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The survival of 137 consecutive chronic lymphocytic leukemia patients, diagnosed between 1960 and 1982 and followed up at the Hematology Clinic of the Chaim Sheba Center, was correlated with demographic, clinical and laboratory data. The median survival time of the whole group was 104 months. Older age, hepatomegaly, anemia, thrombocytopenia and increased percent of lymphocytes in the peripheral blood at diagnosis were all associated with shorter survival. On the other hand, splenomegaly or lymph node enlargement did not influence survival. When divided according to both Rai's and the International Workshop staging systems, the survival of our patients seemed to be better than that reported in most previously published series of similar patients. We assume that this is related to a conservative approach to the treatment of chronic lymphocytic leukemia patients in this center.

Vincristine in a concentration of 0.5 and 4 X 10--(5) M causes a decrease of 16% and 73% respectively, in the synthesis of globin by peripheral blood reticulocytes. At the higher drug concentration alpha/beta ratio is significantly lower than the normal ratio of unity and is 0.83 +/- 0.09. These effects of vincristine are probably related to the ability of the vinca alkaloids to bind to ribosomes and their subunits.

Sixty-three patients with Hodgkin’s disease, in stages I or II, asymptomatic (A) or symptomatic (B), were diagnosed and followed at the Chaim Sheba Medical Center from 1969 to 1976. Only 14 were staged pathologically. Until 1971, the patients received mantle or “inverted Y” therapy only; thereafter, an extended field that included mantle, upper abdomen and spleen irradiation was given. Symptomatic patients, as well as patients with extranodal involvement, received MOPP chemotherapy (nitrogen mustard, vincristine, procarbazine and prednisone) after termination of radiotherapy. Of 51 patients who were in stage IA or IIA, six relapsed 20 to 43 months after irradiation. Three had a pelvic recurrence; two of them were surgically staged. Thus, in only 1 of 51 patients could staging laparotomy possibly have detected pelvic disease and resulted in different therapy. Our results suggest that total nodal irradiation and staging laparotomy are not mandatory in stages IA and IIA of Hodgkin’s disease. The group of 12 symptomatic patients is too small to allow us to draw definite conclusions as to the role of staging laparotomy and adjuvant chemotherapy. However, in view of the high relapse rate in the unstaged symptomatic patients, it seems that chemotherapy should be given to these patients.

Sixty-seven out of 105 (64%) adults with de novo acute myelogenous leukemia (AML), achieving complete remission after induction chemotherapy, entered two successive postremission treatment protocols. Between 1987 and 1989, 35 patients received an intermediate dose of cytarabine (IDAC) along with other drugs. Between 1990 and 1993, 32 patients received high dose cytarabine (HIDAC) with similar other drugs. Patients treated with IDAC had a median survival of 13.8 months (95% CI 11.2-23.1 months) and a 2 year survival of 34.3 +/- 8.0%. Patients receiving HIDAC had a median survival of 35.5 months (95% CI, lower limit 29.8 months) and a 2 year survival of 71.6 +/- 9.4% (P0.002). The 2 year actuarial leukemia-free survival (LFS) was 17.8 +/- 6.6% in the IDAC group and 67.3 +/- 10.0% months in the HIDAC group (P = 0.004). The HIDAC group had a significant 2 year survival advantage over the IDAC group only in patients younger than 45 years. The 2 year survival in the first group was 83.3 +/- 10.8% versus 23.5 +/- 10.3% in the IDAC group (P = 0.0001). In patients older than 45 years, no significant differences in 2 year survival was noticed (52.9 +/- 15.78 versus 44.4 +/- 11.7, P = 0.8). Censoring the 21 patients who underwent bone marrow transplantation (BMT) at BMT did not change significantly the survival analysis of the patients in each group. This study is consistent with previous reports favoring HIDAC intensification in the postremission treatment of young patients with AML.

SUMMARY. Chronic haemolytic anaemia associated with adenylate kinase (AK) deficiency is very rare and only seven cases in five families have been described. We present six children of one family who are deficient of this enzyme and in three of them a combined G6PD deficiency was found. AK deficiency was transmitted by an autosomal recessive gene and heterozygous state was not accompanied by disease, whereas homozygously affected individuals present a congenital chronic non-spherocytic haemolytic anaemia with haemoglobin levels of 8-9 g/dl. Patients also deficient in G6PD suffer from a more severe haemolytic anaemia with haemoglobin levels around 6 g/dl. The AK-deficient children are also mentally retarded. Splenectomy performed in five of the six patients resulted in complete remission of the haemolytic process.

We describe two kindreds of Arab ancestry characterized by multiple cases of acute lymphoblastic leukemia. Consanguinity and intermarriages were prevalent in the two families. Age, mode of presentation, characteristics of the leukemic cells, response to treatment and prognosis were remarkably similar among the patients. A short review of the literature on familial leukemia is given.

