TROPHY registry - status report.

INTRODUCTION: The TROPHY registry has been established to conduct an international multicenter prospective data collection on the surgical management of neonatal intraventricular hemorrhage (IVH)-related hydrocephalus to possibly contribute to future guidelines. The registry allows comparing the techniques established to treat hydrocephalus, such as external ventricular drainage (EVD), ventricular access device (VAD), ventricular subgaleal shunt (VSGS), and neuroendoscopic lavage (NEL). This first status report of the registry presents the results of the standard of care survey of participating centers assessed upon online registration. METHODS: On the standard of treatment forms, each center indicated the institutional protocol of interventions performed for neonatal post-hemorrhagic hydrocephalus (nPHH) for a time period of 2 years (Y1 and Y2) before starting the active participation in the registry. In addition, the amount of patients enrolled so far and allocated to a treatment approach are reported. RESULTS: According to the standard of treatment forms completed by 56 registered centers, fewer EVDs (Y1 55% Y2 46%) were used while more centers have implemented NEL (Y1 39%; Y2 52%) to treat nPHH. VAD (Y1 66%; Y2 66%) and VSGS (Y1 42%; Y2 41%) were used at a consistent rate during the 2 years. The majority of the centers used at least two different techniques to treat nPHH (43%), while 27% used only one technique, 21% used three, and 7% used even four different techniques. Patient data of 110 infants treated surgically between 9/2018 and 2/2021 (13% EVD, 15% VAD, 30% VSGS, and 43% NEL) were contributed by 29 centers. CONCLUSIONS: Our results emphasize the varying strategies used for the treatment of nPHH. The international TROPHY registry has entered into a phase of growing patient recruitment. Further evaluation will be performed and published according to the registry protocol.

Hydrocephalus shunt therapy: current titanium shunt valve implants obstructed by internal tissue proliferations identified as extracellular matrix membranes.

PURPOSE: Shunt valves, required for treatment of hydrocephalus, demand for high performance rates and lifelong excellent function. To overcome problems with traditional silicone materials, adjustable and gravity-adapted titanium valves were developed. Even modern shunt valve systems are still subject to occlusion. The aim of the present study was to investigate dysfunctional silicone and titanium valves for presence of cellular and proteinous materials inside the housings by means of histopathology. METHODS: A total of 19 explanted shunt valves from children between 2 and 182 months of age were investigated following dysfunction. After fixation in formalin and embedding in hard resin, slices were ground to a thickness of 5-30 µ. Besides standard histology, immunohistochemistry was performed using antibodies with markers for microglia, astrocytes, platelets, monocytes, and the proteins laminin, fibronectin, and collagen IV. RESULTS: Traces, layers, and plaques could be demonstrated in every investigated silicone or titanium valve with an implantation time of more than 6 days. Most of the tissue was found adjacent to silicone and titanium surfaces of the inner housing, the adjustment rotor, and ball-in-cone core. Markers for micro and astroglia stained positive in 40-60% of the specimen, mostly demonstrating a proteinous layer positive for laminin (80%), fibronectin (30%), and collagen IV (30%). CONCLUSIONS: Tissue reactions with formation of cellular and proteinous matrix components are common in obstructed silicone and titanium shunt valves. The tissue mimics astrocytic repair mechanisms genuine for basilar membrane matrix. The knowledge of these typical arachnoid patterns of colonization is a prerequisite for developing future shunt devices.

MGMT promoter methylation status and prognosis of patients with primary or recurrent glioblastoma treated with carmustine wafers.

The prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients treated with carmustine (BCNU) wafer implantation is unclear. Here, we report on a retrospective study of 47 patients with either newly diagnosed (30 patients) or recurrent (17 patients) glioblastoma (WHO grade IV) treated with BCNU (bis-chloroethylnitrosourea) wafers. Thirteen of the newly diagnosed patients received local BCNU and irradiation only (first-line BCNU), while 17 patients additionally received concomitant and adjuvant temozolomide (TMZ) radiochemotherapy (first-line BCNU + TMZ). Of the 17 patients treated for recurrent glioblastoma (second-line BCNU), 16 had received radiotherapy with concomitant and adjuvant TMZ as an initial treatment. Median overall survival (OS) did not significantly differ between 19 patients with MGMT promoter methylated tumors when compared to 28 patients with unmethylated tumors (18.9 vs 15.0 months; p = 0.1054). In the first-line BCNU + TMZ group, MGMT promoter methylation was associated with longer OS (21.0 vs 11.1 months, p = 0.0127), while no significant survival differences were detected in the other two subgroups. Progression-free survival did not significantly differ between patients with and without MGMT promoter methylated tumors in the entire patient cohort or any of the three subgroups. The first-line BCNU + TMZ group showed no significant difference in OS when compared to the first-line BCNU group (18.9 vs 14.7 months), but tended to have more therapy-related adverse effects (53% vs 24%, p = 0.105). In summary, MGMT promoter methylation showed a non-significant trend toward longer survival in our patient cohort. The combination of TMZ radiochemotherapy with local delivery of BCNU did not provide a significant survival benefit compared to local BCNU alone, but was associated with a higher rate of adverse effects. Owing to the small number of patients investigated, however, these findings would need to be corroborated in larger patient cohorts.

