Bone marrow biopsy in the diagnosis of fever of unknown origin in patients with acquired immunodeficiency syndrome.

BACKGROUND: Fever is commonly observed in patients with human immunodeficiency virus (HIV) disease and frequently eludes diagnosis. The role of bone marrow biopsy in the diagnosis of fever of unknown origin in patients infected with HIV remains controversial. PATIENTS AND METHODS: One hundred twenty-three consecutive patients with 137 episodes of fever lasting 10 or more days without diagnosis after 1 week of hospitalization were evaluated by bone marrow biopsy. RESULTS: Overall, a specific diagnosis was achieved in 52 episodes by means of culture and histopathological examination (diagnostic yield, 37.9%). Three types of disease were found: mycobacterial infections (n = 36, 69% of documented episodes), including 18 patients with disseminated tuberculosis and 14 with Mycobacterium avium-intracellulare complex infections; non-Hodgkin lymphomas (n = 12, 23%); and visceral leishmaniasis (n = 4, 8%). Although bone marrow cultures were more sensitive than microscopic examination with special stains for the diagnosis of mycobacterial infections, the pathological examination of bone marrow led to a more rapid diagnosis of disease. In addition, the histopathological examination of bone marrow alone led to the diagnosis of a specific condition in 43 episodes (31.3% of all episodes). CONCLUSIONS: Bone marrow biopsy is a useful procedure for the diagnosis of fever in patients with advanced HIV disease, particularly in areas where tuberculosis and leishmaniasis are prevalent. Involvement of the marrow may be the first indication of the existence of extranodal non-Hodgkin lymphoma. For Mycobacterium avium-intracellulare complex infection, blood cultures were more sensitive than bone marrow biopsy.

[Polycythemia vera as a multiphasic clonal panmyelopathy: diagnostic profile, chronic pathological progression and effect of therapy on the survival of 74 cases]. / La policitemia vera como panmielopatía clonal multifásica: perfil diagnóstico, evolución patocrónica y efecto de la terapéutica sobre la supervivencia de 74 casos.

PURPOSE: 1. To recognise the clinico-biological profile of a group of patients diagnosed of polycythaemia vera (PV) in our centre in the last 30 years. 2. To identify the evolutive patterns of haematological transformation. 3. To evaluate the effect of therapy on the survival. PATIENTS AND METHODS: The clinical records of 74 patients (median age 62 years, male/female = 0.94, followed-up for 6-357 months, median 64 months) were reviewed. Clinico-biological data at diagnosis, therapy, complications and evolution of the haematological picture were evaluated in each case. The actuarial survival in the series was compared to that of the normal population. RESULTS: The clinico-analytical data and diagnostic features were identical to other series reported. Mild increases of bone marrow reticulin was present in two thirds of the cases, overt myelofibrosis being found in only 10% of the patients. Abnormal karyotype was seen in 9% of the patients (11q-, -Y). Phlebotomy was the only treatment in eight cases, without increased incidence of thrombotic phenomena. The remainders received myelosuppressive therapy (32P, busulphan, pipobroman, hydroxyurea, etc.), thrombotic complications appearing in 8 cases and haemorrhagic complications in 4 others. One of these latter patients developed oesophageal carcinoma. The haematological picture evolved into toxic aplastic anaemia in 2 cases; myelofibrosis with myeloid metaplasia (MF/MM) in 8; myelodysplastic sindromes (MDS) in 5, three of them RAEB; and acute myelogenous leukaemia in 3 cases, two of them as the final stage of previous MF/MM and MDS/ RAEB. The actuarial survival was 71% at ten years and 46% at fifteen years, and the median survival as a whole was 13.5 years. CONCLUSIONS: 1: The treatment, mostly myelosuppressive, given to these patients attained a survival similar to that of the general population. 2: Of the cases with known evolution, 15.6% developed MF/MM, its incidence being higher in patients treated only with phlebotomy (37%). 3: The incidence of malignant evolution, i.e., to RAEB/AML, amongst those patients followed-up was 10.6%.

