Mark L. Rosenblum

Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation.

We tested the hypothesis that transplantation of bone marrow stromal cells (MSCs) into the spinal cord after a contusion injury promotes functional outcome. Rats (n = 31) were subjected to a weight driven implant injury. MSCs or phosphate buffered saline was injected into the spinal cord I week after injury. Sections of tissue were analyzed by double-labeled immunohistochemistry for MSC identification. Functional outcome measurements using the Basso-Beattie-Bresnehan score were performed weekly to 5 weeks post-injury. The data indicate significant improvement in functional outcome in animals treated with MSC transplantation compared to control animals. Scattered cells derived from MSCs expressed neural protein markers. These data suggest that transplantation of MSCs may have a therapeutic role after spinal cord injury.

Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery

Spine radiosurgery causes a rapid dose fall‐off within the spinal cord. The tolerance of partial volume of the spinal cord may determine the extent of clinical application. The study analyzed the partial volume tolerance of the human spinal cord to single fraction radiosurgery.

Trends in the management of bacterial brain abscesses: a review of 102 cases over 17 years

The records of 102 patients with brain abscesses treated over 17 years were analyzed. In recent years, cardiac and pulmonary causes were less frequent, the abscesses were smaller, and fewer patients were in poor neurological condition. There has been no significant change in the type or number of infective organisms or in the number of abscesses during the study period. Computed tomographic brain scanning was the most important factor in reducing the mortality rate from 41% to 4%. The patients were grouped according to the treatment received: excision (n = 46), aspiration (n = 33), or nonsurgical therapy (n = 17). Patients treated nonsurgically were more likely to have smaller abscesses and multiple lesions than were patients in the other two groups. There were no significant differences in the morbidity or mortality rates between treatment groups. Patients whose abscesses were excised had a significantly shorter course of antibiotics than the other patients. Organisms were identified in 85% of the cultures from surgical specimens. The use of preoperative antibiotics was significantly associated with sterile cultures; 30% of patients who received antibiotics preoperatively had sterile cultures, compared with only 4% of patients who did not receive such treatment. The mortality rate among all treated patients (the diagnosis of brain abscess was missed in 6 patients before computed tomographic scanning became routine) was significantly related to the initial neurological grade and the size of the lesion but not to age, sex, or the number of abscesses. Four of the 8 treated patients who died had congenital cyanotic heart disease; an aggressive surgical approach is recommended for such patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Spinal epidural abscess: evaluation of factors influencing outcome.

OBJECTIVE The goal of this study was to critically evaluate the predictive efficacy of various clinical factors in spinal epidural abscess influencing outcome after surgical and/or medical treatment. METHODS A retrospective analysis of 41 cases of spinal epidural abscess treated at Henry Ford Hospital between 1984 and 1992 was performed. RESULTS Thirty patients underwent open surgery and received antibiotic therapy, and 11 patients received medical treatment alone. After a mean follow-up period of 20.9 months (range, 4-45 mo), 24 patients (58.5%) had no or minimal deficits, 9 patients (22%) had severe paresis or plegia and/or bowel/bladder dysfunction, and 8 patients (19.5%) died. Univariate analysis revealed patient age, degree of thecal sac compression, spinal location, surgical findings, and septic presentation to be significantly associated with outcome. In multiple logistic regression analysis, increasing age and degree of thecal sac compression were the only factors with significant independent association with poor outcome (P = 0.01 for both). A simple grading system (Grades 0-III) was developed, with patient age, degree of thecal sac compression, and duration of symptoms as the determining criteria. The incidence of poor outcome for patients with Grade 0 was 0%, compared to 85.7% for patients with Grade III. CONCLUSION We conclude that long-term outcome after treatment of spinal epidural abscess can be predicted with the use of the proposed grading scheme. Surgical drainage plus parenterally administered antibiotics remains the recommended treatment, although medical treatment alone can also be used for certain patients.

Improved management of multiple brain abscesses: a combined surgical and medical approach.