Between January 1982 and January 1990, 120 newly diagnosed pediatric patients were treated at The Chaim Sheba Medical Center. Sixty three (52.5%) tumors arose in the posterior fossa and 57 (47.5%) appeared supratentorially. A wide variety of histologic subtypes was seen, each requiring tumor-specific treatment. The modern imaging techniques-CT and MRI-offered better planning of operation, treatment and follow up. All children with highly malignant tumors were treated with combination chemotherapy besides the 'conventional radiotherapy'. Since 1987 the "eight in one day" protocol has been used extensively pre- and post-irradiation. Five-year survival, varied significantly according to tumor type, location and stage. The average delay from presentation of symptoms to diagnosis was 6 months. A multidisciplinary approach has been used in the treatment, rehabilitation and follow-up of these children. In this study, the results of treatment are presented and the role of chemotherapy is discussed.

Between 1983-1988, 72 patients with acute leukemia and 4 with aplastic anemia were treated in the Hematology Unit of The Chaim Sheba Medical Center. Ten patients with acute leukemia developed invasive pulmonary aspergillosis and 2 with aplastic anemia developed invasive aspergillosis of the nose and paranasal sinuses. These infections were diagnosed during a period of profound neutropenia while these patients were receiving broad spectrum antibiotics. The diagnosis of pulmonary aspergillosis was based on positive sputum cultures in 4 cases and on the appearance of typical clinical and radiologic features in six. In 2 culture-positive and in one culture-negative patient, the diagnosis was confirmed at autopsy. Thus, the diagnosis was definitive in 5 patients and probable in the remaining five patients. The 5 patients who achieved remission responded to antifungal treatment and recovered, while of the 5 who eventually died from the fungal infection, 4 did not achieve remission, and one died while in complete remission. In the 2 patients with aplastic anemia, aspergillosis was detected in cultures from necrotic nasal tissue. Both patients remained neutropenic, failed to respond to antifungal treatment and died within a short time after diagnosis. From this experience it appears that invasive aspergillosis in neutropenic patients is potentially curable if treated early by amphotericin B, provided that the neutrophil count recovers.

Dental extraction in patients receiving long-term oral anticoagulant therapy is a controversial issue. Continuation of anticoagulation exposes the patient to serious hemorrhage, whereas cessation of therapy increases the risk of thromboembolism. Forty patients treated by coumarin underwent 63 tooth extractions, without a change in the therapeutic protocol of anticoagulation. The biologic adhesive Beriplast was used successfully to achieve local hemostasis at the site of the surgical wound. Apart from one patient who had mild oozing, there were no incidences of postsurgical hemorrhage.

Familial aggregation of nonhematological malignant disorders (NHMD) was compared in 189 families of patients with hematological neoplasms (HN) with a control group of 36 families of patients with benign hematological disorders and a second group of 33 families of patients with diabetes mellitus. A self-administered questionnaire was used requesting from each family a full list of first- and second-degree relatives, their vital status, current age or age at death, and a list of their chronic diseases, including all malignant disorders. There was no evidence of a significantly increased tendency for developing NHMD among relatives of patients with HN as compared to controls (adjusted odds ratio of 0.88; 95% confidence interval 0.61–1.27). Moreover, in the HN group, no significant difference in the frequency of NHMD was found between the families with and without familial aggregation of HN. Based on the present analysis and our previous observations on familial aggregation of HN, we conclude that the increased aggregation of malignant disorders among relatives of patients with HN is unique to the hematopoietic system and might result from a genetic predisposition to HN in these families.

Background. Cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine (COPBLAM-I) is a second generation combination chemotherapy for intermediate-grade non-Hodgkin's lymphoma (NHL). Since the first report by Laurence et al. in 1982, only a few series were reported on the long term results of this regimen. Methods. In this prospective study, the clinical courses of 51 patients with intermediate-grade NHL (F, G, or H according to the International Working Formulation grading criteria) with a median age of 65 years (range, 55–81), who were diagnosed between 1983 and 1992, are reported. Eligibility criteria included at least one full cycle of the regimen and no previous chemotherapy. Results. A mean of seven cycles (range, two to nine) with two escalations (range, zero to six) was administered. In a median follow-up of 2.4 years (range, 0.5–10), 33 patients (65%) experienced complete remission. The projected 3-year overall survival (OS) and progression free survival rates (PFS) were 58% and 77%, respectively, and the projected 5-year OS and PFS were 52% and 72%, respectively. In only 2 patients (4%) were treatment-related deaths observed, whereas nonfatal complications were more common. Patients in the low risk group, according to the international NHL prognostic index, had the best outcome. The mean percentage of projected dose intensity (DI) was 95% (range, 77–109), whereas no difference in DI was found between patients younger or older than 65 years. Conclusions. In a single center, COPBLAM-I combination chemotherapy was safe and effective for patients older than 55 years with intermediate-grade NHL.

