Jumping translocations in leukemia.

Jumping translocations are an unusual phenomenon and have been rarely reported in leukemia. We report three patients whose leukemic cells had multiple related clones resulting from unbalanced jumping translocations of 1q and 7q to chromosomes 1, 8, 15, 21 and 22. The chromosome findings, together with limited published reports, suggest that jumping translocations are new non-random rearrangements and may represent poor prognostic biological markers. Although their origin is unknown, circumstantial evidence suggests that telomeric ends of receptor chromosomes may play a role in stabilizing jumping translocations in dividing malignant cells.

Myelodysplastic syndrome transforming to acute promyelocytic-like leukemia with trisomy and rearrangement of chromosome 11.

Variants of the t(15;17)(q22;q12-q21) chromosomal rearrangement associated with acute promyelocytic leukemia (APL) have been previously described and they frequently involve either chromosome 15 and/or 17. Previously we reported a rare variant t(11;17). We now describe two patients with myelodysplastic syndrome (MDS) that transformed to APL-like leukemia. Both had trisomy 11 at the diagnosis of APL-like leukemia. Following treatment for APL, patient 1 reverted to MDS and showed a normal karyotype. When leukemia recurred, his bone marrow karyotype was 47,XY,t(4;11), +11,der(22)t(1;22). Both patients were treated with all-trans retinoic acid (ATRA) for APL for 5 weeks, but failed to respond. The karyotype of patient 1 after ATRA treatment was 46,XY,t(4;11); the trisomy 11 had been lost and the bone marrow was replaced with immature myeloblasts without promyelocytes. In patient 2, the karyotype remained the same as at diagnosis, i.e., 47,X,-Y,dir ins(4;7),del(5), +6,del(7), +8, + 11,-18. Molecular analysis by reverse transcriptase PCR analysis showed the presence of wild type retinoic acid receptor alpha (RARA) and the absence of the PML-RARA chimeric gene associated with t(15;17). Additional analysis of PLZF, a new zinc finger gene associated with t(11;17), also showed the absence of this hybrid gene. These data support the concept that APL is a heterogeneous disorder and that variants with chromosome 11 rearrangement exist that do not respond to ATRA.

Number of helper T cells and phytohemagglutinin stimulation correlate in cancer patients.

Mononuclear cells from 12 normal controls (co), 10 advanced untreated (c1), and 6 advanced treated cancer patients (c2) have been isolated. The numbers of mononuclear cells bearing Leu1, Leu2, Leu3, Leu2/HLA-DR and LeuM3 were measured with a fluorescence-activated cell sorter. Only the quantity of helper T cells (Leu3) was decreased in cancer patients (co: 0.89, cl: 0.32, c2: 0.44 x 10(9)/l). Expression of all other markers, including activated suppressor T cells (Leu2/HLA-DR), did not differ significantly from the control. The proliferation of the lymphocytes was determined in a phytohemagglutinin-culture assay. The cancer groups showed a significantly decreased response (co: 95.8 x 10(9), cl: 28.7 x 10(9), c2: 25.7 x 10(9) cpm). These values correlated with the number of helper T cells but not with the suppressor T cells. Monocytes of cancer patients absorbed significantly more immunoglobulins than the monocytes of controls. The addition of indomethacin or isoprinosine to phytohemagglutinin-culture assay increased the proliferation of lymphocytes from both the cancer patients and normal controls.

Iatrogenic and idiopathic acute myelogenous leukemia: a comparison of clinical features and treatment complications.

We have compared the clinical and laboratory features as well as treatment complications observed in 6 patients with iatrogenic acute myelogenous leukemia (I-AML) with those of 26 patients with idiopathic acute myelogenous leukemia (AML). I-AML patients were significantly younger and their disease appeared less virulent on admission than in the AML patients. Following identical chemotherapy, hemorrhagic complications and the need for platelet support were found to be similar for both groups. Major infections, including systemic candidiasis and Gram-negative septicemias, occurred 3 times more frequently among I-AML than AML patients. More marked suppression and delayed regeneration of the bone marrow also occurred in I-AML patients. These observations and other factors, such as post-splenectomy state and inherent immune deficiency among surgically staged lymphoma patients as well as radiation induced immunologic impairment, may have contributed to the increased propensity to develop infection observed in this group of patients. Five of the 6 I-AML and 17 of the 26 AML patients achieved remission. We attribute the satisfactory outcome in our I-AML patients to treatment in a protective environment and availability of facilities for hematologic supportive care.

