cys278Leu) in the FGFR2 gene associated with a coccygeal anomaly, which is rare in Pfeiffer syndrome.

  7. A novel mutation (a886g) in exon 5 of FGFR2 in members of a family with Crouzon phenotype and plagiocephaly.

    PubMed Central

    Steinberger, D; Collmann, H; Schmalenberger, B; Müller, U

    1997-01-01

    We identified a novel mutation in members of a family with signs of Crouzon syndrome and plagiocephaly. In affected members of the family an A-->G transition was found at position 886 in exon 5 of the fibroblast growth factor receptor 2 (FGFR2) gene. The base change results in the replacement of a lysine by glutamic acid in Ig-like loop III of FGFR2. The unusual finding of plagiocephaly in these Crouzon patients may either be the result of the type of mutation or because of genetic and environmental factors that affect the phenotype in addition to the mutated FGF receptor. Images PMID:9152842

  8. Apert Syndrome: Molecularly Confirmed C.758C>G (P.Pro253Arg) in FGFR2

    SciTech Connect

    Cha Gon, Lee

    2016-03-21

    A 5-day-old girl was referred to our clinic for evaluation of congenital malformations. She was identified with a pathogenic mutation c.758C>G (p.Pro253Arg) in FGFR2 gene using targeted exome sequencing. The de novo mutation was confirmed with Sanger sequencing in the patient and her parents. She showed occipital plagiocephaly with frontal bossing (Figure A and B). Skull frontal and lateral radiography revealed fusion of most of the sutures except coronal suture, with convolutional markings (Figure D and E). She had complete cleft palate (Figure C). Her fused bilateral hands showed type II syndactyly with complete syndactyly between the ring and the little fingers (Figure F1-F3). Both toes were simple syndactyly with side-to-side fusion of skin (Figure G1-)

  9. Q289P mutation in the FGFR2 gene: first report in a patient with type 1 Pfeiffer syndrome.

    PubMed

    Piccione, Maria; Antona, Vincenzo; Niceta, Marcello; Fabiano, Carmelo; Martines, Manuela; Bianchi, Alberto; Corsello, Giovanni

    2009-09-01

    When normal development and growth of the calvarial sutures is disrupted, craniosynostosis (premature calvarial suture fusion) may result. Classical craniosynostosis syndromes are autosomal dominant traits and include Apert, Pfeiffer, Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In these conditions, there is premature fusion of skull bones leading to an abnormal head shape, ocular hypertelorism with proptosis, and midface hypoplasia. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3 cause craniosynostosis. We report on a child with a clinically diagnosed Pfeiffer syndrome that shows the missense point mutation Q289P in exon 8 of the FGFR2 gene. This is a mutation not previously described in the Pfeiffer syndrome but reported in the Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In this paper, we propose the concept that these disorders may represent one genetic condition with phenotypic variability.

  10. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.

    PubMed

    Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D; Shaleh, Hassan M; Mohamed, Essa A; Chaiteerakij, Roongruedee; Allotey, Loretta K; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S; Ndzengue, Albert; Barr Fritcher, Emily G; Knudson, Ryan A; Greipp, Patricia T; Clark, Karl J; Torbenson, Michael S; Kipp, Benjamin R; Zhou, Jie; Barrett, Michael T; Gustafson, Michael P; Alberts, Steven R; Borad, Mitesh J; Roberts, Lewis R

    2016-09-28

    Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

  11. Tracheal occlusion increases the rate of epithelial branching of embryonic mouse lung via the FGF10-FGFR2b-Sprouty2 pathway

    PubMed Central

    UNBEKANDT, MATHIEU; DEL MORAL, PIERRE MARIE; SALA, FREDERIC; BELLUSCI, SAVERIO; WARBURTON, DAVID; FLEURY, VINCENT

    2008-01-01

    Tracheal occlusion during lung development accelerates growth in response to increased intraluminal pressure. In order to investigate the role of internal pressure on murine early lung development, we cauterized the tip of the trachea, to occlude it, and thus to increase internal pressure. This method allowed us to evaluate the effect of tracheal occlusion on the first few branch generations and on gene expression. We observed that the elevation of internal pressure induced more than a doubling in branching, associated with increased proliferation, while branch elongation speed increased 3-fold. Analysis by RT-PCR showed that Fgf10, Vegf, Sprouty2 and Shh mRNA expressions were affected by the change of intraluminal pressure after 48h of culture, suggesting mechanotransduction via internal pressure of these key developmental genes. Tracheal occlusion did not increase the number of branches of Fgfr2b −/− mice lungs nor of wild type lungs cultured with Fgfr2b antisense RNA. Tracheal occlusion of Fgf10LacZ/- hypomorphic lungs led to the formation of fewer branches than in wild type. We conclude that internal pressure regulates the FGF10-FGFR2b-Sprouty2 pathway and thus the speed of the branching process. Therefore pressure levels, fixed both by epithelial secretion and boundary conditions, can control the branching process via FGF10-FGFR2b-Sprouty2. PMID:18082381

  12. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

    PubMed Central

    Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D.; Shaleh, Hassan M.; Mohamed, Essa A.; Chaiteerakij, Roongruedee; Allotey, Loretta K.; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S.; Ndzengue, Albert; Knudson, Ryan A.; Greipp, Patricia T.; Clark, Karl J.; Torbenson, Michael S.; Kipp, Benjamin R.; Zhou, Jie; Barrett, Michael T.; Gustafson, Michael P.; Alberts, Steven R.; Borad, Mitesh J.; Roberts, Lewis R.

    2016-01-01

    Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions. PMID:27216979

  13. Clinical and Radiographic Delineation of Bent Bone Dysplasia-FGFR2 Type or Bent Bone Dysplasia with Distinctive Clavicles and Angel-Shaped Phalanges

    PubMed Central

    Krakow, Deborah; Cohn, Daniel H.; Wilcox, William R.; Noh, Grace J.; Raffel, Leslie J.; Sarukhanov, Anna; Ivanova, Margarita H.; Danielpour, Moise; Grange, Dorothy K.; Elliott, Alison M.; Bernstein, Jonathan A.; Rimoin, David L.; Merrill, Amy E.; Lachman, Ralph S.

    2017-01-01

    Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer-term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and post-natal findings of Bent Bone Dysplasia–FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. PMID:27240702

  14. The low-risk papillomaviruses.

    PubMed

    Egawa, Nagayasu; Doorbar, John

    2017-03-02

    Human Papillomavirus (HPV) research has been dominated by the study of a subset of Alpha papillomaviruses that together cause almost 5% of human cancers worldwide, with the focus being on the two most prominent of these (HPV16 and 18). These viruses are referred to as 'high-risk' (hrHPV), to distinguish them from the over 200 prevalent HPV types that more commonly cause only benign epithelial lesions. The 'low-risk' (lrHPV) term used to describe this group belies their cumulative morbidity. Persistent laryngeal papillomas, which occur rarely in children and adults, require regular surgical de-bulking to allow breathing. Such infections are not curable, and despite being caused by HPV11 (a lrHPV) are associated with 1-3% risk of cancer progression if not resolved. Similarly, the ubiquitous Beta HPV types, which commonly cause asymptomatic infections at cutaneous sites, can sometimes cause debilitating papillomatosis with associated cancer risk. Recalcitrant genital warts, which affect 1 in 200 young adults in the general population, and even the ubiquitous common warts and verrucas that most of us at some time experience, cannot be reliably eradicated, with treatment strategies advancing little over the last 100 years. The review highlights molecular similarities between high and low-risk HPV types, and focuses on the different pathways that the two groups use to ensure persistent infection and adequate virus shedding from the epithelial surface. Understanding the normal patterns of viral gene expression that underlie lesion formation, and which also prevent loss of the infected basal cells in established lesions, are particularly important when considering new treatment options. Finally, the common requirement for deregulated viral gene expression and genome persistence in development of cancers, unites both high and low-risk HPV types, and when considered alongside viral protein functions, provides us with a working understanding of the mechanisms that underlie

  15. Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy

    PubMed Central

    Gilbert, Rebecca; Martin, Richard M.; Evans, David M.; Tilling, Kate; Davey Smith, George; Kemp, John P.; Lane, J. Athene; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Metcalfe, Chris

    2015-01-01

    Introduction Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. Materials and Methods Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. Results The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). Conclusion We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng

  16. Structural specificity in a FGF7-affinity purified heparin octasaccharide required for formation of a complex with FGF7 and FGFR2IIIb.

    PubMed

    Luo, Yongde; Ye, Sheng; Kan, Mikio; McKeehan, Wallace L

    2006-04-15

    Variations in sulfation of heparan sulfate (HS) affect interaction with FGF, FGFR, and FGF-HS-FGFR signaling complexes. Whether structurally distinct HS motifs are at play is unclear. Here we used stabilized recombinant FGF7 as a bioaffinity matrix to purify size-defined heparin oligosaccharides. We show that only 0.2%-4% of 6 to 14 unit oligosaccharides, respectively, have high affinity for FGF7 based on resistance to salt above 0.6M NaCl. The high affinity fractions exhibit highest specific activity for interaction with FGFR2IIIb and formation of complexes of FGF7-HS-FGFR2IIIb. The majority fractions with moderate (0.30-0.6M NaCl), low (0.14-0.30M NaCl) or no affinity at 0.14M NaCl for FGF7 supported no complex formation. The high affinity octasaccharide mixture exhibited predominantly 7- and 8-sulfated components (7,8-S-OctaF7) and formed FGF7-HS-FGFR2IIIb complexes with highest specific activity. Deduced disaccharide analysis indicated that 7,8-S-OctaF7 comprised of DeltaHexA2SGlcN6S in a 2:1 ratio to a trisulfated and a variable unsulfated or monosulfated disaccharide. The inactive octasaccharides with moderate affinity for FGF7 were much more heterogenous and highly sulfated with major components containing 11 or 12 sulfates comprised of predominantly trisulfated disaccharides. This suggests that a rare undersulfated motif in which sulfate groups are specifically distributed has highest affinity for FGF7. The same motif also exhibits structural requirements for high affinity binding to dimers of FGFR2IIIb prior to binding FGF7 to form FGF7-HS-FGFR2IIIb complexes. In contrast, the majority of more highly sulfated HS motifs likely play FGFR-independent roles in stability and control of access of FGF7 to FGFR2IIIb in the tissue matrix. Copyright (c) 2005 Wiley-Liss, Inc.

  17. A Crouzon syndrome synonymous mutation activates a 5{prime} splice site within the IIIC exon of the FGFR2 gene

    SciTech Connect

    Gatto, F.D.; Breathnach, R.

    1995-06-10

    Crouzon syndrome, an autosomal dominant condition causing premature fusion of cranial structures, appears to be caused by mutations in the FGFR2 gene. Several mutations have been identified in the IIIc or bek exon that alter the amino acid sequence of the receptor in a zone known to be involved in ligand binding. In addition, a synonymous G to A transition has been described in three familial Crouzon syndrome cases (mutation at the third position of the alanine 344 codon). It has been suggested that this mutation may activate a cryptic 5{prime} or 3{prime} splice site. The significance of this latter mutation in Crouzon syndrome will be established only when it is known whether it does in fact affect splicing. If it does, prediction of the structure of the mutated receptor requires us to know whether a cryptic 5{prime} or a cryptic 3{prime} splice site has been activated. Ideally, splicing of the pre-mRNA would be studied in the cell type in which the mutated receptor is supposed to exert its effect. However, in our case this information is not available. An alternative strategy is to study splicing in cultured cells using cloned genes. The validity of this approach has been established in other disease systems, for example, thalassemias. 9 refs., 1 fig.

  18. Mutation c.943G>T (p.Ala315Ser) in FGFR2 Causing a Mild Phenotype of Crouzon Craniofacial Dysostosis in a Three-Generation Family.

    PubMed

    Graul-Neumann, Luitgard M; Klopocki, Eva; Adolphs, Nicolai; Mensah, Martin A; Kress, Wolfram

    2017-03-01

    Crouzon syndrome craniofacial dysostosis type I [OMIM 123500] is caused by mutations in the gene encoding fibroblast growth factor receptor-2 (FGFR2). An overlapping phenotype with Muenke and Crouzon syndrome with acanthosis nigricans (FGFR3 mutations) is known. The clinical diagnosis can be corroborated by molecular studies in about 80-90% of the cases. No clear genotype/phenotype correlation has been identified yet. Here, we describe a second family with a mild phenotype in which the FGFR2 mutation c.943G>T leading to the amino acid substitution p.Ala315Ser was detected. Five affected family members showed craniofacial dysostosis without overt craniosynostosis. They all had midface hypoplasia. Crouzonoid appearance with mild protrusion of bulbi was only apparent in our index patient as well as obstructive sleep apnea episodes leading to reduced oxygen saturation; therefore, surgical intervention was suggested. One other affected family member additionally had iris coloboma.

  19. Mutation c.943G>T (p.Ala315Ser) in FGFR2 Causing a Mild Phenotype of Crouzon Craniofacial Dysostosis in a Three-Generation Family

    PubMed Central

    Graul-Neumann, Luitgard M.; Klopocki, Eva; Adolphs, Nicolai; Mensah, Martin A.; Kress, Wolfram

    2017-01-01

    Crouzon syndrome craniofacial dysostosis type I [OMIM 123500] is caused by mutations in the gene encoding fibroblast growth factor receptor-2 (FGFR2). An overlapping phenotype with Muenke and Crouzon syndrome with acanthosis nigricans (FGFR3 mutations) is known. The clinical diagnosis can be corroborated by molecular studies in about 80–90% of the cases. No clear genotype/phenotype correlation has been identified yet. Here, we describe a second family with a mild phenotype in which the FGFR2 mutation c.943G>T leading to the amino acid substitution p.Ala315Ser was detected. Five affected family members showed craniofacial dysostosis without overt craniosynostosis. They all had midface hypoplasia. Crouzonoid appearance with mild protrusion of bulbi was only apparent in our index patient as well as obstructive sleep apnea episodes leading to reduced oxygen saturation; therefore, surgical intervention was suggested. One other affected family member additionally had iris coloboma. PMID:28611549

  20. FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies.

    PubMed

    Flöttmann, Ricarda; Knaus, Alexej; Zemojtel, Tomasz; Robinson, Peter N; Mundlos, Stefan; Horn, Denise; Spielmann, Malte

    2015-08-01

    Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.

  1. Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway

    PubMed Central

    Yang, Jing; Zhang, Dan; Yu, Ying; Zhang, Run-Ju; Hu, Xiao-Ling; Huang, He-Feng; Lu, Yong-Chao

    2015-01-01

    Fibroblast growth factors (FGF1, FGF2 and FGF4) and fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) have been reported to be expressed in preimplantation embryos and be required for their development. However, the functions of these molecules in trophectoderm cells (TEs) that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts. This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Besides, the present results suggest that FGF2/FGFR2 may act in an autocrine fashion and activate the downstream PKC/p38 pathway in TEs during expanded blastocyst formation. PMID:26378412

  2. FGFR2IIIb-MAPK Activity Is Required for Epithelial Cell Fate Decision in the Lower Müllerian Duct

    PubMed Central

    Terakawa, Jumpei; Rocchi, Altea; Serna, Vanida A.; Bottinger, Erwin P.; Graff, Jonathan M.

    2016-01-01

    Cell fate of lower Müllerian duct epithelium (MDE), to become uterine or vaginal epithelium, is determined by the absence or presence of ΔNp63 expression, respectively. Previously, we showed that SMAD4 and runt-related transcription factor 1 (RUNX1) were independently required for MDE to express ΔNp63. Here, we report that vaginal mesenchyme directs vaginal epithelial cell fate in MDE through paracrine activation of fibroblast growth factor (FGF) receptor-MAPK pathway. In the developing reproductive tract, FGF7 and FGF10 were enriched in vaginal mesenchyme, whereas FGF receptor 2IIIb was expressed in epithelia of both the uterus and vagina. When Fgfr2 was inactivated, vaginal MDE underwent uterine cell fate, and this differentiation defect was corrected by activation of MEK-ERK pathway. In vitro, FGF10 in combination with bone morphogenetic protein 4 and activin A (ActA) was sufficient to induce ΔNp63 in MDE, and ActA was essential for induction of RUNX1 through SMAD-independent pathways. Accordingly, inhibition of type 1 receptors for activin in neonatal mice induced uterine differentiation in vaginal epithelium by down-regulating RUNX1, whereas conditional deletion of Smad2 and Smad3 had no effect on vaginal epithelial differentiation. In conclusion, vaginal epithelial cell fate in MDE is induced by FGF7/10-MAPK, bone morphogenetic protein 4-SMAD, and ActA-RUNX1 pathway activities, and the disruption in any one of these pathways results in conversion from vaginal to uterine epithelial cell fate. PMID:27164167

  3. Morphological comparison of the craniofacial phenotypes of mouse models expressing the Apert FGFR2 S252W mutation in neural crest- or mesoderm-derived tissues

    PubMed Central

    Heuzé, Yann; Singh, Nandini; Basilico, Claudio; Jabs, Ethylin Wang; Holmes, Greg; Richtsmeier, Joan T

    2014-01-01

    Bones of the craniofacial skeleton are derived from two distinct cell lineages, cranial neural crest and mesoderm, and articulate at sutures and synchondroses which represent major bone growth sites. Premature fusion of cranial suture(s) is associated with craniofacial dysmorphogenesis caused in part by alteration in the growth potential at sutures and can occur as an isolated birth defect or as part of a syndrome, such as Apert syndrome. Conditional expression of the Apert FGFR2 S252W mutation in mesoderm was previously shown to be necessary and sufficient to cause coronal craniosynostosis. Here we used micro computed tomography images of mice expressing the Apert mutation constitutively in either mesoderm or neural crest to quantify craniofacial shape variation and suture fusion patterns, and to identify shape changes in craniofacial bones derived from the lineage not expressing the mutation, referred to here as secondary shape changes. Our results show that at postnatal day 0: (i) conditional expression of the FGFR2 S252W mutation in neural crest-derived tissues causes a more severe craniofacial phenotype than when expressed in mesoderm-derived tissues; and (ii) both mesoderm- and neural crest-specific mouse models display secondary shape changes. We also show that premature suture fusion is not necessarily dependent on the expression of the FGFR2 S252W mutation in the sutural mesenchyme. More specifically, it appears that suture fusion patterns in both mouse models are suture-specific resulting from a complex combination of the influence of primary abnormalities of biogenesis or signaling within the sutures, and timing. PMID:24632501

  4. Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair

    PubMed Central

    Quantius, Jennifer; Schmoldt, Carole; Vazquez-Armendariz, Ana I.; Becker, Christin; El Agha, Elie; Wilhelm, Jochen; Morty, Rory E.; Vadász, István; Mayer, Konstantin; Gattenloehner, Stefan; Fink, Ludger; Matrosovich, Mikhail; Li, Xiaokun; Seeger, Werner; Lohmeyer, Juergen; Bellusci, Saverio; Herold, Susanne

    2016-01-01

    Influenza Virus (IV) pneumonia is associated with severe damage of the lung epithelium and respiratory failure. Apart from efficient host defense, structural repair of the injured epithelium is crucial for survival of severe pneumonia. The molecular mechanisms underlying stem/progenitor cell mediated regenerative responses are not well characterized. In particular, the impact of IV infection on lung stem cells and their regenerative responses remains elusive. Our study demonstrates that a highly pathogenic IV infects various cell populations in the murine lung, but displays a strong tropism to an epithelial cell subset with high proliferative capacity, defined by the signature EpCamhighCD24lowintegrin(α6)high. This cell fraction expressed the stem cell antigen-1, highly enriched lung stem/progenitor cells previously characterized by the signature integrin(β4)+CD200+, and upregulated the p63/krt5 regeneration program after IV-induced injury. Using 3-dimensional organoid cultures derived from these epithelial stem/progenitor cells (EpiSPC), and in vivo infection models including transgenic mice, we reveal that their expansion, barrier renewal and outcome after IV-induced injury critically depended on Fgfr2b signaling. Importantly, IV infected EpiSPC exhibited severely impaired renewal capacity due to IV-induced blockade of β-catenin-dependent Fgfr2b signaling, evidenced by loss of alveolar tissue repair capacity after intrapulmonary EpiSPC transplantation in vivo. Intratracheal application of exogenous Fgf10, however, resulted in increased engagement of non-infected EpiSPC for tissue regeneration, demonstrated by improved proliferative potential, restoration of alveolar barrier function and increased survival following IV pneumonia. Together, these data suggest that tropism of IV to distal lung stem cell niches represents an important factor of pathogenicity and highlight impaired Fgfr2b signaling as underlying mechanism. Furthermore, increase of alveolar Fgf10

  5. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride.

    PubMed

    Sáez, C; González-Baena, A C; Japón, M A; Giráldez, J; Segura, D I; Rodríguez-Vallejo, J M; González-Esteban, J; Miranda, G; Torrubia, F

    1999-07-01

    The development of benign prostatic hyperplasia (BPH) is an androgen-dependent process which may be mediated by a number of locally produced growth factors. One of these, the basic fibroblast growth factor (bFGF or FGF2), has a mitogenic effect on prostatic stroma. High expression levels of bFGF have been reported in BPH. FGFR1 and FGFR2 receptors, that exhibit affinity for bFGF, have been identified in normal and hyperplastic prostate. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. This study was designed to assess the effects of finasteride on the expression levels of bFGF, FGFR1, and FGFR2 in patients with BPH. The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH. Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium. In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. These findings were also confirmed by RT-PCR. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. A marked reduction in bFGF levels is seen in BPH treated with finasteride in comparison to untreated BPH. In our opinion, finasteride may act as a negative regulator of b

  6. High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers Identifies KRAS, FGFR2 and PIK3CA to Be Frequently Mutated

    PubMed Central

    Seidel, Danila; Kusonmano, Kanthida; Petersen, Kjell; Mjøs, Siv; Hoivik, Erling A.; Wik, Elisabeth; Halle, Mari Kyllesø; Øyan, Anne M.; Kalland, Karl-Henning; Werner, Henrica Maria Johanna; Trovik, Jone; Salvesen, Helga

    2012-01-01

    Background Despite being the most common pelvic gynecologic malignancy in industrialized countries, no targeted therapies are available for patients with metastatic endometrial carcinoma. In order to improve treatment, underlying molecular characteristics of primary and metastatic disease must be explored. Methodology/Principal Findings We utilized the mass spectrometric-based mutation detection technology OncoMap to define the types and frequency of point somatic mutations in endometrial cancer. 67 primary tumors, 15 metastases corresponding to 7 of the included primary tumors and 11 endometrial cancer cell lines were screened for point mutations in 28 known oncogenes. We found that 27 (40.3%) of 67 primary tumors harbored one or more mutations with no increase in metastatic lesions. FGFR2, KRAS and PIK3CA were consistently the most frequently mutated genes in primary tumors, metastatic lesions and cell lines. Conclusions/Significance Our results emphasize the potential for targeting FGFR2, KRAS and PIK3CA mutations in endometrial cancer for development of novel therapeutic strategies. PMID:23300780

  7. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: Evidence for missense changes, insertions, and a deletion due to alternative RNA splicing

    SciTech Connect

    Meyers, G.A.; Przylepa, K.A.; Scott, A.F.

    1996-03-01

    Fibroblast growth factor receptor 2 (FGFR2) mutations have been associated with the craniosynostotic conditions Crouzon, Jackson-Weiss, and Pfeiffer syndromes. Previously, mutations were described in the exons IIIa and IIIc, which form the extracellular, third immunoglobulin-like domain (IgM) and adjacent linker regions, both of which are normally involved in ligand binding. For all three conditions, mutations were found in exon IIIc. Only in Crouzon syndrome were mutations identified in exon IIIa. In this study, 39 cases with one of these three conditions were screened for exon IIIa or IIIc mutations. Eleven mutations are reported in 17 unrelated cases. Mutations in exon IIIa are identified for not only Crouzon but also Jackson-Weiss and Pfeiffer syndromes. Four mutations in either exon IIIa or exon IIIc reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in exon IIIa in a Crouzon syndrome patient and the other in exon IIIc in a Pfeiffer syndrome patient, were observed. The latter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation was detected in one Pfeiffer syndrome family in which two members had craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders. 16 refs., 3 figs., 1 tab.

  8. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in "paternal age-effect" syndromes.

    PubMed

    Goriely, Anne; Lord, Helen; Lim, Jasmine; Johnson, David; Lester, Tracy; Firth, Helen V; Wilkie, Andrew O M

    2010-08-01

    Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes.

  9. Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma

    PubMed Central

    Nayak, Seema; Goel, Madhu Mati; Makker, Annu; Bhatia, Vikram; Chandra, Saumya; Kumar, Sandeep; Agarwal, S. P.

    2015-01-01

    There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP. PMID:26465941

  10. Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma.

    PubMed

    Nayak, Seema; Goel, Madhu Mati; Makker, Annu; Bhatia, Vikram; Chandra, Saumya; Kumar, Sandeep; Agarwal, S P

    2015-01-01

    There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP.

  11. Molecular heterogeneity in the novel fusion gene APIP-FGFR2: Diversity of genomic breakpoints in gastric cancer with high-level amplifications at 11p13 and 10q26

    PubMed Central

    Okuda, Takashi; Taki, Tomohiko; Nishida, Kazuhiro; Chinen, Yoshiaki; Nagoshi, Hisao; Sakakura, Chouhei; Taniwaki, Masafumi

    2017-01-01

    Several novel fusion transcripts were identified by next-generation sequencing in gastric cancer; however, the breakpoint junctions have yet to be characterized. The present study characterized a plethora of APIP-FGFR2 genomic breakpoints in the SNU-16 gastric cancer cell line, which harbored homogeneously staining regions (hsrs) and double minute chromosomes. Oligonucleotide microarrays revealed high-level amplifications at chromosomes 8q24.1 (0.8 Mb region), 10q26 (1.1 Mb) and 11p13 (1.1 Mb). These amplicons contained MYC and PVT1 at chromosome 8q24.1, BRWD2, FGFR2 and ATE1 at chromosome 10q26, and 24 genes, including APIP, CD44, RAG1 and RAG2, at chromosome 11p13. Based on these findings, reverse transcription-polymerase chain reaction (PCR) was performed using various candidate gene primers to detect possible fusion transcripts, and several products using primer sets for the APIP and FGFR2 genes were detected. Eventually, three in-frame and two out-of-frame fusion transcripts were detected. Notably, PCR analysis of the entire genomic DNA detected three distinct genomic junctions. The breakpoints were within intron 5 of APIP, which contained three distinct breakpoints, and introns 5, 7 and 9 of FGFR2. Fluorescence in situ hybridization showed several fusion signals within hsrs using two short probes (~10-kb segments of a bacterial artificial chromosome clone) containing exons 2–5 of APIP or exons 11–13 of FGFR2. Although, for any given fusion, a multiplicity of transcripts is thought to be created by alternative splicing of one rearranged allele, the results of the present study suggested that genomic fusions of APIP and FGFR2 are generated in hsrs with a diversity of breakpoints that are then faithfully transcribed. PMID:28123544

  12. miR-223 Regulates Adipogenic and Osteogenic Differentiation of Mesenchymal Stem Cells Through a C/EBPs/miR-223/FGFR2 Regulatory Feedback Loop.

    PubMed

    Guan, Xiaohui; Gao, Yifei; Zhou, Jie; Wang, Jun; Zheng, Fang; Guo, Fei; Chang, Ailing; Li, Xiaoxia; Wang, Baoli

    2015-05-01

    Several miRNAs have recently been identified to regulate adipocyte or osteoblast differentiation or both. In this study, miR-223 was found to be involved in the reciprocal regulation of adipocyte and osteoblast differentiation. miR-223 was induced in primary cultured mouse marrow stromal cell, mesenchymal line C3H10T1/2 and stromal line ST2 after adipogenic treatment. Conversely, it was reduced in preosteoblast MC3T3-E1 after osteogenic treatment. Supplementing miR-223 levels using synthetic miR-223 mimics significantly suppressed the growth of the C3H10T1/2 and ST2 cells and induced the progenitor cells to fully differentiate into adipocytes, along with induction of adipocyte-specific transcription factors peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein-α (C/EBPα), and marker genes aP2 and adipsin. By contrast, depletion of the endogenous miR-223 using synthetic miR-223 inhibitor repressed the progenitor cells to differentiate. The effects of miR-223 on adipocyte formation from ST2 cells were also demonstrated by using lentivirus that overexpresses miR-223. Conversely, supplementing miR-223 blocked ST2 to differentiate into osteoblasts. Fibroblast growth factor receptor 2 (Fgfr2), a critical regulator of osteoblast, was shown to be a direct target of miR-223 by using dual luciferase reporter assay. Knockdown of Fgfr2 in C3H10T1/2 downregulated phosphorylation of ERK1/2 and upregulated expression of C/EBPα and dramatically enhanced the differentiation of the cells into adipocytes. Further investigation of mechanisms that control miR-223 expression demonstrated that C/EBPs induced miR-223 expression through binding to the promoter regions of the miR-223. Taken together, our study provides evidences that miR-223 regulates adipocyte and osteoblast differentiation through a novel C/EBPs/miR-223/FGFR2 regulatory feedback loop.

  13. Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case.

    PubMed

    Schaefer, F; Anderson, C; Can, B; Say, B

    1998-01-23

    We have studied an infant with cloverleaf skull, proptosis, radioulnar synostosis and broad thumbs and great toes diagnosed as Pfeiffer syndrome type 2. However, there were many overlapping findings with Antley-Bixler syndrome. The patient was found to have a G to T mutation in codon 290 exon 7 of the FGFR2 gene leading to a substitution of a cys for the normal trp at this locus. This is the third mutation characterized at this codon; therefore, this locus appears to be a mutational hotspot in the gene. However, the other known mutations lead to a milder, Crouzon-like phenotype. The introduction of an additional cys into a region characterized by immunoglobulin-type loops maintained by cys S-S crosslinking may provide an explanation for the severity of the clinical findings of this child.

  14. A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes.

    PubMed

    Hajihosseini, M K; Wilson, S; De Moerlooze, L; Dickson, C

    2001-03-27

    Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.

  15. Dynamic morphological changes in the skulls of mice mimicking human Apert syndrome resulting from gain-of-function mutation of FGFR2 (P253R).

    PubMed

    Du, Xiaolan; Weng, Tujun; Sun, Qidi; Su, Nan; Chen, Zhi; Qi, Huabing; Jin, Ming; Yin, Liangjun; He, Qifen; Chen, Lin

    2010-08-01

    Apert syndrome is caused mainly by gain-of-function mutations of fibroblast growth factor receptor 2. We have generated a mouse model (Fgfr2(+/P253R)) mimicking human Apert syndrome resulting from fibroblast growth factor receptor 2 Pro253Arg mutation using the knock-in approach. This mouse model in general has the characteristic skull morphology similar to that in humans with Apert syndrome. To characterize the detailed changes of form in the overall skull and its major anatomic structures, euclidean distance matrix analysis was used to quantitatively compare the form and growth difference between the skulls of mutants and their wild-type controls. There were substantial morphological differences between the skulls of mutants and their controls at 4 and 8 weeks of age (P < 0.01). The mutants showed shortened skull dimensions along the rostrocaudal axis, especially in their face. The width of the frontal bone and the distance between the two orbits were broadened mediolaterally. The neurocrania were significantly increased along the dorsoventral axis and slightly increased along the mediolateral axis, and also had anteriorly displayed opisthion along the rostrocaudal axis. Compared with wild-type, the mutant mandible had an anteriorly displaced coronoid process and mandibular condyle along the rostrocaudal axis. We further found that there was catch-up growth in the nasal bone, maxilla, zygomatic bone and some regions of the mandible of the mutant skulls during the 4-8-week interval. The above-mentioned findings further validate the Fgfr2(+/P253R) mouse strain as a good model for human Apert syndrome. The changes in form characterized in this study will help to elucidate the mechanisms through which the Pro253Arg mutation in fibroblast growth factor receptor 2 affects craniofacial development and causes Apert syndrome.

  16. Importance of the type I insulin-like growth factor receptor in HER2, FGFR2 and MET-unamplified gastric cancer with and without Ras pathway activation

    PubMed Central

    Saisana, Marina; Griffin, S. Michael; May, Felicity E.B.

    2016-01-01

    Amplification of seven oncogenes: HER2, EGFR, FGFR1, FGFR2, MET, KRAS and IGF1R has been identified in gastric cancer. The first five are targeted therapeutically in patients with HER2-positivity, FGFR2- or MET-amplification but the majority of patients are triple-negative and require alternative strategies. Our aim was to evaluate the importance of the IGF1R tyrosine kinase in triple-negative gastric cancer with and without oncogenic KRAS, BRAF or PI3K3CA mutations. Cell lines and metastatic tumor cells isolated from patients expressed IGF1R, and insulin-like growth factor-1 (IGF-1) activated the PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways. IGF-1 protected triple-negative cells from caspase-dependent apoptosis and anoikis. Protection was mediated via the PI3-kinase/Akt pathway. Remarkably, IGF-1-dependent cell survival was greater in patient samples. IGF-1 stimulated triple-negative gastric cancer cell growth was prevented by IGF1R knockdown and Ras/Raf/MAP-kinase pathway inhibition. The importance of the receptor in cell line and metastatic tumor cell growth in serum-containing medium was demonstrated by knockdown and pharmacological inhibition with figitumumab. The proportions of cells in S-phase and mitotic-phase, and Ras/Raf/MAP-kinase pathway activity, were reduced concomitantly. KRAS-addicted and BRAF-impaired gastric cancer cells were particularly susceptible. In conclusion, IGF1R and the IGF signal transduction pathway merit consideration as potential therapeutic targets in patients with triple-negative gastric cancer. PMID:27437872

  17. Deformed Skull Morphology Is Caused by the Combined Effects of the Maldevelopment of Calvarias, Cranial Base and Brain in FGFR2-P253R Mice Mimicking Human Apert Syndrome

    PubMed Central

    Luo, Fengtao; Xie, Yangli; Xu, Wei; Huang, Junlan; Zhou, Siru; Wang, Zuqiang; Luo, Xiaoqing; Liu, Mi; Chen, Lin; Du, Xiaolan

    2017-01-01

    Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial base and brain, that may all be involved in the pathogenesis of skull malformation of Apert syndrome. To distinguish the differential roles of these components of head in the pathogenesis of the abnormal skull morphology of AS, we generated mouse strains specifically expressing mutant FGFR2 in chondrocytes, osteoblasts, and progenitor cells of central nervous system (CNS) by crossing Fgfr2+/P253R-Neo mice with Col2a1-Cre, Osteocalcin-Cre (OC-Cre), and Nestin-Cre mice, respectively. We then quantitatively analyzed the skull and brain morphology of these mutant mice by micro-CT and micro-MRI using Euclidean distance matrix analysis (EDMA). Skulls of Col2a1-Fgfr2+/P253R mice showed Apert syndrome-like dysmorphology, such as shortened skull dimensions along the rostrocaudal axis, shortened nasal bone, and evidently advanced ossification of cranial base synchondroses. The OC-Fgfr2+/P253R mice showed malformation in face at 8-week stage. Nestin-Fgfr2+/P253R mice exhibited increased dorsoventral height and rostrocaudal length on the caudal skull and brain at 8 weeks. Our study indicates that the abnormal skull morphology of AS is caused by the combined effects of the maldevelopment in calvarias, cranial base, and brain tissue. These findings further deepen our knowledge about the pathogenesis of the abnormal skull morphology of AS, and provide new clues for the further analyses of skull phenotypes and clinical management of AS. PMID:28123344

  18. [Does low-risk delivery exist?].

    PubMed

    Selvi Dogan, F; Calmelet, P; Cottenet, J; Sagot, P; Mace, G

    2013-10-01

    The main objective of our study is to evaluate the rate of call of the obstetrician during childbirth supposed in low-risk and compare it to high-risk deliveries in a maternity service level II. The secondary objective is to assess the level of intervention of the obstetrician with the patient in both groups. This is a prospective study of 490 patients including 259 classified as low risk based on obstetric criteria of Bourgogne Perinatal Network. The criteria considered for the call and/or intervention of the obstetrician were the following: altered fetal heart rate, lactate scalp, instrumental delivery, cesarean section, complete or complicated perineal, serious event during labor (cord prolapse, uterine rupture…), postpartum hemorrhage treated by prostaglandin ocytocic. The high-risk group is taken as reference for the calculation of confidence intervals. The rate of call of the obstetrician in the low versus high risk are: 37% [95% CI: 0.98-2.11] and 29% [95% CI: 1.00] (P=0.0587). The rate of intervention of the obstetrician in the low versus high risk is 21% [95% CI: 1.15-3.07] and 12% [95% CI: 1.00] (P=0.0109). The delivery process is unpredictable and potentially risky. Thirty-seven percent of patients classified as low risk at the beginning of labour have required intervention of the obstetrician and 21% of them his intervention. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  19. Fronto-facial advancement and bipartition in Crouzon-Pfeiffer and Apert syndromes: Impact of fronto-facial surgery upon orbital and airway parameters in FGFR2 syndromes.

    PubMed

    Khonsari, Roman H; Way, Benjamin; Nysjö, Johan; Odri, Guillaume A; Olszewski, Raphaël; Evans, Robert D; Dunaway, David J; Nyström, Ingela; Britto, Jonathan A

    2016-10-01

    A major concern in FGFR2 craniofaciosynostosis is oculo-orbital disproportion, such that orbital malformation provides poor accommodation and support for the orbital contents and peri-orbita, leading to insufficient eyelid closure, corneal exposure and eventually to functional visual impairment. Fronto-facial monobloc osteotomy followed by distraction osteogenesis aims to correct midfacial growth deficiencies in Crouzon-Pfeiffer syndrome patients. Fronto-facial bipartition osteotomy followed by distraction is a procedure of choice in Apert syndrome patients. These procedures modify the shape and volume of the orbit and tend to correct oculo-orbital disproportion. Little is known about the detailed 3D shape of the orbital phenotype in CPS and AS, and about how this is modified by fronto-facial surgery. Twenty-eight patients with CMS, 13 patients with AS and 40 control patients were included. CT scans were performed before and after fronto-facial surgery. Late post-operative scans were available for the Crouzon-Pfeiffer syndrome group. Orbital morphology was investigated using conventional three-dimensional cephalometry and shape analysis after mesh-based segmentation of the orbital contents. We characterized the 3D morphology of CPS and AS orbits and showed how orbital shape is modified by surgery. We showed that monobloc-distraction in CPS and bipartition-distraction in AS specifically address the morphological characteristics of the two syndromes.

  20. The Effects of Tissue-Nonspecific Alkaline Phosphatase Gene Therapy on Craniosynostosis and Craniofacial Morphology in the FGFR2C342Y/+ Mouse Model of Crouzon Craniosynostosis

    PubMed Central

    Wang, E; Nam, HK; Liu, J; Hatch, NE

    2015-01-01

    Objectives Craniosynostosis, the premature fusion of cranial bones, has traditionally been described as a disease of increased bone mineralization. However, multiple mouse models of craniosynostosis display craniosynostosis simultaneously with diminished cranial bone volume and/or density. We propose an alternative hypothesis that craniosynostosis results from abnormal tissue mineralization through the downregulation of tissue-nonspecific alkaline phosphatase (TNAP) enzyme downstream of activating mutations in FGFRs. Material & Methods Neonatal Crouzon (FGFRC342Y/+) and wild type (FGFR+/+) mice were injected with lentivirus to deliver a recombinant form of TNAP. Mice were sacrificed at four weeks post-natal. Serum was collected to test for alkaline phosphatase (AP), phosphorus, and calcium levels. Craniofacial bone fusion and morphology was assessed by micro-computed tomography. Results Injection with the TNAP lentivirus significantly increased serum AP levels (increased serum AP levels are indicative of efficient transduction and production of the recombinant protein), but results were variable and dependent upon viral lot and the litter of mice injected. Morphologic analysis revealed craniofacial form differences for inferior surface (p=.023) and cranial height (p=.014) regions between TNAP lentivirus injected and vehicle-injected Crouzon mice. With each unit increase in AP level, the odds of lambdoid suture fusion decreased by 84.2% and these results came close to statistical significance (p=.068). Conclusion These results suggest that TNAP deficiency may mediate FGFR2-associated craniosynostosis. Future studies should incorporate injection of recombinant TNAP protein, to avoid potential side effects and variable efficacy of lentiviral gene delivery. PMID:25865549

  1. 5'- and 3'-terminal nucleotides in the FGFR2 ISAR splicing element core have overlapping roles in exon IIIb activation and exon IIIc repression.

    PubMed

    Jones, R B; Carstens, R P; Luo, Y; McKeehan, W L

    2001-09-01

    The cell type-specific, mutually-exclusive alternative splicing of the fibroblast growth factor receptor 2 (FGFR2) pre-mRNA is tightly regulated. A sequence termed ISAR (intronic splicing activator and repressor) has been implicated as an important cis regulatory element in both activation of exon IIIb and repression of exon IIIc splicing in epithelial cells. In order to better understand how this single sequence could have dual roles, we transfected minigenes containing a series of 2-bp mutations in the 18 3'-most nucleotides of ISAR that we refer to as the ISAR core. Transfection of cells with dual-exon (IIIb and IIIc) minigenes revealed that mutation of terminal sequences of the core led to decreased exon IIIb inclusion and increased exon IIIc inclusion. Transfection of cells with single-exon IIIb minigenes and single-exon IIIc minigenes revealed that mutation of terminal sequences of the ISAR core led to decreased exon IIIb inclusion and increased exon IIIc inclusion, respectively. Nucleotides of the ISAR core responsible for exon IIIb activation appear to overlap very closely with those required for exon IIIc repression. We describe a model in which ISAR and a 5' intronic sequence known as IAS2 form a stem structure required for simultaneous exon IIIb activation and exon IIIc repression.

  2. Overexpression of FGFR2 contributes to inherent resistance to MET inhibitors in MET-amplified patient-derived gastric cancer xenografts.

    PubMed

    Liu, Kai; Song, Xilin; Zhu, Meirong; Ma, Heng

    2015-10-01

    Gastric cancer is one of the most malignant diseases and one of the leading causes of cancer-associated mortality worldwide. Although advances have been made in surgical techniques, perioperative management and the combined use of surgery with chemotherapy and/or radiotherapy, patients with advanced stage gastric cancer continue to face poor outcomes. Furthermore, it was reported that MET gene amplification and overexpression predicted the sensitivity to MET inhibitors in gastric cancer. However, the identification of drug-resistant tumors has encouraged the pre-emptive elucidation of the possible mechanisms of clinical resistance. The current study assessed a number of patient-derived gastric cancer models with MET amplification and overexpression, including CNGAS028. The tumor tissues were subjected to microarray analysis (using single nucleotide polymorphism 6.0 and human genome U133 arrays) followed by western blotting. The results demonstrated that CNGAS028 xenograft tumors did not respond to treatment with a selective MET inhibitor. Additional analysis indicated that FGFR2 overexpression contributed to the resistance to MET inhibitors. Furthermore, treatment with a combination of fibroblast growth factor receptor 2 and MET inhibitors inhibited the growth of CNGAS028 xenograft tumors in vivo. In conclusion, the current results aid in understanding the mechanism of inherent resistance to selective MET inhibitors as well as provide important information for patient selection and clinical treatment strategies.

  3. The effects of tissue-non-specific alkaline phosphatase gene therapy on craniosynostosis and craniofacial morphology in the FGFR2C342Y/+ mouse model of Crouzon craniosynostosis.

    PubMed

    Wang, E; Nam, H K; Liu, J; Hatch, N E

    2015-04-01

    Craniosynostosis, the premature fusion of cranial bones, has traditionally been described as a disease of increased bone mineralization. However, multiple mouse models of craniosynostosis display craniosynostosis simultaneously with diminished cranial bone volume and/or density. We propose an alternative hypothesis that craniosynostosis results from abnormal tissue mineralization through the downregulation of tissue-non-specific alkaline phosphatase (TNAP) enzyme downstream of activating mutations in FGFRs. Neonatal Crouzon (FGFRC342Y/+) and wild-type (FGFR+/+) mice were injected with lentivirus to deliver a recombinant form of TNAP. Mice were sacrificed at 4 weeks postnatal. Serum was collected to test for alkaline phosphatase (AP), phosphorus, and calcium levels. Craniofacial bone fusion and morphology were assessed by micro-computed tomography. Injection with the TNAP lentivirus significantly increased serum AP levels (increased serum AP levels are indicative of efficient transduction and production of the recombinant protein), but results were variable and dependent upon viral lot and the litter of mice injected. Morphological analysis revealed craniofacial form differences for inferior surface (p=0.023) and cranial height (p=0.014) regions between TNAP lentivirus-injected and vehicle-injected Crouzon mice. With each unit increase in AP level, the odds of lambdoid suture fusion decreased by 84.2% and these results came close to statistical significance (p=0.068). These results suggest that TNAP deficiency may mediate FGFR2-associated craniosynostosis. Future studies should incorporate injection of recombinant TNAP protein, to avoid potential side effects and variable efficacy of lentiviral gene delivery. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Gene variants in the angiogenesis pathway and prostate cancer

    PubMed Central

    Amankwah, Ernest K.; Sellers, Thomas A.; Park, Jong Y.

    2012-01-01

    Although the causes of prostate cancer are still unknown, numerous studies support the role of genetic factors in the development and progression of this disease. Single nucleotide polymorphisms (SNPs) in key angiogenesis genes have been studied in prostate cancer. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. Of the 17 prostate cancer genome-wide association studies (GWAS) conducted to date, only one identified disease-associated SNPs in a region of an angiogenesis pathway gene. An association was observed between aggressive disease and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) in a region on chromosome 10q26 that encompasses FGFR2. The majority (27/32, 84.4%) of primary candidate gene studies reviewed had a small (n < 800, 20/32, 62.5%) to medium sample size (n = 800–2000, 7/32, 21.9%), whereas only five (15.6%) had a large sample size (n ≥ 2000). Results from the large studies revealed associations with risk and aggressive disease for SNPs in NOS2A, NOS3 and MMP-2 and risk for HIF1-α. Meta-analyses have so far been conducted on FGFR2, TGF-β, TNF-α, HIF1-α and IL10 and the results reveal an association with risk for SNPs in FGFR2 and TGF-β and aggressive disease for SNPs in IL-10. Thus, existing evidence from GWAS and large candidate gene studies indicates that SNPs from a limited number of angiogenesis pathway genes are associated with prostate cancer risk and progression. PMID:22523086

  5. Computational mouse atlases and their application to automatic assessment of craniofacial dysmorphology caused by the Crouzon mutation Fgfr2(C342Y).