Patients who have recovered from malignant lymphoma are at an increased risk of secondary acute leukemia (AL), and overt AL is frequently preceded by a myelodysplastic syndrome. Although the statistical risk is significant, only a minority of the patients will be so affected. We have reviewed peripheral blood counts of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) treated in the Departments of Hematology at the Edith Wolfson and Chaim Sheba Medical Centers, Israel. Included were only those who went into a complete remission and remained lymphoma free for extended periods. There were 85 patients with HD and 36 with NHL. In both groups peripheral blood counts at diagnosis were within the normal range. A prolonged follow-up (> 4 y), during which no further treatment was given, revealed a sustained increment over time of MCV (delta MCV) both in HD and NHL. A persistent monocytosis in HD patients was also evident. delta MCV was larger in HD. The difference at the end of the follow-up period was as follows: 10.1 fl + 11.8 in HD vs 5.0 fl + 6.2 in NHL, (P < 0.001). In addition, a significant loss of the normal correlation between the MCV and levels of hemoglobin was seen at the last follow-up. The change in MCV was present in all treatment groups, its magnitude increasing from radiotherapy to chemotherapy to combined radio chemotherapy. This trend is in analogy to the risk of secondary AL which is lower in NHL vs HD. Furthermore, it is lowest post radiotherapy and highest when both treatment modalities are used.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary. Advances in molecular biology techniques suggest that many haematological neoplasms originate from a transformation process at the level of the haemopoietic pluripotential stem cell. While familial aggregation has been reported for many haematological neoplasms, most studies were uncontrolled and examined the presence of the same haematological neoplasm as the index case. We assessed the familial aggregation of all haematological neoplasms in 4061 family members of 189 patients with various haematological neoplasms and two control groups: 955 relatives of 36 patients with non-malignant haematological disorders and 508 relatives of 33 patients with type II diabetes mellitus. Data collection included self-administered questionnaires. The odds ratio for haematological neoplasms among relatives of the index cases adjusted for age, sex, ethnicity, number of relatives in the family, and degree of familial linkage in the study group versus the two control groups was 3.62 (95% confidence interval, 1.44-9.07; P

Immunocytologic analyses of bone marrow can provide clinically useful prognostic information in neuroblastoma. While analyzing the bone marrow with a panel of monoclonal antibodies, which detect neuroblasts and other defining B-, T-, and myloid lineage, we identified two infants with stage IV-S neuroblastoma whose bone marrow contained a large population of common acute lymphoblastic leukemia (ALL)-like cells. This population expressed HLA-DR, CD19(B1), CD10(CALLA), and occasionally CD20(B1). Since 1988, 17 additional patients with advanced neuroblastoma (IV-S, III, and IV) were studied by us. In 10 of the 19 patients, the bone marrow revealed an expanded CD10 population (20-70%). It appears that this group of patients has a better prognosis. Out of 9 patients who did not have an expanded CD10 population, 8 died within 9 months from diagnosis, whereas out of 10 patients with an expanded CD10 population only one died and the others are alive, 6-30 months from diagnosis (P < 0.001). An expanded CD10 population in the bone marrow of disseminated neuroblastoma patients may therefore serve as a prognostic factor. Apart from the prognostic value of this particular population in the single patient, its presence may shed light on the interrelationship between the immune system and the neuroendocrine compartment.

Bladder involvement by extramedullary plasmacytoma is a rare condition. A 46-year-old woman with known IgA-lambda multiple myeloma who developed this condition is described. The patient suffered from massive hematuria, which led to hypovolemic shock. Prompt supportive treatment by blood transfusions, fulguration of the bleeding mucosa and continuous bladder irrigation stopped the bleeding. Subsequent bladder irradiation lead only to partial response of the tumor.

We describe 4 male children infected by the human immunodeficiency virus (HIV) who developed Burkitt's lymphoma during their disease. The clinical picture was characterized by an insidious appearance of symptoms. All the children suffered for several months from abdominal discomfort and a gradual elevation of their blood lactic dehydrogenase (LDH) level prior to diagnosis. Bone marrow involvement was found in 2 of the patients and jaw involvement in the other 2. After confirming the diagnosis of Burkitt's lymphoma, they were treated according to conventional protocols, with no need to reduce the dose intensity. They all went into complete remission and did not suffer from major opportunistic infections during chemotherapy. None of them relapsed. Two patients died from opportunistic infections 1 and 3 years after diagnosis. The other 2 are alive, 7 years and 6 months after diagnosis. The various characteristics of this unique pediatric group are described and the comparison of the clinical picture in adults is made, together with a review of the relevant literature. © 1993 Wiley-Liss, Inc.

