The Hospital at Home program: no place like home.

BACKGROUND: The treatment of children with cancer is associated with significant burden for the entire family. Frequent clinic visits and extended hospital stays can negatively affect quality of life for children and their families. METHODS: Here, we describe the development of a Hospital at Home program (H@H) that delivers therapy to pediatric hematology, oncology, and blood and marrow transplant (bmt) patients in their homes. The services provided include short infusions of chemotherapy, supportive-care interventions, antibiotics, post-chemotherapy hydration, and teaching. RESULTS: From 2013 to 2015, the H@H program served 136 patients, making 1701 home visits, for patients mainly between the ages of 1 and 4 years. Referrals came from oncology in 82% of cases, from hematology in 11%, and from bmt in 7%. Since inception of the program, no adverse events have been reported. Family surveys suggested less disruption in daily routines and appreciation of specialized care by hematology and oncology nurses. Staff surveys highlighted a perceived benefit of H@H in contributing to early discharge of patients by supporting out-of-hospital monitoring and teaching. CONCLUSIONS: The development of a H@H program dedicated to the pediatric hematology, oncology, or bmt patient appears feasible. Our pilot program offers a potential contribution to improvement in patient quality of life and in cost-benefit for parents and the health care system.

Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience.

BACKGROUND: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1-4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors. PATIENTS AND METHODS: A national retrospective study of children ⩽18years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review. RESULTS: There were 50 patients (31 males; median age at diagnosis of 16.7months). Twelve patients were >36months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation. Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5months (0-32). The median survival time of the entire cohort was 13.5months (1-117.5months). Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2years overall survival (OS): 60%±12.6 versus 21.7%±8.5, p=0.03). HDC conferred better outcome (2years OS 47.9%±12.1 versus 27.3%±9.5, p=0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation. CONCLUSION: The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.

The use and effectiveness of temozolomide in children with central nervous system tumours: a survey from the Canadian Paediatric Brain Tumour Consortium.

OBJECTIVE: To describe the use of temozolomide (tmz) in Canadian children treated for brain tumours and to evaluate survival and predictors of survival for children treated with this agent. METHODS: A survey was conducted within the Canadian Paediatric Brain Tumour Consortium (cpbtc), a group of tertiary care centres in pediatric neuro-oncology (n = 16) in Canada that are involved in the treatment of children with central nervous system tumours. RESULTS: In 10 of the 16 participating pediatric oncology centres of the cpbtc, 137 children with brain tumours were treated with tmz between January 2000 and March 2006. Although 33% of the children were enrolled into a clinical trial, 67% were treated outside open studies. Most patients (72%) received tmz treatment on recurrence of their brain tumour (first or subsequent). The most commonly administered regimen was single-agent tmz 150-200 mg/m(2) administered on 5 consecutive days every 28 days. The median duration of tmz treatment was 141 days (range: 4-1102 days). Response data were provided for 127 of the 137 patients, of whom 6 showed a complete response. Sixteen patients experienced a minor or partial response, 53 had stable disease, and 52 had progressive disease. Of 32 patients alive at last follow-up, 19 had a diagnosis of low-grade glioma. CONCLUSIONS: Temozolomide is used in a variety of pediatric brain tumours, often at the time of recurrence. The lack of insight into clear indications for this agent in pediatric brain tumours-used either alone or in combination therapy-may be a result of suboptimal design of phase i and ii studies and a lack of phase iii trials in the pediatric brain tumour population.

Derivation of noncancer reference values for acrylonitrile.

Dose-response assessments were conducted for the noncancer effects of acrylonitrile (AN) for the purposes of deriving subchronic and chronic oral reference dose (RfD) and inhalation reference concentration (RfC) values. Based upon an evaluation of available toxicity data, the irritation and neurological effects of AN were determined to be appropriate bases for deriving reference values. A PBPK model, which describes the toxicokinetics of AN and its metabolite 2-cyanoethylene oxide (CEO) in both rats and humans, was used to assess the dose-response data in terms of an internal dose measure for the oral RfD values, but could not be used in deriving the inhalation RfC values. Benchmark dose (BMD) methods were used to derive all reference values. Where sufficient information was available, data-derived uncertainty factors were applied to the points of departure determined by BMD methods. From this assessment, subchronic and chronic oral RfD values of 0.5 and 0.05 mg/kg/day, respectively, were derived. Similarly, subchronic and chronic inhalation RfC values of 0.1 and 0.06 mg/m(3), respectively, were derived. Confidence in the reference values derived for AN was considered to be medium to high, based upon a consideration of the confidence in the key studies, the toxicity database, dosimetry, and dose-response modeling.

