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Hirokazu Nagawa - One of the best experts on this subject based on the ideXlab platform.

  • Chromosome 18q deletion as a novel molecular predictor for colorectal cancer with simultaneous hepatic metastasis
    Diagnostic Molecular Pathology, 2009
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Joji Kitayama, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Currently, surgical treatment for colorectal hepatic metastasis is performed with low mortality and morbidity rates. However, there is no definitive marker that predicts patient outcome. The aim of this study is to identify the molecular predictor of survival along with its clinical properties. Fifty-six patients were surgically treated for colorectal cancer and synchronous hepatic metastasis from January 1994 to December 2004. Clinicopathologic and molecular factors were reviewed in association with overall survival (OS) and disease-free survival (DFS). Chromosome 18q deletion in the primary tumor was a molecular predictor that affected OS (P=0.021). Decreased expression of the Smad4 protein tended to affect the outcome; however, no statistical significance was observed (P=0.29:OS, P=0.45:DFS). Preoperative carcinoembryonic antigen (P=0.013) and carbohydrate antigen 19-9 (CA19-9) (P<0.0001) levels were poor clinical predictors of OS. The number of primary lymph nodes was the only pathologic factor that affected DFS (P=0.0052). The number and diameter of hepatic metastasis had no influence on survival. In conclusion, we demonstrated that Chromosome 18q deletion, in conjunction with high carcinoembryonic antigen and CA19-9 levels, is an unfavorable prognostic factor. This novel molecular predictor is helpful in identifying patients who would benefit from surgical resection.

  • Chromosome 18q deletion as a novel molecular predictor for colorectal cancer with simultaneous hepatic metastasis.
    Diagnostic molecular pathology : the American journal of surgical pathology part B, 2009
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Joji Kitayama, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Currently, surgical treatment for colorectal hepatic metastasis is performed with low mortality and morbidity rates. However, there is no definitive marker that predicts patient outcome. The aim of this study is to identify the molecular predictor of survival along with its clinical properties. Fifty-six patients were surgically treated for colorectal cancer and synchronous hepatic metastasis from January 1994 to December 2004. Clinicopathologic and molecular factors were reviewed in association with overall survival (OS) and disease-free survival (DFS). Chromosome 18q deletion in the primary tumor was a molecular predictor that affected OS (P=0.021). Decreased expression of the Smad4 protein tended to affect the outcome; however, no statistical significance was observed (P=0.29:OS, P=0.45:DFS). Preoperative carcinoembryonic antigen (P=0.013) and carbohydrate antigen 19-9 (CA19-9) (P

  • loss of smad4 protein expression and 18qloh as molecular markers indicating lymph node metastasis in colorectal cancer a study matched for tumor depth and pathology
    Journal of Surgical Oncology, 2008
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Purpose Chromosome 18q21 deletion and Smad4 protein inactivation have been reported as molecular markers predicting unfavorable outcome in colorectal cancers and, in a previous report, we recently revealed that these molecules are closely associated with distant metastasis, which is one of the clinical factors affecting postoperative survival. However, there has been no discussion as to how these molecules influence another clinical factor, namely, lymph node metastasis. In this report, we studied the significance of Chromosome 18q deletion and loss of Smad4 protein expression in association with lymph node metastasis. Method Forty pairs of colorectal cancer specimens were studied; one group was positive for lymph node metastasis while the other was negative. We examined Smad4 protein expression level and Chromosome 18q deletion in the two groups. Results Immunohistochemical staining revealed that more cases showed a weaker stain for Smad4 protein in the lymph node positive group compared with the negative group (P = 0.00075). Furthermore, a higher ratio of 18q21 deletion was observed in the lymph node positive group (P = 0.029). Conclusion We revealed that Chromosome 18q deletion and Smad4 protein inactivation are the essential molecular events in the process of lymph node metastasis. J. Surg. Oncol. 2008;97:69–73. © 2007 Wiley-Liss, Inc.

  • Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: A study matched for T- and N- classification.
    British journal of cancer, 2006
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Smad4 protein, whose gene is coded at Chromosome 18q21.1, is an important tumour suppressor that mediates transforming growth factor-beta. It has been reported that inactivation of the Smad4 gene and allelic loss of Chromosome 18q correlate with liver metastasis and poorer prognosis in colorectal cancers. Utilising a recently developed method of immunohistochemical staining for Smad4 protein, we focused on the specific impact of Smad4 protein expression on liver metastasis in colorectal cancer. We also evaluated the association between Chromosome18q deletion and liver metastasis. We selected 20 colorectal cancers with liver metastasis for the experimental group, and 20 cases without liver metastasis for the control. In order to exclude the influence of lymph node metastasis, all cases were lymph node negative. In addition, the two groups were matched for tumour depth, tumour differentiation and tumour location. We compared the expression level of Smad4 protein immunohistochemically in these 20 matched pairs. We also compared the loss of heterozygosity status at Chromosome 18q in these 20 matched pairs. Immunohistochemical staining revealed a significant difference (P=0.024) in the level of Smad4 protein between the two groups. We also observed a significantly different (P=0.0054) ratio of allelic deletion at Chromosome 18q21. Smad4 protein expression level and allelic loss at 18q21 are associated with the process of liver metastasis in colorectal cancers evaluated when excluding clinical and pathological features except for liver metastasis.

Robin J Leach - One of the best experts on this subject based on the ideXlab platform.

  • Determination of a minimal region of loss of heterozygosity on Chromosome 18q21.33 in osteosarcoma.
    International journal of cancer, 2003
    Co-Authors: Teresa L. Johnson-pais, M J Nellissery, P Bhatia, Carolyn L. Buller, Robin J Leach, Donald G. Ammerman, Dharmini Pathmanathan, Marc F. Hansen
    Abstract:

    Previous analysis of tumor-specific constitutional LOH had identified a putative tumor-suppressor gene (LOH18CR) active in osteosarcoma tumorigenesis, which mapped to a subregion of Chromosome 18q linked to both familial Paget's disease and FEO. Using 9 new polymorphic loci within the previous minimal region of LOH, we have reduced the minimal region of LOH in osteosarcoma tumors to localize the LOH18CR locus to the distal end of Chromosome 18q21.33. This new region is approximately 500 kb and contains at least 7 known genes; however, it excludes 2 previous candidate genes: TNFRSF11A (RANK) and BCL2. © 2003 Wiley-Liss, Inc.

  • Identification of two distinct regions of allelic imbalance on Chromosome 18q in metastatic prostate cancer
    International journal of cancer, 2000
    Co-Authors: Susan S. Padalecki, Dean A. Troyer, Marc F. Hansen, Tomo Saric, B G Schneider, Peter O'connell, Robin J Leach
    Abstract:

    Like most cancers, prostate cancer (CaP) is believed to be the result of the accumulation of genetic alterations within cells. Previous studies have implicated numerous chromosomal regions with elevated rates of allelic imbalance (AI), using mostly primary CaPs with an unknown disease outcome. These regions of AI are proposed sites for tumor suppressor genes. One of the regions previously implicated as coding for at least one tumor suppressor gene is the long arm of Chromosome 18 (18q). To confirm this observation, as well as to narrow the critical region for this putative tumor suppressor, we analyzed 32 metastatic CaP specimens for AI on Chromosome 18q. Thirty-one of these 32 specimens (96.8%) exhibited AI at one or more loci on Chromosome 18q. Our analysis using 17 polymorphic markers revealed statistically significant AI on Chromosome 18q at 3 markers, D18S35, D18S64 and D18S461. Using these markers as a guide, we have been able to identify 2 distinct minimum regions of AI on 18q. The first region is between the genetic markers D18S1119 and D18S64. The second region lies more distal on the long arm of the Chromosome and is between the genetic markers D18S848 and D18S58. To determine if 18q loss is a late event in the progression of CaP, we also examined prostatic intraepithelial neoplasia (PIN) and primary prostate tumors from 17 patients for AI with a subset of 18q markers. We found significantly higher AI in the metastatic samples. Our results are consistent with 18q losses occurring late in CaP progression.