• Objective. —To evaluate the workup and treatment of children with lymphoma and superior vena cava syndrome. Design. —A retrospective survey. Setting. —State hospital serving as a secondary and tertiary referral center for pediatric oncology and pediatric cardiac surgery. Participants. —Eleven children aged 11 months to 12 years diagnosed as having lymphoma or T-cell acute lymphoblastic leukemia who presented with superior vena cava syndrome during an 11-year period. Interventions. —Lymph node biopsy (two patients), thoracenthesis (five patients), bone marrow aspiration (two patients), and thoracenthesis in addition to bone marrow aspiration (two patients). All aspirates were evaluated with immunohistochemical studies. Chemotherapy was the only management intervention. Results. —T-cell lymphoma or leukemia accounted for nine cases and Hodgkin's disease for two cases. Respiratory symptoms occurred in 10 patients, including tracheal compression in six patients (compression was life-threatening in one patient). Diagnosis of superior vena cava syndrome was achieved in eight patients using surface-marker analysis of aspirates. The syndrome disappeared within 2 to 10 days. Seven of nine children whose conditions were diagnosed more than 1 year before this writing were alive and free of disease after mean follow-up of 37 months. Conclusions. —(1) A specific diagnosis can be achieved in most children with superior vena cava syndrome and lymphoma; (2) Thoracic computed tomographic scans are essential, identifying minute pleural effusions that can aid diagnosis; (3) Anesthetic hazard is related only to severe tracheal compression; (4) Chemotherapy achieves excellent symptomatic relief; and (5) Long-term survival, without disease, is achievable. ( AJDC. 1992;146:1060-1063)

Immunophenotyping of bone marrow mononuclear cells of 2 infants with stage IV-S neuroblastoma revealed the presence of many lymphoblasts and immature lymphocytes. Immunophenotyping showed that a high percentage of bone marrow cells were positive for the HLA-DR, CD19, CD20 and CD10 phenotype, similar to common acute lymphoblastic leukemia cells. Within 6 months of follow-up, without any treatment, complete regression of the tumors was observed. The coexistence of these two unusual populations will be discussed.

Patients undergoing cardiac operations constitute the majority of recipients of fresh frozen plasma. In most centers the reason for transfusing fresh frozen plasma is to replace clotting factors. However, the decrease of clotting factors during cardiopulmonary bypass is not sufficient in most patients to cause abnormal bleeding. One of the major causes of nonsurgical bleeding after cardiac operations is acquired platelet dysfunction, which can be corrected by transfusion of 1 unit of fresh whole blood. Because plasmatic factors in fresh whole blood may be responsible for this improvement, a study was designated to evaluate the effect of transfusing fresh plasma on platelet function after cardiac operations. Forty patients undergoing cardiopulmonary bypass were randomized to receive either fresh plasma or the fresh packed cell fraction. Administration of packed cells increased platelet number (118 +/- 8.5 to 154 +/- 7.6 x 10(9)/L, p less than 0.05), shortened bleeding time (7.57 +/- 0.4 to 4.0 +/- 0.3 minutes, p less than 0.05), and improved platelet aggregation in response to collagen and epinephrine (32% +/- 4.7% to 50% +/- 5.6% and 37% +/- 5.8% to 50% +/- 5.8%, respectively, p less than 0.05). Fresh plasma, however, neither increased platelet number nor improved bleeding time or platelet aggregation. Each group later received the remainder of the blood unit, with similar results. The results suggest that improvement of platelet function in patients receiving fresh whole blood after cardiac operations is not related to plasmatic factors. Therefore the massive use of fresh frozen plasma in patients after cardiopulmonary bypass should be reconsidered.

Patients with uremia have excess levels of parathyroid hormone (PTH). It has been reported that excess PTH is associated with bone marrow fibrosis. The present study was undertaken to examine the in vitro effect of intact 1-34 PTH and the active 1-34 N-terminal fragment on human bone-marrow-derived fibroblasts. Proliferation of fibroblasts was not stimulated by PTH in concentrations present in uremia (5-30 U/ml) nor by uremic sera which contained either high or low PTH levels. The lack of stimulation contrasted with the activity of both PTH preparations in other systems, i.e., inhibitory to erythroid colonies and stimulatory to heart muscle cells.

