Detection and partial characterization of human thymus-leukemia antigens.

Two monkey antisera against human thymocytes after absorption with human erythrocytes and peripheral blood leukocytes were shown to detect human thymus-leukemia (HTL)-like antigens. These sera were cytotoxic for thymocytes (> 90% lysis at a 1:10 dilution) but were nonreactive with enriched peripheral blood T- and B-lymphocytes or with cells from myeloid or B-cell lymphoid leukemias. Most (16/17) sheep erythrocyte rosette-forming acute lymphoblastic leukemia (ALL) cells reacted with these sera. Cells from patients with T-cell chronic lymphocytic leukemia, lymphoblastic lymphoma (LBL), and thymoma were also positive. Three of 4 T-cell lymphoblastoid lines derived from ALL patients reacted with these sera. Absorption of the sera with MOLT-4F cells, thymocytes, or LBL cells removed the reactivity against all types of cells tested. However, sera absorbed with the T-cell line HSB remained cytotoxic for thymocytes, MOLT-4F, and most (6/9) T-cell cancers tested. The peripheral blood cell-absorbed sera precipitated a molecule with an apparent molecular weight of 48,000 from lactoperoxidase-labeled thymocytes but not from similarly labeled peripheral blood lymphocytes. The ability of the sera to precipitate this antigen was decreased by absorption with thymocytes, MOLT-4, or LBL cells but not by absorption with HSB, SB, or non-T, non-B ALL cells. Sequential precipitation studies suggested that the HTL antigen was not associated with beta 2 microglobulin.

Cigarette smoking and risk of acute leukemia: associations with morphology and cytogenetic abnormalities in bone marrow.

BACKGROUND: Cigarette smoking may be a risk factor for leukemia. No detailed biological mechanism has been proposed, but a causal link is made plausible by evidence of systemic effects of cigarette smoke and the presence in cigarette smoke of chemicals that have been associated with leukemia risk. PURPOSE: Our purpose was to investigate the leukemia risk associated with cigarette smoking in a multicenter case-control study of acute leukemias in adults. METHODS: Adults aged 18-79 with newly diagnosed leukemia were contacted to participate in this epidemiologic study when they entered a clinical trial to be treated under protocols sponsored by Cancer and Leukemia Group B. Smoking histories for 610 patients with acute leukemia and 618 population control subjects were obtained by telephone interviews. We examined bone marrow samples and classified patients by morphology of leukocyte precursor cells according to the French-American-British (FAB) classification system and, for 378 patients, by the presence or absence of specific clonal chromosome abnormalities. We calculated odds ratios (ORs) for risk of leukemia associated with smoking cigarettes. ORs were adjusted for age, race, and sex. RESULTS: Smoking was associated with only a modest increase in risk for leukemia overall (adjusted OR = 1.13; 95% confidence interval [CI] = 0.89-1.44). However, among participants aged 60 and older, smoking was associated with a twofold increase in risk for acute myeloid leukemia (AML) (OR = 1.96; 95% CI = 1.17-3.28) and a threefold increase in risk for acute lymphocytic leukemia (ALL) (OR = 3.40; 95% CI = 0.97-11.9). Among older persons, risks increased with amount and duration of smoking. Smoking was associated with increased risk for AML classified as FAB type M2 at all ages, with ORs of 1.70 (95% CI = 1.00-2.90) for those younger than 60 and 3.50 (95% CI = 1.53-8.03) for those aged 60 and older. Smoking was also associated with ALL type L2 at all ages, with ORs of 1.72 (95% CI = 0.90-3.27) for those younger than 60 and 5.34 (95% CI = 1.03-27.6) for those who were older. Smoking was more common among patients with specific chromosome abnormalities in AML [-7 or 7q-, -Y, +13] and in ALL [t(9;22)(q34;q11)]. CONCLUSIONS: Cigarette smoking is associated with increased risk for leukemia and may lead to leukemias of specific morphologic and chromosomal types. The association varies with age. IMPLICATION: Examining discrete subtypes of disease may permit more accurate assessment of risk. As standardized morphologic classification and cytogenetic and molecular evaluation of leukemia patients becomes more common, epidemiologic studies that take advantage of these advances will begin to contribute to the identification of additional risk factors and mechanisms in acute leukemia.

Detection of both T-cell and Ia-like antigens on cells from patients with acute myelomonocytic leukemia and chronic myelogenous leukemia in blast crisis.

