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A Lossos

Publications and source records attributed to A Lossos.

At least 19 recordsLinked to original sources
PubMed2005

Central nervous system involvement in indolent lymphomas.

BACKGROUND: Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. PATIENTS AND METHODS: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. RESULTS: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1-9 years for treated patients (median 2 years). Three patients died of CNS disease. CONCLUSIONS: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.

Adult↗
PubMed2002

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Chorea↗
PubMed2000

Cerebrospinal fluid lactate dehydrogenase isoenzyme analysis for the diagnosis of central nervous system involvement in hematooncologic patients.

BACKGROUND: Central nervous system (CNS) involvement is common in hematooncologic diseases. The aim of the current study was to determine the diagnostic value of cerebrospinal fluid (CSF) lactate dehydrogenase (LDH) isoenzyme analysis for the diagnosis of CNS involvement in hematooncologic patients. METHODS: The study was comprised of 63 consecutive hematooncologic patients without previous CNS disease who underwent CSF examination as an integral part of their initial staging procedures (44 patients) or for the evaluation of neurologic symptoms (19 patients). Fifteen of these patients had CNS involvement by leukemia or lymphoma. The LDH isoenzyme pattern was established in the CSF of all patients and analyzed by the classification and regression trees (CART) method to construct a decision tree for the prediction of CNS involvement. An additional group of 30 consecutive patients comprised a validation set that was used for cross-validation of the CART-derived decision tree. RESULTS: A decision tree, with a single split at LDH5 >/= 2.8% for the prediction of CNS involvement, was constructed and validated by data from a validation set of patients. The decision tree had a sensitivity of 93% and a negative predictive value of 98%. One patient (1.6%) and 2 patients (6.6%) were misclassified in the derivation and validation sets, respectively. Overall, in the combined derivation and validation patient population, the decision tree misclassified 3.2% of patients, whereas CSF cytologic examination misclassified 4.3% of patients. CONCLUSIONS: Analysis of the LDH isoenzyme pattern in CSF fluid may be helpful in the evaluation of CNS involvement in patients with hematologic malignancies. The combination of CSF cytology and LDH isoenzyme analysis may improve the sensitivity of CSF cytology significantly.

Central Nervous System Neoplasms↗
PubMed2000

Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.

OBJECTIVE: To evaluate the pharmacokinetics of methotrexate in ventricular cerebrospinal fluid and serum after osmotic blood-brain barrier disruption and intra-arterial administration compared with intravenous or simple intra-arterial infusion in patients with primary central nervous system lymphoma. METHODS: Serum and ventricular cerebrospinal fluid were sampled after methotrexate administration in 12 patients. Blood-brain barrier disruption was induced on 2 sequential days by mannitol (25%) infusion delivered to the vertebral or internal carotid artery territories followed by intra-arterial methotrexate (dose, 1.4 g/m2; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m2; nine treatments) or intra-arterial (2.8 g/m2; seven treatments) infusion. RESULTS: Ventricular cerebrospinal fluid-methotrexate peak levels after blood-brain barrier disruption of the vertebral and the internal carotid arteries territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 micromol/L (P < .001), and the area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110.0 +/- 12.4 [micromol/L x h, respectively (P < .01). No significant differences were observed in serum levels. After intra-arterial infusion was performed without disruption, the serum peak level was higher than that achieved by intravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 micromol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 micromol/L at 6 hours. The cerebrospinal fluid/serum ratio [AUC(%)] of methotrexate after blood-brain barrier disruption was three to four times greater than that by systemic administration. CONCLUSION: Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration.

Adult↗
PubMed2000

In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans.

OBJECT: Osmotic blood-brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. The authors, therefore assessed the time course to barrier closure after osmotic BBB disruption in humans. METHODS: Disruption of the BBB was demonstrated using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography (SPECT) scanning in 12 patients who were treated monthly with combination chemotherapy in conjunction with BBB disruption. The primary diagnosis was primary central nervous system lymphoma in seven patients and primitive neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480-minute intervals after osmotic BBB disruption, and patients underwent SPECT scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was seen in the other nine studies. The TcGH indices correlated with the degree of BBB disruption as measured postprocedure on contrast-enhanced CT scans (r = 0.852). Mean baseline TcGH indices were 1.02+/-0.07. For the group of patients with good-to-excellent disruptions the mean indices at 1 minute postdisruption measured 2.19+/-0.18. After 40 minutes no significant change was noted (mean index 2.13+/-0.2). Then the indices declined more steeply and at 120 minutes after the disruption the index was 1.36+/-0.02. A very slow decline was noted between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier was still open for all good-to-excellent disruptions (index 1.33+/-0.08) but at 480 minutes the mean indices had returned to the baseline level. CONCLUSIONS: Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols.

