In vitro drug testing in patients with acute leukemia with incubations mimicking in vivo intracellular drug concentrations

The differential staining cytotoxicity (DiSC) assay was evaluated as a predictive test for response to therapy in patients with acute non-lymphoblastic leukemia. Incubations were designed in such a way that the intracellular concentrations of cytostatic drugs in vitro paralleled those in vivo. Leukemic cells were isolated from 53 patients with acute non-lymphocytic leukemia. 13 of these patients died early due to supportive care failure and were not evaluable for the predictive drug testing. Of the remaining 40 patients, 25 entered a complete remission (CR) and 15 had a resistant disease (RD). According to the patients randomization to therapy the cells were incubated with anthracyclines and Ara-C separately and in combination. After 4 days of culturing in liquid medium the in vitro cytotoxicity was determined by dye exclusion according to Weisenthal. The cytotoxic effect in vitro was significantly higher on cells from patients who achieved a CR compared to patients with RD after incubations with anthracyclines 0.2 mumol/l (p less than or equal to 0.005), Ara-C 0.5 mumol/l (p less than or equal to 0.05) and with the combination of anthracyclines with Ara-C (p less than or equal to 0.0005). The best predictive value was achieved when incubations with 0.2 mumol/l anthracyclines and 0.5 mumol/l Ara-C were analyzed together. With these incubations cells from 20 out of 21 patients who achieved CR showed either less than or equal to 60% surviving cells after the anthracycline incubation or less than or equal to 35% surviving cells after the Ara-C incubation. Cells from 11 out of 13 patients with RD did not fulfill either of these criteria. In vitro drug sensitivity was significantly correlated to a prolonged survival (p less than 0.01). We conclude that, when performed with incubations that mimic in vivo tumor cell exposure to cytostatic drugs, the DiSC assay shows a high correlation to clinical outcome for patients with acute non-lymphocytic leukemia.     

Fungal infections in patients with acute leukemia

We reviewed the records of 32 patients with acute leukemia and proved invasive fungal infections to determine the clinical and pathologic characteristics of systemic mycosis in patients undergoing intensive induction chemotherapy. The incidence of invasive fungal infections among our patients was at least 27 percent, and Candida and Aspergillus accounted for the majority of these infections. Patients with systemic candidiasis generally had prolonged severe neutropenia, fever refractory to antibiotics, and evidence of mucosal colonization by fungi. At autopsy, Candida was always widely disseminated. Patients with aspergillosis generally had neutropenia, fever, and pulmonary infiltrates at the time of admission to the hospital and, at autopsy, their infections were primarily confined to the lungs. Patients infected with both Candida and Aspergillus had clinical and pathologic findings that were a combination of the features of each type of infection. A diagnosis of invasive fungal infection was established before death in only nine of the patients, all of whom had systemic candidiasis. Four of these patients were successfully treated and survived their hospitalization. The reasons for frequently misdiagnosing and unsuccessfully treating systemic mycosis in patients with acute leukemia are examined, and suggestions are made for improved management of patients at high risk for these infections. These suggestions are based upon recognition of the clinical settings in which fungal infections occur, the aggressive use of invasive diagnostic procedures, and the early empiric use of amphotericin B.     

Hepatitis in patients with acute nonlymphocytic leukemia

Three consecutive groups (University of Maryland Cancer Center protocols 7110, 7405, and 7802) of patients with acute nonlymphocytic leukemia who achieved a complete hematologic remission with similar antileukemic therapy were reviewed for the development of hepatitis. Ninety-four (73 percent) experienced viral hepatitis; eight had type B hepatitis and 86 had non-A/non-B hepatitis. The hepatitis was mild in all patients. Hepatitis secondary to cytomegalovirus, herpes simplex virus, Epstein-Barr virus, or Toxoplasma gondii was not observed. Antibody to type A hepatitis was common, but acute infection could not be substantiated. All cases of type B hepatitis in which the surface antigen could be serotyped were found to have the less frequently observed ayw marker, suggesting a common donor as the source of infection. The median duration of complete remission was longer (p = 0.03) for patients in Group II (protocol 7405) who contracted hepatitis (247 days) compared with patients without hepatitis (125 days). Median overall survival was also longer (p = 0.01) for these patients in whom hepatitis developed (672 days versus 372 days, respectively). No prolongation of complete remission duration or survival could be demonstrated for patients from Group I (protocol 7110) or Group III (protocol 7802) who contracted hepatitis. In patients with hepatitis, the height of transaminase serum bilirubin levels or duration of abnormal results of liver function tests did not correlate with the duration of complete remission or survival. Hepatitis, a common infection in those patients with acute nonlymphocytic leukemia who undergo induction therapy, had an inconsistent effect on the duration of complete remission interval and overall survival.     

