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ABSTRACT: The significance of BRAF mutations, microsatelite instability (MSI) status and cyclin D1 expression in patients with metastatic colorectal cancer (mCRC) was evaluated.
Primary tumours from 144 patients treated for mCRC were assessed for BRAF (V600E) mutation, MSI status and cyclin D1. The data were correlated with progression-free survival (PFS) and overall survival (OS).
BRAF mutations were detected in 10 (out of 22, 45%) patients with MSI-H tumours compared with 2 (out of 122, 1.6%) in those with microsatellite stable tumours (P<0.001). The presence of BRAF mutations was correlated with cyclin D1 overexpression (7 out of 26 patients, 58% vs 5 out of 118 patients, 14%; P=0.001). Patients with BRAF-mutated primary tumours had a significantly decreased PFS (2.7 vs 9.8 months; P<0.001) and median OS (14 vs 30 months; P<0.001) than patients with wild-type (wt) tumours. Patients with MSI-H and BRAF-mutated tumours experienced significantly lower PFS (3.1 vs 11.4 months; P=0.008) and OS (14.5 vs 35.5 months; P=0.004) than patients with MSI-H and BRAF wt tumours. Similarly, BRAF mutations and cyclin D1 overexpression were correlated with decreased PFS (3.1 vs 8.6 months; P=0.03) and OS (17.8 vs 39.2 months; P=0.01).
BRAF V600E mutations are associated with MSI-H status and cyclin D1 overexpression and characterize a subgroup of patients with poor prognosis.
British Journal of Cancer 06/2010; 102(12):1762-8. · 5.04 Impact Factor
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J Souglakos,
J Philips,
R Wang,
S Marwah,
M Silver, M Tzardi,
J Silver,
S Ogino,
S Hooshmand,
E Kwak,
E Freed,
J A Meyerhardt,
Z Saridaki,
V Georgoulias,
D Finkelstein,
C S Fuchs,
M H Kulke,
R A Shivdasani
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ABSTRACT: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC).
We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively.
KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy.
These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.
British Journal of Cancer 09/2009; 101(3):465-72. · 5.04 Impact Factor
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J Souglakos,
J Philips,
R Wang,
S Marwah,
M Silver, M Tzardi,
J Silver,
S Ogino,
S Hooshmand,
E Kwak,
E Freed,
J A Meyerhardt,
Z Saridaki,
V Georgoulias,
D Finkelstein,
C S Fuchs,
M H Kulke,
R A Shivdasani
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ABSTRACT: Background: Methods: Results: Conclusions: Materials and methods Results Discussion References Acknowledgements Figures and TablesBackground: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC).
British Journal of Cancer 07/2009; 101(3):465-472. · 5.04 Impact Factor
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ABSTRACT: Angiogenesis has been suggested as an integral part of inflammatory bowel disease pathology. Vascular endothelial growth factor has long been considered to play a central, specific role in angiogenesis. Endothelial junction adhesion molecules, such as CD146, have recently been suggested to play a potent role in angiogenesis. CD34 is expressed on vascular endothelium, and it has been reported to be upregulated on endothelium in IBD. We investigated the expression of tissue vascular endothelial growth factor, CD34 and CD146 in the inflamed mucosa of patients with active inflammatory bowel disease compared with no inflamed mucosa of healthy controls.
Forty-two IBD patients [23 ulcerative colitis, 19 Crohn's disease] and ten healthy controls were included in the study. In colonoscopically obtained biopsies, CD34, CD146 and vascular endothelial growth factor expression were evaluated by immunohistochemistry.
Vascular endothelial growth factor was detected in the mucosa of all groups, and its expression was significantly higher in both Crohn's disease and ulcerative colitis compared with controls (p<0.05). Immunohistochemical staining for CD146 in the inflamed mucosa was significantly higher in both Crohn's disease and ulcerative colitis compared with controls (p=0.002). A trend of higher CD34 expression in Crohn's disease and ulcerative colitis compared with controls was also found, but the difference among the three groups was not statistically significant (p=0.09).
