Zytopenien : Anämie, Leukopenie und Thrombopenie.

Hematological alterations can often be observed during rheumatic diseases. The effects can be clinically severe, ranging from anemia of different grades of severity, through increased risk of hemorrhage due to thrombocytopenia up to severe infections as a result of high-grade leukocytopenia. The clinical sequelae for patients are predominantly determined by the extent of cytopenia. The underlying disease itself can initially be considered as the cause. Examples are anemia as a result of chronic inflammation, antibody-mediated thrombocytopenia as in systemic lupus erythematosus (SLE) or granulocytopenia within the framework of Felty's syndrome. Immunosuppressive treatment also often leads to alterations in the blood constituents. Although some substances, such as cyclophosphamide can suppress all three cell types, there are also selective effects, such as isolated thrombocytopenia under treatment with tocilizumab and JAK inhibitors. The differential diagnostic clarification of cytopenia can be difficult and necessitates a systematic work-up of the course of the disease and the subsequent treatment. The reviews of anemia, leukocytopenia and thrombocytopenia presented here summarize the most important components of the differentiation of hematological alterations in patients with rheumatic diseases.

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study).

To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m2, days 1, 15, 29), high-dose methotrexate (3 g/m2 days 2, 16, 30), procarbazine (60 mg/m2 days 2-11) and lomustine (110 mg/m2, day 2)-R-MPL protocol. Owing to infectious complications, we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less ⩾grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.

[Myelodysplastic syndrome, acute leukemia and stem cell transplantation]. / Myelodysplastisches Syndrom, akute Leukämie und Stammzelltransplantation.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders. They are characterized by inefficient hematopoiesis leading to peripheral cytopenia of one or more lineages and a variable risk of transformation into acute myeloid leukemia. They may either arise de novo as well as following exposition to environmental toxins, previous radiotherapy or chemotherapy or in the context of autoinflammatory diseases and related therapy. Characteristic cytogenetic abnormalities, along with the numbers of hematopoietic lineages affected and bone marrow blasts, enable an assessment of the risk of leukemic transformation. Acute leukemias are characterized by an accumulation of immature myeloid or lymphatic progenitor cells with limited differentiation capacity in the bone marrow. Proliferation of blast cells leads to suppression of normal hematopoiesis resulting in peripheral pancytopenia or leukocytosis associated with anemia and thrombocytopenia. Acute leukemias following MDS are defined as high-risk diseases. Intensive induction therapy followed by allogeneic stem cell transplantation is currently regarded as the only potentially curative treatment strategy. In this article the basic aspects of current diagnostics and treatment strategies for MDS and acute leukemia are outlined. Because of similarities with rheumatic inflammatory diseases, manifestations and treatment of graft versus host disease (GvHD) are also included.

Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma.

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Cough, diarrhea, pyrexia and rash were observed in five patients (33%) each. Grade 3/4 events included leukopenia in 6 (40%), neutropenia in 4 (27%) and thrombocytopenia in 2 patients (13%). An objective response was observed in 14/15 patients (93%), including 5 complete response (33%; all MCL). After a median follow-up of 19 months, 67% of patients are without signs of progression. Temsirolimus can be safely added to BR with promising preliminary activity. Recruitment in phase II is ongoing.

Long-term results after proactive management for locoregional control in patients with colonic cancer at high risk of peritoneal metastases.

