Hypermethylation of CpG islands in the promoter region of the p15INK4B gene in childhood acute leukaemia

It has been reported that the cyclin-dependent kinase inhibitor (CDKI) gene p15INK4B is frequently inactivated by genetic alterations and may be responsible for various malignant tumours. Another way of inactivation of this CDKI is by hypermethylation of 5'CpG islands in the promoter region of the p15INK4B gene and this inactivation seems to be a frequent event in various haematological malignancies. In the present study, we investigated the methylation status of the p151NK4B gene to clarify its role in the pathogenesis of childhood acute myeloid (AML) and acute lymphoblastic leukaemia (ALL). The study included 23 cases of B-cell origin ALL, 13 cases of T-cell origin ALL, 32 cases of AML, and 10 apparently healthy controls. Hypermethylation was studied by methylation-specific polymerase chain reaction. Hypermethylation of the p15INK4B gene was more frequent in cases with T-cell origin ALL (46.2%), but similar among children with B-cell origin ALL (13.0%) and AML (18.8%). Hypermethylation of p15INK4B may be involved in the pathogenesis of T-cell origin ALL, but not in that of AML or B-cell origin ALL.     

Multiple forms of anti-acetylcholine receptor antibody in myasthenia gravis

Sera of patients with myasthenia gravis (MG) contain anti-acetylcholine receptor (AChR) lgG antibodies (Ab) which have different antigenic specificities. Three Ab types were detected: (1) MG-I, which forms immune complexes with AChR; (2) MG-C, which decreases binding of AChR to concanavalin A; and MG-B, which blocks α-bungarotoxin binding to AChR. Sera from 152 MG patients were screened for the Ab types. Sixty-one percent contained MG-I, 26% contained MG-C, 10% contained MG-B, and 5% contained both MG-C and MG-B. The latter Ab types were associated with more severe forms of MG but showed no other clinical correlations. IgG antibodies of defined type were purified, and their interaction with unlabeled and toxin-prelabeled AChR from denervated rat muscle was studied in detail. Receptors are homogeneous with respect to determinants recognized by MG-I, but heterogeneous with respect to determinants recognized by MG-C (3 subpopulations, 22%, 28%, and 50% of AChR) and by MG-B (2 subpopulations, 30% and 70% of AChR). The stoichiometry of AChR interaction with the antibodies indicates that for each toxin-binding site, the receptor is divalent as an antigen for MG-I and MG-C but is tetravalent for MG-B. Denervated muscle AChR appears to be a mixture of at least 3 molecular forms of AChR, each of which has distinct immunological features as well as components common to all the receptor subpopulations.     

Association of clinical progression in classic Kaposi's sarcoma with reduction of peripheral B lymphocytes and partial increase in serum immune activation markers

OBJECTIVE: To evaluate various immunologic markers in the peripheral blood of patients with early and advanced classic Kaposi's sarcoma (CKS). DESIGN: Cross-sectional study. SETTING: A major referral center for skin and venereal diseases. PATIENTS: Sixty-eight patients with histologically confirmed CKS staged according to a modified version of the Mitsuyasu-Groopman classification in stage I-II (cutaneous involvement only) and stage IV (skin and systemic involvement). MAIN OUTCOME MEASURES: Concentrations of neopterin and beta2-microglobulin, titer of anti-human herpesvirus 8 antibodies, number of natural killer cells, and numbers of total lymphocytes, B lymphocytes, T lymphocytes, and their subsets in peripheral blood. RESULTS: The median values of beta2-microglobulin and neopterin were elevated in patients with CKS in stage IV (median, 3.679 microg/mL [312.72 nmol/L] and 14.0 nmol/L, respectively) compared with patients in stage I-II (median, 2.406 microg/mL [204.51 nmol/L] and 6.5 nmol/L, respectively). A statistically significant reduction in total lymphocyte and B-lymphocyte counts was observed in patients with advanced-stage CKS (1679/microL and 79/microL, respectively) compared with patients in earlier stages of the disease (2142/microL and 224/microL, respectively). The human herpesvirus 8 antibody titer, determined by latent immunofluorescent assay, decreased from stage I-II to stage IV, although not at a statistically significant level (P = .14). CONCLUSION: The evolution of CKS from the early stages of the disease to the more advanced may be associated with a partial activation of the immune system and a gradual decrease in the number of total and B lymphocytes.     