[Evolutive epidemiologic profile of myelodysplastic syndromes (1959-1993). Comparative study with acute myeloid leukemia and aplastic pancytopenias]. / Perfil epidemiológico evolutivo de los síndromes mielodisplásicos (1959-1993). Estudio comparativo con el de las leucemias agudas mieloides y pancitopenias aplásticas.

PURPOSE: To compare the maximum epidemiologic data attained from myelodysplastic syndromes (MDS) with those of two main panmyelopathies, namely acute myeloblastic leukaemia (AML) and aplastic pancytopenia (AP). PATIENTS AND METHODS: A retrospective analysis was carried out on 21,135 patients included in the Bone Marrow Study Registry of the Jiménez Díaz Foundation along 35 years (1959-1993). The data were grouped into seven five-year periods. Of these, in the first three the study was performed on bone-marrow aspirates; after 1976 the histopathological study of bone-marrow biopsies was introduced, and since 1979 the karyotype has been regularly examined. The MDS were classified in accordance with the FAB system. With these premises borne in mind, the following aspects were considered: diagnostic interpretation of MDS along the years; diagnostic incidence of MDS, AML and AP in each of the five-year periods; relative frequency of those diagnosis with respect to the total number of cases; evolutive profile of sex and age at diagnosis; quantitative significance of secondary MDS-AL and toxic AP along the years; MDS subtypes and their epidemiologic characteristics. RESULTS: A total of 510 MDS, 610 AML and 223 AP cases were identified. With respect to the sex of the MDS patients, some changes have been seen along the years, from an M/F ratio of 1.9 to 1.0; and the mean age at diagnosis raised from 53.3 years (with only 1.7% of the cases over 65 years of age) to 71.4 years (with 76.9% of the cases over 65 years of age), all this within the 1959-1989 period. The incidence of AML and AP has remained stable for the last 20 years; on the contrary, MDS have been increasing continuously along the 35 years of the study, which poses for a higher number of new cases in every period (from 35 to 119) and also for a higher relative frequency in the registry (from 1.37% to 4.40%) within the period 1959-1989. Valuable toxic history was progressively increasing in secondary MDS-AML and progressively decreasing in AP. With respect to the FAB subtypes of MDS, and taking into account the last of the five-year periods, the most frequently diagnosed were RA and RSA followed by RAEB, CMML and RAEB-T. CONCLUSIONS: The increment of the incidence of MDS cases correlates significantly with the increment of the patients aged over 65 years. This incidence appears to be scarcely influenced by previous mutagenic agents (radiotherapy, chemotherapy) and might be due to a better understanding of MDS.

[Essential thrombocythemia: a myeloproliferative state on the rise. Clinico-biological study and course of 44 cases]. / La trombocitemia esencial: un cuadro mieloproliferativo "en alza". Estudio clínico-biológico y evolutivo de 44 casos.

Forty-four cases of essential thrombocytosis (ET) were diagnosed in the last 20 years, 19 males and 24 females (M/F: 0.76), aged between 3 and 86 years (median, 62 years), and 9 of them being under 40 years of age. The M/F ratio for patients under 60 years was 0.5, whereas it was 1.09 for patients over 60. The clinical forms at onset were: asymptomatic, 36.5%; as a bleeding disorder (BD), 20.4%; as thrombotic disease (TD) 22.7%; BD/TD, 13.6%, and others, 6.8%. The most important biological features included platelet count over 1.000 x 10(9)/L (59.1%), abnormal platelet aggregation, chiefly with ADR (56.5), mild reticulin myelofibrosis (55%), abnormal karyotype (2.6%), moderately high LDH levels (56.8%) and pseudo-hyperkalaemia (40%). The initial therapeutic approach was: observation (12 cases), antiaggregating agents (6 cases), and chemotherapy (BSF, HU, etc.) in the remainders. One patient evolved quickly into acute myelogenous leukaemia and two others suffered a late transformation into polycythaemia vera (PV) and myeloid metaplasia, respectively. The median survival was over 11 years, this being longer in patients under 60 years of age, in those with platelet count at diagnosis between 600 and 1000 x 10(9)/L and in those without initial symptoms of thrombosis. The advent of electronic blood-cell counters has made ET no longer a rare chronic myeloproliferative disease, its incidence coming now closer to that of PV; thus, in the last four quinquennial periods the incidence of ET/PV has evolved as following: 1/19, 4/16, 13/18 and 26/29.