  • congenital anomalies and anthropometry of 42 individuals with deletions of Chromosome 18q
    American Journal of Medical Genetics, 1999
    Co-Authors: Jannine D. Cody, Daniel E. Hale, Patricia D Ghidoni, Barbara R Dupont, Susan G Hilsenbeck, Robert F Stratton, Douglas S Hoffman, Shaine Muller, Rebecca L Schaub, Robin J Leach
    Abstract:

    Deletions of Chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280–286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this Chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the Chromosome in which genes responsible for specific abnormal phenotypes are located. Am. J. Med. Genet. 85:455–462, 1999. © 1999 Wiley-Liss, Inc.

  • evidence for a novel osteosarcoma tumor suppressor gene in the Chromosome 18 region genetically linked with paget disease of bone
    American Journal of Human Genetics, 1998
    Co-Authors: M J Nellissery, Susan S. Padalecki, Robin J Leach, Frederick R. Singer, Zoran Brkanac, David G Roodman, Krishnan K Unni, Marc F. Hansen
    Abstract:

    Paget disease of bone, or "osteitis deformans," is a bone disorder characterized by rapid bone remodeling resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3%-5% of subjects aged >40 years. Recent evidence suggests that predisposition to Paget disease may have a genetic component. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of Chromosome 18q near the polymorphic locus D18S42. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occurring after age 60 years. Our analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identified a putative tumor-suppressor locus that maps to Chromosome 18q. We have localized this tumor-suppressor locus between D18S60 and D18S42, a region tightly linked to familial Paget disease. Analysis of osteosarcomas from patients with Paget disease revealed that these tumors also undergo LOH in this region. These findings suggest that the association between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on Chromosome 18.

  • Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss.
    American journal of medical genetics, 1998
    Co-Authors: Kim M. Keppler-noreuil, Jannine D. Cody, Barbara R Dupont, Andrew J. Carroll, Sara C. Finley, Maria Descartes, Robin J Leach
    Abstract:

    We report on a mother and child with a paracentric inversion of the long arm of Chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.

Toshiaki Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • Chromosome 18q deletion as a novel molecular predictor for colorectal cancer with simultaneous hepatic metastasis
    Diagnostic Molecular Pathology, 2009
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Joji Kitayama, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Currently, surgical treatment for colorectal hepatic metastasis is performed with low mortality and morbidity rates. However, there is no definitive marker that predicts patient outcome. The aim of this study is to identify the molecular predictor of survival along with its clinical properties. Fifty-six patients were surgically treated for colorectal cancer and synchronous hepatic metastasis from January 1994 to December 2004. Clinicopathologic and molecular factors were reviewed in association with overall survival (OS) and disease-free survival (DFS). Chromosome 18q deletion in the primary tumor was a molecular predictor that affected OS (P=0.021). Decreased expression of the Smad4 protein tended to affect the outcome; however, no statistical significance was observed (P=0.29:OS, P=0.45:DFS). Preoperative carcinoembryonic antigen (P=0.013) and carbohydrate antigen 19-9 (CA19-9) (P<0.0001) levels were poor clinical predictors of OS. The number of primary lymph nodes was the only pathologic factor that affected DFS (P=0.0052). The number and diameter of hepatic metastasis had no influence on survival. In conclusion, we demonstrated that Chromosome 18q deletion, in conjunction with high carcinoembryonic antigen and CA19-9 levels, is an unfavorable prognostic factor. This novel molecular predictor is helpful in identifying patients who would benefit from surgical resection.