Clinical features, leukemic cell characterization, chromosomal findings, and treatment outcome were analyzed in a retrospective study of 30 cases with acute leukemia of infancy, 24 infants with acute lymphoblastic leukemia (ALL), and six cases with acute nonlymphoblastic leukemia (ANLL). Extensive bulky disease with organomegaly, central nervous system (CNS), and skin involvement were prominent features at diagnosis with a higher frequency in ANLL as compared to ALL. Four of six ANLL patients were classified as monocytic or myelomonocytic. In the ALL group nine of 24 (36%) were non-L1 morphology and six of 17 (33%) were common ALL antigen (CALLA) negative, the majority of them (five of six) were included in the non-L1 group. Immunophenotyping revealed four cases with early B-cell (three patients: Ia+B4+, and one patient: Ia+) and two cases with T-cell. Mixed lineage leukemia was found in five infants. Heavy chain immunoglobulin gene rearrangement was present in six cases tested, two CALLA+, two with Ia+B4+, and two were undifferentiated mixed lineage leukemia. Chromosomal aberrations were detected in ten of 18 patients, mostly in ANLL and CALLA negative ALL. Translocations were detected in six patients, involving 4q21-23 and 11q23 in three and two cases, respectively. The probability of five-year DFS were 27% for the whole group. The worst prognosis was observed in infants younger than 6 months of age, in whom the leukemia cell characteristics was compatible with stem cell: ANLL, very early pre-B, or undifferentiated mixed type. The chromosomal aberrations found in all cases included translocation with the seemingly nonrandom breakpoints at 4q21 and 11q23, and breakpoints that corresponded to known fragile sites. This finding may be suggestive of an underlying genetic predisposition associated with the poor prognosis of leukemia of infancy.

The proliferation of bone marrow (BM)-derived fibroblasts and granulocyte-macrophage progenitors (GM-CFC) was studied in culture in 23 patients with acute leukemia (AL). The number of GM-CFC colonies was significantly lower in patients with infiltrated BM when compared to those in remission: 17 +/- 12 vs. 125 +/- 35 colonies per 2 X 10(5) cells (p less than 0.005). The proliferation of fibroblasts derived from leukemic BM was significantly more active in acute nonlymphocytic (ANLL) than in acute lymphoblastic leukemia (ALL): 6.8 +/- 3.2 X 10(5) vs. 2.8 +/- 1.8 X 10(5) fibroblasts per flask (p less than 0.05). The reduced GM-CFC colony formation correlated significantly (r = 0.84; p less than 0.02) with the reduced fibroblast proliferation in patients with ALL but not in those with ANLL. Supernatants from fibroblast monolayers stimulated additionally normal GM-CFC cultured in the presence of a potent conditioned medium as the source of colony stimulating activity. Fibroblast supernatants derived from BM with leukemic infiltrates, stimulated the incorporation of 3H-thymidine by monolayers of normal bone marrow fibroblasts but had no effect on ANLL fibroblasts.

A group of 76 polycythemia vera patients was followed prospectively with bone marrow examinations at regular intervals. Six terminated in acute leukemia, preceded by an indolent preleukemic phase succeeded by a very fulminant leukemia. At autopsy, all patients had extramedullary hematopoiesis. In one of them, only the bone marrow was leukemic, suggesting that it was the primary site of this transformation. In three with leukemic involvement of nonhematopoietic organs, the infiltrate consisted of myelo- or myelomonoblasts and normoblasts. The preleukemic phase was characterized by a rapidly evolving spontaneous pancytopenia, with a drop from polycythemic blood counts within 2 mo. In the bone marrow, megaloblastoid erythropoiesis with ring sideroblasts was prominent. A similar preleukemic phase evolving in other potentially leukemic conditions, has been described. Therefore, in patients at risk, the appearance of ring sideroblasts may be regarded as an early indicator of imminent acute leukemic transformation.

SummaryTwenty two patients (12 males and 10 females) from all over Israel fulfilled the ‘Criteria for establishing the diagnosis of Glanzmann’s thrombasthenia. All have been observed to have a severe bleeding tendency since infancy or early childhood. In 8 out of 10 adult patients (7 females and 3 males) the bleeding manifestations have persisted over the years. In 2 adult patients major surgery was performed under platelet transfusions which appeared to prevent excessive bleeding. Pedigree analysis was possible for 21 patients who belong to 13 unrelated kindreds. Twelve kindreds are Jewish and one is Arab. Eleven of the 12 Jewish kindreds belong to the Iraqi Jewish community. Analysis of 16 sibships disclosed a corrected segregation ratio of 0.2, which is compatible with an autosomal recessive mode of inheritance. No bleeding manifestation whatsoever were observed in 30 obligatory carriers of thrombasthenia, and the haemostatic functions tested in 12 of them were entirely normal.

The α to β globin chain ratio has been determined in the peripheral red cells of 11 patients with iron deficiency anemia. The mean ratio was found to be 0.74 ± 0.07, which is significantly lower than the ratio of 0.97 ± 0.07 obtained in normals. When the stroma-free hemolysates were purified prior to globin preparation the α to β ratio did not change. On the other hand, globin extracted from whole iron-deficient cells, including the stroma, had a higher α to β ratio, 0.88 ± 0.04, but still significantly lower than normal. These results suggest that in iron deficiency there is a decrease in α-chain synthesis relative to β-chain and that there are membrane-bound globin chains, but no excessive increase in the free α-chain pool. Similar findings have been reported previously in other states of heme deficiency like sideroblastic anemia and lead poisoning.

