[Macrophage activation syndrome, hemophagocytic syndrome]. / Syndrome d'activation macrophagique (syndrome d'hémophagocytose).

Macrophage activation syndrome MAS describes the clinical, biological and histological symptoms related to a probably T lymphocytes/NK cell driven stimulation of macrophages with the consequence of a hemophagocytosis involving numerous organs, preferentially bone marrow, explaining the other term of "hemophagocytic syndrome". Clinical symptoms include cytopenia, multiple organ dysfunction, fever unresponsive to antibiotics, fatigue and rash. Infections (bacteria, virus or parasites), lymphoproliferative disorders, cancers, systemic diseases are the most prevalent triggers or etiologies of M.A.S. Evidence of haemaphagocytosis is obtained in the majority of cases with bone marrow specimens. In some cases haemophagocytosis can spare the bone marrow with involvement confined to other tissues such as liver and spleen. Very high levels of ferritine seem to correlate well with the presence of haemophagocytosis and is a possible marker for an early diagnosis. Early treatment initiation is mandatory. Corticosteroids, cytostatic drugs such as etoposide, cyclosporine A, plasmapherese, intravenous immunoglobulins and anti TNFalpha are proposed but no randomized trials were published.

Pleomorphic medium-sized T-cell lymphoma following Hodgkin's disease (nodular sclerosis type).

We describe a 32-year-old woman who presented with Hodgkin's disease, nodular sclerosis type II, subtype I, which necessitated several treatments over 11 years. The patient then developed pleomorphic, medium-sized T-cell lymphoma, which had a fatal outcome within 13 months. The role of radiotherapy, splenectomy, and chemotherapy in second tumor induction is compared with other sequential T-cell lymphomas. The significance of rare Epstein-Barr virus-infected cells during the T-cell lymphoma extension is discussed.

[Relapsing polychondritis, thrombosis and antiphospholipid antibodies]. / Polychondrite atrophiante, thromboses et anticorps antiphospholipides.

The authors report a case of relapsing polychondritis associated with antiphospholipid antibodies. The initial manifestations were recurrent venous thrombosis which occurred prior to the chondritis. Antiphospholipid antibodies are found in various diseases, some of which are sometimes associated to relapsing polychondritis. However, antiphospholipid-antibodies have not yet been reported in this disease.

Longitudinal melanonychia induced by hydroxyurea: four case reports and review of the literature.

Although the occurrence of skin lesions during long-term hydroxyurea therapy is well known, longitudinal melanonychia (LM) are more rarely described. In the present paper, we report four cases of LM associated with skin lesions induced by long-term daily hydroxyurea therapy (4 to 10 years), characterized by two uncommon aspects: late onset (2.5 to 5 years) and predominance of toenail involvement in three cases.

Cardiac localization of non-Hodgkin's lymphoma: two case reports and review of the literature.

Secondary non-Hodgkin's lymphoma of the heart (SNHLH) are more frequent than primitive non-Hodgkin's lymphoma and represent the third most common malignant tumour of the heart in autopsy studies. Cardiac involvement usually occurs as a late manifestation in patients with disseminated disease. Initial cardiac lymphoma, defined as cardiac involvement at initial diagnosis with concomitant extracardiac localizations, have nevertheless been reported in approximately 42 cases. The present paper concerns two patients with non-Hodgkin's B-cell lymphoma where cardiac involvement occurring 3 and 6 years after initial diagnosis constituted the unique site of relapse. These cases differ from previous reports of the literature by the predominance of extranodal localizations at initial diagnosis and the late onset of cardiac involvement. Clinical and radiological findings were otherwise in accordance with those usually described in such patients. Transthoracic echocardiography revealed the cardiac tumour in the first case, but in the second case transoesophageal echocardiography and magnetic resonance imaging (MRI) were required to demonstrate its presence. As in most reports, the site of tumour involvement was the right cardiac cavity and histology showed high grade B-cell non-Hodgkin's lymphoma. Polychemotherapy, associated with radiotherapy in the second case, led to partial or complete remission of the cardiac tumour without recurrence within the months of follow-up, although both patients died of their disease within one year.

[Varicella-zoster virus pancreatitis in hematologic diseases]. / Pancréatites zostériennes au cours des hémopathies.