[Subleukemic acute monophagocytic leukemia. A biological phenotype close to malignant histiocytosis]. / Leucemia aguda monofagocítica subleucémica. Un fenotipo biológico próximo a la histiocitosis maligna.

An 80 year-old woman presented subleukaemic acute monoblastic leukaemia (AML-M5a). Her bone marrow showed invasion by highly dysplastic histio-monocytic cells of great size and wide cytoplasm, with intense phagocytic activity (erythrophagocytosis was frequently seen), and with abnormal karyotype (50XX, +8, +8, +16, +21). The different malignant and reactive features of the mononuclear phagocytic system are commented, along with the haemophagocytic activity of the histio-monocytic cells in different states. The cytogenetic anomalies more frequently found in AML-M5 are also dealt with as compared to this patient's. The case reported here seems to correspond to subleukaemic acute "monophagocytic" leukaemia, with a biologic phenotype close to that of malignant histiocytosis.

[Iron deficiency dyserythropoiesis in patients with chronic gastrointestinal and gynecologic hemorrhages. Study of 39 cases]. / Diseritropoyesis ferropénica en pacientes con hemorragias crónicas gastrointestinales y ginecológicas. Estudio de 39 casos.

A defect of haemoglobin synthesis is the classically recognized mechanism affecting the erythron functionalism in chronic iron deficiency. The poor erythroblastic bone-marrow response, plus a number of dyserythropoietic nuclear features, have led to think of an impairment of the cell cycle of erythroblasts in iron-lack anaemia. The aim of the present work was to study such hypothesis, not proven so far. Ten subjects with normal haemopoiesis and 39 patients with iron-lack anaemia of different aetiologies (namely, 19 with digestive tract bleeding, 16 with gynaecological bleeding, and 4 with haemorrhages on other locations) were included in a previously reported protocol. The scheme of such protocol consisted of: 1) bone-marrow erythroblast quantification; 2) analysis of their maturation gradient; 3) erythroblast mitotic index; 4) measure of the mitotic time in bone-marrow culture; 5) tritiated-thymidine incorporation to short-term bone-marrow culture and quantification of the erythroblastic labelling index. To these were added the degree of nuclear dyserythropoiesis according to Hill and Lewis, and the reticulocyte production index. The following mean values were found in the control group: erythroblasts, 25.5 (+/- 3.63) %; E1-E4, 47.66 (+/- 3.09) %; IDN, 0.67 (+/- 0.27); MI, 2.82 (+/- 0.66) %; MT, 1.05 (+/- 0.15 hr); LI, 34.88 (+/- 5.82) %. The mean values found in iron-lack anaemias were as follows: erythroblasts 39.42 (+/- 9.1) %; E1-E4, 42.25 (+/- 4.11) %; IDN, 7.77 (+/- 4.69); MT, 1.81 (+/- 0.95) hr; LI, 13.08 (+/- 6.51) %. The statistical analysis (Student's t) showed highly significant differences (p less than 0.001) in the increased IDN and decreased MI and LI in iron deficiency patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Myelodysplastic syndromes. Hematologic phenotypes, cytogenetic expression and clinical course in 133 cases (1979-1989)]. / Síndromes mielodisplásticos. Fenotipos hematológicos, expresión citogenética y patrones evolutivos de 133 casos (1979-1989).