  • Chromosome 18q deletion as a novel molecular predictor for colorectal cancer with simultaneous hepatic metastasis.
    Diagnostic molecular pathology : the American journal of surgical pathology part B, 2009
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Joji Kitayama, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Currently, surgical treatment for colorectal hepatic metastasis is performed with low mortality and morbidity rates. However, there is no definitive marker that predicts patient outcome. The aim of this study is to identify the molecular predictor of survival along with its clinical properties. Fifty-six patients were surgically treated for colorectal cancer and synchronous hepatic metastasis from January 1994 to December 2004. Clinicopathologic and molecular factors were reviewed in association with overall survival (OS) and disease-free survival (DFS). Chromosome 18q deletion in the primary tumor was a molecular predictor that affected OS (P=0.021). Decreased expression of the Smad4 protein tended to affect the outcome; however, no statistical significance was observed (P=0.29:OS, P=0.45:DFS). Preoperative carcinoembryonic antigen (P=0.013) and carbohydrate antigen 19-9 (CA19-9) (P

  • loss of smad4 protein expression and 18qloh as molecular markers indicating lymph node metastasis in colorectal cancer a study matched for tumor depth and pathology
    Journal of Surgical Oncology, 2008
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Purpose Chromosome 18q21 deletion and Smad4 protein inactivation have been reported as molecular markers predicting unfavorable outcome in colorectal cancers and, in a previous report, we recently revealed that these molecules are closely associated with distant metastasis, which is one of the clinical factors affecting postoperative survival. However, there has been no discussion as to how these molecules influence another clinical factor, namely, lymph node metastasis. In this report, we studied the significance of Chromosome 18q deletion and loss of Smad4 protein expression in association with lymph node metastasis. Method Forty pairs of colorectal cancer specimens were studied; one group was positive for lymph node metastasis while the other was negative. We examined Smad4 protein expression level and Chromosome 18q deletion in the two groups. Results Immunohistochemical staining revealed that more cases showed a weaker stain for Smad4 protein in the lymph node positive group compared with the negative group (P = 0.00075). Furthermore, a higher ratio of 18q21 deletion was observed in the lymph node positive group (P = 0.029). Conclusion We revealed that Chromosome 18q deletion and Smad4 protein inactivation are the essential molecular events in the process of lymph node metastasis. J. Surg. Oncol. 2008;97:69–73. © 2007 Wiley-Liss, Inc.

  • Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: A study matched for T- and N- classification.
    British journal of cancer, 2006
    Co-Authors: Toshiaki Tanaka, Toshiaki Watanabe, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Shinsuke Kazama, Hirokazu Nagawa
    Abstract:

    Smad4 protein, whose gene is coded at Chromosome 18q21.1, is an important tumour suppressor that mediates transforming growth factor-beta. It has been reported that inactivation of the Smad4 gene and allelic loss of Chromosome 18q correlate with liver metastasis and poorer prognosis in colorectal cancers. Utilising a recently developed method of immunohistochemical staining for Smad4 protein, we focused on the specific impact of Smad4 protein expression on liver metastasis in colorectal cancer. We also evaluated the association between Chromosome18q deletion and liver metastasis. We selected 20 colorectal cancers with liver metastasis for the experimental group, and 20 cases without liver metastasis for the control. In order to exclude the influence of lymph node metastasis, all cases were lymph node negative. In addition, the two groups were matched for tumour depth, tumour differentiation and tumour location. We compared the expression level of Smad4 protein immunohistochemically in these 20 matched pairs. We also compared the loss of heterozygosity status at Chromosome 18q in these 20 matched pairs. Immunohistochemical staining revealed a significant difference (P=0.024) in the level of Smad4 protein between the two groups. We also observed a significantly different (P=0.0054) ratio of allelic deletion at Chromosome 18q21. Smad4 protein expression level and allelic loss at 18q21 are associated with the process of liver metastasis in colorectal cancers evaluated when excluding clinical and pathological features except for liver metastasis.