ABSTRACT: BACTERIAL BRAIN ABSCESSES occur in approximately 1500 to 2500 patients each year in the United States. Multiple abscesses have been noted in 10 to 50% of these patients. The goal of this study was to better define the roles of surgery and medical management in patients harboring multiple brain abscesses and to develop an algorithmic approach to the treatment of these complex patients. Between 1976 and 1992, 16 patients with multiple brain abscesses were treated by a single physician (M.L.R.). The ages of the patients ranged from 1.5 to 73 years (median, 47 yr). In all patients, a diagnosis of multiple abscesses was made by computed tomography (15 patients) or magnetic resonance imaging (1 patient) brain scans. The number of abscesses per patient ranged from 2 to 30, and the abscesses were located in all regions of the brain. Thirteen received a combination of antibiotics and surgical drainage, and three received antibiotics only. Surgery was performed on abscesses larger than 2.5 cm or on those situated in critical areas of the brain or causing significant mass effect. Excision and open aspiration via craniotomy and stereotactic aspiration were analyzed on the basis of the location of the lesion and infecting organism. Any abscess that enlarged after 2 weeks of antibiotics or that failed to shrink after 3 to 4 weeks of antibiotics was again aspirated or excised. Forty‐three surgical procedures were performed in 13 patients, and 8 (62%) of the patients operated on required more than one surgical procedure. No significant morbidity was observed in any of the surgical procedures. Antibiotics were administered intravenously for an average of 6 to 8 weeks and were adjusted according to organism type and sensitivity to antibiotics. One patient (6%) died, and the remaining 15 patients had resolution of all abscesses and good neurological recovery within 6 months. On the basis of these results, we propose a combined surgical and medical approach to the treatment of patients with multiple brain abscesses. We recommend the aggressive surgical drainage of all abscesses larger than 2.5 cm in diameter, combined with 6 to 8 weeks of intravenous antibiotics. Biweekly computed tomography or magnetic resonance imaging is necessary to closely monitor patients for evidence of abscess growth or failure to resolve despite antibiotics, prompting another operation. The application of this combined approach should yield cure rates of more than 90% in patients with multiple brain abscesses, a result similar to that expected when treating patients with solitary lesions.

Correlations between magnetic resonance spectroscopy and image-guided histopathology, with special attention to radiation necrosis.

OBJECTIVE The differentiation of tumor recurrence from radiation necrosis in patients with malignant gliomas who have been treated previously remains a challenge. Magnetic resonance imaging, single-photon emission computed tomography, and positron emission tomography cannot provide definitive histopathological insight. Multivoxel proton magnetic resonance spectroscopic imaging (1H MRSI) may be reliable in guiding the clinical management of untreated patients; however, its value in managing previously treated patients remains unclear. METHODS Twenty-seven patients who had been treated previously with surgery, radiotherapy, and chemotherapy and reoperated for clinical and/or radiographic signs that caused suspicion for recurrent disease were studied. Tissues were categorized into four groups: spectroscopically normal, pure tumor, mixed tumor and radiation necrosis, and pure radiation necrosis. Spectral data for choline (Cho), lipid-lactate (Lip-Lac), N-acetylaspartate, and creatine (Cr) were analyzed as Cho/normal Cr (nCr), Lip-Lac/Cho, Lip-Lac/nCr, N-acetylaspartate/Cho, N-acetylaspartate/nCr, and Cho/normal Cho (nCho). Stereotactic biopsies were obtained within 48 hours of 1H MRSI and were directly correlated digitally with 1H MRSI data. Logistic regression analysis was performed on the basis of data obtained from 99 1H MRSI observations to determine whether the 1H MRSI ratios varied according to tissue category. RESULTS 1H MRSI ratios were found to distinguish pure tumor from pure necrosis. The odds of a biopsy’s being pure tumor and having either a Cho/nCr value greater than 1.79 or a Lip-Lac/Cho value less than 0.75 are seven times the odds of that biopsy’s being pure necrosis (odds ratio, 7.00;P = 0.0136). The odds of a biopsy’s being pure necrosis and having either a Cho/nCr value less than 0.89 or a Cho/nCho value less than 0.66 are six times the odds of that biopsy’s being pure tumor (odds ratio, 5.71;P = 0.0329). The odds of a biopsy’s being pure necrosis and having either a Lip-Lac/Cho value greater than 1.36 or a Lip-Lac/nCr value greater than 2.84 are more than five times the odds of the biopsy’s being pure tumor (odds ratio, 5.25;P = 0.0322). In addition, although only marginally significant, Lip-Lac/Cho and Lip-Lac/nCr ratios distinguish pure tumor from pure necrosis. No values suggested that mixed specimens could be distinguished in a statistically significant way from either pure tumor or pure necrosis. CONCLUSION The data that we gathered suggest that metabolite ratios derived on the basis of 1H MRSI spectral patterns do allow reliable differential diagnostic statements to be made when the tissues are composed of either pure tumor or pure necrosis, but the spectral patterns are less definitive when tissues composed of varying degrees of mixed tumor and necrosis are examined.