One hundred and thirty-three cases of myelodysplastic syndromes studied during the last ten years were revised. Of them, 79 were males and 54 females, and their ages ranged between 15 and 91 years (median, 69 years). Five patients (3.7%) had secondary myelodysplasias. The haematological phenotype (FAB) of the cases was: RA, 41.3%; SRA, 24%; RAEB, 18%; RAEBT, 3.7%; CMML, 8.3%. Leucopenia/thrombocytopenia without initial anaemia was present in 4.5% of the cases. Abnormal karyotype was found in 54 patients (40.6%), MIKA in 41 cases and MAKA in 13 cases. The cytogenetic anomalies most commonly found were +8, 5q-, -7, 11q- and 13q-. Cytogenetic abnormalities were commonest amongst the RAEB (50%), and least frequent in CMML (18.2%). Thirty-one patients evolved into acute leukaemia (29 ANLL and 2 ALL). Such blastic changes were more frequent in RAEB (62.5%) and rarest in SRA (9.4%), and they appeared mostly in patients with complex karyotype (MAKA) (53.8%) as compared with those who had normal karyotype (17.7%). Short-lasting complete remission was achieved by 40% of the patients treated with conventional chemotherapy. The survival of the group as a whole (median 30 months) varied in accordance with the haematological phenotype: SRA, 81 months; RA, 65 months; CMML, 13 months; RAEB +/- T, 8 months. The finding of a MAKA karyotype significantly shortened the survival (4 months) with regard to MIKA (44 months) or normal karyotype (39 months). The following median survivals were attained after patients' staging (Bournemouth's criteria): stage A, 84 months; stage B, 22 months, and stage C, 5 months.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute promyelocytic leukemias: clinico-biological aspects, prognostic factors, therapeutic response, and possibilities of cure in 34 cases (1970-1988)]. / Leucemias agudas promielocíticas: aspectos clínico-biológicos, factores pronósticos, respuesta terapéutica y posibilidades de curación de 34 casos (1970-1988).

Thirty-four new cases of acute promyelocytic leukaemia (M3) were diagnosed at the authors' Centre between 1970 and 1988 (19 males and 15 females) with ages between 5 and 73 years (median age, 32 years). Three cases were of the hypogranular variant or M3-v (8.8%). The clinical picture included: haemorrhagic diathesis (85%), pallor/malaise (82%), fever/infection (41%), hepatomegaly (26%), splenomegaly (12%). Leucopenia of less than 5 x 10(9)/L was present in 23/34 cases, laboratory signs of DIC in 26/31, increased LDH, over 400 U/mL, in 6/31, and abnormal karyotype in 7/15. One of the patients rejected any treatment; two others died of brain haemorrhage before therapy was started, and seven died in the first two weeks of treatment. Of the 31 patients treated, complete remission (CR) was achieved in 21 cases (67.7%). Allogeneic BMT was carried out in two of them, with further relapse and death. Post-remission treatment was given to the remaining 19 patients, and there were 13 relapses. Six patients have been in CR, 5 of them after cessation of therapy, for the last 1.5-11.5 years. Age under 50 years and leucocyte count below 5 x 10(9)/L at diagnosis were favourable prognostic factors according to the univariate statistical analysis performed. The survival plateau of the actuarial curve was reached beyond 2.75 years by 15% of all the patients treated (33 cases), 23% of the patients who achieved CR (21 cases), 31% of the patients under 50 years of age and 5 x 10(9)/L leucocyte count at diagnosis (15 cases) and 36% of these last achieving CR (13 cases).

[Possibilities of remission of acute lymphoblastic leukemia in adults: retrospective study of 51 patients subjected to a "total therapy" protocol in the period 1969-1983]. / Posibilidades de curación de las leucemias agudas linfoblásticas del adulto: análisis retrospectivo de 51 pacientes sometidos a un protocolo de "terapéutica total" entre 1969-1983.