α, β, and γ globin chain synthesis in bone marrow and peripheral blood reticulocytes were studied in two patients with thalassemia major, two with thalassemia intermedia, one with thalassemia minor, one with Hb H disease, and one with homozygous βδ-thalassemia. Nine nonthalassemic patients served as controls. In thalassemia major, a marked imbalance of α- to β-chain synthesis was found in the bone marrow as well as in reticulocytes. The imbalance, however, was slightly more evident in the latter. In the patients with thalassemia intermedia and minor the α- to β-globin chain ratios in the reticulocytes were of the same order of magnitude, despite the marked clinical differences between thalassemia intermedia and minor. A balanced synthesis was found in the bone marrow of the patient with thalassemia minor. The bone marrow globin synthesis in thalassemia intermedia was not studied. Contrary to that in Hb H disease and βδ-thalassemia, the imbalance was more apparent in the bone marrow. In the latter, no evidence for imbalance was detected in the reticulocytes. These results point out the need for further studies on globin chain synthesis in the bone marrow and reticulocytes of patients With the various thalassemia syndromes and the effect of the free globin chain pool on those results.

An Arab family with three homozygotes for βδ-thalassemia is described. The single hemoglobin present in their red cells is fetal hemoglobin. A mild hemolytic condition was seen in the propositus, while the two other siblings are completely normal. The main differential diagnosis of this condition is homozygosity for persistent fetal hemoglobin gene.

The problem whether patients with sickle cell anemia have not only a pathologic (type S) hemoglobin, but also an abnormal myoglobin, was investigated by means of spectroscopic and electrophoretic methods. Purified, hemoglobin-free met-myoglobin preparations, obtained from normal adults and from individuals with sickle cell anemia, were compared. No differences could be detected with either technic. The electrophoretic studies revealed that adult met-myoglobin moves faster in an acid than in an alkaline buffer. Regardless of the buffer used, adult met-myoglobin moves always slower than either met-hemoglobin A or S. The met-compounds of hemoglobin A and S move faster than their respective oxy-compounds in an acid medium, but slower in an alkaline medium.

Summary. Factor VII was purified from a lyophilized powder of PTC complex (Hemoplex, Cutter Laboratories) and an antiserum was prepared in rabbits to the partially-purified fraction. The antiserum was found to inhibit specifically factor VII of normal plasma and the activity of the purified factor-VII preparation. Inactive factor-VII-like material was detected in the plasma of one out of nine patients with factor-VII deficiency and the Dubin-Johnson syndrome (DJS), as well as in the plasma of patients on short-term Coumadin therapy. No inactive factor VII could be detected in the plasma of patients on prolonged Coumadin therapy or in the plasma of two patients with hereditary factor-VII deficiency. The methodological problems are discussed.

This study was aimed to find a correlation between the extent of concanavalin A (Con A) binding to lymphocytes and the blastogenic effect of the lectin on these cells. 63Ni-labeled Con A was used in the lectin-binding experiments. Binding of Con A to a small fraction (approximately 3%) of Con A binding sites in rat lymphocytes is required for the maximal stimulation of RNA synthesis. Binding of Con A to additional sites resulted in a less stimulatory effect. Lymphocytes from patients with chronic lymphatic leukemia (CLL) are impaired in their blastogenic response to Con A. Maximal stimulation of DNA synthesis induced by Con A in CLL lymphocytes is attained by treatment of the cells with the lectin at concentrations that are smaller than those required for the induction of maximal DNA synthesis in normal lymphocytes. The number of Con A binding sites in CLL lymphocyte is smaller than in normal lymphocyte.

Lymphoma of the small intestine can occur as a late, secondary manifes­ tation of disseminated lymphoma or, far less commonly, as a primary lesion, originating in the small intestine or its mesenteric nodes (1-5). The latter disease can be further subdivided into two categories: (a) solitary lymphoma, occurring most commonly in the terminal ileum and en­ countered most often in young children; (b) diffuse or multi focal small in­ testinal lymphoma, occurring most commonly in the proximal small intestine and encountered primarily in older age groups. The last of these entities differs from the other two in several important respects-most notably in the presence of malabsorption (3-5) . This hallmark of diffuse primary small intestinal lymphoma tends to dominate the clinical course until its ter­ minal stage and may in fact antedate all manifestations of neoplasia by months or years. The latter phenomenon has led inevitably to speculations concerning the existence of antecedent predisposing disorders of the small intestine or of its associated lymphoid elements. Indeed, an impressive num­ ber of cases have reportedly occurred in the course of well-documented ce­ liac sprue, although many others have failed to exhibit evidence discernible by ordinary light microscopy of any pre-existing small bowel disease (611) . The syndrome of intestinal lymphoma with malabsorption, as rigorously defined by Eide1man et al in 1964 (9), occurs only rarely in the highly de­ veloped countries of the WesU Reviewing the medical literature of the West, those authors were able to find only 48 cases (of which they regarded 32 as well-established and 16 as probable) . On the other hand, the syndrome is not at all rare among certain populations whose common denominator appears to be that they are (or were until recently) underprivileged in terms of nutrition, housing, hygiene, and medical care. In Israel, for exam­ ple, the syndrome is relatively prevalent among Arabs and among first and second generation Jewish immigrants from the Middle-East and North Af­ rica, but it is virtually nonexistent among Jews of European origin (1214) . It also appears to be relatively common among several other widely