Older patients with acute myeloid leukemia

Outcomes for older patients with acute myeloid leukemia have not improved over the last three decades, with only a small proportion of patients achieving long-term disease-free survival with standard induction chemotherapy. Older patients are more likely to have comorbidities, diminished functional reserve and other age-related issues, which decrease their tolerability to chemotherapy. Furthermore, the disease is frequently associated with poor-risk features, such as unfavorable cytogenetic abnormalities, antecedent hematologic disorders and expression of the multidrug resistant P-glycoprotein, which are associated with chemoresistant disease. Therefore, is it not only important to develop newer treatment modalities, but also to develop and validate prognostic models to help select the patients who are likely to benefit from and be suitable for intensive therapy, and reproducibly risk-stratify (based on disease biology) a relatively uniform group of older patients onto trials, so that the clinical significance of new therapeutic agents can be evaluated.     

急性髓细胞性白血病和急性早幼粒细胞性白血病的治疗进展

2003年12月5～9日第45届美国血液学年会(ASH) 在美国召开,与会代表2万多人,我国有100多位代表参加了会议.上海第二医科大学瑞金医院王振义院士(the first speaker from Asia to serve as the Ham-Wasserman Lecturer)在大会上作了"Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis"的专题发言,引发了热烈的讨论.现将该次年会中有关急性髓细胞性白血病(AML)和急性早幼粒细胞性白血病(APL)治疗的进展作一介绍.     

Intestinal permeability in patients with acute myeloid leukemia

Intestinal permeability was studied in patients with acute myeloid leukemia (AML) before, during and after chemotherapy. Intestinal permeability was determined by the lactulose (La)/mannitol (Ma) absorption test in 16 adult patients with de novo AML. The hydrogen breath test was used to disclose bacterial fermentation of the test substances in the small intestine. The permeability was found significantly increased (p<0.02) in the patients before induction chemotherapy treatment. During induction treatment and throughout the cytopenic period the intestinal permeability was constantly and significantly increased, compared with controls. In patients with abnormally increased permeability, no increase in hydrogen breath test result was noted. From our results it can be concluded that increased intestinal permeability is present in AML patients before commencing chemotherapy. Factors other than chemotherapy would seem to be more important regarding the occurrence of intestinal disturbances in these patients.     

Invasive aspergillus rhinosinusitis in patients with acute leukemia

Invasive aspergillus rhinosinusitis is a potentially lethal complication of chemotherapy-induced neutropenia in patients with acute leukemia. The majority of cases are caused by Aspergillus flavus. The infection is difficult to diagnose early but should be suspected when a neutropenic patient develops persistent fever without a known source, symptoms of rhinitis or sinusitis, cutaneous findings over the nose or sinuses, symptoms and signs of orbital or cavernous sinus disease, or an ulcerating lesion of the hard palate or gingiva. Careful anterior rhinoscopy followed by computed tomography of the sinus helps establish the diagnosis, which should be confirmed by histologic study and culture of biopsied material. Early treatment with aggressive surgery, high-dose amphotericin B and 5-fluorocytosine, and possibly white blood cell transfusions may produce a cure if the patient's bone marrow recovers. Newer antifungal agents offer promise for prophylaxis and treatment of this infection.     

Invasive fungal infections in patients with acute leukemia

Invasive fungal infections, a serious problem among cancer patients, are increasing in incidence, and can cause morbidity and mortality. Such infections may hinder additional treatment, especially for patients with leukemia. We report here our experiences in the management of invasive fungal infection in patients with acute leukemia. A total of 18 patients were enrolled in the study: 12 had microabscesses of the liver and/or spleen and/or kidneys; four had sinonasal infections; and two had pulmonary infections. Most of the patients (88.9%) received amphotericin B during treatment for fungal infection. Thirteen patients achieved complete response without evidence of fungal infection in follow-up. In the study, there were 11 mortalities, including five patients who died during therapy and six who later died as a result of relapse or refractoriness of the leukemia. We suggest that many patients may have a good response to antifungal therapy, and that fungal infection does not have to preclude additional chemotherapy after proper management. The state of the underlying disease has a strong impact on outcome.     