Appropriately absorbed antisera to the lymphoblastoid cell lines HSB and SB detect a human T-lymphocyte-associated antigen (TLAA) and the human Ia-like antigens, respectively. Cells from some patients with acute myelomonocytic leukemia (AMML) and chronic myelogenous leukemia in blast crisis expressed both TLAA and Ia antigens when tested in a complement-dependent microcytotoxicity assay (greater than 90% lysis with both antisera). When patients were in remission, expression of TLAA and Ia antigens returned to normal values. Quantitative absorption of anti-TLAA serum with increasing numbers of AMML cells showed that these cells could remove reactivity of the serum for both HSB and human thymocytes. Similarly, absorption of anti-Ia serum with AMML cells removed all serological reactivity when this serum was tested on chronic lymphocytic leukemia cells or normal B-cells. These serological findings were confirmed by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis studies using radiolabeled antigens. Cells from an AMML patient were labeled with 125I using lactoperoxidase; both the TLAA and Ia antigens were precipitated from the resulting solubilized membrane preparation. Leukemic cells from one AMML patient and one patient with chronic myelogenous leukemia in blast crisis were studied for Ia and TLAA antigens with a double fluorescence technique. Over 80% of the cells showed dual fluorescence.

Facilitated light microscopic cytochemical diagnosis of acute myelogenous leukemia.

Hydroperoxidase-positive Phi bodies and rods are much more prominent and prevalent than rods visualized with a Romanovsky-type stain (Auer rods) in immature leukocytes of patients with active acute myelogenous leukemia (AML). They are readily observed with the light microscope in peripheral blood or marrow films of AML patients stained to show their peroxidatic activity. In many of these patients, Auer rods, which apparently constitute only a small subpopulation of the hydroperoxidase-positive Phi bodies and rods, were detected with difficulty, if at all. The hydroperoxidase-positive Phi bodies and rods were observed in 92% of 36 patients with active disease. They were never observed in leukocytes of patients with other hematopoietic disorders or of normal individuals. Thus, they facilitated the distinction of AML from acute lymphocytic leukemia and chronic granulocytic leukemia in blast crisis. They were absent in full clinical remission after chemotherapy and were greatly diminished in partial remission. They were present in disease relapse and reappeared in five patients who had been in full remission. These results suggest that these hydroperoxidase-positive enlarged particles are pathognomonic of AML and that monitoring them with the light microscope may aid in guiding its clinical management.

High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer.

To evaluate the effect of high-dose chemotherapy in the treatment of metastatic breast cancer, we performed a phase II trial of a single treatment with high-dose cyclophosphamide (5,625 mg/m2), cisplatin (165 mg/m2), and carmustine (600 mg/m2), or melphalan (40 mg/m2) and bone marrow support as the initial chemotherapy for metastatic breast cancer. Twenty-two premenopausal patients with estrogen receptor negative, measurable metastatic disease were treated. Twelve of 22 patients (54%) obtained a complete response at a median 18 days. The overall response rate is 73% (complete and partial response). Median duration of response in the patients achieving complete response was 9.0 months with a median duration of survival for complete responders that is currently undefined. Relapse occurred predominantly at sites of pretreatment bulk disease or within areas of previous radiation therapy. Toxicity was frequent and five patients died of therapy-related complications. The results indicate that a single treatment with intensive combination alkylating agents with bone marrow support can produce more rapid and frequent complete responses than conventional chemotherapy when used as initial chemotherapy for metastatic breast cancer, although median disease-free and overall survival is not improved. Three patients (14%) remain in unmaintained remission beyond 16 months.

Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered.

PURPOSE: To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either > or = three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared. RESULTS: A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or > or = three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P =.03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received > or = three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P =.04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received > or = three cycles of high-dose cytarabine. CONCLUSION: These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.

Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461.