Inflamed mucosa of patients with active Crohn's disease and ulcerative colitis showed a markedly enhanced expression of VEGF and CD146, than normal mucosa of controls, indicating a possible role of angiogenesis in the pathogenesis of inflammatory bowel disease.
Digestive and Liver Disease 09/2008; 40(8):673-9. · 3.05 Impact Factor
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Digestive and Liver Disease 03/2008; 40(2):144. · 3.05 Impact Factor
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ABSTRACT: The aim of our study was to evaluate the relationship between the expression of HSP70 protein, cell proliferation, the expression of ER receptors and the clinicopathological variables Grade and LNS in breast invasive human tumors along with the role of HSP70 protein in the prognosis of human breast cancer. A strong association between HSP70 expression and ER content, in agreement with previous data, was found which revealed a statistically significant association between HSP70 positivity and ER expression (p<0.008) in 50 cases of invasive primary human breast cancers. We also found a strong correlation between HSP70 expression, Grade and LNS of invasive ductal breast carcinomas. This suggests that the expression of HSP70 plays a significant role in the progression of human breast cancer, and might prove useful in many other malignancies as an important marker for the outcome of the disease.
Journal of experimental & clinical cancer research: CR 09/2007; 26(3):367-8. · 1.50 Impact Factor
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J Souglakos,
A Kalykaki,
L Vamvakas,
N Androulakis,
K Kalbakis,
S Agelaki,
N Vardakis, M Tzardi,
A P Kotsakis,
J Gioulbasanis,
D Tsetis,
G Sfakiotaki,
D Chatzidaki,
D Mavroudis,
V Georgoulias
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ABSTRACT: Cetuximab is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor and is able to reverse the resistance to irinotecan in patients with metastatic colorectal cancer (mCRC). This phase II trial evaluates the safety and efficacy of cetuximab combined with capecitabine and oxaliplatin (CAPOX) in the treatment of patients with mCRC progressing under oxaliplatin-based chemotherapy. Patients and treatment: Forty patients with mCRC were treated with cetuximab (loading dose 400 mg/m(2) and then 250 mg/m(2) i.v. weekly) in combination with CAPOX (d(1): L-OHP 85 mg/m(2) and d(1-7) capecitabine 2000 mg/m(2) every 2 weeks). Thirty-one (77.5%) and nine (22.5%) patients had oxaliplatin-refractory and -resistant disease, respectively; in addition, 32 (80%) patients had also progressed on prior irinotecan-based chemotherapy.
One hundred and thirty-four cycles were administered (median of four cycles per patient). Main toxic effects included grade 3-4 neutropenia (12.5%), grade 3/4 diarrhea (7.5%), grade 3 fatigue (2.5%), and grade 2-3 neurotoxicity (22.5%). One (2.5%) complete and seven (17.5%) partial responses were achieved [overall objective response rate (ORR): 20%; 95% confidence interval (CI): 9% to 32%)], whereas 11 (27.5%) patients had stable disease [disease control rate (DCR): 47.5%; 95% CI: 30.2% to 64.5%]. The ORR and DCR were 18.7% and 46.8%, respectively, in patients with oxaliplatin-refractory disease. The median time to tumor progression was 3 months, the median survival 10.7 months and the probability of 1-year survival rate 53.4%.
The combination of cetuximab plus CAPOX is safe and has a promising activity in patients with mCRC refractory or resistant to oxaliplatin.
Annals of Oncology 03/2007; 18(2):305-10. · 6.43 Impact Factor
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ABSTRACT: Segmental colitis associated with diverticulosis (SCAD) has been defined as chronic colonic inflammation surrounding diverticula with rectal sparing. Distinguishing this condition from inflammatory bowel disease may be difficult. Our aim was to evaluate the epidemiological and clinical characteristics of SCAD in our area.
Retrospective case identification with prospective follow-up was done. Patients with endoscopic findings suggestive of SCAD were enrolled. The epidemiological, clinical, and histological characteristics of these patients were analyzed.