Between 1969 and 1983, 51 (35 men and 16 women) new cases of acute lymphoblastic leukemia (ALL) were diagnosed in patients aged 15 to 85 years (mean 21 yrs.). All patients received a "total therapy" which included: 1st induction (PRD, VCR, DBR, and/or L-ASN); 2nd, Central Nervous System profilaxis (craneal TCT and/or intrathecal MTx); 3rd, maintenance (6MP and MTx) and 4th, reinductions every 3 months (PRD, VCR, and DRB). This treatment lasted for at least 3 years. Complete Remission (CR) was achieved in 45 patients (88.2%): 3 of these patients were referred to other centers to continue treatment, 1 patient developed an early "metamorphosis" to hemophagocytic hystiocytosis and another patient developed a late chronic granulocytic leukemia (Ph +) dying a few months later after an acute myeloblastic worsening. During treatment 16 patients relapsed (9 in bone marrow and 7 in Central Nervous System). Treatment was discontinued in 24 patients with complete remission of which 5 relapsed in bone marrow 17 to 61 months after treatment). In one of the latter (ALL Ph +) an allogenic bone marrow transplant was performed and CR was achieved and maintained 46 months later. The post diagnosis acutarial curve of the 51 patients gave a mean survival of 6 years with a plateau at 43% of the patients after 11 years. The duration of the first uninterrupted CR was of 6.5 years and a plateau was reached at 46% of the patients after 10.5 years. At the present time, 20 patients are in CR (46 to 129 months) without treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hematologic significance of erythrocytic macrocytosis: prospective analysis of 109 successively studied cases]. / Significación hematológica de la macrocitosis eritrocítica: análisis prospectivo de 109 casos sucesivamente estudiados.

The aim of the present work was to perform a prospective analysis of the significance of macrocytic red cells through the study of all patients with MCV higher than 105 fl (those treated with cytotoxic or immunosuppressing drugs were excluded). Conventional clinical, haematologic and biochemical studies were carried out on every patient, along with B12 and folate levels, bone marrow examination and bone marrow karyotype and, whenever B12 deficiency was present, complete Schilling's test. Special attention was paid to the aetiological inquiry and post-therapeutical course. A series of 109 patients was collected. Decreased serum B12 rates with abnormal Schilling's test and response to parenteral therapy were present in 26 cases (24%). Of them, 22 fulfilled the diagnostic criteria for Biermer's anaemia, while in the remaining 4 there was impaired intestinal absorption. Serum or red-cell folate deficiency was found in 34 other cases (31%). Alcoholism was present in 20 of them, abnormal diet in 10, malabsorption syndrome in 2, and excessive demands in 2 others. Hence, vitamin deficiency underlay macrocytosis in 60/109 cases (55%). In the remaining 49 cases (45%) macrocytosis was not accompanying folate or B12 deficiency. Of these, severe liver disease was found in 16 patients (alcoholic in 15 and post-hepatitis in 1 case), with increased serum B12 in 10 cases and increased serum or erythrocytic folate in 3 others. Nineteen patients within this group had primary myelodysplastic syndromes (RA, 8; SRA, 4; RAEB, 7), and the remaining 14 cases had several haematological (AIHA, 4; CLL, 1, T-cell lymphoma 1, M-6, 1, and myelofibrosis with myeloid metaplasia, 2) or non-haematological diseases (heart insufficiency, 2; COPD,3).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute lymphoblastic leukaemia in adults: results of a 'total-therapy' programme in 47 patients over 15 years old.

For the last 13 years, 47 patients with ALL over 15 years old (range 15-72; median 21) entered a 'total-therapy' programme. All cases received a 6-8 week induction course of PRD, VCR, DRB and/or L-ASN. Prophylaxis of CNS was done by cranial radiotherapy plus i.t. MTX in 32/45 patients who attained complete remission (CR). After CR, subsequent therapy involved a programme of maintenance with 6MP and MTX at full doses. Pulses of intermittent reinforcement (PRD, VCR and DRB) were done for 2 weeks, every 3 months, for at least 3 years. CR was achieved in 42/47 patients (89.3%). The median relapse-free survival of the patients who attained CR was 57 months, with an 8-year estimated disease-free survival rate of 43% for those cases. If actuarial assumptions were to be sustained, it would indicate an encouraging cure rate of 38% of all our adult ALL patients (mainly in those cases between 15 and 30 years old).