PURPOSE: To examine the prognostic significance of extramedullary leukemia (EML) at presentation in patients with t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS: Consecutive patients with t(8;21) treated on Cancer and Leukemia Group B de novo acute myeloid leukemia (AML) treatment studies were examined for the presence of EML (granulocytic sarcoma, subcutaneous nodules, leukemia cutis, or meningeal leukemia) at initial presentation. Clinical features and outcome of t(8;21) patients with and without EML were compared. RESULTS: Of 84 patients with t(8;21), eight (9.5%) had EML manifesting as granulocytic sarcoma (five paraspinal, one breast, and one subcutaneous) or symptomatic meningeal leukemia (n = 1). The pretreatment prognostic variables of t(8;21) patients with and without EML were similar. The hematologic complete remission (CR) rate for t(8;21) patients with EML was 50% versus 92% for those without EML (P=.006). The median CR duration for EML patients was 14.7 months. Patients with EML had a shorter survival (P = 0.002, median 5.4 months versus 59.5 months). This poor outcome may relate to inadequate local (radiation or intrathecal) therapy for patients with spinal or meningeal EML, resulting in residual/recurrent EML following induction chemotherapy (n = 2) or at relapse (n = 1) and permanent neurologic deficits (n = 4). Only one of the EML patients received high-dose cytarabine (HDAC) intensification; this is the only EML patient remaining alive in CR. CONCLUSION: Patients with t(8;21) and EML have a low CR rate and overall survival. An aggressive local and systemic induction therapy should be considered for this patient subset. The effectiveness of HDAC intensification in t(8;21) patients with EML is uncertain and warrants further study.

Molecular and cytogenetic characterization of a novel rearrangement involving chromosomes 9, 12, and 17 resulting in ETV6 (TEL) and ABL fusion.

We performed chromosome analysis on the bone marrow of a patient with BCR/ABL negative chronic myelogenous leukemia (CML). By interphase fluorescence in situ hybridization (FISH), an extra ABL signal was present in interphase nuclei and appeared to be located at 17p in the metaphase cells. Chromosome analysis showed a subtle abnormality at 17p13 and 12p13 but no visible rearrangement at 9q34 (ABL). Additional FISH experiments disclosed a rearrangement between the short arms of chromosomes 12 and 17 at approximately bands 12p13 and 17p13, respectively. In addition, subtelomeric FISH analysis confirmed the presence of terminal 12p at 17p13 and showed terminal 9q34 to be intact on each chromosome 9. Taken together, these results indicated a rearrangement involving chromosomes 9, 12, and 17 that suggested the possibility of juxtaposition of part of the ETV6 (also known as TEL) locus (12p13) with a portion of ABL (9q34) together at 17p13. The ETV6/ABL fusion was confirmed by RT-PCR, which showed that the first 5 exons of ETV6 were fused in frame with ABL at exon 2. Wild-type ETV6 and ABL were also expressed, in accordance with the FISH results that showed no loss of the second ETV6 or ABL allele.

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial).

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.

Prevention of amphotericin B-induced rigors by dantrolene.

Three patients had severe amphotericin B-induced rigors refractory to conventional prophylactic measures. Rigors improved or disappeared when dantrolene sodium was given prophylactically or during an episode. These observations suggest that dantrolene is useful as an alternative or adjuvant agent for severe rigors associated with amphotericin 3 infusion.

Autologous marrow transplantation for patients with acute myelogenous leukemia--a preliminary report.

Twelve consecutive adult patients with acute myelogenous leukemia have been entered on a treatment protocol which examines the role of "remission-intensification" during maintenance using high-dose chemoradiotherapy and autologous remission marrow transplantation. Nine patients have achieved complete remission: 5/9 patients have had remission marrow stored followed by high-dose chemoradiotherapy and autologous marrow transfusion; two patients were removed from study because of excessive toxicity during remission-induction precluding high-dose therapy; two patients are currently ready for marrow storage; and two patients are receiving remission-induction therapy. Of the five transplanted patients, four experienced excellent return of blood counts and one patient has had prolonged pancytopenia and continues to require red cell and platelet transfusions. There have been no serious infectious or hemorrhagic problems associated with post-transplant period in any of the patients. Autologous remission bone marrow transplantation following lethal high-dose chemoradiotherapy results in effective restoration of normal hemopoiesis, is associated with acceptable toxicity and may be an effective means of increasing the numbers of acute leukemia patients having long-term complete remission.

Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia.

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

Mitoxantrone in the treatment of relapsed and refractory acute leukemia.