Role of plasmapheresis in primary biliary cirrhosis.

Five patients with primary biliary cirrhosis and prolonged cholestasis underwent intensive plasmapheresis. The indications for plasmapheresis included intractable pruritus or hypercholesterolemia and xanthomatous neuropathy. Patients noted a rapid improvement of pruritus and fatigue which was sustained as long as plasmapheresis was continued. Cholesterol levels were lowered an average of 10.3 mmol/l and xanthomata were reduced in three of four patients. Two patients with painful neuropathy caused by xanthomata experienced relief of this symptom. The liver and spleen size were not affected by plasmapheresis, and activities of aminotransferases, alkaline phosphatase and titres of mitochondrial antibody remained unchanged. We conclude that plasmapheresis has a role in the therapeutic management of patients with advanced primary biliary cirrhosis who are disabled by the complications of pruritus, xanthomatous neuropathy, or hypercholesterolemia with xanthoma formation.

Combination chemotherapy with high-dose methotrexate, bleomycin, and cisplatin in management of head and neck squamous cell carcinoma.

Fifty-nine patients with stage IV head and neck squamous cell cancer were treated with an intensive induction chemotherapy consisting of high-dose methotrexate-leucovorin, bleomycin, and cisplatin. Forty-five patients had recurrent disease following surgery and/or radiation therapy. The response rate in this group was 22%, with a median response duration of 10 weeks and a median survival of 19 weeks. The median survival in responders was 20 weeks and in nonresponders 18 weeks. Fourteen previously untreated patients (13 T4 and one T2) received identical chemotherapy followed by radiation and/or surgery. The response to chemotherapy in previously untreated patients was impressively higher (93%). These patients had a median survival of 48 weeks, and 30% survived 2 years. The initial chemotherapy did not compromise the succeeding radiation therapy or surgery. Toxicities were frequent, but generally well tolerated. It is concluded that prior surgery and/or radiation therapy compromises the efficacy of subsequent chemotherapy in head and neck cancer. Responses to intensive chemotherapy prior to surgery and/or radiation therapy are excellent in patients with T4 tumors and provides a basis for further intensive treatment in attempts to augment cure rates.

The clinical effectiveness and safety of chronic plasmapheresis in patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic nonsuppurative, destructive cholangitis, whose etiology is unknown. Morbidity arises early from pruritus and later from hypercholesterolemia with xanthoma formation. Therapy is supportive and directed at the complications of cholestasis. Plasmapheresis has been reported to benefit patients with hyperlipidemia and PBC; thus a pilot study of plasmapheresis utilizing the Haemonetics Model 30 with replacement by albumin and saline was conducted. Five patients (four female and one male) with a mean age of 43 (range 29-58) and a mean duration of illness of 9.5 years (range 6-21) with marked jaundice, xanthomas, xanthelasma, hepatomegaly, fatigability, anorexia, and pruritus, as well as mild nausea were studied. Peripheral neuropathy was present in two patients. Two patients had splenomegaly. Two patients had an associated Sjogren syndrome. All patients had high serum bilirubin, alkaline phosphatase, and cholesterol levels and mild elevations in aspartate amino transferase and alanine amino transferase activities. Immune complexes measured in four patients were present. Antimitochondrial antibody titers were significant in all patients. Patients underwent a mean of 63 plasmapheresis procedures over a mean of 112 weeks removing a mean of 94.7 liters of plasma. No serious toxicity was seen. All patients showed a reduction in pruritus, xanthomas, xanthelasmas, and serum cholesterol values. The two patients who had evidence of Sjogren syndrome noted subjective improvement. All patients who had fatigue, anorexia and nausea also noted moderate improvement. There was no change in hepatomegaly or splenomegaly in patients demonstrating such organomegaly. Liver function did not change significantly. Overall, four patients had improvement in their condition and one patient achieved stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Extraskeletal Ewing sarcoma with computed tomography correlation.