Adult↗
PubMed1999

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia.

Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3-77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or alpha-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.

Adolescent↗
PubMed1998

Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy.

BACKGROUND: It has been suggested that an aggressive treatment of patients with leptomeningeal metastases (LM) that groups radiotherapy and intra-cerebrospinal fluid (intra-CSF) chemotherapy has improved treatment outcomes. Based on their previous series of 137 patients treated with such an intensive standard protocol, the authors expected 20% of the patients to maintain their responses for at least 6 months after withdrawal of therapy. They also observed that, in patients with solid tumors, a partial response was compatable with sustained off-therapy response and that the maximal response was reached soon after completion of radiotherapy. The authors concluded that the role of intra-CSF chemotherapy, with its associated high rate of complications, is unclear. In this study, which was a further evaluation of this dilemma, they compared the outcomes of two prospective treatment protocols that were identical in their use of radiotherapy and systemic chemotherapy and varied only in their inclusion or exclusion of intra-CSF chemotherapy. METHODS: Adult patients with LM from systemic solid tumors were prospectively included in the treatment protocol active at the time of their diagnosis. Group 1 comprised 54 patients treated by radiotherapy, intra-CSF chemotherapy, and systemic therapy, whereas Group 2 comprised 50 patients treated with radiotherapy, and systemic chemotherapy but no intra-CSF chemotherapy. RESULTS: The analysis of treatment outcomes was performed retrospectively. The median patient age and distribution of primary neoplasms did not differ between the two groups. The proportion of early deaths that occurred during radiotherapy was similar for the two groups, as was the overall rate of response to treatment. The two groups also had the same median survival, which was 4 months for both groups, as well as the same proportion of long term survivors. Thirty-one percent of patients in Group 1 developed early complications related to intra-CSF chemotherapy, whereas patients in Group 2 were spared these complications. Delayed symptomatic leukoencephalopathy was observed in 20% of Group 1 patients compared with none in Group 2 (P = 0.02). CONCLUSIONS: The exclusion of intra-CSF chemotherapy from the treatment schedule of patients with LM does not change their overall response to treatment, their median survival, or the proportion of long term survivors. It does, however, significantly reduce the rate of early and delayed treatment-related complications.

Adult↗
PubMed1998

Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene.

Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by glycogen branching enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1998

Cisplatin-induced non-convulsive encephalopathy.

Cisplatin is a widely used chemotherapeutic agent implicated in a range of adverse effects affecting the nervous system. Among the others, convulsive encephalopathy is rare and its pathogenesis is unknown. We report an 84-year-old woman with adenocarcinoma of the ovary who developed two fully reversible episodes of non-convulsive encephalopathy, each following a course of cisplatin-based chemotherapy and thus confirming a causal relationship to the agent. The patient presented 7 and 10 days after treatment with acute confusional state, a partial left homonymous hemianopia and a left extinction hemihypesthesia. Brain MRI showed old-standing cerebral microvascular changes and EEG revealed right parieto-occipital periodic lateralized epileptiform discharges over a generalized background activity slowing. This case adds further to the clinical diversity of cisplatin toxicity and, in view of the similarity to a recently defined disorder of posterior leukoencephalopathy, suggests regional endovascular injury rather than a direct cerebral toxicity as the initial event in the evolution of encephalopathy.

Adenocarcinoma, Papillary↗
PubMed1998

Intravascular lymphomatosis--an indolent or aggressive entity?

Intravascular lymphomatosis (IVL) is a rare malignancy characterized by neoplastic proliferation of lymphoid cells within the lumens of arteries, small veins and capillaries. We report four patients with IVL and review the recent world literature, relating to incidence, clinical features and possible therapy. In these cases diagnosis was established coincidentally in one patient after prostatectomy. This patient eventually had central nervous system involvement. In two other patients IVL was diagnosed from skin lesions. In the fourth case the diagnosis was established at post-mortem examination, where involvement of most organs was evident but particularly kidneys, myocardium, gastrointestinal tract and lymph nodes. Therapy was given to three patients, but the disease progressed in two and they both died with evidence of central nervous system involvement, while the third patient has had a good partial response to combination chemotherapy but has relapsed within two months of completing chemotherapy. As evident from our patients and the literature review IVL has a variable clinical course and currently, there appears to be no effective therapy for this rare disorder.