PURPOSE: A major problem in treating patients with peritoneal spread from colorectal cancer is that at diagnosis wide peritoneal involvement often precludes all curative attempts. A possible solution is to identify those patients at risk for peritoneal metastases and intervene early to prevent locoregional disease spread before it develops and, thus, to improve outcome. METHODS: We analyzed long-term results from a previous study and compared outcomes in 25 patients with advanced colon cancer considered at high risk for peritoneal spread (pT3/pT4 and mucinous or signet ring cell histology) prospectively included and managed with a proactive surgical approach including target organ resection for peritoneal spread plus hyperthermic intraperitoneal chemotherapy (HIPEC) and in 50 retrospectively well-matched controls who underwent standard surgical resection during the same period and in the same hospital by different surgical teams. RESULTS: At 48 months after the study closed, peritoneal metastases and local recurrence developed significantly less often in proactively managed patients than in controls (4 vs 28%) (p < 0.03). Patients in the proactive group also survived longer than control patients (median overall survival 59.5 vs 52 months). Despite similar morbidity, Kaplan-Meier survival curves disclosed significantly longer disease-free and overall survival in the proactive than in the control group (p < 0.05 and <0.04). CONCLUSIONS: In patients with advanced colon cancer at risk for peritoneal recurrence, the proactive surgical approach plus HIPEC seems to achieve good locoregional control preventing peritoneal spread thus improving outcome without increasing morbidity. These advantages merit investigation in a multicentric randomized trial.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

[Interest of the prosthetic occlusal rehabilitation in improving irritable bowel syndrome at the University Hospital of Cocody (Abidjan)]. / Intérêt de la réhabilitation occluso-prothétique dans l'amélioration des colopathies fonctionnelles au CHU de Cocody (Abidjan).

The functional colopathies are frequent in digestive pathology and are particularly badly felt by African patients. The authors, after the determination of the masticatory efficiency score (classification of Verkindere) of 100 subjects affected by colopathies and diagnosed in the service of gastroenterology of Cocody University Hospital (Abidjan), attempt to determine the importance of the masticatory deficiency in functional colopathies. Among the toothless subjects with functional colopathies, the restoration of the masticatory efficiency by functional prosthetic rehabilitation constitutes an essential therapeutic act in the reduction of the symptoms of the functional colopathies and the improvement of the comfort of the patients. Patients' global care raises the interest of collaboration between odontologists and gastroenterologists for an efficient treatment.

Nonsecretory primary plasma cell leukemia with good response to thalidomide-based treatment.

Primary plasma cell leukemia (PCL) is a rare hematologic disorder with distinct features. The criterion for the diagnosis of PCL is based on the finding of malignant plasma cells in the peripheral blood (more than 2 x 10(9)/L or more than 20% of white blood cells). We report a case of a 74-year-old patient with primary nonsecretory PCL. Examination of blood smears led to the diagnosis of PCL, which was confirmed by bone marrow biopsy. Due to the patient's impaired general condition, intensive chemotherapy could not be administered. After an oral induction chemotherapy consisting of cyclophosphamide and high dose dexamethasone followed by one cycle of high-dose dexamethasone and thalidomide no evidence of the disease in the peripheral blood was detectable. Consequently, the patient was put on a thalidomide maintenance therapy. Six months after first diagnosis, the patient was found to have bone marrow and peripheral blood relapse with anemia and neutropenia in the clinical context of acute on chronic renal failure. After a limited response to further chemotherapy, the patient died 14 months after the first diagnosis while on dexamethasone maintenance. We conclude that monotherapy with thalidomide might be an alternative maintenance strategy with limited response duration for patients with primary PCL in impaired general condition.

Successful treatment of disseminated mucormycosis with a combination of liposomal amphotericin B and posaconazole in a patient with acute myeloid leukaemia.

The combination of resection of infected tissue and antifungal therapy is the treatment of choice in mucormycosis. In disseminated mucormycosis, where surgery is impossible, the mortality is almost 90%. We report the first case of disseminated mucormycosis that was cured with a combination therapy of liposomal amphotericin B and posaconazole without surgical intervention.

