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J. Pinto - One of the best experts on this subject based on the ideXlab platform.
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pagetoid Dyskeratosis is a frequent incidental finding in hemorrhoidal disease
Archives of Pathology & Laboratory Medicine, 2009Co-Authors: Fernando J Valbernal, J. PintoAbstract:Abstract Background.—Pagetoid Dyskeratosis is considered a selective keratinocytic response in which a small part of the normal population of keratinocytes is induced to proliferate. Pagetoid Dyskeratosis has been found incidentally in the squamous epithelium of the skin in various locations and in the ectocervix in uterine prolapse. In cases in which these pale cells are conspicuous, there is a hazard of overdiagnosis. It has been suggested that friction is the most probable inductor of the lesion. To the best of our knowledge, pagetoid cells have not been reported in surgically resected hemorrhoids. Objective and Design.—We here describe the location of pagetoid Dyskeratosis in the squamous epithelium of hemorrhoids and the incidence of this lesion in a group of 100 unselected patients surgically treated for hemorrhoidal disease. In addition to the conventional histologic method, special staining procedures and an immunohistochemical study of cytokeratins were performed in selected cases. Results.—Paget...
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Pagetoid Dyskeratosis Is a Frequent Incidental Finding in Hemorrhoidal Disease
Archives of Pathology & Laboratory Medicine, 2001Co-Authors: J. Fernando Val-bernal, J. PintoAbstract:Abstract Background.—Pagetoid Dyskeratosis is considered a selective keratinocytic response in which a small part of the normal population of keratinocytes is induced to proliferate. Pagetoid Dyskeratosis has been found incidentally in the squamous epithelium of the skin in various locations and in the ectocervix in uterine prolapse. In cases in which these pale cells are conspicuous, there is a hazard of overdiagnosis. It has been suggested that friction is the most probable inductor of the lesion. To the best of our knowledge, pagetoid cells have not been reported in surgically resected hemorrhoids. Objective and Design.—We here describe the location of pagetoid Dyskeratosis in the squamous epithelium of hemorrhoids and the incidence of this lesion in a group of 100 unselected patients surgically treated for hemorrhoidal disease. In addition to the conventional histologic method, special staining procedures and an immunohistochemical study of cytokeratins were performed in selected cases. Results.—Pagetoid Dyskeratosis was found in 68 cases (68%) and was a prominent finding in 22 cases (22%). The cells of pagetoid Dyskeratosis were strongly positive for high–molecular weight cytokeratin. These cells showed an immunohistochemical profile that was different from that of the surrounding squamous cells and indicative of premature keratinization. Conclusions.—In hemorrhoidal disease, the cushions are susceptible to trauma as a result of prolapse. In this setting, friction may be the stimulus for the appearance of pagetoid dyskeratotic cells. These cells must be distinguished from the artifactual clear cells of the squamous epithelium, glycogen-rich cells, and koilocytes. The lesion must also be distinguished from extramammary Paget disease, pagetoid spread of carcinoma cells, pagetoid Bowen disease, and pagetoid melanoma. Pathologists should be familiar with the histologic features of pagetoid Dyskeratosis in hemorrhoidectomy specimens to avoid misdiagnosis. Routine histologic study is usually adequate for recognizing this lesion.
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pagetoid Dyskeratosis of the cervix an incidental histologic finding in uterine prolapse
The American Journal of Surgical Pathology, 2000Co-Authors: J F Valbernal, María Francisca Garijo, J. Pinto, M S GomezAbstract:Pagetoid Dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. The lesion is characterized by pale cells resembling those of Paget's disease within the epidermis. These cells have been seen as an incidental finding in a variety of benign papules most commonly located in intertriginous areas. Among the inductors of the lesion, friction is suspected. To the best of our knowledge, these pale cells have not been reported in the cervix. We describe the location of the lesion in the ectocervix and the incidence of this lesion in a group of 100 unselected patients surgically treated for uterine prolapse. Another group of 100 unselected patients treated for uterine leiomyoma was used as a control. Pagetoid Dyskeratosis was found in 37 cases (37%) of uterine prolapse and in five cases (5%) of uterine leiomyomas. The lesion is more common in uterine prolapse (p <0.001) and is not significantly associated with cornification of the epithelium (p = 0.72343). The cells of pagetoid Dyskeratosis show an immunohistochemical profile different from the surrounding squamous cells characterized by premature keratinization. Pagetoid Dyskeratosis cells have shown positivity for high molecular weight cytokeratin and negative reaction for low molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. Pagetoid Dyskeratosis cells must be distinguished from artefactual clear cells, glycogen-rich cells, koilocytes, extramammary Paget's disease cells, and pagetoid spread of carcinoma cells to the cervix. In cases in which pagetoid Dyskeratosis shows a florid expression, there is a hazard of overdiagnosis. The pathologist should be aware of the histologic features of pagetoid Dyskeratosis in the ectocervix to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.
Sharon A. Savage - One of the best experts on this subject based on the ideXlab platform.