Prospective assessment of emotional distress, cognitive function, and quality of life in patients with cancer treated with chemotherapy

BACKGROUND: The current study sought to delineate prospectively the rates and clinical course of emotional distress, cognitive impairment, and quality of life (QOL) in chemotherapy-naive patients with cancer and to consider the determinants of global QOL. METHODS: Patients who consented to participate were administered the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, the Mini-Mental State Examination (MMSE), and the Hospital Anxiety and Depression Scale before and at the end of treatment (EOT). RESULTS: Of the 102 patients initially assessed, 80 (78.4%) completed the study. Most aspects of QOL did not change considerably over time. At EOT, patients reported only significant increases in fatigue and significant decreases in sleep disturbance. Although no significant changes emerged in the rates of anxiety or depression throughout chemotherapy, nearly one-third of the patients experienced severe emotional distress at both points in time. In addition, the authors observed neither significant alteration in the cognitive performance over time nor reliable associations between scores on the MMSE and subjective cognitive function, emotional distress, or QOL. Finally, depression proved to be the leading predictor of global QOL at baseline and at EOT. CONCLUSIONS: The results indicated that a significant proportion of Greek patients with cancer experienced intense anxiety and depression throughout chemotherapy and confirmed the importance of depression as a strong predictor of global QOL. Routine screening of emotional distress across all phases of cancer is mandatory because it will contribute to the identification of patients who are in need of pharmaceutical and/or psychologic intervention.     

Dose verification in clinical IMRT prostate incidents

PURPOSE: In view of the need for dose-validation procedures on each individual intensity-modulated radiation therapy (IMRT) plan, dose-verification measurements by film, by ionization chamber, and by polymer gel-MRI dosimetry were performed for a prostate-treatment plan configuration. Treatment planning system (TPS) calculations were evaluated against dose measurements. METHODS AND MATERIALS: Intensity-modulated radiation therapy (IMRT) treatments were planned on a commercial TPS. Kodak EDR-2 films were used for the verification of two-dimensional (2D) dose distributions at 1 coronal and 5 axial planes in a water-equivalent phantom. Full three-dimensional (3D) dose distributions were measured by use of a novel polymer gel formulation and a 3D magnetic resonance imaging (MRI) readout technique. Calculations were compared against measurements by means of isocontour maps, gamma-index maps (3% dose difference, 3-mm distance to agreement) and dose-volume histograms. RESULTS: A good agreement was found between film measurements and TPS predictions for points within the 60% isocontour, for all the examined plans (gamma-index <1 for 96% of pixels). Three-dimensional dose distributions obtained with the polymer gel-MRI method were adequately matched with corresponding TPS calculations, for measurements in a gel phantom covering the planning-target volume (PTV). CONCLUSIONS: Measured 2D and 3D dose distributions suggest that, for the investigated prostate IMRT plan configuration, TPS calculations provide clinically acceptable accuracy.     

Prognostic significance of the deleted in colorectal cancer gene protein expression in high-risk resected gastric carcinoma

The deleted in colorectal cancer (DCC) gene is a candidate tumor suppressor gene that may be associated with differentiation and proliferation of normal cells. Loss of heterozygosity (LOH) of 18q, where the gene is located, and absence of DCC protein expression have been associated with worse prognosis in certain subgroups of patients with colorectal adenocarcinoma. We studied the prognostic significance of loss-of-protein expression in 66 patients with resected gastric cancer with a high probability of relapse (T3, T4, N+). The DCC protein was detected with immunohistochemistry using an anti-DCC monoclonal antibody on paraffin-embedded sections. The DCC protein expression was present in 51 cases (77.3%) and absent in 15 cases (22.7%). Poorly differentiated and signet ring carcinomas had significantly lower expression than more differentiated tumors (p < 0.05) as did diffuse-type tumors compared to intestinal and mixed (p < 0.01). There was no correlation with proliferation rate, estimated immunohistochemically using an anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. Absence of DCC protein was an independent favorable prognostic factor (median survival 57 months vs. 18 months, p = 0.0176). The DCC protein expression was correlated with relapse site: all patients with distant metastases were positive for DCC staining, while one-third of patients with local/peritoneal relapse were negative (p < 0.01). In conclusion, DCC protein expression seems to be a significant prognostic factor in high-risk resected gastric cancer. Our results support previous data associating the DCC gene with differentiation and indicate that this gene may play a role in the metastatic potential of these tumors. These findings need to be confirmed by future larger studies.     

Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors

BACKGROUND: We reviewed 36 patients with liver metastases from islet cell tumors of the pancreas (n = 18) and carcinoid tumors (n = 18) who were treated with surgical resection (n = 16) or hepatic chemoembolization (n = 20). METHODS: All resections were complete and included 4 lobectomies, 6 segmental resections, and 6 wedge resections. There were no operative deaths. RESULTS: Median survival has not yet been reached, and the actuarial 5-year survival rate is 70%. Prognostic variables associated with improved disease-free survival included prior resection of the primary tumor and 4 or fewer metastases resected (P <.05). With an average of 3 chemoembolization procedures per patient, 17 of 20 patients (90%) demonstrated either a significant radiographic response (n = 5), stabilization of tumor mass (n = 2), or improvement of clinical symptoms (n = 10). Factors related to a sustained response (more then 1 year) included surgical resection of the primary tumor, 4 or more chemoembolization procedures, and liver metastases of 5 cm or smaller. Median survival after treatment was 32 months (range, 7-63 months), and the actuarial 5-year survival rate was 40%. CONCLUSIONS: Surgical resection of metastatic neuroendocrine tumors provides the best chance for extended survival. Chemoembolization effectively improves clinical symptoms and, in selected patients, may provide sustained tumor control.