Low-dose beta-lactam plus amikacin in febrile neutropenia: cefepime vs. piperacillin/tazobactam, a randomized trial.

Patients with fever and granulocytopenia are at risk of developing severe infection. We performed a prospective, randomized trial to evaluate the efficacy of low-dose cefepime plus amikacin (C-A) compared to low-dose piperacillin/tazobactam plus amikacin (PT-A). Patients received cefepime (2 g/12 h) plus amikacin (15 mg/kg/day) or piperacillin/tazobactam (4 g/500 mg/8 h) plus amikacin. A total of 317 episodes of febrile granulocytopenia in 190 patients were studied (152 in the C-A group, 165 in the PT-A group). A microbiologically documented infection was present in 53 (35%) episodes in the C-A group and 41 (25%) episodes in the PT-A group (p = ns); a clinically documented infection was observed in 39 (26%) and 47 (28%) episodes, respectively. Toxicity was observed in 6 (4%) episodes in the C-A group and in 5 (3%) episodes in the PT-A group. The antibiotic success rate (no change or addition of antibiotics) was recorded in 89 (59%) and 105 (64%) cases, respectively (p = ns). Mortality related to infection was similar in each arm (3.9% vs. 3.6%). Combination therapy of low-dose beta-lactam with an aminoglycoside achieves very good response rates and low rates of toxicity. It might be an attractive option in an environment of increasing resistance among gram-negative bacteria.

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

¿Qué es la psicosomática? / What is psychosomatics?

La definición de Psicosomática recorre un camino triangular en el que la biología, la personalidad y los eventos ambientales cierran los ángulos; está matizado por los recursos de afrontamiento ante diversas situaciones. Una posible nosología transcurre transversalmente todo el abanico de la patología: trastornos somáticos con marcada incidencia psicológica; la deconstruida somatización; la alta morbilidad psicológica en enfermos médico quirúrgicos (30 a 50% de ingresados y 25-30% ambulatorios), con la Psiquiatría de Enlace siempre presente en su abordaje; la Ansiedad por la Enfermedad (primaria o secundaria). Se sintetizan algunos de los modelos más destacados desde el Córticovisceral a la Psiconeuroinmunoendocrinología, pasando por los procesos del estrés. La conclusión es que la psicosomática se integra en el conjunto de la Medicina y potencia los recursos diagnósticos, terapéuticos, de investigación y colaborativos entre los diversos profesionales implicados. (AU)

Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients.

BACKGROUND AND OBJECTIVES: A consecutive series of acute myeloid leukemias (AML) patients was analyzed in conditions which reduce the inter-assay variations (the same flow cytometer, the same observers and the same panel of monoclonal antibodies) in order to investigate the prognostic information provided by flow cytometry. DESIGN AND METHODS: Two hundred and sixty-six bone marrow (BM) samples from 326 patients enrolled in the LMA-99 protocol from the CETLAM group were studied by multiparametric flow cytometry. Immunophenotyping studies were performed on erythrocyte-lysed BM samples. Antigen expression of leukemic cells was analyzed using triple stainings with fluorochrome-conjugated combinations of monoclonal antibodies. RESULTS: CD2 was positive in 21 cases (8%); an associated inv(16) was detected in eight CD2+ cases (38%). Two-year overall survival (OS) rate for CD2+/inv(16)+ patients was 75%, whereas it was 0% for CD2+/inv(16)- patients and 47% for CD2- patients (p=0.0001). CD36 was expressed in 37% of patients (n=98). Two-year leukemia-free survival (LFS) rate was 34% for CD36+ patients and 55% for CD36- patients (p=0.001). In the multivariate analysis, CD2+ (RR=8.4; p=0.0001) and adverse karyotype (RR=10.2; p=0.0001) were associated with a lower CR rate, CD36+ (RR=1.5; p=0.03), CD2+ (RR=2; p=0.04) and adverse karyotype (RR=4; p=0.0001) were associated with a lower OS and CD36+ (RR=2; p=0.002) and adverse karyotype (RR=3.5; p=0.005) predicted a lower LFS. CONCLUSIONS: CD2+ patients had a very poor OS when CD2/inv(16)+ cases were excluded. CD36 and CD2 expression at diagnosis can provide prognostically important information in adult de novo AML.

Maintenance treatment with interferon alpha-2b in multiple myeloma: a prospective randomized study from PETHEMA (Program for the Study and Treatment of Hematological Malignancies, Spanish Society of Hematology).