Patient and physician evaluation of the severity of acute asthma exacerbations

We studied the ability of patients not experienced in the use of peak expiratory flow meters to assess the severity of their asthma exacerbations and compared it to the assessment of experienced clinicians. We also evaluated which data of physical examination and medical history are used by physicians to subjectively evaluate the severity of asthma attacks. Fifty-seven adult patients (15 men and 42 women, with a mean (± SD) age of 37.3 ± 14.5 years and 24.0 ± 17.9 years of asthma symptoms) with asthma exacerbations were evaluated in a University Hospital Emergency Department. Patients and physicians independently evaluated the severity of the asthma attack using a linear scale. Patient score, physician score and forced expiratory volume at the first second (FEV1) were correlated with history and physical examination variables, and were also considered as dependent variables in multiple linear regression models. FEV1 correlated significantly with the physician score (rho = 0.42, P = 0.001), but not with patient score (rho = 0.03; P = 0.77). Use of neck accessory muscles, expiratory time and wheezing intensity were the explanatory variables in the FEV1 regression model and were also present in the physician score model. We conclude that physicians evaluate asthma exacerbation severity better than patients and that physician's scoring of asthma severity correlated significantly with objective measures of airway obstruction (FEV1). Some variables (the use of neck accessory muscles, expiratory time and wheezing intensity) persisted as explanatory variables in physician score and FEV1 regression models, and should be emphasized in medical schools and emergency settings.

Patient and physician evaluation of the severity of acute asthma exacerbations.

We studied the ability of patients not experienced in the use of peak expiratory flow meters to assess the severity of their asthma exacerbations and compared it to the assessment of experienced clinicians. We also evaluated which data of physical examination and medical history are used by physicians to subjectively evaluate the severity of asthma attacks. Fifty-seven adult patients (15 men and 42 women, with a mean (+/- SD) age of 37.3 +/- 14.5 years and 24.0 +/- 17.9 years of asthma symptoms) with asthma exacerbations were evaluated in a University Hospital Emergency Department. Patients and physicians independently evaluated the severity of the asthma attack using a linear scale. Patient score, physician score and forced expiratory volume at the first second (FEV1) were correlated with history and physical examination variables, and were also considered as dependent variables in multiple linear regression models. FEV1 correlated significantly with the physician score (rho = 0.42, P = 0.001), but not with patient score (rho = 0.03; P = 0.77). Use of neck accessory muscles, expiratory time and wheezing intensity were the explanatory variables in the FEV1 regression model and were also present in the physician score model. We conclude that physicians evaluate asthma exacerbation severity better than patients and that physician's scoring of asthma severity correlated significantly with objective measures of airway obstruction (FEV1). Some variables (the use of neck accessory muscles, expiratory time and wheezing intensity) persisted as explanatory variables in physician score and FEV1 regression models, and should be emphasized in medical schools and emergency settings.

Purging in BCR-ABL-positive acute lymphoblastic leukemia using immunomagnetic beads: comparison of residual leukemia and purging efficiency in bone marrow vs peripheral blood stem cells by semiquantitative polymerase chain reaction.

Twenty autologous bone marrow (BM) and 25 peripheral blood stem cell (PBSC) grafts were collected from a total of 40 consecutive patients with BCR-ABL+ acute lymphoblastic leukemia (ALL) in first (n = 37) or second (n = 3) complete morphological remission and subsequently purged with a cocktail of anti-CD19, -CD10, AB4 MoAbs and immunomagnetic beads (IMB). Residual BCR-ABL-positive cells before purging were detected in 19 of 20 BM grafts at a median of 4 (range 0-6) logs and in 17 of 25 evaluable PBSC grafts at a median of 1 (range 0-3) log above the limit of detection assessed by a semiquantitative limiting log10-dilution RT-PCR (P < 0.0001). IMB purging depleted a median of 2.5 (range 1-4) log of residual BCR-ABL+ cells from BM and a median of 1 (range 0-2) log from PBSC grafts, achieving RT-PCR negativity in 1/20 BM and 12/25 PBSC grafts after purging. Cell recoveries were 62% and 86% (P < 0.0001) of MNC and 74% and 97% (P = 0.065) of CD34+ cells after BM and PBSC purging, respectively. BM purging was superior using the triple MoAb cocktail which depleted 2.64 +/- 0.4 log (n = 14) compared to 1.6 +/- 0.4 log (n = 5) using the MoAb cocktail not including AB4 (P = 0. 02). We conclude that unpurged BM grafts contain 2-3 log more residual BCR-ABL+ cells than unpurged PBSC grafts and that purging efficacy is superior in BM compared to PBSC grafts, but median titers in purged BM grafts still exceed those in purged PBSC grafts. Bone Marrow Transplantation (2000) 25, 97-104.

