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Biomedical subjects

M Rosenblum

Publications and source records attributed to M Rosenblum.

At least 37 records · Page 2Linked to original sources
PubMed1995

AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations.

To evaluate the presence and distribution of central nervous system infection by human immunodeficiency virus type 1 (HIV-1), we used immunohistochemical methods to map the HIV-1 p24 core protein in the brains of 55 autopsied patients with acquired immunodeficiency syndrome (AIDS). In a subset of 40 of these patients who had undergone antemortem neurological evaluation of the AIDS dementia complex (ADC), we analyzed the relation between the severities of the viral infection and clinical dysfunction. Viral antigen was detected in macrophages and cells with morphological and immunohistochemical characteristics of microglia as well as multinucleated cells. The distribution of antigen-positive cells preferentially involved certain deep brain structures, especially the globus pallidus, other basal ganglia nuclei, and the central white matter. Overall, the presence and frequency of infected cells were highly correlated with the histological findings of multinucleated-cell encephalitis and in general with the clinical ADC stage. However, infection was often more limited than might be "anticipated" from the severity of patients' clinical dysfunction: Only 61% of patients with at least ADC stage 1 had detectable antigen and of these only approximately 30% of the brain sections were antigen positive. These results suggest a pathogenetic model of ADC where virus- or cell-coded toxins amplify the effect of limited brain infection.

AIDS Dementia Complex↗
PubMed1995

The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation.

A whole blood hemostasis system (Hepcon) provides both activated clotting time and accurate whole blood heparin concentration measurements via an automated protamine titration method. This study was designed to prospectively evaluate the impact of heparin and protamine administration using this system on the incidence and treatment of bleeding after cardiopulmonary bypass. Two hundred fifty-four patients requiring cardiopulmonary bypass were enrolled in this prospective study over a 7-month period. Patients treated with antifibrinolytic agents (aprotinin, epsilon-aminocaproic or tranexamic acid) were excluded. Patients were randomly assigned to either a control (n = 127) or intervention (n = 127) group. For control patients, the anticoagulation protocol consisted of an initial fixed dose of 250 U/kg of heparin, and additional 5000 U heparin doses were administered if the activated clotting time was less than 480 seconds. Heparin was neutralized with an initial fixed dose of protamine (0.8 mg protamine per milligram total heparin). For the intervention group, an initial dose of heparin was based on an automated heparin dose-response assay. Additional heparin doses were administered if the heparin concentration was less than the reference concentration or for an activated clotting time less than 480 seconds. The protamine dose was based on the residual heparin concentration. Treatment of excessive bleeding after cardiopulmonary bypass was based on an algorithm using point-of-care testing with whole blood prothrombin time, activated partial thromboplastin time, heparinase activated clotting time, and platelet count. No differences between the two treatment groups were identified in reference to demographic factors, preoperative anticoagulant medications, preoperative coagulation data, number of reoperations, or combined procedures and duration of cardiopulmonary bypass. Indirect evidence for coagulation factor consumption was demonstrated in control patients by more prolonged whole blood prothrombin time and activated partial thromboplastin time values after cardiopulmonary bypass when compared with values obtained in the intervention group. Patients in the intervention cohort received greater doses of heparin (intervention: 612 +/- 147, control: 462 +/- 114 U/kg, p < 0.0001) and had lower protamine to heparin ratios (intervention: 0.70 +/- 0.64, control: 0.94 +/- 0.21, p = 0.0001) compared with control patients. Patients in the intervention cohort received significantly fewer platelet (intervention: 1.7 +/- 3.6 U, control: 3.7 +/- 6.7 U, p = 0.003), plasma (intervention: 0.4 +/- 1.3 U, control: 1.4 +/- 2.5 U, p = 0.0001), and cryoprecipitate units (intervention: 0.0 +/- 0.0 U, control: 0.2 +/- 1.2 U, p = 0.04) during the perioperative interval than control patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1995

Activation of the Bezold-Jarisch reflex in the sitting position for shoulder arthroscopy using interscalene block.

