Systemic evaluation of Sjögren-like syndrome after bone marrow transplantation in man.

A systematic evaluation of Sjögren-like syndrome (SLS) was performed in 68 bone marrow transplant (BMT) recipients (60 allogeneic and 8 syngeneic recipients). At day 100, the patients underwent clinical evaluation, functional salivary scintigraphy, and lip biopsy. If any findings were abnormal, the examinations were repeated annually for 3 years. Twenty-two patients with SLS and extensive chronic graft-versus-host disease (CGVHD) had abnormal scintiscan and lip biopsy at day 100. Marked keratoconjunctivitis sicca and xerostomia developed between 12 and 24 months after BMT and, thereafter, progressively decreased. Twenty-seven irradiated recipients (7 syngeneic and 20 allogeneic recipients without CGVHD) had isolated xerostomia and disturbed scintiscan but normal biopsy. Seven other patients with limited CGVHD had a lymphocytic infiltrate on lip biopsy but no SLS and a normal scintiscan. Schirmer's test, functional salivary scintigraphy, and lip biopsy allowed us to distinguish SLS from radiotherapy sequelae. As early as day 100, these 3 tests have a predictive value for SLS, one of the criteria for extensive CGVHD.

N-terminal peptide of type III procollagen: a marker for the development of hepatic veno-occlusive disease after BMT and a basis for determining the timing of prophylactic heparin.

We have studied the kinetics of the N-terminal peptide of type III procollagen (NP3P) after BMT as a marker for the development of hepatic fibrosis in veno-occlusive disease (VOD). Four patients with clinically apparent VOD were retrospectively assayed and demonstrated a very high NP3P level. NP3P was also prospectively monitored at the beginning of conditioning and every week (8 patients) or every other day (14 patients) from the day of BMT (day 0) to day +28. Before conditioning the NP3P level (15.5 +/- 5.5 ng/ml) was twice normal and increased during the course of BMT in patients without VOD (21 ng/ml; range 6-35 ng/ml). In four patients who experienced VOD, the NP3P level exceeded 40 ng/ml by day 0 in two. The early rise of NP3P indicates that it is a valuable marker for the development of VOD before it becomes clinically apparent. These data suggest that VOD develops during preparation for BMT and that prophylaxis should therefore be started at this time.

Scintigraphy of the salivary glands in Sjögen's syndrome.

Scintigraphy of the salivary glands with technetium-sodium pertechnetate (99mTc) was undertaken on 320 patients with oral dryness or connective tissue disease using a computer assisted method that gave quantitative results about the major salivary gland function. Compared with clinical and histological data, scintigraphy provides a sensitive method, even though it is not specific, for detecting minimal injuries to salivary glands in patients suspected of having Sjögen's syndrome. Moreover, it might differentiate between the Sjögen-like syndrome and the sequelae of radiotherapy in patients with bone marrow graft. Scintigraphy of the major salivary glands could therefore form part of the routine investigation of patients with Sjögen's syndrome.

[Development of polycythemia to myelofibrosis. Monitoring by the assay of the procollagen III amino-propeptide]. / Evolution des polyglobulies primitives vers la myélofibrose. Surveillance par le dosage de l'amino-propeptide du procollagène III.

The conventional methods used in the follow-up of myelofibrosis being both invasive and expensive, we propose an easy and sensitive immunoassay of the procollagen III aminoterminal peptide (propeptide) which is separated and released in serum during synthesis of collagen III by bone marrow fibroblasts. This propeptide was assayed in the sera of 25 healthy adults (controls), 48 patients with polycythaemia vera and 20 patients with myelofibrosis (secondary to polycythaemia in 14). Significant differences in mean values were found between controls (7.6 +/- 2.1 ng/ml), patients with polycythaemia (9.9 +/- 4.3 ng/ml) and patients with myelofibrosis (38.1 ng/ml). There was some overlapping between values in controls and in patients with polycythaemia, partly due to the fact that 12 of these 48 patients without reticulin bone marrow fibrosis had normal serum propeptide levels. Propeptide values in patients with myelofibrosis were much scattered (range: 13-103 ng/ml). Moreover, values above 25 ng/ml were associated with myelofibrosis of recent onset (less than or equal to 2 years) and values below 25 ng/ml with myelofibrosis of more than 4 years' duration. The procollagen III aminoterminal peptide immunoassay therefore is a non-invasive and sensitive method for accurate assessment of bone marrow progressive involvement in myeloproliferative diseases associated with myelofibrosis. It could also be used to evaluate the effectiveness of antifibrosing agents.

