Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age.

In an effort to improve survival and reduce late adverse effects of radiation therapy (RT), 25 children <3 years of age with malignant brain tumors received tandem high-dose chemotherapy (HDCT) and auto-SCT following six cycles of induction chemotherapy. RT was either not given or deferred until 3 years of age if the patient was in CR after tandem HDCT/auto-SCT. Tumors relapsed or progressed in nine patients (five during induction treatment), and two of these patients survived after receiving salvage treatment, including RT. Two patients died due to toxicities during tandem HDCT/auto-SCT. A total of 16 patients survived to a median follow-up period of 52 months (range 18-96) from the time of diagnosis. Four of these patients did not receive RT, two received local RT (L-RT), three received craniospinal RT (CSRT), and seven received both L-RT and CSRT. The 5-year OS and EFS rates were 67.8±9.4% and 55.5±10.0%, respectively. Neuroendocrine and neurocognitive functions evaluated 3 years after tandem HDCT/auto-SCT were acceptable. Our results indicate that tandem HDCT/auto-SCT may improve survival in young children with malignant brain tumors with an acceptable level of risk of long-term toxicity.

Diagnostic dilemma of pseudoprogression in the treatment of newly diagnosed glioblastomas: the role of assessing relative cerebral blood flow volume and oxygen-6-methylguanine-DNA methyltransferase promoter methylation status.

BACKGROUND AND PURPOSE: Methylation of the MGMT gene promoter is associated with a favorable prognosis in adult patients with GBM treated with TMZ. We determined the incidence of pseudoprogression according to the MGMT methylation status and the potential value of DSC perfusion MR images for predicting pseudoprogression. MATERIALS AND METHODS: New or enlarged enhancing lesions after CCRT in adult patients with newly diagnosed GBMs were prospectively assessed by measuring their rCBV by using DSC perfusion MR images. Tumor tissue was assayed to determine MGMT promoter methylation status. All patients were regularly followed up at an interval of 2 months by MR images, including DSC perfusion MR images. RESULTS: Ninety eligible patients were enrolled in this study. After CCRT, new or enlarged enhanced lesions were found in 59 of 90 patients, which were subsequently classified as pseudoprogression (26 patients, 28.9%) and real progression (33 patients, 36.7%). Overall, there was a significant difference in the mean rCBV between pseudoprogression and real tumor progression (P = .003). The ROC curve revealed that an rCBV ratio >1.47 had an 81.5% sensitivity and a 77.8% specificity. The unmethylated MGMT promoter group had a significant difference of mean rCBV between pseudoprogression and real progression (P = .009), though the methylated MGMT promoter group had no significant difference (P = .258). CONCLUSIONS: The current study suggests that rCBV measured by DSC perfusion MR images has a differential impact on the predictability of pseudoprogression in patients with GBM.

The expression of connective tissue growth factor in pregnancies complicated by severe preeclampsia or fetal growth restriction.

We tested the hypothesis that the expression of placental connective tissue growth factor (CTGF) is enhanced in pregnancies complicated by severe preeclampsia (PE) or fetal growth restriction (FGR). CTGF expression was analyzed using immunostaining, western blot and real-time quantitative PCR in placental samples obtained after third trimester cesarean deliveries without labor from women with severe PE (n=11), idiopathic FGR (n=14), or healthy controls (n=14). Serum CTGF concentrations were analyzed using ELISA. We found that CTGF was stably expressed in villous trophoblasts throughout pregnancy. The expression of CTGF mRNA in placentas from severe PE or FGR was higher than placentas from controls. Whereas the levels of placental CTGF protein were similar between normal and severe PE, maternal and fetal serum CTGF levels were elevated in severe PE. Maternal CTGF levels were also distinctively elevated in women with PE or FGR with histological evidence of placental injury. The enhancement of CTGF expression as well as serum CTGF levels in clinical conditions attributed to placental dysfunction suggests a role for this secretary protein in the pathophysiology of placental injury or its sequelae.

Gliomatosis cerebri: clinicopathologic study of 33 cases and comparison of mass forming and diffuse types.