    PubMed

    Olafsdóttir, Hildur; Darvann, Tron A; Hermann, Nuno V; Oubel, Estanislao; Ersbøll, Bjarne K; Frangi, Alejandro F; Larsen, Per; Perlyn, Chad A; Morriss-Kay, Gillian M; Kreiborg, Sven

    2007-07-01

    Crouzon syndrome is characterized by premature fusion of sutures and synchondroses. Recently, the first mouse model of the syndrome was generated, having the mutation Cys342Tyr in Fgfr2c, equivalent to the most common human Crouzon/Pfeiffer syndrome mutation. In this study, a set of micro-computed tomography (CT) scannings of the skulls of wild-type mice and Crouzon mice were analysed with respect to the dysmorphology caused by Crouzon syndrome. A computational craniofacial atlas was built automatically from the set of wild-type mouse micro-CT volumes using (1) affine and (2) non-rigid image registration. Subsequently, the atlas was deformed to match each subject from the two groups of mice. The accuracy of these registrations was measured by a comparison of manually placed landmarks from two different observers and automatically assessed landmarks. Both of the automatic approaches were within the interobserver accuracy for normal specimens, and the non-rigid approach was within the interobserver accuracy for the Crouzon specimens. Four linear measurements, skull length, height and width and interorbital distance, were carried out automatically using the two different approaches. Both automatic approaches assessed the skull length, width and height accurately for both groups of mice. The non-rigid approach measured the interorbital distance accurately for both groups while the affine approach failed to assess this parameter for both groups. Using the full capability of the non-rigid approach, local displacements obtained when registering the non-rigid wild-type atlas to a non-rigid Crouzon mouse atlas were determined on the surface of the wild-type atlas. This revealed a 0.6-mm bending in the nasal region and a 0.8-mm shortening of the zygoma, which are similar to characteristics previously reported in humans. The most striking finding of this analysis was an angulation of approximately 0.6 mm of the cranial base, which has not been reported in humans. Comparing

  6. Computational mouse atlases and their application to automatic assessment of craniofacial dysmorphology caused by the Crouzon mutation Fgfr2C342Y

    PubMed Central

    Ólafsdóttir, Hildur; Darvann, Tron A; Hermann, Nuno V; Oubel, Estanislao; Ersbøll, Bjarne K; Frangi, Alejandro F; Larsen, Per; Perlyn, Chad A; Morriss-Kay, Gillian M; Kreiborg, Sven

    2007-01-01

    Crouzon syndrome is characterized by premature fusion of sutures and synchondroses. Recently, the first mouse model of the syndrome was generated, having the mutation Cys342Tyr in Fgfr2c, equivalent to the most common human Crouzon/Pfeiffer syndrome mutation. In this study, a set of micro-computed tomography (CT) scannings of the skulls of wild-type mice and Crouzon mice were analysed with respect to the dysmorphology caused by Crouzon syndrome. A computational craniofacial atlas was built automatically from the set of wild-type mouse micro-CT volumes using (1) affine and (2) non-rigid image registration. Subsequently, the atlas was deformed to match each subject from the two groups of mice. The accuracy of these registrations was measured by a comparison of manually placed landmarks from two different observers and automatically assessed landmarks. Both of the automatic approaches were within the interobserver accuracy for normal specimens, and the non-rigid approach was within the interobserver accuracy for the Crouzon specimens. Four linear measurements, skull length, height and width and interorbital distance, were carried out automatically using the two different approaches. Both automatic approaches assessed the skull length, width and height accurately for both groups of mice. The non-rigid approach measured the interorbital distance accurately for both groups while the affine approach failed to assess this parameter for both groups. Using the full capability of the non-rigid approach, local displacements obtained when registering the non-rigid wild-type atlas to a non-rigid Crouzon mouse atlas were determined on the surface of the wild-type atlas. This revealed a 0.6-mm bending in the nasal region and a 0.8-mm shortening of the zygoma, which are similar to characteristics previously reported in humans. The most striking finding of this analysis was an angulation of approximately 0.6 mm of the cranial base, which has not been reported in humans. Comparing

  7. Pathological Outcomes in Men with Low Risk and Very Low Risk Prostate Cancer: Implications on the Practice of Active Surveillance

    PubMed Central

    Tosoian, Jeffrey J.; JohnBull, Eric; Trock, Bruce J.; Landis, Patricia; Epstein, Jonathan I.; Partin, Alan W.; Walsh, Patrick C.; Carter, H. Ballentine

    2014-01-01

    Purpose We assessed oncologic outcomes at surgery in men with low risk and very low risk prostate cancer who were candidates for active surveillance. Materials and Methods In a prospectively collected institutional database, we identified 7,486 subjects eligible for active surveillance who underwent radical retropubic prostatectomy. Candidates were designated as being at low risk (stage T1c/T2a, prostate specific antigen 10 ng/ml or less, and Gleason score 6 or less) or very low risk (stage T1c, prostate specific antigen density 0.15 or less, Gleason score 6 or less, 2 or fewer positive biopsy cores, 50% or less cancer involvement per core) based on preoperative data. Adverse findings were Gleason score upgrade (score 7 or greater) and nonorgan confined cancer on surgical pathology. The relative risk of adverse findings in men at low risk with very low risk disease was evaluated in a multivariate model using Poisson regression. Results A total of 7,333 subjects met the criteria for low risk disease and 153 had very low risk disease. The proportion of subjects at low risk found to have Gleason score upgrade or nonorgan confined cancer on final pathology was 21.8% and 23.1%, respectively. Corresponding values in those at very low risk were 13.1% and 8.5%, respectively. After adjusting for age, race, year of surgery, body mass index, and prostate specific antigen at diagnosis, the relative risk of Gleason score upgrade in men with low risk vs very low risk disease was 1.89 (95% CI 1.21–2.95). The relative risk of nonorgan confined cancer was 2.06 (95% CI 1.19–3.57). Conclusions Men with very low risk prostate cancer were at significantly lower risk for adverse findings at surgery compared to those with low risk disease. These data support the stratification of low risk cancer when selecting and counseling men who may be appropriate for active surveillance. PMID:23643603

  8. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in “paternal age-effect” syndromes

    PubMed Central

    Goriely, Anne; Lord, Helen; Lim, Jasmine; Johnson, David; Lester, Tracy; Firth, Helen V; Wilkie, Andrew OM

    2010-01-01

    Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age (“paternal age effect”). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes. © 2010 Wiley-Liss, Inc. PMID:20635358

  9. 'Observation' Best Option for Most Low-Risk Prostate Cancer

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_167181.html 'Observation' Best Option for Most Low-Risk Prostate Cancer ... majority of men with localized prostate cancer, selecting observation for their treatment choice can help them live ...

  10. 40 CFR 266.109 - Low risk waste exemption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... MANAGEMENT FACILITIES Hazardous Waste Burned in Boilers and Industrial Furnaces § 266.109 Low risk waste... industrial furnace is operated in conformance with (a)(1) of this section and the owner or operator... boiler or industrial furnace that is exempt under this section must conduct dispersion modeling...

  11. 40 CFR 266.109 - Low risk waste exemption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... MANAGEMENT FACILITIES Hazardous Waste Burned in Boilers and Industrial Furnaces § 266.109 Low risk waste... industrial furnace is operated in conformance with (a)(1) of this section and the owner or operator... boiler or industrial furnace that is exempt under this section must conduct dispersion modeling...

  12. 40 CFR 266.109 - Low risk waste exemption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... MANAGEMENT FACILITIES Hazardous Waste Burned in Boilers and Industrial Furnaces § 266.109 Low risk waste... industrial furnace is operated in conformance with (a)(1) of this section and the owner or operator... boiler or industrial furnace that is exempt under this section must conduct dispersion modeling...

  13. MS ANTWERPEN: Emergency Management Training for Low-Risk Environments

    ERIC Educational Resources Information Center

    Strohschneider, Stefan; Gerdes, Jurgen

    2004-01-01

    Emergency management training programs have been developed mostly for trainees from high-risk environments such as aviation or the chemical industry. This article describes a training program for staff members from low-risk environments such as hospitals or hotels, where the awareness of potential dangers is usually low and emergency plans are…

  14. MS ANTWERPEN: Emergency Management Training for Low-Risk Environments

    ERIC Educational Resources Information Center

    Strohschneider, Stefan; Gerdes, Jurgen

    2004-01-01

    Emergency management training programs have been developed mostly for trainees from high-risk environments such as aviation or the chemical industry. This article describes a training program for staff members from low-risk environments such as hospitals or hotels, where the awareness of potential dangers is usually low and emergency plans are…

  15. Optimal management of low-risk gestational trophoblastic neoplasia.

    PubMed

    Goldstein, Donald P; Berkowitz, Ross S; Horowitz, Neil S

    2015-01-01

    Low-risk gestational trophoblastic neoplasia is a highly curable form of gestational trophoblastic neoplasia that arises largely from molar pregnancy and, on rare occasions, from other types of gestations. Risk is defined as the risk of developing drug resistance as determined by the WHO Prognostic Scoring System. All patients with non-metastatic disease and patients with risk scores <7 are considered to have low-risk disease. The sequential use of methotrexate and actinomycin D is associated with a complete remission rate of 80%. The most commonly utilized regimen for the treatment of patients resistant to single-agent chemotherapy is a multiagent regimen consisting of etoposide, methotrexate, actinomycin D, vincristine and cyclophosphamide. The measurement of human chorionic gonadotropin provides an accurate and reliable tumor marker for diagnosis, monitoring the effects of chemotherapy and follow-up to determine recurrence. Pregnancy is allowed after 12 months of normal serum tumor marker. Pregnancy outcomes are similar to those of normal population.

  16. Second Curettage for Low-Risk Nonmetastatic Gestational Trophoblastic Neoplasia.

    PubMed

    Osborne, Raymond J; Filiaci, Virginia L; Schink, Julian C; Mannel, Robert S; Behbakht, Kian; Hoffman, James S; Spirtos, Nick M; Chan, John K; Tidy, John A; Miller, David S

    2016-09-01

    To evaluate the efficacy and safety of second uterine curettage in lieu of chemotherapy for patients with low-risk, nonmetastatic gestational trophoblastic neoplasia (GTN) and to evaluate whether response to second curettage is independent of patient age, World Health Organization (WHO) risk score, registration human chorionic gonadotropin (hCG) level, lesion size, and depth of myometrial invasion measured on ultrasound examination. This was a cooperative group multicenter prospective phase II study. Prestudy testing included quantitative hCG level, pelvic ultrasonography, and chest radiography. Patients were categorized according to WHO risk scoring criteria (low risk with a score of 0-6). Sixty-four women with newly diagnosed low-risk, nonmetastatic GTN were enrolled. Four patients were excluded. Twenty-four patients (40%) (lower 95% confidence limit 27.6%) were cured after second curettage. An additional two patients (3%) achieved a complete response but did not complete follow-up. Overall, 26 of 60 patients were able to avoid chemotherapy. Surgical failure was observed in 34 women (59%) and was more common in women 19 years old or younger or 40 years old or older. One case of grade 1 uterine perforation was successfully managed by observation. Four grade 1 and one grade 3 uterine hemorrhages were reported. New metastatic disease (lung) was identified in one of these women after second curettage. In three patients (surgical failures), the second curettage pathology was placental site trophoblastic tumor, and it was placental nodule in one additional patient. Second uterine curettage as initial treatment for low-risk, nonmetastatic GTN cures 40% of patients without significant morbidity. ClinicalTrials.gov, https://clinicaltrials.gov/, NCT00521118.

  17. Advances in management of low-risk febrile neutropenia.

    PubMed

    Teuffel, Oliver; Sung, Lillian

    2012-02-01

    To describe and discuss the most recent advances in the management of low-risk febrile neutropenia in children with cancer. Several risk stratification tools for children with febrile neutropenia have been developed, although none of these tools have been directly compared and few have been validated in independent populations. However, there is good evidence that, for pediatric patients with febrile neutropenia at low risk for severe infection, outpatient management is a well tolerated and efficacious alternative to inpatient care. Moreover, major progress has been made in obtaining and understanding perceived quality of life and preferences for outpatient management in pediatric cancer patients. Many parents prefer inpatient management although child quality of life is, in general, anticipated to be higher with outpatient intravenous therapy. Finally, outpatient strategies are more cost-effective as compared with traditional management in hospital. Outpatient management is a well tolerated and cost-effective strategy for low-risk febrile neutropenia in children with cancer, although parental preferences are highly variable for outpatient versus inpatient management. Future research should examine the effectiveness of outpatient strategies through conduct of large cohort studies. Other future work could focus on development of decision aids and other tools to facilitate ambulatory approaches.

  18. Predicting Low-Risk Prostate Cancer from Transperineal Saturation Biopsies

    PubMed Central

    van Leeuwen, Pim J.; Siriwardana, Amila; Roobol, Monique; Ting, Francis; Nieboer, Daan; Thompson, James; Delprado, Warick; Haynes, Anne-Marie; Brenner, Phillip; Stricker, Phillip

    2016-01-01

    Introduction. To assess the performance of five previously described clinicopathological definitions of low-risk prostate cancer (PC). Materials and Methods. Men who underwent radical prostatectomy (RP) for clinical stage ≤T2, PSA <10 ng/mL, Gleason score <8 PC, diagnosed by transperineal template-guided saturation biopsy were included. The performance of five previously described criteria (i.e., criteria 1–5, criterion 1 stringent (Gleason score 6 + ≤5 mm total max core length PC + ≤3 mm max per core length PC) up to criterion 5 less stringent (Gleason score 6-7 with ≤5% Gleason grade 4) was analysed to assess ability of each to predict insignificant disease in RP specimens (defined as Gleason score ≤6 and total tumour volume <2.5 mL, or Gleason score 7 with ≤5% grade 4 and total tumour volume <0.7 mL). Results. 994 men who underwent RP were included. Criterion 4 (Gleason score 6) performed best with area under the curve of receiver operating characteristics 0.792. At decision curve analysis, criterion 4 was deemed clinically the best performing transperineal saturation biopsy-based definition for low-risk PC. Conclusions. Gleason score 6 disease demonstrated a superior trade-off between sensitivity and specificity for clarifying low-risk PC that can guide treatment and be used as reference test in diagnostic studies. PMID:27148459

  19. Control of HIF-1{alpha} and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock.

    PubMed

    Scott, C L; Walker, D J; Cwiklinski, E; Tait, C; Tee, A R; Land, S C

    2010-10-01

    Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1α (HIF-1α) vasculogenic activity through an NH(2)-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1α TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1α activity at fetal Po(2) (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1α by mTORC1 was abolished on expression of a HIF-1α (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1(-/-) knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal Po(2), FGF-10 induced mTORC1 and amplified HIF-1α activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1α-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.

  20. Cellulase variants

    DOEpatents

    Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

    2015-07-14

    This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

  1. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3.

    PubMed

    Balek, Lukas; Gudernova, Iva; Vesela, Iva; Hampl, Marek; Oralova, Veronika; Kunova Bosakova, Michaela; Varecha, Miroslav; Nemec, Pavel; Hall, Terence; Abbadessa, Giovanni; Hatch, Nan; Buchtova, Marcela; Krejci, Pavel

    2017-08-18

    Tyrosine kinase inhibitors are being developed for therapy of malignancies caused by oncogenic FGFR signaling but little is known about their effect in congenital chondrodysplasias or craniosynostoses that associate with activating FGFR mutations. Here, we investigated the effects of novel FGFR inhibitor, ARQ 087, in experimental models of aberrant FGFR3 signaling in cartilage. In cultured chondrocytes, ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation, i.e. inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. In ex vivo tibia organ cultures, ARQ 087 restored normal growth plate architecture and eliminated the suppressing FGFR3 effect on chondrocyte hypertrophic differentiation, suggesting that it targets the FGFR3 pathway specifically, i.e. without interference with other pro-growth pathways. Moreover, ARQ 087 inhibited activity of FGFR1 and FGFR2 mutants associated with Pfeiffer, Apert and Beare-Stevenson craniosynostoses, and rescued FGFR-driven excessive osteogenic differentiation in mouse mesenchymal micromass cultures or in ex vivo calvarial organ cultures. Our data warrant further development of ARQ 087 for clinical use in skeletal disorders caused by activating FGFR mutations. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Variants in human papillomavirus receptor and associated genes are associated with type-specific HPV infection and lesion progression of the cervix.

    PubMed

    Zou, Jian; Cao, Zhu; Zhang, Jianyang; Chen, Tingting; Yang, Shizhou; Huang, Yongjie; Hong, Die; Li, Yang; Chen, Xiaojing; Wang, Xinyu; Cheng, Xiaodong; Lu, Weiguo; Xie, Xing

    2016-06-28

    Human papillomavirus (HPV) infects cervical epithelial cells through cellular membrane receptors, and then induces the initiation and progression of cervical cancer. Single nucleotide polymorphisms (SNPs) may impact the susceptibility and outcome of diseases, but it's still unknown whether variant in HPV receptor and associated genes is associated with type-specific HPV infection and cervical lesion progression. We examined 96 SNPs in 8 genes which may participate in the HPV infection process in 875 samples with HPV negative or single HPV16, 18, 52, 58 positive from 3299 cervical exfoliated cell samples, by Illumina BeadXpress VeraCode platform, and analyzed the correlation between the SNPs and type-specific HPV infection and cervical lesions progression. We found rs28384376 in EGFR and rs12034979 in HSPG2 significantly correlated to HPV16 infection; rs2575738, rs2575712, rs2575735 in SDC2 and rs6697265 in HSPG2 significantly correlated to HPV18 infection; rs10510097 in FGFR2, rs12718946 in EGFR significantly correlated to HPV52 infection; rs4947972 in EGFR, rs2981451 in FGFR2, rs2575735 in SDC2 significantly correlated to HPV58 infection. And rs3135772, rs1047057 and rs2556537 in FGFR2, rs12034979 in HSPG2, rs16894821 in SDC2 significantly correlated to cervical lesion progression induced by HPV16 infection; rs6697265 and rs6680566 in HSPG2, rs16860426 in ITGA6 by HPV18 infection; rs878949 in HSPG2, rs12718946 and rs12668175 in EGFR by HPV52 infection; no SNP by HPV58 infection. Our findings suggest that HPV receptor and associated gene variants may influence the susceptibilities to HPV type-specific infection and cervical lesion progression, which might have a potential application value in cervical cancer screening and therapy.

  3. The variable phenotype and low-risk nature of RAS-positive thyroid nodules.

    PubMed

    Medici, Marco; Kwong, Norra; Angell, Trevor E; Marqusee, Ellen; Kim, Matthew I; Frates, Mary C; Benson, Carol B; Cibas, Edmund S; Barletta, Justine A; Krane, Jeffrey F; Ruan, Daniel T; Cho, Nancy L; Gawande, Atul A; Moore, Francis D; Alexander, Erik K

    2015-08-07

    Oncogenic mutations are common in thyroid cancers. While the frequently detected RAS-oncogene mutations have been studied for diagnostic use in cytologically indeterminate thyroid nodules, no investigation has studied such mutations in an unselected population of thyroid nodules. No long-term study of RAS-positive thyroid nodules has been performed. We performed a prospective, blinded cohort study in 362 consecutive patients presenting with clinically relevant (>1 cm) thyroid nodules. Fine needle aspiration cytology and mutational testing were obtained for all nodules. Post-operative histopathology was obtained for malignant or indeterminate nodules, and benign nodules were sonographically followed. Histopathological features were compared between RAS- and BRAF-positive malignancies. RAS-positive benign nodules were analyzed for growth or cellular change from prior aspirations. Overall, 17 of 362 nodules were RAS-positive. Nine separate nodules were BRAF-positive, of which eight underwent surgery and all proved malignant (100%). Out of the 17 RAS-positive nodules, ten underwent surgery, of which eight proved malignant (47%). All RAS-positive malignancies were low risk - all follicular variants of papillary carcinoma, without extrathyroidal extension, metastases, or lymphovascular invasion. RAS-positivity was associated with malignancy in younger patients (P = 0.028). Of the nine RAS-positive benign nodules, five had long-term prospective sonographic follow-up (mean 8.3 years) showing no growth or signs of malignancy. Four of these nodules also had previous aspirations (mean 5.8 years prior), all with similar benign results. While RAS-oncogene mutations increase malignancy risk, these data demonstrate a low-risk phenotype for most RAS-positive cancers. Furthermore, cytologically benign, yet RAS-positive nodules behave in an indolent fashion over years. RAS-positivity alone should therefore not dictate clinical decisions.

  4. Active surveillance for low-risk prostate cancer.

    PubMed

    Bangma, Chris H; Bul, Meelan; van der Kwast, Theo H; Pickles, Tom; Korfage, Ida J; Hoeks, Caroline M; Steyerberg, Ewout W; Jenster, Guido; Kattan, Michael W; Bellardita, Lara; Carroll, Peter R; Denis, Louis J; Parker, Chris; Roobol, Monique J; Emberton, Mark; Klotz, Laurence H; Rannikko, Antti; Kakehi, Yoshiyuki; Lane, Janet A; Schröder, Fritz H; Semjonow, Axel; Trock, Bruce J; Valdagni, Riccardo

    2013-03-01

    Active surveillance (AS) is an important management strategy for men diagnosed with low-risk prostate cancer (PCa). The need for AS is increasing due to the awareness that many PCa are identified that show a low growth potential and therefore are likely to remain clinically asymptomatic during the lifetime of an individual. Currently there is no good method to prevent the overdiagnosis of indolent cancers upfront. During the last decade, several studies on AS around the world have made observations that feed the discussion on how to select and monitor these patients, how to proceed with the research to develop a better and more precise clinical definition of indolent cancers and how to manage men under AS clinically. Furthermore, patients' perspectives have become clearer, and quality of life studies give direction to the practical approach and care for patients and partners. This paper reflects the consensus on the state of the art and the future direction of AS, based on the Inside Track Conference "Active Surveillance for low risk prostate cancer" (Chairmen: C.H. Bangma, NL, and L. Klotz, CA; Co-Chairmen: L.J. Denis, BE, and C. Parker, UK; Scientific Coordinators: M. J. Roobol, NL, and E.W. Steyerberg, NL), organized by the European School of Oncology in collaboration with Europa Uomo in Rotterdam, the Netherlands in January 2012. Topics for discussion were the optimisation of patient selection based on indolent disease definition, the incorporation of therapeutic agents into AS programs, the optimisation of patient care, and the application of emerging technologies and biomarkers.

  5. 7 CFR 3052.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... periods) shall qualify as a low-risk auditee and be eligible for reduced audit coverage in accordance with... part. A non-Federal entity that has biennial audits does not qualify as a low-risk auditee, unless... 7 Agriculture 15 2010-01-01 2010-01-01 false Criteria for a low-risk auditee. 3052.530...

  6. Current Management of Low Risk Differentiated Thyroid Cancer and Papillary Microcarcinoma.

    PubMed

    Tarasova, V D; Tuttle, R M

    2017-01-10

    Each year, the proportion of thyroid cancer patients presenting with low risk disease is increasing. Moreover, the definition of low risk thyroid cancer is expanding and several histological subtypes beyond papillary microcarcinomas are now classified as low risk disease. This shift in the landscape of thyroid cancer presentation is forcing clinicians to critically re-evaluate whether or not traditional management paradigms that were effective in treating intermediate and high risk disease are applicable to these low risk patients. Here we review the definition of low risk disease, examine the various histological subtypes that are considered low risk in the 2015 American Thyroid Association guidelines for the management of thyroid nodules and thyroid cancer, and review our current approach to the management of these low risk tumours.

  7. Low risk of male suicide and lithium in drinking water.

    PubMed

    Ishii, Nobuyoshi; Terao, Takeshi; Araki, Yasuo; Kohno, Kentaro; Mizokami, Yoshinori; Shiotsuki, Ippei; Hatano, Koji; Makino, Mayu; Kodama, Kensuke; Iwata, Noboru

    2015-03-01

    Recently, several epidemiologic studies reported that lithium in drinking water may be associated with lower rates of suicide mortality at the population level, but other studies failed to confirm the association. The objective of the present study is to determine whether lithium in drinking water is associated with lower suicide rate after adjustment of potential confounding factors. From 2010 to 2013, 274 mean lithium levels of 434 lithium samples in drinking water were examined in relation to suicide standardized mortality ratios (SMRs) in 274 municipalities of Kyushu Island in Japan. Weighted least squares regression analysis adjusted for the size of each population was used to investigate the association of lithium levels with suicide SMRs. The associations of lithium levels in drinking water with suicide SMRs (total, male, and female) were investigated adjusting for proportion of elderly people, proportion of 1-person households, proportion of people with college education or more, and proportion of people engaging in primary industry (adjusted model 1), and further adjustment was performed with overall unemployment rate, annual marriage rate, annual mean temperature, and annual postal savings per person (adjusted model 2). Lithium levels in drinking water were significantly (β = -.169, P = .019) and inversely associated with male suicide SMRs but not total or female SMRs in the adjusted model 2. The present findings suggest that lithium in drinking water may be associated with the low risk of male suicide in the general population. Further studies are required to confirm these findings and investigate gender differences. © Copyright 2015 Physicians Postgraduate Press, Inc.

  8. Nonsynonymous variants in MYH9 and ABCA4 are the most frequent risk loci associated with nonsyndromic orofacial cleft in Taiwanese population.

    PubMed

    Peng, Hsiu-Huei; Chang, Nai-Chung; Chen, Kuo-Ting; Lu, Jang-Jih; Chang, Pi-Yueh; Chang, Shih-Cheng; Wu-Chou, Yah-Huei; Chou, Yi-Ting; Phang, Wanni; Cheng, Po-Jen

    2016-08-15

    Nonsyndromic orofacial cleft is a common birth defect with a complex etiology, including multiple genetic and environmental risk factors. Recent whole genome analyses suggested associations between nonsyndromic orofacial cleft and up to 18 genetic risk loci (ABCA4, BMP4, CRISPLD2, GSTT1, FGF8, FGFR2, FOXE1, IRF6, MAFB, MSX1, MTHFR, MYH9, PDGFC, PVRL1, SUMO1, TGFA, TGFB3, and VAX1), each of which confers a different relative risk in different populations. We evaluate the nonsynonymous variants in these 18 genetic risk loci in nonsyndromic orofacial clefts and normal controls to clarify the specific variants in Taiwanese population. We evaluated these 18 genetic risk loci in 103 cases of nonsyndromic orofacial clefts and 100 normal controls using a next-generation sequencing (NGS) customized panel and manipulated a whole-exon targeted-sequencing study based on the NGS system of an Ion Torrent Personal Genome Machine (IT-PGM). IT-PGM data processing, including alignment with the human genome build 19 reference genome (hg19), base calling, trimming of barcoded adapter sequences, and filtering of poor signal reads, was performed using the IT platform-specific pipeline software Torrent Suite, version 4.2, with the plug-in "variant caller" program. Further advanced annotation was facilitated by uploading the exported VCF file from Variant Caller to the commercial software package Ion Reporter; the free online annotation software Vanno and Mutation Taster. Benign or tolerated amino acid changes were excluded after analysis using sorting intolerant from tolerant and polymorphism phenotyping. Sanger sequencing was used to validate the significant variants identified by NGS. Furthermore, each variant was confirmed in asymptomatic controls using the Sequenom MassARRAY (San Diego, CA, USA). We identified totally 22 types of nonsynonymous variants specific in nonsyndromic orofacial clefts, including 19 single nucleotide variants, 2 deletions, and 1 duplication in 10 studied

  9. Giant condyloma of the cervix: an uncommon entity associated with low-risk human papilloma virus infection.

    PubMed

    Parra-Herran, Carlos; Herfs, Michael; Doria, Manuel; Crum, Christopher P; Nucci, Marisa R

    2013-02-01

    "Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were predominantly young and presented with a cervical lesion producing bleeding or a mass effect. Biopsy/excision revealed a uniformly bland, exophytic squamous epithelial proliferation with viral cytopathic changes and absence of stromal invasion. Human papilloma virus types 6 and 11 were detected in all cases. Follow-up was uneventful without recurrence or spread. Giant condylomas of the cervix as defined in this report signify a benign albeit extensive variant of low-risk human papilloma virus infection. This term is proposed as a specific descriptor for such lesions and should be considered in the setting of any large well-differentiated exophytic cervical squamous lesion in young or immunosuppressed women. The term "giant condyloma of Buschke and Loewenstein" should be discontinued given the lack of specificity.

  10. 29 CFR 99.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) shall qualify as a low-risk auditee and be eligible for reduced audit coverage in accordance with § 99... part. A non-Federal entity that has biennial audits does not qualify as a low-risk auditee, unless... 29 Labor 1 2010-07-01 2010-07-01 true Criteria for a low-risk auditee. 99.530 Section 99.530...

  11. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.

    PubMed

    Paumard-Hernández, Beatriz; Berges-Soria, Julia; Barroso, Eva; Rivera-Pedroza, Carlos I; Pérez-Carrizosa, Virginia; Benito-Sanz, Sara; López-Messa, Eva; Santos, Fernando; García-Recuero, Ignacio I; Romance, Ana; Ballesta-Martínez, Juliana María; López-González, Vanesa; Campos-Barros, Ángel; Cruz, Jaime; Guillén-Navarro, Encarna; Sánchez Del Pozo, Jaime; Lapunzina, Pablo; García-Miñaur, Sixto; Heath, Karen E

    2015-07-01

    Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up.

  12. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

    PubMed Central

    Paumard-Hernández, Beatriz; Berges-Soria, Julia; Barroso, Eva; Rivera-Pedroza, Carlos I; Pérez-Carrizosa, Virginia; Benito-Sanz, Sara; López-Messa, Eva; Santos, Fernando; García-Recuero, Ignacio I; Romance, Ana; Ballesta-Martínez, Juliana María; López-González, Vanesa; Campos-Barros, Ángel; Cruz, Jaime; Guillén-Navarro, Encarna; Sánchez del Pozo, Jaime; Lapunzina, Pablo; García-Miñaur, Sixto; Heath, Karen E

    2015-01-01

    Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre–Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up. PMID:25271085

  13. 75 FR 66298 - Prompt Corrective Action; Amended Definition of Low-Risk Assets

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-28

    ... ADMINISTRATION 12 CFR Part 702 RIN 3133-AD81 Prompt Corrective Action; Amended Definition of Low-Risk Assets.... SUMMARY: NCUA is issuing this Interim Final Rule to amend the definition of ``low-risk assets'' for regulatory capital purposes. Assets in this category receive a risk-weighting of zero, reflecting the absence...

  14. 38 CFR 41.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... low-risk auditee and be eligible for reduced audit coverage in accordance with § 41.520: (a) Single... entity that has biennial audits does not qualify as a low-risk auditee, unless agreed to in advance by... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Criteria for a...

  15. 7 CFR 3052.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 15 2014-01-01 2014-01-01 false Criteria for a low-risk auditee. 3052.530 Section 3052.530 Agriculture Regulations of the Department of Agriculture (Continued) OFFICE OF THE CHIEF... ORGANIZATIONS Auditors § 3052.530 Criteria for a low-risk auditee. An auditee which meets all of the following...

  16. 7 CFR 3052.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 15 2011-01-01 2011-01-01 false Criteria for a low-risk auditee. 3052.530 Section 3052.530 Agriculture Regulations of the Department of Agriculture (Continued) OFFICE OF THE CHIEF... ORGANIZATIONS Auditors § 3052.530 Criteria for a low-risk auditee. An auditee which meets all of the following...

  17. 76 FR 16234 - Prompt Corrective Action; Amended Definition of Low-Risk Assets

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-23

    ... ADMINISTRATION 12 CFR Part 702 RIN 3133-AD81 Prompt Corrective Action; Amended Definition of Low-Risk Assets... Interim Final Rule expanding the definition of ``low-risk assets'' to include debt instruments on which... receive a risk-weighting of zero for regulatory capital purposes to reflect the absence of credit risk...

  18. What is low-risk prostate cancer and what is its natural history?

    PubMed

    O'Donnell, Helen; Parker, Chris

    2008-10-01

    This article reviews the definition, incidence, pathological characteristics and natural history of low risk localised prostate cancer. Low risk disease is typically defined as clinical stage T1/T2a, biopsy Gleason score low-risk disease is a broad category with a range of pathological characteristics and clinical behaviour. Many, but not all, low-risk prostate cancers are clinically insignificant, destined never to cause any harm. The challenge of managing low risk localized prostate cancer is to distinguish patients with clinically relevant cancers, who may benefit from radical treatment, from the remainder who do not need any intervention. The natural history of untreated low-risk localised prostate cancer has not been well studied, partly because it is a relatively recent entity, and partly because it has been standard practice for men with low risk disease to receive treatment. Data from watchful waiting in the pre-PSA era, modelling studies to take account of the lead time and overdiagnosis associated with PSA testing, and the early results of active surveillance can all provide insights into the likely natural history of low risk disease. There remains a major unmet need for markers of individual prostate cancer behaviour within the low-risk category. Such markers could be used to distinguish those men with truly indolent disease, suitable for observation, from those with significant prostate cancer that stand to benefit from treatment.

  19. Report: EPA's Fiscal Year 2015 Purchase Card and Convenience Check Program Assessed as Low Risk

    EPA Pesticide Factsheets

    Report #16-P-0124, March 29, 2016. We determined the EPA's purchase card and convenience check program for FY 2015 to be at a low risk for illegal, improper or erroneous purchases and payments due to strengthened internal controls.

  20. Can MRI biomarkers at 3 T identify low-risk ductal carcinoma in situ?

    PubMed

    Rahbar, Habib; Parsian, Sana; Lam, Diana L; Dontchos, Brian N; Andeen, Nicole K; Rendi, Mara H; Lehman, Constance D; Partridge, Savannah C

    2016-01-01

    The objective was to explore whether 3-T magnetic resonance imaging (MRI) can identify low-risk ductal carcinoma in situ (DCIS). Dynamic contrast-enhanced and diffusion-weighted (DWI) MRI features of 36 DCIS lesions [8 low risk, Van Nuys Pathologic Classification (VNPC) 1; 28 high risk, VNPC 2/3] were reviewed. An MRI model that best identified low-risk DCIS was determined using multivariate logistic regression. Low-risk DCIS exhibited different DWI properties [i.e., higher contrast-to-noise ratio (P=.02) and lower normalized apparent diffusion coefficients (P=.04)] than high-risk DCIS. A model combining these DWI features provided best performance (area under receiver operating characteristic curve =0.86). DWI may help identify DCIS lesions requiring less therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Methotrexate on a 21-day cycle for low-risk gestational trophoblastic neoplasia.

    PubMed

    Diaz, Juan; Thomas, M Bijoy; Paz-Pabon, Charlotte; Hernandez, Enrique

    2012-01-01

    To perform an outcome analysis of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with a 5-day intramuscular methotrexate (MTX) regimen on a 21-day cycle. A retrospective review of 31 patients with low-risk GTN treated with a 5-day MTX regimen. A total of 31 patients with low-risk GTN (WHO score < 7) received single-agent MTX at a dose of 0.4 mg/kg daily for 5 days every 21 days (mean number of cycles, 3; 83% remission). The only significant toxicity encountered was grade 2 stomatitis in 8 (26%) patients. A 5-day MTX regimen given every 21 days is convenient, well-tolerated and effective for patients with low-risk GTN.

  2. Serum thyroglobulin levels after thyroxine withdrawal in patients with low risk papillary thyroid carcinoma.

    PubMed

    Sisson, J C; Thompson, N W; Giordano, T J; England, B G; Normolle, D P

    2000-02-01

    We hypothesized that elevated levels of serum thyroglobulin (Tg) are frequently found as the only index of residual neoplasm in patients with low-risk papillary thyroid carcinoma. The records of patients operated on for papillary thyroid carcinoma over a 2-year period were reviewed, and the patients were allocated to risk groups by a validated staging method that does not include Tg levels. Of the 35 patients who manifested a low-risk carcinoma, 9 (26%) exhibited elevated Tg concentrations (11-53 ng/mL) during thyroxine withdrawal after therapies, while clinical, scintigraphic, and radiographic studies at least 1 year later showed no evidence of tumor. Prior scintigraphic imaging of therapeutic doses of 131I in 8 of 9 patients demonstrated no distant metastases, further confirming the low-risk status of this group. The staging method predicts that only 0.9% of patients with low-risk papillary carcinoma will have a cause specific death in 20 years. Elevated Tg concentrations have not been shown to forecast independently the survival of patients with low-risk papillary carcinoma. Thus, although frequently encountered, elevated Tg concentrations are unlikely to predict shortened survival in patients with papillary carcinoma for whom low risk has been determined from other data.

  3. 77 FR 65321 - Importation, Exportation, and Transportation of Wildlife; User Fee Exemption Program for Low-Risk...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-26

    ... program for low-risk importations and exportations as an interim measure while we work on a new economic... program for low-risk importations and exportations as an interim measure while we work on a new economic... Wildlife; User Fee Exemption Program for Low-Risk Importations and Exportations AGENCY: Fish and Wildlife...

  4. Prevalence of Internalizing, Externalizing, and Psychotic Disorders Among Low-Risk Juvenile Offenders.

    PubMed

    Kang, Tamara; Wood, James M; Eno Louden, Jennifer; Ricks, Elijah P

    2017-03-13

    To effectively allocate mental health services, agencies must be able to predict what proportion of youth will have a mental disorder. Prevalence estimates are available for juvenile offenders at intake, detained youth, and incarcerated youth, but there is limited research on prevalence of mental disorders for juvenile offenders who are low-risk to reoffend, many of whom are first time offenders (i.e., low-risk youth). To complicate matters, ethnic minorities are disproportionately represented in the justice system, and specifically, little is known about culturally sensitive clinical interviewing. To aid service providers and administrators in allocating mental health resources for low-risk offenders and to contribute to knowledge on culturally sensitive clinical assessment techniques, the present study reports the prevalence of mental disorders for a mostly Mexican American sample of 503 low-risk youth in diversion programming. We found that approximately 1 of every 6 (17.1%) low-risk juvenile offenders had a current affective, anxiety, or psychotic disorder, and 24.9% of low-risk juvenile offenders met criteria for a current substance/alcohol abuse disorder. These results suggest that allocating a portion of specialty mental health services and substance abuse treatment for low-risk juvenile offenders may help agencies combat the issue of repeat offending by offering public health interventions proactively to indirectly prevent recidivism rather than reacting afterward. Lastly, recommendations are given to help service providers incorporate culturally sensitive techniques into clinical assessment in order to better identify Mexican American juvenile offenders with mental health needs. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  5. Divorcing Diagnosis From Treatment: Contemporary Management of Low-Risk Prostate Cancer

    PubMed Central

    Glass, Allison S.; Punnen, Sanoj

    2013-01-01

    Today, the majority of men with newly diagnosed prostate cancer will present with low-risk features of the disease. Because prostate cancer often takes an insidious course, it is debated whether the majority of these men require radical treatment and the accompanying derangement of quality of life domains imposed by surgery, radiation, and hormonal therapy. Investigators have identified various selection criteria for "insignificant disease," or that which can be monitored for disease progression while safely delaying radical treatment. In addition to the ideal definition of low risk, a lack of randomized trials comparing the various options for treatment in this group of men poses a great challenge for urologists. Early outcomes from active surveillance cohorts support its use in carefully selected men with low-risk disease features, but frequent monitoring is required. Patient selection and disease monitoring methods will require refinement that will likely be accomplished through the increased use of biomarkers and specialized imaging techniques. PMID:23878682

  6. Validation and Refinement of a Prediction Rule to Identify Children at Low Risk for Acute Appendicitis

    PubMed Central

    Kharbanda, Anupam B; Dudley, Nanette C; Bajaj, Lalit; Stevenson, Michelle D; Macias, Charles G; Mittal, Manoj K; Bachur, Richard G; Bennett, Jonathan E; Sinclair, Kelly; Huang, Craig; Dayan, Peter S

    2013-01-01

    Objective To validate and refine a clinical prediction rule to identify which children with acute abdominal pain are at low risk for appendicitis (Low Risk Appendicitis Rule). Design Prospective, multi-center cross-sectional study. Setting Ten pediatric hospital emergency departments. Participants Children 3–18 years old who presented with suspected appendicitis from May 2009 – April 2010. Main Outcome Measures The test performance of the Low Risk Appendicitis Rule. Results Among 2625 patients enrolled, 1018 (38.8%; 95% confidence interval [CI] 36.9% – 40.7%) had appendicitis. Validation of the rule resulted in a sensitivity of 95.5% (95% CI 93.9 – 96.7%), specificity of 36.3% (33.9 – 38.9%) and negative predictive value (NPV) of 92.7% (90.1 – 94.6%). Theoretical application would have identified 573 (24%) as low risk, misclassifying 42 patients (4.5%; 95% CI 3.4% – 6.1%) with appendicitis. We refined the prediction rule, resulting in a model that identified patients at low risk if: a) absolute neutrophil count (ANC) ≤ 6.75 × 103/µL and no maximal tenderness in right lower quadrant (RLQ) or b) ANC ≤ 6.75 × 103/µL, maximal tenderness in the RLQ but no abdominal pain with walking/jumping or coughing. This refined rule had a sensitivity of 98.1% (97.0 – 98.9%), specificity of 23.7% (21.7 – 25.9%) and NPV of 95.3% (92.3 – 97.0%). Conclusions We have validated and refined a simple clinical prediction rule for pediatric appendicitis. For patients identified as low risk, clinicians should consider alternative strategies such as observation or ultrasound, rather than proceed to immediate imaging with CT. PMID:22869405

  7. Interpretations of child compliance in individuals at high- and low-risk for child physical abuse.

    PubMed

    Dopke, Cynthia A; Lundahl, Brad W; Dunsterville, Emma; Lovejoy, M Christine

    2003-03-01

    Our studies compared individuals at high- and low-risk for child physical abuse on measures of social information processing. Two studies were conducted using similar methods. Twenty-eight childless women in Study 1 and 36 mothers in Study 2 read vignettes of parent-child interactions in which the child's level of compliance was difficult to interpret. Participants were asked a series of questions about the child's behavior and their own reactions. Accuracy and bias in identifying compliant behavior were assessed using a signal detection paradigm. In both samples, high- and low-risk participants did not differ in their overall accuracy in identifying children's behaviors. However, they used different evaluation standards such that high-risk participants were biased toward seeing more noncompliance and low-risk participants were biased toward seeing more compliance. High- and low-risk participants also made different types of errors in interpreting children's behavior. Low-risk participants were more likely to misinterpret noncompliant behavior as compliant, and there was a trend for high-risk participants to not perceive compliant behavior when it occurred. There were no differences in reported disciplinary responses in either study and the results for affective reactions were mixed. Specific differences in social information processing between high- and low-risk individuals replicated across samples, suggesting a reliable association between evaluation standards and risk of child physical abuse. However, the absence of differences in reported discipline and inconsistent findings on affective reactions indicate the need to identify the mechanism through which cognition influences parenting behavior.

  8. An accelerated diagnostic protocol for the early, safe discharge of low-risk chest pain patients.

    PubMed

    Altherwi, Tawfeeq; Grad, Willis B

    2015-07-01

    Can an accelerated 2-hour diagnostic protocol using the cardiac troponin I (cTnI) measurement as the only biomarker be implemented to allow an earlier and safe discharge of low-risk chest pain patients? Than M, Cullen L, Aldous S, et al. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol 2012;59(23):2091-8. To determine whether an accelerated diagnostic protocol (ADP) for possible cardiac chest pain could identify low-risk patients suitable for early discharge using cTnI as the sole biomarker.

  9. Clinical factors predicting bacteremia in low-risk febrile neutropenia after anti-cancer chemotherapy.

    PubMed

    Ha, Young Eun; Song, Jae-Hoon; Kang, Won Ki; Peck, Kyong Ran; Chung, Doo Ryeon; Kang, Cheol-In; Joung, Mi-Kyong; Joo, Eun-Jeong; Shon, Kyung Mok

    2011-11-01

    Bacteremia is an important clinical condition in febrile neutropenia that can cause clinical failure of antimicrobial therapy. The purpose of this study was to investigate the clinical factors predictive of bacteremia in low-risk febrile neutropenia at initial patient evaluation. We performed a retrospective cohort study in a university hospital in Seoul, Korea, between May 1995 and May 2007. Patients who met the criteria of low-risk febrile neutropenia at the time of visit to emergency department after anti-cancer chemotherapy were included in the analysis. During the study period, 102 episodes of bacteremia were documented among the 993 episodes of low-risk febrile neutropenia. Single gram-negative bacteremia was most frequent. In multivariate regression analysis, initial body temperature ≥39°C, initial hypotension, presence of clinical sites of infection, presence of central venous catheter, initial absolute neutrophil count <50/mm(3), and the CRP ≥10 mg/dL were statistically significant predictors for bacteremia. A scoring system using these variables was derived and the likelihood of bacteremia was well correlated with the score points with AUC under ROC curve of 0.785. Patients with low score points had low rate of bacteremia, thus, would be candidates for outpatient-based or oral antibiotic therapy. We identified major clinical factors that can predict bacteremia in low-risk febrile neutropenia.

  10. Vocalization Rate and Consonant Production in Toddlers at High and Low Risk for Autism

    ERIC Educational Resources Information Center

    Chenausky, Karen; Nelson, Charles, III.; Tager-Flusberg, Helen

    2017-01-01

    Background: Previous work has documented lower vocalization rate and consonant acquisition delays in toddlers with autism spectrum disorder (ASD). We investigated differences in these variables at 12, 18, and 24 months in toddlers at high and low risk for ASD. Method: Vocalization rate and number of different consonants were obtained from speech…

  11. 29 CFR 99.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Labor Office of the Secretary of Labor AUDITS OF STATES, LOCAL GOVERNMENTS, AND NON-PROFIT ORGANIZATIONS... for each of the preceding two years (or, in the case of biennial audits, preceding two audit periods) shall qualify as a low-risk auditee and be eligible for reduced audit coverage in accordance with § 99...

  12. Reasons hospitals give for not offering hepatitis B vaccine to low-risk newborns.

    PubMed

    Aiken, Kimberly D; Clark, Sarah J; Cabana, Michael D

    2002-01-01

    After a temporary suspension of hepatitis B vaccination (HBV) for low-risk newborns in July 1999, some hospitals still do not offer HBV to these infants. A semi-structured telephone survey of medical directors from a national random sample of 296 hospital nurseries was completed from August 2000 to April 2001 and analyzed using qualitative techniques. Directors of 201 of 290 eligible nurseries (71%) participated. Twenty-ight nurseries have never offered HBV to low-risk newborns ("Never Offered HBV") and 37 nurseries had offered HBV to low-risk newborns before July 1999, but discontinued this practice after the temporary suspension ("Discontinued HBV"). Common reasons for not offering HBV to low-risk newborns were difficulty with reimbursement and convenience of outpatient administration. In addition, directors of "Never Offered HBV" nurseries cited low disease incidence in their patient population, whereas directors of "Discontinued HBV" cited preference for the combination hepatitis B-Haemophilus influenza type b vaccine as important factors. Multi-faceted interventions may be necessary to increase HBV use in the nursery.

  13. Visual Recognition Memory in High- and Low-Risk Infant Pigtailed Macaques (Macaca Nemestrina).

    ERIC Educational Resources Information Center

    Gunderson, Virginia M.; And Others

    1987-01-01

    Study looks at pigtailed macaque in the context of visual recognition problems adapted from a standardized test developed for use with human infants. Results demonstrate that the low-risk group easily differentiated novel from previously seen targets; the high-risk group gave no evidence of recognition. (Author/RWB)

  14. 38 CFR 41.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Criteria for a low-risk auditee. 41.530 Section 41.530 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) AUDITS OF STATES, LOCAL GOVERNMENTS, AND NON-PROFIT ORGANIZATIONS Auditors § 41.530 Criteria for...

  15. Breast SeIf-Examination Behavior Among High and Low Risk Women

    DTIC Science & Technology

    1986-04-10

    melatonin levels monitored for a 24-hour period. Transportation was provided by the Institute. The response rate was 100 per cent. Low risk...20 - for potential health problems in the areas or vision, blood Pressure, diabetes and others). They were informed that this study was one

  16. Visual Recognition Memory in High- and Low-Risk Infant Pigtailed Macaques (Macaca Nemestrina).

    ERIC Educational Resources Information Center

    Gunderson, Virginia M.; And Others

    1987-01-01

    Study looks at pigtailed macaque in the context of visual recognition problems adapted from a standardized test developed for use with human infants. Results demonstrate that the low-risk group easily differentiated novel from previously seen targets; the high-risk group gave no evidence of recognition. (Author/RWB)

  17. Increasing Threat of Brucellosis to Low-Risk Persons in Urban Settings, China

    PubMed Central

    Chen, Shouyi; Zhang, Hao; Liu, Xiaoning; Wang, Wenjing; Hou, Shuiping; Li, Tingting; Zhao, Shuoxian; Yang, Zhicong

    2014-01-01

    Cases of brucellosis were diagnosed in 3-month-old twins and their mother. An epidemiologic survey suggested that raw sheep or goat meat might be the source of Brucella melitensis infection. This finding implies that the increasing threat of brucellosis might affect low-risk persons in urban settings in China. PMID:24377827

  18. A comparison of low versus high radioiodine administered activity in patients with low-risk differentiated thyroid cancer.

    PubMed

    Ben Ghachem, T; Yeddes, I; Meddeb, I; Bahloul, A; Mhiri, A; Slim, I; Ben Slimene, M F

    2017-02-01

    Post-surgical therapeutic management of differentiated thyroid cancer (DTC) is still a controversial subject. Indeed, there is no consensus on the dose of (131)I to be administered, although the current trend towards therapy easing through mini-cures for patients with good prognosis. To confirm the non-inferiority in terms of effectiveness of an ablative mini-cure from 1.11 to 1.85 GBq, over a cure of 3.7 GBq, in patients with DTC operated for low and very low risk. We retrospectively studied 157 patients with very low and low risk DTC, followed in the Nuclear Medicine Department of the Salah Azaiez Institute between 2002 and 2012. These patients had a complementary radioiodine therapy with either low dose (group A) or high dose (group B) with an evaluation at 6 months post treatment and in long-term. The study took place at a referral center. The average age was 42.8 ± 13.7 years with a female predominance (86.7 %). The DTC papillary represented the most common etiology (95 %) with a predominance of pure papillary (68 %) on the follicular variant (27 %). The first cure evaluation did not show statistically significant difference between the two approaches in terms of therapeutic ablative efficiency (p = 0.13). The overall success rate was 77 % (121/157), with 83 % (54/65) in group A and 72.8 % (67/92) in group B. The likelihood of having a remission from the first cure was 1.83 times greater for patients treated with low doses (OR = 1.83, 95 % CI 0.23-1.29). At the end of follow, we have noted one case of refractory disease. The male gender (adjusted OR = 2.71, 95 % CI 0.51-4.23, p = 0.03), and the baseline Tg ≥ 10 (ng/ml) (adjusted OR = 3.48, 95 % CI 1.25-9.67, p = 0.01) were significantly independent predictors of successful first cure ablation. The results provide that mini-dose protocol is not less effective for ablation of the thyroid remnant than 3.7 GBq activity.

