Summary:We prospectively evaluated the neuropathological complications of 180 patients who underwent autopsy studies following bone marrow transplantation (BMT) (177 allogeneic, three autologous). The most frequent underlying disorders included severe aplastic anemia (n = 55), chronic myelogenous leukemia (n = 53), acute myelogenous leukemia (n = 24) and Fanconi anemia (n = 16). There were 114 males and 66 females. Neuropathological findings were detected in 90.55% of the patients. The most frequent findings were subarachnoid hemorrhages (SAH) (n = 57), intraparenchymal hemorrhages (IHP) (n = 49), fungal infections (n = 16), Wernicke's encephalopathy (n = 10), microglial nodular encephalopathy (n = 10) and neurotoxoplasmosis (n = 8). In only 17 patients was the brain within normal limits. Survival time after BMT averaged 5.4 months and the majority of patients died in the first 3 months post BMT (n = 105). Central nervous system (CNS) pathology was the main cause of death in 17% of the patients (n = 31), with a predominance of IHP in this particular group. Furthermore, the survival time of these patients who died of CNS causes (96.3 days) was almost half of the survival time of those who died of extra-cerebral causes (177.8 days) (P = 0.0162). IHP (70.96 vs 27.22%) (P Ͻ 0.001), fungal infections (25.8 vs 8.88%) (P Ͻ 0.001) and toxoplasmosis (9.67 vs 4.44%) (P Ͻ 0.001) were significantly more frequent in the group of patients who died due to CNS causes than in the control group. The findings of this work provide a possible guide to the possible causes of neurological syndromes following BMT. Bone Marrow Transplantation (2000) 25, 301-307. Keywords: central nervous system; bone marrow transplantation; cerebrovascular disorders; infections Bone marrow transplantation (BMT) is used to treat several malignant diseases, severe aplastic anemia, immunodeficiencies and metabolic disorders.1,2 It allows use of potentially lethal doses of chemotherapy and/or irradiation to eradicate systemic malignancy or poorly functioning con-

Toxoplasma infection following bone marrow transplantation (BMT) is infrequently reported. We report 9 cases of disseminated Toxoplasma gondii infection in BMT recipients documented during an 11-year period at our institution. The incidence of T. gondii infection in our institution (1.14 per 100 allogeneic BMT) is higher than previously reported. The most frequently affected sites were the brain, lungs, and heart. Findings common to most patients who developed toxoplasmosis were positive pre-transplant serology, allogeneic transplant and graft-versus-host disease and its treatment, as well as BMT from matched unrelated donors. All 9 patients died and 8 were diagnosed only after autopsy. Heightened awareness of the occurrence of toxoplasmosis in marrow recipients, especially in highly endemic areas, and early diagnosis and therapy are needed for a better outcome.

A chromosomal translocation involving the MYC gene is characteristic of Burkitt lymphoma (BL) and represents a molecular disease marker with diagnostic and clinical implications. The detection of MYC breakpoints is hampered by technical problems, including the distribution of the breakpoints over a very large genomic region of approximately 1,000 kb. In this article, we report on the testing and validation of a segregation fluorescence in situ hybridization (FISH) assay for MYC breakpoints on a large series of BLs. A contig of overlapping genomic clones was generated, and two probe sets flanking the MYC gene were selected. Both probe sets were tested in an interphase FISH segregation assay on 8 B-cell lymphoma cell lines and 32 lymphoma samples with proved 8q24/MYC abnormalities and validated in 47 BLs from The Netherlands, Brazil, and Uganda. MYC translocation breakpoints were identified in 98% of the tumors of the test series and in 89% of the cases of the validation series. In 89% of all positive samples, the breakpoints were located between 190 kb 5' and 50 kb 3' of MYC. Nine cases had more distant breakpoints, and in one patient an insertion of MYC into the IGH region was detected. In two of the three BLs lacking CD10 expression, no breakpoint could be detected, suggesting that CD10 is a discriminative marker of BL. We did not find consistent differences between BL and atypical BL in incidence of an MYC breakpoint.

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Summary:to carbohydrate metabolism, any increase in carbohydrate intake will also raise the need for thiamine to metabolize it, and may constitute an immediate precipitating factor for Wernicke's encephalopathy (WE) is a neuropsychiatric condition generally caused by acute thiamine deficiency some syndromes such as WE. First described by Carl Wernicke, in 1881, 7 WE is an acute neuropsychiatric condition and classically involves the triad of altered mentation, ataxia and ophthalmoplegia. It is most common among caused by thiamine deficiency. It classically involves the triad of ataxia, ophthalmoplegia and altered mental state. 6-8 alcoholics, but several other causes have been identified, including total parenteral nutrition (TPN) use. We It may be followed by a state of amnesia and confabulation, known as Korsakoff psychosis 8 which may cause death in present eight cases of WE in patients undergoing allogeneic BMT, where thiamine deficiency was caused by some patients. We present eight cases of iatrogenic WE in patients undergoing allogeneic BMT. These patients a lack of vitamin supplementation during TPN administration. Clinically, WE presented as a severe refractory presented with severe metabolic acidosis, preceded by a 'raspberry tongue' and followed by the subclinical findings metabolic acidosis, preceded by 'raspberry tongue', and ophthalmologic and neurologic dysfunction. The sites of WE. The final diagnosis was made only after autopsy examination. Data presented here represent the largest sermost affected were the periventricular structures and the thalamus, and no mammilary bodies lesions were ies in the literature and should alert physicians to this unusual entity in BMT patients, alerting them to WE as a found. Keywords: Wernicke's encephalopathy; leukemia; allopossible BMT complication. 9,10 geneic bone marrow transplantation; thiamine deficiency Patients and methods BMT is the treatment of choice for a wide variety of hema-A total of 96 allogeneic BMT were undertaken from Janutological, non-hematological, genetic and immune disary 1988 to May 1990. Autopsy materials from the fatal eases. 1 However, aside from the prolonged neutropenia and cases were studied, and eight cases with WE-like neurorisk of opportunistic infection, 2,3 conditioning may cause pathological abnormalities were diagnosed. There were five several side-effects including nausea, vomiting, mucositis females and three males with ages ranging from 14 to 37 and diarrhea, 4 leading to a reduced caloric intake and malyears (median 25 years). Diagnoses were AML in four, absorption. These complications necessitate TPN regimens CML in two and ALL in two patients. Medical records and their attendant complications. Thiamine, also known as were reviewed for conditioning regimen, clinical course vitamin B1, is a water soluble vitamin, formed by a pyrimand neuropathological features. idine and a thiazole ring linked through a methylene group. 5 In the tissues, thiamine is phosphorylated to its most active BMT procedures coenzyme form, thiamin...