[Polyglobulia vera. Difficulties and complications of treatment by phlebotomy]. / Polyglobulie primitive. Difficultés et complications du traitement par saignées.

The authors report the results of phlebotomy for polyglobulia vera in a series of 73 patients eligible for inclusion in an international co-operative study. Previous studies usually gave actuarial survival curves but failed to mention the complications and discomfort associated with phlebotomy, although these are of importance in clinical practice. Most of the 73 patients were excluded on account of discomfort (20%), vascular thrombosis (almost 50%) or transformation into myelofibrosis within a mean period of 4 years (20%). Only 10% were treated with long-term phlebotomy. Although phlebotomies avoid the long-term risk of leukaemia attached to radiophosphorus or chemotherapy (20% on average after a mean delay of 12 years), they have practical limitations and their own, important risks. In patients over 65 and in those at high vascular risk, the best treatment is myelosuppression. However, younger subjects with polyglobulia vera but no vascular risk and/or thrombocytosis may benefit, at least temporarily, from phlebotomy.

[Gougerot-Sjögren syndrome. Functional study of the salivary glands by scintigraphy]. / Syndrome de Gougerot-Sjögren. Etude fonctionnelle des glandes salivaires par la scintigraphie.

One-hundred and twenty patients with sicca syndrome, connective tissue disease or chronic graft-versus-host disease were investigated in the Saint-Louis Hospital Department of Nuclear Medicine. Technetium scanning of the salivary glands was performed in all patients. The results of the scintigraphic study were closely correlated with clinical and histological data in patients with Sjögren's syndrome. This method, which accurately quantifies the salivary function without danger nor discomfort to the patients, has a number of advantages: (a) it is sensitive enough to detect minimal salivary gland dysfunction; (b) it differentiates between parotid gland and submandibular gland involvement and demonstrates asymmetry in pathological processes; (c) it helps in following up patients with Sjögren's disease and in assessing the results of immunosuppressive or anti-inflammatory treatment.

[Clinical value of determining the amino terminal fragment of procollagen III in myeloproliferative disorders]. / Intérêt clinique des dosages du fragment aminoterminal du procollagène III dans les désordres myéloprolifératifs.

The amino-terminal fragment of procollagen III was assayed by RIA in 186 patients with myeloproliferative disorders, at intervals of 6 to 24 months. The present results suggest that this assay may be useful for discriminating primary and secondary erythrocytosis, for evaluating the evolution of polycythemia vera towards spent phase and/or myelofibrosis, and for estimating the degree of myelofibrosis in patients with myeloid metaplasia of the spleen. However the methodology of the assay still needs technical improvements. An assay of procollagen I is needed. Excessive values of serum procollagen III may be due to hepatic or pulmonary fibrosis. Finally we don't have as yet a follow-up delay long enough to ascertain the prognostic value of the assay in polycythemia vera and in primary myelofibrosis.

Clinical significance of serum pro-collagen III in chronic myeloproliferative disorders.

Pro-collagen III (PC III) has been proposed as a useful value for diagnosis and follow-up of myeloproliferative disorders. A significant difference is observed between polycythaemia vera (PV) and essential thrombocythaemias (ET) on one hand, and the pure erythrocytoses (PE) on the other hand, but a large overlap makes this test of low diagnostic value. High values are observed in primary and post-PV myelofibrosis, but excessive PC III levels in active PV are not predictive of evolution toward myelofibrosis. PC III level is lower in myelo-suppressed patients (32P, or hydroxy-urea) than in active cases or in patients treated by phlebotomies. We conclude that PC III measurement is of low diagnostic value for discriminating PV and PE, does not appear to allow short-term prediction of evolution to myelofibrosis, but may be useful to evaluate the role of treatment in delaying progression of PV toward myelofibrosis.

Type III aminoterminal propeptide of procollagen in some haematological malignancies.