Marc F. Hansen - One of the best experts on this subject based on the ideXlab platform.

  • Determination of a minimal region of loss of heterozygosity on Chromosome 18q21.33 in osteosarcoma.
    International journal of cancer, 2003
    Co-Authors: Teresa L. Johnson-pais, M J Nellissery, P Bhatia, Carolyn L. Buller, Robin J Leach, Donald G. Ammerman, Dharmini Pathmanathan, Marc F. Hansen
    Abstract:

    Previous analysis of tumor-specific constitutional LOH had identified a putative tumor-suppressor gene (LOH18CR) active in osteosarcoma tumorigenesis, which mapped to a subregion of Chromosome 18q linked to both familial Paget's disease and FEO. Using 9 new polymorphic loci within the previous minimal region of LOH, we have reduced the minimal region of LOH in osteosarcoma tumors to localize the LOH18CR locus to the distal end of Chromosome 18q21.33. This new region is approximately 500 kb and contains at least 7 known genes; however, it excludes 2 previous candidate genes: TNFRSF11A (RANK) and BCL2. © 2003 Wiley-Liss, Inc.

  • Identification of two distinct regions of allelic imbalance on Chromosome 18q in metastatic prostate cancer
    International journal of cancer, 2000
    Co-Authors: Susan S. Padalecki, Dean A. Troyer, Marc F. Hansen, Tomo Saric, B G Schneider, Peter O'connell, Robin J Leach
    Abstract:

    Like most cancers, prostate cancer (CaP) is believed to be the result of the accumulation of genetic alterations within cells. Previous studies have implicated numerous chromosomal regions with elevated rates of allelic imbalance (AI), using mostly primary CaPs with an unknown disease outcome. These regions of AI are proposed sites for tumor suppressor genes. One of the regions previously implicated as coding for at least one tumor suppressor gene is the long arm of Chromosome 18 (18q). To confirm this observation, as well as to narrow the critical region for this putative tumor suppressor, we analyzed 32 metastatic CaP specimens for AI on Chromosome 18q. Thirty-one of these 32 specimens (96.8%) exhibited AI at one or more loci on Chromosome 18q. Our analysis using 17 polymorphic markers revealed statistically significant AI on Chromosome 18q at 3 markers, D18S35, D18S64 and D18S461. Using these markers as a guide, we have been able to identify 2 distinct minimum regions of AI on 18q. The first region is between the genetic markers D18S1119 and D18S64. The second region lies more distal on the long arm of the Chromosome and is between the genetic markers D18S848 and D18S58. To determine if 18q loss is a late event in the progression of CaP, we also examined prostatic intraepithelial neoplasia (PIN) and primary prostate tumors from 17 patients for AI with a subset of 18q markers. We found significantly higher AI in the metastatic samples. Our results are consistent with 18q losses occurring late in CaP progression.

  • evidence for a novel osteosarcoma tumor suppressor gene in the Chromosome 18 region genetically linked with paget disease of bone
    American Journal of Human Genetics, 1998
    Co-Authors: M J Nellissery, Susan S. Padalecki, Robin J Leach, Frederick R. Singer, Zoran Brkanac, David G Roodman, Krishnan K Unni, Marc F. Hansen
    Abstract:

    Paget disease of bone, or "osteitis deformans," is a bone disorder characterized by rapid bone remodeling resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3%-5% of subjects aged >40 years. Recent evidence suggests that predisposition to Paget disease may have a genetic component. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of Chromosome 18q near the polymorphic locus D18S42. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occurring after age 60 years. Our analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identified a putative tumor-suppressor locus that maps to Chromosome 18q. We have localized this tumor-suppressor locus between D18S60 and D18S42, a region tightly linked to familial Paget disease. Analysis of osteosarcomas from patients with Paget disease revealed that these tumors also undergo LOH in this region. These findings suggest that the association between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on Chromosome 18.

Zhiwei Zhou - One of the best experts on this subject based on the ideXlab platform.