  19. Choice of hospital for delivery: a comparison of high-risk and low-risk women.

    PubMed Central

    Phibbs, C S; Mark, D H; Luft, H S; Peltzman-Rennie, D J; Garnick, D W; Lichtenberg, E; McPhee, S J

    1993-01-01

    OBJECTIVE. This article tests whether or not the factors that affect hospital choice differ for selected subgroups of the population. DATA SOURCES. 1985 California Office of Statewide Health Planning and Development (OSHPD) discharge abstracts and hospital financial data were used. STUDY DESIGN. Models for hospital choice were estimated using McFadden's conditional logit model. Separate models were estimated for high-risk and low-risk patients, and for high-risk and low-risk women covered either by private insurance or by California Medicaid. The model included independent variables to control for quality, price, ownership, and distance to the hospital. DATA EXTRACTION. Data covered all maternal deliveries in the San Francisco Bay Area in 1985 (N = 61,436). ICD-9 codes were used to classify patients as high-risk or low-risk. The expected payment code on the discharge abstract was used to identify insurance status. PRINCIPAL FINDINGS. The results strongly reject the hypothesis that high-risk and low-risk women have the same choice process. Hospital quality tended to be more important for high-risk than low-risk women. These results also reject the hypothesis that factors influencing choice of hospital are the same for women covered by private insurance as for those covered by Medicaid. Further, high-risk women covered by Medicaid were less likely than high-risk women covered by private insurance to deliver in hospitals with newborn intensive care units. CONCLUSIONS. The results show that the choice factors vary across several broadly defined subgroups of patients with a specific condition. Thus, estimates aggregating all patients may be misleading. Specifically, such estimates will understate actual patient response to quality of care indicators, since patient sensitivity to quality of care varies with the patients' risk status. PMID:8514500

  20. Pathological outcomes and agressiveness of low-risk prostate cancer in Northern African men.

    PubMed

    Ammani, A; Janane, A; Bouzide, B; Dehayni, Y; Lezrek, M; Ghadouane, M; Ameur, A; Abbar, M; Qarro, A; Alami, M

    2016-11-01

    Northern African (NAf) men show a high incidence of advanced prostate cancer (PCa) at diagnosis. Several studies suggested the existence of ethnic differences in the PCa aggressiveness and this has led to some concerns related to the inclusion of some ethnic groups into active surveillance protocols. To evaluate pathological outcomes and aggressiveness of low risk PCa treated by radical prostatectomy in a NAf ethnic group. Data of 147 NAfs, who underwent radical prostatectomy for low risk PCa diagnosed via a 12-core biopsy in 2 academic centers between 2011 and 2015, were reviewed retrospectively to assess rates of worse pathological outcomes defined as: Gleason score upgrade to at least 3+4, upstage to pT3a or higher or pN1, and positive surgical margins. Overall significant upstage and/or upgrade occurred in 20.2% and positive surgical margins occured in18.3%. In multivariate logistic regression analysis, independent variables that predicted for upstage and/or upgrade or positive surgical margins in the entire cohort were: NCCN risk group (low risk>very low risk), advanced age>60 years, PSA>6ng/ml, PSA density≥0.15, more than 2 positive cores in biopsy, more than 50% cancer involvement in positive cores, clinical stage (T2a>T1c) and UCSF-CAPRA-S score>3. Our study found that, at least pathologically, NAf men do not have more aggressive disease than Caucasians and African Americans in both low and very low risk PCa. Thus, we think that active surveillance is a suitable approach for selected patients since there is no definitive data that show a more aggressive natural history of PCa in NAf men. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer.

    PubMed

    Dowdy, S C; Borah, B J; Bakkum-Gamez, J N; Weaver, A L; McGree, M E; Haas, L R; Keeney, G L; Mariani, A; Podratz, K C

    2012-10-01

    Since 1999, patients with low risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. Here we prospectively assess survival, sites of recurrence, morbidity, and cost in this low risk cohort. Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Classification. Thirty-day cost analyses were expressed in 2010 Medicare dollars. Among 1393 consecutive surgically managed cases, 385 (27.6%) met inclusion criteria, accounting for 34.1% of type I EC. There were 80 LND and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5% vs. 19.3%; P<0.001). The prevalence of lymph node metastasis was 0.3% (1/385). Over a median follow-up of 5.4 years only 5 of 31 deaths were due to disease. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was $15,678 for LND cases compared to $11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was $327,866 to $439,990, adding an additional $1,418,189 if all 305 non-LND cases had undergone LND. Lymphadenectomy dramatically increases morbidity and cost of care without discernible benefits in low-risk EC as defined by the Mayo criteria. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be standard of care. Copyright © 2012. Published by Elsevier Inc.

  2. Prospective Quality of Life Outcomes for Low-Risk Prostate Cancer: Active Surveillance versus Radical Prostatectomy

    PubMed Central

    Jeldres, Claudio; Cullen, Jennifer; Hurwitz, Lauren M.; Wolff, Erika M.; Levie, Katherine; Odem-Davis, Katherine; Johnston, Richard B.; Pham, Khanh N.; Rosner, Inger L; Brand, Timothy C.; L’Esperance, James O.; Sterbis, Joseph R.; Etzioni, Ruth B.; Porter, Christopher R.

    2015-01-01

    Background For low-risk prostate cancer (PCa), active surveillance (AS) may confer comparable oncological outcomes to radical prostatectomy (RP). Health-related quality of life (HRQoL) outcomes are important to consider, yet few studies have examined HRQoL for patients managed with AS. This study compared longitudinal HRQoL in a prospective, racially diverse, and contemporary cohort of patients who underwent RP or AS for low-risk PCa. Methods Beginning in 2007, HRQoL data from validated questionnaires (EPIC and SF-36) were collected by the Center for Prostate Disease Research in a multi-center national database. Patients aged ≤75 that were diagnosed with low-risk PCa and elected RP or AS for initial disease management were followed for three years. Mean scores were estimated using generalized estimating equations, adjusting for baseline HRQoL, demographic and clinical patient characteristics. Results Of the patients with low-risk PCa, 228 underwent RP and 77 underwent AS. Multivariable analysis revealed that RP patients had significantly worse sexual function, sexual bother, and urinary function at all time points compared to patients on AS. Differences in mental health between groups were below the threshold for clinical significance at one year. Conclusions This study found no differences in mental health outcomes but worse urinary and sexual HRQoL for RP patients compared to AS patients for up to three years. These data offer support for management of low risk PCa with AS as a means for postponing the morbidity associated with RP without concomitant mental health declines. PMID:25845467

  3. Cost-effective treatment of low-risk carcinoma not invading bladder muscle.

    PubMed

    Green, David A; Rink, Michael; Cha, Eugene K; Xylinas, Evanguelos; Chughtai, Bilal; Scherr, Douglas S; Shariat, Shahrokh F; Lee, Richard K

    2013-03-01

    Study Type - Therapy (cost effectiveness analysis) Level of Evidence 2a What's known on the subject? and What does the study add? Bladder cancer is one of the costliest malignancies to treat throughout the life of a patient. The most cost-effective management for low-risk non-muscle-invasive bladder cancer is not known. The current study shows that employing cystoscopic office fulguration for low-risk appearing bladder cancer recurrences can materially impact the cost-effectiveness of therapy. In a follow-up protocol where office fulguration is routinely employed for low-risk bladder cancers, peri-operative intravesical chemotherapy may not provide any additional cost-effectiveness benefit. To examine the cost-effectiveness of fulguration vs transurethral resection of bladder tumour (TURBT) with and without perioperative intravesical chemotherapy (PIC) for managing low-risk carcinoma not invading bladder muscle (NMIBC). Low-risk NMIBC carries a low progression rate, lending support to the use of office-based fulguration for small recurrences rather than traditional TURBT. A Markov state transition model was created to simulate treatment of NMIBC with vs without PIC, with recurrence treated by formal TURBT vs treatment with fulguration. Costing data were obtained from the Medicare Resource Based Relative Value Scale. Data regarding the success of PIC were obtained from the peer-reviewed literature, as were corresponding utilities for bladder cancer-related procedures. Sensitivity analyses were performed. At 5-year follow-up, a strategy of fulguration without PIC was the most cost-effective (mean cost-effectiveness = US $654.8/quality-adjusted life year), despite a lower recurrence rate with PIC. Both fulguration strategies dominated each TURBT strategy. Sensitivity analysis showed that fulguration without PIC dominated all other strategies when the recurrence rate after PIC was increased to ≥14.2% per year. Similarly, the cost-effectiveness of TURBT becomes more

  4. L1CAM: amending the "low-risk" category in endometrial carcinoma.

    PubMed

    Kommoss, Felix; Kommoss, Friedrich; Grevenkamp, Friederike; Bunz, Anne-Kathrin; Taran, Florin-Andrei; Fend, Falko; Brucker, Sara Y; Wallwiener, Diethelm; Schönfisch, Birgitt; Greif, Karen; Lax, Sigurd; Staebler, Annette; Kommoss, Stefan

    2017-02-01

    Low- and intermediate-risk endometrial carcinomas have an excellent prognosis. Nonetheless, a small subgroup of such patients will experience unexpected relapse. Recently L1CAM was suggested to be a strong prognosticator in endometrial carcinoma. The focus of our study was on low- and intermediate-risk disease, where no or only limited adjuvant treatment is recommended according to current guidelines. Endometrial carcinomas of low, intermediate and high-intermediate risk according to published 2016 consensus guidelines were identified. The study was limited to cases with previous central pathology review focusing on histotype, depth of myometrial invasion, presence of lymphovascular space invasion (LVSI) and MELF pattern of invasion. Standard L1CAM immunohistochemistry was performed. Disease-specific uni- and multivariate survival analyses were calculated. A total of 344 cases were available for immunohistochemistry (low-risk: n = 250; intermediate-risk: n = 67; high-intermediate-risk: n = 27). L1CAM positivity rates were: 29/344 (8.4 %; all cases), 18/250 (7.2 %; low-risk), 6/67 (9.0 %; intermediate-risk) and 5/27 (18.5 %; high-intermediate-risk). Expression of L1CAM was independent of LVSI and MELF. L1CAM was a significant independent prognosticator for disease-specific survival with a hazard ratio of 5.98 [CI 1.50-22.14, p = 0.012]. Adverse prognostic significance of L1CAM positivity was maintained after low-risk subgroup analysis (5-year disease-specific survival rates 71.8 vs. 100 %, p < 0.0001). All four tumour-related deaths in the subgroup of low-risk disease occurred in patients with L1CAM-positive tumours. The current definition of "low-risk" in endometrial carcinoma should be amended. "Low-risk carcinomas" should be limited to L1CAM-negative tumours. L1CAM status will play a key role in future algorithms to tailor adjuvant treatment and patient follow-up strategies.

  5. Necessity of hospitalization and stress testing in low risk chest pain patients.

    PubMed

    Beri, Neil; Marston, Nicholas A; Daniels, Lori B; Nowak, Richard M; Schreiber, Donald; Mueller, Christian; Jaffe, Allan; Diercks, Deborah B; Wettersten, Nicholas; DeFilippi, Christopher; Peacock, W Frank; Limkakeng, Alexander T; Anand, Inder; McCord, James; Hollander, Judd E; Wu, Alan H B; Apple, Fred S; Nagurney, John T; Berardi, Cecilia; Cannon, Chad M; Clopton, Paul; Neath, Sean-Xavier; Christenson, Robert H; Hogan, Christopher; Vilke, Gary; Maisel, Alan

    2017-02-01

    Copeptin is a marker of endogenous stress including early myocardial infarction(MI) and has value in early rule out of MI when used with cardiac troponin I(cTnI). The goal of this study was to demonstrate that patients with a normal electrocardiogram and cTnI<0.040μg/l and copeptin<14pmol/l at presentation and after 2 h may be candidates for early discharge with outpatient follow-up potentially including stress testing. This study uses data from the CHOPIN trial which enrolled 2071 patients with acute chest pain. Of those, 475 patients with normal electrocardiogram and normal cTnI(<0.040μg/l) and copeptin<14pmol/l at presentation and after 2 h were considered "low risk" and selected for further analysis. None of the 475 "low risk" patients were diagnosed with MI during the 180day follow-up period (including presentation). The negative predictive value of this strategy was 100% (95% confidence interval(CI):99.2%-100.0%). Furthermore no one died during follow up. 287 (60.4%) patients in the low risk group were hospitalized. In the "low risk" group, the only difference in outcomes (MI, death, revascularization, cardiac rehospitalization) was those hospitalized underwent revascularization more often (6.3%[95%CI:3.8%-9.7%] versus 0.5%[95%CI:0.0%-2.9%], p=.002). The hospitalized patients were tested significantly more via stress testing or angiogram (68.6%[95%CI:62.9%-74.0%] vs 22.9%[95%CI:17.1%-29.6%], p<.001). Those tested had less cardiac rehospitalizations during follow-up (1.7% vs 5.1%, p=.040). In conclusion, patients with a normal electrocardiogram, troponin and copeptin at presentation and after 2 h are at low risk for MI and death over 180days. These low risk patients may be candidates for early outpatient testing and cardiology follow-up thereby reducing hospitalization. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Use of Advanced Treatment Technologies Among Men at Low Risk of Dying From Prostate Cancer

    PubMed Central

    Jacobs, Bruce L.; Zhang, Yun; Schroeck, Florian R.; Skolarus, Ted A.; Wei, John T.; Montie, James E.; Gilbert, Scott M.; Strope, Seth A.; Dunn, Rodney L.; Miller, David C.; Hollenbeck, Brent K.

    2013-01-01

    Importance The use of advanced treatment technologies (ie, intensity-modulated radiotherapy [IMRT] and robotic prostatectomy) for prostate cancer is increasing. The extent to which these advanced treatment technologies have disseminated among patients at low risk of dying from prostate cancer is uncertain. Objective To assess the use of advanced treatment technologies, compared with prior standards (ie, traditional external beam radiation treatment [EBRT] and open radical prostatectomy) and observation, among men with a low risk of dying from prostate cancer. Design, Setting, and Patients Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified a retrospective cohort of men diagnosed with prostate cancer between 2004 and 2009 who underwent IMRT (n=23 633), EBRT (n=3926), robotic prostatectomy (n=5881), open radical prostatectomy (n=6123), or observation (n=16 384). Follow-up data were available through December 31, 2010. Main Outcomes and Measures The use of advanced treatment technologies among men unlikely to die from prostate cancer, as assessed by low-risk disease (clinical stage ≤T2a, biopsy Gleason score ≤6, and prostate-specific antigen level ≤10 ng/mL), high risk of noncancer mortality (based on the predicted probability of death within 10 years in the absence of a cancer diagnosis), or both. Results In our cohort, the use of advanced treatment technologies increased from 32% (95% CI, 30%–33%) to 44% (95% CI, 43%–46%) among men with low-risk disease (P<.001) and from 36% (95% CI, 35%–38%) to 57% (95% CI, 55%–59%) among men with high risk of noncancer mortality (P<.001). The use of these advanced treatment technologies among men with both low-risk disease and high risk of noncancer mortality increased from 25% (95% CI, 23%–28%) to 34% (95% CI, 31%–37%) (P<.001). Among all patients diagnosed in SEER, the use of advanced treatment technologies for men unlikely to die from prostate cancer increased from 13% (95% CI

  7. Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma.

    PubMed

    del Pino, Marta; Bleeker, Maaike C G; Quint, Wim G; Snijders, Peter J F; Meijer, Chris J L M; Steenbergen, Renske D M

    2012-10-01

    The role of human papillomavirus (HPV) infections in the development of verrucous carcinoma, a well-differentiated variant of squamous cell carcinoma with difficult differential diagnosis, is controversial in the literature. In this study, we analysed verrucous carcinoma from different origins for the presence and activity of a broad spectrum of HPV types, and carefully reviewed the histopathological features. A random series of 27 formalin-fixed, paraffin-embedded specimens of verrucous carcinoma was taken, representing the head and neck region (n=6), anogenital area (n=16) and extragenital skin region (n=5). After review of the histological slides, all samples were subjected to different polymerase chain reaction-based HPV detection techniques, together detecting a total of 83 HPV types, including both mucosal and cutaneous types. Histological revision was carefully performed. Lesions with keratinised papillae, blunt stromal invaginations and minimal cytological atypia were considered verrucous carcinoma. Condylomatous lesions with viral changes were defined as giant condyloma. Verrucous lesions that did not meet those criteria were classified as verrucous hyperplasia. Tumours with stromal infiltration were considered as invasive squamous cell carcinoma. Histological revision revealed that 13 out of 27 cases were verrucous carcinoma (one showing a double infection with HPV 35 and 45), 5 invasive squamous cell carcinomas, 5 verrucous hyperplasia (one with a double infection with HPV 4 and 8), 1 pseudoepitheliomatous hyperplasia and 3 giant condylomas. All three giant condylomas were low-risk HPV positive (HPV 6 and 11) and showed active mRNA transcription. None of the HPV-positive samples tested positive for diffuse p16(INK4A) staining. In conclusion, our results do not support a causal role of HPV in the development of verrucous carcinoma. Testing for LR-HPV, particularly HPV 6 and 11, may help in the differential diagnosis of lesions suspicious of verrucous

  8. Low Risk of Sexual Transmission of Hepatitis C Virus in Somalia

    DTIC Science & Technology

    1994-01-01

    SUF.TITLE :S FUNDING NUMBERS Low risk of sexual transmission of hepatitis C virus in Somalia PE 62787A PR -33M162787A870 6. AUTHOR(S) TA - AR Watts...Distribution I Availability Codes Avail and I or Dist Special 94-18470 &1-201. 6l14 145 14. SUBJECT TERtM?.S 15, N.jMBER OF ;AGES2 sexually transmitted...2SE ’%,tv 2-15) • • , . -ŕ .•$I tC •.S: C *TmaosAc1oIs OF o"m RoYAL SOo " OF Titon.cA Mzno•.%! ,v HrWun! (1994) 81 55-%. 55 Low risk of sexual

  9. Are plain radiographs sufficient to exclude cervical spine injuries in low-risk adults?

    PubMed

    Hunter, Benton R; Keim, Samuel M; Seupaul, Rawle A; Hern, Gene

    2014-02-01

    The routine use of clinical decision rules and three-view plain radiography to clear the cervical spine in blunt trauma patients has been recently called into question. In low-risk adult blunt trauma patients, can plain radiographs adequately exclude cervical spine injury when clinical prediction rules cannot? Four observational studies investigating the performance of plain radiographs in detecting cervical spine injury in low-risk adult blunt trauma patients were reviewed. The consistently poor performance of plain radiographs to rule out cervical spine injury in adult blunt trauma victims is concerning. Large, rigorously performed prospective trials focusing on low- or low/moderate-risk patients will be needed to truly define the utility of plain radiographs of the cervical spine in blunt trauma. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Preoperative Laboratory Investigations: Rates and Variability Prior to Low-risk Surgical Procedures.

    PubMed

    Kirkham, Kyle R; Wijeysundera, Duminda N; Pendrith, Ciara; Ng, Ryan; Tu, Jack V; Boozary, Andrew S; Tepper, Joshua; Schull, Michael J; Levinson, Wendy; Bhatia, R Sacha

    2016-04-01

    Increasing attention has been focused on low-value healthcare services. Through Choosing Wisely campaigns, routine laboratory testing before low-risk surgery has been discouraged in the absence of clinical indications. The authors investigated rates, determinants, and institutional variation in laboratory testing before low-risk procedures. Patients who underwent ophthalmologic surgeries or predefined low-risk surgeries in Ontario, Canada, between April 1, 2008, and March 31, 2013, were identified from population-based administrative databases. Preoperative blood work was defined as a complete blood count, prothrombin time, partial thromboplastin, or basic metabolic panel within 60 days before an index procedure. Adjusted associations between patient and institutional factors and preoperative testing were assessed with hierarchical multivariable logistic regression. Institutional variation was characterized using the median odds ratio. The cohort included 906,902 patients who underwent 1,330,466 procedures (57.1% ophthalmologic and 42.9% low-risk surgery) at 119 institutions. Preoperative blood work preceded 400,058 (30.1%) procedures. The unadjusted institutional rate of preoperative blood work varied widely (0.0 to 98.1%). In regression modeling, significant predictors of preoperative testing included atrial fibrillation (adjusted odds ratio [AOR], 2.58; 95% CI, 2.51 to 2.66), preoperative medical consultation (AOR, 1.68; 95% CI, 1.65 to 1.71), previous mitral valve replacement (AOR, 2.33; 95% CI, 2.10 to 2.58), and liver disease (AOR, 1.69; 95% CI, 1.55 to 1.84). The median odds ratio for interinstitutional variation was 2.43. Results of this study suggest that testing is associated with a range of clinical covariates. However, an association was similarly identified with preoperative consultation, and significant variation between institutions exists across the jurisdiction.

  11. Cost Analysis of Following Up Incomplete Low-Risk Fetal Anatomy Ultrasounds.

    PubMed

    O'Brien, Karen; Shainker, Scott A; Modest, Anna M; Spiel, Melissa H; Resetkova, Nina; Shah, Neel; Hacker, Michele R

    2017-03-01

    To examine the clinical utility and cost of follow-up ultrasounds performed as a result of suboptimal views at the time of initial second-trimester ultrasound in a cohort of low-risk pregnant women. We conducted a retrospective cohort study of women at low risk for fetal structural anomalies who had second-trimester ultrasounds at 16 to less than 24 weeks of gestation from 2011 to 2013. We determined the probability of women having follow-up ultrasounds as a result of suboptimal views at the time of the initial second-trimester ultrasound, and calculated the probability of detecting an anomaly on follow-up ultrasound. These probabilities were used to estimate the national cost of our current ultrasound practice, and the cost to identify one fetal anomaly on follow-up ultrasound. During the study period, 1,752 women met inclusion criteria. Four fetuses (0.23% [95% CI 0.06-0.58]) were found to have anomalies at the initial ultrasound. Because of suboptimal views, 205 women (11.7%) returned for a follow-up ultrasound, and one (0.49% [95% CI 0.01-2.7]) anomaly was detected. Two women (0.11%) still had suboptimal views and returned for an additional follow-up ultrasound, with no anomalies detected. When the incidence of incomplete ultrasounds was applied to a similar low-risk national cohort, the annual cost of these follow-up scans was estimated at $85,457,160. In our cohort, the cost to detect an anomaly on follow-up ultrasound was approximately $55,000. The clinical yield of performing follow-up ultrasounds because of suboptimal views on low-risk second-trimester ultrasounds is low. Since so few fetal abnormalities were identified on follow-up scans, this added cost and patient burden may not be warranted. © 2016 Wiley Periodicals, Inc.

  12. Differences in the sleep states of IUGR and low-risk fetuses: An MCG study

    PubMed Central

    Sriram, Bhargavi; Mencer, Margret A; McKelvey, Samantha; Siegel, Eric R; Vairavan, Srinivasan; Wilson, James D.; Preissl, Hubert; Eswaran, Hari; Govindan, Rathinaswamy B.

    2013-01-01

    Background Intrauterine growth restriction (IUGR) is a fetal condition characterized by growth-rate reduction. Afflicted fetuses tend to display abnormalities in heart rate. Objective To study the differences in the heart-rate variability of low-risk fetuses and IUGR fetuses during different behavioral states. Methods A total of 40 fetal magnetocardiograms were recorded from 20 low-risk and 20 IUGR fetuses using a 151-sensor SQUID-array system. The maternal cardiac signals were attenuated using signal-space projection. Fetal R waves were identified using an adaptive Hilbert transform approach and fetal heart rate calculated. In each three-minute window, the heart rate was classified into patterns reflective of quiet sleep (pattern A) and active sleep (pattern B) using the criteria of Nijhuis. Two adjacent 3-minute windows exhibiting the same pattern were selected for analysis from every dataset. Heart-rate variability in that 6-minute window was characterized using three measures, Standard Deviation of Normal to Normal (SDNN), Root Mean Square of Successive Differences (RMSSD) and Phase Plane Area (PPA). Results All three measures tended to be lower in the IUGR group compared to the low-risk group. However, when the measures were analyzed in patterns, only PPA showed significant difference between the risk groups in Pattern A, where as both PPA and SDNN showed highly significant risk-group differences in Pattern B. RMSSD did not show any significant risk-group difference. Conclusion The result signifies that the heart-rate variability of IUGR fetuses is different from that of low-risk fetuses, and only PPA was able to capture the HRV differences in both quiet and active states. The difference between these two groups of fetuses shows that the fetal-activity states are potential confounders when characterizing heart-rate variability. PMID:23907090

  13. Overweight and Severe Acute Maternal Morbidity in a Low-Risk Pregnant Population in The Netherlands

    PubMed Central

    Witteveen, Tom; Zwart, Joost J.; Gast, Karin B.; Bloemenkamp, Kitty W. M.; van Roosmalen, Jos

    2013-01-01

    Objective To investigate the association between overweight and severe acute maternal morbidity (SAMM) in a low-risk pregnant population. Design Nationwide case-control study. Setting The Netherlands, august 2004 to august 2006. Population 1567 cases from initially primary care and 2994 women from primary care practices as controls, out of 371 012 women delivering in the Netherlands during the study period Methods Cases were women with SAMM obtained from a nationwide prospective study. All women in this cohort who initially had low-risk pregnancies were compared with low-risk women without SAMM to calculate odd ratios (ORs) to develop SAMM by body mass index (BMI) category. We divided body mass index in three overweight categories and calculated the ORs (95% CI) of total SAMM and per specific endpoint by logistic regression, with normal weight as reference. We adjusted for age, parity and socio-economic status. Main Outcome Measures SAMM, defined as Intensive Care Unit (ICU)-admission, Uterine Rupture, Eclampsia or Major Obstetric Haemorrhage (MOH) Results SAMM was reported in 1567 cases which started as low-risk pregnancies. BMI was available in 1097 (70.0%) cases and 2994 control subjects were included. Analysis showed a dose response relation for overweight (aOR, 1.3; 95% CI, 1.0-1.5), obese (aOR, 1.4; 95% CI, 1.1-1.9) and morbidly obese (aOR, 2.1; 95% CI, 1.3-3.2) women to develop SAMM compared to normal weight. Sub analysis showed the same dose response relation for ICU-admission, Uterine Rupture and Eclampsia. We found no association for MOH. Conclusion Overweight without pre-existent co-morbidity is an important risk-indicator for developing SAMM. This risk increases with an increasing body mass index. PMID:24069316

  14. Costs and inconsistencies in US IRB review of low-risk medical education research.

    PubMed

    Kano, Miria; Getrich, Christina M; Romney, Crystal; Sussman, Andrew L; Williams, Robert L

    2015-06-01

    Advances in communication technologies over the last two decades have transformed the way medical education research is conducted, creating opportunities for multi-institution national and international studies. Although these studies enable researchers to gain broader understandings of educational processes across institutions, they increase the need for multiple institutional review board (IRB) reviews to ensure the protection of human subjects. This study describes the process of obtaining multiple IRB approvals of the same protocol for a multi-site, low-risk, medical education research project in the USA. The burden of obtaining those reviews and their consistency are assessed. The associated time and costs, and implications for the research process are detailed. Following review by the investigators' parent institution IRB, the project team circulated a uniform protocol for conduct of a low-risk, medical education survey to the IRBs of 89 US medical schools for review. The processes and time required to obtain approvals were recorded to estimate associated research team personnel costs. Approval could not be obtained from five IRBs as a result of insurmountable procedural barriers. A total of 67 IRBs eventually deferred to the parent IRB determination. The remaining IRBs required a variety of additional procedural processes before ultimately agreeing with the original determination. The personnel costs associated with obtaining the 84 approvals amounted to US$121,344. Considering the value of multi-site designs to address a range of research questions, enhance participant diversity and develop representative findings, solutions must be found to counter inefficiencies of current IRB review processes for low-risk research, such as that usually conducted in medical education. Although we acknowledge that local review is an essential protective measure for research involving identifiable communities that are uniquely susceptible to social or economic harm, this

  15. Omission of lymphadenectomy is possible for low-risk corpus cancer.

    PubMed

    Hidaka, T; Kato, K; Yonezawa, R; Shima, T; Nakashima, A; Nagira, K; Nakamura, T; Saito, S

    2007-02-01

    The objective of this study is to ascertain whether omission of lymphadenectomy is possible when endometrial cancer is considered low-risk based on intraoperative pathologic indicators. A total of 128 patients were deemed to be low-risk based on intraoperative evaluation, including frozen-section determination of grade and myometrial invasion. We divided these 128 patients into 2 groups, the total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) with lymphadenectomy (LA group, n=68) and the TAH-BSO without lymphadenectomy (non-LA group, n=60) group. The only adjuvant treatment used was chemotherapy, and the decision to use chemotherapy was based on stage, grade, or lymphovascular space involvement. A retrospective review of the medical records was performed, and disease-free survival (DFS), overall survival (OS), operative time, estimated blood loss during operation, percentage of transfusion requirement, incidence of post-operative leg lymphedema and post-operative deep vein thrombosis were evaluated. The 5-year DFS and OS rates were 95.6% and 98.5% in the LA group, and 98.3% and 98.3% in the non-LA group, respectively, and were not significantly different. In the LA group, pelvic lymph node metastasis was observed in only 1 case. In the LA group, blood loss during operation, percentage of transfusion requirement and the incidence of post-operative leg lymphedema were significantly higher than those in the non-LA group. Lymphadenectomy did not provide a significant survival advantage in the patients with low-risk corpus cancer. Additionally, some peri- and post-operative morbidities and complications were increased by the addition of lymphadenectomy. The present findings suggest that lymphadenectomy should be limited for low-risk corpus cancer.

  16. Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

    PubMed Central

    Palomo, Laura; Garcia, Olga; Arnan, Montse; Xicoy, Blanca; Fuster, Francisco; Cabezón, Marta; Coll, Rosa; Ademà, Vera; Grau, Javier; Jiménez, Maria-José; Pomares, Helena; Marcé, Sílvia; Mallo, Mar; Millá, Fuensanta; Alonso, Esther; Sureda, Anna; Gallardo, David; Feliu, Evarist; Ribera, Josep-Maria; Solé, Francesc; Zamora, Lurdes

    2016-01-01

    Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC. PMID:27486981

  17. Allergy Testing in Children With Low-Risk Penicillin Allergy Symptoms.

    PubMed

    Vyles, David; Adams, Juan; Chiu, Asriani; Simpson, Pippa; Nimmer, Mark; Brousseau, David C

    2017-08-01

    Penicillin allergy is commonly reported in the pediatric emergency department (ED). True penicillin allergy is rare, yet the diagnosis results from the denial of first-line antibiotics. We hypothesize that all children presenting to the pediatric ED with symptoms deemed to be low-risk for immunoglobulin E-mediated hypersensitivity will return negative results for true penicillin allergy. Parents of children aged 4 to 18 years old presenting to the pediatric ED with a history of parent-reported penicillin allergy completed an allergy questionnaire. A prespecified 100 children categorized as low-risk on the basis of reported symptoms completed penicillin allergy testing by using a standard 3-tier testing process. The percent of children with negative allergy testing results was calculated with a 95% confidence interval. Five hundred ninety-seven parents completed the questionnaire describing their child's reported allergy symptoms. Three hundred two (51%) children had low-risk symptoms and were eligible for testing. Of those, 100 children were tested for penicillin allergy. The median (interquartile range) age at testing was 9 years (5-12). The median (interquartile range) age at allergy diagnosis was 1 year (9 months-3 years). Rash (97 [97%]) and itching (63 [63%]) were the most commonly reported allergy symptoms. Overall, 100 children (100%; 95% confidence interval 96.4%-100%) were found to have negative results for penicillin allergy and had their labeled penicillin allergy removed from their medical record. All children categorized as low-risk by our penicillin allergy questionnaire were found to have negative results for true penicillin allergy. The utilization of this questionnaire in the pediatric ED may facilitate increased use of first-line penicillin antibiotics. Copyright © 2017 by the American Academy of Pediatrics.

  18. Association between percentage of tumor involvement and Gleason score upgrading in low-risk prostate cancer.

    PubMed

    Fu, Qiang; Moul, Judd W; Bañez, Lionel L; Sun, Leon; Mouraviev, Vladimir; Xie, Dongha; Polascik, Thomas J

    2012-12-01

    To find the predictors of Gleason score upgrading in a cohort of low-risk prostate cancer patients, data were analyzed comprising 1,632 consecutive men with low-risk prostate cancer who underwent radical prostatectomy between 1993 and 2009. Assessment focused on preoperative parameters including patient age, race, diagnostic prostate-specific antigen (PSA) levels, clinical stage and biopsy Gleason score, along with pathological parameters including percentage of tumor involvement (PTI), tumor laterality, pathological stage, extra-capsular extension, seminal vesicle invasion, and surgical margins. These parameters were analyzed using univariate and multivariate methods. Kaplan-Meier curves compared differences in biochemical disease-free survival in men having cancers with and without Gleason score upgrading. Cases involving pathological Gleason score upgrading were identified in 723 (44.3 %) of 1,632 patients. Kaplan-Meier PSA recurrence-free survival curves showed a difference in outcome between men with and without Gleason score upgrading (p < 0.001). Of Gleason score upgraded patients, 35 (4.8 %) men had PTI of <5 %, 237 (32.8 %) had PTI of 5-9.9 %, 177 (24.5 %) had PTI of 10-14.9 %, and 274 (37.9 %) had PTI ≥ 15 % (p < 0.001). PTI (p < 0.001) along with diagnostic PSA, patient age, diagnostic biopsy Gleason score, pathologic stage, and surgical margin status were independent predictors of pathological Gleason score upgrading on multivariate logistic regression. PTI correlates closely with Gleason score upgrading in a low-risk prostate cancer cohort. Low-risk prostate cancer patients with clinical findings suggestive of high PTI or large volume cancers should not benefit from active surveillance strategies.

  19. IL-8 predicts pediatric oncology patients with febrile neutropenia at low risk for bacteremia.

    PubMed

    Cost, Carrye R; Stegner, Martha M; Leonard, David; Leavey, Patrick

    2013-04-01

    Despite a low bacteremia rate, pediatric oncology patients are frequently admitted for febrile neutropenia. A pediatric risk prediction model with high sensitivity to identify patients at low risk for bacteremia is not available. We performed a single-institution prospective cohort study of pediatric oncology patients with febrile neutropenia to create a risk prediction model using clinical factors, respiratory viral infection, and cytokine expression. Pediatric oncology patients with febrile neutropenia were enrolled between March 30, 2010 and April 1, 2011 and managed per institutional protocol. Blood samples for C-reactive protein and cytokine expression and nasopharyngeal swabs for respiratory viral testing were obtained. Medical records were reviewed for clinical data. Statistical analysis utilized mixed multiple logistic regression modeling. During the 12-month period, 195 febrile neutropenia episodes were enrolled. There were 24 (12%) episodes of bacteremia. Univariate analysis revealed several factors predictive for bacteremia, and interleukin (IL)-8 was the most predictive variable in the multivariate stepwise logistic regression. Low serum IL-8 predicted patients at low risk for bacteremia with a sensitivity of 0.9 and negative predictive value of 0.98. IL-8 is a highly sensitive predictor for patients at low risk for bacteremia. IL-8 should be utilized in a multi-institution prospective trial to assign risk stratification to pediatric patients admitted with febrile neutropenia.

  20. [Clinical guideline for management of patients with low risk differentiated thyroid carcinoma].

    PubMed

    Díez, Juan José; Oleaga, Amelia; Álvarez-Escolá, Cristina; Martín, Tomás; Galofré, Juan Carlos

    2015-01-01

    Incidence of thyroid cancer is increasing in Spain and worldwide. Overall thyroid cancer survival is very high, and stratification systems to reliably identify patients with worse prognosis have been developed. However, marked differences exist between the different specialists in clinical management of low-risk patients with thyroid carcinoma. Almost half of all papillary thyroid carcinomas are microcarcinomas, and 90% are tumors < 2 cm that have a particularly good prognosis. However, they are usually treated more aggressively than needed, despite the lack of adequate scientific support. Surgery remains the gold standard treatment for these tumors. However, lobectomy may be adequate in most patients, without the need for total thyroidectomy. Similarly, prophylactic lymph node dissection of the central compartment is not required in most cases. This more conservative approach prevents postoperative complications such as hypoparathyroidism or recurrent laryngeal nerve injury. Postoperative radioiodine remnant ablation and strict suppression of serum thyrotropin, although effective for the more aggressive forms of thyroid cancer, have not been shown to be beneficial for the treatment of low risk patients, and may impair their quality of life. This guideline provides recommendations from the task force on thyroid cancer of the Spanish Society of Endocrinology and Nutrition for adequate management of patients with low-risk thyroid cancer. Copyright © 2015 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

  1. Treatment of low-risk ductal carcinoma in situ: is nothing better than something?

    PubMed

    Benson, John R; Jatoi, Ismail; Toi, Masakazu

    2016-10-01

    The heterogeneous nature of ductal carcinoma in situ has been emphasised by data for breast-cancer screening that show substantial increases in the detection of early-stage non-invasive breast cancer but no noteworthy change in the incidence of invasive and distant metastatic disease. Indolent non-progressive forms of ductal carcinoma in situ are managed according to similar surgical strategies as high-risk disease, with extent of resection dictated by radiological and pathological estimates of tumour dimensions. Although adjuvant treatments might be withheld for low-risk lesions, surgical treatments incur potential morbidity, especially when mastectomy and breast reconstruction are done for widespread low-grade or intermediate-grade ductal carcinoma in situ. Low rates of deaths from breast cancer coupled with overdiagnosis within screening programmes have prompted a fundamental rethink of approaches to the management of both low-risk and high-risk ductal carcinoma in situ. Changes include active surveillance for low-risk lesions and a watchful waiting policy with intervention when invasive local recurrence after breast-conserving surgery is detected. Prediction of ipsilateral invasive recurrence is likely to be improved by integration of molecular biomarkers with conventional histopathological parameters. Moreover, further genetic interrogation of ductal carcinoma in situ might lead to a reclassification of some low-grade lesions as non-cancerous entities.

  2. Image-Guided Hypofractionated Radiotherapy in Low-Risk Prostate Cancer Patients

    PubMed Central

    Valeriani, Maurizio; Carnevale, Alessia; Bonome, Paolo; Montalto, Adelaide; Nicosia, Luca; Osti, Mattia F.; De Sanctis, Vitaliana; Minniti, Giuseppe; Maurizi Enrici, Riccardo

    2014-01-01

    Aim. To evaluate efficacy and toxicity of image-guided hypofractionated radiotherapy (HFRT) in the treatment of low-risk prostate cancer. Outcomes and toxicities of this series of patients were compared to another group of 32 low-risk patients treated with conventional fractionation (CFRT). Methods. Fifty-nine patients with low-risk prostate cancer were analysed. Total dose for the prostate and proximal seminal vesicles was 60 Gy delivered in 20 fractions. Results. The median follow-up was 30 months. The actuarial 4-year overall survival, biochemical free survival, and disease specific survival were 100%, 97.4%, and 97.4%, respectively. Acute grade 1-2 gastrointestinal (GI) and genitourinary (GU) toxicity rates were 11.9% and 40.7%, respectively. Grade 1 GI and GU late toxicity rates were 8.5% and 13.6%, respectively. No grade ≥2 late toxicities were recorded. Acute grade 2-3 GU toxicity resulted significantly lower (P = 0.04) in HFRT group compared to the CFRT group. The cumulative 4-year incidence of grade 1-2 GU toxicity was significantly higher (P < 0.001) for HFRT patients. Conclusions. Our study demonstrated that hypofractionated regimen provided excellent biochemical control in favorable risk prostate cancer patients. The incidence of GI and GU toxicity was low. However, HFRT presented higher cumulative incidence of low-grade late GU toxicity than CFRT. PMID:24864248

  3. Vocalization Rate and Consonant Production in Toddlers at High and Low Risk for Autism.

    PubMed

    Chenausky, Karen; Nelson, Charles; Tager-Flusberg, Helen

    2017-04-14

    Previous work has documented lower vocalization rate and consonant acquisition delays in toddlers with autism spectrum disorder (ASD). We investigated differences in these variables at 12, 18, and 24 months in toddlers at high and low risk for ASD. Vocalization rate and number of different consonants were obtained from speech samples from a prospective study of infant siblings of children with ASD. Three groups were compared: 18 toddlers at low risk for ASD (low-risk control), 18 high-risk siblings without ASD (HRA-), and 10 high-risk siblings with ASD (HRA+). All groups' mean language scores were within the normal range. HRA+ toddlers showed consistently lower vocalization rate; vocalization rate did not predict number of different consonants at 12 months for HRA+. HRA-, not HRA+, toddlers had the smallest number of different consonants and produced significantly fewer different consonants than predicted by their vocalization rate at 12 months. Consonant-acquisition trajectories differed between groups, with HRA- showing the greatest increase from 12 to 18 months. Lower vocalization rate was not associated with reduced number of different consonants in these toddlers. Between-groups differences in developmental trajectories are discussed in the context of the social feedback loop and differential ability to benefit from adult feedback between groups.

  4. [Postoperative radioiodine ablation in patients with low risk differentiated thyroid carcinoma].

    PubMed

    Díez, Juan J; Grande, Enrique; Iglesias, Pedro

    2015-01-06

    Most patients with newly diagnosed differentiated thyroid carcinoma have tumors with low risk of mortality and recurrence. Standard therapy has been total or near total thyroidectomy followed by postoperative radioiodine remnant ablation (RRA). Although RRA provides benefits, current clinical guidelines do not recommend it universally, since an increase in disease-free survival or a decrease in mortality in low risk patients has not been demonstrated so far. Advancements in our understanding of the biological behavior of thyroid cancer have been translated into the clinic in a personalized approach to the patients based on their individual risk of recurrence and mortality. Current evidence suggests that RRA is not indicated in most low-risk patients, especially those with papillary carcinomas smaller than 1cm, without extrathyroidal extension, unfavorable histology, lymph node involvement or distant metastases. Follow-up of these patients with serial measurements of serum thyroglobulin and neck ultrasound is adequate. Careful evaluation of all risk factors of clinical relevance will allow a more realistic assessment of each individual patient. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  5. Histone Variants and Epigenetics

    PubMed Central

    Henikoff, Steven; Smith, M. Mitchell

    2015-01-01

    Histones package and compact DNA by assembling into nucleosome core particles. Most histones are synthesized at S phase for rapid deposition behind replication forks. In addition, the replacement of histones deposited during S phase by variants that can be deposited independently of replication provide the most fundamental level of chromatin differentiation. Alternative mechanisms for depositing different variants can potentially establish and maintain epigenetic states. Variants have also evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, and other processes. Investigations into the evolution, structure, and metabolism of histone variants provide a foundation for understanding the participation of chromatin in important cellular processes and in epigenetic memory. PMID:25561719

  6. Pathological characteristics of low risk prostate cancer based on totally embedded prostatectomy specimens.

    PubMed

    Swanson, Gregory P; Epstein, Jonathan I; Ha, Chul S; Kryvenko, Oleksandr N

    2015-03-01

    Surveillance and focal therapy are increasingly considered for low risk prostate cancer (PC). We describe pathological characteristics of low risk PC at radical prostatectomy in contemporary patients. Five-hundred-fifty-two men from 2008 to 2012 with low risk (stage T1c/T2a, PSA ≤ 10 ng/ml, Gleason score ≤6) PC underwent radical prostatectomy. Slides were re-reviewed to grade and stage the tumor, map separate tumor nodules, and calculate their volumes. Ninety-three (16.9%) men had prostatectomy Gleason score 3 + 4 = 7 or higher and were excluded. Five (0.9%) men had no residual carcinoma. Remaining 454 patients composed the study cohort. The median age was 57 years (36-73) and median PSA 4.4 ng/ml (0.4-9.9). Racial distribution was 77.5% Caucasian, 15.5% African American, and 7% other. The median total tumor volume was 0.38 cm(3) (0.003-7.22). Seventy percent of the patients had bilateral tumor and 34% had a tumor nodule >0.5 cm(3) . The index lesion represented 89% (median) of the total tumor volume. Extraprostatic extension and positive margin were present in 5.7% and 9% of cases, respectively. The tumor nodules measuring >0.5 cm(3) were located almost equally between the anterior (53%) and peripheral (47%) gland. The relationship between PSA and total tumor volume was weak (r = 0.13, P = 0.005). The relationship between PSA density and total tumor volume was slightly better (r = 0.26, P < 0.001). Low risk prostate cancer is generally a low volume disease. Gleason score upgrade is seen in 16.9% of cases at radical prostatectomy. While the index lesion accounts for the bulk of the disease, the cancer is usually multifocal and bilateral. Neither PSA nor PSA density correlates well with the total tumor volume. Prostate size has a significant contribution to PSA level. These factors need to be considered in treatment planning for low risk prostate cancer. © 2014 Wiley Periodicals, Inc.

  7. A clinical decision rule to identify children at low risk for appendicitis.

    PubMed

    Kharbanda, Anupam B; Taylor, George A; Fishman, Steven J; Bachur, Richard G

    2005-09-01

    Computed tomography (CT) has gained widespread acceptance in the evaluation of children with suspected appendicitis. Concern has been raised regarding the long-term effects of ionizing radiation. Other means of diagnosing appendicitis, such as clinical scores, are lacking in children. We sought to develop a clinical decision rule to predict which children with acute abdominal pain do not have appendicitis. Prospective cohort study was conducted of children and adolescents who aged 3 to 18 years, had signs and symptoms suspicious for appendicitis, and presented to the emergency department between April 2003 and July 2004. Standardized data-collection forms were completed on eligible patients. Two low-risk clinical decision rules were created and validated using logistic regression and recursive partitioning. The sensitivity, negative predictive value (NPV), and negative likelihood ratio of each clinical rule were compared. A total of 601 patients were enrolled. Using logistic regression, we created a 6-part score that consisted of nausea (2 points), history of focal right lower quadrant pain (2 points), migration of pain (1 point), difficulty walking (1 point), rebound tenderness/pain with percussion (2 points), and absolute neutrophil count of >6.75 x 10(3)/microL (6 points). A score < or =5 had a sensitivity of 96.3% (95% confidence interval [CI]: 87.5-99.0), NPV of 95.6% (95% CI: 90.8-99.0), and negative likelihood ratio of .102 (95% CI: 0.026-0.405) in the validation set. Using recursive partitioning, a second low-risk decision rule was developed consisting of absolute neutrophil count of <6.75 x 10(3)/microL, absence of nausea, and absence of maximal tenderness in the right lower quadrant. This rule had a sensitivity of 98.1% (95% CI: 90.1-99.9), NPV of 97.5% (95% CI: 86.8-99.9), and negative likelihood ratio of 0.058 (95% CI: 0.008-0.411) in the validation set. Theoretical application of the low-risk rules would have resulted in a 20% reduction in CT. Our low-risk

  8. Predictors of high-risk and low-risk oral HPV infection in the United States.

    PubMed

    Orosco, Ryan K; Kedarisetty, Suraj; Hecht, Avram S; Chang, David C; Coffey, Charles S; Weissbrod, Philip A

    2016-06-01

    Determine predictors of high-risk and low-risk oral HPV infection in the United States. Retrospective analyses of National Health and Nutrition Examination Survey cross-sectional data of U.S. population from 2009 to 2012. Database queried for subjects aged 18 to 69 with oral rinse human papillomavirus (HPV) DNA data. Logistic regression identified factors associated with high-risk and low-risk infection. Covariates included age, gender, ethnicity, income-to-poverty (IP) ratio, sexual orientation, human immunodeficiency virus infection, other sexually transmitted infections, lifetime sexual partners, and lifetime oral sex partners. In total, 9,256 subjects were identified with mean age of 42.1 years. Oral HPV infection was present in 8.1% (N = 747); 55.7% were high-risk and 55.3% were low-risk types, including 11% with both. Oral infection had a negative association with female gender (odds ratio [OR] 0.3, P < 0.001), IP ratio ≥ 3 (OR 0.7, P = 0.02), and one lifetime oral sex partner (OR 0.7, P = 0.03). Increasing oral sex behavior (6-21+ lifetime partners) was positively associated with oral HPV (OR 1.4-3.0, P = 0.03). Low-risk infection had negative associations with female gender (OR 0.4, P < 0.001) and non-Hispanic white ethnicity (OR 0.6, P = 0.02), IP ratio ≥ 3 (OR 0.6, P = 0.01), and positive association with > 20 sexual partners (all sex OR 1.7, P = 0.04; oral sex OR 1.9, P = 0.02). Predictors of high-risk HPV infection included male gender and increasing oral sex partners. Increasing oral sex partners is positively associated with oral HPV infection; female sex and higher socioeconomic class are negatively associated. The risk-factor profiles for high-risk and low-risk HPV types are distinct, with similar trends related to sexual behaviors. 4. Laryngoscope, 126:1365-1372, 2016. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

  9. Detection of fetal congenital heart disease in a low-risk population.

    PubMed

    Hafner, E; Scholler, J; Schuchter, K; Sterniste, W; Philipp, K

    1998-08-01

    Our purpose was to evaluate the efficacy of level two ultrasound screening for the detection of congenital heart defects (CHD) in a low-risk population by using three standardized cuts. Within a period of four years a total of 6727 pregnant women of a low-risk population undertook several ultrasound examinations on the basis of screening for fetal malformations. All ultrasound examinations were performed by three experienced doctors. At every single scan three standardized cuts (apical and lateral four-chamber view, crossing over of the great arteries) were obtained in order to detect congenital heart defects. Of 87 CHDs (1.33 per cent of the examined women) 39 (43.8 per cent) were diagnosed prenatally. The detection rate was 10/48 (20.8 per cent) in the presence of VSD, ASD2 or combined ASD2 + VSD, the detection rate was 29/39 (74.3 per cent) in the presence of other forms of congenital heart disease. None of the 38 missed cases in the first group but three of the ten missed CHDs in the second group had emergency neonatological problems. Aneuploidy and/or other malformations existed in 22/87 cases of CHD. The obstetrical management was changed in nearly all cases after the diagnosis of a CHD. Twenty-two women opted for termination of pregnancy because of additional fetal malformations or chromosomal defects. Five women were transferred prenatally to a tertiary centre for neonatal cardiac surgery. Ten deliveries were performed in the presence of a neonatologist. Good detection rates for CHD can be achieved in a low-risk population on the basis of level two ultrasound screening by using the above mentioned three cuts and thus, the perinatal mortality and morbidity can be improved.

