Perfusion computed tomography assessments of peri-enhancing brain tissue in high-grade gliomas.

PURPOSE: This study was undertaken to identify tumoural infiltration of peri-enhancing brain tissue in patients with glioblastoma by means of perfusion computed tomography (PCT) parameters, cerebral blood volume (CBV) and permeability surface (PS). MATERIALS AND METHODS: Eight patients with surgically treated glioblastoma who were eligible for radiotherapy and nine patients with brain metastases from lung and breast cancer underwent CT before and after injection of contrast medium. CBV and PS were calculated in the contrast-enhancing lesion area, in the area of perilesional oedema and in the normal-appearing white matter (NAWM), normalised to contralateral symmetrical areas. RESULTS: No significant differences were found for normalised CBV (nCBV) and nPS in NAWM regions between metastasis and glioma. Significant differences in nPS (p<0.005) were found between the typically vasogenic oedema surrounding the metastases and signal alteration surrounding the glial neoplasm. On the contrary, no significant differences were detected in the same areas for nCBV. CONCLUSIONS: PCT can analyse the histopathological substrate underlying the hypodense peritumoural halo and differentiate between vasogenic oedema and neoplastic infiltration on the basis of the PS parameter. In our study, PS was more informative than CBV. These findings can be used to integrate plans for radiation therapy and/or surgery.

Characterization of a recurrent translocation t(2;3)(p15-22;q26) occurring in acute myeloid leukaemia.

Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5' to EVIl as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5' region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold over-expression of the EVIl gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34+ CD117+ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5' region of EVIl at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5' region of EVIl with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.

bcr-abl rearrangement in adult T-lineage acute lymphoblastic leukemia.

The bcr-abl rearrangement in T-lineage ALL has been rarely described. In the last three years we studied all new patients with ALL at diagnosis by cytogenetic and molecular analysis. Three out of eleven T-lineage ALL patients presented the rearrangement and only one was Philadelphia positive.

Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases. GIMEMA Infection Program (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto).

A retrospective study of 37 patients with haematological malignancy (21 acute myeloid leukaemia, 11 acute lymphoid leukaemia, two lymphoma, two hairy cell leukaemia, one Hodgkin's disease) and histologically documented mucormycosis was conducted to evaluate the clinical characteristics and ascertain the factors which influenced the outcome from mycotic infection. Patients were admitted to 18 haematology divisions in tertiary care or university hospitals in Italy between 1987 and 1995. Fever, thoracic pain, dyspnoea and cough were the most frequent presenting symptoms. At the onset, 89% patients were neutropenic (neutrophil counts < 0.5 x 10(9)/l) with a median duration of previous neutropenia of 14 d (range 6-60). The most frequent sites of infection were lungs (81%), CNS (27%), sinus (16%), liver (16%) and orbital space (10%). Only three patients were asymptomatic. A correct in vivo diagnosis was made in only 13 (35%) patients. When performed, thoracic and cranial CT scan were the most useful diagnostic investigations. Despite the fact that 26 febrile patients were treated with empirical antifungal treatment, 28 of the 37 patients (76%) died from fungal infection at a median time of 17 d from the onset of clinical symptoms. Nine patients were cured by antifungal therapy plus, in five cases, radical surgery procedures. An analysis of factors influencing outcome demonstrated that the resolution of chemotherapy-induced neutropenia and prolonged treatment with amphotericin B and, if feasible, radical surgical debridement treatment, were significantly correlated with recovery from infection. Mucormycosis, a rare filamentous fungal infection that occurs most frequently in neutropenic acute leukaemia patients, is characterized by a high mortality rate. Extensive and aggressive diagnostic and therapeutic procedures are essential to improve the prognosis in these patients.

A new pericentric inv(8) in acute nonlymphocytic leukemia.

Chromosome studies were carried out on unstimulated bone marrow cells from a patient with a diagnosis of acute nonlymphocytic leukemia (FAB M6 ANLL). Cytogenetic analysis revealed a mosaic chromosome pattern 46,XX/46,XX,inv(8)(p21q24). This pericentric inversion has not been previously described in ANLL. Because, fragile sites, zinc finger gene loci, and the MYC protooncogene have been localized to band 8q24, a putative role for these sites and genes could be considered.

Treatment of malignant lymphomas with very-high-dose CVB followed by transplantation of autologous blood stem cells collected after mobilizing chemotherapy.

