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PubMed1999

Ultrasound imaging of apoptosis: high-resolution non-invasive monitoring of programmed cell death in vitro, in situ and in vivo.

A new non-invasive method for monitoring apoptosis has been developed using high frequency (40 MHz) ultrasound imaging. Conventional ultrasound backscatter imaging techniques were used to observe apoptosis occurring in response to anticancer agents in cells in vitro, in tissues ex vivo and in live animals. The mechanism behind this ultrasonic detection was identified experimentally to be the subcellular nuclear changes, condensation followed by fragmentation, that cells undergo during apoptosis. These changes dramatically increase the high frequency ultrasound scattering efficiency of apoptotic cells over normal cells (25- to 50-fold change in intensity). The result is that areas of tissue undergoing apoptosis become much brighter in comparison to surrounding viable tissues. The results provide a framework for the possibility of using high frequency ultrasound imaging in the future to non-invasively monitor the effects of chemotherapeutic agents and other anticancer treatments in experimental animal systems and in patients.

Animals↗
PubMed1997

Risk of extramedullary relapse following allogeneic bone marrow transplantation for acute myelogenous leukemia with leukemia cutis.

Leukemia cutis (LC) is a rare feature of acute myeloblastic leukemia (AML). Little information is available regarding its prognostic influence on post-transplant outcome. In our institution, 202 patients with AML received an allogeneic HLA-identical marrow transplant from related donors between March 1982 and January 1994. Thirteen patients had prior leukemic involvement of the skin (leukemia cutis or LC group) while 189 patients did not (non-LC group). There was a higher incidence of patients with the M4-M5 FAB subtypes in the LC group (83%) as compared to the non-LC group (33%). In addition, the percentage of patients transplanted in relapse was also higher in the LC group (69 vs 15%). While there were no differences observed in the rates of relapse post-transplant in the LC and non-LC groups when matched for stage of disease at transplant, the sites of relapse differed markedly. Five of six relapses in the LC group involved extramedullary sites as compared to only six of 38 relapses in the non-LC group (P = 0.002), with a 6-year probability of extramedullary relapse of 38.5% in the LC group as compared to 3.9% in the non-LC group. This increased probability of extramedullary relapse was independent of the FAB morphology (50 vs 2% for patients with the M4-M5 subtypes in the LC and the non-LC group respectively) and of disease status at the time of transplant. Moreover, only three relapses post-transplant involved the skin, all of which were in the LC group, with a probability of skin relapse of 23.1% in this group. Patients with AML and leukemia cutis have a remarkable propensity to relapse in extramedullary sites following marrow transplantation. These relapses occur in the skin as well as other organs. Further investigations are needed to understand the biological basis of this clinical feature.

Adult↗
PubMed2003

The prevalence of ocular disease in chronic lymphocytic leukaemia.

AIM: Previous surveys of ocular disease in leukaemia patients have shown the retina, choroid, and orbit as the most commonly involved sites. Depending on the type of leukaemia and the study design, the prevalence of ocular disease in leukaemia varies from 30 to 90%. Although chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries, the prevalence of ocular disease in CLL is not known. The aim of this prospective study was to estimate the prevalence of ocular disease in CLL. PATIENTS AND METHODS: All CLL patients attending either a teaching or district general hospital haematology clinic were invited to undergo a full eye examination. The clinical stage of the CLL (Binet) at the time of the eye examination and the most recent full blood count (FBC) indices were recorded for each patient. RESULTS: Over 6 months, 25 patients with an average age of 65 were recruited. A total of 18 patients had Binet stage A disease, three had stage B, and four stage C. The mean FBC indices at the time of examination were haemoglobin 13.5 g/dl, white cell count 37.4 x 10(9)/l, and platelets 172 x 10(9)/l. Only three patients (12%) had ocular disease that was likely to be a secondary complication of CLL. These secondary complications included bilateral posterior subcapsular cataract following radiotherapy, unilateral acute retinal necrosis, and unilateral conjunctival vascular anomalies. The presence of ocular complications was not related to the CLL stage or to the current FBC parameters. DISCUSSION: This study demonstrates that ocular involvement in CLL is uncommon, a reflection of the indolent course of CLL as compared to other leukaemias. Although sight-threatening ocular complications have been documented in this and other studies, the low prevalence of complications and the lack of association with disease parameters make it impossible to identify a 'high-risk' group. Routine screening of CLL patients for ocular complications is not justified.