A retrospective analysis of 116 patients who underwent shoulder arthroscopy in the sitting position with interscalene block (ISB) revealed 20 patients who experienced potentially dangerous vasovagal events characterized by sudden severe hypotension and bradycardia (Group 1). The event occurred 61 +/- 18 min after the block placement. Ninety-six patients (Group 2) did not experience a vasovagal event. Of the patients in Group 2, 18 received beta-adrenergic blockers for increasing heart rate and/or arterial blood pressure (Group 2B) while 78 did not (Group 2A). The number receiving beta-adrenergic blockers was significantly greater than in Group 1 (18/96 vs 0/20, P < 0.05). There were no significant demographic or baseline hemodynamic differences between groups, but the beta-adrenergic blocker and vagal groups showed significantly greater intraoperative peak heart rates (P < 0.05). All patients received epinephrine in their local anesthetic for ISB, incision sites, and articular irrigating solution. Total and weight-corrected epinephrine doses differed significantly between groups (lowest in Group 2A, P < 0.01). Activation of the Bezold-Jarisch reflex, induced by increased circulating epinephrine levels and the sitting position, is the postulated mechanism.

Adult↗
PubMed1995

Primary amyloidoma of the brain: CT and MR presentation.

We present CT and MR imaging studies of a histologically proved case of a primary intraaxial amyloidoma of the brain. Noncontrast CT and T1-weighted MR images revealed increased density and hyperintensity respectively of amyloid tissue. There was mixed intensity on proton-density and T2-weighted sequences, and marked contrast enhancement was demonstrated on both modalities.

Amyloidosis↗
PubMed1995

The use of oral transmucosal fentanyl citrate for painful procedures in children.

OBJECTIVE: To investigate the efficacy and safety of oral transmucosal fentanyl (OTFC) in providing analgesia and sedation for painful diagnostic procedures in children. DESIGN: Randomized, placebo-controlled clinical trial. METHOD: Forty-eight children referred to the University Connecticut Division of Pediatric Hematology/Oncology for bone marrow aspiration or lumbar puncture were randomized to receive either OTFC (15 to 20 micrograms/kg) or a placebo lollipop. Thirty minutes after administration, the procedure was begun. An anesthesiologist monitored the child's heart rate, blood pressure, and oxygen saturation every 10 minutes. At the conclusion of the procedure, the nurse, the child's parent, and all children over 8 years of age were asked to rate the pain associated with the procedure using a 1 to 10 visual analogue scale. Young children (less than 8) used a modified scale, the Oucher, yielding a 0 to 5 score. RESULTS: Significant differences in pain ratings between the OTFC and placebo groups were noted on the pain scores of the parents (P = .005), nurses (P = .001), younger children (P = .006), and older children (P = .013), and median pain scores in the OTFC group were reduced to tolerable levels. Vomiting (P = .003) and itching (P = .001) were more common in the OTFC group, but no clinically significant vital sign deviations occurred. CONCLUSION: OTFC is safe and effective for use in relieving the pain of pediatric procedures, but frequency of vomiting may restrict its clinical usefulness.

Administration, Buccal↗
PubMed1994

Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia.

Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days. In view of these findings, we conducted an escalating dose trial of 2-CdA in adult patients with relapsed or resistant AML. Thirty-six patients who had received extensive prior therapy were treated at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5 days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of 36 cases; however, bone marrow hypoplasia was seen only at daily dose levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1 at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these responses persisted for 3, 2, and 3 months, respectively. Although prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for 5 days, the most important adverse effect was the development of a sensorimotor peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at the 21 mg/m2/d level. Pathologically, this process was characterized by axonal degeneration and secondary demyelination. Other side effects included reactivation of a posttransplant Epstein-Barr virus-related lymphoma in 1 patient and tumor lysis syndrome. We conclude that the maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days) in approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neuropathic disorder. We confirm that this drug has definite activity in AML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This agent deserves further evaluation in patients with both AML and acute lymphoblastic leukemia at these higher doses and perhaps as part of a preparative regimen for patients undergoing bone marrow transplantation.

Adolescent↗
PubMed1994

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma.

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.

Adult↗
PubMed1994

Development of a non-selecting, non-perturbing method to study human brain tumor cell invasion in murine brain.

The infiltrative nature of glial and some meningeal neoplasms is responsible for the failure of surgical removal and high recurrence rate of these tumors. Modeling of this process in vitro and in vivo will lead to a better understanding of the pathophysiology of this process and identify targets for novel therapy directed towards this phenotype. We present the results of the development and refinement of two model systems of tumor invasion: one in vitro barrier assay using the basement membrane extract Matrigel, and one in vivo where molecular detection of tumor cells allows single cell discrimination by in situ hybridization histochemistry. These techniques have strong correlations which validate their utility as measures of nervous system tumor invasion.

Animals↗
PubMed1993

Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers.

