Herbert E. Fuchs

Risk Factors for Pediatric Ventriculoperitoneal Shunt Infection and Predictors of Infectious Pathogens

Identification of risk factors for shunt infection and predictors of infectious pathogens may improve current methods to prevent and treat shunt infections. We reviewed data on 820 consecutive ventriculoperitoneal (VP) shunt placement procedures in 442 pediatric patients at our institution during 1992-1998. Ninety-two shunts (11%) developed infection a median of 19 days (interquartile range, 11-35 days) after insertion. Premature birth (relative risk [RR], 4.81; 95% confidence interval [CI], 2.19-10.87), previous shunt infection (RR, 3.83; 95% CI, 2.40-6.13), and intraoperative use of the neuroendoscope (RR, 1.58; 95% CI, 1.01-2.50) were independent risk factors for shunt infection. The bacterial organisms early after shunt surgery (<14 days) were the same as those late after shunt surgery (>14 days). As determined by an analysis of the 92 infected shunts, hospital stay of >3 days at the time of shunt insertion (odds ratio [OR], 5.27; 95% CI, 1.15-25.3) and prior Staphylococcus aureus shunt infection (OR, 5.91; 95% CI, 1.35-25.9) independently increased the odds that S. aureus was the causal pathogen.

Cerebrospinal Fluid Shunt Survival and Etiology of Failures: A Seven-Year Institutional Experience

Background: Innovations in shunt technology and neuroendoscopy have been increasingly applied to shunt management. However, the relative life span of shunts and the etiology of shunt failure have not been characterized recently. Methods: We reviewed the records of all shunting procedures at our institution between January 1992 and December 1998. Independent predictors of shunt failure were analyzed via multivariate Cox regression analysis in 836 shunting procedures. Independent predictors of the etiology of failure (infection, proximal obstruction, distal malfunction) were analyzed via multivariate logistic regression analysis in the 383 shunts which failed. Results: A total of 353 pediatric patients underwent 308 shunt placements and 528 revisions. The risk (hazard ratio; HR) of shunt failure decreased as a function of time in both primary placements and revised shunts. In failed shunts, the odds of infection decreased 4-fold per year of shunt function, while the odds of distal malfunction increased 1.45-fold per year. Increasing number of shunt revisions (HR 1.31, p < 0.05), decreasing patient age in years (HR 1.04, p < 0.001), gestational age <40 weeks (HR 2.15, p < 0.001) but not the etiology of hydrocephalus were associated with an increased risk of shunt failure. Revisions versus primary placements, Dandy-Walker cysts and gestational age <40 weeks were independently associated with proximal, distal and infectious causes of failure, respectively. Conclusions: The long-term shunt revision rates observed here are similar to those reported over the past 2 decades. Shunt life span remains poorer in shunt revisions and in younger patients. Patient characteristics may suggest a specific risk and mechanism of failure, aiding in the long-term management of shunted hydrocephalus.

Prognostic implications of chromosome 17p deletions in human medulloblastomas.

DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of theTP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), orMDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p=0.045 by the logrank test).TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, orMDM2 genes. These results demonstrate that, while only rare medulloblastomas containTP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.

High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Children and Adults With Newly Diagnosed Pineoblastomas

PURPOSE We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL). PATIENTS AND METHODS Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR. RESULTS A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively. CONCLUSION The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.

In vivo catabolism of α1-proteinase inhibitor-trypsin, antithrombin III-thrombin and α2-macroglobulin-methylamine

The clearances of 125I-labeled alpha 1-proteinase inhibitor-trypsin, antithrombin III-thrombin and alpha 2-macroglobulin-methylamine (CH3NH2) were compared in our previously described mouse model. alpha 1-Proteinase inhibitor-trypsin cleared with a t 1/2 of 20 min, antithrombin III-thrombin of 7 min and 125I-labeled alpha 2-macroglobulin-methylamine of 2 min. Competition studies were performed to determine whether one or several pathways clear these three ligands. The clearance of 125I-labeled alpha 1-proteinase inhibitor-trypsin and 125I-labeled antithrombin III-thrombin was blocked by large molar excesses of either ligand, but not by alpha 2-macroglobulin-methylamine. The clearance of 125I-labeled alpha 2-macroglobulin-methylamine can be blocked by a large molar excesses of unlabeled alpha 2-macroglobulin-methylamine but not by alpha 1-proteinase inhibitor-trypsin. These studies demonstrate that the clearance of alpha 1-proteinase inhibitor-trypsin complexes is independent of alpha 2-macroglobulin-methylamine and utilizes the same pathway which is involved in the clearance of antithrombin III-thrombin complexes.