Aged↗
PubMed2006

Ameliorating skin-homing receptors on malignant T cells with a fluorosugar analog of N-acetylglucosamine: P-selectin ligand is a more sensitive target than E-selectin ligand.

Expression of E- and P-selectin ligands is required for T cell entry into skin. Sialyl Lewis X moieties are critical for ligand activity and are elevated on malignant skin-homing T cells. We hypothesize that these glycosylations are selectable targets for treating the dermal tropism associated with cutaneous lymphomas. In this study, we analyzed the efficacy of a novel 4-fluorinated analog of N-acetylglucosamine (GlcNAc) on E- and P-selectin ligands expressed by malignant skin-homing T cells. We also examined the specificity of 4-F-GlcNAc (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose) action by contrasting the effects on sialyl Lewis X expression displayed by P-selectin glycoprotein ligand-1 (PSGL-1) with sialylated O-glycans expressed by CD43. Using parallel-plate flow analysis, we found that 4-F-GlcNAc elicited 5-fold more potent inhibition on P-selectin ligand activity than on E-selectin ligand activity. To determine whether glycosylations conferring E- and P-selectin ligand activities were inhibited, we analyzed the expression of sialyl Lewis X and sialyl-fucosylated core 2 O-glycan (CHO-131 antigen), respectively. We found that 4-F-GlcNAc treatment resulted in dose-dependent ablation of sialyl Lewis X and CHO-131 antigen expression on PSGL-1, whereas sialylated O-glycans on CD43 were minimally affected. These results indicate that 4-F-GlcNAc treatment can selectively downregulate the P-selectin ligand activity and potentially prevent dermal dissemination of cutaneous lymphomas.

Acetylglucosamine↗
PubMed1998

Extramedullary relapse after favorable molecular response to donor leukocyte infusions for recurring acute leukemia.

Donor leukocyte infusions (DLI) have turned out to be an efficient way to re-establish complete remission (CR) in chronic myeloid leukemia (CML) patients relapsing after allogeneic bone marrow transplantation (BMT). In these patients, absence of PCR bcr-abl fusion transcripts confirmed the potency of donor leukocytes to induce molecular response in relapsed CML. This ensured sustained remission and long-term survival. In this study, the capacity of DLI to induce molecular remission in acute leukemia relapse after BMT was analyzed. The results showed that following DLI, leukemic cell eradication gradually occurred over a prolonged time period. The time to complete disappearance of the molecular marker of the disease was 30 weeks in RT-PCR analysis. A sustained and persistent elimination of an AML1/ETO-positive leukemic clone in an AML-M2 patient was observed. In contrast, an AML-M5 with t(11;19) and an E2A/PBX1-positive ALL achieving cytogenetic and molecular bone marrow CR developed following DLI unusual sites of extramedullary leukemia relapse, despite continued bone marrow remission. This study adds further proof of the benefit of donor cell therapy in acute leukemia but shows that complete leukemic cell eradication appears to require a critical interval in order to establish effective immune responses at all sites where leukemic cells persist.

Adult↗
PubMed1999

A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies.

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.

Adolescent↗
PubMed2000

Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report.