  10. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation

    PubMed Central

    Alvarez-Larrán, Alberto; Pereira, Arturo; Guglielmelli, Paola; Hernández-Boluda, Juan Carlos; Arellano-Rodrigo, Eduardo; Ferrer-Marín, Francisca; Samah, Alimam; Griesshammer, Martin; Kerguelen, Ana; Andreasson, Bjorn; Burgaleta, Carmen; Schwarz, Jiri; García-Gutiérrez, Valentín; Ayala, Rosa; Barba, Pere; Gómez-Casares, María Teresa; Paoli, Chiara; Drexler, Beatrice; Zweegman, Sonja; McMullin, Mary F.; Samuelsson, Jan; Harrison, Claire; Cervantes, Francisco; Vannucchi, Alessandro M.; Besses, Carlos

    2016-01-01

    The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding. PMID:27175028

  11. Identification of Low-Risk Patients with Acute Symptomatic Pulmonary Embolism for Outpatient Therapy.

    PubMed

    Maestre, Ana; Trujillo-Santos, Javier; Riera-Mestre, Antoni; Jiménez, David; Di Micco, Pierpaolo; Bascuñana, José; Vela, Jerónimo Ramón; Peris, Luísa; Malfante, Pablo César; Monreal, Manuel

    2015-08-01

    Patients with acute symptomatic pulmonary embolism (PE) deemed to be at low risk for early complications might be candidates for partial or complete outpatient treatment. To develop and validate a clinical prediction rule that accurately identifies patients with PE and low risk of short-term complications and to compare its prognostic ability with two previously validated models (i.e., the Pulmonary Embolism Severity Index [PESI] and the Simplified PESI [sPESI]) Multivariable logistic regression of a large international cohort of patients with PE prospectively enrolled in the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) registry. All-cause mortality, recurrent PE, and major bleeding up to 10 days after PE diagnosis were determined. Of 18,707 eligible patients with acute symptomatic PE, 46 (0.25%) developed recurrent PE, 203 (1.09%) bled, and 471 (2.51%) died. Predictors included in the final model were chronic heart failure, recent immobilization, recent major bleeding, cancer, hypotension, tachycardia, hypoxemia, renal insufficiency, and abnormal platelet count. The area under receiver-operating characteristic curve was 0.77 (95% confidence interval [CI], 0.75-0.78) for the RIETE score, 0.72 (95% CI, 0.70-0.73) for PESI (P < 0.05), and 0.71 (95% CI, 0.69-0.73) for sPESI (P < 0.05). Our RIETE score outperformed the prognostic value of PESI in terms of net reclassification improvement (P < 0.001), integrated discrimination improvement (P < 0.001), and sPESI (net reclassification improvement, P < 0.001; integrated discrimination improvement, P < 0.001). We built a new score, based on widely available variables, that can be used to identify patients with PE at low risk of short-term complications, assisting in triage and potentially shortening duration of hospital stay.

  12. Increasing low risk prostate cancer incidence in United States Air Force servicemen and selection of treatments.

    PubMed

    del Junco, Deborah J; Fox, Erin E; Cooper, Sharon; Goldhagen, Marc; Koda, Erik; Rogers, David; Canby-Hagino, Edith; Kim, Jeri; Pettaway, Curtis; Boyd, Douglas D

    2011-06-01

    Periodic Health Assessments have been mandated for United States Air Force servicemen since the mid 1990s. Thus, we determined whether United States Air Force prostate cancer incidence rates increased thereafter and how these tumors segregate into low and intermediate/high risk categories. We also identified treatment choices. We queried the Department of Defense Automated Central Tumor Registry for prostate cancer diagnosed in United States Air Force servicemen between 1991 and 2008 to determine incidence rates, disease risk category and treatments. Age adjusted rates in white active duty servicemen diagnosed for the most recent period of 2005 to 2008 increased 3-fold relative to the rate in the earliest period of 1991 to 1994. A similar trend was evident in black servicemen. Relative to the Surveillance, Epidemiology and End Results population prostate cancer rates in active duty United States Air Force men between 1995 and 2008 were significantly increased for the 2 racial groups. A significantly greater proportion of active duty servicemen than retirees (62% vs 40%) presented with low risk disease, defined as prostate specific antigen less than 10 ng/ml, Gleason sum less than 7 and clinical stage T1a-T2a. Of those with low risk disease significantly more active duty servicemen elected curative surgery than retirees (93% vs 53%). Prostate cancer incidence rates in United States Air Force servicemen have increased with time, exceeding rates in the Surveillance, Epidemiology and End Results population. While most cases are characterized as low risk, aggressive management is elected. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  13. African American Men With Low-Risk Prostate Cancer Are Candidates for Active Surveillance: The Will-Rogers Effect?

    PubMed

    Qi, Robert; Moul, Judd

    2017-08-01

    It is controversial whether African American men(AAM) with low-risk prostate cancer (PC) should be placed on active surveillance (AS). Recent literature indicates AAM diagnosed with low-risk disease have increased pathologic upgrading and disease progression. We evaluated the surgical pathology of AAM and Caucasians who underwent prostatectomy to assess the suitability of AAM for AS. We retrospectively reviewed 1,034 consecutive men who underwent open prostatectomy between 2004 and 2015; 345 Caucasians and 58 AAM met the American Urological Association criteria for low-risk PC. We excluded from analysis two men whose prostatectomies were aborted. Chi-square test, Fisher's exact test, and Wilcoxon rank sum test were used for statistical analysis. AAM with low-risk PC have a lower rate of surgical upgrading and similar rates of adverse pathology compared with Caucasians. 29.8% of AAM (17/57) diagnosed with low-risk disease but 44.5% of Caucasians (153/344) had disease upgrading at prostatectomy ( p < .04), although AAM overall were less likely to be clinically diagnosed with low-risk cancer (33.1 vs. 41.7%, p < .05). AAM with low-risk pathology were younger (median 55 vs. 59 years, p < .001) and had smaller prostates (32 vs. 35 g, p < .04). AAM with preoperative low-risk disease have lower rates of surgical upgrading and similar adverse pathology compared with Caucasians. There may be a Will-Rogers effect as AAM with aggressive disease appear more likely to be stratified into intermediate- and high-risk groups, leaving those AAM diagnosed with low-risk disease fully eligible for AS. Our results support that AS for AAM should remain a viable option.

  14. Induction of Labor and Risk of Postpartum Hemorrhage in Low Risk Parturients

    PubMed Central

    Khireddine, Imane; Le Ray, Camille; Dupont, Corinne; Rudigoz, René-Charles; Bouvier-Colle, Marie-Hélène; Deneux-Tharaux, Catherine

    2013-01-01

    Objective Labor induction is an increasingly common procedure, even among women at low risk, although evidence to assess its risks remains sparse. Our objective was to assess the association between induction of labor and postpartum hemorrhage (PPH) in low-risk parturients, globally and according to its indications and methods. Method Population-based case-control study of low-risk women who gave birth in 106 French maternity units between December 2004 and November 2006, including 4450 women with PPH, 1125 of them severe, and 1744 controls. Indications for labor induction were standard or non-standard, according to national guidelines. Induction methods were oxytocin or prostaglandins. Multilevel multivariable logistic regression modelling was used to test the independent association between induction and PPH, quantified as odds ratios. Results After adjustment for all potential confounders, labor induction was associated with a significantly higher risk of PPH (adjusted odds ratio, AOR1.22, 95%CI 1.04–1.42). This excess risk was found for induction with both oxytocin (AOR 1.52, 95%CI 1.19–1.93 for all and 1.57, 95%CI 1.11–2.20 for severe PPH) and prostaglandins (AOR 1.21, 95%CI 0.97–1.51 for all and 1.42, 95%CI 1.04–1.94 for severe PPH). Standard indicated induction was significantly associated with PPH (AOR1.28, 95%CI 1.06–1.55) while no significant association was found for non-standard indicated inductions. Conclusion Even in low risk women, induction of labor, regardless of the method used, is associated with a higher risk of PPH than spontaneous labor. However, there was no excess risk of PPH in women who underwent induction of labor for non-standard indications. This raises the hypothesis that the higher risk of PPH associated with labor induction may be limited to unfavorable obstetrical situations. PMID:23382990

  15. A case series of Nasopharyngeal Carcinoma among Indians, a low risk population, in Perak State, Malaysia.

    PubMed

    Anusha, B; Philip, R; Norain, K; Harvinder, S; Gurdeep, S M

    2012-12-01

    Nasopharyngeal carcinoma (NPC) is rare among people of Indian ethnicity. A short retrospective case review of clinical records of Indian patients diagnosed with nasopharyngeal carcinoma in a period of 5 years was conducted. Their slides were further subjected to EBV encoded RNA (EBER) - In- situ Hybridization (ISH). The histologic subtype was nonkeratinizing carcinoma in all 4 patients. All were Epstein Barr Virus (EBV) positive. We believe that the crucial factor responsible for nasopharyngeal carcinoma is genetics; either a genetic susceptibility among high risk groups or genetic resistance/immunity in low risk groups. Further genetic studies are required to look for somatic or inherited chromosomal mutations among the various risk populations.

  16. The efficacy of incentive spirometers in post-operative protocols for low-risk patients.

    PubMed

    Davies, B L; MacLeod, J P; Ogilvie, H M

    1990-01-01

    Incentive spirometry offered no statistically significant advantages to pulmonary function when compared to unstructured or structured deep breathing and coughing exercise programs, for patients at low risk of developing pulmonary complications. The additional cost of incentive spirometer equipment does not seem warranted in these patients. Furthermore, patients with or without an incentive spirometer were willing to comply with a structured breathing exercise program with the same frequency of practice sessions. Patients in this diagnostic category did not require a technical device to reward and motivate them for performing maximal inspiratory manoeuvres.

  17. Patients' beliefs regarding informed consent for low-risk pragmatic trials.

    PubMed

    Dal-Ré, Rafael; Carcas, Antonio J; Carné, Xavier; Wendler, David

    2017-09-18

    The requirement to obtain written informed consent may undermine the potential of pragmatic randomized clinical trials (pRCTs) to improve evidence-based care. This requirement could compromise trials statistical power or even force it to close them down prematurely. However, recent data from the U.S. and Spain suggest that a majority of the public endorses written consent for low-risk pRCTs. The present manuscript assesses whether this view is shared by patients. This was a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent versus verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing 2 drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. This web-based survey was conducted in May 2016. Two-thousand and eight adults who were representative of the Spanish population participated in the survey (response rate: 61%). Of these 2008 respondents, 338 indicated that they had been diagnosed with hypertension and were being treated with prescription medicines for this condition at the time of responding to the survey. The primary outcome measures were respondents' personal preference and recommendation to a research ethics committee regarding the use of written informed consent versus verbal consent or general notification. Overall, 74% of the 338 patient respondents endorsed written consent. In both scenarios, general notification received significantly more support (30.6%-44.7%) than verbal consent (13.3%-17.6%). 43% of respondents preferred and/or recommended general notification rather than written consent. As in the survey of the general public, more patients endorsed written consent than the alternative option. However, two factors suggest that a different approach to written consent should be investigated for low-risk pRCTs: a) a substantial minority of respondents supported general

  18. Transthoracic Biopsy Causes Massive Subcutaneous Emphysema in a Low Risk Patient

    PubMed Central

    Dag, Yusuf

    2016-01-01

    Subcutaneous Emphysema (SE) can be defined as air leakage under skin from the respiratory or gastrointestinal system. It is frequently accompanied by pneumomediastinum. Thoracentesis, image-guided lung biopsies, pulmonary diseases and therapies resulting in necrosis can cause this pathology. The risk of pneumothorax and SE increased with the distance of the lesion to the pleura, and small size of the lesion. Although, our patient had low risk for SE, there were minimal pneumothoraces and massive SE. We consider that tumour necrosis and subcutaneous tissue may be related via transthoracic biopsy and this leads to massive SE. PMID:28050477

  19. Active Surveillance Compared With Initial Treatment for Men With Low-Risk Prostate Cancer

    PubMed Central

    Hayes, Julia H.; Ollendorf, Mr. Daniel A.; Pearson, Steven D.; Barry, Michael J.; Kantoff, Philip W.; Stewart, Susan T.; Bhatnagar, Vibha; Sweeney, Christopher J.; Stahl, James E.; McMahon, Pamela M.

    2011-01-01

    Context In the United States, 192 000 men were diagnosed as having prostate cancer in 2009, the majority with low-risk, clinically localized disease. Treatment of these cancers is associated with substantial morbidity. Active surveillance is an alternative to initial treatment, but long-term outcomes and effect on quality of life have not been well characterized. Objective To examine the quality-of-life benefits and risks of active surveillance compared with initial treatment for men with low-risk, clinically localized prostate cancer. Design and Setting Decision analysis using a simulation model was performed: men were treated at diagnosis with brachytherapy, intensity-modulated radiation therapy (IMRT), or radical prostatectomy or followed up by active surveillance (a strategy of close monitoring of newly diagnosed patients with serial prostate-specific antigen measurements, digital rectal examinations, and biopsies, with treatment at disease progression or patient choice). Probabilities and utilities were derived from previous studies and literature review. In the base case, the relative risk of prostate cancer–specific death for initial treatment vs active surveillance was assumed to be 0.83. Men incurred short- and long-term adverse effects of treatment. Patients Hypothetical cohorts of 65-year-old men newly diagnosed as having clinically localized, low-risk prostate cancer (prostate-specific antigen level <10 ng/mL, stage ≤T2a disease, and Gleason score ≤6). Main Outcome Measure Quality-adjusted life expectancy (QALE). Results Active surveillance was associated with the greatest QALE (11.07 quality-adjusted life-years [QALYs]), followed by brachytherapy (10.57 QALYs), IMRT (10.51 QALYs), and radical prostatectomy (10.23 QALYs). Active surveillance remained associated with the highest QALE even if the relative risk of prostate cancer–specific death for initial treatment vs active surveillance was as low as 0.6. However, the QALE gains and the optimal

  20. Obesity is associated with risk of progression for low-risk prostate cancers managed expectantly.

    PubMed

    Bhindi, Bimal; Kulkarni, Girish S; Finelli, Antonio; Alibhai, Shabbir M H; Hamilton, Robert J; Toi, Ants; van der Kwast, Theodorus H; Evans, Andrew; Hersey, Karen; Jewett, Michael A S; Zlotta, Alexandre R; Trachtenberg, John; Fleshner, Neil E

    2014-11-01

    Active surveillance (AS) is an expectant management strategy for prostate cancer (PCa). The impact of obesity on progression is not well characterized in this population. To determine if obesity is associated with progression in men on AS for low-risk PCa. Men undergoing AS for low-risk PCa (no Gleason pattern ≥4, three or fewer cores involved or one-third or less of the total number of cores involved, and no core with >50% cancer involvement) were identified at our institution. The outcomes were pathologic progression (defined as no longer meeting low-risk criteria on follow-up biopsy) and therapeutic progression (defined as intent to initiate active treatment). Kaplan-Meier curves and multivariable logistic regression and Cox proportional hazards models were used, with separate models for reclassification at confirmatory biopsy (first biopsy after diagnostic biopsy) and progression beyond confirmatory biopsy. In this cohort of 565 men (median follow-up: 48 mo), 124 (22%) were obese (body mass index [BMI] ≥30kg/m(2)). Pathologic and therapeutic progression occurred in 168 men (30%) and 172 men (30%), respectively. No association was noted between obesity and risk of progression at the confirmatory biopsy. However, beyond confirmatory biopsy, obesity was associated with a greater probability of pathologic progression (p=0.007) and therapeutic progression (p=0.007) in Kaplan-Meier analyses. In adjusted Cox models, each 5-unit increase in BMI was associated with an increased risk of pathologic progression (hazard ratio [HR]: 1.5; 95% confidence interval [CI], 1.1-2.1; p=0.02) and therapeutic progression (HR: 1.4; 95% CI, 1.0-1.9; p=0.05). The main limitation is the retrospective design, limiting the ability to assess BMI changes over time. Obesity was associated with a significantly increased risk of progression beyond the confirmatory biopsy. This suggests an increased risk of long-term biologic progression rather than solely misclassification. As opposed to

  1. Behavioral factors explaining the low risk for cervical carcinoma in Utah Mormon women.

    PubMed

    Gardner, J W; Sanborn, J S; Slattery, M L

    1995-03-01

    We used data from a population-based case-control study conducted in Utah from 1984 to 1987 to determine whether the low incidence of cervical carcinoma in Mormon women can be explained by adherence to their religious teachings, which proscribe smoking and extramarital sexual relations. Mormon women had substantially lower risk for cervical carcinoma than non-Mormons [odds ratio (OR) = 0.39; 95% confidence interval (CI) = 0.28-0.54]; this low risk was confined to those who attended church frequently. The protective effect disappeared after controlling for differences in age, sexual behavior, and smoking (OR = 1.22; 95% CI = 0.80-1.87).

  2. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

    PubMed

    Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd; Vijai, Joseph; Korn, Joshua M; Guiducci, Candace; Segrè, Ayellet V; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; GEMO Study Collaborators; Hogervorst, Frans B L; Rookus, Matti A; Collée, J Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E P; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V; Caldés, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T; Barkardottir, Rosa B; Devilee, Peter; Olopade, Olofunmilayo I; Neuhausen, Susan L; Wang, Xianshu; Fredericksen, Zachary S; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Tim; Spurdle, Amanda B; Chen, Xiaoqing; Holland, Helene; John, Esther M; Hopper, John L; Buys, Saundra S; Daly, Mary B; Southey, Melissa C; Terry, Mary Beth; Tung, Nadine; Overeem Hansen, Thomas V; Nielsen, Finn C; Greene, Mark H; Greene, Mark I; Mai, Phuong L; Osorio, Ana; Durán, Mercedes; Andres, Raquel; Benítez, Javier; Weitzel, Jeffrey N; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K; Schmutzler, Rita K; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J; Couch, Fergus J; Chenevix-Trench, Georgia; Easton, Douglas F; Daly, Mark J; Antoniou, Antonis C; Altshuler, David M; Offit, Kenneth

    2010-10-28

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

  3. Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

    PubMed Central

    Guiducci, Candace; Segrè, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; GEMO Study Collaborators; Hogervorst, Frans B. L.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldés, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E.; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Tim; Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary Beth; Tung, Nadine; Overeem Hansen, Thomas V.; Nielsen, Finn C.; Greene, Mark I.; Mai, Phuong L.; Osorio, Ana; Durán, Mercedes; Andres, Raquel; Benítez, Javier; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J.; Couch, Fergus J.; Chenevix-Trench, Georgia; Easton, Douglas F.; Daly, Mark J.; Antoniou, Antonis C.; Altshuler, David M.; Offit, Kenneth

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. PMID:21060860

  4. Factors Associated With Mortality in Low-Risk Pediatric Critical Care Patients in The Netherlands.

    PubMed

    Verlaat, Carin W; Visser, Idse H; Wubben, Nina; Hazelzet, Jan A; Lemson, Joris; van Waardenburg, Dick; van der Heide, Douwe; van Dam, Nicolette A; Jansen, Nicolaas J; van Heerde, Mark; van der Starre, Cynthia; van Asperen, Roelie; Kneyber, Martin; van Woensel, Job B; van den Boogaard, Mark; van der Hoeven, Johannes

    2017-04-01

    To determine differences between survivors and nonsurvivors and factors associated with mortality in pediatric intensive care patients with low risk of mortality. Retrospective cohort study. Patients were selected from a national database including all admissions to the PICUs in The Netherlands between 2006 and 2012. Patients less than 18 years old admitted to the PICU with a predicted mortality risk lower than 1% according to either the recalibrated Pediatric Risk of Mortality or the Pediatric Index of Mortality 2 were included. None. In total, 16,874 low-risk admissions were included of which 86 patients (0.5%) died. Nonsurvivors had more unplanned admissions (74.4% vs 38.5%; p < 0.001), had more complex chronic conditions (76.7% vs 58.8%; p = 0.001), were more often mechanically ventilated (88.1% vs 34.9%; p < 0.001), and had a longer length of stay (median, 11 [interquartile range, 5-32] d vs median, 3 [interquartile range, 2-5] d; p < 0.001) when compared with survivors. Factors significantly associated with mortality were complex chronic conditions (odds ratio, 3.29; 95% CI, 1.97-5.50), unplanned admissions (odds ratio, 5.78; 95% CI, 3.40-9.81), and admissions in spring/summer (odds ratio, 1.67; 95% CI, 1.08-2.58). Nonsurvivors in the PICU with a low predicted mortality risk have recognizable risk factors including complex chronic condition and unplanned admissions.

  5. Accuracy of ultrasound elastography in the diagnosis of thyroid cancer in a low-risk population.

    PubMed

    Vidal-Casariego, A; López-González, L; Jiménez-Pérez, A; Ballesteros-Pomar, M D; Kyriakos, G; Urioste-Fondo, A; Álvarez-San Martín, R; Cano-Rodríguez, I; Jiménez-García de la Marina, J M

    2012-11-01

    Stiffness has been associated to malignancy in prostate and breast, as well as thyroid. Ultrasound elastography objectively measures tissue elasticity, and previous studies have described it as a high sensitivity and specificity technique for the detection of malignant thyroid nodules in high-risk populations. The aim was to assess the accuracy of elastography in a population with low risk of malignancy. 128 consecutive patients with nodular goiter were recruited. Elastography and ultrasound-guided fine-needle aspiration were performed. When malignancy was suspected by citology, surgery was recommended. Thyroid nodules were classified by elastography according the criteria described by Ueno, and an alternative classification. Sensitivity, specificity, predictive values, and odds ratio were calculated. Most patients were female, aged 56.1 year, with single nodule (52.0%) or multinodular goiter (45.6%), and a few thyroiditis (2.4%). The majority of nodules were mostly elastic. Fine-needle aspiration found 86% of benign nodules, 9.3% of indeterminate, and 4.7% possibly malignant. After surgery, 3 malignant nodules were confirmed, all of them being papillary carcinomas. All the malignant nodules were mostly elastic, as well as 75% of indeterminate nodules. Low values of sensitivity and specificity were found for elastic nodules being benign and hard nodules malignant. In a low-risk population for thyroid cancer, elastography lacks accuracy for the diagnosis of malignant nodules. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  6. Free plasma metanephrines as a screening test for pheochromocytoma in low-risk patients.

    PubMed

    Václavík, Jan; Stejskal, David; Lacnák, Borek; Lazárová, Marie; Jedelský, Libor; Kadalová, Lenka; Janosová, Marie; Frysák, Zdenek; Vlcek, Petr

    2007-07-01

    Detection of free plasma metanephrines seems to be the most exact method for biochemical diagnosis of pheochromocytoma, but their diagnostic efficacy in the common low-risk clinical settings is debated. A cross-sectional multicentre study including 1260 subjects assessed the diagnostic efficacy of free plasma metanephrine and normetanephrine in low-risk patients screened for resistant or markedly accelerated hypertension, paroxysmal hypertension, 'flushes' and, in a small proportion, for adrenal incidentaloma or genetic predisposition to pheochromocytoma. Pheochromocytoma was identified and verified by histology in 25 subjects (2%), with the diagnosis not confirmed by long-term follow-up or use of imaging techniques in the remaining 1235 individuals. The combined assay of free plasma metanephrines was a highly sensitive (100%) and specific (96.7%) measure, yielding a negative predictive value of 100%. The satisfactory diagnostic efficacy of free plasma metanephrines allows their use as a single screening test in cases of suspected pheochromocytoma in the population with a low pretest probability.

  7. Vaginal flora alterations and clinical symptoms in low-risk pregnant women.

    PubMed

    Gondo, Fausto; da Silva, Márcia G; Polettini, Jossimara; Tristao, Andréa da R; Peracoli, José C; Witkin, Steven S; Rudge, Marilza V C

    2011-01-01

    To evaluate associations between alterations in vaginal flora and clinical symptoms in low-risk pregnant women. Vaginal specimens from 245 pregnant women were analyzed by microscopy for vaginal flora. Signs and symptoms of vaginal infection were determined by patient interviews and gynecologic examinations. Abnormal vaginal flora was identified in 45.7% of the subjects. The final clinical diagnoses were bacterial vaginosis (21.6%), vaginal candidosis (10.2%), intermediate vaginal flora (5.2%), aerobic vaginitis (2.9%), mixed flora (2.9%) and other abnormal findings (2.9%). The percentage of women with or without clinical signs or symptoms was not significantly different between these categories. The presence of vaginal odor or vaginal discharge characteristics was not diagnostic of any specific flora alteration; pruritus was highly associated with candidosis (p < 0.0001). Compared to women with normal flora, pruritus was more prevalent in women with candidosis (p < 0.0001), while vaginal odor was associated with bacterial vaginosis (p = 0.0026). The prevalence of atypical vaginal flora is common in our low-risk pregnant population and is not always associated with pathology. The occurrence of specific signs or symptoms does not always discriminate between women with different types of atypical vaginal flora or between those with abnormal and normal vaginal flora. Copyright © 2010 S. Karger AG, Basel.

  8. Surgical Management of Periocular Cancers: High- and Low-Risk Features Drive Treatment.

    PubMed

    Allen, Richard C

    2017-09-01

    Recent advances in the treatment of eyelid tumors have centered on the excision, evaluation of margins, role of sentinel lymph node biopsy, and adjunctive/adjuvant systemic and radiation therapy. The purpose of this review is to elaborate on these advances. Mohs excision of basal cell carcinoma and squamous cell carcinoma continues to provide the greatest success in complete excision of the cancer, especially in those cases of high-risk disease including medial canthal location and recurrent disease. Sentinel lymph node biopsy has proven useful in the assessment of early regional metastasis in sebaceous cell carcinoma, melanoma, and Merkel cell carcinoma. The pathologic finding of perineural invasion is a high-risk feature in all periocular cancers, and adjuvant therapy should be considered. Targeted therapy shows great potential in situations that are not amenable to complete excision without sacrificing the globe. Identification of high- and low-risk features in eyelid cancers allows a stratified approach to treatment. While high-risk features may require adjuvant therapy, larger margins, and sentinel lymph node biopsy, low-risk features may allow topical therapy to adequately address the condition. Monoclonal antibodies and small molecule inhibitors show great promise in the treatment of extensive disease.

  9. Subpubic Arch Angle and Mode of Delivery in Low-Risk Nulliparous Women.

    PubMed

    Youssef, Aly; Ghi, Tullio; Martelli, Federica; Montaguti, Elisa; Salsi, Ginevra; Bellussi, Federica; Pilu, Gianluigi; Rizzo, Nicola

    2016-01-01

    To assess whether subpubic arch angle (SPA) measurement before labor onset can predict labor outcome among low-risk pregnant women. 3D ultrasound volume was transperineally acquired from a series of nulliparous women with uncomplicated pregnancy at term before the onset of labor. SPA was measured offline using Oblique View Extended Imaging (OVIX) on each volume performed by an investigator not involved in the clinical management. Labor outcome was prospectively investigated in the whole study group. Overall, 145 women were enrolled in the study. Of these, 83 underwent spontaneous vaginal delivery, whereas obstetric intervention was performed in 62 cases (Cesarean section in 40 and vacuum extraction in 22). The SPA appeared to be significantly narrower in the women submitted to obstetric intervention compared with those undergoing spontaneous vaginal delivery (116.8 ± 10.3° vs. 123.7 ± 9.6°, p < 0.01). At multivariate analysis SPA and maternal age were identified as independent predictors of the mode of delivery. On the other hand, the duration of labor did not show a significant relationship with SPA. In low-risk nulliparous women at term gestation, SPA measurement obtained by 3D ultrasound before the onset of labor seems to predict the likelihood of an obstetric intervention but not the duration of labor. © 2015 S. Karger AG, Basel.

  10. Second trimester fetal nasal bone length in a low-risk Turkish population.

    PubMed

    Yanik, Filiz Fatma; Eroglu, Derya; Baser, Eralp; Dursun, Polat; Karakaya, Burcu Kisa

    2011-10-01

    To define normal values of second trimester fetal nasal bone length (NBL) in a low-risk Turkish population. Prenatal records of singleton fetuses who underwent second trimester ultrasonographic examination in the 16 to 23 weeks of pregnancy were retrospectively analyzed for NBL and biometric measurements (BPD, FL and HL). The relationship among NBL and gestational age (GA), biparietal diameter (BPD), femur length (FL) and humerus length (HL) was determined. Additionally, percentile values of NBL for each gestational week were provided. A total of 1467 fetuses were included in this study. There was a significant linear association among NBL and GA (R(2) = 0.709), BPD (R(2) = 0.752), FL (R(2) = 0.742) and HL (R(2) = 0.747). Fifth percentile values of fetal NBL were 3.11 mm for 16th, 3.50 mm for 17th, 3.70 mm for 18th, 4.10 mm for 19th, 4.50 mm for 20th, 4.62 mm for 21st, 5.24 mm for 22nd and 5.37 mm for 23rd gestational weeks. The study provides normal ranges of NBL between 16 and 23 weeks of pregnancy in a low-risk Turkish population. Future studies with larger sample sizes including pregnancies carrying high risk for aneuploidy are needed to define cut-off values for NBL. Copyright © 2011 John Wiley & Sons, Ltd.

  11. Wide Variation Found In Hospital Facility Costs For Maternity Stays Involving Low-Risk Childbirth.

    PubMed

    Xu, Xiao; Gariepy, Aileen; Lundsberg, Lisbet S; Sheth, Sangini S; Pettker, Christian M; Krumholz, Harlan M; Illuzzi, Jessica L

    2015-07-01

    Childbirth is the leading cause of hospital admission in the United States, yet there has been little research on variation in hospital costs associated with childbirth. Using data from the 2011 Nationwide Inpatient Sample, we characterized the variation in estimated facility costs of hospitalizations for low-risk childbirth across US hospitals. We found that the average estimated facility cost per maternity stay ranged from $1,189 to $11,986 (median: $4,215), with a 2.2-fold difference between the 10th and 90th percentiles. Estimated facility costs were higher at hospitals with higher rates of cesarean delivery or serious maternal morbidity. Hospitals having government or nonprofit ownership; being a rural hospital; and having relatively low volumes of childbirths, low proportions of childbirths covered by Medicaid, and long stays also had significantly higher costs. The large variation in estimated facility cost for low-risk childbirths among hospitals suggests that hospital practices might be an important contributor to variation in cost and that there may be opportunities for cost reduction. The safe reduction of cesarean deliveries, increasing the coordination of care, and emphasizing value of care through new payment and delivery systems reforms may help reduce hospital costs and cost variation associated with childbirth in the United States. Project HOPE—The People-to-People Health Foundation, Inc.

  12. Patient selection for TAVI 2015 - TAVI in low-risk patients: fact or fiction?

    PubMed

    Haussig, Stephan; Linke, Axel

    2015-09-01

    For decades, surgical aortic valve replacement (SAVR) has been the standard treatment for severe aortic stenosis (AS). With the clinical introduction of the concept of transcatheter aortic valve implantation (TAVI), a rapid development took place and, based on the results of landmark randomised controlled trials, within a few years TAVI became first-line therapy for inoperable patients with severe AS and an alternative to SAVR in operable high-risk patients. Indeed, data from a recent randomised controlled trial suggest that TAVI is superior to SAVR in higher-risk patients with AS. New TAVI devices have been developed to address current limitations, to optimise results further and to minimise complications. First results using these second-generation valves are promising. However, no data from randomised controlled trials assessing TAVI in younger, low-risk patients are yet available. While we await the results of trials addressing these issues (e.g., SURTAVI [NCT01586910] and PARTNER II [NCT01314313]), recent data from TAVI registries suggest that treatment of low-risk patients is already fact and no longer fiction.

  13. Induction of labor compared to expectant management in low-risk women and associated perinatal outcomes.

    PubMed

    Cheng, Yvonne W; Kaimal, Anjali J; Snowden, Jonathan M; Nicholson, James M; Caughey, Aaron B

    2012-12-01

    We sought to examine the association of labor induction and perinatal outcomes. This was a retrospective cohort study of low-risk nulliparous women with term, live births. Women who had induction at a given gestational age (eg, 39 weeks) were compared to delivery at a later gestation (eg, 40, 41, or 42 weeks). Compared to delivery at a later gestational age, those induced at 39 weeks had a lower risk of cesarean (adjusted odds ratio [aOR], 0.90; 95% confidence interval [CI], 0.88-0.91) and labor dystocia (aOR, 0.88; 95% CI, 0.84-0.94). Their neonates had lowered risk of having 5-minute Apgar <7 (aOR, 0.81; 95% CI, 0.72-0.92), meconium aspiration syndrome (aOR, 0.30; 95% CI, 0.19-0.48), and admission to neonatal intensive care unit (aOR, 0.87; 95% CI, 0.78-0.97). Similar findings were seen for women who were induced at 40 weeks compared to delivery later. Induction of labor in low-risk women at term is not associated with increased risk of cesarean delivery compared to delivery later. Copyright © 2012 Mosby, Inc. All rights reserved.

  14. Fetal Hemodynamic Parameters in Low Risk Pregnancies: Doppler Velocimetry of Uterine, Umbilical, and Middle Cerebral Artery

    PubMed Central

    Dertkigil, M. S.; Pereira, S. L.; Bennini, J. R.; Mayrink, J.

    2016-01-01

    Objective. To elaborate curves of longitudinal reference intervals of pulsatility index (PI) and systolic velocity (SV) for uterine (UtA), umbilical (UA), and middle cerebral arteries (MCA), in low risk pregnancies. Methods. Doppler velocimetric measurements of PI and SV from 63 low risk pregnant women between 16 and 41 weeks of gestational age. Means (±SD) for intervals of gestational age and percentiles 5, 50, and 95 were calculated for each parameter. The Intraclass Correlation Coefficients (ICC) were also estimated for assessing intra- and intervariability of measurements. Results. Mean PI of UtA showed decreasing values during pregnancy, but no regular pattern was identified for mean SV. For UA, PI decreased and SV increased along gestation. MCA presented PI increasing values until 32–35 weeks. SV showed higher levels with increasing gestation. High ICC values indicated good reproducibility. Conclusions. Reference intervals for the assessment of SV and PI of UtA, UA, and MCA were established. These reference intervals showed how a normal pregnancy is expected to progress regarding these Doppler velocimetric parameters and are useful to follow high risk pregnancies. The comparison between results using different curves may provide insights about the best patterns to be used. PMID:27957524

  15. Mucopolysaccharidosis: A New Variant?

    ERIC Educational Resources Information Center

    Primrose, D. A.

    1972-01-01

    Described is a possibly new variant of mucopolysaccharidosis characterized by progressive mental and motor deficiency, bone abnormalities, a generalized skin lesion, and abnormal mucopolysaccharides in the urine as seen in a 20-year-old female. (DB)

  16. Cost-effectiveness of Telemetry for Hospitalized Patients With Low-risk Chest Pain

    PubMed Central

    Ward, Michael J.; Eckman, Mark H.; Schauer, Daniel P.; Raja, Ali S.; Collins, Sean

    2015-01-01

    Background The majority of chest pain admissions originate in the emergency department (ED). Despite a low incidence of cardiac events, limited telemetry availability, and its questionable benefit, these patients are routinely admitted to a monitored setting. Objectives The objectives were to analyze the cost-effectiveness of admission to telemetry versus admission to an unmonitored hospital bed in low-risk chest pain patients and explore when the use of telemetry may be cost-effective. Methods The authors constructed a decision analytic model to evaluate the scenario of an ED admission of an otherwise healthy 55-year-old patient with low-risk chest pain defined as an acute coronary syndrome (ACS) probability of 2%. Costs were estimated from 2009 Medicare data for hospital reimbursement and physician services, as well as published data on disability costs. Published studies were used to estimate the risk of ACS, cardiac arrest, time to defibrillation, survival, long-term disability, and quality of life. Results In the base case, telemetry was more effective (0.0044 quality-adjusted life-years [QALYs]) but more costly ($299.67) than a floor bed, resulting in a high marginal cost-effectiveness ratio (mCER) of $67,484.55 per QALY. In comprehensive sensitivity analyses, the mCER crossed below the willingness-to-pay (WTP) threshold of $50,000 per QALY when the following scenarios were met: the probability of ACS exceeds 3%, the probability of cardiac arrest is greater than 0.4%, the probability of shockable dysrhythmia is above 83%, the probability of delay in telemetry bed availability is below 52%, and the opportunity cost of delay to telemetry bed placement is below $119. Conclusions Telemetry may be a “cost-effective” use of health care resources for chest pain patients when patients have a probability of ACS above 3% or for patients with a minimal delay and cost associated with obtaining a monitored bed. Further research is needed to better stratify low-risk

  17. Public preferences on written informed consent for low-risk pragmatic clinical trials in Spain.

    PubMed

    Dal-Ré, Rafael; Carcas, Antonio J; Carné, Xavier; Wendler, David

    2017-09-01

    Pragmatic randomized clinical trials (pRCTs) collect data that have the potential to improve medical care significantly. However, these trials may be undermined by the requirement to obtain written informed consent, which can decrease accrual and increase selection bias. Recent data suggest that the majority of the US public endorses written consent for low-risk pRCTs. The present study was designed to assess whether this view is specific to the US. The study took the form of a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent vs. verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing two drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. The primary outcome measures were respondents' personal preference and hypothetical recommendation to a research ethics committee regarding the use of written informed consent vs. the alternatives. A total of 2008 adults sampled from a probability-based online panel responded to the web-based survey conducted in May 2016 (response rate: 61%). Overall, 77% of respondents endorsed written consent. In both scenarios, the alternative of general notification received significantly more support (28.7-37.1%) than the alternative of verbal consent (12.7-14.0%) (P = 0.001). Forty per cent of respondents preferred and/or recommended general notification rather than written consent. The results suggested that, rather than attempting to waive written consent, current pRCTs should focus on developing ways to implement written consent that provide sufficient information without undermining recruitment or increasing selection bias. The finding that around 40% of respondents endorsed general notification over written consent raises the possibility that, with educational efforts, the majority of Spaniards might accept general notification for low-risk pRCTs. © 2017 The

  18. Electrocardiograms in Low-Risk Patients Undergoing an Annual Health Examination.

    PubMed

    Bhatia, R Sacha; Bouck, Zachary; Ivers, Noah M; Mecredy, Graham; Singh, Jasjit; Pendrith, Ciara; Ko, Dennis T; Martin, Danielle; Wijeysundera, Harindra C; Tu, Jack V; Wilson, Lynn; Wintemute, Kimberly; Dorian, Paul; Tepper, Joshua; Austin, Peter C; Glazier, Richard H; Levinson, Wendy

    2017-09-01

    Clinical guidelines advise against routine electrocardiograms (ECG) in low-risk, asymptomatic patients, but the frequency and impact of such ECGs are unknown. To assess the frequency of ECGs following an annual health examination (AHE) with a primary care physician among patients with no known cardiac conditions or risk factors, to explore factors predictive of receiving an ECG in this clinical scenario, and to compare downstream cardiac testing and clinical outcomes in low-risk patients who did and did not receive an ECG after their AHE. A population-based retrospective cohort study using administrative health care databases from Ontario, Canada, between 2010/2011 and 2014/2015 to identify low-risk primary care patients and to assess the subsequent outcomes of interest in this time frame. All patients 18 years or older who had no prior cardiac medical history or risk factors who received an AHE. Receipt of an ECG within 30 days of an AHE. Primary outcome was receipt of downstream cardiac testing or consultation with a cardiologist. Secondary outcomes were death, hospitalization, and revascularization at 12 months. A total of 3 629 859 adult patients had at least 1 AHE between fiscal years 2010/2011 and 2014/2015. Of these patients, 21.5% had an ECG within 30 days after an AHE. The proportion of patients receiving an ECG after an AHE varied from 1.8% to 76.1% among 679 primary care practices (coefficient of quartile dispersion [CQD], 0.50) and from 1.1% to 94.9% among 8036 primary care physicians (CQD, 0.54). Patients who had an ECG were significantly more likely to receive additional cardiac tests, visits, or procedures than those who did not (odds ratio [OR], 5.14; 95% CI, 5.07-5.21; P < .001). The rates of death (0.19% vs 0.16%), cardiac-related hospitalizations (0.46% vs 0.12%), and coronary revascularizations (0.20% vs 0.04%) were low in both the ECG and non-ECG cohorts. Despite recommendations to the contrary, ECG testing after an AHE is relatively

  19. Preferred place of birth: characteristics and motives of low-risk nulliparous women in the Netherlands.

    PubMed

    van Haaren-Ten Haken, Tamar; Hendrix, Marijke; Nieuwenhuijze, Marianne; Budé, Luc; de Vries, Raymond; Nijhuis, Jan

    2012-10-01

    to explores preferences, characteristics and motives regarding place of birth of low-risk nulliparous women in the Netherlands. a prospective cohort study of low-risk nulliparous women and their partners starting their pregnancy in midwifery-led care or in obstetric-led care. Data were collected using a self-administered questionnaire, including questions on demographic, psychosocial and pregnancy factors and statements about motives with regard to place of birth. Depression, worry and self-esteem were explored using the Edinburgh Depression Scale (EDS), the Cambridge Worry Scale (CWS) and the Rosenberg Self Esteem Scale (RSE). participants were recruited in 100 independent midwifery practices and 14 hospitals from 2007 to 2011. 550 low-risk nulliparous women; 231 women preferred a home birth, 170 women a hospital birth in midwifery-led care and 149 women a birth in obstetric-led care. Significant differences in characteristics were found in the group who preferred a birth in obstetric-led care compared to the two groups who preferred midwifery-led care. Those women were older (F (2,551)=16.14, p<0.001), had a higher family income (χ(2) (6)=18.87, p=0.004), were more frequently pregnant after assisted reproduction (χ(2)(2)=35.90, p<0.001) and had a higher rate of previous miscarriage (χ(2)(2)=25.96, p<0.001). They also differed significantly on a few emotional aspects: more women in obstetric-led care had symptoms of a major depressive disorder (χ(2)(2)=6.54, p=0.038) and were worried about health issues (F (2,410)=8.90, p<0.001). Women's choice for a home birth is driven by a desire for greater personal autonomy, whereas women's choice for a hospital birth is driven by a desire to feel safe and control risks. the characteristics of women who prefer a hospital birth are different than the characteristics of women who prefer a home birth. It appears that for women preferring a hospital birth, the assumed safety of the hospital is more important than type of care

  20. Radioiodine remnant ablation in low-risk differentiated thyroid cancer: the "con" point of view.

    PubMed

    Lamartina, Livia; Cooper, David S

    2015-09-01

    A growing body of evidence is challenging the indiscriminate use of postoperative radioiodine for remnant ablation (RRA) in low-risk (LR) differentiated thyroid cancer patients. We critically reviewed the current evidence on which the rationale for RRA is based for LR patients and analyzed the new evidence-based recommendations for LR patients from the draft of the 2015 American Thyroid Association (ATA) guidelines. Cost-effective tools for staging and follow-up, such as neck ultrasonography and serial thyroglobulin testing, are useful for monitoring non-RRA-treated patients. Recurrence rates are very low in non-RRA-treated LR patient cohorts. Most RRA side effects are mild and transient, but can impair a patient's quality of life. RRA is appropriately not routinely recommended in LR patients according to the draft 2015 ATA guidelines and should be reserved for higher-risk patients.

  1. Elective amniocentesis in low-risk pregnancies: decision making in the era of information and uncertainty.

    PubMed Central

    Lesser, Y; Rabinowitz, J

    2001-01-01

    OBJECTIVES: Rational choice theory was applied to explain women's use of amniocentesis. Variables included knowledge about prenatal diagnostics, attitudes, and emotional preferences. METHODS: Using structured instruments at 9 to 14 and at 29 to 34 weeks' gestation, we interviewed 232 Israeli women who had low-risk pregnancies. RESULTS: Women who had elective amniocentesis (n = 39) were more knowledgeable about prenatal diagnostics, risks of invasive procedures, and probability of fetal abnormality in high maternal age; had fewer children; and had less favorable attitudes toward parenthood than those who had medically indicated amniocentesis (n = 57) and those who did not have amniocentesis (n = 136). CONCLUSIONS: The use and possible overuse of amniocentesis were associated with having more information about prenatal diagnostics and definite emotional preferences. PMID:11291381

  2. Elective amniocentesis in low-risk pregnancies: decision making in the era of information and uncertainty.

    PubMed

    Lesser, Y; Rabinowitz, J

    2001-04-01

    Rational choice theory was applied to explain women's use of amniocentesis. Variables included knowledge about prenatal diagnostics, attitudes, and emotional preferences. Using structured instruments at 9 to 14 and at 29 to 34 weeks' gestation, we interviewed 232 Israeli women who had low-risk pregnancies. Women who had elective amniocentesis (n = 39) were more knowledgeable about prenatal diagnostics, risks of invasive procedures, and probability of fetal abnormality in high maternal age; had fewer children; and had less favorable attitudes toward parenthood than those who had medically indicated amniocentesis (n = 57) and those who did not have amniocentesis (n = 136). The use and possible overuse of amniocentesis were associated with having more information about prenatal diagnostics and definite emotional preferences.

  3. [Draft of the best medical treatment in patients with low-risk thyroid cancer].

    PubMed

    Vlček, Petr; Nováková, Dagmar; Vejvalka, Jan; Zimák, Jaroslav; Křenek, Martin; Vošmiková, Květuše; Smutný, Svatopluk; Bavor, Petr; Astl, Jaromír; Lukáš, Jindřich

    2015-09-01

    The incidence of well-differentiated low-risk thyroid cancer have increased globally over the last three decades. Thyroid cancer treatment relates to a suitable surgical procedure and the use of adjuvant radio-iodine therapy in selected patients. Evaluation of prognostic factors and risk stratification are critical for determining appropriate treatment. Survival of patients with low-risk thyroid cancer is excellent. Appropriate choice of medical treatment resulted in full recovery in most patients. Relapse risk increases with the size of the primary tumor, along with the findings of the risk factors in men. Our study included a total of 1 980 patients in whom were diagnosed T1a and T1b tumors between the years 2003 to 2012. The population included 1 675 women (84.6 %) of average age of 45.22 years and 305 men (15.4 %) of average age of 50.0 years. The bulk of the file represented papillary carcinomas (1 868; 94.4 %), and smaller group of follicular carcinomas (112; 5.6 %). Patients were divided into four groups according to tumor size. Patients were evaluated according to risk factors: unifocality no other risk factors, multifocality - more bearings in thyroid tumor, metastases in regional lymph nodes, distant metastases or combination of risk factors. Group A: In the monitored set of 678 patients with papillary and follicular microcarcinoma up to 5 mm, during histological input, the findings revealed one bearing (unifocal type of cancer) in 566 patients. Multifocality was found in 112 patients, local nodal metastasis were demonstrated in 24 cases and pulmonary metastasis was discove-red in 1 case. Group B: In this group there were 576 study patients with papillary and follicular microcarcinoma size of 5-10 mm. Histological findings were captured input one bearing carcinoma in 434 patients, 142 patients with multifocality, in 53 cases of local nodal metastasis, and 1 case of bone metastases. Group C: In this group there were 467 study patients with papillary

  4. Cellular transformation by human papillomaviruses: Lessons learned by comparing high- and low-risk viruses

    PubMed Central

    Klingelhutz, Aloysius J.; Roman, Ann

    2013-01-01

    The oncogenic potential of papillomaviruses (PVs) has been appreciated since the 1930s yet the mechanisms of virally-mediated cellular transformation are still being revealed. Reasons for this include: a) the oncoproteins are multifunctional, b) there is an ever-growing list of cellular interacting proteins, c) more than one cellular protein may bind to a given region of the oncoprotein, and d) there is only limited information on the proteins encoded by the corresponding non-oncogenic PVs. The perspective of this review will be to contrast the activities of the viral E6 and E7 proteins encoded by the oncogenic human PVs (termed high-risk HPVs) to those encoded by their non-oncogenic counterparts (termed low-risk HPVs) in an attempt to sort out viral life cycle-related functions from oncogenic functions. The review will emphasize lessons learned from the cell culture studies of the HPVs causing mucosal/genital tract cancers. PMID:22284986

  5. Patients with traumatic subarachnoid hemorrhage are at low risk for deterioration or neurosurgical intervention.

    PubMed

    Borczuk, Pierre; Penn, Joshua; Peak, David; Chang, Yuchiao

    2013-06-01

    Current standard of care for patients with traumatic intracranial hemorrhage (TIH) includes neurosurgical consultation and/or transfer to a trauma center with neurosurgical backup. We hypothesize that a set of low-risk criteria can be applied to such patients to identify those who may not require neurosurgical evaluation. This is a cross-sectional study of consecutive emergency department patients in 2009 and 2010 with TIH on computerized tomographic scan owing to blunt head trauma. Patients presented to an urban academic Level I trauma center (volume, 92,000) were older than 15 years and had a Glasgow Coma Scale (GCS) score of 13 or greater. Charts were abstracted using a standardized data form by two emergency physicians. Our principal outcome was deterioration represented by a composite of neurosurgical intervention, clinical deterioration, or worsening computerized tomographic scan result. During the study period, 404 patients were seen with TIH and met our inclusion criteria, and 48 of those patients (11.8%) deteriorated. Patients with isolated subarachnoid hemorrhage, were less likely to deteriorate (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.011-0.58). Characteristics associated with deterioration were subdural hematomas (OR, 2.63; 95% CI, 1.198-5.81) or presenting GCS of less than 15 (OR, 2.12; 95% CI, 1.01-4.43).The use of anticoagulant medications or antiplatelet agents were not associated with deterioration for warfarin, aspirin, or clopidogrel; however bleeding diatheses were corrected with vitamin K, fresh frozen plasma, and platelets as necessary. Patients with isolated traumatic subarachnoid hemorrhage are at low risk for deterioration. These individuals may not need neurosurgical consultation or transfer to a trauma center where neurosurgical backup is available. Those patients with subdural hematoma or a GCS of less than 15 have a higher risk of deterioration and require neurosurgical evaluation. Therapeutic/care management, level IV.