Out of 605 patients with diverticulosis, 23 cases of SCAD were identified (3.8%). Four patients had histological characteristics suggestive of ulcerative colitis, in 1 case the histology was suggestive of ischemic colitis, 6 patients had histology compatible with SCAD, and the remaining patients had either transitional mucosa or minimal lesions. Four cases were refractory to conservative treatment (mesalamine and antibiotics) and surgery was required. No cases of extension of colonic inflammation in diverticula-free areas were found.
Segmental colitis associated with diverticulosis is not a rare disorder. It may occur with a spectrum of clinical and histologic features and may be confused with ulcerative colitis. The majority of the cases respond to medical therapy with antibiotics and/or mesalamine, whereas few cases are refractory and need surgery. No evolution to inflammatory bowel disease was observed.
International Journal of Colorectal Disease 02/2005; 20(1):28-32. · 2.38 Impact Factor
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Phytomedicine 02/2004; 11(1):83-4. · 3.27 Impact Factor
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ABSTRACT: We describe the first case of a primary gastric plasmacytoma stage I completely regressed following Helicobacter pylori (H.pylori) eradication. The patient, a 61-year-old man, had a long history of chronic gastritis and gastric ulcers with recurrent gastrointestinal hemorrhage. Diagnosis of H.pylori infection was based on the positive urease breath test, the elevated titers of serum anti- H.pylori antibodies, and the detection of the bacterium in gastric mucosa biopsy specimens. Diagnosis of gastric plasmacytoma was based on the findings of histopathology, immunocytochemistry and in situ hybridization. Eradication of H.pylori with antibiotics was followed by disappearance of endoscopic and histopathologic features of the gastric tumor 3 months after the completion of the treatment. No relapse has been documented 20 months after the initial diagnosis of plasmacytoma. A possible causal relationship between the tumor and the underlying H.pylori infection is discussed.
Annals of Hematology 10/2003; 82(9):589-92. · 2.62 Impact Factor
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ABSTRACT: Gastric carcinoid is a rare tumour that is associated with chronic atrophic gastritis in the majority of cases. It usually occurs in the 6th or 7th decade of life and is rarely diagnosed in patients under 30 years of age.
We describe a case of multiple gastric carcinoids in a 23-year-old woman with systemic lupus erythematosus and atrophic autoimmune gastritis--an association that has not been reported previously.
The combination of atrophic autoimmune gastritis and gastric carcinoid with other autoimmune disorders has rarely been reported in the English medical literature.
The fact that it mostly concerns (relatively) young patients may suggest a potential causative relation between those autoimmune disorders and the early development of atrophic gastritis with hypergastrinaemia, which subsequently leads to the occurrence of gastric carcinoid tumours at a young age.
Scandinavian Journal of Gastroenterology 06/2003; 38(5):477-81. · 2.02 Impact Factor
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Gut 01/2003; 51(6):894-5; author reply 895. · 10.11 Impact Factor
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ABSTRACT: The presence of CRH and urocortin (Ucn), members of the CRH family of neuropeptides, was examined in human gastric biopsies from normal controls and in patients with active gastritis from Helicobacter pylori (H. pylori) and after eradication treatment. RT-PCR analysis showed the presence of the Ucn transcript in biopsies (obtained by gastroscopy) from normal and inflamed gastric mucosa, whereas the CRH transcript was not detectable. Immunoreactive (ir-) Ucn was localized (by immunohistochemistry) in gastric epithelial cells and in inflammatory elements of the surrounding negative for Ucn gastric stroma. The level of ir-Ucn was higher in gastric biopsies from the group of patients with active H. pylori gastritis than in normal controls (10.4 +/- 1.8 vs. 2.0 +/- 1.3 pg/ micro g total protein; P < 0.001). After the apparent eradication of H. pylori infection (by clinical and morphological criteria) ir-Ucn levels increased dramatically to 43.1 +/- 9.8 pg/ micro g total protein, (P < 0.001) compared with pretreatment values. Interestingly, nonresponders to the eradication treatment did not show any significant change in ir-Ucn levels (18.7 +/- 12.3 pg/ micro g total protein) compared with their pretreatment values. In conclusion, our data suggest that in human gastric epithelium Ucn is present and plays an important physiological role, whereas CRH is absent. In addition, and in contrast to what has been found for CRH in ulcerative colitis, a highly significant, but negative, correlation has been found between Ucn levels and gastric inflammation, suggesting that Ucn may exert an antiinflammatory effect in gastric mucosa.