In 8 patients (age 25 +/- 46 years, mean 34.5), 4 with Hodgkin's disease (HD) and 4 with non-Hodgkin's lymphoma (NHL), circulating stem cells (CSC) collected at the time of rapid leukocyte and platelet recovery after intense chemotherapy were employed for autologous hematological reconstitution after very-high-dose chemotherapy (CVB combination). At the time of graft 2 patients were in 1st remission and 2 in 2nd, while the remaining 4 had persistence or progression of disease. Autografted patients received 3.4 +/- 8.3 (mean 5.2) x 10e8/Kg mononuclear cells and 2.1 +/- 40.5 (mean 22.5) x 10e4/Kg CFU-GM. All patients had prompt and sustained engraftment, though in one case platelets never reached normal levels. Recovery time was respectively 10 +/- 17 days (mean 13.2) for granulocytes 0.5 x 10e9/L, and 10 +/- 49 days (mean 20.3) for platelets greater than 50.0 x 10e9/L, with an interval of less than 4 days from greater than 0.5 to greater than 1.0 granulocytes in 7 out of the 8 patients. All patients are currently alive at 57 +/- 645 (median 262) days, and 7 in remission at 61 +/- 645 (median 297) days from autologous blood stem cell transplantation (ABSCT). Our study demonstrates that CSC collected after mobilizing chemotherapy are able to promptly restore and sustain hemopoiesis after marrow ablative chemotherapy in patients with malignant lymphoma. CSC reduce toxicity and hospitalization so impressive, that in malignant lymphomas ABSCT could rapidly be considered for first line strategy.

Collection, processing and storage of peripheral blood stem cells (PBSC).

Eight patients with hematological malignancies were treated with autologous blood stem cell transplantation (ABSCT). Hemopoietic precursor cells were mobilized into the peripheral blood (PB) by chemotherapeutic induction of transient myelosuppression followed by an overshooting of blood stem cell concentration. PB CFU-GM showed a 15-20 fold increase on days 15-20 after chemotherapy. Peripheral blood stem cells were collected by 5-8 continuous flow leukaphereses using a Fenwall CS 3000 blood cell separator when platelet and WBC count was rising rapidly (platelet greater than 50 x 10e9/L and WBC greater than 1 x 10e9/L). Mean CFU-GM collected per run by leukapheresis were 10.85 x 10e4/Kg (procedure 3), 10.03 x 10e4/Kg (modified procedure 1). Mononuclear cell suspension in 10% DMSO was frozen at controlled rate freezer (-1 degree C to -4 degrees C) and stored in the liquid phase of nitrogen. After thawing CFU-GM recoveries ranged from 13.8% to 81.5%; 55-70% of recovered cells excluded trypan blue dye.

Wernicke-like encephalopathy after autologous bone marrow transplantation.

A 15-year-old boy with non-T ALL in early 2nd remission was autografted using a regimen with busulphan 4 mg/kg/day, po, from day -9 to -6, and cyclophosphamide 50 mg/kg/day, iv, from day -5 to -2. During busulphan administration he experienced a few generalized seizures, and starting on day 25 post ABMT he developed a progressively severe neurological symptomatology characterized by nystagmus, right VIth cranial nerve palsy, truncal ataxia and, finally, confusion and coma. MRI showed lesions in the periaqueductal gray matter, thalamus, mammillary bodies and putamen. Within 24 hours of treatment with thiamine he improved dramatically, but during the following weeks permanent neurologic damage with memory deficit, truncal ataxia and nystagmus became evident. To our knowledge this is the first case of Wernicke's encephalopathy reported after BMT. We suspect in this case a contribution of busulphan to the development of the syndrome.

Circulating stem cell autograft in malignant lymphomas.

Autologous peripheral blood stem cells (PBSC) collected after an intensive course of chemotherapy were employed for hematological reconstitution in 3 patients (age 24-44 years), 2 with Hodgkin's and 1 with high-grade non-Hodgkin's lymphoma, in 2nd complete or partial remission. PBSC collections were performed with a Fenwal CS-3000 cell separator (programs "3" and "1-modified"). After collection and partial RBC removal, cells were cryopreserved and stocked in liquid nitrogen. In all patients the CVB combination was employed as myeloablative transplant regimen. Patients received respectively 28.0, 33.1 and 12.3 x 10(4)/Kg peripheral blood CFU.GM. Hematologic recovery was prompt and complete in 2 patients, while a patient with Hodgkin's lymphoma who had previously been treated with combined modality, is still moderately thrombocytopenic and granulocytopenic 148 days post graft. Patients are currently alive and disease-free 148-301 days post graft.

Additional chromosomal abnormalities to Ph during the clinical course in patients with acute lymphoblastic leukemia.

Cytogenetic findings obtained during the clinical course in two patients (one child and one adult) with Ph-positive acute lymphoblastic leukemia (ALL) are reported. Chromosomal abnormalities in addition to Ph chromosome were detected in both patients. At the beginning of the disease, such abnormalities consisted of the trisomy of chromosome 1 and monosomy of chromosomes 8 and 9, with a sub-line 45, XY, Ph, -8 in the child; in the adult patient a hyperdiploid clone with 57-59 chromosomes and Ph duplication was present. At relapse, the same karyotypic anomalies reappeared in the child, whereas in the adult a high frequency of chromosomal rearrangements, such as ring and dicentric chromosomes, was observed after cranial irradiation. The occurrence of chromosomal abnormalities additional to Ph during the clinical course in ALL patients is discussed, taking into account data from the literature concerning the lymphoid blastic crisis in chronic myeloid leukemia patients.