OBJECTIVE: Gliomatosis cerebri (GC) is defined as a diffuse neoplastic glial cell infiltration of the brain with the preservation of anatomical architecture and the sparing of neurons and can be classified into Type 1 (diffuse) and Type 2 (mass forming) GCs macroscopically. There is little information on subtypes of GC. The aim of this study was to evaluate the clinicopathologic findings of GCs and to compare the clinicopathologic findings between Type 1 and Type 2 GCs. MATERIAL: A total of 33 cases of GC were obtained from pathology file of Samsung Medical Center. The diagnosis was based on magnetic resonance imaging findings and histological confirmation for all patients. Fifteen cases were classified into Type 1 and 18 were Type 2 based on the MR images. METHODS: Clinical information included patients' age, sex, tumor extent, treatment modality and survival. Pathologic features included the amount of rod cells and cytologic anaplasia such as multinucleated tumor giant cells, endothelial cell proliferation, or mitosis. Immunohistochemical study was performed for GFAP, O1, Gal-C, Ki-67, and p53. Clinicopathologic comparison between subtypes and statistical analysis were performed. RESULTS: Median age at diagnosis was older (56 years) in Type 1 than in Type 2 (44 years). Male to female ratio was about 1.54:1. Mean survival time was shorter (21 months) in Type 2 than in Type 1 GCs (24 months) (p = 0.0447). Histologically, 33 cases of GC were classified into two histologic grades (low and high grade) by cytologic anaplasia. High-grade GC was more common in Type 2 than Type 1 (p = 0.027). Immunohistochemical results demonstrated that the infiltrating tumor cells were undifferentiated cells with astrocytic or oligodendroglial differentiation. Ki-67 labeling index was correlated with subtypes (p = 0.0096). Pathologic features were not correlated with survival. CONCLUSIONS: Type 1 and 2 GCs are somewhat different in clinical presentation and pathologic features. The age group, survival time, histologic grade, and Ki-67 labeling index were significantly correlated with subtypes ofGCs. Type 2 GC was correlated with poor survival but histologic grade was not.

A T1 hyperintense perilesional signal aids in the differentiation of a cavernous angioma from other hemorrhagic masses.

BACKGROUND AND PURPOSE: A cavernous angioma is a developmental vascular malformation with a high risk of hemorrhage. The purpose of this work was to retrospectively determine whether an MR sign of T1 hyperintense perilesional signal intensity is useful for the differentiation of cavernous angioma from other hemorrhagic cerebral masses. MATERIALS AND METHODS: The institutional review board approved this study. We retrospectively evaluated the MR images of 72 patients with acute or subacute cerebral hemorrhagic lesions with perilesional edema (29 cavernous angiomas, 13 glioblastomas, 1 oligodendroglioma, 16 metastatic tumors, and 13 intracerebral hemorrhages) for the presence of T1 hyperintense perilesional signal intensity. In addition, T1 signal intensities of a perilesional edema were quantitatively analyzed. In cavernous angiomas, volumes of hemorrhagic lesions and perilesional edemas, lesion locations, presence of contrast enhancement, and time intervals between symptom onset and MR imaging were also assessed. Data were analyzed using unpaired t test or Fisher exact test. RESULTS: T1 hyperintense perilesional signal intensity sign was found in 18 (62.1%) of 29 cavernous angiomas, in 1 (6.3%) of 16 metastases, and in 0 primary brain tumors or intracerebral hemorrhages. Sensitivity, specificity, and positive predictive value of this sign for cavernous angioma were 62%, 98%, and 95%, respectively. The perilesional T1 hyperintensity was significantly higher in cavernous angiomas (P = .045) than in normal white matter. Perilesional edema volumes were larger in cavernous angiomas with the MR sign than in cavernous angiomas without the sign (P = .009). CONCLUSION: When the MR sign of T1 hyperintense perilesional signal intensity is present, there is a high probability of cavernous angioma being present in the brain, and this MR sign may be helpful for differentiating cavernous angioma from hemorrhagic tumors and intracerebral hemorrhages.

Tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma.

