Propionibacterium as a cause of postneurosurgical infection in patients with dural allografts: report of three cases.

OBJECTIVE AND IMPORTANCE: Although Propionibacterium acnes is a common inhabitant of human skin, it is an uncommon pathogen in postoperative infections. We report three cases of postoperative wound infection/osteomyelitis caused by P. acnes. CLINICAL PRESENTATION: Three patients underwent craniotomy for a supratentorial meningioma and had a dural allograft at the time of closure. The patients presented several weeks after surgery with clinical evidence of a wound infection. INTERVENTION: All patients were diagnosed with P. acnes infection and treated for this pathogen with appropriate antibiotics. The bone flap was removed in two patients. After antibiotic therapy, all patients demonstrated no further evidence of infection. CONCLUSION: To our knowledge, this is the first published report of P. acnes infection in patients with a dural substitute. The source of infection cannot be confidently ascertained; however, two patients had strains of P. acnes from one brand of graft, which were indistinguishable by pulsed field gel electrophoresis typing.

Tc-99m LL-2 Fab' monoclonal antibody imaging in acquired immune deficiency syndrome-related lymphoma.

BACKGROUND: Both systemic and primary central nervous system (CNS) non-Hodgkin's lymphomas (NHL) occur in people with acquired immune deficiency syndrome (AIDS). The radiographic manifestations may be similar to other neoplasms and opportunistic infections that are also found frequently in AIDS. Furthermore, these diseases may coexist with NHL in the AIDS patient. METHODS: To evaluate the use of Tc-99m Lymphoscan (the Fab' fragment of the anti-CD-22 antibody LL-2; Immunomedics, Inc., Morris Plains, NJ) in patients with suspected AIDS lymphoma, we studied 7 patients with 35 sites of suspected disease. Six had CNS lesions suspicious for parenchymal brain lymphoma. Each patient underwent planar and single photon emission computed tomography imaging at 3-5 and 18-24 hours after administration of Lymphoscan. Scintigraphic results were compared with results of conventional diagnostic modalities. RESULTS: Overall, the sensitivity of Lymphoscan was 92% and the specificity was 86%. In brain lesions, there was 100% sensitivity and 100% specificity. Lymphoscan also had 100% sensitivity for sites of lymphomatous lymphadenopathy and for liver involvement. Although less specific in extracranial sites, Lymphoscan was correctly negative in sites of coexisting adenocarcinoma and pneumonia. Two patients had both parenchymal CNS and systemic lymphoma proven by biopsy. CONCLUSIONS: Lymphoscan appears to be a sensitive and specific method for diagnosing CNS lymphoma in AIDS patients. Although slightly less specific in extracranial sites, it may be helpful in differentiating lymphoma from other etiologies in these patients at risk for multiple neoplasms and opportunistic infections.

Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma.

BACKGROUND: The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. METHODS: Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. RESULTS: The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 +/- 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 +/- 3.7 weeks), with 1/18 alive at 1 year (> 6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. CONCLUSIONS: Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted.

Modern management of spinal tuberculosis.

The resurgence of pulmonary tuberculosis in the United States has been paralleled by a concomitant rise in tuberculosis of the spine (Pott's disease). The appearance of drug-resistant strains of tuberculosis, infection in large numbers of immunocompromised hosts, newer imaging modalities, and the development of more effective spinal reconstruction techniques have raised important issues regarding the management of Pott's disease. In spite of this, there has been little published recently on the modern management of Pott's disease in developed countries. We report our experience with the management of 20 patients with Pott's disease in the past 5 years, 16 of whom were admitted during the last 18 months of this retrospective study. The mean patient age was 49 years. Sixteen (80%) were men. Nineteen (95%) had a positive tuberculin skin test, and 13 (65%) had pulmonary tuberculosis. Symptoms consisted of spinal pain, weakness, sensory complaints, and flank mass in order of decreasing frequency. Ten patients were neurologically intact; the remainder had motor deficits of variable severity. The thoracic spine was involved in 13 patients, the lumbar spine was involved in 4, the cervical spine was involved in 2, and the thoracolumbar spine was involved in 1. Spinal deformity was present in 11 patients, spinal epidural compression was present in 13, and a paraspinal mass was present in 18. Operative indications included motor deficits, spinal deformity, nondiagnostic computer tomographic-guided needle biopsy, and noncompliance with, or lack of, response to medical therapy. Eleven patients underwent operations. Six patients had vertebrectomy and bone grafting with posterior instrumentation when indicated; three had laminectomy, debridement, and abscess drainage; one had laminectomy and posterior instrumentation; and one had paraspinal abscess drainage. Two patients have died; the remainder have been monitored for at least 1 year and are neurologically improved or normal without residual infection. The average angulation decreased from 31 to 24 degrees by the follow-up examination. In selected patients, early operative treatment with instrumentation, when indicated, minimizes neurological deterioration and spinal deformity, allows early ambulation, and results in excellent neurological outcome.

Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors.

To characterize some of the genetic events underlying the development of glioblastoma multiforme, the authors analyzed 65 astrocytic tumors (seven pilocytic astrocytomas, eight astrocytomas, 16 anaplastic astrocytomas, and 34 glioblastomas multiforme) for loss of heterozygosity for chromosome 17p, loss of heterozygosity for chromosomes 10p and 10q, amplification of the epidermal growth factor receptor (EGFR) gene, and amplification of the oncogenes N-myc, c-myc, and N-ras using Southern blot analysis. Alterations of the p53 gene (positive immunostaining for p53 protein in tumors with or without p53 gene mutations) in these 65 tumors were analyzed previously. None of the 65 tumors showed amplification or rearrangement of N-myc, c-myc, or N-ras oncogenes. The molecular analysis presented here demonstrates distinct variants of astrocytic tumors, with at least three genetic pathways leading to glioblastoma multiforme. One pathway was characterized by 43 astrocytomas with alterations in p53. Glioblastomas with p53 alterations may represent tumors that progress from lower-grade astrocytomas. This variant was more likely to show loss of chromosome 17p than tumors without p53 alterations (p < 0.04). Seventy-five percent of tumors with loss of one 17p allele demonstrated mutations in the p53 gene. Loss of chromosome 10 was associated with progression from anaplastic astrocytoma (13%) to glioblastoma (38%) (p < 0.04). Amplification of the EGFR gene was a rare (7%) but late event in tumor progression (p < 0.03). A second pathway was characterized by six astrocytomas without p53 alterations and may represent clinically de novo high-grade tumors. These tumors were more likely to show amplification of the EGFR gene (83%) than tumors with p53 alterations. Sixty percent of tumors with EGFR amplification also showed loss of chromosome 10; loss of chromosome 17p was infrequent in this variant. One or more alternative pathways were characterized by 16 astrocytomas without p53 alterations and with none of the genetic changes analyzed in this study. Glioblastomas are a heterogeneous group of tumors that may arise via multiple genetic pathways.

High frequency of p53 protein accumulation without p53 gene mutation in human juvenile pilocytic, low grade and anaplastic astrocytomas.

We analysed 31 non-glioblastoma astrocytomas for alterations in p53 protein expression and for mutations in the p53 gene. Immunohistochemistry detected p53 protein accumulation in 71% (five of seven) of juvenile pilocytic astrocytomas (WHO grade I), 63% (five of eight) of astrocytomas (WHO grade II), and 63% (10 of 16) of anaplastic astrocytomas (WHO grade III). The single strand conformation polymorphism (SSCP) assay of exons 2-11 of the p53 gene and direct DNA sequencing identified p53 mutations in 14% (one of seven) of grade I, 25% (two of eight) of grade II, and 19% (three of 16) of grade III astrocytomas. This is the first report of a p53 mutation in grade I juvenile pilocytic astrocytomas. Immunohistochemistry and SSCP analyses gave concordant results in 55% (17 of the 31) of the tumors. A total of 14 tumors, 60-80% within each grade, showed p53 protein accumulation in the absence of detectable mutations of the p53 gene. No mdm-2 gene amplification was found in these tumors. The similar frequency of p53 alterations in tumors of grades I-III suggests that the p53 gene plays a significant role early in the formation of astrocytomas rather than late in tumor progression to higher grade. The data suggest that mechanisms other than p53 gene inactivation by mutation or mdm-2 complex formation result in the accumulation of P53 protein in > 70% of non-glioblastoma astrocytomas.

A correlative study of p53 protein alteration and p53 gene mutation in glioblastoma multiforme.

The p53 tumor suppressor gene is frequently mutated in glioblastomas. Mutations within the p53 gene often result in aberrant expression of the p53 protein leading to protein accumulation within the nucleus of the cells which can be detected by immunochemistry. Many studies have correlated alterations of p53 protein expression with p53 gene mutations. Positive staining of tumor cells for p53 protein has been widely assumed, perhaps incorrectly, to signify the presence of p53 gene mutations. This study compared the immunostaining patterns for p53 protein in 37 glioblastomas with the molecular genetic data obtained by the single strand conformation polymorphism assay. p53 gene mutations were detected in 46% (17 of 37) of glioblastomas, while 65% (24 of 37) of glioblastomas were positive for protein accumulation by immunohistochemistry. Although 30 of 37 glioblastomas analyzed showed concordance for p53 protein expression and p53 gene mutations, a subset of seven glioblastomas showed discordant accumulation of the p53 protein in the absence of any detectable p53 gene mutations. The mdm-2 gene was assessed in 17 glioblastomas for gene rearrangements or amplification, but none were found. This result suggests that a mechanism other than p53 gene mutation can result in altered p53 protein expression.

p53 mutations in human malignant gliomas: comparison of loss of heterozygosity with mutation frequency.