Glioma infiltration of the corpus callosum: early signs detected by DTI.

The most frequent primary brain tumors, anaplastic astrocytomas (AA) and glioblastomas (GBM): tend to invasion of the surrounding brain. Histopathological studies found malignant cells in macroscopically unsuspicious brain parenchyma remote from the primary tumor, even affecting the contralateral hemisphere. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is suspected. The purpose of this study was to investigate the value of DTI as a possible instrument of depicting evidence of tumor invasion into the corpus callosum (CC). Preoperatively, 31 patients with high-grade brain tumors (8 AA and 23 GBM) were examined by MRI at 3 T, applying a high-resolution diffusion tensor imaging (DTI) sequence. ADC- and FA-values were analyzed in the tumor-associated area of the CC as identified by fiber tracking, and were compared to matched healthy controls. In (MR-)morphologically normal appearing CC the ADC values were elevated in the tumor patients (n = 22; 0.978 × 10(-3) mm²/s) compared to matched controls (0.917 × 10(-3) mm²/s, p < 0.05), and the corresponding relative FA was reduced (rFA: 88 %, p < 0.01). The effect was pronounced in case of affection of the CC visible on MRI (n = 9; 0.978 × 10(-3) mm²/s, p < 0.05; rFA: 72 %, p < 0.01). Changes in diffusivity and anisotropy in the CC can be interpreted as an indicator of tumor spread into the contralateral hemisphere not visible on conventional MRI.

Toxicity and survival in primary glioblastoma patients treated with concomitant plus adjuvant temozolomide versus adjuvant temozolomide: results of a single-institution, retrospective, matched-pair analysis.

BACKGROUND: To compare survival and hematological toxicity rates between two postoperative therapy regimens in patients with primary glioblastoma (GBM), namely temozolomide (TMZ) concomitant to radiation, followed by adjuvant TMZ, versus adjuvant TMZ after radiation only. PATIENTS AND METHODS: A total of 191 patients with primary GBM were postoperatively treated with either radiation and concomitant TMZ, followed by adjuvant TMZ (Stupp protocol) (n = 154), or radiation followed by adjuvant TMZ (n = 37). The incidence of hematological adverse effects (AE) was recorded for all patients. From both treatment groups, 26 patients were matched according to age, Karnofsky performance scale (KPS) score, and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. RESULTS: Hematological AEs were mild in both unmatched groups, but were significantly more frequent in the concomitant plus adjuvant TMZ group (p < 0.001). Matched-pair analysis confirmed significantly more frequent hematological AEs in the concomitant and adjuvant group compared to the sequential (adjuvant) TMZ group (p = 0,012). Patients treated with concomitant plus adjuvant TMZ showed significantly longer progression-free survival (PFS) (10.6 versus 6.6 months; p = 0.014), but no prolonged overall survival (OS) (16.9 vs. 15.6 months; p = 0.717) compared to patients who received the sequential treatment regimen. CONCLUSION: In this retrospective study, the OS in patients with primary GBM treated with sequential TMZ following radiation appeared to be similar to that in patients treated with concomitant plus adjuvant TMZ. Given the significantly higher risk of hematological AE for concomitant treatment, the role of concomitant plus adjuvant TMZ use compared to sequential administration of TMZ, especially for patients with MGMT-unmethylated tumors, should be further evaluated.

High expression levels of erythropoietin and its receptor are not correlated with shorter survival in human glioblastoma.