The presence of a temporal order in living systems is manifested in biological rhythms. Attention was focused on the presence of diurnal and circadian rhythms. In view of the easy availability of leucocytes on the one hand and their involvement in numerous pathological conditions on the other, a study on the diurnal activity of six white blood cell (WBC) enzymes was performed in normal individuals. In one group of subjects the activities of four of the enzymes were measured twice a day for three consecutive days and in another group the enzyme activities were determined every 4 hrs for 24 hrs. Diurnal variations in the total WBC number, as well as in the relative amounts of lymphocytes, granulocytes and monocytes were observed. Oscillation in the enzymatic activities demonstrated a nearly circadian rhythm. Since the enzymatic activities differ from day to day, it is plausible that the diurnal rhythm is part of a more complicated (weekly or monthly) oscillatory process.

Surgical specimens, postmortem material, or both from 22 patients with the syndrome designated as “Mediterranean abdominal lymphoma with malabsorption” were studied in detail. All patients exhibited a malabsorption syndrome. In most of those carefully followed from the onset of the disease, the syndrome seemed to have preceded the development of palpable abdominal masses. In 20 of the 22 patients, intestinal tissues were available for histologic study. In all specimens, diffuse severe plasma cell infiltrations were evident in the intestinal mucosa and submucosa. Malignant lymphomas in the form of single or multiple circumscribed intestinal tumors occurred in 14 of these 20 patients and malignant lymphomas of the mesenteric lymph nodes in two. In four patients, no malignant lymphomas were evident. These observations suggest that the diffuse plasma cell infiltrations, rather than the malignant lymphomas, were responsible for the malabsorption syndrome. There was no morphological evidence that the malignant lymphomas observed in 75% (16 of 20) of the patients were histogenetically related to the diffuse plasma cell infiltration. The possibility is suggested that this abnormal, though not provably neoplastic, proliferation of plasma cells is a morphological manifestation of an immune deficiency state which predisposes the patients to the development of malignant lymphoreticular neoplasms.

A patient with Hageman factor (HF) deficiency is described. This syndrome is characterized by complete absence of any hemorrhagic tendency in the presence of laboratory findings which, as a rule, are associated with severe disturbances in the hemostatic mechanism. The clotting time was markedly prolonged, the plasma prothrombin time was normal, but prothrombin consumption was decreased. The thromboplastin generation test revealed that HF is essential for blood thromboplastin formation at least in vitro. Procedures for the differentiation of HF deficiency from AHF, PTC and PTA deficiency syndromes are outlined. Transfusions of as little as 50 cc. of 20 day old blood normalized the abnormal clotting tests immediately for a period of about 36 hours. The basis for the apparent lack of need for preoperative preparation with blood transfusions in HF deficiency is discussed.

Rosenthal, Dreskin and Rosenthal (1953) described a familial haemorrhagic disorder due to plasma thromboplastin antecedent (PTA) deficiency. Further studies have established the properties of this factor and its action in the early phase of thromboplastin generation (Rosenthal, 1954; Rosenthal, Dreskin and Rosenthal, 1955; Ramot, Angelopoulos and Singer, 1955; Campbell, Mednikoff and Dameshek, 1957; Cavins and Wall, 1960). The mode of hereditary transmission of this deficiency has been discussed by various authors (Cavins and Wall, 1960; Campbell et al., 1957; Rosenthal et al., 1955). Recently Rapaport, Proctor, Patch and Yettra (1961), using a quantitative assay of PTA, suggested that this deficiency is transmitted by an intermediate gene, which produces major PTA deficiency in the homozygote and minor PTA deficiency in the heterozygote. In the present communication, 10 families with PTA deficiency will be described and the mode of its inheritance will be discussed.

A case of acute myeloid leukemia supervening upon a long-standing stable chronic lymphatic leukemia (CLL) diagnosed ten years earlier, is described. Thirty-three cases of acute leukemia terminating CLL were reported. All but three were treated prior to the emergence of the acute leukemia. The question of whether acute leukemia and other malignancies are more frequent in CLL is still controversial. The literature is reviewed.