Two-generation reproductive toxicity study of inhaled acrylonitrile vapors in Crl:CD(SD) rats.

To assess the effects of acrylonitrile (AN) exposure on reproduction, Sprague-Dawley rats (25/sex/group) were exposed to vapor atmospheres of AN via whole-body inhalation at concentrations of 0, 5, 15, 45 (two offspring generations) and 90 ppm (one offspring generation), 6 h daily, 1 litter/generation, through F2 weanlings on postnatal day 28. After approximately 3 weeks of direct exposure following weaning, exposure of the F1 animals at 90 ppm was terminated due to excessive systemic toxicity in the males. There were no exposure-related mortalities in adult animals, no functional effects on reproduction or effects on reproductive organs, and no evidence of cumulative toxicity or of enhanced toxicity in pregnant and lactating dams or in developing animals. Adult systemic toxicity was limited to body weight and/or food consumption deficits in both sexes and generations (greater in males) at 45 and 90 ppm and increased liver weights in the 90 ppm F0 males and females and 45 ppm F1 males. Neonatal toxicity was expressed by F1 offspring weight decrements at 90 ppm. Clinical signs of local irritation during and immediately following exposure were observed at 90 ppm. Microscopic lesions of the rostral nasal epithelium, representing local site-of-contact irritation, were observed in some animals at 5 to 45 ppm. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity over two generations and neonatal toxicity of AN administered to rats via whole-body inhalation was 45 ppm. The NOAEL for reproduction was 90 ppm for the first generation. The NOAEL for parental systemic toxicity was 15 ppm.

Epidemiological survey of central nervous system germ cell tumors in Canadian children.

OBJECTIVES: To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada. METHOD: A national retrospective review of hospital charts was done on all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers. RESULTS: One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT. CONCLUSION: The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Cancer dose--response assessment for acrylonitrile based upon rodent brain tumor incidence: use of epidemiologic, mechanistic, and pharmacokinetic support for nonlinearity.

A cancer dose-response assessment was conducted for acrylonitrile (AN) using updated information on mechanism of action, epidemiology, toxicity, and pharmacokinetics. Although more than 10 chronic bioassays indicate that AN produces multiple tumors in rats and mice, a number of large, well-conducted epidemiology studies provide no evidence of a causal association between AN exposure and cancer mortality of any type. The epidemiological data include early industry exposures that are far higher than occur today and that approach or exceed levels found to be tumorigenic in animals. Despite the absence of positive findings in the epidemiology data, a dose-response assessment was conducted for AN based on brain tumors in rats. Mechanistic studies implicate the involvement of oxidative stress in rat brain due to a metabolite (2-cyanoethylene oxide or CEO, cyanide), but do not conclusively rule out a potential role for the direct genotoxicity of CEO. A PBPK model was used to predict internal doses (peak CEO in brain) for 12 data sets, which were pooled together to provide a consistent characterization of the dose-response relationship for brain tumor incidence in the rat. The internal dose corresponding to a 5% increase in extra risk (ED 05=0.017 mg/L brain) and its lower confidence limit (LED 05=0.014 mg/L brain) was used as the point of departure. The weight-of-evidence supports the use of a nonlinear extrapolation for the cancer dose-response assessment. A quantitative comparison of the epidemiology exposure-response data (lung and brain cancer mortality) to the rat brain tumor data in terms of internal dose adds to the confidence in the nonlinear extrapolation. Uncertainty factors of 200 and 220 (for the oral and inhalation routes, respectively) were applied to the LED 05 to account for interspecies variation, intraspecies variation, and the severity of the response measure. Accordingly, oral doses below 0.009 mg/kg-day and air concentrations below 0.1mg/m(3) are not expected to pose an appreciable risk to human populations exposed to AN.