DAB486IL-2, a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with interleukin-2 (IL-2), has displayed significant activity in patients with chemotherapy refractory hematological cancers. To further investigate the safety and antitumor effect of this agent, we conducted a single arm, dose escalation study of a 90-min infusion of DAB486IL-2 daily for 5 days. Patients with cancers of a histology previously reported to express the p55 component of the IL-2 receptor and who could not receive potentially more effective therapy were eligible for enrollment. Fifteen men and 8 women with a median age of 49 years were given a total of 51 courses of DAB486IL-2. The maximum tolerated dose was 0.3 mg/kg/day defined by renal insufficiency associated with hemolysis and thrombocytopenia. The clearance of DAB486IL-2 from serum fit a one-compartment model with a half-life of 11.5 +/- 4.3 (SD) min at the 0.2-mg/kg dose. Two patients sustained a partial response and 4 patients had tumor reduction not qualifying for an objective response. No tumors that were negative for expression of the p55 subunit of the receptor responded to DAB486IL-2 treatment. Reduction in size occurred in 2 tumors in which p55 expression was unknown and 4 patients with tumors that were known to be p55 positive. Dosing determined by specific activity rather than mass also appeared to be an important determinant of response. This study suggests that the presence of p55 expression on tumor cells is necessary, but alone may not be sufficient to achieve a tumor response. The correlation of additional variables such as specific activity of DAB486IL-2 and tumor expression of the p75 subunit of the IL-2 receptor and receptor function will also require further study.

Adult↗
PubMed1993

Treatment of spinal epidural neuroblastoma xenografts in rats using anti-GD2 monoclonal antibody 3F8.

Epidural neuroblastoma xenografts in nude rats causing paraparesis were treated with intravenous injection of an anti-GD2 monoclonal antibody 3F8. Metastatic or primary epidural tumors in humans cause rapid neurologic compromise. Treatment is often unsatisfactory. An animal model was established to study antibody targeted therapy of epidural tumor. Human neuroblastoma was xenotransplanted into the thoracic epidural space of nude rats. When paraparesis developed, animals were treated intravenously with an anti-GD2 monoclonal antibody, 3F8, either alone or radiolabeled with 131Iodine. Improvement in neurologic function occurred in 2 of 20 (10%) animals receiving no treatment or control antibody, 14 of 17 (82%) animals receiving 3F8 alone and all 9 animals receiving 131I-3F8 (p < 0.0001 for 3F8 or 131I-3F8 vs. control). Six animals treated with 3F8 alone recovered normal neurologic function and remained well until sacrifice 10 days later. Four animals treated with 3F8 alone had no tumor evident on pathologic examination. The percent injected dose of 131I-3F8/g tumor in 5 samples ranged from 0.73% to 3.8%. These observations demonstrate that neoplastic epidural compression of the spinal cord in the rat can be treated successfully with intravenous unmodified monoclonal antibody and that signs of neurologic dysfunction can be reversed. The potential of this approach in treating patients with epidural tumors and other neoplasms, especially those that are not sensitive to chemotherapy or radiotherapy, deserves to be explored.

Animals↗
PubMed1993

Neoplastic meningitis as the presentation of occult primitive neuroectodermal tumors.

Seven children and young adults initially presented with subacute meningitis and/or increased intracranial pressure. The diagnosis of neoplastic meningitis secondary to a primitive neuroectodermal neoplasm was delayed by the absence of an obvious primary tumor. The neuroradiologic appearance was that of a basimeningeal infiltrative process, complicated by communicating hydrocephalus or "pseudotumor cerebri." Myelography was important in the diagnosis of disseminated meningeal malignancy in four cases. Cerebrospinal fluid cytologic diagnosis was insensitive but ultimately confirmed in five cases. All seven patients experienced progressive disease despite neuraxis radiotherapy and intensive chemotherapy; six have died. Systemic dissemination to bone and/or peritoneum occurred in three patients while on therapy. In two, a primary parenchymal brain or spinal cord tumor could not be identified at postmortem examination. The presentation of a primitive neuroectodermal tumor as subacute meningitis without an evident primary tumor heralds an aggressive and refractory neoplasm.

Adolescent↗
PubMed1993

Nerve stimulator polarity and brachial plexus block.

To determine whether needle polarity significantly affects nerve stimulation during peripheral nerve block, we performed a randomized double-blinded study of 10 patients undergoing axillary block for upper extremity surgery. Using an insulated needle, we determined the minimum current necessary to elicit muscle contraction with positive and negative needle polarity at two needle placements: (A) where stimulation was first observed and (B) where stimulation was maximal. At Position A, stimulation required significantly more current when the needle was positive (2.32 +/- 0.45 mA, mean +/- SEM) than when it was negative (1.05 +/- 0.23 mA, P < 0.001). Similarly, at Position B, stimulation required more current when the needle was positive (1.49 +/- 0.49 mA) than when it was negative (0.47 +/- 0.15 mA, P < 0.001). The mean ratio of positive to negative threshold stimulation current at Position B (3.11 +/- 0.20) was significantly greater than that at Position A (2.37 +/- 0.19, P < 0.05). Our results emphasize the importance of attaching the negative terminal of the nerve stimulator to the stimulating electrode. Use of the positive terminal could lead to abandoning a block if stimulation were not obtained at a low enough current; alternatively, motor contraction might not be observed before neural contact or vascular puncture.