  6. Factors influencing men undertaking active surveillance for the management of low-risk prostate cancer.

    PubMed

    Davison, B Joyce; Oliffe, John L; Pickles, Tom; Mroz, Lawrence

    2009-01-01

    To identify and describe decision-making influences on men who decide to manage their low-risk prostate cancer with active surveillance. Qualitative, semistructured interview. The Prostate Centre at Vancouver General Hospital in Canada. 25 patients diagnosed with low-risk prostate cancer and on active surveillance. An interpretative, descriptive, qualitative design. Factors that influenced men's decisions to take up active surveillance. The specialists' description of the prostate cancer was the most influential factor on men choosing active surveillance. Patients did not consider their prostate cancer to be life threatening and, in general, were relieved that no treatment was required. Avoiding treatment-related suffering and physical dysfunction and side effects such as impotence and incontinence was cited as the major reason to delay treatment. Few men actively sought treatment or health-promotion information following their treatment decision. Female partners played a supportive role in the decision. The need for active treatment if the cancer progressed was acknowledged. Patients were hopeful that new treatments would be available when and if they needed them. Being older and having comorbidities did not preclude the desire for future active treatment. Patients carried on with their lives as usual and did not report having any major distress related to being on active surveillance. The study findings indicate that men are strongly influenced by the treating specialist in taking up active surveillance and planning future active treatments. As such, most men relied on their specialists' recommendation and did not perceive the need for any adjunct therapy or support until the cancer required active treatment. Oncology nurses should work collaborative-ly with specialists to ensure that men receive the information they need to make informed treatment decisions.

  7. Lymphovascular space invasion portends poor prognosis in low-risk endometrial cancer

    PubMed Central

    dos Reis, Ricardo; Burzawa, Jennifer K.; Tsunoda, Audrey T.; Hosaka, Masayoshi; Frumovitz, Michael; Westin, Shannon N.; Munsell, Mark F.; Ramirez, Pedro T.

    2015-01-01

    Objective The prognostic significance of lymphovascular space invasion (LVSI) in patients with early-stage endometrial cancer is not established. We sought to determine if LVSI status in patients with early-stage low-risk endometrial cancer correlates with recurrence and survival. Methods The records of all women who underwent hysterectomy for primary treatment of endometrial cancer from January 2006 through January 2011 at one academic institution were reviewed. Patients with grade 1 or 2 endometrioid histology, myometrial invasion less than 50%, and disease confined to the uterus (clinical FIGO stage IA) were analyzed. Fisher’s exact test and the Wilcoxon rank-sum test were applied to compare patients with and without LVSI. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results Two hundred forty patients met the inclusion criteria. Forty (16.7%) had LVSI. Ninety-one patients (37.9%) underwent lymphadenectomy. Median tumor size was 30 mm in patients with and 26 mm in patients without LVSI (p=0.150). Thirty patients (12.5%) received adjuvant therapy. Site of recurrence did not differ between patients with and without LVSI. Patients with LVSI were more likely to have myometrial invasion (p<0.001), postoperative pathologic grade 2 disease (p<0.001), to undergo lymphadenectomy (p=0.049) and receive adjuvant therapy (p<0.001). The 5-year cumulative incidence of recurrence was 3.8% in the no-LVSI group and 14.2% in the LVSI group (p=0.053). The presence of LVSI was significantly associated with worse RFS (p=0.002) and OS (p=0.013). Conclusion Patients with low-risk endometrial cancer and LVSI have worse RFS and OS despite being more likely to undergo lymphadenectomy and adjuvant therapy. PMID:26067863

  8. Factors associated with the prevalence of periodontal disease in low-risk pregnant women.

    PubMed

    Vogt, Marianna; Sallum, Antonio W; Cecatti, José G; Morais, Sirlei S

    2012-01-24

    To evaluate the prevalence of periodontal disease (PD) among Brazilian low-risk pregnant women and its association with sociodemographic factors, habits and oral hygiene. This cross-sectional study included 334 low-risk pregnant women divided in groups with or without PD. Indexes of plaque and gingival bleeding on probing, probing pocket depth, clinical attachment level and gingival recession were evaluated at one periodontal examination below 32 weeks of gestation. Independent variables were: age, race/color, schooling, marital status, parity, gestational age, smoking habit, alcohol and drugs consumption, use of medication, presence of any systemic diseases and BMI (body mass index). Statistical analyses provided prevalence ratios and their respective 95%CI and also a multivariate analysis. The prevalence of PD was 47% and significantly associated with higher gestational age (PR 1.40; 1.01-1.94 for 17-24 weeks and PR 1.52; 1.10-2.08 for 25-32 weeks), maternal age 25-29 years, obesity (PR 1.65; 1.02-2.68) and the presence of gingival bleeding on probing (OR(adj) 2.01, 95%CI 1.41-2.88). Poor oral hygiene was associated with PD by the mean values of plaque and bleeding on probing indexes significantly greater in PD group. The prevalence of PD is high and associated with gingival bleeding on probing, more advanced gestational age and obesity. A program of oral health care should be included in prenatal care for early pregnancy, especially for low-income populations.

  9. Neonatal Outcomes of Low-Risk, Late-Preterm Twins Compared With Late-Preterm Singletons.

    PubMed

    Salem, Shimrit Yaniv; Kibel, Mia; Asztalos, Elizabeth; Zaltz, Arthur; Barrett, Jon; Melamed, Nir

    2017-09-01

    To test the hypothesis that the risk of neonatal morbidity among late-preterm twins is similar to that of late-preterm singletons. We conducted a retrospective cohort study of all women with twin or singleton pregnancy who gave birth during the late-preterm period in a single tertiary center between 2008 and 2015. Neonatal outcomes of low-risk, late-preterm twins were compared with those of low-risk, late-preterm singletons. The primary outcome was the same primary composite respiratory morbidity variable that was used in the randomized controlled trial of Gyamfi-Bannerman et al on the administration of antenatal corticosteroids during the late-preterm period. A total of 922 singleton and 721 twin late-preterm neonates met the inclusion criteria. The rates of composite respiratory morbidity and severe composite respiratory morbidity were similar for twins and singletons (8.3% compared with 7.4%, P=.5 and 6.8% compared with 6.0%, P=.5, respectively), but were lower than the rates of the same composite respiratory morbidity variable in the randomized controlled study described previously. The odds for respiratory morbidity were similar for twins and singletons for both composite respiratory morbidity (adjusted odds ratio [OR] 0.73, 95% CI 0.48-1.12) and severe composite respiratory morbidity (adjusted OR 0.79, 95% CI 0.50-1.24). The risk of respiratory morbidity among late-preterm twins is similar to that of late-preterm singletons. Still, the low absolute rates of the composite respiratory morbidity in our population suggest that administration of antenatal corticosteroids may be mostly justified among neonates born closer to 34 weeks of gestation.

  10. Sickle cell anemia: intracranial stenosis and silent cerebral infarcts in children with low risk of stroke.

    PubMed

    Arkuszewski, Michal; Krejza, Jaroslaw; Chen, Rong; Ichord, Rebecca; Kwiatkowski, Janet L; Bilello, Michel; Zimmerman, Robert; Ohene-Frempong, Kwaku; Melhem, Elias R

    2014-03-01

    Children with sickle cell anemia (SCA), who have mean blood flow velocities <170 cm/s in the terminal internal carotid (tICA) or middle cerebral (MCA) arteries on transcranial Doppler ultrasonography (TCD), are considered to be at low risk of stroke. The prevalence of intracranial stenosis, which raises the risk of stroke, is not known in these children. Here, we estimated the prevalence of stenosis and explored its association with silent cerebral infarcts determined based on Magnetic Resonance (MR) scans. We studied prospectively a cohort of 67 children with SCA without prior clinically overt stroke or TIA (median age 8.8 years; range limits 2.3-13.1 years; 33 females) and with TCD mean velocity <170 cm/s. They underwent MR imaging of the brain and MR angiography of intracranial arteries. In 7 children (10.5%, 95% CI: 4.9-20.3%) we found 10 stenoses, including 4 with isolated left tICA stenosis and 3 with multiple stenoses. We found silent infarcts in 26 children (37.7%, 95% CI: 27.2-49.5%). The median number of infarcts in an affected child was 2 (range limits: 1-9), median volume of infarcts was 171 mm(3) (range limits: 7-1060 mm(3)), and median infarct volume in relation to total brain volume was 0.020% (range limits: 0.001-0.101%). The number and volume of infarcts were significantly higher in children with arterial stenosis (both p=0.023). The prevalence of intracranial arterial stenosis in children with SCA classified as at low risk of stroke by TCD mean velocity <170 cm/s is high. Children with stenosis are at higher risk of brain parenchymal injury as they have more silent cerebral infarcts. Copyright © 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  11. Determinants of prenatal health care utilisation by low-risk women: a prospective cohort study.

    PubMed

    Feijen-de Jong, Esther I; Jansen, Danielle E M C; Baarveld, Frank; Boerleider, Agatha W; Spelten, Evelien; Schellevis, François; Reijneveld, Sijmen A

    2015-06-01

    Prenatal health care is pivotal in providing adequate prevention and care to pregnant women. We examined the determinants of inadequate prenatal health care utilisation by low-risk women in primary midwifery-led care in the Netherlands. We used longitudinal data from the population-based DELIVER study with 20 midwifery practices across the Netherlands in 2009 and 2010 as the experimental setting. The participants were 3070 pregnant women starting pregnancy care in primary midwifery care. We collected patient-reported data on potential determinants of prenatal care utilisation derived from the Andersen model. Prenatal health care utilisation was measured by a revised version of the Kotelchuck Index, which measures a combination of care entry and number of visits. Low-risk pregnant women (not referred during pregnancy) were more likely to use prenatal care inadequately if they intended to deliver at a hospital, if they did not use folic acid adequately periconceptionally, or if they were exposed to cigarette smoke during pregnancy. Among those who were referred to secondary care, women reporting a chronic illnesses or disabilities, and women who did not use folic acid periconceptionally were more likely to make inadequate use of prenatal care. Inadequate prenatal health care use in primary midwifery care is more likely in specific groups, and the risk groups differ when women are referred to secondary care. The findings suggest routes that can target interventions to women who are at risk of not adequately using prenatal prevention and care services. Copyright © 2015 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.

  12. Care management for low-risk patients with heart failure: a randomized, controlled trial.

    PubMed

    DeBusk, Robert Frank; Miller, Nancy Houston; Parker, Kathleen Marie; Bandura, Albert; Kraemer, Helena Chmura; Cher, Daniel Joseph; West, Jeffrey Alan; Fowler, Michael Bruce; Greenwald, George

    2004-10-19

    Nurse care management programs for patients with chronic illness have been shown to be safe and effective. To determine whether a telephone-mediated nurse care management program for heart failure reduced the rate of rehospitalization for heart failure and for all causes over a 1-year period. Randomized, controlled trial of usual care with nurse management versus usual care alone in patients hospitalized for heart failure from May 1998 through October 2001. 5 northern California hospitals in a large health maintenance organization. Of 2786 patients screened, 462 met clinical criteria for heart failure and were randomly assigned (228 to intervention and 234 to usual care). Nurse care management provided structured telephone surveillance and treatment for heart failure and coordination of patients' care with primary care physicians. Time to first rehospitalization for heart failure or for any cause and time to a combined end point of first rehospitalization, emergency department visit, or death. At 1 year, half of the patients had been rehospitalized at least once and 11% had died. Only one third of rehospitalizations were for heart failure. The rate of first rehospitalization for heart failure was similar in both groups (proportional hazard, 0.85 [95% CI, 0.46 to 1.57]). The rate of all-cause rehospitalization was similar (proportional hazard, 0.98 [CI, 0.76 to 1.27]). The findings of this study, conducted in a single health care system, may not be generalizable to other health care systems. The overall effect of the intervention was minor. Among patients with heart failure at low risk on the basis of sociodemographic and medical attributes, nurse care management did not statistically significantly reduce rehospitalizations for heart failure or for any cause. Such programs may be less effective for patients at low risk than those at high risk.

  13. Stress testing in young low-risk patients with potential acute coronary syndromes.

    PubMed

    Hamilton, Baker; Shofer, Frances S; Walsh, Kristy M; Decker, Christopher S; Calderone, Mary; Le, Jeffrey A; Hollander, Judd E

    2012-06-01

    Young patients are at low risk for an acute coronary syndrome (ACS); however, many of these patients still enter a "rule-out ACS" pathway and receive stress testing. We hypothesized that stress testing in patients younger than 40 years without known coronary disease will not identify patients at high risk for 30-day adverse cardiovascular events. We conducted a cohort study of patients younger than 40 years evaluated in the emergency department for potential ACS. Patients were excluded if they used cocaine, had known cardiac disease, or had an abnormal electrocardiogram. Patients were followed up in-house; follow-up was performed by direct telephone contact and medical record review. The main outcome was a composite of death, acute myocardial infarction (AMI), and revascularization at 30 days. Comparisons between patients with and without stress testing were done using χ2 or t test, as appropriate; 95% confidence intervals were reported for the main outcomes. Of 8816 patient visits, 1144 patients met inclusion criteria. Within 30 days, 82 patients (7.2%) received stress testing, 2 of whom led to cardiac catheterization. Death (n=2), AMI (n=3), and revascularization (n=1) were not different between patients who did and did not receive stress testing (2.4% [0.2%-8.5%] vs 0.4% [0.1%-1.0%]). The 30-day cardiovascular complication rate is not different between young patients without known heart disease who do and do not receive stress testing when they present with symptoms of a potential ACS. Testing of young patients at low risk for disease should be reconsidered. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Prospective Validation of Modified NEXUS Cervical Spine Injury Criteria in Low-risk Elderly Fall Patients.

    PubMed

    Tran, John; Jeanmonod, Donald; Agresti, Darin; Hamden, Khalief; Jeanmonod, Rebecca K

    2016-05-01

    The National Emergency X-radiography Utilization Study (NEXUS) criteria are used extensively in emergency departments to rule out C-spine injuries (CSI) in the general population. Although the NEXUS validation set included 2,943 elderly patients, multiple case reports and the Canadian C-Spine Rules question the validity of applying NEXUS to geriatric populations. The objective of this study was to validate a modified NEXUS criteria in a low-risk elderly fall population with two changes: a modified definition for distracting injury and the definition of normal mentation. This is a prospective, observational cohort study of geriatric fall patients who presented to a Level I trauma center and were not triaged to the trauma bay. Providers enrolled non-intoxicated patients at baseline mental status with no lateralizing neurologic deficits. They recorded midline neck tenderness, signs of trauma, and presence of other distracting injury. We enrolled 800 patients. One patient fall event was excluded due to duplicate enrollment, and four were lost to follow up, leaving 795 for analysis. Average age was 83.6 (range 65-101). The numbers in parenthesis after the negative predictive value represent confidence interval. There were 11 (1.4%) cervical spine injuries. One hundred seventeen patients had midline tenderness and seven of these had CSI; 366 patients had signs of trauma to the face/neck, and 10 of these patients had CSI. Using signs of trauma to the head/neck as the only distracting injury and baseline mental status as normal alertness, the modified NEXUS criteria was 100% sensitive (CI [67.9-100]) with a negative predictive value of 100 (98.7-100). Our study suggests that a modified NEXUS criteria can be safely applied to low-risk elderly falls.

  15. Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias

    PubMed Central

    Richette, Pascal; Chevalier, Xavier; Ea, Hang Korng; Eymard, Florent; Henrotin, Yves; Ornetti, Paul; Sellam, Jérémie; Cucherat, Michel; Marty, Marc

    2015-01-01

    Background The effectiveness of intra-articular hyaluronic acid (IAHA) injection for knee osteoarthritis (KOA) is debated. Objectives To evaluate the effect of IAHA for patients with KOA by analysing data from trials of IAHA versus placebo with low risk of bias, to provide the highest level of evidence. Methods A systematic review and meta-analysis was conducted. Randomised controlled trials (RCTs) with a low risk of bias (adequate randomisation and concealment and double-blind design) that investigated IAHA versus placebo (saline solution) injection were eligible. The primary efficacy measure was pain intensity and secondary outcome function at 3 months. The treatment effect was summarised with the standardised mean difference (SMD) calculated from differences in means of pain and function measures between treatment and control groups at 3 months. Trials were pooled by a random-effects model with DerSimonian and Laird weights. Statistical heterogeneity was explored by a visual exploration of forest plots and the I2 statistic. Results A total of eight RCTs (2 199 randomised patients) met our inclusion criteria. IAHA significantly reduced the pain intensity (SMD=−0.21, 95% CI (95% CI) −0.32 to −0.10) and improved function (SMD=−0.12, 95% CI −0.22 to −0.02). Trials showed no heterogeneity. Conclusions This meta-analysis of high-quality trials of IAHA versus placebo shows that IAHA provides a moderate but real benefit for patients with KOA. PMID:26509069

  16. Addition of a biomarker panel to a clinical score to identify patients at low risk for appendicitis.

    PubMed

    Depinet, Holly; Copeland, Karen; Gogain, Joseph; Hennes, Halim; Paradis, Norman A; Andrews-Dickert, Rebecca; Vance, Cheryl W; Huckins, David S

    2016-12-01

    The diagnosis of pediatric acute appendicitis can be difficult. Although scoring systems such as the Pediatric Appendicitis Score (PAS) are helpful, they lack adequate sensitivity and specificity as standalone diagnostics. When used for risk stratification, they often result in large percentages of moderate-risk patients requiring further diagnostic evaluation. We applied a biomarker panel (the APPY1 Test) that has high sensitivity and negative predictive value (NPV) to patients with PAS in the moderate-risk range (3-7) and reclassified those patients with a negative result to the low-risk group. We compared the specificity, sensitivity, and NPV of the original and reclassified low-risk groups at several different PAS low-risk cutoffs. The application of a negative biomarker panel to a group of patients with a moderate risk for appendicitis (PAS, 3-7) resulted in 4 times more patients (586 vs 145) being safely classified as low risk. Reclassification increased the overall specificity or the proportion of patients without appendicitis who were correctly identified as low risk, from 10.3% to 42.0%. The high NPV (97.2%) in the original group was preserved (97.6%) in the reclassified low-risk group, as was the sensitivity (original 99.1% vs reclassified 96.9%). The addition of negative biomarker test results to patients with a moderate risk of appendicitis based on the PAS can safely reclassify many to a low-risk group. This may allow clinicians to provide more conservative management in children with suspected appendicitis and decrease unnecessary resource utilization. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. First-line chemotherapy in low-risk gestational trophoblastic neoplasia

    PubMed Central

    Alazzam, Mo’iad; Tidy, John; Hancock, Barry W; Osborne, Raymond; Lawrie, Theresa A

    2014-01-01

    Background This is an update of a Cochrane review that was first published in Issue 1, 2009. Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear. Objectives To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN. Search methods In September 2008, we electronically searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2008), MEDLINE and EMBASE. In addition, we searched online trial registers, conference proceedings and reference lists of identified studies. We re-ran these searches in February 2012 for this updated review. Selection criteria For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated version of the review, we included only RCTs. Data collection and analysis Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed by pooling the risk ratio (RR) of individual trials. Main results We included five moderate to high quality RCTs (517 women) in the updated review. These studies all compared methotrexate with dactinomycin. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) dactinomycin (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV dactinomycin (75 women) and one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV dactinomycin (49 women). Overall, dactinomycin was associated

  18. Antenatal Care Utilisation and Content between Low-Risk and High-Risk Pregnant Women

    PubMed Central

    Yeoh, Ping Ling; Hornetz, Klaus; Dahlui, Maznah

    2016-01-01

    Background The purpose of antenatal care is to monitor and improve the wellbeing of the mother and foetus. The World Health Organization recommends risk-oriented strategy that includes: (i) routine care to all women, (ii) additional care for women with moderately severe diseases and complications, (iii) specialised obstetrical and neonatal care for women with severe diseases and complications. Antenatal care is concerned with adequate care in order to be effective. Measurement for adequacy of antenatal care often applies indexes that assess initiation of care and number of visits. In addition, adequacy of care content should also be assessed. Results of studies in developed settings demonstrate that women without risk factors use antenatal services more frequently than recommended. Such over-utilisation is problematic for low-resourced settings. Moreover, studies show that a substantial proportion of high-risk women had utilisation or content of care below the recommended standard. Yet studies in developing countries have seldom included a comparison between low-risk and high-risk women. The purpose of the study was therefore to assess adequacy of care and pregnancy outcomes for the different risk groups. Methods A retrospective study using a multistage sampling technique, at public-funded primary health care clinics was conducted. Antenatal utilisation level was assessed using a modified Adequacy of Prenatal Care Utilisation index that measures the timing for initiation of care and observed-to-expected visits ratio. Adequacy of antenatal care content assessed compliance to routine care based on the local guidelines. Results Intensive or “adequate-plus” antenatal care utilisation as defined by the modified index was noted in over half of the low-risk women. On the other hand, there were 26% of the high-risk women without the expected intensive utilisation. Primary- or non-educated high-risk women were less likely to have a higher antenatal care utilisation

  19. Value of transrectal power Doppler sonography in the detection of low-risk prostate cancers.

    PubMed

    Sauvain, J-L; Sauvain, E; Rohmer, P; Louis, D; Nader, N; Papavero, R; Bremon, J-M; Jehl, J

    2013-01-01

    To evaluate the risk of low-risk prostate cancer or prostate cancer that may benefit from surveillance in patients with a PSA level less than 10 ng/ml, a normal digital rectal examination (DRE) and a transrectal power Doppler sonography (PDS) without anomaly. Two hundred and forty-three consecutive patients with a PSA level less than 10 ng/ml and a DRE without anomaly had PDS-guided biopsies: 12 to 15 samples were systematically taken and echo-guided in the suspect areas. The PDS results were rated from 1 to 4: 1: normal, 2: slightly hypoechogenic avascular area in which the hypo-echogenicity disappears after compression by probe, 3: hypoechogenic avascular area, 4: hypoechogenic vascularised area with power Doppler sonography. Patients rated 3 or 4 were considered to be pathological. D'Amico's criteria were used to assess the risk of a biological recurrence after treatment and those of Dall'Era were used to select the patients that could benefit from active surveillance (AS). The PDS was considered to be a true positive if at least one biopsy was positive in the same sextant as the suspect image. In a prospective manner, 106 cancers were diagnosed that could be qualified as low-risk in 84% of the cases (89% with a normal PDS and 79% with an abnormal PDS). Sixty-nine percent of the cases could be subject to AS (86% of the normal PDS cases and 47% of the abnormal PDS cases; P<0.001). The PDS was normal in 159 of the 243 patients (65%). With a normal PDS, there was a 96% probability of not having a high-risk cancer. With an abnormal PDS, at least one biopsy was positive in 57% of the cases and the probability of having a significant cancer was 30% according to the Dall'Era criteria. A significant reduction was noted with a normal PDS, to 36% and 5%, respectively (VPN=95%) (P=0.015). A normal PDS in patients presenting a PSA level less than 10 ng/ml and a DRE without anomaly may be used to put off the indication for a biopsy in order to reduce their number as well as

  20. Corneal arcus is a sign of cardiovascular disease, even in low-risk persons.

    PubMed

    Ang, Marcus; Wong, Wanling; Park, Judy; Wu, Renyi; Lavanya, Raghavan; Zheng, Yingfeng; Cajucom-Uy, Howard; Tai, E Shyong; Wong, Tien Yin

    2011-11-01

    To examine the association of corneal arcus to cardiovascular disease (CVD) in an adult, ethnic Indian population. Population-based cross-sectional study. Population-based study of ethnic South Asian Indians 40 to 80 years of age in Singapore from June 2007 through March 2009. We obtained a 75.5% response rate (3397/4497). All participants underwent standardized interview and systemic and ocular examinations, followed by nonfasting blood sampling. Corneal arcus was detected using a standardized slit-lamp examination. The main outcome measure was CVD, defined from a self-reported history of previous myocardial infarction, angina, or stroke. Corneal arcus, found in 1701 (50.1%) of 3397 participants, was associated with older age (odds ratio [OR], 3.07; 95% CI, 2.78 to 3.40; P < .001), male gender (OR, 2.17; 95% CI, 1.81 to 2.62; P < .001), higher levels of total cholesterol (OR, 1.14; 95% CI, 1.05 to 1.24; P = .002), hypertension (OR, 1.14; 95% CI, 1.05 to 1.24; P = .013), and cigarette smoking (OR, 1.59; 95% CI, 1.25 to 2.03; P < .001). Corneal arcus was associated with CVD (OR, 1.31; 95% CI, 1.02 to 1.7; P = .0038) independent of the above-named cardiovascular risk factors. Participants with low-risk Framingham scores were more likely to be associated with CVD if they had corneal arcus (men: OR, 2.02; 95% CI, 1.20 to 3.40; P = .008; women: OR, 2.78; 95% CI, 1.36 to 3.01; P < .001). Corneal arcus was associated with CVD independent of the Framingham score (men: Akaike information criterion, 1524.39 for Framingham Score and corneal arcus vs 1527.38 for Framingham Score alone; women: 1000.14 vs 1003.54, respectively). Corneal arcus is associated with CVD, independent of risk factors in ethnic Indian adults, even in those at low risk for vascular disease. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Chapter 4: Variant descriptions

    Treesearch

    Duncan C. Lutes; Donald C. E. Robinson

    2003-01-01

    The Fire and Fuels Extension (FFE) to the Forest Vegetation Simulator (FVS) simulates fuel dynamics and potential fire behavior over time, in the context of stand development and management. This report documents differences between geographic variants of the FFE. It is a companion document to the FFE "Model Description" and "User's Guide."...

  2. Obstetric interventions during labor and childbirth in Brazilian low-risk women.

    PubMed

    Carmo Leal, Maria do; Pereira, Ana Paula Esteves; Domingues, Rosa Maria Soares Madeira; Theme Filha, Mariza Miranda; Dias, Marcos Augusto Bastos; Nakamura-Pereira, Marcos; Bastos, Maria Helena; Gama, Silvana Granado Nogueira da

    2014-08-01

    This study evaluated the use of best practices (eating, movement, use of nonpharmacological methods for pain relief and partograph) and obstetric interventions in labor and delivery among low-risk women. Data from the hospital-based survey Birth in Brazil conducted between 2011 and 2012 was used. Best practices during labor occurred in less than 50% of women and prevalence of the use of these practices was lower in the North, Northeast and Central West Regions. The rate of use of oxytocin drips and amniotomy was 40%, and was higher among women admitted to public hospitals and in women with a low level of education. The uterine fundal pressure, episiotomy and lithotomy were used in 37%, 56% and 92% of women, respectively. Caesarean section rates were lower in women using the public health system, nonwhites, women with a low level of education and multiparous women. To improve the health of mothers and newborns and promote quality of life, a change of approach to labor and childbirth that focuses on evidence-based care is required in both the public and private health sectors.

  3. Associations of Anogenital Low-Risk Human Papillomavirus Infection With Cancer and Acquisition of HIV.

    PubMed

    Bennetts, Liga E; Wagner, Monika; Giuliano, Anna R; Palefsky, Joel M; Steben, Marc; Weiss, Thomas W

    2015-10-01

    α-Mucosal human papillomavirus (HPV) types are implicated in a range of clinical conditions and categorized as "low-risk" (LR) and "high-risk" (HR) types according to their degree of association with cervical cancers. The causative role of LR HPV infection in the development of anogenital warts and in low-grade squamous intraepithelial lesions is well established. In addition, there is a growing body of evidence that infection with LR HPV types may be associated with an elevated risk of cancers and potentiation of coinfections. Prospective and case-control studies consistently report a higher risk of anogenital cancers in men and women with a history of anogenital warts. Based on currently available evidence, this higher risk may be due to shared exposure to HR HPV types or an underlying immune impairment, rather than a direct role of LR HPV types in subsequent cancer risk. Data also suggest that infection with LR HPV, HR HPV, or both may increase the risk of HIV acquisition, although the relative contribution of different HPV types is not yet known. There is also evidence implicating HPV clearance, rather than HPV infection, in increased risk of HIV acquisition.

  4. Families at high and low risk for depression: a three-generation startle study.

    PubMed

    Grillon, Christian; Warner, Virginia; Hille, Jeffrey; Merikangas, Kathleen R; Bruder, Gerard E; Tenke, Craig E; Nomura, Yoko; Leite, Paul; Weissman, Myrna M

    2005-05-01

    Anxiety symptoms might be a vulnerability factor for the development of major depressive disorder (MDD). Because elevated startle magnitude in threatening contexts is a marker for anxiety disorder, the present study investigated the hypothesis that enhanced startle reactivity would also be found in children and grandchildren of individuals with MDD. The magnitude of startle was investigated in two tests (anticipation of an unpleasant blast of air and during darkness) in children (second generation) and grandchildren (third generation) of probands with (high risk) or without (low risk) MDD (first generation). Startle discriminated between the low- and high-risk groups. In the probands' children, the high-risk group showed increased startle magnitude throughout the fear-potentiated startle test. In the probands' grandchildren, a gender-specific abnormality was found in the high-risk group with high-risk girls, but not boys, exhibiting elevated startle magnitude throughout the procedure. Increased startle reactivity in threatening contexts, previously found in patients with anxiety disorder and in children of parents with an anxiety disorder, might also constitute a vulnerability marker for MDD. These findings suggest that there might be common biologic diatheses underlying depression and anxiety.

  5. Posture Development in Infants at Heightened vs. Low Risk for Autism Spectrum Disorders

    PubMed Central

    Nickel, Lindsay R.; Thatcher, Alyssa R.; Keller, Flavio; Wozniak, Robert H.; Iverson, Jana M.

    2013-01-01

    Evidence suggests that children and adults diagnosed with autism spectrum disorders (ASD) exhibit difficulties with postural control. Retrospective video studies of infants later diagnosed with ASD indicate that infants who eventually receive an ASD diagnosis exhibit delays in postural development. This study investigates early posture development prospectively and longitudinally in 22 infants at heightened biological risk for ASD (HR) and 18 infants with no such risk (Low Risk; LR). Four HR infants received an autism diagnosis (AD infants) at 36 months. Infants were videotaped at home at 6, 9, 12, and 14 months during everyday activities and play. All infant postures were coded and classified as to whether or not they were infant-initiated. Relative to LR infants, HR infants were slower to develop skill in sitting and standing postures. AD infants exhibited substantial delays in the emergence of more advanced postures and initiated fewer posture changes. Because posture advances create opportunities for infants to interact with objects and people in new and progressively more sophisticated ways, postural delays may have cascading effects on opportunities for infant exploration and learning. These effects may be greater for infants with ASD, for whom posture delays are more significant. PMID:24027437

  6. Potential Utility of Novel Biomarkers in Active Surveillance of Low-Risk Prostate Cancer

    PubMed Central

    Kim, Jeong Hyun; Hong, Sung Kyu

    2015-01-01

    Active surveillance (AS) is now an accepted management strategy for men with low-risk localized prostate cancer (PCa). However, detecting disease progression in a patient selected for AS remains a challenge. It is crucial to know what will serve as the best parameter to correctly identify tumors that progress to a more aggressive phenotype so as not to miss the window of curability. Several biomarkers are now being actively investigated as novel tools to improve PCa risk assessments. To date, several serum, urinary, and tissue biomarkers have shown promising prognostic value. %[−2]proPSA and PHI showed improved predictive value for an unfavorable biopsy conversion at annual surveillance biopsy in the AS program. PCA3 and TMPRSS2:ERG had additional independent predictive value for the prediction of PCa detection and progression, although PCA3 was limited in predicting aggressive cancer. Other tissue biomarkers also showed promising ability to predict disease progression. Although several of these novel biomarkers have an improved predictive accuracy that is better than classical parameters, there is still a need for further well-designed, large, multicenter, prospective trials to avoid common bias and clinical validation. PMID:26339615

  7. Periodontal disease and some adverse perinatal outcomes in a cohort of low risk pregnant women

    PubMed Central

    2010-01-01

    Objective To evaluate the association of periodontal disease (PD) in pregnancy with some adverse perinatal outcomes. Method This cohort study included 327 pregnant women divided in groups with or without PD. Indexes of plaque and gingival bleeding on probing, probing pocket depth, clinical attachment level and gingival recession were evaluated at one periodontal examination below 32 weeks of gestation. The rates of preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) neonates and prelabor rupture of membranes (PROM) were evaluated using Risk Ratios (95%CI) and Population Attributable Risk Fractions. Results PD was associated with a higher risk of PTB (RRadj. 3.47 95%CI 1.62-7.43), LBW (RRadj. 2.93 95%CI 1.36-6.34) and PROM (RRadj. 2.48 95%CI 1.35-4.56), but not with SGA neonates (RR 2.38 95%CI 0.93 - 6.10). Conclusions PD was a risk factor for PT, LBW and PROM among Brazilian low risk pregnant women. PMID:21047427

  8. Strategies for obstacle crossing in older adults with high and low risk of falling.

    PubMed

    Pan, Hui-Fen; Hsu, Horng-Chaung; Chang, Wei-Ning; Renn, Jenn-Huei; Wu, Hong-Wen

    2016-05-01

    [Purpose] Tripping is a frequent cause of falls among aging adults. Appropriate limb movements while negotiating obstacles are critical to trip avoidance. The aim of our study was to investigate the mechanics of obstacle crossing in older adults at low or high risk of falling. [Subjects and Methods] Twenty community-dwelling adults aged ≥55 years, were evaluated with the Tinetti Balance and Gait scale and classified as being at high or low risk of falling. Between-group comparisons of kinematics were evaluated for obstacle heights of 10%, 20%, and 30% of leg length. [Results] The high-risk group demonstrated greater toe-obstacle clearance of the leading leg. Increasing obstacle height led to increased maximal toe-obstacle clearance, toe-obstacle distance, and shortened swing phase of the leading limb. Adaptation of clearance height was greater for the trailing leg. Individuals at high risk of falling demonstrated less symmetry between the leading and trailing legs and a narrower step width, features that increase the likelihood of tripping. [Conclusion] Kinematic parameters of obstacle clearance, including the symmetry index described in our study, could provide clinicians with a quick screening tool to identify patients at risk of falling and to evaluate outcomes of training programs.

  9. Intermittent hypoxia: a low-risk research tool with therapeutic value in humans.

    PubMed

    Mateika, Jason H; El-Chami, Mohamad; Shaheen, David; Ivers, Blake

    2015-03-01

    Intermittent hypoxia has generally been perceived as a high-risk stimulus, particularly in the field of sleep medicine, because it is thought to initiate detrimental cardiovascular, respiratory, cognitive, and metabolic outcomes. In contrast, the link between intermittent hypoxia and beneficial outcomes has received less attention, perhaps because it is not universally understood that outcome measures following exposure to intermittent hypoxia may be linked to the administered dose. The present review is designed to emphasize the less recognized beneficial outcomes associated with intermittent hypoxia. The review will consider the role intermittent hypoxia has in cardiovascular and autonomic adaptations, respiratory motor plasticity, and cognitive function. Each section will highlight the literature that contributed to the belief that intermittent hypoxia leads primarily to detrimental outcomes. The second segment of each section will consider the possible risks associated with experimentally rather than naturally induced intermittent hypoxia. Finally, the body of literature indicating that intermittent hypoxia initiates primarily beneficial outcomes will be considered. The overarching theme of the review is that the use of intermittent hypoxia in research investigations, coupled with reasonable safeguards, should be encouraged because of the potential benefits linked to the administration of a variety of low-risk intermittent hypoxia protocols.

  10. Strategies for obstacle crossing in older adults with high and low risk of falling

    PubMed Central

    Pan, Hui-Fen; Hsu, Horng-Chaung; Chang, Wei-Ning; Renn, Jenn-Huei; Wu, Hong-Wen

    2016-01-01

    [Purpose] Tripping is a frequent cause of falls among aging adults. Appropriate limb movements while negotiating obstacles are critical to trip avoidance. The aim of our study was to investigate the mechanics of obstacle crossing in older adults at low or high risk of falling. [Subjects and Methods] Twenty community-dwelling adults aged ≥55 years, were evaluated with the Tinetti Balance and Gait scale and classified as being at high or low risk of falling. Between-group comparisons of kinematics were evaluated for obstacle heights of 10%, 20%, and 30% of leg length. [Results] The high-risk group demonstrated greater toe-obstacle clearance of the leading leg. Increasing obstacle height led to increased maximal toe-obstacle clearance, toe-obstacle distance, and shortened swing phase of the leading limb. Adaptation of clearance height was greater for the trailing leg. Individuals at high risk of falling demonstrated less symmetry between the leading and trailing legs and a narrower step width, features that increase the likelihood of tripping. [Conclusion] Kinematic parameters of obstacle clearance, including the symmetry index described in our study, could provide clinicians with a quick screening tool to identify patients at risk of falling and to evaluate outcomes of training programs. PMID:27313384

  11. Understanding why low-risk patients accept vaccines: a socio-behavioral approach.

    PubMed

    Wiemken, Timothy L; Carrico, Ruth M; Kelley, Robert R; Binford, Laura E; Peyrani, Paula; Ford, Kimbal D; Welch, Verna; Ramirez, Julio A

    2015-12-23

    Vaccines are one of the most important public health interventions. Understanding factors associated with vaccine acceptance is critical. The objectives of this study were to evaluate the impact of the three constructs of the Theory of Planned Behavior (TPB) on the intention to be vaccinated among healthy individuals being seen for pre-travel care, and to evaluate if behavioral intention was associated with vaccine acceptance. We surveyed individuals seeking vaccination at the University of Louisville Vaccine and International Health and Travel Clinic. Linear and two stage least squares regression models were used to define the associations between constructs of the TPB and the intention to be vaccinated, as well as the association between the intention to be vaccinated and vaccine acceptance. A total of 183 individuals were included in the analysis. None of the constructs of the TPB were associated with intention to be vaccinated. Behavioral intention was not associated with vaccination acceptance. This study suggests that the TPB does not predict the intention to get vaccinated among individuals attending our Vaccine and International Health and Travel Clinic. It will be critical to define better predictors of vaccine uptake in healthy, low-risk individuals to increase vaccine acceptance.

  12. The characteristics of large bowel cancer in the low-risk black population of the Witwatersrand.

    PubMed

    Boytchev, H; Marcovic, S; Oettle, G J

    1999-12-01

    Sporadic colorectal cancer may follow a different pathogenic pathway in low-risk populations. The black population of the Witwatersrand has been urbanized for a long time, and has a westernized lifestyle, but colorectal cancer is still infrequent. This study aimed to define the characteristics of the disease in this group. All histologically proven large bowel cancers arising in blacks resident in the Witwatersrand in 1991 and 1996 were extracted from the registry records. Mean age was 54.3 years (range 16-90 years); 6% occurred before 30 years and 22% before 40 years. Male:female ratio was 1.32:1. Over three-quarters of the tumours arose in the rectum and sigmoid; there was no evidence of a right-sided preponderance. More than half the cases were advanced at presentation, and nearly one third were mucinous or signet ring on pathological assessment. Associated adenomata were rare (5.2%), suggesting a different pathogenic pathway from the classical adenoma-carcinoma sequence.

  13. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty.

    PubMed

    Blount, Andrew L; Martin, Matthew D; Lineberry, Kyle D; Kettaneh, Nicolas; Alfonso, David R

    2013-05-01

    The safety of augmentation mammaplasty has increased dramatically in the past 20 years. Capsular contracture (CC) is the most commonly reported complication of augmentation mammaplasty. The authors report the incidence of CC in a low-risk patient population after primary augmentation. The authors retrospectively reviewed the charts of 856 consecutive patients who underwent primary augmentation mammaplasty between 1999 and 2009. This series did not include patients who underwent breast augmentation-mastopexy, secondary augmentation, revision, and/or reconstruction. Data points included demographics, functional and aesthetic outcomes, complications, and revision rate/type. The overall incidence of CC in 856 patients was 2.8%. Average follow-up time was 14.9 months. Antibiotic irrigation decreased CC rates from 3.9% to 0.4% (P = .004). Tobacco users had higher rates of contracture than nonsmokers (5.5% vs 1.9%; P = .036). Saline implants had a higher CC rate than silicone gel (4.3% vs 1.3%; P = .032). Using multivariate logistic regression, CC was 7.89 times more likely in saline implants than in silicone gel (P = .027, 95% confidence interval, 1.26-49.00). Based on our findings, it is apparent that the early CC rate in primary augmentation can be less than 1%. To avoid CC, we advocate an inframmamary approach, submuscular implant placement, and antibiotic irrigation of the breast pocket. 3.

  14. Regional brain volume reduction and cognitive outcomes in preterm children at low risk at 9 years of age.

    PubMed

    Arhan, Ebru; Gücüyener, Kıvılcım; Soysal, Şebnem; Şalvarlı, Şafak; Gürses, M Ali; Serdaroğlu, Ayşe; Demir, Ercan; Ergenekon, Ebru; Türkyılmaz, Canan; Önal, Esra; Koç, Esin; Atalay, Yıldız

    2017-08-01

    More information is needed on "low-risk" preterm infants' neurological outcome so that they can be included in follow-up programs. A prospective study was performed to examine the regional brain volume changes compared to term children and to assess the relationship between the regional brain volumes to cognitive outcome of the low-risk preterm children at 9 years of age. Subjects comprised 22 preterm children who were determined to be at low risk for neurodevelopmental deficits with a gestational age between 28 and 33 weeks without a major neonatal morbidity in the neonatal period and 24 age-matched term control children term and matched for age, sex, and parental educational and occupational status. Regional volumetric analysis was performed for cerebellum, hippocampus, and corpus callosum area. Cognitive outcomes of both preterm and control subjects were assessed by Weschler Intelligence Scale for Children Revised (Turkish version), and attention and executive functions were assessed by Wisconsin Card Sorting Test and Stroop Test TBAG version. Low-risk preterm children showed regional brain volume reduction in cerebellum, hippocampus, and corpus callosum area and achieved statistical significance when compared with term control. When the groups were compared for all WISC-R subscale scores, preterm children at low risk had significantly lower scores on information, vocabulary, similarities, arithmetics, picture completion, block design, object assembly, and coding compared to children born at term. Preterm and term groups were compared on the Stroop Test for mistakes and corrections made on each card, the time spent for completing each card, and total mistakes and corrections. In the preterm group, we found a positive correlation between regional volumes with IQ, attention, and executive function scores. Additionally, a significant correlation was found between cerebellar volume and attention and executive function scores in the preterm group. Low-risk preterm

  15. A proposal of a new nomogram for predicting upstaging in contemporary D'Amico low-risk prostate cancer patients.

    PubMed

    Leyh-Bannurah, Sami-Ramzi; Dell'Oglio, Paolo; Tian, Zhe; Schiffmann, Jonas; Shariat, Shahrokh F; Suardi, Nazareno; Francesco, Montorsi; Alberto, Briganti; Heinzer, Hans; Huland, Hartwig; Graefen, Markus; Budäus, Lars; Karakiewicz, Pierre I

    2017-02-01

    Unfavorable prostate cancer (PCa) disease at final pathology affects at least 10 % of D'Amico low-risk patients. Thus, conservative therapies including active surveillance may be wrongfully applied. The purposes were to assess the rate of upstaging in a contemporary cohort of D'Amico low-risk PCa patients and to develop and externally validate a nomogram as upstaging prediction tool in two European cohorts. Analyses were restricted to 2007 patients who harbored low-risk PCa at ≥10-cores initial biopsy according to D'Amico classification (PSA <10.0 ng/ml, Gleason score <7 and clinical stage ≤T2a). Patients underwent radical prostatectomy at a high-volume center in Hamburg, Germany, from 2010 to 2015. The Hamburg cohort was randomly divided into development (n = 1338) and validation cohorts (n = 669). The development cohort was used to devise a nomogram predicting upstaging, defined as presence of ≥pT3 and/or lymph node invasion. The nomogram was externally validated in two European validation cohorts (Hamburg, n = 669; Milan, n = 465). Upstaging was observed in 187/1338 (14.0 %) of low-risk patients. In multivariable models, four of ten tested variables achieved independent predictor status: age (OR 1.07, 95 % CI 1.04-1.09), PSA (OR 1.21, 95 % CI 1.12-1.31), prostate volume (OR 0.97, 95 % CI 0.96-0.98) and percentage of positive cores (OR 1.02, 95 % CI 1.01-1.03). In external validation, the nomogram demonstrated 70.8 % (Hamburg) and 70.0 % (Milan) accuracy, respectively, with excellent concordance between predicted and observed values. Our proposed nomogram is capable to accurately identify D'Amico low-risk patients at risk of upstaging, utilizing four routinely available clinical variables, age, PSA, prostate volume and percentage of positive biopsy cores. Unfavorable prostate cancer disease at final pathology affects at least 10 % of D'Amico low-risk patients. Thus, we developed and externally validated a new nomogram based on contemporary

  16. A new paradigm in low-risk papillary microcarcinoma: active surveillance

    PubMed Central

    Garcia, Michelle Mangual; González, Paula Jeffs; Garcia, Miosotis; Villarmarzo, Guillermo; Martinez, Jose Hernán

    2017-01-01

    Classical papillary thyroid microcarcinoma (PTMC) is a variant of papillary thyroid carcinoma (PTC) known to have excellent prognosis. It has a mortality of 0.3%, even in the presence of distance metastasis. The latest American Thyroid Association guidelines state that although lobectomy is acceptable, active surveillance can be considered in the appropriate setting. We present the case of a 37-year-old female with a history of PTMC who underwent surgical management consisting of a total thyroidectomy. Although she has remained disease-free, her quality of life has been greatly affected by the sequelae of this procedure. This case serves as an excellent example of how first-line surgical treatment may result more harmful than the disease itself. Learning points: Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis with a mortality of less than 1% even with the presence of distant metastases. Active surveillance is a reasonable management approach for appropriately selected patients. Patients should be thoroughly oriented about the risks and benefits of active surveillance vs immediate surgical treatment. This discussion should include the sequelae of surgery and potential impact on quality of life, especially in the younger population. More studies are needed for stratification of PTMC behavior to determine if conservative management is adequate for all patients with this specific disease variant. PMID:28924477

  17. Variants of Uncertainty

    DTIC Science & Technology

    1981-05-15

    Variants of Uncertainty Daniel Kahneman University of British Columbia Amos Tversky Stanford University DTI-C &%E-IECTE ~JUNO 1i 19 8 1j May 15, 1981... Dennett , 1979) in which different parts have ac- cess to different data, assign then different weights and hold different views of the situation...2robable and t..h1 provable. Oxford- Claredor Press, 1977. Dennett , D.C. Brainstorms. Hassocks: Harvester, 1979. Donchin, E., Ritter, W. & McCallum, W.C

  18. Who is willing to participate in low-risk pragmatic clinical trials without consent?

    PubMed

    Dal-Ré, Rafael; Carcas, Antonio J; Carné, Xavier

    2017-09-12

    General notification offers a possible alternative to written informed consent for pragmatic randomized controlled trials (pRCTs). It involves patients being informed through brochures, posters, and letters that research is being conducted simultaneously to providing clinical care and that patients will be enrolled in pRCTs without study-specific consent. A previous survey found that a substantial minority of respondents endorsed general notification. We aimed to know who is willing to enroll in this type of trials using general notification rather than written consent. The previous study was a cross-sectional, probability-based survey, with a 2 × 2 factorial design. Two scenarios were assessed: two low-risk pRCTs in hypertension, one comparing two drugs with similar benefit/risk ratio and the other taking the same drug in the morning or at night. Each scenario had two routes: written consent vs verbal consent and written consent vs general notification. In this study, we were interested in the latter route in both scenarios. Respondents' preferences were measured based on their recommendation to the research ethics committee and the respondent's personal preference. We aimed to investigate the characteristics of those supporting general notification in either outcome or the variables explaining consistency and inconsistency between their personal preference and their recommendation. Based on the results of the original survey, we aimed to have at least 200 inconsistent respondents; to this end, the sample size was increased accordingly in a second wave of the survey. One thousand six hundre and ten respondents were included; 1003 from the original survey and 607 new ones belonging to the second wave. Thirty-nine percent of respondents chose general notification as personal preference and/or recommendation. Respondents with lower education levels were more prone to accept general notification than those holding a university degree [OR (95% CI)], primary school

  19. Foot length measurements of newborns of high and low risk pregnancies.

    PubMed

    Salge, Ana Karina Marques; Rocha, Érika Lopes; Gaíva, Maria Aparecida Munhoz; Castral, Thaíla Correa; Guimarães, Janaína Valadares; Xavier, Raphaela Maioni

    2017-03-09

    Comparing foot length measurements of newborns in high and low risk pregnancies at a public hospital in Goiânia, GO, Brazil. A cross-sectional study carried out between April, 2013 and May, 2015, with a sample consisting of 180 newborns; 106 infants of women from high-risk pregnancies and 74 of women from low-risk pregnancies. Data were descriptively analyzed. Foot length measurement was performed using a stiff transparent plastic ruler, graduated in millimeters. The length of both feet was measured from the tip of the hallux (big toe) to the end of the heel. A statistically significant relationship was found between the foot length and newborn's weight, between the cephalic and thoracic perimeters in the high-risk group and between the cephalic perimeter in the control group. There is a need for creating cut-off points to identify newborns with intrauterine growth disorders using foot length. Comparar as medidas do comprimento hálux-calcâneo de recém-nascidos em gestações de alto e baixo risco em um hospital público de Goiânia, GO. Estudo transversal, realizado no período de abril de 2013 a maio de 2015, cuja amostra constituiu-se de 180 recém-nascidos, 106 filhos de mulheres com gestação de alto risco e 74 de mulheres com gestação de baixo risco. Os dados foram analisados descritivamente. A medida do comprimento hálux-calcâneo foi realizada utilizando-se de régua plástica transparente rígida, graduada em milímetros. Foram medidos ambos os pés, aferindo-se o comprimento da ponta do hálux até a extremidade do calcâneo. Foi encontrada relação estatisticamente significante entre o comprimento hálux-calcâneo e o peso do recém-nascido, entre os perímetros cefálico e torácico no grupo de alto risco e entre o perímetro cefálico no grupo controle. Existe necessidade da criação de pontos de corte para identificar recém-nascidos com desvios de crescimento intrauterino utilizando-se do comprimento hálux-calcâneo. Comparar las mediciones

  20. To what extent do English language RCT meta-analysis justify induction of low-risk pregnancy for postdates?

    PubMed

    Cohain, J S

    2015-05-01

    Induction for postdates in low-risk pregnancy was adopted with the intent to prevent post-term antepartum stillbirth, the most common cause of perinatal death, based on evidence derived in English language RCT meta-analysis. Systematic English language meta-analysis of RCT studies of induction for postdates in low-risk pregnancy report perinatal mortality rates (PMRs) for low-risk pregnancy ranging from 2.6 to 7.6/1000, based on 2-5 stillbirths among 13-16 perinatal deaths, including diabetic pregnancies as well as other high-risk pregnancies irrelevant to the study question. Baseline PMR≥41 weeks in large international databases for high and low risk pregnancies before routine induction 1998-2003 range from 0.9 to 2.4/1000 or about 300% lower than the reported PMR rates for postdate pregnancies in the expectant management arm in English language RCT meta-analysis. Deaths in the first week far exceed stillbirths in the RCT meta-analysis, the opposite of what is expected. These 2 implausible results bring into question the evidence used to justify induction for postdates≥41 weeks. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. LUGH, the Proposed Mercury Express Mission, as an Ideal, Current, Low-Cost, Low-Risk Option for Mercury Exploration

    NASA Technical Reports Server (NTRS)

    Clark, P. E.; Lawlor, S. McKenna; Curtis, S.; Marr, G.; Giles, B.