The teaching of basic clinical skills at School of Medicine, University of São Paulo.

This article describes how is the teaching of basic clinical skills given to the 3rd in the undergraduate program, at the School of Medicine, University of São Paulo. This course has been implementing some techniques of teaching-learning for last years in order to become it more dynamic and interesting. Small group teaching is the main feature of the course "Basic Clinical Skills" given at the University of São Paulo, School of Medicine. This technique is improved by keeping each group with a teacher for a long time to allow better integration between them and to facilitate a better acquisition of attitudes towards the patient and all the team involved in the care of patient. All the classes are practical with early contact with real cases. Medical students learn how to take down the medical history, how to perform an adequate physical examination and make diagnoses under supervision of their teachers. Discussion cases, recognition of medical patterns and hypothetic-deductive strategy are used to develop an efficient medical reasoning. The authors show the results obtained through questionnaires filled in by the students at the end of the course and the analysis of which demonstrates that the students are highly satisfied with these kind of strategies and profit better from them. In 1996 and 1997, respectively, the course's satisfaction was 93.13% and 88.08% (excellent + good). The students' capacity to perform their objectives is situated in their majority between 6 and 8, these values represent a good and sufficient to very good performance.

Residual leukemia and immunomagnetic bead purging in patients with BCR-ABL-positive acute lymphoblastic leukemia.

Residual leukemia was evaluated in autologous bone marrow grafts harvested in first (n = 11) or second (n = 3) complete remission from 14 patients with BCR-ABL-positive acute lymphoblastic leukemia after treatment according to the German multicenter ALL protocols. The intervals from diagnosis to BM harvest were median 159 (range 78-463) and from preceding chemotherapy to BM harvest median 39 (range 26-69) days, respectively. A limiting log(10)-dilution RT-PCR was used to semiquantify BCR-ABL-positive cells. All autografts appeared to be significantly contaminated with residual leukemic cells. The BCR-ABL-specific titers ranged from 1:10(3) to 1:10(6) (median 1:10(4)) above the limit of detection. This was the rationale to purge the grafts using two cycles of IgM anti-CD10, CD19, and AB4 MoAbs-coated immunomagnetic beads (IMB). Purging depleted median 3 (range 2-4) logs of residual leukemia, resulting in a median 1:10(1) (range 1:10(0) to 1:10(3)) postpurge BCR-ABL-specific titer. The second purging cycle accounted for 1 log of depletion. The mean +/- s.e.m. post-purge recoveries of MNC and CFU-GM were 59 +/- 4%, and 61 +/- 9%, respectively. We conclude that all BCR-ABL-positive ALL patients achieving CR by cytological criteria have critically high levels of residual leukemia in their bone marrow, which can be reduced by median 3 log using immunomagnetic bead purging.

Purging of peripheral blood stem cells yields BCR-ABL-negative autografts in patients with BCR-ABL-positive acute lymphoblastic leukemia.