We report four cases of varicella-zoster pancreatitis in immunocompromised hosts. All 4 patients presented a severe immunodeficiency because of chronic lymphoproliferative disorders (mainly lymphoma and Hodgkin disease) and long-term immunosuppressive therapy. Varicella zoster pancreatitis is a very unusual presentation of varicella-zoster infection. Few cases of pancreatitis occurring after bone marrow transplantation have been reported. All 4 patients presented with acute epigastric pain associated with transient elevation of serum amylase. The vesicular rash followed the presenting symptoms of severe abdominal pain by 8 days. This clinical presentation, occurring in immunocompromised patients, defines a set of symptoms which should lead the physician to suspect varicella-zoster pancreatitis, even in the initial absence of the characteristic skin vesicular eruption. Early institution of antiviral therapy seems mandatory.

Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells.

All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with "virgin"-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.

Association between leukemic erythroid progenitors and bone marrow macrophages.

Previous ultrastructural investigations have shown that the erythroblastic island is composed of erythroblasts at different stages of maturation which are intimately associated with a central macrophage. However, it is still unclear at which stage of erythroid differentiation this interaction occurs, mainly because of the lack of purified populations of normal erythroid progenitors [erythroid colony-forming units (CFU-E) and erythroid burst-forming units (BFU-E)] and early precursor cells (proerythroblasts) and because of our limited knowledge of their ultrastructural characteristics. In the present work we analyzed the ultrastructure of CFU-E enriched from normal human bone marrow by avidin-biotin immune rosetting and leukemic blasts of erythroid origin from two patients. Normal and leukemic CFU-Es were defined as glycophorin A (GPA)-negative blasts, devoid of rhopheocytosis, containing some ferritin molecules, either free in the cytoplasm or associated with theta-granules (theta-Gr) in the Golgi zone. Peroxidase activity was detected in the endoplasmic reticulum of these blasts. A preproerythroblast stage was identified, which corresponded to an intermediate phenotype with few GPA sites and rhopheocytosis. In contrast to hemoglobin synthesis, which was absolutely dependent on the presence of erythropoietin (Epo) during culture for 24 hours, ferritin molecules accumulated in the absence of Epo. Interestingly, leukemic CFU-E-like blasts were always in contact with bone marrow macrophages and adhesion between these cell types resisted mechanical dissociation. This result suggests that erythroid progenitors may be part of the erythroblastic island. The mechanisms involved in erythroblast-macrophage binding are still unknown, but the expression by macrophages and erythroid progenitors of receptors for fibronectin and thrombospondin (TSP), as well as their respective ligands in the case of macrophages, suggests that these molecules could be involved in the formation of the erythroblastic island.

Expression of platelet glycoproteins by erythroid blasts in four cases of trisomy 21.

In four patients with trisomy 21 (three constitutional, one acquired) with a morphological undifferentiated leukemia, diagnosis of erythroid leukemia was established by both immunophenotyping and ultrastructural studies. Indeed, a majority of blasts from three patients expressed several erythroid markers such as carbonic anhydrase 1, spectrin beta chain, and glycophorin A. In addition, band 3 and hemoglobin were immunologically detected in a fraction of the blast cells from two cases. At ultrastructural level, a majority or all blast cells exhibited erythroid differentiation features such as theta granules and ferritin molecules. However, platelet glycoproteins GP Ib, GP IIb, and GP IIIa were also immunologically detected in a fraction (from 14-82%) of the blasts. Since the ultrastructural study indicated that some promegakaryoblasts were also present in three patients, double labeling between erythroid markers (glycophorin A or carbonic anhydrase I) and platelet glycoprotein (Ib or IIIa) was performed and showed a clear overlap between the two kinds of markers. A similar approach was performed at ultrastructural level and indicated that blast cells with ultrastructural erythroid features of differentiation may have three distinct phenotypes, i.e., presence of glycophorin A without platelet glycoproteins or, conversely, the presence of platelet glycoproteins without glycophorin A and coexpression of glycophorin A and platelet glycoproteins. Expression of glycophorin A correlated directly with the differentiation level of the erythroid blasts, whereas platelet glycoproteins were essentially expressed in the more primitive leukemic erythroid cells. The GP Ib synthesized by these blasts was subsequently studied. The GP Ib alpha mRNA analyzed by Northern blot from these erythroid cells was identical in size with that from megakaryocytic cells as was the molecular weight of the GP Ib molecule from both after immunoprecipitation by a monoclonal antibody. Therefore, "in vivo" erythroid leukemic cells may express the main platelet glycoproteins including GP Ib.