    2000-01-01

    We propose an ESA Flexi Mission, LUGH, Mercury Express Mission, an extremely fast, low cost, low risk, high return, three-platform, multiple flyby mission which would provide data which are unique and complimentary to recently selected long lead time Mercury missions.

  2. A Comparative Study of Two Groups of Sex Offenders Identified as High and Low Risk on the Static-99

    ERIC Educational Resources Information Center

    Coxe, Ray; Holmes, William

    2009-01-01

    The purpose of this study was to identify possible differences between high- and low-risk sex offenders. The subjects included 285 sex offenders on probation. They were evaluated with the Static-99, Abel Assessment, Raven's, and MMPI-2. A criminal history review identified the number of prior offenses and the age/sex category in the index offense.…

  3. First-trimester uterine artery Doppler velocimetry in the prediction of birth weight in a low-risk population.

    PubMed

    Sarmiento, Andres; Casasbuenas, Alexandra; Rodriguez, Nadiezhda; Angarita, Ana M; Sarmiento, Piedad; Sepulveda, Waldo

    2013-01-01

    To study the relationship between first-trimester uterine artery (UtA) Doppler velocimetry and birth weight in an unselected, low-risk obstetric population. This is a prospective study of 415 low-risk pregnant women who underwent a first-trimester ultrasound evaluation between 11 and 13 weeks of gestation. Blood flow velocimetry waveforms from both UtAs were obtained and the pulsatility index (PI) measured and recorded. Clinical records were reviewed for pregnancy outcomes. Birth weight was expressed as z-scores, and the Spearman correlation coefficient (ρ) was used to calculate the relationship between the mean, delta, and lowest UtA PI values and birth weight. There was no correlation between the mean and delta UtA PI values and birth weight. However, a significant correlation between the lowest UtA PI value and birth weight (ρ = -0.121; p = 0.013) was noted. Our study found a clinically significant correlation between the lowest UtA PI value and birth weight in an unselected, low-risk pregnant population. Because fetal growth is a multifactorial process in which placentation is only one of the factors involved, the use of a single parameter such as Doppler velocimetry remote from the delivery to predict birth weight in a low-risk population seems to be less useful than in the high-risk population. © 2012 John Wiley & Sons, Ltd.

  4. LUGH, the Proposed Mercury Express Mission, as an Ideal, Current, Low-Cost, Low-Risk Option for Mercury Exploration

    NASA Technical Reports Server (NTRS)

    Clark, P. E.; Lawlor, S. McKenna; Curtis, S.; Marr, G.; Giles, B.

    2000-01-01

    We propose an ESA Flexi Mission, LUGH, Mercury Express Mission, an extremely fast, low cost, low risk, high return, three-platform, multiple flyby mission which would provide data which are unique and complimentary to recently selected long lead time Mercury missions.

  5. A Comparative Study of Two Groups of Sex Offenders Identified as High and Low Risk on the Static-99

    ERIC Educational Resources Information Center

    Coxe, Ray; Holmes, William

    2009-01-01

    The purpose of this study was to identify possible differences between high- and low-risk sex offenders. The subjects included 285 sex offenders on probation. They were evaluated with the Static-99, Abel Assessment, Raven's, and MMPI-2. A criminal history review identified the number of prior offenses and the age/sex category in the index offense.…

  6. The outcome of midwife-led labor in low-risk women within an obstetric referral unit.

    PubMed

    Ferrazzi, Enrico; Visconti, Elena; Paganelli, Andrea M; Campi, Carmen M; Lazzeri, Cristina; Cirillo, Federico; Livio, Stefania; Piola, Cinzia

    2015-09-01

    To analyze maternal and neonatal outcomes of midwife-led labor in low-risk women at term. Prospective observational cohort of 1788 singleton low-risk pregnancies in spontaneous term labor, managed according to a specific midwife-led labor protocol. Primary outcomes were mode of delivery, episiotomy, 3rd-4th degree lacerations, post-partum hemorrhage (PPH), need for blood transfusions, pH and Apgar score and NICU admissions. A total 1754 low-risk women (50.3% of all deliveries) were included in the analysis. Epidural analgesia was performed in 29.8% of cases. The rate of cesarean section was 3.7%. Episiotomy was performed in 17.6% of women. PPH > 1000 ml occurred in 1.7% of cases. 3.2% and 0.3% of the cases had an Apgar score <7 and pH < 7.10, respectively, while 0.3% of the newborns were admitted to NICU. Consultant-led labor was required for emerging risk factors during 1st and 2nd stage of labor in 16.1 and 8.6% of cases, respectively. Although maternal outcome were worse in women with emerging risk factors in labor, while neonatal outcomes were not affected by the presence these complications. In hospital settings, midwife-led labor in low-risk women might unfold its major advantages without additional risks of medicalization for the mother and the neonate.

  7. Identification of patients at low risk for thyroidectomy-related hypocalcemia by intraoperative quick PTH.

    PubMed

    Di Fabio, Francesco; Casella, Claudio; Bugari, Giovanna; Iacobello, Carmelo; Salerni, Bruno

    2006-08-01

    Transient hypoparathyroidism is a frequent and challenging complication following total thyroidectomy. The aim of the study was to identify patients at risk of developing thyroidectomy-related hypocalcemia and symptoms by means of the intraoperative quick parathyroid hormone (PTH) assay. Eighty-one patients undergoing total thyroidectomy were included in the study. Quick PTH levels were measured at induction of anaesthesia and 10 minutes after total thyroidectomy. A sample of 10 patients who underwent unilateral thyroid lobectomy was considered as a control group. The accuracy of intraoperative PTH decline in predicting postoperative hypoparathyroidism was analysed. After total thyroidectomy, 27 patients (33.3%) developed postoperative hypocalcemia. Symptoms were reported by 21 patients (25.9%). The mean percentage decline of intraoperative quick PTH was 81% in hypocalcemic compared with 39% in normocalcemic patients (P<0.001), and it was 83% in symptomatic compared with 42% in asymptomatic patients (P<0.001). Mean proportion decline of quick PTH after unilateral lobectomy was 20%, significantly lower than the 53% registered after total thyroidectomy (P=0.005). Analysis of variation of intraoperative quick PTH with the receiver operator characteristics (ROC) curve showed a 75.7% decline as the cut-off value predicting postoperative hypocalcemia with the highest accuracy (91.4%) (sensitivity: 81.5% specificity: 96.3% positive likelihood ratio: 22; negative likelihood ratio: 0.2). Regarding the prediction of postoperative symptoms, a 79.5% decline was the most accurate (92.6%) cut-off point (sensitivity: 76.2% specificity: 98.3% positive likelihood ratio: 46; negative likelihood ratio: 0.2). Quick PTH monitoring during total thyroidectomy is a useful means for identifying low-risk patients for postoperative hypoparathyroidism and candidates for early, safe discharge. Furthermore, it is an objective method complementary to the surgeon's judgement of the intraoperative

  8. High Intratumoral Stromal Content Defines Reactive Breast Cancer as a Low-risk Breast Cancer Subtype.

    PubMed

    Dennison, Jennifer B; Shahmoradgoli, Maria; Liu, Wenbin; Ju, Zhenlin; Meric-Bernstam, Funda; Perou, Charles M; Sahin, Aysegul A; Welm, Alana; Oesterreich, Steffi; Sikora, Matthew J; Brown, Robert E; Mills, Gordon B

    2016-10-15

    The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior. Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging. A subtype of breast cancers designated "Reactive," previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05). A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers. Clin Cancer Res; 22(20); 5068-78. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Portrayal of Alcohol Consumption in Movies and Drinking Initiation in Low-Risk Adolescents

    PubMed Central

    Sargent, James D.; Hunt, Kate; Sweeting, Helen; Engels, Rutger C.M.E.; Scholte, Ron H.J.; Mathis, Federica; Florek, Ewa; Morgenstern, Matthis

    2014-01-01

    OBJECTIVES: To investigate the hypothesis that exposure to alcohol consumption in movies affects the likelihood that low-risk adolescents will start to drink alcohol. METHODS: Longitudinal study of 2346 adolescent never drinkers who also reported at baseline intent to not to do so in the next 12 months (mean age 12.9 years, SD = 1.08). Recruitment was carried out in 2009 and 2010 in 112 state-funded schools in Germany, Iceland, Italy, Netherlands, Poland, and Scotland. Exposure to movie alcohol consumption was estimated from 250 top-grossing movies in each country in the years 2004 to 2009. Multilevel mixed-effects Poisson regressions assessed the relationship between baseline exposure to movie alcohol consumption and initiation of trying alcohol, and binge drinking (≥ 5 consecutive drinks) at follow-up. RESULTS: Overall, 40% of the sample initiated alcohol use and 6% initiated binge drinking by follow-up. Estimated mean exposure to movie alcohol consumption was 3653 (SD = 2448) occurrences. After age, gender, family affluence, school performance, TV screen time, personality characteristics, and drinking behavior of peers, parents, and siblings were controlled for, exposure to each additional 1000 movie alcohol occurrences was significantly associated with increased relative risk for trying alcohol, incidence rate ratio = 1.05 (95% confidence interval, 1.02–1.08; P = .003), and for binge drinking, incidence rate ratio = 1.13 (95% confidence interval, 1.06–1.20; P < .001). CONCLUSIONS: Seeing alcohol depictions in movies is an independent predictor of drinking initiation, particularly for more risky patterns of drinking. This result was shown in a heterogeneous sample of European youths who had a low affinity for drinking alcohol at the time of exposure. PMID:24799536

  10. Vitamin D deficiency and placental calcification in low-risk obstetric population: are they related?

    PubMed

    Bedir Findik, Rahime; Ersoy, Ali Ozgur; Fidanci, Vildan; Tasci, Yasemin; Helvacioglu, Yeksin; Karakaya, Jale

    2016-10-01

    We aimed to evaluate the relationship between placental calcification and maternal and cord blood 25-hydroxyvitamin-D3 [25(OH)D] and calcium concentrations in low-risk obstetric population at term and their consequences. Sixty non-complicated pregnant women at term admitted to maternity clinic were included in this prospective case-control study and classified into one of two groups according to grade of placental calcification by defined the Grannum classification: Group 1 (n=30), with Grade 3 placenta and Group 2 (n=30), the control group, no placental calcification noted. Baseline characteristics, maternal serum and umbilical cord 25(OH)D and calcium levels were compared between groups. The mean age of subjects was 26.4 ± 5.7 years. The mean serum 25(OH)D concentration of women (n=60) was 9.3 ± 3.4 (range 5.59-15.48) ng/mL. The prevalence of vitamin D deficiency [25(OH)D <20 ng/mL] was 100%. Maternal serum and cord blood calcium levels were significantly higher in Group 1 (p=0.036; p=0.037, respectively). In Group 2, maternal serum and cord blood 25(OH)D levels were higher than Group 1 (11.35 ± 6.54 and 10.22 ± 3.59 versus 9.6 ± 4.2 and 9.07 ± 2.43 ng/mL); but the difference is not statistically significant. Higher maternal calcium and lower 25(OH)D levels detected in patients with Grade 3 placental calcification indicated the importance of placenta on vitamin D regulation.

  11. Costing Alternative Birth Settings for Women at Low Risk of Complications: A Systematic Review

    PubMed Central

    Scarf, Vanessa; Catling, Christine; Viney, Rosalie; Homer, Caroline

    2016-01-01

    Background There is demand from women for alternatives to giving birth in a standard hospital setting however access to these services is limited. This systematic review examines the literature relating to the economic evaluations of birth setting for women at low risk of complications. Methods Searches of the literature to identify economic evaluations of different birth settings of the following electronic databases: MEDLINE, CINAHL, EconLit, Business Source Complete and Maternity and Infant care. Relevant English language publications were chosen using keywords and MeSH terms between 1995 and 2015. Inclusion criteria included studies focussing on the comparison of birth setting. Data were extracted with respect to study design, perspective, PICO principles, and resource use and cost data. Results Eleven studies were included from Australia, Canada, the Netherlands, Norway, the USA, and the UK. Four studies compared costs between homebirth and the hospital setting and the remaining seven focussed on the cost of birth centre care and the hospital setting. Six studies used a cost-effectiveness analysis and the remaining five studies used cost analysis and cost comparison methods. Eight of the 11 studies found a cost saving in the alternative settings. Two found no difference in the cost of the alternative settings and one found an increase in birth centre care. Conclusions There are few studies that compare the cost of birth setting. The variation in the results may be attributable to the cost data collection processes, difference in health systems and differences in which costs were included. A better understanding of the cost of birth setting is needed to inform policy makers and service providers. PMID:26891444

  12. Clinical trial registration was not an indicator for low risk of bias.

    PubMed

    Farquhar, Cynthia M; Showell, Marian G; Showell, Emily A E; Beetham, Penny; Baak, Nora; Mourad, Selma; Jordan, Vanessa M B

    2017-04-01

    To determine the prevalence of registered trials and to evaluate the risk of bias between registered and unregistered clinical trials. The Cochrane Gynecology and Fertility Group's specialized register was searched on November 5, 2015, for randomized controlled trials published from 2010 to 2014. Studies were selected if they had randomized women or men for fertility treatments, were published in full text and written in English. Two reviewers then independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. Of 693 eligible randomized controlled trials, only 44% were found to be registered. Unregistered clinical trials had smaller sample sizes than registered trials (P < 0.001). A random subsample of 125 registered and 125 unregistered trials was assessed for risk of bias using five of the Cochrane Risk of Bias "domains." Registered and unregistered trials differed in their risk of bias for random sequence generation (P = 0.001), allocation concealment (P = 0.003), and selective reporting (P < 0.001) but not blinding or incomplete outcome data (P > 0.05) domains. Only 54 (43.2%) of the 125 registered trials were registered prospectively. This study has the following limitations. Only English language trials were included in this review. We were unable to obtain protocols for the unregistered trials and therefore were unable to assess the risk of bias in the selective reporting domain. All available trials should be included in systematic reviews and assessed for risk of bias as there are both registered trials with high risk of bias and unregistered trials with low risk of bias and by excluding unregistered trials more than half of the available evidence will be lost. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Ultrasonographic study and Doppler flow velocimetry of maternal kidneys and liver in low-risk pregnancy*

    PubMed Central

    Daher, Cibele Helena; Gomes, Andrea Cavalanti; Kobayashi, Sergio; Cerri, Giovanni Guido; Chammas, Maria Cristina

    2015-01-01

    Objective Longitudinal study with B-mode ultrasonography and Doppler ultrasonography of maternal kidneys and liver in low-risk pregnancy, to establish and quantify normality parameters, correlating them with physiological changes. Materials and Methods Twenty-five pregnant women were assessed and selected to participate in the study, each of them undergoing four examinations at the first, second, third trimesters and postpartum. Results Findings during pregnancy were the following: increased renal volume, pyelocaliceal dilatation with incidence of 45.4% in the right kidney, and 9% in the left kidney; nephrolithiasis, 18.1% in the right kidney, 13.6% in the left kidney. With pyelocaliceal dilatation, mean values for resistivity index were: 0.68 for renal arteries; 0.66 for segmental arteries; 0.64 for interlobar arteries; 0.64 for arcuate arteries. Without pyelocaliceal dilatation, 0.67 for renal arteries; 0.64 for segmental arteries; 0.63 for interlobar arteries; and 0.61 for arcuate arteries. Portal vein flow velocities presented higher values in pregnancy, with mean value for maximum velocity of 28.9 cm/s, and 22.6 cm/s postpartum. The waveform pattern of the right hepatic vein presented changes persisting in the postpartum period in 31.8% of the patients. Cholelithiasis was observed in 18.1% of the patients. Conclusion Alterations in renal volume, pyelocaliceal dilatation, nephrolithiasis, cholelithiasis, changes in portal vein flow velocity, alterations in waveform pattern of the right hepatic vein, proved to be significant. PMID:26185338

  14. Quantification of CT images for the classification of high- and low-risk pancreatic cysts

    NASA Astrophysics Data System (ADS)

    Gazit, Lior; Chakraborty, Jayasree; Attiyeh, Marc; Langdon-Embry, Liana; Allen, Peter J.; Do, Richard K. G.; Simpson, Amber L.

    2017-03-01

    Pancreatic cancer is the most lethal cancer with an overall 5-year survival rate of 7%1 due to the late stage at diagnosis and the ineffectiveness of current therapeutic strategies. Given the poor prognosis, early detection at a pre-cancerous stage is the best tool for preventing this disease. Intraductal papillary mucinous neoplasms (IPMN), cystic tumors of the pancreas, represent the only radiographically identifiable precursor lesion of pancreatic cancer and are known to evolve stepwise from low-to-high-grade dysplasia before progressing into an invasive carcinoma. Observation is usually recommended for low-risk (low- and intermediate-grade dysplasia) patients, while high-risk (high-grade dysplasia and invasive carcinoma) patients undergo resection; hence, patient selection is critically important in the management of pancreatic cysts.2 Radiologists use standard criteria such as main pancreatic duct size, cyst size, or presence of a solid enhancing component in the cyst to optimally select patients for surgery.3 However, these findings are subject to a radiologist's interpretation and have been shown to be inconsistent with regards to the presence of a mural nodule or solid component.4 We propose objective classification of risk groups based on quantitative imaging features extracted from CT scans. We apply new features that represent the solid component (i.e. areas of high intensity) within the cyst and extract standard texture features. An adaptive boost classifier5 achieves the best performance with area under receiver operating characteristic curve (AUC) of 0.73 and accuracy of 77.3% for texture features. The random forest classifier achieves the best performance with AUC of 0.71 and accuracy of 70.8% with the solid component features.

  15. Patients with severe emphysema have a low risk of radiation pneumonitis following stereotactic body radiotherapy

    PubMed Central

    Ishijima, M; Itonaga, T; Tajima, Y; Shiraishi, S; Okubo, M; Mikami, R; Tokuuye, K

    2015-01-01

    Objective: To evaluate the risk of radiation pneumonitis (RP) after stereotactic radiotherapy (SBRT) for patients presenting with severe pulmonary emphysema. Methods: This study included 40 patients with Stage I non-small-cell lung cancer who underwent SBRT, 75 Gy given in 30 fractions, at the Tokyo Medical University, Tokyo, Japan, between February 2010 and February 2013. The median age of the patients was 79 years (range, 49–90 years), and the male:female ratio was 24:16. There were 20 T1 and 20 T2 tumours. 17 patients had emphysema, 6 had slight interstitial changes on CT images and the remaining 17 had no underlying lung disease. The level of emphysema was classified into three groups according to the modified Goddard's criteria (severe: three patients, moderate: eight patients and mild: six patients). Changes in the irradiated lung following SBRT were evaluated by CT. Results: On CT images, RP was detected in 34 (85%) patients, and not in 6 (15%) patients, during a median observation period of 313 days. Of the six patients, three had severe emphysema and three had no underlying lung disease. Patients with severe emphysema had lower risk of RP than those with moderate emphysema (p = 0.01), mild emphysema (p = 0.04) and no underlying lung disease (p = 0.01). Conclusion: Patients with severe emphysema had a low risk of RP following SBRT. Advances in knowledge: Little is known about the association between RP and pulmonary emphysema. Patients with severe emphysema had lower risk of RP than those with no underlying lung disease. PMID:25490255

  16. Outcomes associated with planned place of birth among women with low-risk pregnancies

    PubMed Central

    Hutton, Eileen K.; Cappelletti, Adriana; Reitsma, Angela H.; Simioni, Julia; Horne, Jordyn; McGregor, Caroline; Ahmed, Rashid J.

    2016-01-01

    Background: Previous studies have shown that planned home birth is associated with a decreased likelihood of intrapartum intervention with no difference in neonatal outcomes compared with planned hospital birth. The purpose of our study was to evaluate different birth settings by comparing neonatal mortality, morbidity and rates of birth interventions between planned home and planned hospital births in Ontario, Canada. Methods: We used a provincial database of all midwifery-booked pregnancies between 2006 and 2009 to compare women who planned home birth at the onset of labour to a matched cohort of women with low-risk pregnancies who had planned hospital births attended by midwives. We conducted subgroup analyses by parity. Our primary outcome was stillbirth, neonatal death (< 28 d) or serious morbidity (Apgar score < 4 at 5 min or resuscitation with positive pressure ventilation and cardiac compressions). Results: We compared 11 493 planned home births and 11 493 planned hospital births. The risk of our primary outcome did not differ significantly by planned place of birth (relative risk [RR] 1.03, 95% confidence interval [CI] 0.68–1.55). These findings held true for both nulliparous (RR 1.04, 95% CI 0.62–1.73) and multiparous women (RR 1.00, 95% CI 0.49–2.05). All intrapartum interventions were lower among planned home births. Interpretation: Compared with planned hospital birth, planned home birth attended by midwives in a jurisdiction where home birth is well-integrated into the health care system was not associated with a difference in serious adverse neonatal outcomes but was associated with fewer intrapartum interventions. PMID:26696622

  17. Pilot Study of Physiologic Partograph Use Among Low-Risk, Nulliparous Women With Spontaneous Labor Onset.

    PubMed

    Neal, Jeremy L; Lowe, Nancy K; Nacht, Amy S; Koschoreck, Kate; Anderson, Jessica

    2016-01-01

    Neal and Lowe developed a physiologic partograph to give clinicians an evidence-based, uniform approach to assessing active labor progress and diagnosing dystocia in high-resource settings. The aim of this pilot study was to examine the feasibility of implementing the Neal and Lowe partograph for in-hospital labor assessment. A descriptive study of low-risk, nulliparous women with spontaneous labor onset was performed at an academic medical center. Eight certified nurse-midwives from a single practice used the Neal and Lowe partograph for the assessment of labor progress. Descriptive statistics were used to summarize characteristics, interventions, and outcomes for women with partograph-assessed labors. Labors assessed by nurse-midwives (n = 83) or obstetricians (n = 75) using their usual assessment strategies were also described for the year prior to partograph introduction to contextualize partograph-assessed labor findings. Inferential statistical tests were not performed. Thirty-one of 34 (91.2%) partographs were used correctly. Seventy-one percent (n = 22) of these women progressed to complete dilatation within expected physiologic time frames while the remaining women (n = 9) experienced labor dystocia. Similar proportions of women in the partograph and usual labor assessment groups received oxytocin during labor. The cesarean rate was lower in the partograph group than in the usual care groups. No cesareans were performed for dystocia in active labor for women whose labors were assessed via partograph. Implementation of the Neal and Lowe partograph for in-hospital labor assessment is feasible. Incorrect plotting and/or interpretation of the partograph may be further minimized by providing clinicians opportunities for ongoing partograph training after implementation or through partograph software development. The Neal and Lowe partograph may assist clinicians in safely and significantly decreasing primary cesarean births performed for active labor dystocia in

  18. Interactions Between High- and Low-Risk HPV Types Reduce the Risk of Squamous Cervical Cancer.

    PubMed

    Sundström, Karin; Ploner, Alexander; Arnheim-Dahlström, Lisen; Eloranta, Sandra; Palmgren, Juni; Adami, Hans-Olov; Ylitalo Helm, Nathalie; Sparén, Pär; Dillner, Joakim

    2015-10-01

    The clinical significance of co-infections with high-risk (HR) and low-risk (LR) human papillomavirus (HPV) in the etiology of cervical cancer is debated, as prospective evidence on this issue is limited. However, the question is of increasing relevance in relation to HPV-based cancer prevention. In two population-based nested case-control studies among women participating in cervical screening with baseline normal smears, we collected 4659 smears from women who later developed cancer in situ (CIS; n = 524) or squamous cervical cancer (SCC; n = 378) and individually matched control subjects who remained free of disease during study follow-up. The median follow-up until diagnosis was 6.4 to 7.8 years. All smears were tested for HPV. We used conditional logistic regression models with two-way interaction terms to estimate relative risks (RRs) for CIS and SCC, respectively. All statistical tests were two-sided. Compared with women who were infected with HRHPV only, women who were also infected with LRHPV had a lower risk for SCC (RR = 0.2, 95% confidence interval [CI] = 0.04 to 0.99, P = .049). This interaction was not shown for CIS (RR = 1.1, 95% CI = 0.4 to 3.6). Women who were positive for both HRHPV and LRHPV had, on average, a 4.8 year longer time to diagnosis of SCC than women who were positive for HRHPV only (P = .006). Results were highly robust in sensitivity analyses. Co-infection with LRHPV is associated with a lower risk of future invasive disease and longer time to diagnosis than infection with HRHPV alone. We propose that co-infection with LRHPV interferes with the rate of progression to invasive cervical cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Preoperative Laboratory Testing in Patients Undergoing Elective, Low-Risk Ambulatory Surgery

    PubMed Central

    Benarroch-Gampel, Jaime; Sheffield, Kristin M.; Duncan, Casey B.; Brown, Kimberly M.; Han, Yimei; Townsend, Courtney M.; Riall, Taylor S.

    2012-01-01

    Background Routine preoperative laboratory testing for ambulatory surgery is not recommended. Methods Patients who underwent elective hernia repair (N = 73,596) were identified from the National Surgical Quality Improvement Program (NSQIP) database (2005–2010). Patterns of preoperative testing were examined. Multivariate analyses were used to identify factors associated with testing and postoperative complications. Results A total of 46,977 (63.8%) patients underwent testing, with at least one abnormal test recorded in 61.6% of patients. In patients with no NSQIP comorbidities (N = 25,149) and no clear indication for testing, 54% received at least one test. In addition, 15.3% of tested patients underwent laboratory testing the day of the operation. In this group, surgery was done despite abnormal results in 61.6% of same day tests. In multivariate analyses, testing was associated with older age, ASA (American Society of Anesthesiologists) class >1, hypertension, ascites, bleeding disorders, systemic steroids, and laparoscopic procedures. Major complications (reintubation, pulmonary embolus, stroke, renal failure, coma, cardiac arrest, myocardial infarction, septic shock, bleeding, or death) occurred in 0.3% of patients. After adjusting for patient and procedure characteristics, neither testing nor abnormal results were associated with postoperative complications. Conclusions Preoperative testing is overused in patients undergoing low-risk, ambulatory surgery. Neither testing nor abnormal results were associated with postoperative outcomes. On the basis of high rates of testing in healthy patients, physician and/or facility preference and not only patient condition currently dictate use. Involvement from surgical societies is necessary to establish guidelines for preoperative testing. PMID:22868362

  20. A Low Risk Strategy for the Exploration of Near-Earth Objects

    NASA Technical Reports Server (NTRS)

    Landis, Rob R.

    2011-01-01

    The impetus for asteroid exploration is scientific, political, and pragmatic. The notion of sending human explorers to asteroids is not new. Piloted missions to these primitive bodies were first discussed in the 1960s, pairing Saturn V rockets with enhanced Apollo spacecraft to explore what were then called "Earth-approaching asteroids." Two decades ago, NASA's Space Exploration Initiative (SEI) also briefly examined the possibility of visiting these small celestial bodies. Most recently, the U.S. Human Space Flight Review Committee (the second Augustine Commission) suggested that near-Earth objects (NEOs) represent a target-rich environment for exploration via the "Flexible Path" option. However, prior to seriously considering human missions to NEOs, it has become clear that we currently lack a robust catalog of human accessible targets. The majority of the NEOs identified by a study team across several NASA centers as "human-accessible" are probably too small and have orbits that are too uncertain to consider mounting piloted expeditions to these small worlds. The first step in developing such a catalog is, therefore, to complete a space-based NEO survey. The resulting catalog of candidate NEOs would then be transformed into a matrix of opportunities for robotic and human missions for the next several decades. This initial step of a space-based NEO survey first is the linchpin to laying the foundation of a low-risk architecture to venture out and explore these primitive bodies. We suggest such a minimalist framework architecture from 1) extensive ground-based and precursor spacecraft investigations (while applying operational knowledge from science-driven robotic missions), 2) astronaut servicing of spacecraft operating at geosynchronous Earth orbit to retain essential skills and experience, and 3) applying the sum of these skills, knowledge and experience to piloted missions to NEOs.

  1. Statin Therapy in Low-Risk Air Force Aviators with Isolated Hypercholesterolemia.

    PubMed

    Tvaryanas, Anthony P; Mahaney, Heather J; Schroeder, Valarie M; Maupin, Genny M

    2017-08-01

    This study evaluated the use of statin therapy in U.S. Air Force (USAF) aviators with isolated hypercholesterolemia in terms of compliance with clinical practice guidelines (CPGs) and effectiveness in reducing low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) risk. This was a mixed design, 8-yr retrospective study that included 8185 participants with isolated hypercholesterolemia, of which 1458 (17.81%) were prescribed statin monotherapy. Overall agreement between CPG recommendations and patient-clinician decision makers was 0.920 (95% confidence interval: 0.955, 0.959) and 0.891 (95% confidence interval: 0.843, 0.851) per 2002 and 2013 CPGs, respectively. Overall agreement was primarily driven by the negative proportion of specific agreement; positive agreement was moderate for the 2002 CPG and poor for the 2013 CPG. LDL-C levels marginally decreased for all participants except non-CPG-recommended statin users per the 2002 CPG. CHD risk was minimally reduced for all participants per the 2002 CPG with the exception of CPG-recommended statin users, for whom risk increased; CHD risk decreased for CPG-recommended statin users, but increased for non-CPG-recommended statin users per the 2013 CPG. No one statin medication was found to be more clinically effective in reducing LDL-C or CHD risk, regardless of dose intensity. Aerospace medicine practitioners are following CPG recommendations for statin therapy. Statins provided minimal benefit, however, and CPG recommendations proved irrelevant in reducing LDL-C and CHD risk in this population of Air Force aviators. This result is attributable, in part, to the young age of the study cohort and the short follow-up period.Tvaryanas AP, Mahaney HJ, Schroeder VM, Maupin GM. Statin therapy in low-risk air force aviators with isolated hypercholesterolemia. Aerosp Med Hum Perform. 2017; 88(8):752-759.

  2. Applicator-guided volumetric-modulated arc therapy for low-risk endometrial cancer.

    PubMed

    Cilla, Savino; Macchia, Gabriella; Sabatino, Domenico; Digesù, Cinzia; Deodato, Francesco; Piermattei, Angelo; De Spirito, Marco; Morganti, Alessio G

    2013-01-01

    The aim of this study was to report the feasibility of volumetric-modulated arc therapy (VMAT) in the postoperative irradiation of the vaginal vault. Moreover, the VMAT technique was compared with 3D conformal radiotherapy (3D-CRT) and fixed-field intensity-modulated radiotherapy (IMRT), in terms of target coverage and organs at risk sparing. The number of monitor units and the delivery time were analyzed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a 2D array of ionization chambers. Twelve patients with endometrial carcinoma who underwent radical hystero-adenexectomy and fixed-field IMRT treatments were retrospectively included in this analysis; for each patient, plans were compared in terms of dose-volume histograms, homogeneity index, and conformity indexes. All techniques met the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformity at all dose levels. VMAT resulted in significant reduction of rectal and bladder volumes irradiated at all dose levels compared with 3D-CRT. No significant differences were found with respect to IMRT. Moreover, a significant improvement of the dose conformity was reached by VMAT technique not only at the 95% dose level (0.74 vs. 0.67 and 0.62) but also at 50% and 75% levels of dose prescription. In addition, VMAT plans showed a significant reduction of monitor units by nearly 28% with respect to IMRT, and reduced treatment time from 11 to <3 minutes for a single 6-Gy fraction. In conclusion, VMAT plans can be planned and carried out with high quality and efficiency for the irradiation of vaginal vault alone, providing similar or better sparing of organs at risk to fixed-field IMRT and resulting in the most efficient treatment option. VMAT is currently our standard approach for radiotherapy of low-risk endometrial cancer. Copyright © 2013 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights

  3. Margin involvement at prostatectomy for clinically localized prostate cancer: does a low-risk group exist?

    PubMed

    Watkins, John M; Laszewski, Michael; Watkins, Patricia L; Dufan, Tarek A; Adducci, Christopher

    2015-01-01

    To determine whether additional pathology details may provide risk stratification for patients with involved surgical margins at radical prostatectomy (RP). Eligible patients underwent RP between 2003 and 2010. Patients with preoperative prostate-specific antigen (PSA) ≥20, follow-up <12 months, lymph node or seminal vesicle involvement, or who received radiation therapy or hormone therapy prior to PSA relapse were excluded. Surgical specimens were reviewed by a study pathologist, blinded to outcomes. Survival analysis methods were employed to assess disease control and survival rates, as well as association of patient-, tumor-, and treatment-specific factors for endpoints. Of 355 RP cases, 279 patients were eligible for the present analysis. At a median follow-up of 53 months (range, 16-127), 31/114 (27%) of patients with involved surgical margins experienced PSA relapse, as compared with 7/165 (4%) for negative margins (hazard ratio, 4.997; 95% confidence interval, 2.425-10.296; P < .0001). Detailed pathology review demonstrated associations between PSA relapse and Gleason score at RP, extent of margin involvement (width), capsule penetration, and perineural invasion. Subgroup analysis identified low risk (4%) of 5-year PSA relapse for patients with Gleason ≤6 mm and margin width ≤4 mm (single maximal or cumulative). All subgroups with higher Gleason score or wider margin were associated with >20% risk of PSA relapse at 5 years. Within the present study, Gleason score, 6 patients with margin width ≤4 mm appear to have low rates of early PSA relapse following RP. Low-grade cases with larger extent of margin involvement or higher risk Gleason score patients with any margin involvement have high rates of early PSA relapse. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

  4. Applicator-guided volumetric-modulated arc therapy for low-risk endometrial cancer

    SciTech Connect

    Cilla, Savino; Macchia, Gabriella; Sabatino, Domenico; Digesù, Cinzia; Deodato, Francesco; Piermattei, Angelo; De Spirito, Marco; Morganti, Alessio G.

    2013-04-01

    The aim of this study was to report the feasibility of volumetric-modulated arc therapy (VMAT) in the postoperative irradiation of the vaginal vault. Moreover, the VMAT technique was compared with 3D conformal radiotherapy (3D-CRT) and fixed-field intensity-modulated radiotherapy (IMRT), in terms of target coverage and organs at risk sparing. The number of monitor units and the delivery time were analyzed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a 2D array of ionization chambers. Twelve patients with endometrial carcinoma who underwent radical hystero-adenexectomy and fixed-field IMRT treatments were retrospectively included in this analysis; for each patient, plans were compared in terms of dose-volume histograms, homogeneity index, and conformity indexes. All techniques met the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformity at all dose levels. VMAT resulted in significant reduction of rectal and bladder volumes irradiated at all dose levels compared with 3D-CRT. No significant differences were found with respect to IMRT. Moreover, a significant improvement of the dose conformity was reached by VMAT technique not only at the 95% dose level (0.74 vs. 0.67 and 0.62) but also at 50% and 75% levels of dose prescription. In addition, VMAT plans showed a significant reduction of monitor units by nearly 28% with respect to IMRT, and reduced treatment time from 11 to <3 minutes for a single 6-Gy fraction. In conclusion, VMAT plans can be planned and carried out with high quality and efficiency for the irradiation of vaginal vault alone, providing similar or better sparing of organs at risk to fixed-field IMRT and resulting in the most efficient treatment option. VMAT is currently our standard approach for radiotherapy of low-risk endometrial cancer.

  5. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2017-07-11

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  6. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2013-02-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  7. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

    2011-04-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  8. Enhanced variants of IDE algorithm

    NASA Astrophysics Data System (ADS)

    Bujok, Petr

    2017-07-01

    The performance of a new mechanism applied on a differential evolution algorithm with an individual-dependent mechanism (IDE) is studied experimentally. Three new IDE variants are proposed and compared with the original IDE variant. The performance of all studied algorithms was compared on each problem of CEC 2015 test suite. The newly proposed IDE variants mostly outperformed the original IDE variant significantly. The results show that the best results are for the newly proposed IDE variant with an enhanced mutation scheme and IDE with the control of the population diversity.

  9. Quantifying the benefits of achieving or maintaining long-term low risk profile for cardiovascular disease: The Doetinchem Cohort Study.

    PubMed

    Hulsegge, Gerben; Smit, Henriëtte A; van der Schouw, Yvonne T; Daviglus, Martha L; Verschuren, W M Monique

    2015-10-01

    Studies investigating the relation between risk profiles and cardiovascular disease have measured risk at baseline only. We investigated maintenance and changes of risk profiles over time and their potential impact on incident cardiovascular disease. Population-based cohort study. Risk factors were measured at baseline (1987-1991) among 5574 cardiovascular disease-free adults aged 20-59 years. They were classified into four risk categories according to smoking status, presence of diabetes and widely accepted cut-off values for blood pressure, total cholesterol/HDL-ratio and body mass index. Categories were subdivided (maintenance, deterioration, improvement) based on risk factor levels at six and 11 years of follow-up. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cardiovascular disease incidence 5-10 years following the risk-change period were fitted using Cox proportional hazards models. Only 12% of participants were low risk at baseline, and only 7% maintained it. Participants who maintained a low risk profile over 11 years had seven times lower risk of cardiovascular disease (HR: 0.14, 95% CI: 0.05-0.41) than participants with long-term high risk profile, whereas those low risk at baseline whose profile deteriorated had three times lower risk (HR: 0.36, 95% CI: 0.18-0.71). Our results suggest that, within each baseline risk profile group, compared with a stable profile, improving profiles may be associated with up to two-fold lower HRs, and deteriorating profiles with about two-fold higher HRs. Our study, using long-term risk profiles, demonstrates the full benefits of low risk profile. These findings underscore the importance of achieving and maintaining low risk from young adulthood onwards. © The European Society of Cardiology 2014.

  10. A prognostic score to identify low-risk outpatients with acute deep vein thrombosis in the upper extremity.

    PubMed

    Rosa-Salazar, V; Trujillo-Santos, J; Díaz Peromingo, J A; Apollonio, A; Sanz, O; Malý, R; Muñoz-Rodriguez, F J; Serrano, J C; Soler, S; Monreal, M

    2015-07-01

    No studies have identified which patients with upper-extremity deep vein thrombosis (DVT) are at low risk for adverse events within the first week of therapy. We used data from Registro Informatizado de la Enfermedad TromboEmbólica to explore in patients with upper-extremity DVT a prognostic score that correctly identified patients with lower limb DVT at low risk for pulmonary embolism, major bleeding, or death within the first week. As of December 2014, 1135 outpatients with upper-extremity DVT were recruited. Of these, 515 (45%) were treated at home. During the first week, three patients (0.26%) experienced pulmonary embolism, two (0.18%) had major bleeding, and four (0.35%) died. We assigned 1 point to patients with chronic heart failure, creatinine clearance levels 30-60 mL min(-1) , recent bleeding, abnormal platelet count, recent immobility, or cancer without metastases; 2 points to those with metastatic cancer; and 3 points to those with creatinine clearance levels < 30 mL min(-1) . Overall, 759 (67%) patients scored ≤ 1 point and were considered to be at low risk. The rate of the composite outcome within the first week was 0.26% (95% confidence interval [CI] 0.004-0.87) in patients at low risk and 1.86% (95% CI 0.81-3.68) in the remaining patients. C-statistics was 0.73 (95% CI 0.57-0.88). Net reclassification improvement was 22%, and integrated discrimination improvement was 0.0055. Using six easily available variables, we identified outpatients with upper-extremity DVT at low risk for adverse events within the first week. These data may help to safely treat more patients at home. © 2015 International Society on Thrombosis and Haemostasis.

  11. Validation and comparison of SCAP as a predictive score for identifying low-risk patients in community-acquired pneumonia.

    PubMed

    España, Pedro P; Capelastegui, Alberto; Quintana, José M; Bilbao, Amaia; Diez, Rosa; Pascual, Silvia; Esteban, Cristóbal; Zalacaín, Rafael; Menendez, Rosario; Torres, Antoni

    2010-02-01

    (1) To validate the Severe Community Acquired Pneumonia (SCAP) score in predicting 30-day mortality. (2) To validate its ability to identifying patients at low risk of death. (3) To compare it against the Pneumonia Severity Index (PSI), and the British Thoracic Society's CURB-65 rules. The SCAP score was validated to predict 30-day mortality in an internal validation cohort of consecutive adult patients seen in one hospital. Consecutive inpatients from other three hospitals were used to externally validate the score and compare the SCAP with the PSI and CURB-65. The discriminatory power of these rules to predict 30-day mortality was tested by the Area under Curve (AUC), and their predictive accuracy with the sensitivity, specificity and predictive values. The 30-day mortality rate increased directly with increasing SCAP score (class 0: 0.5%, to class 4: 66.5% risk) in the internal validation cohort, and from 1.3% to 29.2% in external cohort (P<0.001) with an AUC of 0.83 and 0.75, respectively (P=0.024). The SCAP score identified 62.4% (95% IC 58.8-66.0) low-risk patients, 52.5% (95% IC 48.8-56.2) the PSI and 46.2% (95% CI 42.5-49.9) the CURB-65 in the external cohort. Patients classified as low risk by the three rules had similar 30-day mortality (SCAP: 2.5%, PSI: 1.6% and CURB-65: 2.7%). The SCAP is valid to predict 30-day mortality among low-risk patients and identifies a larger proportion of patients as low-risk than the other studied rules. Copyright 2009. Published by Elsevier Ltd.

  12. Heavy drinking occasions in Australia: do context and beverage choice differ from low-risk drinking occasions?

    PubMed

    Callinan, Sarah; Livingston, Michael; Dietze, Paul; Room, Robin

    2014-07-01

    The aim of the current study is to look for differences in drink choice and drinking location between a recent heavy drinking occasion (RHDO) and usual low-risk occasions among those that recently had both types of drinking occasion. Seven hundred and seventy-four respondents to a population-based survey reported having a RHDO [8 + Australian standard drinks (ASD) for females, 11 + ASD for males] in the past six months also reported that their usual drinking occasion in at least one location involved less than five ASD. Drink choice and drinking locations for the RHDO and usual low-risk occasions were compared using confidence intervals. The RHDO was more likely than usual low-risk occasions to occur away from licensed premises (59%), despite a higher percentage of respondents reporting drinking at a pub, bar or nightclub on a RHDO (28%) than on a usual low-risk night (12%). A higher percentage of respondents nominated bottled spirits (33%) as their main drink for their RHDO, with 11% primarily drinking bottled spirits on a usual low-risk occasion; the converse was true for bottled wine (20% and 33%, respectively). While the high proportion of RHDOs that occurred at least in part at pubs or nightclubs was not surprising, a high proportion also occur in private homes. Previously found links between heavy drinking and beer may be a reflection of the usual drink choice of heavier drinkers, rather a choice specific to a particularly heavy occasion. © 2014 Australasian Professional Society on Alcohol and other Drugs.

  13. Prospective quality-of-life outcomes for low-risk prostate cancer: Active surveillance versus radical prostatectomy.

    PubMed

    Jeldres, Claudio; Cullen, Jennifer; Hurwitz, Lauren M; Wolff, Erika M; Levie, Katherine E; Odem-Davis, Katherine; Johnston, Richard B; Pham, Khanh N; Rosner, Inger L; Brand, Timothy C; L'Esperance, James O; Sterbis, Joseph R; Etzioni, Ruth; Porter, Christopher R

    2015-07-15

    For patients with low-risk prostate cancer (PCa), active surveillance (AS) may produce oncologic outcomes comparable to those achieved with radical prostatectomy (RP). Health-related quality-of-life (HRQoL) outcomes are important to consider, yet few studies have examined HRQoL among patients with PCa who were managed with AS. In this study, the authors compared longitudinal HRQoL in a prospective, racially diverse, and contemporary cohort of patients who underwent RP or AS for low-risk PCa. Beginning in 2007, HRQoL data from validated questionnaires (the Expanded Prostate Cancer Index Composite and the 36-item RAND Medical Outcomes Study short-form survey) were collected by the Center for Prostate Disease Research in a multicenter national database. Patients aged ≤75 years who were diagnosed with low-risk PCa and elected RP or AS for initial disease management were followed for 3 years. Mean scores were estimated using generalized estimating equations adjusting for baseline HRQoL, demographic characteristics, and clinical patient characteristics. Of the patients with low-risk PCa, 228 underwent RP, and 77 underwent AS. Multivariable analysis revealed that patients in the RP group had significantly worse sexual function, sexual bother, and urinary function at all time points compared with patients in the AS group. Differences in mental health between groups were below the threshold for clinical significance at 1 year. In this study, no differences in mental health outcomes were observed, but urinary and sexual HRQoL were worse for patients who underwent RP compared with those who underwent AS for up to 3 years. These data offer support for the management of low-risk PCa with AS as a means for postponing the morbidity associated with RP without concomitant declines in mental health. © 2015 American Cancer Society.

  14. Variants of callous-unemotional conduct problems in a community sample of adolescents.

    PubMed

    Fanti, Kostas A; Demetriou, Chara A; Kimonis, Eva R

    2013-07-01

    Callous-unemotional traits are believed to be a childhood precursor to psychopathy, and among youth with conduct problems they designate those showing a particularly severe, stable, and aggressive pattern of antisocial behavior. Youth with callous-unemotional traits are a heterogeneous population and, analogous to adults with psychopathy, research suggests that lower anxious primary and high-anxious secondary variants exist. Using a community sample of 2,306 Greek-Cypriot adolescents (M age = 16 years; 49.7 % female), the first aim of the study was to examine whether variants of callous-unemotional traits could be identified using latent profile analysis of scores on measures of callous-unemotional traits, conduct problems, and anxiety. Additional aims of the study were to compare the identified clusters on external measures theorized to distinguish them (i.e., self-esteem, narcissism, impulsivity, sensation seeking and proactive/reactive aggression) and social factors relevant to adolescent development. Results indicated that, in addition to low risk (i.e., low scores on callous-unemotional traits, conduct problems, and anxiety) and anxious (i.e., high scores on anxiety, low scores on callous-unemotional traits and conduct problems) subgroups, two groups of youth scoring high on callous-unemotional traits and conduct problems were identified. High-anxious secondary callous-unemotional variants were distinguished by lower self-esteem in combination with greater narcissism, aggression, and markedly higher conduct problems, whereas lower anxious primary variants showed higher self-esteem. Secondary callous-unemotional variants also reported greater susceptibility to peer pressure and popularity striving than primary variants. Both variants exhibited poorer outcomes relative to low risk and anxious youth, although anxious youth reported lower self-esteem and higher impulsivity and reactive aggression scores in comparison with low risk youth. Findings integrate two

  15. Identification of Patients at Very Low Risk of Local Recurrence After Breast-Conserving Surgery

    SciTech Connect

    Smith, Sally L.; Truong, Pauline T.; Lu, Linghong; Lesperance, Mary; Olivotto, Ivo A.