Marrow fibrosis is involved in some haematological malignancies. Either because of sampling errors, variations of focal distribution of fibrosis or the discomfort for patients of bone biopsies, conventional histology appears to be unsuitable for the follow-up of myelofibrosis. During collagen synthesis by marrow fibroblasts, the aminoterminal propeptide is removed from procollagen III and released in the serum. Thus, a sensitive radioimmunoassay of type III aminoterminal propeptide of procollagen (PC III) has been tested in myeloproliferative and lymphoproliferative disorders with a marked bone marrow fibrosis. In polycythaemia vera, PC III level was significantly increased as compared to controls and was related to marrow fibrosis of grade I. The more increased PC III values were observed in spent polycythaemia cases initially treated by phlebotomy alone. Follow-up showed a transformation into myeloid metaplasia. In contrast, PC III remained stable in patients treated with radiophosphorus 32P or hydroxyurea who did not transform. In myeloid metaplasia, results of PC III were significantly higher than in controls or polycythaemia vera cases. Myelofibrosis of recent onset (less than 2 years) gave higher values than chronic myelofibrosis. Increased PC III values were also emphasized in chronic myelocytic leukaemia, and in a few cases of refractory anaemia with excess of blasts, hairy cell leukaemia and chronic lymphocytic leukaemia.

Diagnostic and prognostic value of bone marrow biopsy in aplastic anemia. A study of 119 cases.

A retrospective analysis of 119 bone marrow biopsies, performed at the time of aplastic anemia (AA) diagnosis, emphasized the prognostic value of several pathological features. Cellularity was evaluated with a better accuracy from biopsies as compared to aspirates and iron kinetics. Only bone marrow biopsies assessed myeloid "hot spots", which featured as favorable prognostic parameters in addition to the usual prognostic indices. The presence of megakaryocytes provided another positive prognostic influence. In contrast, lymphocytosis, plasmocytosis, and stroma injuries were negative in terms of prognosis. Such histological data should be systematically studied in AA at the time of initial evaluation and taken into account prior to choice of therapy.

[Biermer's disease without anemia, nor megaloblastosis. Value of the study of antibodies, vitamin assays, and the dU suppression test for the early diagnosis]. / Maladie de Biermer sans anémie, ni mégaloblastose. Intérêt de la recherche des anticorps, des dosages vitaminiques, et du test de dU suppression pour le diagnostic précoce.

In two patients, a diagnosis of pernicious anemia was made without anemia, megaloblastosis and even macrocytosis. The diagnosis of pernicious anemia was suggested by the autoimmune abnormalities which are frequently associated with this disease: goitre with anti-thyroid and anti parietal cell antibodies, and besides this, idiopathic thrombocytopenic purpura in the first patient, vitiligo in the second. The morphological abnormalities were limited to slight macrocytosis in the first patient and to hypersegmentation of polymorphonuclear leucocyte in both. Vitamin B12 deficiency was demonstrated by serum assay as well as deoxyuridine suppression test ("dU suppression"). The diagnosis was confirmed by demonstration of atrophic gastritis, failure of secretion of Intrinsic Factor and Schilling test. These observations show that the Addison-Biermer disease can be detected early in persons at high risk by looking for vitamin B12 deficiency and specific antibodies.

The 'spent' phase of polycythaemia vera: hypersplenism in the absence of myelofibrosis.

A clinical phase (spent phase) in the course of polycythaemia vera (PV) cases is described as enlargement of the spleen in spite of treatment, frequent cytopenia of one or several lines, persistent red cell hypervolaemia with considerable increase of plasma volume, persistence of myeloid hyperplasia with no collagen myelofibrosis or osteomyelosclerosis, absence of hepatosplenic erythroblastic metaplasia, as shown by radio-iron kinetics and/or 111In-transferrin scintigraphy. The frequency of this phase was 5% in a study where it was not systematically sought, but it could in fact be greater. Its occurrence is not related to the clinical and biological parameters of PV. On the other hand, it is significantly more frequent and earlier in patients treated by phlebotomies than in those treated by myelosuppression (32P). In four of the 12 cases, this phase was rapidly followed by an acute leukaemia. In eight cases there was a 1-5 year interval before a myelofibrosis with splenic myeloid metaplasia. This evolution could at this stage be delayed by chemotherapy. The efficacy of splenectomy should be studied.

Acute leukemia and myelodysplasia in polycythemia vera. A clinical study with long-term follow-up.