High dose chemotherapy and autologous bone marrow transplantation in refractory Hodgkin's disease.

Seventeen patients with Hodgkin's disease (HD) were treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT). Eleven patients were resistant to initial therapy. Three patients had relapsed and were still responders to second or third line therapy. Three patients had relapsed but were progressing under second or third line therapy. Pre-ABMT chemotherapy included high dose cyclophosphamide in all patients (50 mg Kg-1 day-1 bolus for 4 days), most often associated with BCNU or CCNU, aracytine and 6 thioguanine. Four patients received additional TBI (10 Gy). In 9 patients complete remission (CR) was achieved, 4 failed to respond and 4 cases were not evaluable due to early death. Among CR patients, 2 died from late toxicity, 4 relapsed between the 2nd and 5th months, but 3 patients remain in CR, off therapy at 25+, 43+, and 66+ months, including 1/11 initially resistant and 2/6 who had relapsed. There were 9 treatment related deaths: 6 due to infection, 1 cardiac failure and 2 multiorgan failure. The high complete response rate in these heavily pretreated patients suggests that there may be an indication for high dose therapy earlier in resistant HD. Moreover under such conditions, treatment related morbidity would be expected to be lower.

Combined modality in Hodgkin's disease. Comparison of six versus three courses of MOPP with clinical and surgical restaging.

Between 1972 and 1979, 121 patients with Hodgkin's disease (clinical Stages IInA, IB, IIB, and III) were treated by two different, successive, therapeutic protocols. The first group received six MOPP (mechlorethamine, vincristine, procarbazine, prednisone) cycles before radiotherapy, whereas the second group received only three MOPP cycles before irradiation. A total of 118 patients underwent surgical restaging with splenectomy before irradiation. Clinical criteria used in defining complete remission were verified by surgical restaging. Three MOPPs were just as effective as six MOPPs when combined with radiotherapy in achieving complete remission and in treating occult splenic disease. Following extended-field irradiation, complete remission rates were 96% for three MOPPs versus 94% for six MOPPs. The actuarial survival rates, 4 years after therapy completion, were 89% for three MOPPs and 94% for six MOPPs, with a relapse-free survival rate of 88% and 96.6%, respectively.

Hodgkin's disease in children. Results of therapy in a mixed group of 178 clinical and pathologically staged patients over 13 years.

One hundred seventy-eight previously untreated children with biopsy-proven Hodgkin's disease of clinical Stages I and II were treated and followed between 1965 and 1978. Staging laparotomy was performed in 30 patients. Ninety-four percent of the patients obtained a complete remission; 24 patients have died. The actuarial survival rate for all patients was 90% at 5 years, and 81% at 10 years. The disease-free survival rate was 69% at 5 years, and 65% at 10 years. When nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) chemotherapy was added to either extended field or involved field irradiation, the relapse rate was significantly decreased as compared with the protocols without MOPP and prophylactic para-aortic irradiation. The authors believe that surgical staging may not be necessary as splenic involvement may be treated in some patients by MOPP chemotherapy alone or in association with splenic paraaortic radiotherapy. However, the side effects of MOPP need further study by other chemotherapy programs.

[Hodgkin's disease: analysis of a reduction of chemotherapy]. / Maladie de Hodgkin: analyse d'une réduction de la chimiothérapie.

From April 1972 to September 1979, 121 patients with Hodgkin's disease clinical stages IInA, IB, IIB or III successively received MOPP 6 courses in a first trial and 3 courses in a second trial, prior to extended field irradiation; 118 patients underwent surgical restaging prior to irradiation. Anatomical findings demonstrated that 3 courses of MOPP were as effective as 6 courses to treat occult splenic disease. Comparison between clinical and surgical restaging confirmed the reliability of clinical criteria of complete remission after chemotherapy. After extended field irradiation, actuarial survival and relapse-free survival at 4 years were the same whether the patients had received 6 or 3 courses of MOPP.