Contemporary chemotherapy has significantly improved event-free survival among patients with T cell-lineage acute lymphoblastic leukemia (T-ALL). Unlike B-precursor ALL, most investigators are still using cranial radiation (CRT) and are hesitant to rely solely on intrathecal therapy for T-ALL. In this study we assessed the effects of CRT upon event-free survival and central nervous system (CNS) relapses in a cohort of children with high risk features of T cell leukemia. In a series of six consecutive studies (1987-1995) patients were non-randomly assigned their CNS prophylaxis per individual protocol. These protocols were based on POG 8704 which relied on rotating drug combinations (cytarabine/cyclophosphamide, teniposide/Ara-C, and vincristine/doxorubicin/6-MP/prednisone) postinduction. Modifications such as high-dose cytarabine, intermediate-dose methotrexate, and the addition of G-CSF, were designed to give higher CNS drug levels (decreasing the need for CRT), to eliminate epidophyllotoxin (decreasing the risk of secondary leukemia), and to reduce therapy-related neutropenia (pilot studies POG 9086, 9295, 9296, 9297, 9398). All patients included in this analysis qualified for POG high risk criteria, WBC >50000/mm3 and/or CNS leukemia. Patients without CNS involvement received 16 doses of age-adjusted triple intra-thecal therapy (TIT = hydrocortisone, MTX, and cytarabine) whereas patients with CNS disease received three more doses of TIT during induction and consolidation. Patients who received CRT were treated with 2400 cGy (POG 8704) or 1800 cGy (POG 9086 and 9295). CNS therapy included CRT in 144 patients while the remaining 78 patients received no radiation by original protocol design. There were 155 males and 57 females with a median age of 8.2 years. The median WBC for the CRT+ and CRT- patients were 186000/mm3 and 200000/mm3, respectively. CNS involvement at diagnosis was seen in 16% of the CRT+ and 23% of the CRT- groups. The complete continuous remission rate (CCR) was not significantly different for the irradiated vs. non-irradiated groups (P = 0.46). The 3-year event-free survival was 65% (s.e. 6%) and 63% (s.e. 4%) for the non-irradiated vs. the radiated group. However, the 3-year CNS relapse rate was significantly higher amongst patients who did not receive CRT; 18% (s.e. 5%) vs. 7% (s.e. 3%) in the irradiated group (P = 0.012). Our analysis in a non-randomized setting, suggests that CRT did not significantly correlate with event-free survival but omitting it had an adverse effect on the CNS involvement at the time of relapse.

Adolescent↗
PubMed2002

Ear involvement in acute promyelocytic leukemia at relapse: a disease-associated 'sanctuary'?

Extramedullary (EM) involvement occurs infrequently in acute promyelocytic leukemia (APL) and usually involves skin and CNS. We describe seven patients (four observed at a single institution) who relapsed in various sites of the auditory apparatus, including the external canal and middle ear (temporal bone). Front-line treatment included ATRA and chemotherapy (six patients) or chemotherapy alone (one patient). Three patients had concomitant hematologic relapse, two had molecular relapse and two were in hematologic and molecular remission when ear localization was documented. Local symptoms that stimulated further diagnostic studies included ear bleeding/discharge in the first patient, but were mild in the others (hypoacusia, five patients; earache, two patients). Ear involvement by leukemia was documented by histological and/or molecular studies after local surgery in five cases, and by CT scan or NMR in the remaining patients. We suggest that the ear might represent a specific sanctuary for disease involvement in APL.

Adolescent↗
PubMed2001

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia.

The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid differentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL efficiently induces a myeloproliferative disorder (MPD) in mice, but progression to CML blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid differentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BCR-ABL and AME in mice can block myeloid differentiation and rapidly induce an AML. Our results suggest that block of myeloid differentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription.

Acute Disease↗
PubMed2002

Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital.