From June 1997 to August 2005, 52 consecutive newly diagnosed stage 4 neuroblastoma patients over 1 year of age were assigned to receive tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) as consolidation therapy. Fifty of the 52 patients underwent a first HDCT/ASCR and 44 patients underwent a second HDCT/ASCR. Eight patients (15.4%) died from treatment-related toxicity (seven during the second HDCT/ASCR). Total body irradiation (TBI) in the first HDCT/ASCR and a shorter interval (< 12 weeks) between the first and second HDCT/ASCR were associated with a higher rate of treatment-related death in the second HDCT/ASCR (P = 0.032 and 0.095, respectively). The tumor relapsed or progressed in 11 patients, and 33 patients remained event free with a median follow-up of 53 months (range 19-117) from diagnosis. The 5-year event-free survival (EFS) (+/- 95% confidence interval) for all 52 patients was 62.1+/-13.7%. The application of TBI and local radiotherapy, and a longer interval between the first and second HDCT/ASCR were independently associated with a better EFS (P = 0.026, 0.007 and 0.020, respectively). However, further studies will be needed to decrease the toxic death rate in the second HDCT/ASCR while reducing the relapse rate.

Malignant lymphoma of the central nervous system: difficult histologic diagnosis after glucocorticoid therapy prior to biopsy.

Four cases of central nervous system (CNS) lymphoma are reported which presented obstacles in diagnosis due to steroid treatment prior to biopsy. Reliable diagnoses were provided by molecular analysis. Malignant lymphoma of the CNS may be indistinguishable from other conditions, even in view of the gravity of the diagnosis. All patients had a previous history of glucocorticoid injection, for 2-18 days prior to stereotactic brain biopsy. The pathologic examination revealed in all cases axonal destruction and reactive gliosis with a variable infiltration of B- or T lymphocytes and macrophages. Characteristically, scattered degenerating small round cells with pyknotic or fragmented nuclei were also observed. However, the molecular assessment of paraffin-embedded tissues revealed the monoclonal IgH gene rearrangement, which allowed the confident diagnosis of B cell lymphoma. The histopathological findings of the present cases suggest that the tumor cells might be selectively destroyed by steroid treatment, which may render diagnosis impossible. Thus, molecular genetic investigation constitutes an important tool for establishing a diagnosis of CNS lymphoma obscured by steroid administration. This is especially true in cases where a paucity of tumor cells is observed or when monoclonality fails to be demonstrated by immunohistochemical tests.

Sclerosing meningioma: immunohistochemical analysis of five cases.

Sclerosing meningioma is a rare morphologic subtype of meningioma and may be mistaken for atypical or malignant meningioma and astrocytoma or schwannoma because of marked collagen deposits and a sparse population of cells with little resemblance to meningothelial cells. Authors describe the histopathologic and immunophenotypic features of five cases of sclerosing meningioma. Histologically, all the cases consisted of paucicellular collagenous tissue containing spindle cells with or without small foci of meningothelial cell proliferation. The morphology and immunohistochemical profile of the spindle cells were different from those of conventional meningothelial cells. The meningothelial cells showed a typical immunoreactivity of conventional meningiomas, while the spindle cells displayed a strong expression of vimentin. The Ki-67 labelling index was uniformly low in all cases, and none of cases expressed p53 protein. In summary, the recognition of meningothelial cells in massively sclerotic lesions is helpful for a correct diagnosis. In the cases with a total absence of meningothelial cells, however, the vague collagenous whorls are more diagnostic rather than immunohistochemistry. Considering association with clear cell meningioma, prospective and retrospective long-term follow-up is necessary for deciding whether reminiscent clear cell meningiomas should be separated from sclerosing meningioma or not.

Expression of cyclin A and topoisomerase IIalpha of oligodendrogliomas is correlated with tumour grade, MIB-1 labelling index and survival.

