Disseminated neuroblastomas under 1 year of age: cell biology and prognosis

Tumor specimens of 203 infants with neuroblastomas of different clinical stages — registered in successive multicenter clinical trials of the German Society of Pediatric Oncology — could be examined for N-myc amplification, chromosome 1-ploidy and — structure, CD₄₄ std. expression (in tumor tissue, and also in patients sera).Eightyseven (= 43%) of these infants had a non-localized, disseminated neuroblastoma, mainly involving sympathetic nerve tissue, lymphnodes, liver, skin, bone marrow and bones (46 patients were classified into the 4_s group, 41 patients in the true 4 group).If the clinical classification between stage 4 and stage 4_swas neglected, then 17 of these infants (= 20%) had N-myc amplification (4—64 copies) with 16 already dead. Seven of 9 examined patients with true stage 4 had chromosome 1p aberrations (with N-myc amplification in 5), and among the dead there were 2 with CD₄₄ negative expression.In another series, serum CD₄₄ std. was measured by ELISA, and the highest (significantly different) Kruskal-Wallis mean rank values (147.8) were found in infants (n = 6) with stage 4_s compared to the low mean-rank-value of 71.9 in patients with stage 4 (n = 65). Stage 1—3 patients (n = 42) had values of 99.8—88.6.Thus, infants with disseminated neuroblastomas, showing non-diploidy, normal chromosome 1p structure, non-N-myc amplification and high CD₄₄ std. expression in tumor tissue, and also high CD₄₄ std. values in serum, will have the highest chance of survival due to tumor-non-progression.On the other hand, N-myc amplification in the tumor cells was found to be characteristic for stage 4_s neuroblastoma patients with tumor progression (n=6). Therefore, 4_s neuroblastoma-patients with N-myc amplified tumors should be aggressively treated like true stage 4 tumor patients!     

Karyotypic abnormalities in adenocarcinomas of the lung

Cytogenetic analysis of 114 adenocarcinomas of the lung revealed clonal abnormalities in 67 tumors. The chromosome numbers ranged from near-diploid to hypertetraploid. Clonal abnormalities seen as the sole anomaly were loss of the Y chromosome (21 tumors), trisomy 7 (2 tumors), and trisomy 12 (1 tumor). A supernumerary ring chromosome was the only clonal change in 4 tumors. The bands most often affected were 17p11-13 (13 cases), 1q10-12 and 1p22 (10 cases each), 1p11-13 and 1q21 (9 cases each), and 11p11, 11p15 and 15p11-13 (6 cases each). The chromosomes most frequently involved in structural rearrangements were chromosomes 1 (30 cases), 11 (20 cases), 3 (17 cases), 17 and 7 (16 cases each). Repeated loss of material from chromosome arms 1p, 3p, 6q, 11p, and 17p and gains of 1q were found. Recurrent structural changes were del(1)(p22) and i(5)(p10) (5 cases each) i(1)(q10), i(13)(q10), i(14)(q10) and del(17)(p11) (3 cases each). We found no abnormalities that seemed to be specifically associated with pulmonary adenocarcinomas, but isochromosomes i(1)(q10), i(5)(p10) and i(13)(q10) and changes of 6q were present in our series at frequencies higher than those generally seen in the other main types of lung cancer.     

Surgical Resection and Intraperitoneal Chemotherapy for Recurrent Abdominal Sarcomas

Background: Recurrent abdominal sarcomas have an extremely high rate of recurrence and poor overall survival. A prospective study was initiated to assess the feasibility, toxicity, and benefit of surgical resection and intraperitoneal chemotherapy for improving local control of disease and overall survival.Methods: Fifty-four patients underwent surgical excision of all gross disease and postoperative intraperitoneal chemotherapy with mitoxantrone. Thirty-five patients had peritoneal disease only (stage II), and 19 patients had peritoneal disease with hepatic metastases (stage III).Results: Nine (17%) patients remain free of disease with a mean follow-up of 37 months. The remaining 45 patients (83%) have had recurrence, with a mean interval to recurrence of 11 months. Stage (P 5.001) and grade (P 5.005) were the only two variables found to significantly affect recurrence. There was an overall peritoneal recurrence rate of 48% and an overall hepatic failure rate of 69%. Nineteen (35%) of the patients are alive, with a mean follow-up of 46 months. The overall 5-year survival was 31%. The 5-year survival for stage II patients was 46%; for stage III patients, it was only 5%. Stage (P 5.001) and grade (P 5.056) were the only two variables found to significantly affect survival. There were no treatment-related deaths, and only 5 patients (9%) developed local complications.Conclusions: Aggressive surgical resection and intraperitoneal chemotherapy for recurrent abdominal sarcomas is a feasible treatment approach with minimal toxicity. Although this treatment had little effect on the hepatic spread of this disease and thus overall survival, it appears to have significantly lowered the rate of peritoneal recurrence and may provide a survival benefit for patients with disease limited to the peritoneum.     

Effects of computer-assisted documentation in orthopedic surgery on budget and reimbursement

Summary Since 1995 German health maintenance laws require hospitals to document and code all referals, admissions and discharges using the 4-digit ICD. Operative procedures are documented and coded using the ICPM. Beginning in January 1996, reimbursement for health services requires a diagnosis-related billing and payment for special procedures. The decision for billing is based on documented diagnosis and therapy. This extended request for documentation makes an online access to diagnosis and therapy with a computer-assisted coding system advisable. In 1996 in our hospital each diagnosis and operation was manually documented and coded on a form. Since the beginning of 1997, documentation and coding has been exclusively computer-assisted. On the basis of documented diagnosis and therapy the computer provides the route of reimbursement. Retrospectively we evaluated the number of charged diagnosis-related billings and payments for special procedures from January to April of 1996 and 1997. It became evident that with computer-assisted documentation and coding the number of detected and charged diagnosis-related billings and payments for special procedures was significantly increased in comparison with the previous year.      