Journal of Clinical Endocrinology & Metabolism 01/2003; 88(1):478-83. · 6.50 Impact Factor
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ABSTRACT: Apoptosis may be an important mechanism of hepatocyte death in chronic viral liver disease.
We studied apoptosis in liver biopsies from 30 patients with chronic viral hepatitis and 8 patients with viral cirrhosis by the TUNEL method. 12 cases of non-alcoholic steatohepatitis and 12 cases of primary biliary cirrhosis were used as non-viral disease controls. Immunohistochemical expression of p53, p21/waf1, bcl-2 and mdm-2 proteins was also studied in the same patients.
A statistically significant increase of apoptotic liver cells was found in severe chronic viral hepatitis (5.3 +/- 0.3%), cirrhosis (3.4 +/- 0.5%) and PBC (4.4 +/- 0.4%) cases compared to patients with non-alcoholic steatohepatitis (0.8 +/- 0.3%). The expression of p53 protein was increased in the cases of viral cirrhosis and in chronic severe viral hepatitis whereas in the cases of chronic mild hepatitis, PBC and non-alcoholic steatohepatitis we found no expression of p53. P21/waf1 expression was increased in severe chronic hepatitis, cirrhosis and PBC cases compared to mild hepatitis and non-alcoholic steatohepatitis cases. However no induction of mdm-2 was observed in the subgroups of chronic liver disease. Bcl-2 was expressed only in epithelium of bile ducts and mononuclear cells of the portal tracts and liver lobules. A weaker Bcl-2 expression was noted in the epithelium of bile ducts of 7/12 PBC cases.
Our results provide evidence of increased apoptosis in severe chronic viral liver disease, suggesting that apoptotic cell death might be involved in the pathogenesis of hepatocellular damage of viral hepatitis and cirrhosis. Furthermore we analysed part of the apoptotic pathways implicated in the above process and found an increased expression of p21/waf1, probably p53 mediated, without overexpression of the apoptosis inhibiting bcl-2 and mdm-2 proteins. By contrast p21/waf1 overexpression in PBC seems to be propagated by a p53 independent mechanism.
APOPTOSIS 05/2002; 7(2):133-41. · 4.79 Impact Factor
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ABSTRACT: It is currently unclear whether intestinal metaplasia at the esophagogastric junction and in the distal esophagus represent a continuum of the same underlying disease process, i.e., gastroesophageal reflux, or constitute different entities with a different pathogenesis. Biopsies below the Z line might show specialized epithelium in some patients and the question is whether this is another form of short segment Barrett's esophagus or whether it is related to a generalized atrophic process of the stomach. Data from recent studies regarding the expression of cytokeratin CK7 and CK20 in intestinal metaplasia (IM) found at the gastroesophageal junction are conflicting. Prompted by these data we undertook the present study: a) to evaluate the expression of CK7 and CK20 in IM of the gastric cardia and to compare the findings with those in patients with Barrett's esophagus and IM of the gastric corpus and antrum mucosa; and b) to evaluate the immunophenotype of non-intestinalized cardiac mucosa and to compare it with that of normal gastric epithelium. We studied the expression of CK7 and CK20 on biopsy specimens from patients with long-segment Barrett's esophagus (n=17) and surgical resection and biopsy specimens of gastric cardia (n=15), corpus (n=14) and antrum (n=22) from patients with histological evidence of IM. Eighty-four biopsy specimens from 42 patients (antrum n=15, corpus n=20, cardia n=7) without evidence of IM were studied as a control group. We observed an immunophenotype characterised by diffuse moderate to strong CK7 staining on the surface and crypt epithelium combined with strong CK20 staining on the surface and superficial part of the crypts in 94.1% (16/17) of the cases with long-segment Barrett's esophagus, but in none of the 36 cases with IM in distal stomach (antrum and corpus). IM in the gastric cardia expressed the immunophenotype seen in IM of the gastric mucosa in 93.3% (14/15) of the cases. On the other