AIMS: This study was designed to investigate immunoexpression of cyclin A and D1, and topoisomerase IIalpha in oligodendrogliomas and to evaluate the correlation with MIB-1 (Ki67), tumour grade, and survival of the patients. METHODS AND RESULTS: Forty cases of oligodendrogliomas (20 high- and 20 low-grade) were studied immunohistochemically with the above-mentioned monoclonal antibodies. RESULTS: Normal brain tissues included in tumour sections did not express any of cyclin A, MIB-1 and topoisomerase IIalpha except cyclin D1, which was shown in perineuronal and interfascicular normal oligodendroglial cells. In low-grade and high-grade oligodendrogliomas, the mean cyclin A labelling index (LI) was 1.18 +/- 0.98% versus 4.65 +/- 1.99%, respectively; the mean topoisomerase IIalpha LI was 1.32 +/- 1.04% versus 6.63 +/- 4.31%, respectively; and the mean MIB-1 LI was 1.69 +/- 1.55% versus 9.46 +/- 4.66%, respectively. Interestingly, cyclin D1 was not expressed in any oligodendrogliomas. Both cyclin A and topoisomerase IIalpha LI showed a significant positive correlation with MIB-1 LI and histological grade of oligodendrogliomas (P < 0.01) and an inverse correlation with overall survival (P < 0.01). Univariate analysis showed that cyclin A and topoisomerase IIalpha LIs with a cut-off point at 3% were a significant prognostic factor (P: cyclin A = 0.0040, topoisomerase IIalpha = 0.0033). CONCLUSION: Cyclin A and topoisomerase IIalpha expression are closely correlated with anaplastic oligodendrogliomas and worse clinical outcomes. Cyclin D1 seems not to be involved in the tumorigenesis of oligodendrogliomas.

Gliofibroma with extensive calcified deposits.

Gliofibroma is a rare astrocytic neoplasm of young people that shows abundant deposition of collagenous matrix around glial cells. It shares some clinical and pathologic features with desmoplastic cerebral astrocytoma of infancy or desmoplastic infantile ganglioglioma. However, histogenesis or clinical behavior of these tumors is not fully known. Here, we report a case of gliofibroma with unusual extensive calcification which complicated radiologic as well as pathologic diagnosis.

Intraperitoneal gene delivery mediated by a novel cationic liposome in a peritoneal disseminated ovarian cancer model.

We have previously synthesized a new cationic liposome that displays high efficiency and low toxicity, 3 beta[l-ornithinamide-carbamoyl] cholesterol (O-Chol), using solid-phase synthesis. In this study, O-Chol was applied to in vitro and in vivo models of ovarian cancer. Intraperitoneal gene delivery for peritoneal disseminated ovarian cancer in nude mice was achieved using a stable chloramphenicol acetyl transferase (CAT)-expressing ovarian cancer cell line (OV-CA-2774/CAT), which allowed us to quantify the exact tumor burden of organs. When luciferase and beta-galactosidase genes were used as reporter genes, O-Chol showed better efficiency than other commercial transfection reagents such as lipofectin, lipofectAMINE, DC-Chol, and FuGENE 6, both in vitro and in vivo. Moreover, the transfection efficiency of this new cationic lipid reagent remained high in serum-containing medium and under serum-free conditions. Furthermore, in vivo transfection with O-Chol showed high levels of gene expression specific to peritoneal tumor cells. Consequently, the O-Chol:DNA lipoplex appears to offer potential advantages over other commercial transfection reagents because of (1) its higher level of gene expression in vitro and in vivo; (2) its reduced susceptibility to serum inhibition; and (3) its highly selective transfection into tumor cells. These results suggest that the O-Chol:DNA lipoplex is a promising tool in gene therapy for patients with peritoneal disseminated ovarian cancer.

Protracted diarrhea: results of the five-year survey in a tertiary hospital in Korea.

The syndrome of protracted diarrhea (PD) includes several diseases with diverse etiologies. This study was conducted to characterize the spectrum of causes, clinical manifestations, and the outcomes of PD. A retrospective analysis of the clinical and pathological findings was performed on 25 patients with diarrhea starting within the first 2 yr of life and a requirement of parenteral nutrition (PN). According to the intestinal histopathology, patients were classified into four groups: immune enteropathy (12 cases), lymphangiectasia (6 cases), epithelial dysplasia (5 cases), and unclassified (2 cases). All patients with epithelial dysplasia had earlier onset of diarrhea and longer duration of PN than those in the other groups. Three patients (12%) had an evidence of a familial condition. Five patients (three with microvillous inclusion disease and two with immune enteropathy) died. Sixteen patients recovered, and three (two with primary lymphangiectasia and one with microvillous inclusion disease) still had diarrhea. One patient underwent intestinal transplantation for tufting enteropathy. In conclusion, infants with PD should be referred to specialized centers where advanced diagnostic and therapeutic facilities are available, because histological analysis is critical for the diagnosis of PD, and PN or intestinal transplantation is the only therapeutic option in a subset of cases.

Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas.

Several molecular and genetic changes have been found in pituitary adenomas. We looked for correlations between these changes and the degree of invasiveness of the tumors. The invasiveness of 11 pituitary adenomas was graded by Hardy classification. We examined the retinoblastoma gene (RB1.20 on chromosome 13q) and the region around the MEN1 locus (chromosome 11q13.1-5) for loss of heterozygosity. Also examined are p53 mutations using single strain conformation polymorphism, p53 protein overexpression using immuno cytochemistry, homozygous deletions of p15 and p16 by polymerase chain reaction, and cellular proliferative activity using MIB-1 antibody. Six tumors (54.5%) had an LOH at either RB1.20 or the MEN1 locus. LOHs were found more frequently in Grade 4 and stage E tumors (72% and 67%) than in Grade 3 and stage D tumors (25% and 40%). However, no mutation or overexpression of p53 was found. No homozygous deletions of p15 or p16 were identified. The cell proliferative index ranged from 0 to 3%. LOH at 11q13 and 13q may be valuable in predicting the invasiveness of pituitary adenomas.

Thymic ultrasound. I. Intrathymic anatomy in infants.

BACKGROUND: The gross appearance and echogenicity of the normal thymus have been described, but specific intrathymic anatomy has not been evaluated with imaging. SUBJECTS AND METHODS: The thymus from a 34-week-gestation stillborn male was examined with ultrasound, and the images were correlated with microscopic findings. Thymic ultrasound was performed in 12 infants without any evidence of thymic abnormality, severe infection, or chronic illness. Images were evaluated focusing on intrathymic parenchymal anatomy and compared to the liver, spleen, and thyroid gland. RESULTS: In the specimen thymus, ultrasound demonstrated connective-tissue septa as echogenic linear structures. The cortex was relatively hypoechoic, whereas the medulla was echogenic. The blood vessels within the septa were seen as discrete echoes. In vivo ultrasound demonstrated multiple branching echogenic linear structures and foci throughout the parenchyma, representing connective-tissue septa or blood vessels within the septa. The normal thymus was easily differentiated from the liver, spleen, and thyroid glands. CONCLUSION: Ultrasound is capable of demonstrating intrathymic anatomy, including the medulla, cortex, septa, and blood vessels in a fresh specimen. In vivo connective-tissue septa and blood vessels in the thymic parenchyma produce a unique echo pattern.

Thymic ultrasound. II. Diagnosis of aberrant cervical thymus.

BACKGROUND: The aberrant cervical thymus is an uncommon entity to be considered in the differential diagnosis of neck masses in children, so a preoperative diagnosis has rarely been made. OBJECTIVE: The purpose of this study was to assess the ultrasound features of aberrant cervical thymus and determine if recognition of the previously described unique intrathymic echo pattern allows us to make a specific diagnosis. MATERIALS AND METHODS: We present four patients with an aberrant cervical thymus and one patient with a cervical thymic cyst. All five patients had ultrasound, which was evaluated with special attention to the detailed echo pattern of the mass. In two patients, the mass was surgically removed. Four patients had MRI, which was evaluated. Medical records were reviewed. RESULTS: In all cases, the mass was painless and nontender. All occurred in the expected path of the thymopharyngeal duct. In four patients, ultrasound demonstrated multiple echogenic linear structures and foci previously described as characteristic echo pattern of normal thymic tissue. In one patient, ultrasound showed a large cystic mass and echogenic solid component superiorly with a characteristic echo pattern of normal thymus. CONCLUSIONS: The ultrasound appearance of thymic tissue is unique, allowing a specific diagnosis of aberrant cervical thymus. Biopsy or other imaging is probably not indicated when it presents with typical clinical features.

CD99 immunoreactivity in ependymoma.