Adult↗
PubMed1993

Microtubule aggregates in a clival chordoma.

We report a case of a clival chordoma in a 21-year-old man that ultrastructurally demonstrated large numbers of microtubule aggregates within the rough endoplasmic reticulum. Histologically, the tumor demonstrated classic chordoma architecture characterized by numerous physaliphorous cells and an abundant extracellular matrix. The tumor cells stained strongly for cytokeratin, S100 protein, and epithelial membrane antigen, indicative of the epithelial origin of this tumor. Ultrastructurally, the most conspicuous feature of this tumor consisted of parallel bundles of criss-crossing microtubules within the rough endoplasmic reticulum. These microtubules had a diameter of approximately 27 nm and did not demonstrate an internal structure. To our knowledge, this is the first report of microtubule aggregates in a spheno-occipital chordoma. We note that microtubule aggregates have been described in a number of different entities, and though proposed as a specific feature of "chondroid chordoma," they are a nonspecific finding.

Adult↗
PubMed1992

Developmental regulation of annexin II (Lipocortin 2) in human brain and expression in high grade glioma.

In experiments to identify molecules that might be important in the pathogenesis of glioblastoma multiforme, the most common malignant brain tumor, we found that annexin II (Lipocortin 2, p36), a likely second messenger in several different mitogenic pathways, was highly expressed in tumor tissue of glioblastoma multiforme (9 of 9) and highly anaplastic astrocytoma (2 of 6), but not in astrocytomas of lower pathological grade (0 of 6). We also detected high levels of annexin II expression in fetal brain during the period when radial glia proliferate, although annexin II expression was not detected in normal adult brain. These data demonstrate that annexin II expression is developmentally regulated in the human central nervous system and suggest that the early progenitor radial glia share important characteristics with highly malignant glial tumors.

Amino Acid Sequence↗
PubMed1992

Epstein-Barr virus in acquired immune deficiency syndrome (AIDS) and non-AIDS primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) still occurs mainly in patients who are immunosuppressed, but its incidence is rising dramatically among immunocompetent individuals. The Epstein-Barr virus (EBV) has been detected by in situ hybridization in PCNSL tumor tissue from patients who are immunodeficient, but not from patients who are immunocompetent. Using the more sensitive polymerase chain reaction (PCR) technique, the authors analyzed PCNSL tissue from 13 patients with acquired immune deficiency syndrome (AIDS) and 13 patients who were immunocompetent for the presence of EBV genome. METHODS: DNA was extracted from paraffin-embedded biopsy or autopsy specimens. PCR was run using primers for EBV (from the first internal repeat segment of the EBV genome), and identical samples were run simultaneously with primers against actin or the p53 gene as controls to establish the presence of DNA in the sample. Reaction products were also Southern blotted to confirm EBV specificity. RESULTS: EBV was detected in the tumor tissue of 11 of 13 patients (85%) with AIDS and of 7 of 13 patients (54%) who did not have AIDS. There was a history of illness that might suggest or predispose to immune compromise in 5 of 13 patients without AIDS; however, prior illness did not predict EBV-positive tumors. CONCLUSIONS: Although mechanisms remain to be clarified, EBV was present in a high percentage of patients with AIDS-related PCNSL and non-AIDS-related PCNSL:

Acquired Immunodeficiency Syndrome↗
PubMed1992

Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor.

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

Adult↗
PubMed1992

p53 gene mutations in primary lung tumors are conserved in brain metastases.

The p53 product is frequently mutated in human tumors. Both acquired and inherited mutations have been described. These mutations transform p53 from a growth suppressor gene to a transforming oncogene. We examined tissue from 6 patients with primary lung carcinoma and the corresponding brain metastases for the presence of p53 mutations by immunohistochemistry. We then confirmed and characterized the mutations by single strand conformation analysis and by direct sequence analysis. All 6 patients had primary and metastatic tumor expressing a mutant p53. The mutations were all G-T transversions and mapped to exons 5, 6, 7, and 8. The mutations in the primary tumors were precisely conserved in the brain metastases.

Aged↗