Regulation of factor IXa in vitro in human and mouse plasma and in vivo in the mouse. Role of the endothelium and the plasma proteinase inhibitors.

The regulation of human Factor IXa was studied in vitro in human and mouse plasma and in vivo in the mouse. In human plasma, approximately 60% of the 125I-Factor IXa was bound to antithrombin III (ATIII) by 2 h, with no binding to alpha 2-macroglobulin or alpha 1-proteinase inhibitor, as assessed by gel electrophoresis and IgG- antiproteinase inhibitor-Sepharose beads. In the presence of heparin, virtually 100% of the 125I-Factor IXa was bound to ATIII by 1 min. The distribution of 125I-Factor IXa in mouse plasma was similar. The clearance of 125I-Factor IXa was rapid (50% clearance in 2 min) and biphasic and was inhibited by large molar excesses of ATIII-thrombin and alpha 1-proteinase inhibitor-trypsin, but not alpha 2-macro-globulin-trypsin; it was also inhibited by large molar excesses of diisopropylphosphoryl - (DIP-) Factor Xa, DIP-thrombin, and Factor IX, but not by prothrombin or Factor X. The clearance of Factor IX was also rapid (50% clearance in 2.5 min) and was inhibited by a large molar excess of Factor IX, but not by large molar excesses of Factor X, prothrombin, DIP-Factor Xa, or DIP-thrombin. Electrophoresis and IgG- antiproteinase inhibitor-Sepharose bead studies confirmed that by 2 min after injection into the murine circulation, 60% of the 125I-Factor IXa was bound to ATIII. Organ distribution studies with 125I-Factor IXa demonstrated that most of the radioactivity was in the liver. These studies suggest that Factor IXa binds to at least two classes of binding sites on endothelial cells. One site apparently recognizes both Factors IX and IXa, but not Factor X, Factor Xa, prothrombin, or thrombin. The other site recognizes thrombin, Factor Xa, and Factor IXa, but not the zymogen forms of these clotting factors. After this binding, Factor IXa is bound to ATIII and the complex is cleared from the circulation by hepatocytes.

Parameters of Care for Craniosynostosis

Background A multidisciplinary meeting was held from March 4 to 6, 2010, in Atlanta, Georgia, entitled “Craniosynostosis: Developing Parameters for Diagnosis, Treatment, and Management.” The goal of this meeting was to create parameters of care for individuals with craniosynostosis. Methods Fifty-two conference attendees represented a broad range of expertise, including anesthesiology, craniofacial surgery, dentistry, genetics, hand surgery, neurosurgery, nursing, ophthalmology, oral and maxillofacial surgery, orthodontics, otolaryngology, pediatrics, psychology, public health, radiology, and speech-language pathology. These attendees also represented 16 professional societies and peer-reviewed journals. The current state of knowledge related to each discipline was reviewed. Based on areas of expertise, four breakout groups were created to reach a consensus and draft specialty-specific parameters of care based on the literature or, in the absence of literature, broad clinical experience. In an iterative manner, the specialty-specific draft recommendations were presented to all conference attendees. Participants discussed the recommendations in multidisciplinary groups to facilitate exchange and consensus across disciplines. After the conference, a pediatric intensivist and social worker reviewed the recommendations. Results Consensus was reached among the 52 conference attendees and two post hoc reviewers. Longitudinal parameters of care were developed for the diagnosis, treatment, and management of craniosynostosis in each of the 18 specialty areas of care from prenatal evaluation to adulthood. Conclusions To our knowledge, this is the first multidisciplinary effort to develop parameters of care for craniosynostosis. These parameters were designed to help facilitate the development of educational programs for the patient, families, and health-care professionals; stimulate the creation of a national database and registry to promote research, especially in the area of outcome studies; improve credentialing of interdisciplinary craniofacial clinical teams; and improve the availability of health insurance coverage for all individuals with craniosynostosis.