The analysis of 288 cases of polycythemia vera (PV) with a minimal follow-up of 10 years enabled us to study the characteristics of acute leukemia as observed in 33 patients (11.4%). In 50% of the patients (16 of 33), the malignant transformation is of the refractory anemia with excess of blasts (RAEB) type. Half of these further transform to acute nonlymphocytic leukemia (ANLL). Their life expectancy is not better than patients who abruptly develop ANLL. Leukemic transformation shows a frequency peak in the eighth year after initial evaluation in PV treated with chemotherapy and in the 11th year in patients treated with radiotherapy. In 30% of the patients myelofibrosis, or the spent phase of PV, is present before the transformation to acute leukemia (AL). This complication is, however, part of the natural history of PV and is observed in 20% of PV patients at 10 years when leukemic transformation is absent. Marrow fibrosis can therefore not be considered as a preleukemic phase. It was also noted that the occurrence of myeloid metaplasia/myelofibrosis is more frequent and begins earlier in patients treated by phlebotomy alone, and who do not transform to leukemia. The clinical characteristics of these AL, including high frequency of partial marrow invasion, difficulties in cytologic classification, a peak incidence similar to that in patients treated by chemotherapy or radiotherapy for a prior malignancy, multiple chromosome abnormalities, and poor response to therapy are all highly suggestive of secondary leukemias.

[Septicemia caused by Pseudomonas aeruginosa serotype O 16 in a hemato-oncology department. Review of 17 cases]. / Septicémie à Pseudomonas aeruginosa de sérotype O 16 dans un service d'hémato-oncologie. Revue de 17 cas.

Seventeen cases of Pseudomonas aeruginosa serotype O 16 septicaemia in patients with immune deficiencies are reported. All patients had a poor prognosis from the onset because of the advanced stage of their illness, the particular clinical form of their disease or because of the confirmed inefficacy of their anti-leukaemic chemotherapy. The neutrophil leukocyte count was less than 0.5 X 10(9)/l in all cases and 13 patients had also received wide-spectrum antibiotic therapy for at least 15 days. The septicaemia was accompanied by pelvic sepsis in 6 cases. The prognosis was very poor and 12 patients died rapidly in a state of shock. P. aeruginosa was an infrequent cause of infection during the 31 months period of observation but the O 16 serotype was the commonest in our department. The source of contamination seemed to be a chronic carrier state. P. aeruginosa is resistant to most of the antibiotics which would be expected to be effective.

Diagnostic value of bone marrow imaging with 111indium-transferrin and 99m technetium-colloids in myelofibrosis.

111Indium--transferrin (111In) and 99mTechnetium-colloids (99mTc) bone marrow imaging of 55 myelofibrosis (MF) cases has been compared with clinical, histological, and iron-kinetics data. The best correlations are seen between the splenic uptake of 111In with the spleen/sacrum ratio of 59Fe at the first hour (r = 0.69, P less than 0.001) and also with the splenic erythropoiesis histologically assessed in ten splenectomized patients (r = 0.75, P less than 0.01). Moreover, sacrum uptake of 111In, when compared with sacrum uptake of 59Fe (r = 0.51, P less than 0.001) and with hematopoietic cellularity of the bone marrow (r = 0.57, P less than 0.001) reflects faithfully the hematopoietic cell content of the marrow. Thus, 111In bone marrow imaging provides a noninvasive and useful tool for the diagnosis of myeloid metaplasia in MF. Ferrokinetic studies still appreciate with better insight the amount of ineffective erythropoiesis or hemolysis and remains therefore of great value when splenectomy is discussed.

Thrombocytopenia in venocclusive disease after bone marrow transplantation or chemotherapy.

Hepatic venocclusive disease (VOD) is a frequent complication of bone marrow transplantation (BMT). Analysis of 13 cases observed during a 3-year period in our BMT center shows that VOD is associated with a constant peripheral thrombocytopenia and refractoriness to platelet transfusion. These signs appear in the very early stage of VOD, five to ten days before the classical signs, painful hepatomegaly and sudden weight gain. Analysis of platelet consumption, frequency of platelet transfusion and platelet recovery, and examination of known causes of peripheral thrombocytopenia (mainly allo- and autoimmunization, disseminated intravascular coagulation [DIC] and splenomegaly) lead to the conclusions that this association is not coincidental. The exact mechanism of platelet consumption in VOD is unknown.