Extraosseous Ewing sarcoma--a rare clinical entity--is described and the radiographic and histologic features discussed. Histologically this type of tumor may be differentiated from other soft tissue malignancies, but the ultrastructural glycogen content of the cytoplasm makes it frequently inseparable from the conventional osseous form of Ewing sarcoma. In spite of the presence of a huge paraosseal mass with bone erosion or periosteal new bone, computed tomography was the only preoperative modality able to provide evidence of non-involvement of the marrow cavity. However, histologic documentation is necessary to prove that one is dealing with a totally extraosseous Ewing sarcoma.

Role of opsonins in clinical response to granulocyte transfusion in granulocytopenic patients.

Fifty febrile severely granulocytopenic patients were given four daily transfusions of 2.2 X 10(10) normal donor granulocytes. Twenty-three (46 percent) responded clinically, although both responders and nonresponders were similar in clinical characteristics at the outset. This study examines the relation between serum opsonic activity before initiation of granulocyte administration and clinical response. Opsonic activity to three test organisms (Escherichia coli 286 and ON 2, and Staphylococcus aureus) and to 15 blood stream isolates from 14 patients was measured as serum-dependent uptake of heat-killed 14C-labeled bacteria by normal donor leukopheresis granulocytes in an in vitro assay and compared with results obtained with a standard normal serum in each assay. At a concentration of 8 percent serum, all patient groups were equivalent to standard (90 to 102 percent) for the three test organisms. When rate-limiting concentrations of serum (1 to 2 percent) were employed, opsonic activity remained similar to standard for S. aureus in all patient groups and for the two E. coli strains in responders (82 to 98 percent). In contrast, opsonins for E. coli decreased to 41 to 50 percent of standard in nonresponders (p less than 0.01). When patients with proved infection were separately analyzed, opsonin activity for E. coli 286 and ON 2 was significantly greater in responders than nonresponders (73.6 versus 34.9 percent and 124.8 versus 58.1 percent, respectively for the two strains) (p less than 0.01). Patients with opsonin activity of 50 percent or greater of standard had a greater response rate (73 versus 19 percent and 45 versus 0 percent for the two E. coli strains) (p less than 0.005 and p = 0.08, respectively). Eight of 10 patients with 75 percent or greater of standard for opsonic activity against their own blood stream isolates also responded, whereas zero of four with opsonins less than 75 percent of standard had a favorable outcome. These results indicate that serum opsonic activity may be a determinant of clinical response to granulocyte transfusion in infected granulocytopenic patients and may be predictive of outcome. We conclude that opsonic activity should be assessed in such patients before granulocyte administration and suggest a trial of plasma infusion in opsonin-deficient patients.

Therapeutic leukapheresis in a patient with hairy cell leukemia presenting with a white cell count greater than 500,000 /microliter.

A 49-year-old man presented with anemia, thrombocytopenia, and white cell count over 500,000 /microliters. Studies were diagnostic of hairy cell leukemia. Splenectomy was considered hazardous because of his general poor condition and the danger of leukostasis from the high white cell count. He was managed with leukapheresis with reduction in the white cell count from 556,000 /microliters to 20,000 /microliters followed by an uneventful splenectomy. Leukapheresis should be considered for patients with hairy cell leukemia and extremely elevated white cell counts.

Acetylcholine receptor antibodies in myasthenia gravis.

A multivariate statistical analysis of levels of serum acetylcholine receptor antibody (AChR Ab) obtained from 197 patients with various clinical forms of myasthenia gravis (MG) was performed. Elevated AChR Ab levels are specific for MG, but normal AChR Ab levels do not rule out MG. Patients in remission or with purely ocular MG had the lowest incidence of elevation of serum AChR Ab levels, while patients with generalized, severe MG, particularly in the presence of thymoma, tended to have the greatest antibody elevations. Corticosteroids depressed AChR Ab levels, but thymectomy did not exert a consistent effect on antibody levels within a 24- to 30-month postoperative period. The relatively low 55% positivity of antibody elevations in all 197 patients probably reflects the use of heterologous (rat) AChR.