Major histocompatibility complex-restricted lysis of neuroblastoma cells by autologous cytotoxic T lymphocytes.

Vigorous host immune reactivity to neuroblastoma may correlate with better prognosis, but identification of human cytotoxic T-lymphocyte (CTL) responses has been relatively unsuccessful. We generated neuroblastoma-reactive CTL lines from two human leukocyte antigen (HLA) A2+ neuroblastoma patients by stimulation of peripheral blood lymphocytes (PBLs) with irradiated autologous tumor cells pretreated with interferon-gamma in the presence of low concentrations of interleukin-2 (5 U/mL). These lines lyse autologous tumor cells but do not kill HLA mismatched allogeneic tumor cells, Epstein-Barr virus-transformed autologous B cells, or standard natural killer cell targets. Cytotoxic T lymphocytes generated from one patient recognize tumor cells from several HLA-A2 matched children, although the other patient's CTLs do not kill tumor cells from other HLA-A2+ individuals. Pretreatment of CTLs or target cells with appropriate standard monoclonal antibodies demonstrates that these CTLs are major histocompatibility complex class I (HLA-A2) restricted and that the effector cell population is CD8+. Our findings suggest that these tumor cells express at least one common HLA-A2 restricted antigen and at least one unique private epitope. Autologous tumor-specific CTLs can be readily generated from patients' PBLs and maintained in long-term culture using standard techniques.

Antineuronal nuclei immunohistochemical staining patterns in childhood ependymomas.

NeuN, the mouse-derived monoclonal antibody to the reportedly neuron-specific nuclear protein, has been observed to react with many different types of normal, postmitotic neurons throughout the central and peripheral nervous systems. We retrospectively examined 23 surgical specimens (collected from 20 patients) originally diagnosed at our institution between 1983 and 1999 as ependymoma (9), myxopapillary ependymoma (1), anaplastic/malignant ependymoma (10), and primitive neuroectodermal tumor with ependymal differentiation (3). The ependymomas included lesions from the spine (3), cerebrum (5), and posterior fossa (15). Representative formalin-fixed, paraffin-embedded sections from each tumor were subjected to immunohistochemical staining with antibody against NeuN (Chemicon International, Inc, Temecula, CA). Five astrocytomas, four primitive neuroectodermal tumors, and normal cerebral cortex and ependyma from autopsy brains of premature newborns, term infants, and older children served as controls. Thirteen ependymal tumors had positive nuclear staining ranging from rare tumor cells to numerous groups of cells; of these, 9 were anaplastic ependymomas and had the most staining. These studies suggest that some ependymomas arise from a pluripotential neuroglial cell.

Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study.

PURPOSE: This study was designed to determine the feasibility and safety of delivering four consecutive cycles of high-dose cyclophosphamide, cisplatin, and vincristine, each followed by stem-cell rescue, every 4 weeks, after completion of risk-adapted craniospinal irradiation to children with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: Fifty-three patients, 19 with high-risk disease and 34 with average-risk disease, were enrolled onto this study. After surgical resection, high-risk patients were treated with topotecan in a 6-week phase II window followed by craniospinal radiation therapy and four cycles of high-dose cyclophosphamide (4,000 mg/m2 per cycle), with cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5-mg/m2 doses per cycle). Support with peripheral blood stem cells or bone marrow and with granulocyte colony-stimulating factor was administered after each cycle of high-dose chemotherapy. Treatment of average-risk patients consisted of surgical resection and craniospinal irradiation, followed by the same chemotherapy given to patients with high-risk disease. The expected duration of the chemotherapy was 16 weeks, with a cumulative cyclophosphamide dose of 16,000 mg/m2 and a planned dose-intensity of 1,000 mg/m2/wk. RESULTS: Fifty of the 53 patients commenced high-dose chemotherapy, and 49 patients completed all four cycles. The median length of chemotherapy cycles one through four was 28, 27, 29, and 28 days, respectively. Engraftment occurred at a median of 14 to 15 days after infusion of stem cells or autologous bone marrow. The intended dose-intensity of cyclophosphamide was 1,000 mg/m2/wk; the median delivered dose-intensity was 1,014, 1,023, 974, and 991 mg/m2/wk for cycles 1 through 4, respectively; associated median relative dose-intensity was 101%, 102%, 97%, and 99%. No deaths were attributable to the toxic effects of high-dose chemotherapy. Early outcome analysis indicates a 2-year progression-free survival of 93.6% +/- 4.7% for the average-risk patients. For the high-risk patients, the 2-year progression-free survival is 73.7% +/- 10.5% from the start of therapy and 84.2% +/- 8.6% from the start of radiation therapy. CONCLUSION: Administering four consecutive cycles of high-dose chemotherapy with stem-cell support after surgical resection and craniospinal irradiation is feasible in newly diagnosed patients with medulloblastoma/supratentorial PNET with aggressive supportive care. The early outcome results of this approach are very encouraging.