The objectives of the present study were to investigate whether interferon alpha (IFN) maintenance could prolong response duration and survival in patients with multiple myeloma (MM) in objective response and to analyze the characteristics of relapse and subsequent survival. From January 1991 to November 1994, 92 patients from the Spanish Cooperative Group PETHEMA with MM in objective response after 12 courses of VCMP/VBAP chemotherapy were randomized to receive IFN maintenance vs no treatment until relapse. Prognostic factors at diagnosis were similar in both groups. IFN was administered at a starting dose of 3 mU/m2 three times per week. The IFN toxicity was moderate with granulocytopenia and fatigue being the most common adverse effects. Median duration of response from randomization until relapse was 13 months in the IFN group vs 7.7 months in the no treatment arm (P = 0.042). Median survival from randomization was 38.8 months for patients given IFN vs 32.7 months for those allocated to the no treatment arm (P = 0.12). Features at relapse were similar in patients who received IFN maintenance and in those assigned to no treatment. Finally, survival from relapse was identical in both groups. In summary, our results show a significant prolongation of response in patients maintained with IFN with no significant influence on survival. In addition, in our series features at relapse and subsequent outcome were similar in both groups.

Plerixafor in patients with lymphoma and multiple myeloma: effectiveness in cases with very low circulating CD34+ cell levels and preemptive intervention vs remobilization.

This retrospective study presents data from 105 consecutive multiple myeloma and lymphoma patients who had PB CD34+ cell counts <10/µL on day 4 of steady-state G-CSF mobilization for autologous hematopoietic cell transplantation. Our results confirm the capacity of plerixafor to improve mobilization outcomes in this clinical setting. In addition, they show that the effectiveness of plerixafor, compared with G-CSF only, translates to patients with very low (<3.5/µL) circulating CD34+ cell counts: overnight CD34+ cell count expansion (5.3- vs 1.7-fold), overall CD34+ cell yield (2.29 vs 0.15 × 10(6) CD34+ cells per kg) and patients yielding ⩾2 × 10(6) CD34+ cells per kg (63% vs 3%). Furthermore, our data also show that preemptive plerixafor is significantly more effective and more efficient than in remobilization: CD34+ cell yield in the first apheresis (3.28 vs 2.0 × 10(6) CD34+ cells per kg) and overall (3.73 vs 2.44 × 10(6) CD34+ cells per kg), patients yielding ⩾2 × 10(6) CD34+ cells per kg in the first apheresis (85% vs 44%) and overall (92% vs 64%), all this requiring less days and doses of plerixafor treatment (1.08 vs 1.48). These data would advocate using plerixafor as an early preemptive intervention based on day 4 circulating CD34+ counts, including very high-risk patients with very low circulating levels.

The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (⩾60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P=0.0025), shorter leukemia-free survival (P=0.026) and higher cumulative incidence of relapse (P=0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P=0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML.

Transjugular liver biopsy in BMT.

With the aim of evaluating liver disturbances after BMT in 76 patients, the hepatic venous pressure gradient was measured and a transvenous liver biopsy was performed through the jugular vein. Catheterization was successful in 71 patients (93%). In 11 cases the procedure was performed twice, yielding a total number of 82 studies. In five (6%) liver biopsies were non-evaluable. Complications were rare (7%), minor and reversible. As a result of this procedure, the diagnosis was modified in 45%, with both the diagnosis and treatment being modified in 30% of patients. Veno-occlusive disease (VOD) was histologically demonstrated in 15 out of 26 patients (58%) in whom this complication was suspected and in two out of 33 (6%) in whom it was not. Acute GVHD of the liver was confirmed in 15 out of the 35 patients (43%) in whom this complication was suspected and in four of 24 (17%) in whom it was not. The hepatic venous pressure gradient was significantly higher in VOD than in liver GVHD. Whereas 14/17 (82%) patients with VOD had a gradient pressure higher than 9 mmHg, no patient with GVHD had a gradient above this value. We conclude that transjugular liver biopsy is an effective, safe, and useful technique to evaluate BMT related liver dysfunction.

Increased conventional chemotherapy does not improve survival in multiple myeloma: long-term results of two PETHEMA trials including 914 patients.

BACKGROUND: Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. METHODS: From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). RESULTS: Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) were similar in the three groups. MP produced a higher degree of thrombocytopenia than combination chemotherapy at standard (P = 0.002) or high dose (P = 0.01), this leading to a significantly higher dose reduction in the MP arm (P < 0.001 and P = 0.003 for VCMP/VBAP 'SD' and VCMP/VBAP 'HD', respectively). CONCLUSION: In these trials the response rate significantly correlated with the regimen intensity. However, no significant differences in response duration and survival were found. This highlights the limited role of conventional chemotherapy in MM and the need for further trials, aimed at determining the impact of new treatment approaches such as high-dose therapy/autotransplantation.

Generalized amyloidosis: a rare complication of cystic fibrosis.