    2014-07-01

    Purpose: To identify clinical and pathological factors that identify groups of women with stage I breast cancer with a 5-year risk of local recurrence (LR) ≤1.5% after breast-conserving therapy (BCS) plus whole-breast radiation therapy (RT). Methods and Materials: Study subjects were 5974 patients ≥50 years of age whose cancer was diagnosed between 1989 and 2006, and were referred with pT1 pN0 invasive breast cancer treated with BCS and RT. Cases of 5- and 10-year LR were examined using Kaplan-Meier methods. Recursive partitioning analysis was performed in patients treated with and without endocrine therapy to identify combinations of factors associated with a 5-year LR risk ≤1.5%. Results: The median follow-up was 8.61 years. Median age was 63 years of age (range, 50 to 91). Overall 5-year LR was 1.5% (95% confidence interval [CI], 1.2%-1.9%) and 10-year LR was 3.4% (95% CI, 2.8%-4.0%). Of 2830 patients treated with endocrine therapy, patient subsets identified with 5-year LR ≤1.5% included patients with grade 1 histology (n=1038; LR, 0.2%; 95% CI, 0%-0.5%) or grade 2 histology plus ≥60 years of age (n=843; LR, 0.5%; 95% CI, 0%-1.0%). Ten-year LR for these groups were 0.8% (95% CI, 0.1%-1.6%) and 0.9% (95% CI, 0.2%-1.6%), respectively. Of 3144 patients treated without endocrine therapy, patients with grade 1 histology plus clear margins had 5-year LR ≤1.5% (n=821; LR, 0.6%; 95% CI, 0.1%-1.2%). Ten-year LR for this group was 2.2% (95% CI, 1.0%-3.4%). Conclusions: Histologic grade, age, margin status, and use of endocrine therapy identified 45% of a population-based cohort of female patients over age 50 with stage I breast cancer with a 5-year LR risk ≤1.5% after BCS plus RT. Prospective study is needed to evaluate the safety of omitting RT in patients with such a low risk of LR.

  16. Are Campylobacter cases low risk for public health follow-up?

    PubMed

    Lee, Marilyn B; Gournis, Effie; Meldrum, Richard J

    2013-10-31

    Most Campylobacter cases are treated as low risk enterics (LRE) and receive a mailed letter from Toronto Public Health (TPH) with a questionnaire to gather basic risk information. This study sought to identify reasons why Campylobacter cases who were sent this questionnaire did not respond to the letter and to determine whether any of these cases were working in a high-risk occupation. Cases reported to TPH between June 11, 2012 and December 6, 2012 who had not returned the questionnaire within 30 days were telephoned. Participants were asked about awareness of the original letter, reasons for not responding, and whether they worked in a high-risk occupation. Of the 226 cases identified as not responding to the letter, 172 (76.1%) were reached, and 162 (71.7%) answered the survey questions. The most frequent reason chosen for not responding to the original letter was "forgot" (54.4%). The most common suggestion chosen for ways to encourage response to the original letter was "more information on importance of returning questionnaire" (19.1%). Of the 119 cases with a known occupation, 3 (2.4%) were employed in a sensitive occupation - these include a family physician, a food server, and a line cook. None worked while ill. When prompted with a list of reasons for not returning the questionnaire, the majority of respondents indicated that they "forgot" (54.4%); the next most frequent response was "recovered by illness no longer considered it relevant" (21.5%). To increase response rates in the future, a cover letter should more clearly explain why the response is being solicited by Public Health, even after recovery from the illness, and the form should be simplified for mail return. A very small number of clients originally not reached through the course of the routine LRE program were working in sensitive occupations. Since none reported working while ill, the likelihood of direct or indirect transmission of Campylobacter from these three individuals was low. Using

  17. Shared decision making in patients with low risk chest pain: prospective randomized pragmatic trial

    PubMed Central

    Hollander, Judd E; Schaffer, Jason T; Kline, Jeffrey A; Torres, Carlos A; Diercks, Deborah B; Jones, Russell; Owen, Kelly P; Meisel, Zachary F; Demers, Michel; Leblanc, Annie; Shah, Nilay D; Inselman, Jonathan; Herrin, Jeph; Castaneda-Guarderas, Ana; Montori, Victor M

    2016-01-01

    Objective To compare the effectiveness of shared decision making with usual care in choice of admission for observation and further cardiac testing or for referral for outpatient evaluation in patients with possible acute coronary syndrome. Design Multicenter pragmatic parallel randomized controlled trial. Setting Six emergency departments in the United States. Participants 898 adults (aged >17 years) with a primary complaint of chest pain who were being considered for admission to an observation unit for cardiac testing (451 were allocated to the decision aid and 447 to usual care), and 361 emergency clinicians (emergency physicians, nurse practitioners, and physician assistants) caring for patients with chest pain. Interventions Patients were randomly assigned (1:1) by an electronic, web based system to shared decision making facilitated by a decision aid or to usual care. The primary outcome, selected by patient and caregiver advisers, was patient knowledge of their risk for acute coronary syndrome and options for care; secondary outcomes were involvement in the decision to be admitted, proportion of patients admitted for cardiac testing, and the 30 day rate of major adverse cardiac events. Results Compared with the usual care arm, patients in the decision aid arm had greater knowledge of their risk for acute coronary syndrome and options for care (questions correct: decision aid, 4.2 v usual care, 3.6; mean difference 0.66, 95% confidence interval 0.46 to 0.86), were more involved in the decision (observing patient involvement scores: decision aid, 18.3 v usual care, 7.9; 10.3, 9.1 to 11.5), and less frequently decided with their clinician to be admitted for cardiac testing (decision aid, 37% v usual care, 52%; absolute difference 15%; P<0.001). There were no major adverse cardiac events due to the intervention. Conclusions Use of a decision aid in patients at low risk for acute coronary syndrome increased patient knowledge about their risk, increased

  18. Impact of relative contraindications to home management in emergency department patients with low-risk pulmonary embolism.

    PubMed

    Vinson, David R; Drenten, Carrieann E; Huang, Jie; Morley, J Eileen; Anderson, Megan L; Reed, Mary E; Nishijima, Daniel K; Liu, Vincent

    2015-05-01

    Studies of adults presenting to the emergency department (ED) with acute pulmonary embolism (PE) suggest that those who are low risk on the PE Severity Index (classes I and II) can be managed safely without hospitalization. However, the impact of relative contraindications to home management on outcomes has not been described. To compare 5-day and 30-day adverse event rates among low-risk ED patients with acute PE without and with outpatient ineligibility criteria. We conducted a retrospective multicenter cohort study of adults presenting to the ED with acute low-risk PE between 2010 and 2012. We evaluated the association between outpatient treatment eligibility criteria based on a comprehensive list of relative contraindications and 5-day adverse events and 30-day outcomes, including major hemorrhage, recurrent venous thromboembolism, and all-cause mortality. Of 423 adults with acute low-risk PE, 271 (64.1%) had no relative contraindications to outpatient treatment (outpatient eligible), whereas 152 (35.9%) had at least one contraindication (outpatient ineligible). Relative contraindications were categorized as PE-related factors (n = 112; 26.5%), comorbid illness (n = 42; 9.9%), and psychosocial barriers (n = 19; 4.5%). There were no 5-day events in the outpatient-eligible group (95% upper confidence limit, 1.7%) and two events (1.3%; 95% confidence interval [CI], 0.1-5.0%) in the outpatient-ineligible group (P = 0.13). At 30 days, there were five events (two recurrent venous thromboemboli and three major bleeding events) in the outpatient-eligible group (1.8%; 95% CI, 0.7-4.4%) compared with nine in the ineligible group (5.9%; 95% CI, 2.7-10.9%; P < 0.05). This difference remained significant when controlling for PE severity class. Nearly two-thirds of adults presenting to the ED with low-risk PE were potentially eligible for outpatient therapy. Relative contraindications to outpatient management were associated with an increased frequency of

  19. A comparative study of two groups of sex offenders identified as high and low risk on the static-99.

    PubMed

    Coxe, Ray; Holmes, William

    2009-01-01

    The purpose of this study was to identify possible differences between high- and low-risk sex offenders. The subjects included 285 sex offenders on probation. They were evaluated with the Static-99, Abel Assessment, Raven's, and MMPI-2. A criminal history review identified the number of prior offenses and the age/sex category in the index offense. The high- and low-risk groups were compared on 26 variables: intelligence, age, criminal history, denial patterns, measured sexual interest in children, admission of sexual interests, a childhood history of sexual abuse, victim's age, and personality variables. Four variables significantly accounted for 64% of the variance: age, prior number of felonies, the Cognitive Distortion Score, and the MMPI-2 Infrequency scale score.

  20. Joint Attention Development in Low-risk Very Low Birth Weight Infants at Around 18 Months of Age.

    PubMed

    Yamaoka, Noriko; Takada, Satoshi

    2016-10-18

    The purpose of this study was to clarify the developmental characteristics of joint attention in very low birth weight (VLBW) infants with a low risk of complications. Section B of the Checklist for Autism in Toddlers (CHAT) was administered to 31 VLBW and 45 normal birth weight (NBW) infants aged 18-22 months, while the sessions were recorded with a video camera. A semi-structured observation scale was developed to assess infants' joint attention from the video footage, and was shown to be reliable. VLBW, compared to NBW, infants showed significantly poorer skills in 2 of 4 items on responding to joint attention, and in 6 of 10 items on initiating joint attention. VLBW infants need more clues in order to produce joint attention. The difficulty was attributed to insufficient verbal and fine motor function skills. Continuous follow-up evaluation is essential for both high-risk and low-risk VLBW infants and their parents.

  1. Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.

    PubMed

    Lybol, C; Sweep, F C G J; Harvey, R; Mitchell, H; Short, D; Thomas, C M G; Ottevanger, P B; Savage, P M; Massuger, L F A G; Seckl, M J

    2012-06-01

    Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. From 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. In 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p=0.006). Although patients from The Netherlands had a higher level of hCG (p<0.001) and more patients had metastases before the start of treatment (p=0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p=0.375). Relapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Electrophysiological correlates of decision-making in high-risk versus low-risk conditions of a gambling game.

    PubMed

    Yang, Juan; Zhang, Qinglin

    2011-10-01

    The majority of studies investigating risky decision making focus on the high-conflict condition, and very few consider the low-conflict condition in which there is either a very high or a very low probability of risk. Even though the high-risk condition and low-risk condition are both considered low-conflict decision scenarios and both behavioral outcomes are highly predictable, these conditions still differ in terms of the probabilities of reward and punishment. In the following study, we investigated both behavioral and electrophysiological correlates associated with high- and low-risk conditions within the low-conflict scenario, as well as high-conflict condition, in a modified gambling game. The behavioral results showed that, within the low-conflict scenario, the participants took more time to make the decision in the high-risk condition compared to the low-risk condition. The event-related potentials (ERP) data showed that, during the decision making, the high-risk condition evoked a more negative ERP deflection than did the low-risk condition in the time window of 300-500 ms (N400), which had a frontocentral focus of scalp distribution. The results suggested that the high-risk condition was associated with a higher conflict between the participants' "motivationally based" tendency to want to receive cards and the task instructions, which stated that the face value of the first two cards will strongly predict a low probability of success. It was further speculated that the N400 in the present study might be associated with anticipation of negative rewards, which was functionally equivalent to the FRN (feedback-related negativity) to negative outcomes.

  3. Effect of the Low Risk Ankle Rule on the frequency of radiography in children with ankle injuries

    PubMed Central

    Boutis, Kathy; Grootendorst, Paul; Willan, Andrew; Plint, Amy C.; Babyn, Paul; Brison, Robert J.; Sayal, Arun; Parker, Melissa; Mamen, Natalie; Schuh, Suzanne; Grimshaw, Jeremy; Johnson, David; Narayanan, Unni

    2013-01-01

    Background: The Low Risk Ankle Rule is a validated clinical decision rule that has the potential to safely reduce radiography in children with acute ankle injuries. We performed a phased implementation of the Low Risk Ankle Rule and evaluated its effectiveness in reducing the frequency of radiography in children with ankle injuries. Methods: Six Canadian emergency departments participated in the study from Jan. 1, 2009, to Aug. 31, 2011. At the 3 intervention sites, there were 3 consecutive 26-week phases. In phase 1, no interventions were implemented. In phase 2, we activated strategies to implement the ankle rule, including physician education, reminders and a computerized decision support system. In phase 3, we included only the decision support system. No interventions were introduced at the 3 pair-matched control sites. We examined the management of ankle injuries among children aged 3–16 years. The primary outcome was the proportion of children undergoing radiography. Results: We enrolled 2151 children with ankle injuries, 1055 at intervention and 1096 at control hospitals. During phase 1, the baseline frequency of pediatric ankle radiography at intervention and control sites was 96.5% and 90.2%, respectively. During phase 2, the frequency of ankle radiography decreased significantly at intervention sites relative to control sites (between-group difference −21.9% [95% confidence interval [CI] −28.6% to −15.2%]), without significant differences in patient or physician satisfaction. All effects were sustained in phase 3. The sensitivity of the Low Risk Ankle Rule during implementation was 100% (95% CI 85.4% to 100%), and the specificity was 53.1% (95% CI 48.1% to 58.1%). Interpretation: Implementation of the Low Risk Ankle Rule in several different emergency department settings reduced the rate of pediatric ankle radiography significantly and safely, without an accompanying change in physician or patient satisfaction. Trial registration: Clinical

  4. A prognostic score to identify low-risk outpatients with acute deep vein thrombosis in the lower limbs.

    PubMed

    Trujillo-Santos, Javier; Lozano, Francisco; Lorente, Manuel Alejandro; Adarraga, Dolores; Hirmerova, Jana; Del Toro, Jorge; Mazzolai, Lucia; Barillari, Giovanni; Barrón, Manuel; Monreal, Manuel

    2015-01-01

    No prior studies have identified which patients with deep vein thrombosis in the lower limbs are at a low risk for adverse events within the first week of therapy. We used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to identify patients at low risk for the composite outcome of pulmonary embolism, major bleeding, or death within the first week. We built a prognostic score and compared it with the decision to treat patients at home. As of December 2013, 15,280 outpatients with deep vein thrombosis had been enrolled. Overall, 5164 patients (34%) were treated at home. Of these, 12 (0.23%) had pulmonary embolism, 8 (0.15%) bled, and 4 (0.08%) died. On multivariable analysis, chronic heart failure, recent immobility, recent bleeding, cancer, renal insufficiency, and abnormal platelet count independently predicted the risk for the composite outcome. Among 11,430 patients (75%) considered to be at low risk, 15 (0.13%) suffered pulmonary embolism, 22 (0.19%) bled, and 8 (0.07%) died. The C-statistic was 0.61 (95% confidence interval [CI], 0.57-0.65) for the decision to treat patients at home and 0.76 (95% CI, 0.72-0.79) for the score (P = .003). Net reclassification improvement was 41% (P < .001). Integrated discrimination improvement was 0.034 for the score and 0.015 for the clinical decision (P < .001). Using 6 easily available variables, we identified outpatients with deep vein thrombosis at low risk for adverse events within the first week. These data may help to safely treat more patients at home. This score, however, should be validated. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Performance of multiparametric magnetic resonance imaging in the evaluation and management of clinically low-risk prostate cancer

    PubMed Central

    Dianat, Seyed Saeid; Carter, H. Ballentine; Macura, Katarzyna J.

    2014-01-01

    Objective The purpose of this article is to review the multiparametric magnetic resonance imaging (mMRI) of the prostate and MR-guided prostate biopsy, and their role in the evaluation and management of men with low-risk prostate cancer. Methods We performed a literature review based on the MEDLINE database search for publications on the role of mMRI (a) in detection and localization of prostate cancer, prediction of tumor aggressiveness and progression and (b) in guiding targeted prostate biopsy. Results The mMRI, particularly diffusion-weighted imaging with T2-weighted imaging, is a useful tool for tumor localization in low-risk prostate cancer as it can detect lesions that are more likely missed on extended biopsy schemes and can identify clinically significant disease requiring definitive treatment. The MR-guided biopsy of the most suspicious lesions enables more accurate and safer approach to guide enrollment into the active surveillance program. However, the MR-guided biopsy is complex. The fusion of MRI data with transrectal ultrasound for the purpose of biopsy provides a more feasible technique with documented accurate sampling. Conclusion Although the mMRI is not routinely used for risk stratification and prognostic assessment in prostate cancer, it can provide valuable information to guide management of men with low-risk disease. Incorporation of mMRI into the workup and monitoring of patients with low-risk prostate cancer can help discriminate clinically significant disease from indolent disease. Targeted biopsy of MR-suspicious lesions enables accurate sampling of potentially aggressive tumors that may affect outcomes. PMID:23787297

  6. Thyrotropin Suppressive Therapy for Low-Risk Small Thyroid Cancer: A Propensity Score-Matched Cohort Study.

    PubMed

    Park, Suyeon; Kim, Won Gu; Han, Minkyu; Jeon, Min Ji; Kwon, Hyemi; Kim, Mijin; Sung, Tae-Yon; Kim, Tae Yong; Kim, Won Bae; Hong, Suck Joon; Shong, Young Kee

    2017-09-01

    Thyrotropin (TSH) suppression has improved the clinical outcomes of patients with differentiated thyroid cancer (DTC). However, the efficacy of TSH suppressive therapy (TST) is unclear in patients with low-risk DTC. This study aimed to evaluate the efficacy of TST and optimal TSH levels of patients with low-risk DTC. This retrospective propensity score-matched cohort study included DTC patients (n = 446) who underwent lobectomy from 2002 to 2008 with or without TST (TST group and No-TST group). Disease-free survival (DFS) and dynamic risk stratification were compared between both groups using serum TSH levels. Approximately 74% of TST patients and 11% of No-TST patients had suppressed serum TSH levels (<2 mIU/L). The median follow-up period was 8.6 years. During follow-up, the disease recurred in 10 (2.7%) patients, with no significant difference in DFS between the groups (p = 0.63). The proportion of patients with excellent treatment response was similar between the TST (65.2%) and No-TST (64.4%) groups. Incomplete biochemical response was noted in 17.2% of the TST group patients and 9.4% of the No-TST group patients. No significant difference was observed in the DFS between both groups by comparing serum TSH level (p = 0.57). TST did not improve clinical outcomes, and serum TSH levels were not associated with recurrence in patients with low-risk small DTC. No clinical benefits were shown for TSH suppression in low-risk patients who underwent lobectomy. Thus, levothyroxine is not necessary for patients without evidence of hypothyroidism.

  7. Alcohol-related hospitalization is associated with increased risk of ischaemic stroke among low-risk patients with atrial fibrillation.

    PubMed

    Al-Khalili, Faris; Benson, Lina; Friberg, Leif

    2017-02-23

    Patients with atrial fibrillation (AF) under the age of 65 and CHA2DS2-VASc risk score of 0 in men or 1 in women are considered to be at low risk for ischaemic stroke, and therefore without benefit of oral anticoagulation therapy. The objective of this study is to assess the incidence and predictors of ischaemic stroke among low-risk patients with AF identified from a National Patient Register. A retrospective study of 25 252 low-risk AF patients (age 18-64) out of total 345 123 AF patients identified from the Swedish Nationwide Patient Register for the period 1 January 2006 to 31 December 2012. During a median follow-up of 5.0 (interquartile range 2.9-6.8) years, ischaemic stroke occurred at an annual rate of 0.34 per 100 patient-years [95% confidence interval (CI) 0.31-0.38]. Significant predictors of stroke were age, hazard ratio (HR) 1.06 (CI 1.05-1.08) per incremental year, and previous alcohol-related hospitalization HR 2.01 (CI 1.45-2.79). Intracerebral bleeding events were rare and not statistically different HR 2.05 (CI 0.76-5.56) between patients with and without alcohol-related hospitalizations. Use of oral anticoagulants was associated with lower risk for ischaemic stroke, HR 0.78 (CI 0.63-0.97). The presence of a previous hospitalization with an alcohol-related disease was associated with a small but significant increase in the risk of stroke among low-risk AF patients. More research about relation between alcohol use and ischaemic stroke in AF patients is warranted.

  8. [C-section rate in low-risk women: a useful indicator to compare hospitals attending deliveries with different risks].

    PubMed

    Librero, Julián; Peiró, Salvador; Belda, Ana; Calabuig, Julia

    2014-01-01

    the C-section rate has been criticized as a performance indicator for not considering that different hospitals manage deliveries with diverse risks. In this work we explore the characteristics of a new indicator restricted to low C-section risk deliveries. retrospective cohort of all births (n=214,611) in all public hospitals during 2005-2010 in the Valencia Region, Spain (source: minimum basic dataset). A low-risk subpopulation consisting of women under-35, no history of c-section, between 37 and 41 gestational weeks, and with a single fetus, with cephalic presentation and normal weight (2500-3999 g) was constructed. We analyzed variability in the new indicator, its correlation with the crude indicator and, using multilevel logistic regression models, the presence of residual risks. a total of 117 589 births (58.4% of the whole deliveries) were identified as low C-section risk. The c-section rate in these women was 11.9% (24.4% for all deliveries) ranging between hospitals from 7.0% to 28.9%. The c-section rate in low-risk and total deliveries correlated strongly (r=0.88). The remaining risks in the population of low risk did not alter the hospital effect on the c-section rate. the percentage of C-section in low risk women include a high volume of deliveries, correlated with the crude indicator and residual risks are not differentially influenced by hospitals, being a useful indicator for monitoring the quality of obstetric care in the National Health System.

  9. Narrowing Resection of Parametrial Tissues Is Feasible in Low-Risk Cases of Stage IA2-IB1 Cervical Cancer

    PubMed Central

    Li, Xue-Lian; Liu, Xiao-Xia; Cao, Guan-Shu; Ju, Dan-Dan; Jiang, Hua

    2016-01-01

    BACKGROUND: Radical hysterectomy with pelvic lymphadenectomy is the standard surgical treatment for patients with stage IA2-IB1 cervical cancer, but the wide excision increases the complications. OBJECTIVE: To analyze the feasibility of narrowing resection of parametrial tissues in stage IA2-IB1 cervical cancer. STUDY DESIGN: Retrospectively analyzed the pathological and clinical data of patients with stage IA2-IB1 cervical cancer who received radical hysterectomy with pelvic lymphadenectomy in OB/GYN Hospital, Fudan University, China from Jan 2008 to Dec 2011. The affected factors of parametrial metastases and outcomes were discussed. The single factor analysis was made with χ2 test, and the relationship of the resection width of parametrial tissues and the patients' outcomes was analyzed with χ2 test and log-rank. P-values <0.05 were considered statistically significant. RESULTS: There were 31 cases recurred, 26 cases died of cervical cancer in 513 patients during the follow-up period (from 2 months to 66 months, averaged 39 months). The low-risk factors included diameter of tumor ≤2cm, depth of cervical myometrial invasion<1/2 and without lymph vascular involvement. There were no parametrial metastases in cases with all three low-risk factors. Whether the resection width of parametrial tissues ≥3cm or not had no statistically significant effect on progression free survival (PFS) or overall survival (OS) of low-risk patients. D2-40 and CD31 were related with parametrial metastases, but not with recurrence or outcomes. CONCLUSIONS: The resection width of parametrial tissues has no effect on PFS and OS of low-risk patients, and narrowing resection of parametrial tissues (<3cm) is feasible. PMID:27471564

  10. Long-Term Prognosis of Low-Risk Women Presenting to the Emergency Department with Chest Pain.

    PubMed

    Eddin, Moneer; Venugopal, Sandhya; Chatterton, Brittany; Thinda, Angela; Amsterdam, Ezra A

    2017-04-29

    Prognosis of low-risk women presenting to the emergency department (ED) with chest pain has not been clarified. We assessed early and long-term outcomes of such patients and determined the need for predischarge testing. Retrospective assessment of consecutive low-risk women presenting to the ED with chest pain evaluated in a chest pain unit (CPU). Criteria of low risk: age ≤51 years; no history of cardiovascular disease, diabetes, or smoking; negative initial electrocardiogram (ECG); and cardiac troponin. Predischarge testing (treadmill or stress imaging) was performed at the discretion of the CPU attending physician. The study group comprised 214 consecutive women. Predischarge testing was performed in 142 patients (66%, age 43.9 years) and 72 patients (34%, age 43.1 years) had no predischarge testing. Predischarge testing comprised exercise treadmill (n = 102, 72%) or stress imaging (n = 40, 28%). Length of stay with no predischarge testing was 4.1 hours, compared with 8.6 hours with predischarge testing (P = .04). There were no cardiovascular events in the index presentation; during a 5-year interval (100% follow-up), there were 2 cardiovascular events (fatal heart failure, 1 patient; fatal stroke, 1 patient [total, 2/214, 0.93%]). Low-risk women presenting to the ED with chest pain have an excellent short- and long-term prognosis. A majority of patients did not receive predischarge testing, and their length of stay was reduced by >50% compared with those with predischarge testing. These findings suggest that such patients may not require predischarge testing for disposition from a CPU, which can reduce length of stay, decrease cost, and improve resource utilization. Copyright © 2017. Published by Elsevier Inc.

  11. Alternative versus standard packages of antenatal care for low-risk pregnancy

    PubMed Central

    Dowswell, Therese; Carroli, Guillermo; Duley, Lelia; Gates, Simon; Gülmezoglu, A Metin; Khan-Neelofur, Dina; Piaggio, Gilda GP

    2014-01-01

    Background The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. Objectives To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (April 2010), reference lists of articles and contacted researchers in the field. Selection criteria Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, with standard care. Data collection and analysis Two authors assessed trial quality and extracted data independently. Main results We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more ‘goal oriented’. Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (five trials; risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (2 trials; RR 0.90; 95% CI 0.45 to 1.80); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (3 trials RR 1.15; 95% CI 1.01 to 1

  12. Intravenous fluids for reducing the duration of labour in low risk nulliparous women.

    PubMed

    Dawood, Feroza; Dowswell, Therese; Quenby, Siobhan

    2013-06-18

    Several factors may influence the progression of normal labour. It has been postulated that the routine administration of intravenous fluids to keep women adequately hydrated during labour may reduce the period of contraction and relaxation of the uterine muscle, and may ultimately reduce the duration of the labour. It has also been suggested that intravenous fluids may reduce caesarean sections (CS) for prolonged labour. However, the routine administration of intravenous fluids to labouring women has not been adequately elucidated although it is a widely-adopted policy, and there is no consensus on the type or volume of fluids that are required, or indeed, whether intravenous fluids are at all necessary. Women may be able to adequately hydrate themselves if they were allowed oral fluids during labour.Furthermore, excessive volumes of intravenous fluids may pose risks to both the mother and her newborn and different fluids are associated with different risks. To evaluate whether the routine administration of intravenous fluids to low-risk nulliparous labouring women reduces the duration of labour and to evaluate the safety of intravenous fluids on maternal and neonatal health. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). Randomised controlled trials of intravenous fluid administration to spontaneously labouring low-risk nulliparous women. The review authors independently assessed trials for inclusion, trial quality and extracted data. We included nine randomised trials with 1781 women. Three trials had more than two treatment arms and were included in more than one comparison.Two trials compared women randomised to receive up to 250 mL/hour of Ringer's lactate solution as well as oral intake versus oral intake only. For women delivering vaginally, there was a reduction in the duration of labour in the Ringer's lactate group (mean difference (MD) -28.86 minutes, 95% confidence interval (CI) -47.41 to -10.30). There

  13. [Open clinical trial with oral acyclovir for the prophylaxis of disease by Cytomegalovirus in low risk liver transplant recipients].

    PubMed

    Moreno, J; Montero, J L; Gavilán, F; Costán, G; Herrero, C; Cárdenas, M; Sánchez-Guijo, P; Torre-Cisneros, J

    1999-10-01

    Checking the first 70 low risk liver transplantation performed in our hospital, who did not receive prophylaxis for Cytomegalovirus, we found that the incidence of Cytomegalovirus-infection and Cytomegalovirus-disease were 47% and 16% respectively. For this reason we started a prospective, open clinical study, to address the safety of acyclovir prophylaxis in low-risk liver transplant patients. Seventy patients did not receive acyclovir. Fifty patients received oral acyclovir during 3 months (800-3,200 mg/day). The occurrence of Cytomegalovirus infection was not modified (40%) but Cytomegalovirus disease decreased dramatically (4%, p < 0.01) during the first year after transplantation. Acyclovir was well tolerated. The incidence of leukopenia and renal failure were similar in both groups. Acyclovir did not improved the global survival of patients. Thus, oral acyclovir does not reduce Cytomegalovirus infection although it is efficient and safe in the prevention of Cytomegalovirus disease in low-risk liver transplantation, and prevents Herpes-simplex and Varicela-zoster symptomatic disease in this group of patients.

  14. Application of a neonatal assessment of visual function in a population of low risk full-term newborn.

    PubMed

    Ricci, Daniela; Romeo, Domenico M M; Serrao, Francesca; Cesarini, Laura; Gallini, Francesca; Cota, Francesco; Leone, Daniela; Zuppa, Antonio A; Romagnoli, Costantino; Cowan, Frances; Mercuri, Eugenio

    2008-04-01

    We have previously developed and described a battery of 9 items suitable for assessing different clinical aspects of visual function in newborn infants. Application of the test battery to a cohort of low risk term-born infants at 48 and 72 h after birth 1) to define the normative distribution of results for each item and 2) to document any effect of postnatal age. 124 term-born low risk infants were assessed at 48 h; fifty of them were re-assessed 24 h later at 72 h. The visual test battery was successfully completed in 110 of the 124 infants assessed at 48 h and in all the 50 infants assessed at 72 h after birth. For 3 of the 9 items (fixation on a black/white target of concentric circles, on a coloured (red/yellow) face and horizontal tracking), the findings were very similar at both ages. For the remaining 6 items the range of findings was wider. There was a statistical difference in the responses obtained at 48 and 72 h for vertical and arc tracking (p<0.05) and the ability to discriminate stripes and attention at distance (p<0.001). Our results provide information on the visual abilities in a low risk population of term-born infants and the distribution of frequency of their visual responses to our battery of visual tests. These findings may be used as reference data when using our visual test battery in both clinical and research settings.

  15. Results of allogeneic stem cell transplantation in the Spanish MDS registry: prognostic factors for low risk patients.

    PubMed

    Díez Campelo, M; Sánchez-Barba, M; de Soria, V Gómez-García; Martino, R; Sanz, G; Insunza, A; Bernal, T; Duarte, R; Amigo, M L; Xicoy, B; Tormo, M; Iniesta, F; Bailén, A; Benlloch, L; Córdoba, I; López-Villar, O; Del Cañizo, M C

    2014-10-01

    Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics.

  16. Identification of patients at low risk of dying after acute myocardial infarction, by simple clinical and submaximal exercise test criteria.

    PubMed

    Campbell, S; A'Hern, R; Quigley, P; Vincent, R; Jewitt, D; Chamberlain, D

    1988-09-01

    A consecutive series of 559 hospital survivors of acute myocardial infarction aged less than 66 years were studied; 93 were designated prospectively as low-risk because they were suitable for early submaximal exercise testing and had none of the following clinical or exercise test 'risk factors': (1) angina for at least one month prior to infarction; (2) symptomatic ventricular arrhythmias, or (3) recurrent ischaemic pain, both after the first 24 h of infarction; (4) cardiac failure; (5) cardiomegaly; and (6) an abnormal exercise test (angina, ST-depression or poor blood pressure response). Altogether 301 patients were exercised; their mortality over a median follow-up of 2.4 years was 10.2%, versus 24.6% in the 258 patients not exercised (P = 0.0005). Absence of clinical 'risk factors' alone, in the exercised patients, identified 156 with a mortality of 5.4% versus 15.6% in the 145 with at least one clinical 'risk factor' (P = 0.004). The fully defined low-risk group comprised 93 of the former patients who had neither clinical nor exercise test 'risk factors'. None of these patients died compared with 19 of those with at least one 'risk factor' (mortality = 14.7%; P = 0.002). Their respective rates of non-fatal reinfarction were similar and never exceeded 5% per annum. Therefore, simple clinical and exercise test criteria can positively identify low-risk patients after infarction in whom secondary prevention may be inappropriate.

  17. Cognitive and Affective Representations of Active Surveillance as a Treatment Option for Low-Risk Prostate Cancer.

    PubMed

    Lyons, Kathleen D; Li, Hsin H; Mader, Emily M; Stewart, Telisa M; Morley, Christopher P; Formica, Margaret K; Perrapato, Scott D; Seigne, John D; Hyams, Elias S; Irwin, Brian H; Mosher, Terry; Hegel, Mark T

    2016-06-29

    Benefits of early diagnosis and treatment remain debatable for men with low-risk prostate cancer. Active surveillance (AS) is an alternative to treatment. The goal of AS is to identify patients whose cancer is progressing rapidly while avoiding treatment in the majority of patients. The purpose of this study was to explore cognitive and affective representations of AS within a clinical environment that promotes AS a viable option for men with low-risk prostate cancer. Participants included patients for whom AS and active treatment were equally viable options, as well as practitioners who were involved in consultations for prostate cancer. Data were generated from semistructured interviews and audits of consultation notes and were analyzed using thematic analysis. Nineteen patients and 16 practitioners completed a semistructured interview. Patients generally viewed AS as a temporary strategy that was largely equated with inaction. There was variation in the degree to which inaction was viewed as warranted or favorable. Patient perceptions of AS were generally malleable and able to be influenced by information from trusted sources. Encouraging slow deliberation and multiple consultations may facilitate greater understanding and acceptance of AS as a viable treatment option for low-risk prostate cancer. © The Author(s) 2016.

  18. Qualitative insights into how men with low-risk prostate cancer choosing active surveillance negotiate stress and uncertainty.

    PubMed

    Mader, Emily M; Li, Hsin H; Lyons, Kathleen D; Morley, Christopher P; Formica, Margaret K; Perrapato, Scott D; Irwin, Brian H; Seigne, John D; Hyams, Elias S; Mosher, Terry; Hegel, Mark T; Stewart, Telisa M

    2017-05-08

    Active surveillance is a management strategy for men diagnosed with early-stage, low-risk prostate cancer in which their cancer is monitored and treatment is delayed. This study investigated the primary coping mechanisms for men following the active surveillance treatment plan, with a specific focus on how these men interact with their social network as they negotiate the stress and uncertainty of their diagnosis and treatment approach. Thematic analysis of semi-structured interviews at two academic institutions located in the northeastern US. Participants include 15 men diagnosed with low-risk prostate cancer following active surveillance. The decision to follow active surveillance reflects the desire to avoid potentially life-altering side effects associated with active treatment options. Men on active surveillance cope with their prostate cancer diagnosis by both maintaining a sense of control over their daily lives, as well as relying on the support provided them by their social networks and the medical community. Social networks support men on active surveillance by encouraging lifestyle changes and serving as a resource to discuss and ease cancer-related stress. Support systems for men with low-risk prostate cancer do not always interface directly with the medical community. Spousal and social support play important roles in helping men understand and accept their prostate cancer diagnosis and chosen care plan. It may be beneficial to highlight the role of social support in interventions targeting the psychosocial health of men on active surveillance.

  19. Group B streptococcal opacity variants.

    PubMed Central

    Pincus, S H; Cole, R L; Wessels, M R; Corwin, M D; Kamanga-Sollo, E; Hayes, S F; Cieplak, W; Swanson, J

    1992-01-01

    Colony opacity variants were detected for type III group B streptococci (GBS). Transparent colonies predominate in the parent GBS, with occasional colonies having opaque portions. Two stable opaque variants (1.1 and 1.5) were compared with three transparent clones (1.2, 1.3, and 1.4). All grew well on blood agar and on GC medium, but variant 1.1 failed to grow on Todd-Hewitt medium. Scanning and transmission electron microscopy demonstrated that colony opacity correlated with bacterial aggregation status, with opaque variants forming longer and more organized chains. Opaque-transparent switches were observed in both directions for most variants, with transparent to opaque noted most frequently, but 1.5 did not switch at all. Switching of the opacity phenotype was observed both in vitro and in neonatal mice. Relationships between colony opacity and several cell surface phenomena were explored. (i) Opaque variant 1.1 had two surface proteins (46 and 75 kDa) that were either unique or greatly overexpressed. (ii) Variant 1.1 was deficient in type III polysaccharide, while 1.5 lacked group B antigen. Diminished capsular polysaccharide of variant 1.1 was reflected in reduced negative electrophoretic mobility and in increased buoyant density. (iii) Transparent variant colonies growing closest to a penicillin disk were opaque, but colonial variants did not differ in their sensitivity to penicillin. These data indicate that GBS can exist in both opaque and transparent forms, with opaque appearance occurring by multiple routes. Opaque variants grow poorly on Todd-Hewitt medium generally used for isolation of GBS, so any possible relationships between opacity variation and pathogenesis of GBS infection are unknown. Images PMID:1592825

  20. Variants of windmill nystagmus.

    PubMed

    Choi, Kwang-Dong; Shin, Hae Kyung; Kim, Ji-Soo; Kim, Sung-Hee; Choi, Jae-Hwan; Kim, Hyo-Jung; Zee, David S

    2016-07-01

    Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration.

  1. [FRAX® thresholds to identify people with high or low risk of osteoporotic fracture in Spanish female population].

    PubMed

    Azagra, Rafael; Roca, Genís; Martín-Sánchez, Juan Carlos; Casado, Enrique; Encabo, Gloria; Zwart, Marta; Aguyé, Amada; Díez-Pérez, Adolf

    2015-01-06

    To detect FRAX(®) threshold levels that identify groups of the population that are at high/low risk of osteoporotic fracture in the Spanish female population using a cost-effective assessment. This is a cohort study. Eight hundred and sixteen women 40-90 years old selected from the FRIDEX cohort with densitometry and risk factors for fracture at baseline who received no treatment for osteoporosis during the 10 year follow-up period and were stratified into 3 groups/levels of fracture risk (low<10%, 10-20% intermediate and high>20%) according to the real fracture incidence. The thresholds of FRAX(®) baseline for major osteoporotic fracture were: low risk<5; intermediate ≥ 5 to <7.5 and high ≥ 7.5. The incidence of fracture with these values was: low risk (3.6%; 95% CI 2.2-5.9), intermediate risk (13.7%; 95% CI 7.1-24.2) and high risk (21.4%; 95% CI12.9-33.2). The most cost-effective option was to refer to dual energy X-ray absorptiometry (DXA-scan) for FRAX(®)≥ 5 (Intermediate and high risk) to reclassify by FRAX(®) with DXA-scan at high/low risk. These thresholds select 17.5% of women for DXA-scan and 10% for treatment. With these thresholds of FRAX(®), compared with the strategy of opportunistic case finding isolated risk factors, would improve the predictive parameters and reduce 82.5% the DXA-scan, 35.4% osteoporosis prescriptions and 28.7% cost to detect the same number of women who suffer fractures. The use of FRAX ® thresholds identified as high/low risk of osteoporotic fracture in this calibration (FRIDEX model) improve predictive parameters in Spanish women and in a more cost-effective than the traditional model based on the T-score ≤ -2.5 of DXA scan. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  2. Setting up low-risk bone marrow transplantation for children with thalassemia may facilitate pediatric cancer care.

    PubMed

    Faulkner, Lawrence B

    2013-07-01

    In many South Asian countries there is shortage of centers providing care for pediatric malignancies. This report describes the experience of the Cure2Children Foundation (C2C) in supporting, both financially and professionally, the startup of two bone marrow transplant (BMT) centers, one in Pakistan and one in India, for the cure of transfusion-dependent thalassemia. Even though transplantation is generally considered as a more complex and advanced step relatively to basic pediatric cancer care, the authors argue that BMT for low-risk thalassemia patients with a matched sibling is a relatively simple procedure amenable to focused training. Since 2008 the C2C, an Italian Nongovernmental Organization (NGO), has supported a BMT network in Pakistan. The primary aim of this project was to assess feasibility, outcomes, and costs of matched-related BMT for thalassemia in young low-risk children employing a well established and quite tolerable strategy employed in Italy. This initiative relied primarily on focused training and task-shift strategies within a structured cooperation program. The initial success of that strategy led to its replication in India with 100 total BMTs performed over the past 4 years, 91 of which were for thalassemia major. Low-risk matched-related BMT in children younger than 5 years could deliver a 92% thalassemia-free survival with 100% performance score and no extensive chronic graft versus host disease (GVHD), for an average cost of 10,000 USD per BMT. Within an existing hospital facility, 50,000 USD were sufficient to renovate and fully equip a 2-3 bedded start up BMT unit capable of performing safe low-risk compatible marrow transplantation. In low resource settings matched-related low-risk BMT for thalassemia can be performed with outcomes comparable to richer countries and with a fraction of the costs. Within structured and intensive cooperation, good outcomes can be obtained from the very beginning. This observation may have important

  3. Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone.

    PubMed

    Couder, Florence; Massardier, Jérôme; You, Benoît; Abbas, Fatima; Hajri, Touria; Lotz, Jean-Pierre; Schott, Anne-Marie; Golfier, François

    2016-07-01

    Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86-8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR = 5.96; 95% CI, 1.40-25.4, P = .016), a number of methotrexate courses superior to 5 courses (5-8 courses vs 1-4: HR = 6.19; 95% CI, 1.43-26.8, P = .015; 9 courses and more vs 1-4: HR = 6.80; 95% CI, 1.32-35.1, P = .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR = 1.27; 95% CI, 1.09-1.49, P = .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia

  4. Election 2016: Voting on Variants.

    PubMed

    Cho, Raymond J; Collisson, Eric A

    2016-07-01

    Genome sequencing studies increasingly identify variants of unknown significance in provocative genes. Kim and colleagues present a system with which to functionally annotate such variants in a high-throughput, biologically relevant series of assays. Cancer Discov; 6(7); 694-6. ©2016 AACRSee related article by Kim et al., p. 714.

  5. Variant (Swine Origin) Influenza Viruses in Humans

    MedlinePlus

    ... Types Seasonal Avian Swine Variant Other Variant Influenza Viruses: Background and CDC Risk Assessment and Reporting Language: ... Background CDC Assessment Reporting Background On Variant Influenza Viruses Swine flu viruses do not normally infect humans. ...

  6. Cellobiohydrolase variants and polynucleotides encoding same

    DOEpatents

    Wogulis, Mark

    2013-09-24

    The present invention relates to variants of a parent cellobiohydrolase II. The present invention also relates to polynucleotides encoding the variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

  7. Cellobiohydrolase variants and polynucleotides encoding same

    DOEpatents

    Wogulis, Mark

    2014-10-14

    The present invention relates to variants of a parent cellobiohydrolase II. The present invention also relates to polynucleotides encoding the variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

  8. Cellobiohydrolase variants and polynucleotides encoding the same

    DOEpatents

    Wogulis, Mark

    2014-09-09

    The present invention relates to variants of a parent cellobiohydrolase. The present invention also relates to polynucleotides encoding the cellobiohydrolase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the cellobiohydrolase variants.

  9. Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus.

    PubMed

    Camp, Nicola J; Lin, Wei-Yu; Bigelow, Alex; Burghel, George J; Mosbruger, Timothy L; Parry, Marina A; Waller, Rosalie G; Rigas, Sushilaben H; Tai, Pei-Yi; Berrett, Kristofer; Rajamanickam, Venkatesh; Cosby, Rachel; Brock, Ian W; Jones, Brandt; Connley, Dan; Sargent, Robert; Wang, Guoying; Factor, Rachel E; Bernard, Philip S; Cannon-Albright, Lisa; Knight, Stacey; Abo, Ryan; Werner, Theresa L; Reed, Malcolm W R; Gertz, Jason; Cox, Angela

    2016-04-01

    The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916-25. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. Risk assessment of lymph node metastasis before surgery in endometrial cancer: do we need a clinical trial for low-risk patients?

    PubMed

    Kang, Sokbom; Todo, Yukiharu; Watari, Hidemichi

    2014-02-01

    Due to advances of radiological imaging and tumor biomarkers, the extent of information provided by preoperative assessment is rapidly growing. The Korean Gynecologic Oncology Group (KGOG) recently proposed new preoperative criteria to identify patients at low risk for lymph node metastasis in endometrial cancer. In the multicenter study, serum carbohydrate antigen 125 levels and three magnetic resonance imaging parameters were found to be independent risk factors for nodal metastasis, and classified 53% of patients as part of a low-risk group. The false-negative predictive value (NPV) was 1.7%, and was 1.4% in the validation set. Furthermore, the KGOG low-risk criteria were validated in 319 Japanese patients with endometrial cancer. The criteria identified 181 of 319 patients as a low-risk group (51%), and three false-negative cases were found (1.9%). These results indicate that we are able to identify low-risk patients with a negligible NPV before surgery. In addition, the low false NPV implies that there is great difficulty in performing a randomized trial to determine the efficacy of routine lymphadenectomy in patients at low risk of lymph node metastasis. Based on these data, the challenges and possible solutions for developing a consensus on the optimized management of low-risk endometrial cancer will be discussed in this review. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  11. Once-daily, oral levofloxacin monotherapy for low-risk neutropenic fever in cancer patients: a pilot study in China.

    PubMed

    He, Lixian; Zhou, Caicun; Zhao, Su; Weng, Heng; Yang, Guowang

    2015-03-01

    This pilot study assesses the safety and efficacy of once-daily, oral levofloxacin monotherapy in Chinese patients with low-risk febrile neutropenia. In this prospective, single-arm, open-label, multicenter clinical trial, 46 adult Chinese patients with solid tumors and low-risk febrile neutropenia were included. Patients received oral levofloxacin monotherapy (500 mg orally/day) until day 12, followed by 7 days of follow-up (day 19). Body temperature was measured three times per day. On days 2, 3, 5-7, 9, 12, and 19, disease symptoms and vital signs were recorded, adverse drug reactions were assessed, and blood samples were collected to determine the whole-blood cell count and the absolute neutrophil count. Blood cultures and chest radiographs were performed simultaneously until negative results were found. Oral levofloxacin was effective and well tolerated in 97.6% of patients irrespective of the cancer type and cause of fever. Body temperature began to decline in 24.4, 68.3, and 90.2% of patients, respectively, at 12, 24, and 48 h after initiating levofloxacin therapy. On days 5 and 7, 95.1 and 97.6% of the patients had complete defervescence, respectively. The median time for absolute neutrophil count recovery to at least 1500/mm after initiation of treatment was 3 days. Only one patient reported mild diarrhea. This pilot study showed that oral levofloxacin quickly and effectively reduced fever, initiated neutrophil recovery, and was well tolerated in Chinese low-risk febrile neutropenic patients with solid tumors. Further study is needed to compare patient data of levofloxacin with the standard amoxicillin/ciprofloxacin protocol in this population for both safety and efficacy.

  12. Molecular genotyping of HPV L1 gene in low-risk and high-risk populations in Bangkok

    PubMed Central

    Leaungwutiwong, Pornsawan; Bamrungsak, Busara; Jittmittraphap, Akanitt; Maneekan, Pannamas; Kosoltanapiwat, Nathamon; Kalambaheti, Thareerat; Kelley, James F.

    2015-01-01

    Background Human papillomavirus (HPV) infections in Thailand are a public health concern but information on HPV infection in sex workers and men who have sex with men (MSM) is limited. The aim of this study was to measure the prevalence and genotype distribution of HPV among low- and high-risk, HIV-negative populations. Methods A total of 300 participants were categorized as general women, female sex workers, MSM, and MSM sex workers. HPV infections were identified by the Papanicolaou (Pap) test and nested-PCR. A phylogenetic analysis of partial HPV L1 genes was performed. Results Abnormal cytology was found in 5% of general women, 10% of female sex workers, 24% of MSM and 28% of MSM sex workers. HPV was detected in 9% of general women, 13% of female sex workers and 30% in both MSM and the MSM sex workers. The prevalence of HPV high-risk genotypes was significantly higher in female sex workers and MSM while low-risk genotypes and genital warts were significantly higher in MSM sex workers. Significantly more patients with genital warts and CIN I/AIN I harbored low-risk genotypes while those with CIN II/AIN II harbored high-risk genotypes. Conclusion High- and low-risk HPV genotypes persist in high-risk groups in Bangkok. Some genotypes infecting at-risk populations are not vaccine-preventable. These findings may help to elucidate the prevalence of HPV infections in Thailand and serve as the basis for additional investigations into risk factors for these populations. PMID:25763674

  13. Validation of a predictive model for identifying febrile young infants with altered urinalysis at low risk of invasive bacterial infection.