Neutrophil surface markers in patients with acute leukemia

The presence of complement and Fc receptors on neutrophils from patients with acute leukemia was investigated at different stages of the leukemic process. Both Fc receptors (Fc-H and Fc-R) and one complement receptor (C3d) were normal when patients were studied at diagnosis, in relapse, and in remission. In contrast, the C3b receptor was significantly reduced on te neutrophils at the time of diagnosis, but returned to normal levels when patients entered remission. Variable amounts of C3b activity were observed in patients relapse, with approximately one-half of the patients showing decreased C3b activity. To determine whether the reduction inC3b receptors was specific for patients at diagnosis, three patients were studied at different times during their diseases. Normal receptor levels were detected in these patients during remission, but the C3b receptor was markedly reduced at diagnosis and at relapse.     

Open lung biopsy in patients with acute leukemia

The results of open lung biopsy in 15 patients with acute leukemia, pulmonary infiltrates, neutropenia, and fever were reviewed. The patients averaged 26 hospital days of neutropenia and 20 hospital days of fever before open lung biopsy, and all patients received broad-spectrum antibacterial agents (mean 17 days) before open lung biopsy. Nine (67 percent) received amphotericin B prior to open lung biopsy (mean 22 days). Open lung biopsy yielded a specific clinically helpful diagnosis in six patients, but only two of these patients survived the hospitalization during which open lung biopsy was performed. Open lung biopsy detected fungus in four patients and leukemic infiltrates in two patients. Management was appropriately modified in these patients. In nine patients, a specific diagnosis of the pulmonary infiltrate was not obtained by open lung biopsy. Antimicrobial regimens were not changed substantially for these patients. In six patients, the results of open lung biopsy may have been misleading. Two patients had pulmonary fungal diseases at autopsy, undetected by open lung biopsy eight days and five weeks prior to death. Another patient had invasive aspergillosis and one had cytomegalovirus pneumonitis not detected by open lung biopsy. Two patients had false-positive preliminary histologic reports of pulmonary infection. On the basis of this experience, in this specific population of patients, open lung biopsy was often of little help in directing medical therapy or influencing clinical outcome.     

Alterations in electrolyte equilibrium in patients with acute leukemia

BACKGROUND AND AIM: A wide array of disturbances in electrolyte equilibrium is commonly seen in patients with acute leukemia (AL). These abnormalities present a potential hazard in these patients, as that of enhancing the cardiotoxic effects of certain chemotherapeutic regimens. The literature dealing with AL-related electrolyte abnormalities and their interactions in leukemic patients was reviewed. DATA SYNTHESIS: Sources included MEDLINE and EMBASE. The search strategy was based on the combination of 'acute leukemia', 'electrolyte abnormalities', 'acid-base disorders', 'potassium', 'sodium', 'magnesium', 'calcium', and 'phosphorus'. References of retrieved articles were also screened. A decrease in serum potassium, mainly owing to lysozyme-induced tubular damage, appears to be one of the most frequent and potentially hazardous abnormalities. Other clinically significant metabolic perturbations include hyponatremia and hypercalcemia. CONCLUSION: A broad spectrum of electrolyte abnormalities is encountered in the clinical setting of AL, which are related to the disease process per se and/or to the therapeutic interventions. Clinicians should be vigilant for early detection and appropriate management of these disorders before the initiation of chemotherapy regimens as well as during treatment.     

Development of acute myeloid leukemia in patients with untreated chronic lymphocytic leukemia

The development of acute myeloid leukemia (AML) in patients with untreated chronic lymphocytic leukemia (CLL) is rare. We experienced a 65-year-old man who developed AML with aberrant CD7 expression and monoallelic CEBPA mutation during watchful waiting for CLL. He failed to achieve complete response (CR) by standard induction therapy for AML. We retrospectively reviewed 27 patients who developed AML with untreated CLL published between 1973 and 2016. The median age at diagnosis of AML was 68 years, and the median duration between the diagnoses of AML and CLL was 4.2 years. Diagnosis of AML and CLL was made simultaneously in 16 patients. The CR rate of AML was 42.9%, and the median survival was only 1.5 months after the diagnosis of AML. Patients who achieved CR tended to survive longer than those who did not. Our results demonstrated that the development of AML in patients with untreated CLL was associated with a poor response to chemotherapy and an extremely poor prognosis.     