"Large cell/anaplastic" medulloblastomas: a Pediatric Oncology Group Study.

495 medulloblastomas (MBs) from 6 Pediatric Oncology Group (POG) protocols were reviewed to assess the incidence and prognostic significance of "large cell" and "anaplastic" variants. "Large cell" medulloblastomas (LC MBs) were those with focal or diffuse, large, round neoplastic cells with prominent nucleoli. "Anaplastic" MBs (A MBs) were those with nuclei that were also large but markedly atypical with coarse chromatin and irregular shapes. Twenty-one cases were identified in the combined LC/A MB group, comprising about 4% of all MBs. Survival curves and Kaplan-Meier estimates of survival probabilities were examined separately for the LC/A MB and control groups. The logrank test for detecting poorer survival in the 21 cases was significant (p < 0.0001). Fluorescence in situ hybridization for c-myc showed amplification in 4 of 11 cases of the LC/A phenotype and 1 additional case of high level gain at 8q24 was disclosed by comparative genomic hybridization. Comparative genomic hybridization confirmed c-myc amplification and found evidence for isochromosome 17q in 3 of 4 LC/A cases studied successfully. One additional tumor showed high level gain restricted to 2p13 consistent with n-myc amplification. Monosomy 22, common in atypical teratoid/rhabdoid tumors, was not found. These results suggest that LC/A MB phenotype could be, at least in part, a correlate of c-myc, and possibly n-myc, amplification. The study thus confirms original observations about the LC MB in regard to histological features, immunohistochemical findings, c-myc amplification, cytogenetic findings, and poor prognosis.

Rat two-generation reproduction and dominant lethal study of acrylamide in drinking water.

Fischer 344 (F344) F(0) weanling rats, 30/sex/group, were exposed to acrylamide in drinking water at 0.0, 0.5, 2.0, or 5.0 mg/kg/day for 10 weeks and then mated. Exposure of F(0) females continued through gestation and lactation of F(1) litters. F(0) males, after F(0) mating, were removed from exposure and mated (one male: two untreated females) for the dominant lethal (DL) assay. Thirty F(l) weanlings/sex/group were exposed for 11 weeks to the same dose levels as their parents, and then mated to produce F(2) offspring. F(0) and F(l) parents and F(1) and F(2) weanlings were necropsied. Prebreeding exposure of F(0) and F(l) animals resulted in systemic toxicity at 2.0 to 5.0 mg/kg/day, with head tilt and/or foot splay increased at 0.5 to 5.0 mg/kg/day. F(0) and F(l) reproductive indices and gestational length were unaffected. Implantations and live pups/litter at birth were reduced at 5.0 mg/kg/day. Survival of F(l) and F(2) pups was reduced at 5.0 mg/kg/day for PND 0 through 4 only. In the DL assay, total and live implants were reduced, pre- and postimplantation loss was increased, and the frequency of DL factors (F(L)%) was increased at 5.0 mg/kg/day. At 5.0 mg/kg/day, adult F(l) male peripheral nerves exhibited axonal fragmentation and/or swelling; F(l) female spinal cord sections were unremarkable. The NOEL for prenatal DL was 2.0 mg/kg/day; the NOEL for adult systemic toxicity, including neurotoxicity, was < or = 0.5 mg/kg/day. Therefore, neurotoxicity and DL were differentially affected.

Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling: an analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat.

Historically, U.S. regulators have derived cancer slope factors by using applied dose and tumor response data from a single key bioassay or by averaging the cancer slope factors of several key bioassays. Recent changes in U.S. Environmental Protection Agency (EPA) guidelines for cancer risk assessment have acknowledged the value of better use of mechanistic data and better dose-response characterization. However, agency guidelines may benefit from additional considerations presented in this paper. An exploratory study was conducted by using rat brain tumor data for acrylonitrile (AN) to investigate the use of physiologically based pharmacokinetic (PBPK) modeling along with pooling of dose-response data across routes of exposure as a means for improving carcinogen risk assessment methods. In this study, two contrasting assessments were conducted for AN-induced brain tumors in the rat on the basis of (1) the EPA's approach, the dose-response relationship was characterized by using administered dose/concentration for each of the key studies assessed individually; and (2) an analysis of the pooled data, the dose-response relationship was characterized by using PBPK-derived internal dose measures for a combined database of ten bioassays. The cancer potencies predicted for AN by the contrasting assessments are remarkably different (i.e., risk-specific doses differ by as much as two to four orders of magnitude), with the pooled data assessments yielding lower values. This result suggests that current carcinogen risk assessment practices overestimate AN cancer potency. This methodology should be equally applicable to other data-rich chemicals in identifying (1) a useful dose measure, (2) an appropriate dose-response model, (3) an acceptable point of departure, and (4) an appropriate method of extrapolation from the range of observation to the range of prediction when a chemical's mode of action remains uncertain.

CNS tumors and exposure to acrylonitrile: inconsistency between experimental and epidemiology studies.

Acrylonitrile is a potent CNS tumorigen in rats leading to concern that it may be a tumorigen in humans. There have been 12 epidemiology studies of 37,352 workers exposed to acrylonitrile which evaluate CNS cancers. We summarize and evaluate these epidemiology studies for CNS cancers using the methods of meta-analysis. Our analyses indicate that workers with acrylonitrile exposure have null findings for CNS cancer (relative risk = 1.1, 95% confidence interval 0.8-1.5), which are in stark contrast to the projected risk to humans using the rat findings (relative risk = 3.5, 95% confidence interval 3.0-4.0). We discuss several explanations for the inconsistency between animal and human findings, including the possibility that the acrylonitrile-induced rat CNS tumors may not be relevant to humans. Given the rarity of CNS tumors in humans and a lack of understanding of the causal mechanisms of these tumors in rats, however, a more definitive conclusion will have to await additional experimental and observational data. Nevertheless, the epidemiology evidence indicates that acrylonitrile is not a potent CNS tumorigen.

Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study.

Fifty-five patients with atypical teratoid/rhabdoid tumors of the central nervous system were studied to define the clinical and pathologic features of this newly described neoplasm. The lesion occurred primarily in children younger than 2 (mean age at diagnosis, 17 months). The neoplasms were located in the posterior fossa (36 patients) and the supratentorial compartment (17 patients) or were multifocal in both compartments (2 patients) at presentation. Histologically, the tumors were composed of small cells and large, pale cells in a jumbled architectural arrangement. The small cell component resembled medulloblastoma and occasionally had cords of cells in a mucinous background, simulating chordoma. The cytoplasm of the larger cells was conspicuous with a somewhat "rhabdoid" appearance, although rhabdoid features were not always prominent. Epithelioid features in the form of poorly formed glands or Flexner-Wintersteiner rosettes were noted in a minority of lesions. The neoplasms showed striking polyphenotypic immunoreactivity, including that for vimentin, glial fibrillary acidic protein, epithelial membrane antigen, cytokeratins, synaptophysin, chromogranin, and smooth muscle actin. Using a probe for chromosome 22, seven of eight scorable cases showed a solitary signal by fluorescence in situ hybridization (FISH) consistent with monosomy 22. The eighth scorable case showed three signals by fluorescence in situ hybridization and had a translocation involving chromosome 22 reported by conventional cytogenetics. In contrast to patients with medulloblastoma, the neoplasm with which these lesions are often confused, the outcome of the patients was uniformly poor. The mean postoperative survival of patients with atypical teratoid/rhabdoid tumors was only 11 months. Local recurrence, seeding of the cerebrospinal fluid pathways, or both, were common terminal events. This study underscores the distinctive clinical, histopathologic, immunohistochemical, and cytogenetic character of this unusually aggressive tumor.