Bias due to incomplete follow up in a cohort study

AIM: To investigate the bias introduced by incomplete follow up in a cohort study of ocular outcome after premature birth. METHODS: A geographically defined cohort of children born before 32 weeks' gestation was prospectively recruited at birth to study the ocular outcome at 2 years. On the basis of attendance at 2 years, the children's families were allocated to one of three groups: group 1 attended for follow up, group 2 were difficult to trace, and group 3 were very reluctant for assessment. All children were examined by a single ophthalmologist, masked to these groupings. RESULTS: 558 children (98.8% of study group) were examined, of whom 505 were in group 1, 20 in group 2, and 33 in group 3. The groups which were more difficult to study (groups 2 and 3) showed a significantly higher prevalence of ocular abnormalities, including strabismus (p=0. 02) and cicatricial retinopathy of prematurity (p=0.002) compared with those attending for follow up. Further, not all of these cases could have been identified by review of the children's previous records. Ocular abnormalities would be underestimated by 16% (11.3% in group 1 compared with 13.4% in the total cohort, p=0.77). CONCLUSIONS: This study suggests that the prevalence of abnormalities would be underestimated by incomplete follow up, as those subjects who were most difficult to obtain for study had a significantly higher prevalence of abnormalities.     

Vitrectomy for macular pucker and vitreomacular traction syndrome

During the course of a so-called posterior vitreous detachment, a thin layer of the posterior vitreous cortex often remains adherent to the underlying retina. Tangential stretch of this vitreous pseudomembrane may cause vitreomacular traction syndrome, edema, and macular hole formation. The same process appears to underlie the development of true epimacular membranes (idiopathic macular pucker). Vitrectomy is generally agreed to be the most appropriate treatment for these clinical situations. We evaluated the incidence of vitreomacular adhesion and of visual improvement after vitrectomy of eyes with macular pucker (group 1; n=60) and vitreomacular traction syndrome (group 2; n=50). Vitreomacular attachment was assessed during vitrectomy under the condition of continuous air infusion. In the two groups, complete or partial vitreous attachment to the macula was observed in 57.4% and 74%, respectively. We conclude that vitreomacular adhesion is a common feature of the two clinical situations. Visual improvement was achieved in 73% of both groups. High rates of postoperative visual acuities of 20/50 or better (60.6% in group-1; 65.7% in group-2 cases) occurred only in eyes with preoperative values of 20/100 or better. It is reported that the visual outcome of vitreoretinal surgery for the two clinical conditions deteriorates with increasing duration after initial manifestation. Vitrectomy should not be postponed in patients who complain of disturbing visual symptoms such as reduced visual acuity, metamorphopsia and disturbance of binocular reading. This revised version was published online in July 2006 with corrections to the Cover Date.     

Intensity dependence of auditory evoked potentials (AEPs) as biological marker for cerebral serotonin levels: effects of tryptophan depletion in healthy subjects

Rationale: The intensity dependence of the auditory evoked potentials (AEP) has been suggested to be a specific biological marker of central serotonergic activity. Objective: While previous studies used circumstantial evidence to support this hypothesis, we manipulated (decreased) cerebral levels of serotonin directly by using tryptophan depletion. Methods: Twelve healthy young subjects were investigated using placebo and two different amino acid mixtures in a double blind cross over design on three different occasions. AEPs recorded during tryptophan depletion were analyzed by dipole analysis and regional sources using methods published in the literature. Results: For none of the mixtures a significant effect of tryptophan depletion was found. There was a trend towards reduced intensity dependency after tryptophan depletion, especially in the right hemisphere. This reduction correlated with the amount of reduced tryptophan in plasma. Conclusions: The results indicate, in contrast to earlier indirect studies, that the intensity dependence of AEPs is not a specific marker of central serotonergic activity. Received: 8 March 1999 / Final version: 25 May 1999     

Human plasma kallikrein and tissue kallikrein binding to a substrate based on the reactive site of a factor Xa inhibitor isolated from Bauhinia ungulata seeds

Kunitz type Bauhinia ungulata factor Xa inhibitor (BuXI) was purified from B. ungulata seeds. BuXI inactivates factor Xa and human plasma kallikrein (HuPK) with Ki values of 18.4 and 6.9 nM, respectively. However, Bauhinia variegata trypsin inhibitor (BvTI) which is 70% homologous to BuXI does not inhibit factor Xa and is less efficient on HuPK (Ki = 80 nM). The comparison between BuXI and BvTI reactive site structure indicates differences at Met59, Thr66 and Met67 residues. The hydrolysis rate of quenched fluorescence peptide substrates based on BuXI reactive site sequence, Abz-VMIAALPRTMFIQ-EDDnp (leading peptide), by HuPK and porcine pancreatic kallikrein (PoPK) is low, but hydrolysis is enhanced with Abz-VMIAALPRTMQ-EDDnp, derived from the leading peptide shortened by removing the dipeptide Phe-Ileu from the C-terminal portion, for HuPK (Km = 0.68 microM, k(cat)/Km = 1.3 x 10(6) M(-1) s(-1)), and the shorter substrate Abz-LPRTMQ-EDDnp is better for PoPK (Km = 0.66 microM, k(cat)/Km = 2.2 x 10(3) M(-1) s(-1)). The contribution of substrate methionine residues to HuPK and PoPK hydrolysis differs from that observed with factor Xa. The determined Km and k(cat) values suggest that the substrates interact with kallikreins the same as an enzyme and inhibitor interacts to form complexes.