Erythropoietin (EPO) is used to treat anemia in neoplastic disease. EPO also exerts neuroprotective effects on neuronal cells, making a prophylactic use against the neurocognitive effects of radiochemotherapy probable. However, EPO/EPO-receptor (EPOR) signalling has been also detected in glioblastoma cells. Data collected in vitro and in vivo show conflicting results on the effect of EPO on malignant gliomas. The association between EPO and EPOR expression and the prognosis of human glioblastomas was analyzed. Probes of human glioblastomas with complete documentation of clinical course and treatment were assessed by immunohistochemistry for the expression of EPO and EPOR (n=80). Using univariate and multivariate survival analysis, the association with age, gender, radiation, chemotherapy and extent of resection was determined. High levels of EPOR were correlated with a median survival advantage of 7 months (p<0.01). By univariate, but not multivariate, analysis, high levels of EPO and EPOR were associated with a significant prolongation of 7 months median survival when compared to low levels of both molecules. In patients treated with radiochemotherapy adjuvant to surgery, the median survival was 6.5 months longer in patients with high levels of EPOR (p<0.04). According to previous studies, longer patient survival is associated with EPOR expression. Therefore, EPO appears to be safe for the treatment of anemia in glioblastoma patients. However, a prophylactic use, i.e., for neuroprotection, is not recommended in light of the functional studies described in the literature.

Risk management in the treatment of malignant gliomas with BCNU wafer implants.

Implantation of BCNU wafers (Gliadel®) into the resection cavity has demonstrated a survival benefit for patients with newly diagnosed malignant gliomas. The follow-up of two phase III trails has further shown that the number of long-term survivors was significantly increased by BCNU wafer treatment. BCNU wafer implantation may be integrated into current multimodal first line strategies. In the setting of recurrent disease BCNU wafer implantation has also shown a survival benefit and now extends the treatment options in a patient population that typically has undergone extensive pretreatment. An analysis of the literature has helped to clearly identify the risks associated with topic BCNU treatment. Here we summarize the incidence and time course of adverse events associated with local chemotherapy and propose solutions. The growing body of experience with BCNU wafer implantation may serve as a basis to develop adequate risk management strategies with regard to patient selection, surgical techniques, and follow-up schedules.

Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas.

Treatment of recurrent malignant glioma, which has a poor patient prognosis, has not been standardised. Moreover, it is unclear whether repeated treatment with temozolomide is effective in patients who received previous temozolomide treatment before developing a recurrence. Here, we present the results of a high-dose individually adapted 21-day regimen demonstrating that rechallenge is effective even in patients expressing O6-methylguanine-DNA methyltransferase (MGMT) in the tumor. Twenty-one patients with recurrent malignant gliomas pre-treated with temozolomide, 18 WHO IV glioblastoma (GBM) and 3 WHO III patients, received 100 mg/m2 temozolomide on days 1-21/28. The GBM patients had a median Karnofsky performance status of 60% and a median age of 54.8 years. Blood counts decreased continuously, enabling a gradual dose adaptation. When blood counts dropped below normal values, temozolomide was applied on days 1-5/7. Dosage was reduced to 50-75 mg/m2 in 11 patients and gradually increased up to 130 mg/m2 in 3 patients. WHO grade 3/4 toxicity was hematological in 3 patients and non-hematological in 3 patients. In GBM patients (n=18), response after >3 months was complete in 3 patients, partial in 1 (22%), stable disease in 7 (39%) and progressive disease in 7 (39%). Progression-free survival at 6 months (PFS-6M) was 39%. Median survival was 9.1 months from relapse and 17.9 months overall. Of the patients with unmethylated MGMT promoter, 2/7 were progression-free for >6 (15 and 19) months. The data indicate that rechallenge with near-continuous, higher-dose temozolomide (100 mg/m2 on days 1-21/28 or days 1-5/7 with individual dose adaptation) is also feasible in patients with critical blood counts. Objective responses can be achieved even after relapse during a conventional 5/28-day regimen. The resistance of tumors characterized by unmethylated MGMT promoter may be overcome by near continuous temozolomide administration, which is probably most effective with a 5/7-day schedule. In spite of the relatively poor clinical prognosis, the data indicate that rechallenge with temozolomide with a dose-dense and long-lasting administration protocol is tolerable and comparable with other reported treatment protocols involving temozolomide.

Expression of glutathione S-transferase T1 (GSTT1) in human brain tumours.