In view of the reported associations of Hodgkin's disease and ferritin, an electron microscopic study of the peripheral blood lymphocytes of these patients was done. In 5 out of the 6 patients studied intracellular ferritin deposits were seen. No such deposits were seen in the lymphocytes of healthy subjects or in those of a patient with beta-thalassemia. The lymphocyte ferritin accumulation in Hodgkin's disease can arise either from increased synthesis or from phagocytosis.

Serum immunoglobulin levels were periodically determined in 70 CLL patients and the changes were correlated with several clinical and laboratory parameters. It was found that the IgG and IgA levels decreased significantly as the disease progressed. A low IgG concentration was found at the time of diagnosis in 18.7% and after six years in about 50% of the patients. The IgM concentration, although initially low, increased during the follow-up in 43% of the patients and in four of them a monoclonal fraction appeared in the serum. The changes in the immunoglobulins did not correlate with age, sex or initial leukocyte count. Stage O patients as well as untreated patients also had a decrease in their immunoglobulin levels but advanced disease stage and especially continuous chemotherapy seemed to augment the drop in the immunoglobulin levels. Neither the initial immunoglobulin levels nor the subsequent changes, absolute or relative, had a significant prognostic value.

SUMMARY. The activities of glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP oxidoreductase, G6PD), 6 phosphate glucono dehydrogenase (6 phospho-D-gluconate: NADP oxido reductase, 6PGD) lactate dehydrogenase (D-lactate: NAD oxidoreductase, LDH), glutamate oxaloacetate transaminase (L-aspartate: 2-oxo-glutarate aminotransferase, GOT) and hexokinase(ATP: D-hexo-6-phosphotrans-ferase, Hx) were measured over 24 h in isolated lymphocytes of normal subjects and in white cells of patients with chronic lymphatic leukaemia (CLL). The activity patterns of all enzymes in the normal lymphocytes were similar. A computed pattern of all the results exhibited a circadian rhythm of activity with the highest level at 16.00 hours. The oscillations in the activities of the same enzymes in the CLL cells differed among the patients, although all the enzymes of the same individual showed a similar diurnal rhythmic pattern. All peaks in this group appeared between 20.00 and 08.00 hours. The possible importance of these observations in setting up therapeutic schedules was raised.

The effect of extracorporeal circulation on platelet count and size (mean platelet volume) was studied in 65 patients (nine bleeders and 56 nonbleeders). In addition to the above, in 20 of the patients platelet aggregation response to adenosine diphosphate, collagen, and ristocetin was measured. Platelet counts dropped postoperatively both in the bleeder and in the nonbleeder groups. The difference between them was not significant. However, the bleeders had a significantly lower mean platelet volume (7.7 +/- 0.84 versus 8.68 +/- 1.1 fl) and lower volume percentage of platelets in whole blood (0.075% +/- 0.02% versus 0.116% +/- 0.04%) (p less than 0.05) than the nonbleeders. None of the bleeders had a volume percentage of platelets in whole blood higher than 0.095%. All 20 patients studied for platelet functions had an abnormal postoperative aggregation response to adenosine diphosphate, collagen, and ristocetin. Three patterns of disturbed response to ristocetin were observed: grade I, delayed onset (14 patients); grade II, incomplete aggregation (five patients); and grade III, total lack of aggregation (one patient). All patients with delayed-onset response to ristocetin had a normal bleeding time, whereas the six patients with grade II and III responses had prolonged bleeding times and three of them had clinically significant bleeding. Factor VIII procoagulant activity, factor VIII-related antigen, factor VIII-ristocetin cofactor, and factor VIII two-dimensional electrophoresis were found normal, which suggests that the von Willebrand-like reaction to ristocetin observed in this study was caused by a defect in platelet membrane rather than by factor VIII changes.

We report 2 patients with idiopathic refractory sideroblastic anemia who developed chronic myelomonocytic leukemia 1 to 5 yr later. This observation supports the decision of the FAB cooperative group to include both conditions in the category of myelodysplastic syndrome.

Intracranial hemorrhage (ICH) is a life-threatening complication of hemophilia. Seven of the 288 hemophiliacs living in Israel suffered eight episodes of ICH during the years 1972 to 1982. All episodes occurred in hemophilia A patients, with a higher incidence among patients with factor VIII inhibitor. Diagnosis was confirmed by computed tomographic scan in seven of the eight episodes. Four of the 7 patients died despite adequate factor replacement and supportive therapy, probably due to a conservative and hesitant neurosurgical approach. The correction of factor VIII to hemostatic level alone is inadequate in the majority of cases, and there is sudden deterioration in the patient's condition and death. Operation is strongly recommended when no improvement is noted within a few hours.