Microsatellite analysis of childhood brain tumors

Loss of heterozygosity at specific chromosomal locations has been taken as evidence of a tumor suppressor gene located in that area. We performed a genomic allelotyping study on 46 childhood brain tumors of different histopathological types in order to identify and confirm common areas of deletion in different tumor types. Two hundred microsatellite DNA probes equally distributed over the 22 autosomes were applied, covering the genome in steps of approximately 25 cM. Our results confirm frequent loss of heterozygosity of chromosome arms 9q, 10q, 11p, 11q, 16q, and 22q in high‐grade gliomas, medulloblastomas, and ependymomas. In addition, we found a new region of loss on chromosome segment 2p21‐23 affected predominantly in high‐grade gliomas and medulloblastomas. Genes Chromosom Cancer 15:54–63 (1996).

Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high‐dose Cyclophosphamide

Leptomeningeal dissemination of childhood pilocytic astrocytoma (PA) is a rare event with little information available regarding therapy. We report here four children with disseminated PA whom we treated with high doses of cyclophosphamide with clinical benefit. The patients were aged 2.5 to 8 years. Three patients presented with PA localized in the posterior fossa, initially treated with surgical resection (n = 3) and radiotherapy (n = 1). Leptomeningeal dissemination occurred at 32, 44, and 8 months from diagnosis, respectively. The fourth patient presented with an optic pathway tumor with leptomeningeal dissemination at diagnosis. At commencement of cyclophosphamide therapy, disease was present in the subarachnoid space (intracranial, n = 2; spinal, n = 4), cerebral ventricles (n = 2), and primary site (n = 3). Histology was identical at diagnosis and recurrence in the two biopsied cases and cerebrospinal fluid was negative in all cases. Treatment was with cyclophosphamide 4-5 g/m2/cycle given every 4 weeks for a total of two cycles (n = 1) and four cycles (n = 3). One patient achieved disease stabilization (duration 27 months at the time of publication) and three patients experienced significant reductions in tumor burden. Subsequent intrathecal therapy was administered to two patients. Two patients developed disease progression at 10 and 9 months from cessation of chemotherapy. The one re-treated patient responded to further, lower dose, cyclophosphamide. This is the first report of the use of high dose cyclophosphamide for disseminated PA. The recurrence of disease in two cases with a further response to lower dose cyclophosphamide has implications for the optimal duration of therapy for these low grade, aggressive tumors.

Comparison of revision rates following endoscopically versus nonendoscopically placed ventricular shunt catheters.

BACKGROUND Endoscopic placement of ventriculoperitoneal (VP) shunt catheters in pediatric patients has been increasingly used in an attempt to minimize the unacceptably high rates of revision. Although this procedure carries an increased expense, there is currently no evidence to support an improved long-term outcome. This paper compares the rates of revision following ventricular catheter placement for shunted hydrocephalus with and without the use of endoscopy. METHODS We retrospectively reviewed the records of all pediatric patients who had undergone shunt placement for hydrocephalus between April 1992 and February 1998. All shunts placed before March 1995 were performed without the endoscope; all subsequent shunts were placed endoscopically. The independent effect of endoscopic versus nonendoscopic shunt placement on subsequent shunt failure was analyzed via multivariate proportional hazards regression model. Multiple logistic regression analyses were used to determine the independent effect of endoscopic placement on subsequent etiology of failure (infection, proximal obstruction, distal malfunction) in the 511 failing shunts. RESULTS There were 447 pediatric patients who underwent a total of 965 shunt placements or revisions. Six hundred and five (63%) catheters were placed with the use of the endoscope. Three hundred and sixty (37.3%) were placed without the use of the endoscope. Neuroendoscopy did not independently affect the risk of subsequent shunt failure [Hazard Ratio (95% Confidence Interval) = 1.08 (0.84-1.41)]. Endoscopic placement independently decreased the odds [Odds Ratio (95% Confidence Interval) = 0.56 (0.32-0.93)] of proximal obstruction, increased the odds of distal malfunction [1.52 (1.02-2.72)], and was not associated with infection [1.42 (0.78-2.61)]. CONCLUSIONS Endoscopic assisted ventricular catheter placement decreased the odds of proximal obstruction but failed to improve overall shunt survival in this 6 year experience.