Glutathione S-transferases (GSTs) play a central role in a number of metabolic processes. Glutathione S-transferase T1 (GSTT1) is a polymorphic cytosolic enzyme and a member of the theta class of GSTs. Typical substrates for GSTT1 are industrial compounds, such as dichloromethane and ethylene oxide. It has been shown that also chemotherapeutic drugs such as BCNU [i.e. 1,3-bis(2-chloroethyl)-1-nitrosourea] are efficiently inactivated by GSTT1. BCNU is a drug which is increasingly used locally in the chemotherapy of glioblastoma multiforme WHO grade IV. Therefore, if GSTT1 were expressed in neoplastic cells of brain tumours it could be a factor for chemoresistance. In order to clarify a possible role of GSTT1 in chemoresistance, as a first step, we localized this enzyme in malignant gliomas such as glioblastoma multiforme WHO grade IV and oligodendroglioma WHO grade II. Because of its polymorphism we first genotyped the samples for GSTT1 by PCR. Using in situ hybridization, we then demonstrated that GSTT1 transcripts are expressed in neoplastic cells of both tumour types. Immunohistochemistry revealed then that whereas neoplastic cells in glioblastoma multiforme WHO grade IV contain GSTT1, it was not localized in oligodendroglioma cells. Given the polymorphism of GSTT1 and its potential activity towards BCNU, the localization of GSTT1 in glioblastoma cells can be considered as a possible factor of non-homogeneous chemotherapy response among patients with different GSTT1 genotypes.

The small proteoglycans decorin and biglycan in human articular cartilage of late-stage osteoarthritis.

OBJECTIVE: Disturbances in proteoglycan metabolism of hyaline cartilage play an essential role in the pathology of degenerative joint disease. We investigated the relation between transcript expression, protein synthesis and the ultrastructural localization of the matrix-organizing proteoglycans decorin and biglycan within intra- and extracellular compartments of late-stage osteoarthritic human articular cartilage. METHODS: Human cartilage samples of a macroscopically intact area, the adjoining area and an area of the main defect from knee joints of 10 patients with late stage osteoarthritis were investigated. In situ hybridization and immunogold histochemistry were carried out separately and in combination at the light and electron microscopic level. RESULTS: Ultrastructurally, three main chondrocyte types were identified. The highest levels of mRNA of decorin and biglycan were produced by elongated secretory type 2 cells, already known to synthesize type I collagen. Cells with high levels of mRNA also translated the corresponding proteins to be found in the extracellular compartment. The highest production rate of decorin and biglycan was seen in the tissue area adjoining the main defect. CONCLUSION: The results indicate that at late stages of osteoarthritis the levels of transcription and translation for decorin and biglycan are up-regulated, probably in an effort to compensate for the general proteoglycan loss, characteristic of this disease stage.

Accuracy of bar codes versus handwriting for recording trauma resuscitation events.

STUDY OBJECTIVES: To compare the accuracy of computerized bar code data entry with conventional handwritten data entry during videotaped trauma resuscitations. SETTING: Laboratory; video simulation. TYPE OF PARTICIPANTS: Twenty-four emergency nurses. DESIGN: The nurses viewed videotapes of four different major trauma resuscitations during a single session. Each nurse recorded resuscitation events by handwritten entry in two cases and by bar code entry in another two. A computerized bar code system was designed specifically for contemporaneous charting of rapidly occurring events during trauma resuscitations. The handwritten and bar-coded records then were compared with a master list of events, and the number of entry errors were counted. Errors were defined as "omissions" (failing to record an event), "commissions" (recording an event that did not occur), or "inaccuracies" (errors in recording details of an event). ANALYSIS: Differences in the number of entry errors between the two recording methods were compared using unpaired t-tests. Differences in the number of errors after adjusting for the different nurses, different case being viewed, and order of viewing were analyzed using balanced analysis of variance techniques. P < .05 was considered significant. MAIN RESULTS: The mean +/- SEM number of total errors per record for bar codes was 2.63 +/- 0.24 compared with 4.48 +/- 0.30 for handwriting (P < .0001). The mean number of omissions per record for bar codes was 2.25 +/- 0.21 compared with 3.65 +/- 0.27 for handwriting (P = .0001). The mean number of inaccuracies per record for bar codes was 0.38 +/- 0.10 compared with 0.83 +/- 0.12 for handwriting (P = .0038). There were no commission-type errors. CONCLUSION: Computerized bar code data entry of trauma resuscitation events had significantly fewer entry errors than handwritten data entry in a laboratory setting. Potential advantages of bar code data entry include keyless data entry, automatic time-stamping, standardization of documentation, legibility of the medical record, and "point-of-care" data capture.

Field verification methodology using bar coding to record data.

Bar codes, the ubiquitous labels on consumer products, can be used to record patient care data. Bar code entry offers precise, time-stamped, data records. Bar code readers, coupled with a personal computer, can produce an electronic medical record as well as analyze data trends.

Using regression analysis to predict emergency patient volume at the Indianapolis 500 mile race.

