Circulating CD52 and CD20 levels at end of treatment predict for progression and survival in patients with chronic lymphocytic leukaemia treated with fludarabine,cyclophosphamide and rituximab (FCR)

CD52 and CD20 antigens are important therapeutic targets for the monoclonal antibodies (mAbs) alemtuzumab and rituximab respectively. Circulating CD52 (cCD52) and CD20 (cCD20) have prognostic utility in lymphoid malignancies. The efficacy of mAb therapy in patients with chronic lymphocytic leukaemia (CLL) may be adversely affected by cCD52 or cCD20. In this report, blood and bone marrow (BM) cCD52 and cCD20 were measured at response assessment in previously treated (N = 235) patients with CLL who received fludarabine, cyclophosphamide, and rituximab (FCR). Univariate and multivariate statistical models evaluated correlations of pre‐ and response variables with progression‐free (PFS) and overall survival (OS). Response variables included 1996 National Cancer Institute‐Working Group (NCI‐WG) response, polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGHV) in BM, and cCD52 and cCD20 levels (blood and BM) at response assessment. Using multivariate analysis, response blood and BM cCD52, blood cCD20, and NCI‐WG response were significant independent predictors of PFS. At the time of response assessment, BM cCD52 correlated with OS in univariate analysis. cCD52 and cCD20, therefore appear useful in predicting survival and may be important for monitoring patients following salvage FCR (fludarabine, cyclophosphamide, rituximab) therapy. These data further indicate that plasma may be a good target to evaluate for minimal residual disease using cCD52/cCD20 levels.     

Hearing loss in Beh?et syndrome.

OBJECTIVE: To determine the prevalence and characteristics of hearing loss in Beh?et syndrome. STUDY DESIGN AND SETTING: This study included 27 patients with Beh?et syndrome and 35 sex-and age-matched controls. A complete audiological evaluation was performed. RESULTS: The average pure-tone audiograms from both groups showed a statistically significant hearing loss in the Beh?et group. Sixteen patients (59.26%) showed some degrees of sensorineural hearing loss (SNHL), with the high-frequency type (4, 8, 10, and 12 kHz) being the most common pattern (93.75%). Hearing loss was the fourth most common manifestation. Although the patient's age, sex, and the duration of the disease were not related to hearing loss, there was a significant correlation between a negative pathergy test and hearing loss in patients with Beh?et syndrome. CONCLUSION: We should consider audiovestibular involvement in Beh?et syndrome as a common finding.     

Abnormal expression of MDM-2 in breast carcinomas

MDM-2 is a cellular oncoprotein that binds to the p53 protein and abrogates its growth-suppressing function. At least seven MDM-2 mRNAs and five proteins (p90, p85, p76, p74, and p57) have been reported in tissue culture. MDM-2 gene amplification occurs in human sarcomas and high-grade gliomas. MDM-2 overexpression without gene amplification has been reported in leukemias and lymphomas. Here we report MDM-2 mRNA overexpression in 24 (73%) out of 33 cases of human breast carcinoma as compared with normal breast tissue. The MDM-2 overexpression was seen in the absence of MDM-2 gene amplification. MDM-2 protein expression was studied by western blot analysis in 21 of these cases of carcinoma. We found complete concordance between MDM-2 mRNA overexpression and MDM-2 protein levels. MDM-2 proteins were overexpressed in 15 of 21 breast carcinoma tissue samples but not in normal breast tissue controls. Ten of these fifteen cases overexpressed MDM-2 p57 protein, two cases overexpressed both p57 and p90, and three cases overexpressed only p90. MDM-2 overexpression was confirmed by immunohistochemistry. p53 overexpression was also studied by immunohistochemistry; 69% of breast carcinomas that overexpressed the MDM-2 mRNA had detectable nuclear p53 protein. These findings demonstrate that MDM-2 oncoprotein expression is altered in primary human breast carcinomas at both mRNA and protein levels. In addition, our results suggest that MDM-2 p57 protein represents the main MDM-2 protein altered in breast carcinomas.     

Aberrant p16 methylation, a possible epigenetic risk factor in familial esophageal squamous cell carcinoma

Aim. Detection of methylation in the p16 gene, an inhibitor of cyclin D-dependent protein kinase, as a new tumor marker for early detection of esophageal squamous cell carcinoma (ESCC) in DNA derived from blood and serum. Method. A large family with clustering of ESCC was assessed in Khorasan province in northeastern Iran. The family had three histologically proven cases of ESCC in two consecutive generations and several other deceased cases with histories of ESCC. DNA from blood of 28 living family members in three consecutive generations, 30 sporadic ESCC cases (from serum, blood, and tumor tissues), and 30 healthy volunteers (from blood) were examined for the methylation status of p16 promoter using methylation-specific PCR (MSP). Results. Aberrant p16 promoter methylation was found in 64.3% (n=28) of ESCC family members and none (n=30) of our normal volunteers. Five of the 28 family members with esophageal cancer symptoms had negative endoscopy results for ESCC, while four of these members had p16 hypermethylation in their blood. The family members with negative endoscopy and positive p16 promoter methylation are being monitored closely for signs of ESCC development through regular check-ups and chromoendoscopies. In sporadic ESCC in northeastern Iran, 73.3% (n=30) of tumor tissue samples had p16 hypermethylation. Serum and blood samples from the same patients showed p16 hypermethylation in 26.6% and 43.3% of the samples, respectively. Conclusion. Aberrant p16 methylation may be a valuable diagnostic tool as a tumor marker for the early identification of individuals in high risk ESCC families.     

AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia.

Resistance to or intolerance of imatinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.     

Comparison of 1,2-propanediol and ethylene glycol for cryopreservation of slow-cooled mouse zygotes and their subsequent development

Purpose : This study was conducted on cryoprotective activity of ethylene glycol (ETG) and propanediol (PROH) on cleavage rate of mouse zygotes. Methods : Mouse oocytes were excised from fallopian tube of gonadotropin-treated mice, then inseminated with spermatozoa. After 16.5–17.5 h, zygotes were randomly allocated into three groups; control, toxicity, and frozen. In the latter, zygotes were slowly cooled with ETG and PROH similar to those used for human embryo cryopreservation. The survived zygotes cultured for 120 h and their later stages of development were compared with nonfrozen embryos. Results : The toxicity test showed that no differences were observed in cleavage rate between exposed and nonexposed embryos. The survival and expanded hatching blastocyst rate of embryos frozen with PROH was significantly better than with ETG (92.8 vs. 58.2% and 68.2 vs. 39.1%, respectively). Conclusions : ETG does not appear to be a good alternative to the classical PROH for freezing of mouse zygotes.     

Cicatrix endometriosis of the abdominal wall

Endometriosis is a rare entity, related after operation on the uterus or uterine tubes or a laparotomy procedures or other extrapelvic procedures, when seeding of endometrial fragments were shed into the peritoneal cavity. We report the case of a menopaused woman with a subcutaneous incisional scar mass that appeared 22 years after a caesarean section. The diagnosis was made by histological examination.     

Confirmation of genetic homogeneity of syndactyly type 1 in an Iranian family

Syndactyly type 1 (SD1) is the most common type of syndactyly, inherited in an autosomal dominant fashion and characterized by complete or partial webbings between the third and fourth fingers and/or between the second and third toes. We recently encountered an Iranian family in which 33 members in six generations were affected with SD1. As a locus of SD1 in a German family has recently been assigned to chromosome 2q34–q36, we performed a linkage analysis of the Iranian SD1 in order to know whether the disorder is genetically homogeneous. With the analysis on 15 affected and 16 unaffected persons in the Iranian family, using dinucleotide repeat polymorphisms as markers, we mapped the SD1 locus to 2q34–q36 with a maximum LOD score of 6.92 at a recombination fraction θ = 0.00 (penetrance = 1.00) for the D2S2179 locus. The result not only confirmed the gene assignment, but also suggests genetic homogeneity of the disease. © 2001 Wiley‐Liss, Inc.     

Expression profile of MDM-2 proteins in chronic lymphocytic leukemia and their clinical relevance

The MDM-2 oncoprotein exists in an autoregulatory feedback loop with the tumor suppressor protein p53. Therefore, intracellular levels of these two proteins may play important roles in cell proliferation and tumorigenesis. Several MDM-2 proteins (Mr 35–100 Kd) have been demonstrated in human cell lines. We report here the expression profile of MDM-2 and p53 proteins in 87 cases of chronic lymphocytic leukemia (CLL) as detected by immunoblot analysis. The MDM-2 proteins (p57, p59, p67, and p90) were found to be overexpressed in different combinations in 56/87 (64%) of cases of CLL when compared with normal volunteers. The MDM-2 protein p57 was predominantly overexpressed 46/87 (53%) in CLL. In 22/87 (25%) cases of CLL p57 was overexpressed alone, and in 24/87 (28%) cases it was co-overexpressed with other MDM-2 proteins p59/p67/p90. Six of the 87 cases of CLL showed overexpression of the tumor suppressor protein p53 by immunoblot analysis, and five of those cases also co-overexpress MDM-2 protein p57. No statistically significant correlation of MDM-2 protein overexpression to clinical disease stage and history of previous chemotherapy of CLL patients has been found. However, considering the oncogenic potential of overexpressed MDM-2 proteins, a possible role of MDM-2 proteins in the promotion of CLL disease remains to be evaluated. Am. J. Hematol. 54:189–195 © 1997 Wiley-Liss, Inc.     

Evaluation of moving and static two point discriminations of volar forearm skin before and after transfer as a sensate radial forearm island flap in reconstruction of degloving injury of the thumb.

In degloving injury of the thumb the large skin defect needs cover with sensate, glabrous and pliable skin. Although coverage of this defect with a sensate free flap from the foot is the best choice, most commonly, cover is achieved using a non-sensate distant pedicle flap. Between 2001 and 2003, degloving injuries of the thumb in eight patients were reconstructed using a sensate radial forearm flap in the sensory territory of the lateral ante-brachial nerve of the forearm which was repaired to the digital nerve of the thumb (six cases) or to a branch of the sensory radial nerve (two cases). Follow-up period ranged from 17 to 41 months (mean: 29.9 months). Sensory evaluation was performed using the moving two point discrimination (M-2PD) and static two point discrimination (S-2PD) of the volar forearm skin. These altered significantly after transfer and their values approached those of the contra-lateral thumb but never reached normal sensation (p<0.01). Sensate radial forearm island flap is a reliable option to cover a large defect of the thumb such as degloving injury and the sensation produced is acceptable.