OBJECTIVE: Adrenal metastases are frequently encountered during autopsy but uncommonly present clinically. The aim of this study was to evaluate the clinical and pathological impact of adrenal metastases in a large series of patients. PATIENTS: Four hundred and sixty-four patients (288 men, 176 women) with metastatic disease in the adrenal glands over a 30-year period were included in the study. MEASUREMENTS: The clinical records and pathological features were reviewed. RESULTS: The frequencies of adrenal metastases at autopsies, adrenalectomies and fine-needle aspiration biopsies were 3.1%, 7.5% and 33%, respectively. The lesions were often seen in elderly patients (mean age, 62, SD = 13 years). Many of the metastatic lesions in the adrenal gland occurred shortly after the detection of a primary tumour (mean latent period = 7 months). Four per cent of the adrenal lesions (n = 20) were symptomatic. The symptomatic adrenal lesions, as compared with asymptomatic ones, were bigger and seen in younger patients. Five patients presented with adrenal insufficiency (Addison's disease) and one had massive peritoneal haemorrhage because of metastatic carcinoma. Ninety per cent (n = 421) of the metastatic adrenal tumours were carcinomas and 56% of these were adenocarcinoma. Lung was the most common primary tumour site (35%), followed by the stomach (14%), the oesophagus (12%) and the liver/bile ducts (10%). The adrenal metastases were bilateral in approximately half of the patients (49%, n = 229). The mean diameter of the adrenal metastases was 2 cm (SD = 1.9 cm). The mean weight of the right adrenal gland harbouring the metastasis was 19 g, while that of the left 20 g. The median survival of the 20 patients with symptomatic adrenal lesions was 3 months (range, 0-75 months) after the detection of adrenal metastases. Patients with surgically removed adrenal metastases had slightly better survival rates than those without surgical resection. CONCLUSIONS: A variety of tumours may give rise to adrenal metastases. They are often asymptomatic and detected as part of multiorgan metastases. Symptomatic cases, albeit rare, may occur. Long-term survival may be achieved in selected patients in whom an aggressive surgical approach may be adopted.

Adenocarcinoma↗
PubMed2004

Association of non-alcoholic steatohepatitis (NASH) with chronic neutrophilic leukemia.

A 54-yr-old female having chronic neutrophilic leukemia (CNL) associated with severe liver injury is presented. Physical examination on admission showed severe jaundice, hepatosplenomegaly, massive ascites, and pretibial edema. Complete blood count showed a hemoglobin level of 9.1 g/dL, platelet count of 25.8 x 10(4)/microL, and white blood cell count of 36.6 x 10(3)/microL with 89.7% neutrophils. Blood chemistry showed hyperbilirubinemia (21.9 mg/dL) with normal transaminase levels. There was no abnormality in serum cholesterol, triglyceride, or glucose levels. Neutrophil alkaline phosphatase activity was significantly elevated. Bone marrow aspiration showed myeloid hyperplasia with normal karyotype. Rearrangement of the bcr/abl was not detected by either polymerase chain reaction or fluorescence in situ hybridization. Human androgen receptor gene assay (HUMARA) of the bone marrow cells showed clonal proliferation of neutrophils. The patient was diagnosed as having CNL. To evaluate the pathogenesis of the liver injury, a needle biopsy was performed, which showed steatohepatitis with infiltration of neutrophils. As the patient had no history of alcohol abuse, a diagnosis of non-alcoholic steatohepatitis (NASH) was made. Assuming that the infiltration of abnormal neutrophils into the liver contributed to the development of NASH, she was treated with cytoreductive chemotherapy (cytosine arabinoside: 100 mg/d, 1-3 doses/wk). With decreases in white blood cell counts, serum bilirubin levels decreased gradually to 1.5 mg/mL. A postchemotherapy liver biopsy specimen showed marked improvement of the fatty degenerative change. To our knowledge, this is the first report describing the development of NASH in a myeloproliferative disorder. We believe that the infiltration of leukemic cells contributed to the development of NASH in this patient.

Antimetabolites, Antineoplastic↗
PubMed2000

Mycosis fungoides and chronic lymphocytic leukaemia--composite T-cell and B-cell lymphomas presenting in the skin.

Composite lymphomas involving cutaneous B-cell and T-cell lymphomas are very uncommon. We report here the unique circumstance of a patient with mycosis fungoides (primary cutaneous T-cell lymphoma) who later developed chronic lymphocytic leukaemia (B-cell lymphoproliferation, B-CLL), which presented in the skin (leukaemia cutis) as a composite lymphoma affecting an earlobe. The presence of both lymphoproliferative disorders was confirmed with immunophenotyping and the finding of both immunoglobulin gene rearrangements and T-cell receptor gene rearrangements in the ear and the same T-cell receptor gene rearrangement in a plaque lesion of mycosis fungoides on the arm.

Aged↗