Eleven academic institutions were selected to study mitoxantrone administered on a schedule of 10 mg/m2/d for five days initially and later at 12 mg/m2/d for five days, each given as a 30 minute intravenous (IV) infusion each day. Patients with acute or chronic leukemia were stratified by leukemic type and clinical status and included one group of patients considered to be in relapse after complete remission from previous chemotherapy and another group of patients considered refractory to standard induction and/or salvage chemotherapy. During the initial treatment schedule, complete remissions were obtained in two of seven patients with acute nonlymphoblastic leukemia, in one of three patients with acute lymphoblastic leukemia, but in none of the patients with chronic granulocytic leukemia in blast crisis. The durations of remission for these three patients were 22, 57, and 78 days, respectively. An increase in mitoxantrone dose to 12 mg/m2/d produced complete remissions in 8 of 19 evaluable patients with acute nonlymphoblastic leukemia, in one of ten patients with refractory acute nonlymphoblastic leukemia, and in one of four patients with chronic granulocytic leukemia in blast crisis. Each of these patients required only a single course of mitoxantrone to achieve remission; the median time to remission was 37 days (range 18 to 64 days). Remission duration ranged from 35 days (chronic granulocytic leukemia) to 186 days, with the median duration for those patients with acute nonlymphoblastic leukemia achieving remission being 135 days. Of the six patients with acute lymphoblastic leukemia, none achieved remission at the higher dose level. Drug-related gastrointestinal toxicity included mucositis (25%), diarrhea (21%), and nausea and vomiting (61%). Systemic infection (nonfatal) was experienced by 21% of patients and alopecia by 17%. Other side effects that occurred occasionally were hepatic dysfunction, decreased renal function, confusion, lethargy, anxiety, and fever. Possible drug-related phlebitis developed in one patient, and a single episode of minor epistaxis was reported in another. Cardiovascular toxicity was low. At a mitoxantrone dose of 10 mg/m2/d for five days, one patient developed hypotension, and one episode of congestive heart failure was reported in another. At the higher dose of 12 mg/m2/d, no drug-related hypotension, congestive heart failure, tachycardia, or chest pain were reported. These data indicate that mitoxantrone is a promising single drug for the treatment of acute nonlymphoblastic leukemia and possibly for acute lymphoblastic leukemia.

Intraluminal thrombus and bowel obstruction in acute leukemia due to bleeding Meckel's diverticulum.

Gastrointestinal bleeding from Meckel's diverticulum resulted in small bowel obstruction by thrombus in two patients with acute myelogenous leukemia during bone marrow aplasia and recovery from induction chemotherapy. Although gastrointestinal symptoms and complications are common in acute leukemia, these two cases are unique and describe a new syndrome that requires prompt recognition and surgical intervention. The complication of localized bowel obstruction by intraluminal thrombus is heretofore unreported.

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy.

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodgkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients (p less than 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients (p less than 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recurred with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality therapy patients developed acute leukemia.

Left axis deviation and left anterior hemiblock among 8,000 Japanese-American men.

Electrocardiographic patterns of left axis deviation and left anterior hemiblock, defined by a frontal plane QRS axis of minus 30 degrees to minus 44 degrees and minus 45 degrees to minus 90 degrees, respectively, with normal QRS duration, were found to be fairly common (2.6 and 1.5 percent, respectively) in a community population of 8,000 Japanese-American men aged 45 to 69 years. More than 60 percent of men with these electrocardiographic patterns had no other cardiovascular abnormalities, and the incidence of fatal or nonfatal coronary heart disease and stroke in this group during observation periods of 3 to 6 years was not significantly different from that of control normal men. A significant association was found between these electrocardiographic patterns and the prevalence of hypertension, myocardial infarction and stroke. However, the association of myocardial infarction with left anterior hemiblock appeared to be coincidental and was attributed largely to the similarity of the electrocardiographic manifestations of left anterior hemiblock and inferior wall myocardial infarction. Men with left axis deviation were fatter and had higher blood pressure than the control population. No such difference could be demonstrated for men with left anterior hemiblock although this group was significantly older than control subjects and men with left axis deviation. The results of our study suggest that there are qualitative differences between the causative mechanisms and clinical features of left axis deviation and those of left anterior hemiblock.

Predictors of outcome of tricuspid valve replacement in carcinoid heart disease.