BACKGROUND: Emergency physicians often plan and provide on-site medical care for mass gatherings. Most of the mass gathering literature is descriptive. Only a few studies have looked at factors such as crowd size, event characteristics, or weather in predicting numbers and types of patients at mass gatherings. PURPOSE: We used regression analysis to relate patient volume on Race Day at the Indianapolis Motor Speedway to weather conditions and race characteristics. METHODS: Race Day weather data for the years 1983 to 1989 were obtained from the National Oceanic and Atmospheric Administration. Data regarding patients treated on 1983 to 1989 Race Days were obtained from the facility hospital (Hannah Emergency Medical Center) data base. Regression analysis was performed using weather factors and race characteristics as independent variables and number of patients seen as the dependent variable. Data from 1990 were used to test the validity of the model. RESULTS: There was a significant relationship between dew point (which is calculated from temperature and humidity) and patient load (P less than .01). Dew point, however, failed to predict patient load during the 1990 race. No relationships could be established between humidity, sunshine, wind, or race characteristics and number of patients. CONCLUSION: Although higher dew point was associated with higher patient load during the 1983 to 1989 races, dew point was a poor predictor of patient load during the 1990 race. Regression analysis may be useful in identifying relationships between event characteristics and patient load but is probably inadequate to explain the complexities of crowd behavior and too simplified to use as a prediction tool.

Demographics of emergency medical care at the Indianapolis 500 mile race (1983-1990).

BACKGROUND: The Indianapolis 500 Mile Race, the largest single-day, single-venue sporting event in the world, is attended by an estimated 400,000 people. Major illness and injury are treated at the Hanna Emergency Medical Center, the track hospital. Minor illness is treated at ten outlying aid stations. PURPOSE: We describe the demographics of emergency medical care at the Hanna Emergency Medical Center. DESIGN: Descriptive. METHODS: Patient care data for patients treated at the medical center are first recorded on paper charts and then coded and transferred to computer. Data regarding patients treated at the medical center during eight consecutive races (1983-1990) were analyzed. Frequency of treatment and medical cardiac arrest rates were calculated. Aid station data and medical center records from nonrace days were not analyzed. RESULTS: The average number of patients treated per year at the track hospital was 139. The total number treated over the eight-year period was 1,113, yielding a frequency of treatment of 0.35 per 1,000. Analysis showed 16.2% of the proprietary treatment codes involved intoxication; 15.4%, lacerations (other than feet); 11.0%, pre-existing conditions; and 8.5%, heat illness. During the eight years, there were four medical cardiac arrests (incidence of 0.0125 per 10,000 spectators), all resulting in death. A fifth spectator died after being struck by a wheel from a race car. There were no driver deaths on race day. CONCLUSION: Descriptive data regarding medical care of crowds may be useful to emergency specialists who must staff, order supplies, and plan treatment facilities for similar mass gatherings. It is evident from this and other mass-gathering studies that there is a need for consistency in nomenclature and data collection. This will allow more accurate comparisons of emergency medical care between venues.

Financial analysis of an inner-city helicopter service: charges versus collections for patients transferred from another acute care facility.

Emergency helicopter services provided by trauma centers are now being perceived as contributing to the financial burden of the hospital because of recent changes in trauma reimbursement under the Medicare Prospective Payment System (PPS) and because of the general perception that collection rates are lower among trauma patients. The use of helicopters to transfer patients from one acute care facility to another may also be concentrating the patients with low collection rates at the receiving hospital. We examined retrospectively the demographic and clinical factors associated with the collection experience in a series of 288 trauma patients transferred by helicopter from another acute care facility to an inner-city hospital. Factors affecting payment at 180 and 360 days included patient age, insurance class, discharge status, and size of the hospital charge. As long as reimbursement continues to be cost-based for nonMedicare patients, collection rates remain an important consideration in determining the financial viability of using helicopters to transfer patients.

Financial analysis of an inner-city helicopter service: charges versus collections.

Trauma centers are now being perceived as financial burdens because of recent changes in trauma reimbursement for the Medicare Prospective Payment System population and the perception that collection rates are lower among trauma patients. We examined the demographic and clinical factors associated with the collection experience in a series of 114 trauma patients transferred by helicopter from the accident site to an inner-city trauma center. Factors affecting payment at 30, 60, 90, and 180 days included patient age, insurance class, and discharge status. While not as high as the collection rate for the facility as a whole, we found an average 71.2% collection rate for trauma patients at 180 days. As long as trauma reimbursement continues to be cost based for nonMedicare patients, collection rates remain an important consideration in determining the financial viability of trauma centers.

Computerized mega code recording.

A system has been developed to facilitate recording of advanced cardiac life support mega code testing scenarios. By scanning a paper "keyboard" using a bar code wand attached to a portable microcomputer, the person assigned to record the scenario can easily generate an accurate, complete, timed, and typewritten record of the given situations and the obtained responses.