Monitoring and predicting ototoxic damage using distortion-product otoacoustic emissions: pediatric case study.

Young children undergoing cisplatin chemotherapy are known to be at risk for progressive sensorineural hearing loss. Early detection of such hearing loss is important for providing management options. However, in ill and/or young children, behavioral audiometry may not be sufficiently precise to detect the early stages of hearing loss. This case illustrates that distortion-product otoacoustic emissions (DPOAEs) may be an appropriate cross-check measure to supplement and confirm pediatric behavioral data. Perhaps more importantly, this study suggests that DPOAEs may have the potential to predict the earliest stages of progressive hearing loss before such changes are seen in audiometric thresholds.

Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood.

In 1987, a distinctive brain tumor arising in young children was first described. This tumor contained neuroepithelial, peripheral epithelial, and mesenchymal elements, but lacked divergent tissue differentiation characteristic of malignant teratomas. It was originally designated as atypical teratoid tumor, but because of the prominent rhabdoid component, the tumor designation was modified to atypical teratoid/rhabdoid tumors (AT/RT) of infancy and childhood. AT/RTs occur most commonly in infants under 2 years of age, often have central nervous system (CNS) dissemination, do not respond to therapy, and typically are fatal within 1 year. Most are located in the cerebellum (65%), but they may arise at any CNS site. Histologically, various patterns can be present within the same tumor, but they all have a population of rhabdoid cells, and 70% contain fields typical of a primitive neuroectodermal tumor (PNET/medulloblastoma). Less frequently, malignant mesenchymal tissue and/or an epithelial component are found. Necrosis and brisk mitotic activity are common. The immunocytochemical profile is complex, but germ cell markers are consistently negative. Ultrastructural features vary and depend on the site sampled, but whorled bundles of cytoplasmic intermediate filaments are a distinctive finding in cells of the rhabdoid component. The authors report 4 AT/RTs (2 males, 2 females, age range 6 months to 4 1/2 years, 3 cerebellar, 1 cerebral). All cases showed a variety of histologic patterns with necrosis. Typical rhabdoid cells, PNET areas, undifferentiated bland large cell regions, dense connective tissue, and solid clusters of epithelial cells were present. Immunocytochemistry showed strong vimentin reactivity, whereas epithelial membrane antigen, cytokeratin, glial fibrillary acidic protein, S-100 protein, desmin, and smooth muscle actin were present to a lesser extent in most cases. Germ cell markers were negative. Ultrastructurally, many cells contained aggregates of cytoplasmic intermediate filaments, and some cells had a basal lamina on one aspect. Cells with interdigitating cytoplasmic borders were seen and rare cells had microtubules. Cytogenetic studies were normal in 2 cases. Follow-up has shown that 3 children have died of disease (< 1 year after diagnosis) and 1 child is alive with disease (18 months after diagnosis). Separation of AT/RT from PNET based on histopathologic and biologic evaluation is important, because AT/RTs are aggressive tumors with a dismal prognosis and currently there is no effective treatment. Neither clinical signs and symptoms nor radiologic features will distinguish AT/RTs from PNETs.

Primary malignant rhabdoid tumor of the central nervous system.