Remission marrow from patients with BCR-ABL+ acute lymphoblastic leukemia (ALL) achieving clinical remission (CR) after induction or consolidation chemotherapy according to the German multicenter adult ALL (GMALL) protocol showed high titers of residual BCR-ABL+ cells. Therefore, we initiated a pilot study to monitor circulating BCR-ABL+ cells and to collect, purge, and autograft peripheral blood stem cells (PBSC) in these patients. After GMALL 05/93 high-risk phase II of induction chemotherapy (high-dose AraC 3 g/m2 x 8 does and mitoxantrone 10 mg/m2 x 3 doses), patients received 5-10 micrograms/kg subcutaneous recombinant human granulocyte colony-stimulating factor (rhG-CSF) daily. Mobilized CD34+ cells peaked between 20 and 26 days after starting chemotherapy at 4.8-75.6 (median 10.8) x 10(4)/mL peripheral blood (PB) (n = 5). Patients treated with additional chemotherapy cycles failed to mobilize adequate numbers of CD34+ cells. PB stem cells (PBSC) were purged using a cocktail of CD10, CD19, and AB4 monoclonal antibodies (mAbs) coupled to immunomagnetic beads (IMB). The median recoveries of total nucleated cells (TNC) and CD34+ cells after mAb/IMB purging were 84 and 81%. The peak numbers of CD34+ cells collected in a single leukapheresis were median 8.6 x 10(6)/kg pre- and 5.2 x 10(6)/kg postpurge (n = 4). The absolute prepurge CD19+ cells were as low as median 2.7 (range 1.4-19) x 10(6) per leukapheresis. Residual BCR-ABL+ cells in unpurged leukapheresis products were assessed by limiting-log10-dilution nested reverse-transcriptase polymerase chain reaction (RT-PCR) as one in 10(5) to one in 10(6) normal cells and were consistently undetectable in all purged PBSC autografts. We conclude that sufficient numbers of CD34+ cells for PBSCT can be collected after phase II but not at later stages of the GMALL 05/93 high risk protocol; PBSC grafts are 3 log less contaminated with residual BCR-ABL+ cells compared to an historical series of 13 autologous BM grafts; and purging of PBSC with mAb/IMB is feasible with minor loss of CD34+ cells and abolished BCR-ABL signals in the grafts.

In patients with BCR-ABL-positive ALL in CR peripheral blood contains less residual disease than bone marrow: implications for autologous BMT.

Residual leukemic cells are detectable at frequencies as low as 1 in 10(6) normal cells in patients with Philadelphia chromosome/BCR-ABL-positive leukemias in complete remission (CR) using reverse-transcriptase polymerase chain reaction (RT-PCR) with specific nested primers. The level of minimal residual disease (MRD) in the bone marrow (BM) and the peripheral blood (PB) may favor one of the two as the source for an autologous graft. In order to quantify MRD with RT-PCR we analyzed patients ficolled cells after limiting logarithmic dilutions in normal ficolled buffy-coat cells. In six patients with BCR-ABL-pos ALL who were in CR by conventional criteria (5 in CR1 and 1 in CR2), we studied a total of nine paired BM and PB samples prior to scheduled ABMT. A positive RT-PCR signals was detectable in all samples up to dilutions ranging from 1:10(1) to 1:10(3) in PB, and at higher titers ranging from 1:10(3) to 1:10(5) in the BM. The BM titers exceeded the corresponding PB titers in all nine sample pairs by at least 1 log. The mean difference was 1.55 log (geometric mean, n = 9) and is statistically significant (p < 0.03). We conclude that residual leukemia in BCR-ABL-positive ALL preferentially locates in the BM compartment, and we assume that PB may yield autologous grafts with significantly less leukemic contamination.

Preventing hypoxemia and hemodynamic compromise related to endotracheal suctioning.

OBJECTIVE: To help the clinician bridge the gap between research and practice in determining ways to minimize side effects of endotracheal suctioning. DATA SOURCES: This article summarizes four previous reviews of research and studies published between 1984 and 1991 related to oxygenation techniques before, during and after endotracheal suctioning, and hemodynamic consequences of the suctioning procedure. STUDY SELECTION: Studies were reviewed by type of subject: animals, human subjects with normal lung function, and human subjects with abnormal lung function. Research of pediatric and head-injured populations was excluded from this review. DATA EXTRACTION: Oxygenation protocol, endotracheal suction characteristics, outcomes and measurement times, sample and setting, and findings were presented. CONCLUSIONS: Conclusions relate to the effectiveness of various endotracheal suction protocols on prevention of hypoxemia and hemodynamic compromise in intubated patients. DATA SYNTHESIS: An algorithm to guide clinical decision making is presented based on the conclusions of this review of the research.

[Acute lethal intoxication caused by mercury vapor]. / Intoxicação aguda letal por vapor de mercúrio.

Nowadays mercury poisoning usually results from the oral ingestion of methylmercury or from inhalation of mercury vapor. Mercury intoxication in a gold prospector after inhalation of mercury vapor is described. The patient presented a history of fever, tachypnea and headache. Despite the treatment with dimercaprol, penicillamine and intensive supportive care the patient died with symptoms of acute respiratory distress.