Mutations in the p53 gene were analyzed in 40 gliomas using the single strand conformation polymorphism assay together with restriction fragment length polymorphism analysis to assess loss of heterozygosity for 17p alleles in the same tumors. Mutations occurred in 40% of the gliomas and were found in exons 4-8 of the p53 gene. G:C to T:A transversions, which occur in high frequency in some lung (greater than 50%), liver (greater than 80%), breast (30%), and esophageal cancers (25%), were noted in greater than 25% of the gliomas studied here. These transversions were clustered in exon 5 from codons 156 to 168, a region of the p53 gene not previously associated with a high frequency of mutation, and may represent a new hot spot for mutations in certain cancers. The majority of gliomas (27 of 38) analyzed here retained both 17p alleles. The frequency of p53 mutations was 37% in this group of tumors and increased to 64% in tumors with one 17p allele. Allelic loss for chromosome 17p occurred in 4 of 11 gliomas independently of mutations in the p53 gene. Absence of p53 mutations in 36% of the tumors with one 17p allele suggests that a tumor suppressor gene other than p53 may be located on chromosome 17p and involved in progression to malignancy of some gliomas.

c-src structure in human cancers with elevated pp60c-src activity.

We used RNAase protection and restriction fragment length polymorphism assays to detect activating mutations of c-src in a spectrum of human tumours. No mutations were detected at codons 98, 381, 444, and 530. We conclude that mutational activation is not the mechanism of enhancement of pp60c-src-specific kinase activity found in a number of human cancer types.

Synaptophysin: a sensitive and specific marker for ganglion cells in central nervous system neoplasms.

Synaptophysin, a 38-kilodalton glycoprotein found in synaptic vesicle membranes, has been shown to be a sensitive marker of neuroendocrine differentiation in non-central nervous system (CNS) tumors. We analyzed the patterns of synaptophysin immunoreactivity in CNS neoplasms in comparison with various normal CNS sites in biopsies. Normal gray matter structures all showed a diffuse punctate granular pattern of neuropil staining without staining of neuronal cell bodies. In contrast, neoplastic ganglion cells in 18 of 18 gangliogliomas/gangliocytomas showed intense immunoreactivity outlining the borders of the cell bodies. Focal staining was also seen in five of 16 primitive neuroectodermal tumors and in one of three central neurocytomas, but these tumors had a finely granular neuropil pattern of immunoreactivity more like that of normal gray matter than like that of the gangliogliomas. All 35 examples of pure gliomas of various types showed no immunoreactivity. Our data highlight synaptophysin as a sensitive and specific marker of both neuronal lineage and neoplastic character in gangliogliomas.

Synaptophysin: a sensitive and specific marker for ganglion cells in central nervous system neoplasms.

Synaptophysin, a 38-kilodalton glycoprotein found in synaptic vesicle membranes, has been shown to be a sensitive marker of neuroendocrine differentiation in non-central nervous system (CNS) tumors. We analyzed the patterns of synaptophysin immunoreactivity in CNS neoplasms in comparison with various normal CNS sites in biopsies. Normal gray matter structures all showed a diffuse punctate granular pattern of neuropil staining without staining of neuronal cell bodies. In contrast, neoplastic ganglion cells in 18 of 18 gangliogliomas/gangliocytomas showed intense immunoreactivity outlinging the borders of the cell bodies. Focal staining was also seen in five of 16 primitive neuroectodermal tumors and in one of three central neurocytomas, but these tumors had a finely granular neuropil pattern of immunoreactivity more like that of normal gray matter than like that of the gangliogliomas. All 35 examples of pure gliomas of various types showed no immunoreactivity. Our data highlight synaptophysin as a sensitive and specific marker of both neuronal lineage and neoplastic character in gangliogliomas.

Adrenal medullary transplants as a treatment for advanced Parkinson's disease.

Open autologous adrenal medullary to caudate nucleus transplantation was performed in 12 patients with advanced Parkinson's disease (PD). Ten of these patients had diurnal response fluctuations including "wearing off" and "on/off" phenomena. All of the patients were no longer satisfactorily responding to levodopa/carbidopa and dopamine agonists. The mean age of the patients was 55.1 years (range 37-65 yrs); mean duration of PD was 11.7 years (range 4-40 yrs); mean stage "on" was 3.3 (range 2-4); mean stage "off" was 4.8 (range 4-5). Mean duration of follow up from surgery was 10.4 months (range 2-17 months). Three patients improved dramatically with major changes in their lifestyle. The course of improvement in these 3 patients was different in each, implying that different mechanisms were responsible for the improvement. One of the patients died unexpectedly. In this patient, there were no surviving adrenal cells. Three patients improved moderately. Patients reported that they were "on" longer and had to take medication less often and were less dependent on individual doses of levodopa/carbidopa. The improvement has been sustained in two patients. However, in one of these patients there had to be frequent changes in scheduling to maintain the improvement. Two patients after technically successful implants did not improve. One of these patients subsequently died. In this patient there were a few surviving adrenal medullary cells. Four patients suffered major complications. One patient had a cerebral infarction and two had cerebral hemorrhages. One of these patients has shown a good recovery. One patient with autonomic insufficiency had a cardiac arrest with cerebral anoxia one week after surgery. This patient has shown a partial recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical analysis of caudate nucleus biopsy samples from parkinsonian patients.