Aged↗
PubMed1997

Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic study.

BACKGROUND: Niemann-Pick type C disease is an autosomal recessive neurometabolic disorder of unknown origin mapped to chromosome 18q11-12 in most of the studied families. In contrast to the sphingomyelin lipidoses, in Niemann-Pick type C disease, fibroblasts are impaired in intracellular homeostatic responses to exogenous low-density lipoprotein (LDL) cholesterol. Biochemical heterogeneity of the disorder in relation to abnormal LDL processing is associated with various clinical presentations, but adult-onset Niemann-Pick type C disease is rare and has not been comprehensively characterized. OBJECTIVE: To describe clinical, biochemical, and genetic features of adult-onset Niemann-Pick type C disease in 3 siblings. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS: The 3 siblings manifested a variable combination of vertical supranuclear ophthalmoplegia, ataxia, and splenomegaly. Brain magnetic resonance imaging showed cerebellar atrophy; brainstem auditory evoked responses were unobtainable, and bone marrow examination disclosed typical foam cells. The patients were 20, 26, and 28 years old and belonged to a sibship of 13 born of consanguineous healthy parents. METHODS: Esterification of exogenous LDL cholesterol in cultured skin fibroblasts and filipin staining for free intracellular cholesterol. Polymerase chain reaction-based DNA linkage study using AC microsatellite markers D18S40, D18S44, D18S480, and D18S66. RESULTS: Fibroblasts of the 3 patients showed a 23% to 58% block in the induced cholesterol esterification after 4 1/2 hours and a mild to moderate accumulation of free cholesterol. DNA study demonstrated linkage to the major 18q11-12 Niemann-Pick type C locus and identified unaffected carriers. CONCLUSIONS: These results confirm the diagnosis of the least biochemically affected Niemann-Pick type C phenotype in this family with adult-onset disease and support a correlation between the mild laboratory and clinical findings in this age group.

Adult↗
PubMed1997

Intrafamilial heterogeneity of movement disorders: report of three cases in one family.

We report three members of a single family with an apparently autosomal dominant, nonparoxysmal, hyperkinetic movement disorder with onset in adolescence. The proband, a 56-year-old woman, manifested dystonia, tremor and myoclonus; one of her daughters exhibited myoclonus with tremor, and the other demonstrated myoclonus with chorea later accompanied by tremor and dystonia. The slowly progressive but not debilitating symptoms were restricted to the head, arms and hands and were only moderately affected by alcohol. Laboratory investigations failed to identify any abnormality, and linkage analysis excluded the region containing the DYT1 locus, indicating that the gene responsible for idiopathic torsion dystonia was not implicated in this family. While this disorder shares manifestations with myoclonic dystonia, essential myoclonus and benign chorea, the marked intrafamilial heterogeneity and the sex-limited phenotype expressed only in females of two generations appear to be unique.

Adolescent↗
PubMed1996

Electric shock-like sensations in 42 cancer patients: clinical characteristics and distinct etiologies.

We retrospectively evaluated 42 consecutive cancer patients manifesting electric shock-like sensations. Fourty three percent presented with Lhermitte's sign (LS), 24% with the previously described outstretching ir. abduction maneuver (OAM) of the arms, and 33% had both phenomena. Twenty nine patients had underlying polyneuropathy related to cisplatin-based chemotherapy in 27 and to thiamine deficiency in 2. Thirtreen patients had myelopathy which was induced by radiotherapy in 11. Patients with polyneuropathy manifested both LS and OAM, while patients with myelopathy more often presented with LS. Neurologic signs suggestive of spinal cord involvement were present in 3 patients with polyneuropathy and in 7 of 11 irradiated patients. MRI disclosed cervical spinal cord swelling in 3 patients with LS. Prolonged cervical latencies on SSER were noted in 5 of 15 patients. All had LS and 3 also had OAM associated with abnormal latencies in the brachial plexi. We conclude that LS and OAM are positive sensory manifestations of increased mechanosensitivity of the damaged central or peripheral sensory axons in the cervico-brachial area. In cancer patients, these phenomena largely manifest treatment-induced myelopathy or polyneuropathy. Auxillary studies help to confirm diagnosis and to depict the uncommon but treatable causes.

Adult↗