Nocardial Brain Abscess: Treatment Strategies and Factors Influencing Outcome

The successful management of nocardial brain abscess remains problematic. The authors report 11 cases of nocardial brain abscess treated between 1971 and 1993 and review 120 cases reported since 1950. The clinical findings included focal deficits in 55 patients (42%), nonfocal findings in 36 (27%), and seizures in 39 (30%). Extraneural nocardiae were present in 66% of the cases; pulmonary (38%) and cutaneous/subcutaneous (20%) locations were the most frequent. The abscesses were single in 54% of the patients, multiple in 38%, and of unknown number in 8%. Forty-four of 131 patients (34%) were immunocompromised; since 1975, 18 of 40 immunocompromised patients (45%) were transplant recipients and six (15%) had human immunodeficiency virus. The mortality rate was 24% after initial craniotomy and excision (11/45), 50% after aspiration/drainage (17/34), and 30% after nonoperative therapy (7/23); 29 cases (22%) were diagnosed at autopsy. The mortality rate was 33% in patients with single abscesses and 66% in those with multiple abscesses (P < 0.0003). There was no difference in the mortality rates of immunocompromised and nonimmunocompromised patients treated before computed tomography (CT) was available; since the advent of CT, however, the mortality rate has been significantly higher in immunocompromised patients (55% vs. 20%, P < 0.05). Although the mortality rate for nocardial brain abscesses has dropped almost 50% since the advent of CT, it has remained virtually unchanged in immunocompromised patients and is three times higher than that of other bacterial brain abscesses (30% vs. 10%). The authors recommend image-directed stereotactic aspiration for diagnosis; however, craniotomy and total excision are necessary in most cases, because nocardial abscesses are usually multiloculated. Patients with minimal neurological deficits or small abscesses may be treated initially with antibiotics alone. Sulfonamides, alone or in combination with trimethoprim, are most effective and should be continued for at least 1 year. Minocycline, imipenem, or aminoglycoside in combination with a third-generation cephalosporin may be used with reasonably good success as second-line agents in cases of allergy or nonresponsiveness to sulfa agents.

The 9L rat brain tumor: Description and application of an animal model

SummaryAnimal models allow determination of tumor response to anticancer agents under various experimental conditions. The chemically induced 9L rat brain tumor has been developed as both in vivo and in vitro models. Animal survival, clonogenic cell survival, and tumor growth delay provide means to measure the effectiveness of treatment modalities in this tumor model. Monolayer cultures, multicellular spheroid cultures, brain tumors, and flank tumors have been used to study the influence of different biological entities of the 9L model on the response to treatment with radiation and/or BCNU (1,3- bis (2-chloroethyl)-1-nitrosourea).ZusammenfassungDie Behandlung von Tumoren unterliegt den Einflüssen verschiedener Umgebungsfaktoren, die an Tiertumormodellen erforscht werden konnten. Für den chemisch induzierten 9L Hirntumor der Ratte wurden in vivo- and in vitro-Systeme entwickelt. Überlebensraten von Tieren oder clonogenen Zellen und Wachstumsverzögerung von Tumoren können gemessen werden, um die Wirksamkeit verschiedener Tumorbehandlungen zu bestimmen. Monolayer- und Spheroidkulturen sowie intracerebral oder subcutan wachsende Tumoren wurden verwendet, um den Einfluß unterschiedlicher Tumorgestalt auf die Wirkung von Strahlen und/oder BCNU (1,3- bis (2-chloroethyl)-1-nitrosourea) bei 9L Zellen zu demonstrieren.

Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas.

Genetic aberrations, such as gene amplification, deletions, and loss of heterozygosity, are hallmarks of cancer and are thought to be major contributors to the neoplastic process. Established cancer cell lines have been the primary in vitro and in vivo models for cancer for more than 2 decades; however, few such cell lines have been extensively characterized at the genomic level. Here, we present a high-resolution genome-wide chromosomal alteration and gene expression analyses of five of the most commonly used glioma cell lines and compare the findings with those observed in 83 primary human gliomas. Although genomic alterations known to occur in primary tumors were identified in the cell lines, we also observed several novel recurrent aberrations in the glioma cell lines that are not frequently represented in primary tumors. Additionally, a global gene expression cluster distinct from primary tumors was identified in the glioma cell lines. Our results indicate that established cell lines are generally a poor representation of primary tumor biology, presenting a host of genomic and gene expression changes not observed in primary tissues, although some discrete features of glioma biology were conserved in the established cell lines. Refined maps of genetic alterations and transcriptional divergence from the original tumor type, such as the one presented here, may help serve as a guideline for a more biologically rational and clinically relevant selection of the most appropriate glioma model for a given experiment. (Mol Cancer Res 2008;6(1):21–30)

Associations among Magnetic Resonance Spectroscopy, Apparent Diffusion Coefficients, and Image-guided Histopathology with Special Attention to Radiation Necrosis

OBJECTIVE:In patients with malignant glioma previously treated with surgery, radiation, and chemotherapy, clinical and radiographic signs of recurrent disease often require differentiation between radiation necrosis and recurrent tumor. Published work suggests that although magnetic resonance spectroscopy (MRS) can reliably differentiate pure tumor, pure necrosis, and spectroscopically normal tissues, it may not be particularly helpful because most patients have mixed histological findings comprised of necrosis and tumor. To improve our clinical ability to discriminate among these histological entities, we have analyzed MRS in conjunction with apparent diffusion coefficient (ADC) sequences derived from magnetic resonance imaging. METHODS:In 18 patients, spectroscopic and diffusion-weighted images were obtained before surgery for suspected recurrent neoplastic disease. Spectral data for pure tumor, pure necrosis, and mixed tumor and necrosis were derived from 65 spectroscopic observations in patients with previously treated gliomas (n = 16) and metastatic tumors (n = 2). Spectral data for choline (Cho), N-acetylaspartate (NAA), creatine (Cr), and lipid-lactate were analyzed separately and in conjunction with ADCs in all patients (15 observations of pure tumor, 33 observations of pure necrosis, and 13 observations of mixed tumor and necrosis). Histological specimens were obtained stereotactically at the time of surgery (<48 h after image acquisition) for recurrent disease and digitally co-registered with MRS data. RESULTS:ADC values for pure tumor, pure necrosis, and mixed tumor and necrosis were 1.30, 1.60, and 1.42, respectively. Cho/NAA less than 0.20, NAA/normal Cr greater than 1.56, and NAA/Cho greater than 1.32 increase the odds that a tissue biopsy will be pure necrosis versus mixed tumor and necrosis. Although various values of all MRS ratios analyzed may provide positive correlations for histopathological differentiation of tissue between that of pure tumor and that of pure necrosis, the addition of ADC values to only NAA/Cho and NAA/normal Cr increases the odds of correct differentiation between pure tumor and pure necrosis. The addition of ADC values does not provide additional information beyond that of MRS in distinguishing specimens of mixed tumor and necrosis from either pure tumor or pure necrosis. CONCLUSION:It has been demonstrated that MRS ratio analysis may allow for the clinical discrimination between specimens of pure tumor and pure necrosis, and the addition of ADC data into this analysis may enhance this specific differentiation. However, although a trend toward correlation between ADC values and the various histopathological features was noted, the direct addition of ADC data does not seem to allow further discrimination, beyond that provided by MRS, among specimens of mixed tumor and necrosis and either pure tumor or pure necrosis.