Biochemical analyses of caudate nucleus biopsy samples from patients with Parkinson's disease undergoing autologous adrenal transplantation were performed. Activity of the dopamine biosynthetic enzyme tyrosine hydroxylase, and concentrations of dopamine and its primary metabolite homovanillic acid were significantly greater than anticipated on the basis of previously published postmortem values. These data suggest that postmortem changes in various biochemical parameters of dopamine function are more rapid than has been generally appreciated. Further analysis of striatal biopsy samples may reveal predictive relationships between striatal indices of dopamine function and therapeutic response to adrenal transplantation.

Posterior stabilization of cervical spine fractures and subluxations using plates and screws.

Posterior stabilization of cervical spine fractures and subluxations with metal plates and screws is commonly used in Europe, but has rarely been employed by neurosurgeons in North America, where stabilization has usually been achieved with wires supplemented by bone grafts or acrylic. The limitations of the more commonly used stabilization techniques include the failure to achieve rotational stability, the necessity for intact laminae, and the requirement for bone grafting. We therefore examined the efficacy of posterior cervical plating in 19 patients who had posttraumatic instability of the cervical spine between C3 and C7 without residual spinal cord compression and 1 patient who had a subluxation as a result of osteomyelitis. Two patients had no neurological deficit, 4 had partial deficits, and 14 had no neurological function below the level of injury. Operation was performed after patients were medically stable and maximal reduction of fractures was achieved (usually within 48 hours). The plates are made of vitallium and contain two or three holes 13 mm apart through which 16-mm screws are placed bilaterally into the center of the articular masses of two or three adjacent vertebrae to stabilize one or two motion segments. Bone grafting is not performed. Patients are mobilized on the day after operation in a Philadelphia collar, which is worn for 3 months. Fourteen patients had stabilization of one motion segment and 6 had stabilization over two motion segments. The mean follow-up is 9.2 months. In a single patient with ankylosing spondylitis, plate fixation failed when screws pulled out. No patient experienced neurological deterioration as a result of the operative procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytologic findings in progressive multifocal leukoencephalopathy. Report of two cases.

Cytologic preparations from two cases of progressive multifocal leukoencephalopathy (PML) were obtained by stereotactically guided needle biopsies using computerized tomograms of the brain. Case 1 was a 32-year-old man with an acquired immunodeficiency syndrome-related complex. Case 2 was a 71-year-old man with chronic lymphocytic leukemia. Smears showed moderate cellularity, consisting of moderately to markedly atypical cells with enlarged hyperchromatic nuclei. The chromatin pattern showed smudging, with or without clumping, similar in pattern to the human polyomavirus-infected "decoy" cells seen in urine cytology. Nuclei were predominantly round to oval, smoothly contoured and often stripped of cytoplasm. Occasional bizarre lobulated or multinucleated forms were seen. Some atypical cells had abundant cytoplasm exhibiting stellate projections. Histologic sections of the biopsy material confirmed the diagnosis in each case. In both cases, electron microscopy demonstrated intranuclear polyoma-type virus particles. The present findings suggest that PML should be considered in the differential diagnosis of marked cytologic atypia in brain aspirates from immunocompromised patients.

Supraophthalmic intracarotid infusion of BCNU for malignant glioma.

We treated five patients with 11 supraophthalmic infusions of BCNU at 200 mg/m2 every 2 months. All three patients with residual tumors showed marked CT response after one infusion. Two patients with bilateral tumors had no response on the contralateral side. All four evaluable cases showed evidence of BCNU neurotoxicity. CT findings superficially resembled tumor recurrence, but white matter changes, nonspecific gyral enhancement, and delayed calcification were more indicative of neurotoxicity. There were no procedure-related complications. One autopsy suggested that direct parenchymal damage might be responsible for delayed neurotoxicity. Supraophthalmic BCNU infusion, at this dosage, is too toxic for cerebral tissue.

An unusual CT presentation of cerebral toxoplasmosis.

Intracranial opportunistic infections have been widely reported in patients with acquired immune deficiency syndrome (AIDS). We report an unusual presentation of Toxoplasma gondii infection in a patient with AIDS.