hand, normal cardiac epithelium expressed patchy strong CK7 staining on the surface epithelium and on both, superficial and deep parts of the pits combined with patchy strong CK20 staining on the surface epithelium and superficial pits, a feature permitting distinction of the normal cardiac epithelium from those of the normal gastric antrum and corpus epithelium. We conclude that the expression of cytokeratins 7 and 20 can be used to distinguish the origin of IM of the gastroesophageal junction. The CK7/20 immunophenotype of IM in the gastric cardia closely resembles that of the IM in the gastric antrum and corpus and is different from IM in long-segment Barrett's esophagus. In contrast, the CK7/20 immunophenotype of the cardiac epithelium is different from that of the gastric antrum and corpus mucosa, suggesting that cardiac epithelium might not be a native normal gastric epithelium but one that is acquired as a consequence of longstanding inflammation. Changing pattern of CK7 and CK20 expression from normal to intestinalized epithelium suggests that IM arising from cardiac epithelium might have distinctive features.
Histology and histopathology 05/2002; 17(2):445-54. · 2.48 Impact Factor
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ABSTRACT: Aim of the present study is to ascertain the importance of diminutive colorectal polyps and define the need for removal according to their characteristics and malignant potential.
A total of 4,723 patients who underwent colonoscopy were evaluated and 624 patients with 826 polyps were recorded. There were 352 patients with 443 diminutive polyps, studied according to their distribution. Of these, 371 were removed, histologically examined and correlated to patient characteristics and occurrence of synchronous neoplasms.
Of the right colon polyps, 81/115 were diminutive, versus 362/711 of the left colon (p<0.0001). Adenomas were more common in patients over 50 years of age, (p<0.0001). In all colonic segments, diminutive adenomas prevailed over hyperplastic polyps, whereas the proportion of diminutive adenomas predominated in the right colon (p=0.0015). Adenomas were classified as tubular 39%, tubulovillous 55.7% and villous 5.3%. The degree of dysplasia was mild in 45.5%, moderate in 51% and severe in 3.5%. The prevalence of synchronous neoplasms was 37.4%. They were more frequently found in males over 50 years of age and in patients with diminutive adenomas compared to those with diminutive hyperplastic polyps (p=0.0078).
The majority of right colon polyps are diminutive. The proportion of diminutive adenomas is higher in patients over 50 years and in the right vs left colon. Diminutive polyps should be removed taking into account the high prevalence of adenomas with a villous component and their significant degree of dysplasia.
Digestive and Liver Disease 02/2002; 34(2):137-40. · 3.05 Impact Factor
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ABSTRACT: To determine the Bcl-2 and Bax expressions in endometriotic and adenomyotic tissues. In addition, to evaluate the Bcl-2/Bax status during the menstrual cycle in these tissues.
A total of 56 women were retrospectively recruited from a University hospital setting. A total of 25 had endometriosis and 31 adenomyosis. Tissue samples were collected during gynaecological surgery and confirmed by histology to have endometriosis or adenomyosis. Bcl-2 and Bax expressions were investigated on 56 formalin-fixed and paraffin-embedded tissue by immunohistochemical staining and electron microscopy.
The difference of Bcl-2-positive protein between endometriosis and adenomyosis was not significant. No significant difference was found between Bcl-2 expression and the proliferative and secretory phase of the cycle in women with endometriosis, but this comparison was highly significant (P<0.001) in women with adenomyosis. The difference of Bax-positive protein between endometriosis and adenomyosis was not significant. In addition, no significant differences were found between the various phases of the cycle. We have found a stronger inverse correlation between the expression of Bcl-2 and Bax in endometriosis than in adenomyosis.