The authors retrospectively assess the autopsy findings of central nervous system (CNS) infections in marrow transplant recipients. From July 1987 to June 1998, 845 patients at our institution were submitted to bone marrow transplantation (BMT). The CNS of 180 patients was studied through autopsy and these patients had their medical records reviewed. Twenty-seven (15%) patients presented brain parenchyma infection. Fungi were isolated in approximately 60% of the cases. Mean survival time was 153 days (0-1,264 days) and the majority of the patients died during the first 3 months after BMT (18 cases; 67%). Aspergillus sp. were the most prevalent fungi (approximately 30%), followed by Candida sp. infection (approximately 18%). There was one case of Fusarium sp. infection and two cases of unidentified fungus. All patients with fungal infections had documented involvement at widespread sites. Toxoplasma gondii encephalitis was demonstrated in 8 patents (approximately 30%). Bacterial abscesses were responsible for approximately 11% of the findings. Eleven (41%) of the 27 patients died secondary to cerebral causes. These results show that infectious compromise of the CNS following BMT is a highly fatal event, caused mainly by fungi and T. gondii. Furthermore, they provide a likely guide to the possible causes of brain abscesses following BMT.

Stress-inducible phosphoprotein 1 (STI1), a cochaperone for Hsp90, has been shown to regulate multiple pathways in astrocytes, but its contributions to cellular stress responses are not fully understood. We show that in response to irradiation-mediated DNA damage stress STI1 accumulates in the nucleus of astrocytes. Also, STI1 haploinsufficiency decreases astrocyte survival after irradiation. Using yeast two-hybrid screenings we identified several nuclear proteins as STI1 interactors. Overexpression of one of these interactors, PIAS1, seems to be specifically involved in STI1 nuclear retention and in directing STI1 and Hsp90 to specific sub-nuclear regions. PIAS1 and STI1 co-immunoprecipitate and PIAS1 can function as an E3 SUMO ligase for STI. Using mass spectrometry we identified five SUMOylation sites in STI1. A STI1 mutant lacking these five sites is not SUMOylated, but still accumulates in the nucleus in response to increased expression of PIAS1, suggesting the possibility that a direct interaction with PIAS1 could be responsible for STI1 nuclear retention. To test this possibility, we mapped the interaction sites between PIAS1 and STI1 using yeast-two hybrid assays and surface plasmon resonance and found that a large domain in the N-terminal region of STI1 interacts with high affinity with amino acids 450-480 of PIAS1. Knockdown of PIAS1 in astrocytes impairs the accumulation of nuclear STI1 in response to irradiation. Moreover, a PIAS1 mutant lacking the STI1 binding site is unable to increase STI1 nuclear retention. Interestingly, in human glioblastoma multiforme PIAS1 expression is increased and we found a significant correlation between increased PIAS1 expression and STI1 nuclear localization. These experiments provide evidence that direct interaction between STI1 and PIAS1 is involved in the accumulation of nuclear STI1. This retention mechanism could facilitate nuclear chaperone activity.

BACKGROUND Prognostic factors in oligodendrogliomas are an area of controversy in neuropathology. Although grading and the study of some morphologic variables may be of value as prognostic parameters, the variability of postoperative disease free survival in patients with World Health Organization Grade 2 oligodendroglioma indicates that the biologic behavior of this entity remains unknown. The objective of the current study was to evaluate immunoexpression of the proliferation index (PI), epidermal growth factor receptor (EGFR), and bcl‐2 as prognostic factors in patients with Grade 2 oligodendroglioma. METHODS In a series of 19 cases of pure Grade 2 oligodendroglioma, we assessed the mitotic count, labeling index for MIB‐1 and PCNA, and immunoreactivity for EGFR and bcl‐2 with semiquantitative parameters and compared these with postoperative disease free survival. Statistical analyses using the Cox–Mantel nonparametric test and Spearman correlation coefficient were used to evaluate the data. RESULTS Disease free survival was significantly shorter when the MIB‐1 PI was > 5% (P = 0.0096) and the PCNA PI was > 9% (P = 0.00011) and when mitoses were observed (P = 0.00004). The paired variables also were found to correlate: MIB‐1 versus PCNA (P = 0.04), MIB‐1 versus mitotic count (P = 0.0184), and PCNA versus mitotic count (P = 0.0079). In all cases, there was immunoreactivity for EGFR; conversely, all cases were negative for bcl‐2 in the cells with an oligodendrocyte phenotype. CONCLUSIONS The PI was found to correlate with the postoperative disease free survival in patients with Grade 2 oligodendroglioma; therefore, the authors suggest a possible subdivision of Grade 2 oligodendrogliomas into two groups based on the mitotic count and PI. Cancer 2000;88:862–9. © 2000 American Cancer Society.