A new case of cystic fibrosis complicated with secondary amyloidosis is reported. We reviewed ten cases described up to now in the literature, emphasizing the rarity of this association. The usefulness of serum trypsin concentration as an index of exocrine pancreatic function and the accuracy and simplicity of the abdominal fat biopsy in the histologic diagnosis of amyloidosis were evaluated.

Efficacy of ABVD Therapy in Resistant Hodgkin's Disease.

Between January 1979 and June 1987, 46 patients with Hodgkin's disease '(HD) resistant to first-line combination chemotherapy or in early relapse were treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Twenty-two of 42 patients (52%) evaluable for response achieved a complete remission (CR), and eight (19%) a partial remission (PR). Median survival was 42.9 months with a probability of being alive at 5 years of 25 % (95 % CI: 10-40%). Median CR duration was 36.6 months and the probability of being alive and in CR at 5 years for the whole series was 20% (95 % CI: 8-32%). No clinical or laboratory data present before therapy with ABVD were associated with a higher index of response or longer survival. This studv confirms the efficacy of ABVD combination chemotherapy in resistant or relapsed HD.

Numerical Hydrodynamics in Special Relativity.

This review is concerned with a discussion of numerical methods for the solution of the equations of special relativistic hydrodynamics (SRHD). Particular emphasis is put on a comprehensive review of the application of high-resolution shock-capturing methods in SRHD. Results obtained with different numerical SRHD methods are compared, and two astrophysical applications of SRHD flows are discussed. An evaluation of the various numerical methods is given and future developments are analyzed. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.12942/lrr-1999-3.

[Quantification of myocardial tomography with thallium in coronary disease. Evaluation of the Cedars-Sinai technique]. / Cuantificación de la tomografía miocárdica con talio en la enfermedad coronaria. Valoración del método Cedars-Sinai.

OBJECTIVE: The aim of this study is to evaluate the contribution of the Cedars-Sinai quantification tomographic method (CS) in the diagnosis and localization of ischemic areas in coronary artery disease (CAD) and to optimize the threshold values proposed by CS. PATIENTS AND METHODS: Fifty patients with clinical suspicion of CAD performed a maximal stress test by cycloergometer; thallium myocardial tomographic images were obtained; applying the CS program afterwards. The sensitivity and specificity variations obtained by changing the criteria for extent of myocardial hypoperfusion (range 1% to 100%) were used to calculate the new thresholds (CS-I), using the results of coronariographic studies as a reference. The data determined by qualitative analysis were compared with that obtained by quantitative analysis by means of CS and CS-I using coronary angiography as the standard of reference. RESULTS: The coronary angiography showed coronary disease in 37 patients. The sensitivity for the diagnosis of CAD was superior using CS (97%) at the expense of low specificity (15%) which nevertheless improved with CS-I (54%). For the location of CAD, the visual analysis was statistically significant (p < 0.05) in the left anterior descending and right coronary arteries, CS being superior in the diagnosis of 3 vessel disease. CONCLUSIONS: The quantification of tomographic studies with thallium by means of CS needs a readjustment of the thresholds. The tested values (CS-I) improved the CS results, although they require prospective validation. Quantitative study permits the confirmation of visual findings, being a complementary method that can be rapidly and easily interpreted, although it is not recommended as a single technique for the diagnosis of coronary disease.

[Alfa-2b interferon in the treatment of thrombocytosis associated to chronic non leukemic myeloproliferative syndromes]. / Interferón alfa-2b en el tratamiento de la trombocitosis asociada a síndromes mieloproliferativos crónicos no leucémicos.

BACKGROUND: The effect of interferons in the correction of thrombocytosis in chronic myeloproliferative syndromes is well known. In this study the efficacy of alpha-2b interferon in a regimen of induction followed by a phase of sequential maintenance to progressively decreasing doses was evaluated with the aim of knowing the minimum doses necessary to maintain response. METHODS: The response to treatment with alpha-2b interferon was prospectively studied in a group of 37 patients with chronic myeloproliferative syndromes with associated thrombocytosis (excluding chronic myeloid leukemia). Likewise, the toxicity of the treatment was analyzed. RESULTS: Sixty-seven percent of the patients responded (platelets lower than 600 x 10(9)/1) to the daily administration of 3 or 5 MU of interferon. Forty percent of the patients who responded to the daily schedule of administration maintained the response upon receiving 3 doses weekly for 4 months. Half of the 8 patients who received 2 weekly doses of interferon for 4 months continued maintaining the responses. Only two of the 4 patients who received one sole weekly dose during the following 4 months maintained the response. Only one of the 37 patients who initiated treatment underwent progression of the symptoms present at the beginning of the study. Toxicity was high and was the cause of 12 discontinuations of treatment (32% of the patients) during the daily treatment phase (9 patients) or during maintenance of 3 weekly doses (3 patients). No toxicity was observed in the schedule of one or two weekly doses. CONCLUSIONS: Alpha-2b interferon is effective in the treatment of thrombocytosis of the chronic myeloproliferative syndromes (excluding chronic myeloid leukemia) when administered daily and is ever less so when the doses are spaced at 3, 2 or 1 week. The toxicity of interferon treatment is high when administered at affective doses.