Our results suggest that the pathogenesis of ovarian endometriosis may be different from that of adenomyosis and the persistence of Bcl-2 and Bax expressions during both phases of the cycle in ovarian endometriotic tissues may have important implications for the survival and proliferation of the ectopic endometrial tissue.
European Journal of Obstetrics & Gynecology and Reproductive Biology 12/2001; 99(2):256-60. · 1.97 Impact Factor
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ABSTRACT: The presence of Epstein-Barr virus (EBV) in the Hodgkin's/Reed-Sternberg (HRS) cells of a significant proportion of cases of Hodgkin's lymphoma (HL) is a matter of consideration when a case of presumptive HL has to be differentiated from infectious mononucleosis (IM). A 15-y-old boy was admitted with a presumptive diagnosis of extranodal HL, based on the biopsy of a painless ulcer on the right mandibular alveolar crest. Histologic examination of the lesion was consistent with mixed cellularity HL. The patient additionally presented with hepatosplenomegaly and regional lymphadenopathy. Serology for EBV was indicative of acute infection. Histological examination of regional lymphoid tissue was consistent with immunologic activation due to primary EBV infection. The patient was left untreated, under close observation. All clinical findings resolved within 3 mo and EBV viral capsid antigen (VCA) IgM antibodies converted to negative after 6 mo. A 3-y follow-up period was uneventful.
Acta Paediatrica 03/2001; 90(2):227-9. · 2.07 Impact Factor
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ABSTRACT: To assess the value of quantitative methods in the differential diagnosis between ovarian carcinoma cells and mesothelial cells in ascitic fluids.
Ninety ascitic fluid samples, previously reported as positive for ovarian carcinoma (30 cases), suspicious for malignancy (30) and negative for malignancy, containing only reactive mesothelial cells (30), were retrieved from the files. In each of these specimens the nuclear area, perimeter, roundness and shape coefficient of 100 cells were determined at 630 x magnification. Statistical analysis was performed using analysis of variance and, for multiple comparisons, the Student-Newman-Keuls technique.
Mean values for nuclear area and perimeter were higher in malignant cells as compared to reactive mesothelial cells, whereas those for roundness and shape coefficients were lower. All differences were statistically significant, the former two at a .05 level and the latter at the .001 level.
Quantitative methods can reliably support the differential diagnosis between ovarian carcinoma cells and mesothelial cells in ascitic fluid specimens.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 05/2000; 22(2):139-42. · 0.41 Impact Factor
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ABSTRACT: CD43 (leukosialin, sialophorin) is a cell surface mucin expressed at high levels on most leukocytes and is reported to be involved in adhesion, anti-adhesion, and signal transduction prodders. Regulation of its expression is thought to take place through methylation of the DNA in the nonproducing cells, and the methylation inhibitor 5-azacytidine induces expression of the sialophorin gene. Here we report three cases of patients with myelodysplastic syndromes in which acquired severe deficiency of the CD43 antigen on the surface of most hemopoietic cells was observed. Peripheral blood mononuclear (PBMC) cells from 32 MDS patients and 20 healthy individuals were analyzed by flow cytometry after labeling with an anti-CD43 (DF-T1) monoclonal antibody. In 1 patient with refractory anemia with excess of blasts (RAEB) and 2 patients with refractory anemia with excess of blasts in transformation (RAEB-t), the percentages of CD43(+) PBMC were 3.8%, 6%, and 9.9%, respectively. The deficiency was observed at protein and RNA level as confirmed by western and southern blot, while analysis of the DNA by single-strand conformation polymorphism and sequencing did not reveal any difference in the gene sequence between the CD43(+) and CD43(-) cells of these patients. It is known that patients with MDS may have normal and dysplastic population of hemopoietic cells. Further studies are needed to reveal the mechanism of downregulation of the gene in these 3 patients and whether the phenomenon is related to the dysplastic population only or not.
American Journal of Hematology 02/2000; 63(1):20-7. · 4.67 Impact Factor