Since the initial description of malignant rhabdoid tumor (MRT) of the kidney by Beckwith in 1978, MRTs have been established as a distinct clinicopathologic entity lacking nephrogenic and myogenic differentiation. MRTs are highly aggressive neoplasms with characteristic histopathologic, immunocytochemical, and ultrastructural features. Many reports have appeared documenting primary extrarenal rhabdoid tumors (ERRTs) occurring at diverse sites, including infratentorial and supratentorial compartments of the central nervous system (CNS). The authors report 2 cases of primary CNS-MRT in young male children (6.5 and 7 years of age) and review the literature on CNS-MRTs. Neuroimaging studies showed an inhomogeneous parasagittal mass in the left anterior parietal region involving the motor strip and attached to the lateral aspect of the superior sagittal sinus in one case, and a right parietal parasagittal tumor with a cystic component in the other case. Metastatic workup, including abdominal CT, was negative in both cases. Histologic examination of the resected tumors showed irregular clusters and nests of cells with variable desmoplasia in both cases. Large areas of tumor necrosis and apoptotic tumor cells were present. Prominent eosinophilic cytoplasmic inclusions and eccentric, indented nuclei with conspicuous nucleoli characterized many of the tumor cells. Diffuse strong vimentin reactivity and focal strong reaction for epithelial membrane antigen (EMA) were demonstrated. Cytogenetic analyses reported a normal male karyotype in one case and an abnormal male karyotype with loss of both normal copies of chromosome 22 and gain of one structurally rearranged chromosome 22 in the other case. Ultrastructural examination displayed tumor cells with avoid to indented nuclei, marginated chromatin, and prominent nucleoli. Intercellular junctions were not found. Masses of cytoplasmic intermediate filaments in a characteristic whorled configuration were present. CNS-MRTs are consistently vimentin positive (100%) and usually EMA positive (90%). Glial fibrillary acidic protein, neuron-specific enolase, and S-100 protein are variably expressed. Markers for myogenous differentiation are invariably absent. Ultrastructural characteristics include aggregates of intermediate filaments. Monosomy 22 occurs in some CNS rhabdoid tumors, while most renal rhabdoid tumors are cytogenetically normal with only isolated cases having del(13q), del(11p), del(22)(q11), and unbalanced reciprocal translocation involving chromosomes 8 and 22. The prognosis for CNS rhabdoid tumors is dismal and almost two-thirds of patients are dead of disease shortly after diagnosis; one-third have been reported to be alive with disease, but have been followed for only short periods; and a single patient is reported to be free of disease at 5 years.

Chemotherapy for patients with recurrent or refractory neuroblastoma: a POG Phase II study.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of three different salvage regimens (Rx) in children with recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Forty-six children with recurrent or refractory neuroblastoma received treatment according to one of three regimens: Rx 1 (five patients), high-dose cisplatin (HDP) (200 mg/m2) with concurrent sodium thiosulfate (STS) (9.9 g/m2) as a nephroprotectant and etoposide (VP-16) (200 mg/m2/day for 3 days); Rx 2 (22 patients), high-dose carboplatin (HD-CBDCA) (500 mg/m2/day for 2 days) and VP-16 (100 mg/m2/day for 3 days); Rx 3 (19 patients), ifosfamide (1.5 g/m2/day for 3 days) followed by CBDCA (400 mg/m2) on day 4. Chemotherapy was administered every 3-4 weeks. Responses were assessed following four courses with or without surgery. Patients achieving less than a partial response (PR) on their primary treatment were crossed over to the next regimen (i.e., Rx 1 --> Rx 2 <--> Rx 3). RESULTS: Rx 1 was ended early owing to grade 4 nephrotoxicity in two patients following their first course. Ten of 22 evaluated patients (45%) primarily (n = 19) or secondarily (n = 3) treated by Rx 2 responded [five complete response (CR) and five PRs]. Nine of the 23 evaluated patients (39%) on Rx 3 as primary (n = 18) or secondary (n = 5) treatment responded (one CR and eight PRs). Grades 3-4 neutropenia and thrombocytopenia occurred after 80% and 50% of courses administered on Rx 2 and Rx 3, respectively. Central venous line infections were the most commonly documented infections on these regimens. CONCLUSIONS: Rx 2 and Rx 3 are active combinations in patients with recurrent or refractory neuroblastoma and are associated with manageable toxicity. HDP administered as a short i.v. infusion with concurrent STS infusion cannot be safely given to children with neuroblastoma pretreated with cisplatin.