The expression of CD99 in normal ependymal cells and ependymoma has been reported. However, only limited numbers of tumors have been studied, and the pattern of CD99 expression has not been described. The authors' purpose was to investigate CD99 immunoreactivity in ependymoma and its use for differential diagnosis. Twenty-five ependymomas were immunostained with antibody directed at CD99. The result of immunostaining of ependymomas was compared with 63 nonependymal tumors that histologically resemble ependymal neoplasms. The nonependymal tumors included 19 astrocytic tumors, 6 oligodendroglial tumors, 8 choroid plexus neoplasms, 2 central neurocytomas, 5 medulloblastomas, 10 primitive neuroectodermal tumors (PNET), and 13 pituitary adenomas. All ependymomas showed strong expression of CD99 in membranous pattern with intracytoplasmic or intercellular dots (ICDs). The expression pattern of CD99 was not correlated with histologic type or grade of ependymomas. Among 63 nonependymal tumors, 11 (17.5%) showed incomplete membrane staining for CD99; diffuse in 4 PNETs and focal in 5 choroid plexus neoplasms (3 papillomas and 2 carcinomas) and one each of pituitary adenoma and oligodendroglioma. The ICD was not found in nonependymal tumors except a case of choroid plexus papilloma. However, membrane staining or ICD for CD99 was not distinctive in nonependymal tumors. In conclusion, the characteristic pattern of anti-CD99 antibody, i.e., diffuse strong membranous immunostaining with ICDs, is useful in distinguishing ependymomas from the central nervous system tumors that histologically mimic ependymoma.

Cutaneous bronchogenic cyst of the abdominal wall.

We report a case of the unusual location of a cutaneous bronchogenic cyst on the abdominal wall. The patient was a 9-month-old boy who had presented with a 1.5 cm-sized polypoid mass, present since birth. Pathological examination of the excised mass revealed multiple small cystic structures surrounded by the fibroadipose tissue. The lining epithelium consisted of either pseudostratified ciliated columnar epithelium with goblet cells or a single layer of ciliated or non-ciliated cuboidal to columnar cells. The cystic walls contained a well-developed smooth muscle bundle, mucous glands and hyaline cartilage plate. This lesion was adherent to the peritoneum, but there was no direct communication with the abdominal cavity. Cutaneous bronchogenic cyst located in the abdominal wall has not been described in the English literature. The present case suggests a possible origin from a downward migration, from the sequestered bud of a tracheobronchial tree primordium along the midline of the body surface, during embryonic development.

Surgical treatment of intractable epilepsy accompanying cortical dysplasia.

OBJECT: Surgical treatment of cortical dysplasia (CD) together with intractable seizures is challenging because both visualization and localization of the lesion are difficult, correlation with seizure foci requires comprehensive study, and the surgical outcomes reported thus far are unsatisfactory. The authors report their experience in the surgical treatment of CD classified according to a surgical point of view. METHODS: The definition of CD used in this study was a dysplastic lesion visible on magnetic resonance (MR) images or a lesion that, although not visible on MR images, was diagnosed as moderate-to-severe dysplasia by using pathological analysis. During the last 4.5 years, the authors treated 36 patients with intractable epilepsy accompanied by CD. They divided the 36 cases of CD into four characteristic groups: Group A, diffuse bilateral hemispheric dysplasia; Group B, diffuse lobar dysplasia; Group C, focal dysplasia; and Group D, a moderate to severe degree of CD with a normal appearance on MR images. All but one patient in Group C were monitored in the epilepsy monitoring unit by using subdural electrodes for seizure localization and functional mapping. The incidence of CD among a cohort of 291 patients who had undergone epilepsy surgery at the authors' center during the study period was 12.4%. The mean age of the 36 patients was 21.3 years and the mean age at seizure onset was 8.5 years. The mean follow-up period was 26 months. Twenty-six patients (72.2%) belonged to Engel Class I or II (20 and six, respectively). There were five cases in Group A, nine in Group B, nine in Group C, and 13 in Group D. Patients in Groups A and B were significantly younger at seizure onset and had significantly poorer surgical outcomes compared with patients in Groups C and D (p < 0.05). If outcome is compared on the basis of the extent of removal of CD, patients in whom CD was completely removed had significantly better outcomes than those in whom CD was only partially removed (p < 0.001). CONCLUSIONS: The authors conclude that intractable epilepsy accompanied by CD can be treated surgically using comprehensive preoperative approaches. Deliberate resective procedures aimed at complete removal of dysplastic tissue ensure excellent seizure control without permanent neurological deficit.