Plasmapheresis in refractory generalized myasthenia gravis.

A group of 16 patients with severe generalized myasthenia gravis (MG) (five with thymoma) that was resistant to anticholinesterases, thymectomy, and corticosteroids were treated by plasmapheresis. Twelve patients showed an excellent clinical response. Plasmapheresis is an effective treatment modality for many patients with severe generalized MG resistant to other forms of therapy. Unfortunately, the beneficial results are only transient and periodic plasmapheresis treatments are necessary.

Filtration versus gravity leukapheresis in febrile granulocytopenic patients: a randomized prospective trial.

Forty-eight patients with fever greater than 38.3 degrees C for at least 24 hr despite broad spectrum antibiotics and an absolute granulocyte count less than 1000/microliter were randomly allocated to 4 days of granulocyte transfusions obtained by leukapheresis using filtration (n = 27) or gravity (n = 21) techniques, the latter permitting simultaneous nonmechanical collection of granulocytes and platelets utilizing hydroxyethyl starch as a sedimenting agent. Patient characteristics and dose of granulocytes obtained from both techniques were similar. Complete response to granulocyte transfusions was established by a reduction in temperature to less than 37.2 degrees C sustained for at least 48 hr after the fourth transfusion with sterilization of cultures where previously positive and diminution of measurable infection when present. This occurred in 6/21 (29%) for gravity leukapheresis and 9/27 (33%) for filtration leukapheresis. An additional group had diminution in temperature and clinical improvement during transfusions (6/21 gravity leukapheresis versus 10/27 filtration leukapheresis). Eighty-six percent of patients transfused with gravity leukapheresis cells were alive at day 20 compared with 81% for filtration leukapheresis cells. Transfusion reactions were comparable. Thus, gravity leukapheresis appears to be as efficacious as filtration leukapheresis for treating granulocytopenic febrile patients, with the added advantages of availability to any blood bank without new equipment, of having platelets as by-products, and of not requiring donor heparinization.

High dose methotrexate followed by citrovorum factor reversal in patients with advanced cancer.

High dose methotrexate followed by citrovorum factor reversal has been utilized in twenty-six patients with advanced cancer. Four of 10 patients with head and neck cancer had an objective response. One of 7 patients with metastatic osteosarcoma to the lungs had stabilization with twenty treatments over 23 months. One patient with acute lymphocytic leukemia developed marrow aplasia but did not attain remission. The regimen was well tolerated when meticulous attention was paid to hydration, urine alkalinization, renal function and third space fluid accumulation. Life-threatening or lethal toxicity was encountered when these phenomena were not scrupulously observed.

Therapeutic leukopheresis of acute myelo-monocytic leukemia in pregnancy.

Cytopheresis techniques have proven useful in the provision of platelets and granulocytes for transfusion to the pancytopenic patient. Mechanical cell removal has been applied to the treatment of chronic myelocytic and lymphocytic leukemias and the Sezary syndrome. We have treated a 16-year-old pregnant acute myelomonocytic leukemia (AMML) patient for 12 weeks solely with the use of intensive leukopheresis utilizing batch processing centrifugation and packed red cell transfusions. The patient presented with a white blood cell count of 54,000/mm3 with 64% myelomonoblasts, a platelet count of 45,000/mm3, marked gingival hyperplasia, and splenomegaly. Patient had a normal spontaneous delivery of a 2.5-kg male infant without complications. At the time of delivery, 12 weeks later, the white blood count had fallen to 4,9000/mm3 with 8% blasts and the platelet count had risen to over 100,000/mm3. Gingival hyperplasia decreased and the patient felt well. We have treated an additional small group of patients with acute myelogenous leukemia (AML) with high white counts with short term intensive leukopheresis followed by chemotherapy with promising results.