    PubMed

    Velasco, R; Gómez, B; Hernández-Bou, S; Olaciregui, I; de la Torre, M; González, A; Rivas, A; Durán, I; Rubio, A

    2017-02-01

    In 2015, a predictive model for invasive bacterial infection (IBI) in febrile young infants with altered urine dipstick was published. The aim of this study was to externally validate a previously published set of low risk criteria for invasive bacterial infection in febrile young infants with altered urine dipstick. Retrospective multicenter study including nine Spanish hospitals. Febrile infants ≤90 days old with altered urinalysis (presence of leukocyturia and/or nitrituria) were included. According to our predictive model, an infant is classified as low-risk for IBI when meeting all the following: appearing well at arrival to the emergency department, being >21 days old, having a procalcitonin value <0.5 ng/mL and a C-reactive protein value <20 mg/L. IBI was considered as secondary to urinary tract infection if the same pathogen was isolated in the urine culture and in the blood or cerebrospinal fluid culture. A total of 391 patients with altered urine dipstick were included. Thirty (7.7 %) of them developed an IBI, with 26 (86.7 %) of them secondary to UTI. Prevalence of IBI was 2/104 (1.9 %; CI 95% 0.5-6.7) among low-risk patients vs 28/287 (9.7 %; CI 95% 6.8-13.7) among high-risk patients (p < 0.05). Sensitivity of the model was 93.3 % (CI 95% 78.7-98.2) and negative predictive value was 98.1 % (93.3-99.4). Although our predictive model was shown to be less accurate in the validation cohort, it still showed a good discriminatory ability to detect IBI. Larger prospective external validation studies, taking into account fever duration as well as the role of ED observation, should be undertaken before its implementation into clinical practice.

  14. Retrospective comparison of the Low Risk Ankle Rules and the Ottawa Ankle Rules in a pediatric population.

    PubMed

    Ellenbogen, Amy L; Rice, Amy L; Vyas, Pranav

    2017-09-01

    A recent multicenter prospective Canadian study presented prospective evidence supporting the Low Risk Ankle Rules (LRAR) as a means of reducing the number of ankle radiographs ordered for children presenting with an ankle injury while maintaining nearly 100% sensitivity. This is in contrast to a previous prospective study which showed that this rule yielded only 87% sensitivity. It is important to further investigate the LRAR and compare them with the already validated Ottawa Ankle Rules (OAR) to potentially curb healthcare costs and decrease unnecessary radiation exposure without compromising diagnostic accuracy. We conducted a retrospective chart review of 980 qualifying patients ages 12months to 18years presenting with ankle injury to a commonly staffed 310 bed children's hospital and auxiliary site pediatric emergency department. There were 28 high-risk fractures identified. The Ottawa Ankle Rules had a sensitivity of 100% (95% CI 87.7-100), specificity of 33.1% (95% CI 30.1-36.2), and would have reduced the number of ankle radiographs ordered by 32.1%. The Low Risk Ankle Rules had a sensitivity of 85.7% (95% CI 85.7-96), specificity of 64.9% (95% CI 61.8-68), and would have reduced the number of ankle radiographs ordered by 63.1%. The latter rule missed 4 high-risk fractures. The Low Risk Ankle Rules may not be sensitive enough for use in Pediatric Emergency Departments, while the Ottawa Ankle Rules again demonstrated 100% sensitivity. Further research on ways to implement the Ottawa Ankle Rules and maximize its ability to decrease wait times, healthcare costs, and improve patient satisfaction are needed. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Molecular genotyping of human papillomavirus l1 gene in low-risk and high-risk populations in Bangkok.

    PubMed

    Leaungwutiwong, Pornsawan; Bamrungsak, Busara; Jittmittraphap, Akanitt; Maneekan, Pannamas; Kosoltanapiwat, Nathamon; Kalambaheti, Thareerat; Kelley, James F

    2015-04-01

    Human papillomavirus (HPV) infections in Thailand are a public health concern, but information on HPV infection in sex workers and men who have sex with men (MSM) is limited. The aim of this study was to measure the prevalence and genotype distribution of HPV among low- and high-risk, HIV-negative populations. A total of 300 participants were categorized as general women, female sex workers, MSM, and MSM sex workers. Human papillomavirus infections were identified by the Papanicolaou test and nested polymerase chain reaction. A phylogenetic analysis of partial HPV L1 genes was performed. Abnormal cytology was found in 5% of general women, 10% of female sex workers, 24% of MSM, and 28% of MSM sex workers. Human papillomavirus was detected in 9% of general women, 13% of female sex workers, and 30% in both MSM and the MSM sex workers. The prevalence of HPV high-risk genotypes was significantly higher in female sex workers and MSM, whereas low-risk genotypes and genital warts were significantly higher in MSM sex workers. Significantly more patients with genital warts and cervical intraepithelial neoplasia I/anal intraepithelial neoplasia I harbored low-risk genotypes, whereas those with cervical intraepithelial neoplasia II/anal intraepithelial neoplasia II harbored high-risk genotypes. High- and low-risk HPV genotypes persist in high-risk groups in Bangkok. Some genotypes infecting at-risk populations are not vaccine preventable. These findings may help to elucidate the prevalence of HPV infections in Thailand and serve as the basis for additional investigations into risk factors for these populations.

  16. High-dose-rate brachytherapy delivered in two fractions as monotherapy for low-risk prostate cancer

    PubMed Central

    Alwers, Elizabeth; Cifuentes, Javier; Bobadilla, Ivan; Torres, Felipe; Arbelaez, Juan; Gaitan, Armando; Cortes, Helber; Acevedo, Yenny; Quintero, Paulo; Vasquez, Jaider

    2015-01-01

    Purpose High-dose-rate (HDR) brachytherapy has been accepted as an effective and safe method to treat prostate cancer. The aim of this study was to describe acute toxicity following HDR brachytherapy to the prostate, and to examine the association between dosimetric parameters and urinary toxicity in low-risk prostate cancer patients. Material and methods Patients with low-risk prostate cancer were given HDR brachytherapy as monotherapy in two 12.5 Gy fractions. Planning objectives for the planning target volume (PTV) were V100% ≥ 90% and V150% ≤ 35%. Planning objectives for organs at risk were V75% ≤ 1 cc for the bladder, rectum and perineum, and V125% ≤ 1 cc for the urethra. Toxicity was assessed three months after treatment using the Common Terminology Criteria for Adverse Events. Results Seventy-three patients were included in the analysis. Thirty-three patients (45%) reported having any type of toxicity in the three months following HDR brachytherapy. Most toxicity cases (26%) were grade 1 urinary toxicity. Mean coverage index was 0.89 and mean V100 was 88.85. Doses administered to the urethra were associated with urinary toxicity. Patients who received more than 111.3% of the prescribed dose in 1 cc of the urethra were four times more likely to have urinary toxicity compared to patients receiving less than 111.3% (OR = 4.71, 95% CI: 1.43-15.6; p = 0.011). Conclusions High-dose-rate brachytherapy administered as monotherapy for prostate cancer proved to be a safe alternative treatment for patients with low-risk prostate cancer. Urinary toxicity was associated with the dose administered to 1 cc and 0.1 cc of the urethra and was remarkably inferior to the reported toxicity in similar studies. PMID:25829931

  17. Transcriptomic analyses of genes differentially expressed by high-risk and low-risk human papilloma virus E6 oncoproteins.

    PubMed

    Ganguly, Pooja; Ganguly, Niladri

    2015-09-01

    Human papilloma virus is the causative agent for cervical cancer with 99 % of cervical cancer cases containing HPV. The high risk HPV-16, 18 and 31 are the major causative agents. The low risk HPV-6, 11 have been reported to cause penile, laryngeal, bronchogenic and oesophageal cancer. Since E6 oncoprotein is frequently over expressed in cancers, we did gene expression studies to compare between the E6 genes of high-risk (HPV18) or low-risk (HPV11)stably transfected in epithelial cell line EPC-2 or mock transfected with the basic vector pCDNA3.1. Microarray studies showed a total of 697 genes showing differential expression between the samples. Genes involved in several key cellular processes such as cell adhesion, angiogenesis, transcription regulation, cell cycle regulation and cell division showed altered expression between the samples. Gene Ontology mapping of 44 genes according cellular pathways revealed 13 pathways namely angiogenesis, alzhemier's, Wnt, p53, interleukin, TGF-β, cadherin, integrin, PI3-kinase, catennin, insulin, chemokine and G protein signalling pathways. The microarray results were confirmed by quantitative real-time PCR for some representative genes like IFI27, CTNNA1, OSMR, CYP1B1, TNFSF13, LAMA2 and COL5A3. Analysis of differentially expressed genes by high-risk and low-risk HPV E6 proteins might help in identification of potential biomarkers for diagnosis, progression and therapy of oesophageal cancer. The understanding of mechanisms of activation of these genes as well as the function of gene products will give a further insight into their roles in oesophageal cancer.

  18. Cost-effectiveness analysis of multiparametric MRI with increased active surveillance for low-risk prostate cancer in Australia.

    PubMed

    Gordon, Louisa G; James, Robbie; Tuffaha, Haitham W; Lowe, Anthony; Yaxley, John

    2017-05-01

    To evaluate the cost-effectiveness of multiparametric magnetic resonance imaging (mpMRI) to diagnose prostate cancer and direct all low-risk patients into active surveillance (AS). A Markov cohort model was developed to assess three scenarios: 1) no mpMRI and current AS; 2) mpMRI and current AS; and 3) mpMRI and increased AS. Men were tracked from diagnosis to end-of-life. Estimates to populate the model were derived from systematic reviews, meta-analyses, epidemiological publications, and national cost reports. An Australian Government perspective was used. Outcomes included healthcare costs, survival, quality-adjusted life years (QALYs), number of biopsies, and significant and insignificant cancers. Extensive sensitivity analyses were undertaken to address possible variation in the modeled inputs. Mean lifetime costs per patient were AU$23,191 for Scenario 1, AU$23,387 for Scenario 2 and AU$21,064 for Scenario 3. Corresponding QALYs were 7.81, 7.77, 7.83 for Scenarios 1, 2, and 3, respectively. At the current uptake of AS in Australia, mpMRI alone does not appear cost-effective (16.9% likelihood). However, mpMRI with AS for all men with low-risk disease is strongly cost-effective (86.9% likelihood) at a willingness-to-pay AU$50,000 per QALY gained. For the mpMRI options, for every 1000 men suspected of prostate cancer, using mpMRI would avoid 340 biopsies, detect an additional 20 significant cancers, and detect 10 fewer insignificant cancers. Diagnosis of prostate cancer through mpMRI technology would be cost-effective if it leads to increased uptake of AS for men with confirmed very-low- or low-risk prostate cancer. 2 J. MAGN. RESON. IMAGING 2017;45:1304-1315. © 2016 International Society for Magnetic Resonance in Medicine.

  19. Routine prophylactic central neck dissection for low-risk papillary thyroid cancer: a cost-effectiveness analysis.

    PubMed

    Zanocco, Kyle; Elaraj, Dina; Sturgeon, Cord

    2013-12-01

    Routine prophylactic central neck dissection (pCND) after total thyroidectomy (TTX) for low-risk papillary thyroid cancer (PTC) offers the potential to decrease disease recurrence but may increase operative complications. We hypothesized that routine pCND is not cost-effective in low-risk PTC. A Markov transition-state model was constructed to compare TTX with and without pCND. Outcome probabilities, utilities, and costs were estimated on the basis of literature review. The threshold for cost-effectiveness was $100,000 per quality-adjusted life year. Sensitivity analysis was used to examine model uncertainty. pCND cost $10,315 and produced an effectiveness of 23.785 quality-adjusted life years. This strategy was more costly and less effective than TTX without pCND and was therefore dominated. pCND became cost-effective when the probability of recurrence increased from 6% to 10.3%, cost of reoperation for recurrence increased from $8,900 to $26,120, or added probabilities of recurrent laryngeal nerve injury and hypoparathyroidism due to pCND were less than 0.20% and 0.18% during 2-way sensitivity analysis. Monte Carlo simulation showed that pCND was not cost-effective in 97.3% of iterations. Routine pCND for low-risk PTC is not cost-effective unless the recurrence rate is greater than 10.3%. Application of pCND should be individualized based on risk of recurrence and added complications.

  20. Routine prophylactic central neck dissection for low-risk papillary thyroid cancer is not cost-effective.

    PubMed

    Garcia, Arturo; Palmer, Barnard J A; Parks, Nancy A; Liu, Terrence H

    2014-11-01

    The role of routine prophylactic central neck dissection (CND) in papillary thyroid cancer (PTC) remains controversial. The aim of this study was to evaluate the cost utility of the addition of routine CND in patients with low-risk PTC compared with total thyroidectomy (TT) alone. A Markov model for low-risk PTC was constructed with a treatment algorithm based on the American Thyroid Association guidelines for well-differentiated thyroid carcinoma. Utilities and outcome probabilities were derived from published medical literature. US 2010 costs were examined from a society perspective using Medicare reimbursement rates and opportunity loss based on published US government data. Monte Carlo simulation and sensitivity analysis were used to examine the uncertainty of probability, cost and utility estimates. Initial TT alone is more cost-effective than TT with CND, resulting in a cost savings of US $5763 per patient with slightly higher effectiveness per patient (0·03 QALY) for a cost savings of $285 per QALY. Sensitivity analysis shows that TT alone offers no advantage when radioactive iodine (RAI) becomes more detrimental to a patient's state of health, when the incidence of non-neck recurrence increases above 5% in patients undergoing TT alone or decreases below 3·9% in patients undergoing TT with CND or when the rate of permanent hypocalcaemia rises above 4%. TT with CND is not a cost-effective strategy in low-risk PTC. Initial TT alone is favourable because of the low complication rates and low recurrence rates associated with the initial surgery. Alternative strategies such as unilateral prophylactic neck dissection require additional study to assess their cost-effectiveness. © 2014 John Wiley & Sons Ltd.

  1. Identification of patients with low-risk pulmonary embolism suitable for outpatient treatment using the pulmonary embolism severity index (PESI).

    PubMed

    McCabe, A; Hassan, T; Doyle, M; McCann, B

    2013-06-01

    There is increasing evidence that outpatient treatment of patients with low-risk stable pulmonary embolism (PE) is safe, effective and potentially reduces costs. It is not clear how many patients presenting to an Irish Emergency Department (ED) are potentially suitable for outpatient management. To identify how many patients presenting to our ED over a 1-year period who were diagnosed with acute PE are potentially suitable for outpatient treatment. A retrospective observational study was conducted over a 1-year period. Clinical notes for patients who had a positive computed tomographic pulmonary angiogram (CTPA) within 24 h of presentation to the ED were examined to risk stratify the patients according to the pulmonary embolism severity index (PESI). Forty-seven patients who presented to our ED were diagnosed with a PE. Clinical notes were missing for 3 cases, and 44 cases were analysed further. The mean age was 64.3 (±16.8 SD) years and 24 (54.5 %, 95 % CI 40-68.3 %) were males. Six patients (13.6 %, 95 % CI 6.4-26.7 %) had a background of cancer. Fifteen cases (34.1 %, 95 % CI 21.9-48.7 %) were deemed to be low risk as they were categorised as PESI risk class I or II. Our study found that 61/420 (14.5 %, 95 % CI 11.5-18.2) of CTPAs done were positive for PE. This study suggests that a significant percentage of patients diagnosed with acute PE are low risk as per PESI and therefore potentially suitable for outpatient management.

  2. Quantifying the Shift Toward Transcatheter Aortic Valve Replacement in Low-Risk Patients: A Meta-Analysis.

    PubMed

    De Sciscio, Paolo; Brubert, Jacob; De Sciscio, Michele; Serrani, Marta; Stasiak, Joanna; Moggridge, Geoff D

    2017-06-01

    In recent years, use of transcatheter aortic valve replacement has expanded to include patients at intermediate- and low-risk cohorts. We sought to determine disease prevalence and treatment distribution including transcatheter aortic valve replacement eligibility in low-risk patients across 37 advanced economies. Four systematic searches were conducted across MEDLINE, EMBASE, and the Cochrane database for studies evaluating disease prevalence, severity, decision making, and survival in patients with aortic stenosis. Estimates of disease prevalence and treatment eligibility were calculated using stochastic simulation and population data for the 37 countries comprising the International Monetary Fund's advanced economies index. Fifty-six studies comprising 42 965 patients were included across 5 domains: prevalence, severity, symptom status, treatment modality, and outcome. The pooled prevalence in the general population aged 60 to 74 years and >75 years was 2.8% (95% confidence interval [CI], 1.4%-4.1%) and 13.1% (95% CI, 8.2%-17.9%), respectively-corresponding to an estimated 16.1 million (95% CI, 12.2-20.3) people in 37 advanced economies. Of these, an estimated 3.2 million (95% CI, 2.2-4.4) patients have severe aortic stenosis with 1.9 million (95% CI, 1.3-2.6) eligible for surgical aortic valve replacement. There are ≈485 230 (95% CI, 284 550-66 7350) high-risk/inoperable patients, 152 690 (95% CI, 73 410-263 000) intermediate-risk patients, and 378 890 (95% CI, 205 130-610 210) low-risk patients eligible for transcatheter aortic valve replacement. With a prevalence of 4.5%, an estimated 16.1 million people aged ≥60 years across 37 advanced economies have aortic stenosis. Of these, there are ≈1.9 million patients eligible for surgical aortic valve replacement and 1.0 million patients eligible for transcatheter aortic valve replacement. © 2017 American Heart Association, Inc.

  3. The reliability of transabdominal cervical length measurement in a low-risk obstetric population: Comparison with transvaginal measurement.

    PubMed

    Peng, Cheng-Ran; Chen, Chie-Pein; Wang, Kuo-Gon; Wang, Liang-Kai; Chen, Chen-Yu; Chen, Yi-Yung

    2015-04-01

    To determine the correlation between transabdominal (TA) and transvaginal (TV) cervical length measurement in a low-risk obstetric population in Taiwan. Women with a singleton pregnancy between 20 weeks and 24 weeks of gestation underwent postvoid TA and TV cervical length measurements. Differences between the measurements obtained using the two methods were evaluated. Two hundred and five women agreed to participate in the study. Paired TA and TV measurements were obtained in 174 women. The mean TA cervical length was 36.0 ± 4.9 mm and the mean TV cervical length was 37.6 ± 5.4 mm. The mean TA cervical length was shorter than the mean TV cervical length by 1.6 mm. The 5(th) percentile of TA and TV cervical length was 29 mm and 29.1 mm, respectively. The discrepancies between the two methods were not significantly correlated with maternal body mass index (BMI). All women with TV cervical length <25 mm had a corresponding TA cervical length <29 mm. The TA cervical length could be obtained in the majority of the low-risk pregnant women in the present study, and the TA cervical length was closely correlated with the TV cervical length. The use of TA ultrasound could be an effective initial tool for cervical length screening in low-risk pregnant women. TA cervical length <29 mm (5(th) percentile) could be used as a cut-off value for further TV ultrasound. Copyright © 2015. Published by Elsevier B.V.

  4. Physiologic partograph to improve birth safety and outcomes among low-risk, nulliparous women with spontaneous labor onset

    PubMed Central

    Neal, Jeremy L.; Lowe, Nancy K.

    2011-01-01

    Oxytocin augmentation and cesarean rates among low-risk, term, nulliparous women with a spontaneous onset of labor in the United States approximate 50% and 26.5%, respectively. This indicates that the quality of obstetrical care is much less than optimal in this nation. Exorbitant oxytocin use, the intervention most commonly associated with preventable adverse perinatal outcomes, jeopardizes birth safety while the high cesarean rate in this high-volume group compromises population health and increases health care costs. Dystocia, characterized by the slow, abnormal progression of labor, is the most commonly reported indication for primary cesareans, accounting directly for approximately 50% of all nulliparous cesareans and indirectly for most repeat cesareans. Diagnoses of dystocia are most often based on ambiguously defined delays in cervical dilation beyond which labor augmentation is deemed justified. Dystocia is known to be over-diagnosed which undoubtedly contributes to contemporary oxytocin augmentation and primary cesarean rates. Labor attendants would benefit from an evidence-based framework for homogenous labor assessment. To this end, we present a physiologically-based partograph for `in-hospital' use in assessing the labors of low-risk, term, nulliparous women with spontaneous labor onset. This tool incorporates several evidence-based labor principles that combine to give needed clinical meaning to `dystocia' as a diagnosis. It is hypothesized that our partograph will safely limit diagnoses of dystocia to only the slowest 10% of low-risk, nulliparous women. This should, in turn, safe-guard against unnecessary, injudicious, and potentially harmful use of oxytocin when labor is already adequately progressing while also indicating when its use may be justified. We further hypothesize that cesareans performed for dystocia in this population will decrease by ≥ 50%. No significant influence on other labor process or labor outcome variables is expected with

  5. Physiologic partograph to improve birth safety and outcomes among low-risk, nulliparous women with spontaneous labor onset.

    PubMed

    Neal, Jeremy L; Lowe, Nancy K

    2012-02-01

    Oxytocin augmentation and cesarean rates among low-risk, term, nulliparous women with a spontaneous onset of labor in the United States approximate 50% and 26.5%, respectively. This indicates that the quality of obstetrical care is less than optimal in this nation. Exorbitant oxytocin use, the intervention most commonly associated with preventable adverse perinatal outcomes, jeopardizes birth safety while the high cesarean rate in this high-volume group compromises population health and increases health care costs. Dystocia, characterized by the slow, abnormal progression of labor, is the most commonly reported indication for primary cesareans, accounting directly for approximately 50% of all nulliparous cesareans and indirectly for most repeat cesareans. Diagnoses of dystocia are most often based on ambiguously defined delays in cervical dilation beyond which labor augmentation is deemed justified. Dystocia is known to be over-diagnosed which undoubtedly contributes to contemporary oxytocin augmentation and primary cesarean rates. Labor attendants would benefit from an evidence-based framework for homogenous labor assessment. To this end, we present a physiologically-based partograph for 'in-hospital' use in assessing the labors of low-risk, term, nulliparous women with spontaneous labor onset. This tool incorporates several evidence-based labor principles that combine to give needed clinical meaning to 'dystocia' as a diagnosis. It is hypothesized that our partograph will safely limit diagnoses of dystocia to only the slowest 10% of low-risk, nulliparous women. This should, in turn, safe-guard against unnecessary, injudicious, and potentially harmful use of oxytocin when labor is already adequately progressing while also indicating when its use may be justified. We further hypothesize that cesareans performed for dystocia in this population will decrease by ≥ 50%. No significant influence on other labor process or labor outcome variables is expected with

  6. Single-Nucleotide Polymorphism–Based Noninvasive Prenatal Screening in a High-Risk and Low-Risk Cohort

    PubMed Central

    Pergament, Eugene; Cuckle, Howard; Zimmermann, Bernhard; Banjevic, Milena; Sigurjonsson, Styrmir; Ryan, Allison; Hall, Megan P.; Dodd, Michael; Lacroute, Phil; Stosic, Melissa; Chopra, Nikhil; Hunkapiller, Nathan; Prosen, Dennis E.; McAdoo, Sallie; Demko, Zachary; Siddiqui, Asim; Hill, Matthew; Rabinowitz, Matthew

    2014-01-01

    Objective To estimate performance of a single-nucleotide-polymorphism–based noninvasive prenatal screen for fetal aneuploidy in high-risk and low-risk populations upon single venopuncture. Methods One thousand sixty-four maternal blood samples from 7 weeks of gestation and beyond were included; one thousand fifty-one were within specifications, 518 (49.3%) low-risk. Cell-free DNA was amplified, sequenced, and analyzed using the Next-generation Aneuploidy Test Using SNPs algorithm. Samples were called as trisomies 21, 18, 13, or monosomy X, or euploid, and male or female. Results Nine hundred sixty-six samples (91.9%) successfully generated a cell-free DNA result. Among these, sensitivity was 100% for trisomy 21 (58/58, CI: 93.8–100%), trisomy 13 (12/12, CI: 73.5–100%), and fetal sex (358/358 female, CI:99.0–100%; 418/418 male, CI: 99.1–100%), 96.0% for trisomy 18 (24/25, CI: 79.7–99.9%), and 90% for monosomy X (9/10, CI: 55.5–99.8%). Specificity for trisomies 21 and 13 was 100% (905/905 [CI: 99.6–100%] and 953/953 [CI: 99.6–100%], respectively) and for trisomy 18 and monosomy X was 99.9% (938/939 [CI: 99.4–100%] and 953/954 [CI: 99.4–100%], respectively). However, 16% (20/125) of aneuploid samples did not return a result; 50% (10/20) had a fetal fraction below the 1.5th percentile of euploid pregnancies. Aneuploidy rate was significantly higher in these samples (p<0.001, odds ratio: 9.2, CI: 4.4–19.0). Sensitivity and specificity did not differ in low-risk and high-risk populations. Conclusions This noninvasive prenatal screen performed with high sensitivity and specificity in high-risk and low-risk cohorts. Aneuploid samples were significantly more likely to not return a result; the number of aneuploidy samples was especially increased among samples with low fetal fraction. This underscores the importance of redraws or, in rare cases, invasive procedures based on low fetal fraction. PMID:25004354

  7. Trajectory of platelets in pregnancy - do low-risk women need an intrapartum full blood count prior to epidural?

    PubMed

    Duong, Christine; Kidson-Gerber, Giselle; Peters, Nancy; Listijono, Dave R; Henry, Amanda

    2015-10-01

    This study aimed to investigate whether pregnant women with a normal 28-week gestation platelet count and no high-risk conditions for thrombocytopenia require a pre-epidural platelet count. All 1844 included women (platelet count > 150 × 10(9) /L at 28 weeks' gestation, term singleton birth, no thrombocytopenia risk conditions) had a platelet count > 100 × 10(9) /L prebirth, suggesting low-risk pregnant women do not require pre-epidural full blood count solely to check platelet count.

  8. Accuracy of a sequential approach to identify young febrile infants at low risk for invasive bacterial infection.

    PubMed

    Mintegi, Santiago; Bressan, Silvia; Gomez, Borja; Da Dalt, Liviana; Blázquez, Daniel; Olaciregui, Izaskun; de la Torre, Mercedes; Palacios, Miriam; Berlese, Paola; Benito, Javier

    2014-10-01

    Much effort has been put in the past years to create and assess accurate tools for the management of febrile infants. However, no optimal strategy has been so far identified. A sequential approach evaluating, first, the appearance of the infant, second, the age and result of the urinanalysis and, finally, the results of the blood biomarkers, including procalcitonin, may better identify low risk febrile infants suitable for outpatient management. To assess the value of a sequential approach ('step by step') to febrile young infants in order to identify patients at a low risk for invasive bacterial infections (IBI) who are suitable for outpatient management and compare it with other previously described strategies such as the Rochester criteria and the Lab-score. A retrospective comparison of three different approaches (step by step, Lab-score and Rochester criteria) was carried out in 1123 febrile infants less than 3 months of age attended in seven European paediatric emergency departments. IBI was defined as isolation of a bacterial pathogen from the blood or cerebrospinal fluid. Of the 1123 infants (IBI 48; 4.2%), 488 (43.4%) were classified as low-risk criteria according to the step by step approach (vs 693 (61.7%) with the Lab-score and 458 (40.7%) with the Rochester criteria). The prevalence of IBI in the low-risk criteria patients was 0.2% (95% CI 0% to 0.6%) using the step by step approach; 0.7% (95% CI 0.1% to 1.3%) using the Lab-score; and 1.1% (95% CI 0.1% to 2%) using the Rochester criteria. Using the step by step approach, one patient with IBI was not correctly classified (2.0%, 95% CI 0% to 6.12%) versus five using the Lab-score or Rochester criteria (10.4%, 95% CI 1.76% to 19.04%). A sequential approach to young febrile infants based on clinical and laboratory parameters, including procalcitonin, identifies better patients more suitable for outpatient management. Published by the BMJ Publishing Group Limited. For permission to use (where not already

  9. Derivation and Validation of a Novel Prediction Model to Identify Low-Risk Patients With Acute Pulmonary Embolism.

    PubMed

    Subramanian, Muthiah; Gopalan, Sowmya; Ramadurai, Srinivasan; Arthur, Preetam; Prabhu, Mukund A; Thachathodiyl, Rajesh; Natarajan, Kumaraswamy

    2017-08-15

    Accurate identification of low-risk patients with acute pulmonary embolism (PE) who may be eligible for outpatient treatment or early discharge can have substantial cost-saving benefit. The purpose of this study was to derive and validate a prediction model to effectively identify patients with PE at low risk of short-term mortality, right ventricular dysfunction, and other nonfatal outcomes. This study analyzed data from 400 consecutive patients with acute PE. We derived and internally validated our prediction rule based on clinically significant variables that are routinely available at initial examination and that were categorized and weighted using coefficients in the multivariate logistic regression. The model was externally validated in an independent cohort of 82 patients. The final model (HOPPE score) consisted of 5 categorized patient variables (1, 2, or 3 points, respectively): systolic blood pressure (>120, 100 to 119, <99 mm Hg), diastolic blood pressure (>80, 65 to 79, <64 mm Hg), heart rate (<80, 81 to 100, >101 beats/min), arterial partial pressure of oxygen (>80, 60 to 79, <59 mm Hg), and modified electrocardiographic score (<2, 2 to 4, >4). The 30-day mortality rates were 0% in low risk (0 to 6 points), 7.5% to 8.5% in intermediate risk (7 to 10), and 18.2% to 18.8% in high-risk patients (≥11) across the derivation and validation cohorts. In comparison with the previously validated PESI score, the HOPPE score had a higher discriminatory power (area under the curve 0.74 vs 0.85, p = 0.033) and significantly improved both the discrimination (integrated discrimination improvement, p = 0.002) and reclassification (net reclassification improvement, p = 0.003) of the model for short-term mortality. In conclusion, the HOPPE score accurately identifies acute patients with PE at low risk of short-term mortality, right ventricular dysfunction, and other nonfatal outcomes. Prospective validation of the prediction model is necessary before implementation

  10. Freestanding midwifery unit versus obstetric unit: a matched cohort study of outcomes in low-risk women

    PubMed Central

    Møller, Anna Margrethe; Fenger-Grøn, Morten; Knudsen, Lisbeth B; Sandall, Jane

    2011-01-01

    Objective To compare perinatal and maternal morbidity and birth interventions in low-risk women giving birth in two freestanding midwifery units (FMUs) and two obstetric units (OUs). Design A cohort study with a matched control group. Setting The region of North Jutland, Denmark. Participants 839 low-risk women intending FMU birth and a matched control group of 839 low-risk women intending OU birth were included at the start of care in labour. OU women were individually chosen to match selected obstetric/socio-economic characteristics of FMU women. Analysis was by intention to treat. Main outcome measures Perinatal and maternal morbidity and interventions. Results No significant differences in perinatal morbidity were observed between groups (Apgar scores <7/5, <9/5 or <7/1, admittance to neonatal unit, asphyxia or readmission). Adverse outcomes were rare and occurred in both groups. FMU women were significantly less likely to experience an abnormal fetal heart rate (RR: 0.3, 95% CI 0.2 to 0.5), fetal–pelvic complications (0.2, 0.05 to 0.6), shoulder dystocia (0.3, 0.1 to 0.9), occipital–posterior presentation (0.5, 0.3 to 0.9) and postpartum haemorrhage >500 ml (0.4, 0.3 to 0.6) compared with OU women. Significant reductions were found for the FMU group's use of caesarean section (0.6, 0.3 to 0.9), instrumental delivery (0.4, 0.3 to 0.6), and oxytocin augmentation (0.5, 0.3 to 0.6) and epidural analgesia (0.4, 0.3 to 0.6). Transfer during or <2 h after birth occurred in 14.8% of all FMU births but more frequently in primiparas than in multiparas (36.7% vs 7.2%). Conclusion Comparing FMU and OU groups, there was no increase in perinatal morbidity, but there were significantly reduced incidences of maternal morbidity, birth interventions including caesarean section, and increased likelihood of spontaneous vaginal birth. FMU care may be considered as an adequate alternative to OU care for low-risk women. Pregnant prospective mothers should be given an

  11. WITHDRAWN: Can the conventional sextant prostate biopsy reliably diagnose unilateral prostate cancer in low-risk, localized, prostate cancer?

    PubMed

    Mayes, J M; Mouraviev, V; Sun, L; Madden, J F; Polascik, T J

    2008-05-13

    The authors hereby retract the e-publication dated 13 May 2008 and entitled, 'Can the conventional sextant prostate biopsy reliably diagnose unilateral prostate cancer in low-risk, localized, prostate cancer?' The authors are submitting a revised version with the same title. This article's statistics were performed for predicting bilateral prostate cancer outcomes. The article was written to help predict unilateral prostate cancer. Although the statistical numbers are correct, they are backwards. We apologize that the statistics indicate a contrary outcome (eg predicting bilateral cancer instead of unilateral disease).

  12. Compliance with outpatient stress testing in low-risk patients presenting to the emergency department with chest pain.

    PubMed

    Milano, Peter; Carden, Donna L; Jackman, Kelly M; Rongkavilit, Arada; Groves, Kevin; Tyndall, Joseph; Moll, Joel

    2011-03-01

    Recent evidence suggests that stress testing prior to emergency department (ED) release in low-risk chest pain patients identifies those who can be safely discharged home. When immediate stress testing is not feasible, rapid outpatient stress testing has been recommended. The objective of this study was to determine compliance rate and incidence of adverse cardiac events in patients presenting to the ED with low-risk chest pain referred for outpatient stress testing. Retrospective chart and social security death index review were conducted in 448 consecutive chest pain patients who presented to a university hospital and level I trauma center between April 30 and December 31, 2007. Patients were evaluated with an accelerated chest pain protocol defined as a 4-hour ED rule out and referral for outpatient stress testing within 72 hours of ED release. Only patients without known cardiac disease, a thrombolysis in myocardial infarction risk score ≤2, negative serial ECGs and cardiac biomarkers, and benign ED course were eligible for the protocol. Primary outcome measures included compliance with outpatient stress testing and documented 30-day incidence of adverse cardiac events following ED release. The social security death index was queried to determine 12-month incidence of all-cause mortality in enrolled patients. Logistic regression analysis of characteristics associated with outpatient stress test compliance was determined and incidence of adverse cardiac events in those who were and were not compliant with outpatient stress testing was compared. Significance was set at P < 0.05. A total of 188 patients (42%) completed outpatient stress testing, but only 27 (6%) completed testing within 72 hours of ED discharge. Compliance was correlated with insurance and race, but not patient age, gender, or thrombolysis in myocardial infarction risk score. No significant differences in adverse cardiac events were documented in patients who did and did not comply with

  13. Relationship between polycythemia and in-hospital mortality in chronic obstructive pulmonary disease patients with low-risk pulmonary embolism

    PubMed Central

    Guo, Lu; Chughtai, Aamer Rasheed; Jiang, Hongli; Gao, Lingyun; Yang, Yan; Yang, Yang; Liu, Yuejian

    2016-01-01

    Backgrounds Pulmonary embolism (PE) is frequent in subjects with chronic obstructive pulmonary disease (COPD) and associated with high mortality. This multi-center retrospective study was performed to investigate if secondary polycythemia is associated with in-hospital mortality in COPD patients with low-risk PE. Methods We identified COPD patients with proven PE between October, 2005 and October, 2015. Patients in risk classes III–V on the basis of the PESI score were excluded. We extracted demographic, clinical and laboratory information at the time of admission from medical records. All subjects were followed until hospital discharge to identify all-cause mortality. Results We enrolled 629 consecutive patients with COPD and PE at low risk: 132 of them (21.0%) with and 497 (79.0%) without secondary polycythemia. Compared with those without polycythemia, the polycythemia group had significantly lower forced expiratory volume in one second (FEV1) level (0.9±0.3 vs. 1.4±0.5, P=0.000), lower PaO2 and SpO2 as well as higher PaCO2 (P=0.03, P=0.03 and P=0.000, respectively). COPD patients with polycythemia had a higher proportion of arrhythmia in electrocardiogram (ECG) (49.5% vs. 35.7%, P=0.02), a longer hospital duration time (15.3±10.1 vs. 9.7±9.1, P=0.001), a higher mechanical ventilation rate (noninvasive and invasive, 51.7% vs. 30.3%, P=0.04 and 31.0% vs. 7.9%, P=0.04, respectively), and a higher in-hospital mortality (12.1% vs. 6.6%, P=0.04). Multivariate logistic regression analysis revealed that polycythemia was associated with mortality in COPD patients with low-risk PE (adjusted OR 1.11; 95% CI, 1.04–1.66). Conclusions Polycythemia is an independent risk factor for all-cause in-hospital mortality in COPD patients with PE at low risk. PMID:28066591

  14. Is malignant nodule topography an additional risk factor for metastatic disease in low-risk differentiated thyroid cancer?

    PubMed

    Campennì, Alfredo; Giovanella, Luca; Siracusa, Massimiliano; Stipo, Maria Elena; Alibrandi, Angela; Cucinotta, Mariapaola; Ruggeri, Rosaria M; Baldari, Sergio

    2014-11-01

    Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. In recent decades, the incidence has been increasing, largely due to increased detection of patients with low-risk or very low-risk DTC. According to European Thyroid Association and American Thyroid Association guidelines, radioiodine (RAI) thyroid remnant ablation is not indicated in very low-risk patients, while its role is still debated in low-risk patients. Accordingly, risk stratification of DTC patients is pivotal when deciding for or against RAI ablation. Presently, risk stratification is based on pTNM staging integrated with clinical parameters. The aim of our study was to evaluate the relationship between location of malignant thyroid nodules within the thyroid gland and the presence of loco-regional and/or distant metastases in patients with pT1a-pT1b DTCs. We reviewed the records of 246 patients (214 women, 32 men; female-to-male ratio 6.7:1) affected by unifocal DTC ≤ 2 cm, who had undergone RAI thyroid remnant ablation (activity ranged 555-4588 MBq) after levothyroxine withdrawal or after recombinant human TSH (rhTSH) stimulation. The majority of the patients (91.5%) were affected by papillary thyroid carcinoma. Metastases were discovered by posttreatment whole-body scintigraphy in 29 out of 246 (11.8%) patients. In patients with metastases, malignant thyroid nodules were located in the right lobe (14/123, 11.4%), left lobe (7/95, 7.4%), and isthmus (8/27, 29.6%). The prevalence of metastases was significantly higher in patients with DTC located in the isthmus, compared to other sites (χ(2) = 9.6, p = 0.002). Our data show for the first time that a location of a thyroid cancer in the isthmus is an additional risk factor for RAI avid metastatic disease in pT1a-pT1b DTC patients, regardless of the presence or absence of other risk factors.

  15. Heteromorphic variants of chromosome 9

    PubMed Central

    2013-01-01

    Background Heterochromatic variants of pericentromere of chromosome 9 are reported and discussed since decades concerning their detailed structure and clinical meaning. However, detailed studies are scarce. Thus, here we provide the largest ever done molecular cytogenetic research based on >300 chromosome 9 heteromorphism carriers. Results In this study, 334 carriers of heterochromatic variants of chromosome 9 were included, being 192 patients from Western Europe and the remainder from Easter-European origin. A 3-color-fluorescence in situ hybridization (FISH) probe-set directed against for 9p12 to 9q13~21.1 (9het-mix) and 8 different locus-specific probes were applied for their characterization. The 9het-mix enables the characterization of 21 of the yet known 24 chromosome 9 heteromorphic patterns. In this study, 17 different variants were detected including five yet unreported; the most frequent were pericentric inversions (49.4%) followed by 9qh-variants (23.9%), variants of 9ph (11.4%), cenh (8.2%), and dicentric- (3.8%) and duplication-variants (3.3%). For reasons of simplicity, a new short nomenclature for the yet reported 24 heteromorphic patterns of chromosome 9 is suggested. Six breakpoints involved in four of the 24 variants could be narrowed down using locus-specific probes. Conclusions Based on this largest study ever done in carriers of chromosome 9 heteromorphisms, three of the 24 detailed variants were more frequently observed in Western than in Eastern Europe. Besides, there is no clear evidence that infertility is linked to any of the 24 chromosome 9 heteromorphic variants. PMID:23547710

  16. Variants of beta-glucosidase

    DOEpatents

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2009-12-29

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  17. Variants of beta-glucosidase

    SciTech Connect

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2015-07-14

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  18. Variants of beta-glucosidases

    SciTech Connect

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2014-10-07

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  19. Variants of beta-glucosidases

    DOEpatents

    Fidantsef, Ana; Lamsa, Michael; Clancy, Brian Gorre

    2008-08-19

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  20. Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells.

    PubMed

    Nikamo, Pernilla; Cheuk, Stanley; Lysell, Josefin; Enerbäck, Charlotta; Bergh, Kerstin; Xu Landén, Ning; Eidsmo, Liv; Ståhle, Mona

    2014-06-01

    Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and the exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset in patients between 0-9 (n=207), 10-20 (n=394), and 21-40 (n=468) years with healthy controls (n=1,529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (odds ratio=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in 80% higher promoter activity (P=0.012) compared with a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant produced 1.7 times more IL-22 compared with low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate the onset of psoriasis at an early age.

  1. The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population.

    PubMed

    Cooley, Sharon M; Donnelly, Jennifer C; Walsh, Thomas; McMahon, Corrina; Gillan, John; Geary, Michael P

    2011-03-01

    To ascertain the impact of placental architecture on antenatal course and labor delivery in a low-risk primigravid population. This study involves prospective recruitment of 1011 low-risk primigravids with placental ultrasound at 22?24 weeks and 36 weeks. Detailed postnatal review of all mothers and infants was undertaken. Retrospective analysis of ultrasound and clinical outcome data was performed. Eight hundred ten women with complete outcome data were available. Anterior placentation was statistically associated with intrauterine growth restriction (IUGR) and preterm birth and fundal placentation was significantly associated with a higher incidence of pregnancy-induced hypertension and infants with a birthweight less than the 9th centile. Placental infarcts in the third trimester was significantly increased in cases complicated by pre-eclampsia (PET) and in cases with fetal acidosis. Placental calcification was associated a 40-fold increase in the incidence of IUGR. Placental lakes in the second trimester were more prevalent in patients with threatened miscarriage. Increased placental thickness was associated with a higher rate of fetal acidosis. The Grannum grade of the placenta was higher with threatened first or second trimester loss, PET and in infants born less than 9th centile for gestation. Placental site and architecture impact on the incidence of maternal and fetal disease.

  2. LH/hCG-Receptor Expression May Have a Negative Prognostic Value in Low-Risk Endometrial Cancer.

    PubMed

    Noci, Ivo; Sorbi, Flavia; Mannini, Luca; Projetto, Elisabetta; Pillozzi, Serena; Ghizzoni, Viola; Lottini, Tiziano; Moncini, Daniela; Baroni, Gianna; Mungai, Francesco; Arcangeli, Annarosa; Fambrini, Massimiliano

    2016-01-01

    A 51 year-old woman was diagnosed with endometrial cancer (EC) and underwent surgical staging. Pathological evaluation showed a 2 cm × 1 cm G2 endometrioid EC with a 30% myometrial deep invasion (FIGO Stage 1A). The patient was classified as low risk of recurrence, and no adjuvant treatment was offered. Six months after surgery, the patient developed an early vescico-vaginal recurrence, and chemotherapy treatment was started. Few months later, a subsequent involvement of vaginal wall, ileum, and omentum was detected, and the patient underwent second surgery. LH/hCG-receptor (LH/hCG-R) expression has been previously reported to be associated with an invasive phenotype in EC cells. Moreover, in a preclinical mouse model of EC behaves as a prometastatic molecular device. We analyzed the expression level of LH/hCG-R in cancer specimens collected during surgeries. Molecular and immunohistochemical analyses showed a strong expression of both mRNA and protein for LH/hCG-R in all specimens. LH/hCG-R expression may be assessed together with other clinicopathological parameters in order to better predict the risk of recurrence in low-risk EC patients. Further clinical trials are warranted in order to validate LH/hCG-R as biomarker in EC.

  3. Outcome of preimplantation genetic diagnosis using FISH analysis for recurrent miscarriage in low-risk reciprocal translocation carriers.

    PubMed

    Pundir, Jyotsna; Magdalani, Laurice; El-Toukhy, Tarek

    2016-08-01

    To assess PGD outcome using FISH analysis in couples with a history of recurrent miscarriage associated with a parental carrier of reciprocal translocation. Couples in whom one partner was a carrier of a reciprocal translocation and had a history of two or more miscarriages and a low risk of a live born offspring with an unbalanced chromosomal rearrangement, underwent PGD treatment between 2000 and 2012. 91 couples started 171 fresh and 11 frozen PGD cycles. Of the fresh cycles, 162 (95%) reached oocyte retrieval and 107 (63%) had embryo transfer. In 14 cycles (8%), surplus embryos were cryopreserved. Pregnancy was achieved in 52 fresh PGD cycles, leading to 20 miscarriages and 32 live births. Eleven frozen embryo transfer cycles resulted in two miscarriages and three live births. The overall live birth rate was 19% per fresh and frozen PGD cycle started (35/182) and miscarriage rate was 39% per pregnancy (22/57). The cumulative live birth rate was 32% per couple (29/91). After PGD for recurrent miscarriage in low-risk reciprocal translocation carriers, the miscarriage risk remains high and chance of live birth is low. For those translocation carriers, natural conception may be a better option. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. The effect of parity on first trimester uterine artery Doppler waveforms in low-risk singleton pregnancies.

    PubMed

    Ulkumen, Burcu Artunc; Pala, Halil Gursoy; Uyar, Yildiz; Baytur, Yesim Bulbul; Koyuncu, Faik Mumtaz

    2014-12-01

    The aim of the study was to evaluate the effeot of parity on uteroplacental blood flow during the first trimester in low-risk singleton pregnancies. Uterine artery Doppler examinations were performed in 190 singleton pregnancies between 11-14 gestational weeks. Twenty-five pregnancies were excluded from the study due to history ci preeclampsia, diabetes mellitus or inherited thrombophilia. A total of 165 low-risk singleton pregnancies were included in the study Mean uterine artery pulsatility index (P1) was recorded and compared between nulliparous and multiparous women. The relation between maternal age, gestational week, maternal weight, parity biochemica, markers and abnormal uterine artery Doppler flows was evaluated. T-test and logistic regression analyses were used for the statistical analysis. A total of 165 singleton pregnancies without any risk factors for uteroplacental insufficiency were includec in the study Of them, 58 (36.7%) were nulliparous and 107(63.3%) were parous. Correlation analysis revealed that the uterine artery pulsatifity indices during the first trimester were not affected by maternal age and parity: Mean uterine artery pulsatility indices are not different in nulliparous and multiparous low nisA pregnancies at 11-14 weeks of gestation.

  5. Membrane sweeping to induce labor in low-risk patients at term pregnancy: a randomised controlled trial.

    PubMed

    Yildirim, Gokhan; Güngördük, Kemal; Karadağ, Ozge Idem; Aslan, Halil; Turhan, Erdem; Ceylan, Yavuz

    2010-07-01

    To evaluate the efficacy of membrane sweeping at initiation of labor induction in low-risk patients at term pregnancy (38-40 gestational weeks). This prospective study included 351 antenatal women who were randomly assigned to one of two groups: a sweeping of the membranes group (n = 181) and a no sweeping control group (n = 170). The primary outcome measure was the proportion of women who entered spontaneous labor within 1 week of entry into the study. Secondary outcome measures included mode of delivery and maternal and fetal complications. Five patients (two in the sweeping group and three in the no sweeping group) were excluded from the study because of breech presentation at labor. There were no statistically significant differences between the two groups regarding maternal age, parity or Bishop score. The proportion of subjects who entered spontaneous labor before 41 weeks of gestation was significantly different between the two groups (p < 0.0001). The mode of delivery did not differ significantly between the groups and there was no statistically significant difference in maternal or fetal complications. Sweeping of membranes is a safe method to reduce the length of term in pregnancy and the incidence of prolonged gestation in a low-risk population. There is no evidence that sweeping the membranes increases the risk of maternal or neonatal adverse outcomes.

  6. Levels of drunkenness of customers leaving licensed premises in Perth, Western Australia: a comparison of high and low 'risk' premises.

    PubMed

    Stockwell, T; Rydon, P; Gianatti, S; Jenkins, E; Ovenden, C; Syed, D

    1992-06-01

    A measure of the risk of licensed premises having customers involved in road traffic accidents and drink-driving offences was utilised in order to identify seven 'High Risk' and eight 'Low Risk' premises in metropolitan Perth, Western Australia. This measure, or 'Risk Ratio', was defined as the ratio of incidents of alcohol-related harm to an estimate of on-premises alcohol sales for a particular establishment. A study was conducted to test the hypothesis that a High Risk status would be associated with greater levels of customer intoxication. Interviews concerning drinking behaviour and breathalyser readings were collected from 74.2% of 414 customers exiting from the chosen premises between 8 p.m. and midnight on Friday and Saturday nights. High Risk premises had three times more customers whose readings were in excess of 0.15 mg/ml (p less than 0.01). The proportion of customers with BAL's above 0.15 correlated strongly with the premises' Risk Ratio (r = 0.63, p less than 0.01). There were also significantly more patrons from High than from Low Risk establishments who were rated as appearing moderately or severely intoxicated but refused to be interviewed or breath-tested. It is argued that these results support the need for strategies which aim to reduce very high levels of intoxication on licensed premises in order to reduce alcohol-related accidents, injuries and offences.

  7. Educational Impact of the Neonatal Resuscitation Program in Low-Risk Delivery Centers in a Developing Country

    PubMed Central

    Carlo, Waldemar A.; Wright, Linda L.; Chomba, Elwyn; McClure, Elizabeth M.; Carlo, Maria E.; Bann, Carla M.; Collins, Monica; Harris, Hillary

    2010-01-01

    Objective To evaluate the effectiveness of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP) in improving knowledge, skills, and self-efficacy of nurse midwives in low-risk delivery clinics in a developing country. Study design We used the content specifications of the NRP materi