[Intense neutropenia of 14 years duration as the only manifestation of a myelodysplastic syndrome]. / Neutropenia intensa de 14 años de duración como única manifestación de un síndrome mielodisplásico.

Myelodysplastic syndromes (MDS) are a group of acquired hemopathies characterized by peripheral cytopenias due to ineffective hematopoiesis and a high risk of transformation into acute non lymphoblastic leukemia (ANLL) which, in most cases, usually occurs from 6 months to 4 years after diagnosis. A patient with extreme neutropenia with intense dysgranulopoiesis as the only manifestations of MDS is described. The patient was controlled over 14 years and presented multiple infectious episodes, in various locations, throughout the evolution, some being very severe and generally caused by gram-negative germs. Likewise, during this time the patient received different treatments (oxymetholone, prednisone and lithium carbonate) with no hematologic response being observed. The leukocyte count remained around 3 x 10(9)/L with a mean proportion of neutrophils of 12% with no variations being found in the bone marrow aspirates carried out throughout the evolution (total of 9). At 14 years the diagnosis of MDS evolved to ANLL. The patient died shortly after the acute transformation due to respiratory failure secondary to bilateral pneumonia. In this case three peculiar features are of note: the almost exclusive involvement of the granulopoietic series without either anemia or thrombocytopenia, the long evolution of AREB, with acute transformation 14 years after diagnosis and the severity of the infections, among which recurrent lingual granulopenic ulcers were of note.

[Thyrotropic hormone in an adult population seeking care at a primary health care center]. / Hormona tirotropa en la población adulta demandante de un centro de atención primaria.

In a study of the need for detecting subclinical hypothyroidism in a population aged 60-80 years, the measurement of thyrotropin with the immunofluorometric technique in 446 individuals seeking attention identified 58 with high TSH (greater than 4 microU/ml); only 33 of these were evaluated in a specialized endocrinological unit. The abnormality was confirmed by radioimmunometric technique in 19 patients (4%), and in the remaining 14 individuals disease was ruled out. The prevalence in this group of individuals is comparable to that found in other studies which recommend screening for subclinical hypothyroidism, but the requirement for the implementation of such a screening program in our area should be carefully evaluated before it could be recommended.

[Bone marrow autotransplant: preliminary results in 20 patients with acute leukemia]. / Autotrasplante de medula ósea: resultados preliminares en 20 pacientes con leucemia aguda.

The results of bone marrow autograft (BMAG) in 20 patients with acute leukemia (AL) consecutively treated from October 1985 and May 1988 are reported. The follow up was continued until November 1988. The mean age of the patients was 20 years (range 10-48) and their diagnoses were acute myeloblastic leukemia (AML) in 12 and acute lymphoblastic leukemia (ALL) in 8. The preparation for BMAG included cyclophosphamide and whole body radiation in all cases. The procedure was carried out in the first complete remission (CR-1) in 5 patients, in CR-2 in 11, in CR-3 in 2, and in CR-4 in another 2. Two patients died as a direct consequence of BMAG, 11 relapsed and 7 are alive and free from relapse. The likelihood of survival free from prolonged illness was calculated as 24% for the whole series, 60% for the cases of BMAG in CR-1 and 50% for the group of patients with AML. The results were poor in the cases of BMAG carried out for AL in an advanced stage. On the basis of these results the experience of other authors with this therapeutic modality is reviewed, and its current indications are discussed.

Bilateral pigmented villonodular synovitis in a dog.

Villonodular synovitis is an extremely rare condition of the synovial membrane in the dog. A 10-year-old, neutered crossbreed was presented with bilateral, progressive hindlimb lameness. Periarticular swelling was noted in both stifle joints. No craniocaudal instability was noted. Radiographs showed massive intra-articular soft tissue proliferation in both joints, with no bony involvement. Arthrocentesis was unsuccessful. Exploratory arthrotomy of the left stifle revealed a greatly thickened, florid, proliferative synovial membrane. An incisional biopsy was carried out and the histopathological diagnosis was chronic active villonodular synovitis. A radical synovectomy was carried out in the right stifle joint 10 days later. Corticosteroid treatment was initiated 10 days after the second surgery and continued for six weeks, with a continuous clinical improvement. Eighteen months after discontinuation of the steroid therapy, the owners reported no recurrence of clinical signs although a mild stiffness was still present.