The cardiac valvular surgical experience of patients in the Duke Carcinoid Database was reviewed to assess operative outcome. Of the 604 patients in the database, 19 patients with carcinoid heart disease were identified by cardiac catheterization or echocardiography, or both. Eight of these underwent tricuspid valve replacement surgery with bioprostheses (2 also had open pulmonic valvuloplasty). Compared with patients medically managed, surgically treated patients were similar with the exception that they had higher right atrial mean (17 +/- 6 vs 9 +/- 4 mm Hg, p = 0.03) and v-wave (27 +/- 6 vs 17 +/- 7 mm Hg, p = 0.04) pressures. Of the 8 surgical patients, 5 (63%) died within 30 days. Causes of death included tricuspid valve thrombosis, cerebral vascular accident, coagulopathy, renal failure, and intractable right heart failure. High comorbidity was present in all 8 patients. There was a weak trend (p = 0.17) toward lower Charlson comorbidity indexes in survivors (6.7 +/- 0.6) compared with nonsurvivors (7.6 +/- 0.9). Age was significantly lower (p = 0.036) in survivors (46 +/- 13 years) compared with nonsurvivors (69 +/- 4 years). Extended follow-up revealed 2 patients who survived beyond a decade. Review of 47 carcinoid valve replacement cases (Duke Carcinoid Database and 39 published cases) revealed a 30-day mortality of 56% for patients > 60 years of age, and 0% for those < or = 60 years of age (p < 0.0001). Although valve replacement surgery can afford prolonged palliation from carcinoid heart disease, it is associated with a significant mortality risk. Careful preoperative risk stratification by age and comorbidity may provide a means for optimal selection of surgical candidates.

Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells.

Freshly isolated acute non-lymphocytic leukemia (ANLL) cells were treated with the nitric oxide (NO)-liberating compounds sodium nitroprusside or S-nitrosoacetyl penicillamine and analyzed for viability, growth, and differentiation at 3-5 days. NO decreased the viability and the growth of freshly isolated ANLL cells in vitro. NO treatment significantly increased expression of CD14 in blast cells from patients with M5 ANLL, and increased at least one differentiation parameter in M4 or M5 cells. It had little or no effect on parameters of differentiation in other ANLL cells. We conclude that in vitro culture with NO decreases the growth and viability of most freshly isolated ANLL cells. NO also induces the differentiation of ANLL cells with a monocytic phenotype.

Hepatosplenic T-cell lymphoma: an unusual case of a gamma delta T-cell lymphoma with a blast-like terminal transformation.

We describe a case of a middle-aged women who presented with anemia and mild hepatosplenomegaly and who was found to have an unusual peripheral T-cell lymphoma with only subtle morphologically abnormal but mature-appearing cells noted in the blood and bone marrow. Less than 2 years after diagnosis the patient presented with an increasing white blood cell count to 26 x 10(9)/L, and numerous blasts were noted in the periphery. Flow cytometry studies showed cells with an unusual T-cell phenotype expressing the gamma delta T-cell receptor and restricted expression of the V delta 1 but not the V delta 2 protein, indicating the clonal nature of the proliferation. A clonal T-cell receptor gene rearrangement was seen with a V delta 1 probe. The patient died and was found at autopsy to have extensive hepatic sinusoidal infiltration by abnormal cells. The histopathologic, immunophenotypic, and molecular findings are those of "hepatosplenic T-cell lymphoma." In spite of the striking morphologic change during the course of the patient's disease the same phenotype and clonal rearrangement were found both at initial diagnosis and during terminal phase, indicating that this change represented a blast-like transformation of the patient's original lymphoproliferative disorder.

Familial aggregation of multiple myeloma and central nervous system diseases.

Degenerative central nervous system diseases such as Alzheimer's disease and lymphoreticular malignancies such as multiple myeloma occur with increased frequency with advancing age. Relatives of early-onset Alzheimer's disease patients may have an increased risk of lymphoreticular malignancies. This led us to evaluate the family history of central nervous system diseases in a case-control study of multiple myeloma. Thirteen of 439 multiple myeloma cases had one or more first-degree relatives with degenerative or demyelinating central nervous system disease. In comparison, there were nine "positive" family histories in 1,317 matched hospital controls (relative risk = 4.4, 95% confidence interval = 1.9-10.3). Relative risks for the component categories of Parkinson's disease, multiple sclerosis, and miscellaneous degenerative central nervous system diseases were 3.0, 4.0 and 11.9, respectively. Our findings suggest that the degenerative and demyelinating central nervous system diseases and the lymphoreticular malignancies may comprise an etiologically related group of "protean diseases." These diseases may have a shared genetic susceptibility, possibly an immunologic abnormality. The varied disease manifestation in family members suggests a second necessary etiologic step of a variable and possibly environmental nature.