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cancer in the national cancer institute inherited bone marrow failure syndrome cohort after fifteen years of follow up
Haematologica, 2018Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, Dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and Dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in Dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by Dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers. clinicaltrials.gov Identifier: 00027274.
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Telomere length in inherited bone marrow failure syndromes
Haematologica, 2014Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with Dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in Dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (−2.326 = 1st percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most Dyskeratosis congenita telomere lengths were below the 1st percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated Dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in Dyskeratosis congenita, telomere lengths in patients with non-Dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. clinicaltrials.gov identifier: 00027274
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telomere length is associated with disease severity and declines with age in Dyskeratosis congenita
Haematologica, 2012Co-Authors: Blanche P Alter, Neelam Giri, Philip S Rosenberg, Gabriela M Baerlocher, Peter M Lansdorp, Sharon A. SavageAbstract:Background Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology. Design and Methods We studied 65 patients with Dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age). Results We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of Dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1 , TINF2 , or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of Dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data. Conclusions Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for Dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with Dyskeratosis congenita have accelerated telomere shortening. This study is registered at [www.clinicaltrials.gov][1] (identifier: [NCT00027274][2]). [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00027274&atom=%2Fhaematol%2F97%2F3%2F353.atom
Philip S Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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cancer in the national cancer institute inherited bone marrow failure syndrome cohort after fifteen years of follow up
Haematologica, 2018Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, Dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and Dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in Dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by Dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers. clinicaltrials.gov Identifier: 00027274.
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Telomere length in inherited bone marrow failure syndromes
Haematologica, 2014Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with Dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in Dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (−2.326 = 1st percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most Dyskeratosis congenita telomere lengths were below the 1st percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated Dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in Dyskeratosis congenita, telomere lengths in patients with non-Dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. clinicaltrials.gov identifier: 00027274
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telomere length is associated with disease severity and declines with age in Dyskeratosis congenita
Haematologica, 2012Co-Authors: Blanche P Alter, Neelam Giri, Philip S Rosenberg, Gabriela M Baerlocher, Peter M Lansdorp, Sharon A. SavageAbstract:Background Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology. Design and Methods We studied 65 patients with Dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age). Results We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of Dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1 , TINF2 , or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of Dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data. Conclusions Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for Dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with Dyskeratosis congenita have accelerated telomere shortening. This study is registered at [www.clinicaltrials.gov][1] (identifier: [NCT00027274][2]). [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00027274&atom=%2Fhaematol%2F97%2F3%2F353.atom
Blanche P Alter - One of the best experts on this subject based on the ideXlab platform.
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cancer in the national cancer institute inherited bone marrow failure syndrome cohort after fifteen years of follow up
Haematologica, 2018Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, Dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and Dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in Dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by Dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers. clinicaltrials.gov Identifier: 00027274.
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Telomere length in inherited bone marrow failure syndromes
Haematologica, 2014Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with Dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in Dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (−2.326 = 1st percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most Dyskeratosis congenita telomere lengths were below the 1st percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated Dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in Dyskeratosis congenita, telomere lengths in patients with non-Dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. clinicaltrials.gov identifier: 00027274
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telomere length is associated with disease severity and declines with age in Dyskeratosis congenita
Haematologica, 2012Co-Authors: Blanche P Alter, Neelam Giri, Philip S Rosenberg, Gabriela M Baerlocher, Peter M Lansdorp, Sharon A. SavageAbstract:Background Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology. Design and Methods We studied 65 patients with Dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age). Results We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of Dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1 , TINF2 , or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of Dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data. Conclusions Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for Dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with Dyskeratosis congenita have accelerated telomere shortening. This study is registered at [www.clinicaltrials.gov][1] (identifier: [NCT00027274][2]). [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00027274&atom=%2Fhaematol%2F97%2F3%2F353.atom
Justine D Miller - One of the best experts on this subject based on the ideXlab platform.
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telomere elongation in induced pluripotent stem cells from Dyskeratosis congenita patients
Nature, 2010Co-Authors: Suneet Agarwal, Erin M Mcloughlin, Junjiu Huang, Inhyun Park, Justine D MillerAbstract:Patients with Dyskeratosis congenita, a disorder of telomere maintenance, suffer degeneration of multiple tissues. Agarwal et al. use iPS (induced pluripotent stem) cell technology to study the mechanisms underlying the disease in humans, and in doing so they discover that reprogramming restores telomere elongation in Dyskeratosis congenita cells despite genetic lesions affecting telomerase. The reprogrammed Dyskeratosis congenita cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors. Strategies designed to increase TERC expression may therefore be therapeutically beneficial in Dyskeratosis congenita patients. Here, iPS cell technology is used to study the mechanisms underlying Dyskeratosis congenita in humans. Reprogramming restores telomere elongation in Dyskeratosis congenita cells despite genetic lesions affecting telomerase. The reprogrammed cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors. Patients with Dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues1,2,3. Patient-specific induced pluripotent stem (iPS) cells4 represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)5,6,7. We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3′ deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.