Reduced intracellular Mg concentrations in patients with acute asthma

STUDY OBJECTIVES: To determine the intracellular and extracellular Mg concentrations in patients with acute asthma and their correlation with parameters expressing the disease severity. PATIENTS: Thirty patients with acute asthma (FEV(1), 56% predicted [SD, 14.5]), 20 patients with stable asthma (FEV(1), 97% predicted [SD, 10]), and 20 healthy subjects (FEV(1), 97% predicted [SD, 8]). METHODS: Mg concentrations in erythrocytes and plasma were measured four times: at hospital admission, after 2 days, after 5 days, and at hospital discharge. Percentage of predicted FEV(1) and peak expiratory flow rate variability were recorded simultaneously. Similar measurements were carried in all study groups. RESULTS: Mg concentrations of healthy subjects and patients with stable asthma remained unchanged in both plasma and erythrocytes. Initial Mg content in erythrocytes was significantly lower in patients with acute asthma (1.77 fmmol per cell; 95% confidence interval [CI], 1.71 to 1.83) compared to normal subjects (1.94 fmmol per cell; 95% CI, 1.82 to 2.00) and patients with stable asthma (1.92 fmmol per cell; 95% CI, 1.87 to 1.96) [p < 0.0001], and it increased significantly after the resolution of the exacerbation (from 1.77 fmmol per cell [95% CI, 1.71 to 1.83] at hospital admission to 1.90 fmmol per cell [95% CI, 1.83 to 1.98] at hospital discharge; p < 0.0001). No correlation was observed between parameters of disease severity and the initial values of Mg concentrations in erythrocytes and plasma. CONCLUSIONS: Acute asthma is associated with lower erythrocyte Mg content while plasma levels remain unchanged. This decrease in intracellular Mg content occurs regardless of the severity of the exacerbation and returns to normal values after control has been achieved.     

急性冠脉综合征患者血钾情况分析

目的研究急性冠脉综合征患者血钾（血K^＋）浓度的变化情况。方法记录294例急性冠脉综合征患者胸痛发作距急检采血的间隔时间以及急检化验血U的结果。依据应用B受体阻滞剂情况以及是否患糖尿病对患者进行分组研究。结果患者血钾浓度于发病≤2h时最低[（4．0±0．5）mmol／L]，2-4h逐渐上升[（4．3±0．6）mmol／L]，4-6h最高[（4．4±0．3）mmol／L]，〉6h后略有下降[（4．3±0．5）mmol／L]，构成胸痛时间-血钾浓度曲线。应用13受体阻滞剂者该曲线变得平坦，糖尿病患者该曲线变得异常，不稳定型心绞痛患者该改变表现得更明显。结论急性冠脉综合征患者血钾浓度于发病早期较低，6h内迅速上升，6h后略有下降，构成胸痛时间-血钾浓度曲线。该曲线在糖尿病及应用岱受体阻滞剂者中受到抑制，心肌损害程度较轻者抑制改变表现得更明显。     

Chromosome abnormalities in Down's syndrome patients with acute leukemia

Chromosome and cytologic studies were performed on three Down's syndrome (DS) patients with acute nonlymphocytic leukemia (ANLL). All three patients had an aneuploid clone in their leukemic cells: 50, XX, +6, +19, +21, +22, +8, XX, +21, and 47,XY, +8, - 21 +dic(21;21)(p13;p11). Every patient appeared to have acute undifferentiated leukemia when the blast cells were examined with Wright-Giemsa stain; cytochemistry studies, however, showed that the leukemic blasts were in an early stage of myeloid differentiation. The two patients with +8 had a preleukemic phase; the blast cells of the patient with an extra no. 19 and no.22 could not be differentiated morphologically from those of the two patients with an extra no. 8. Our findings and a review of data on 40 other patients suggest that most DS children with ANLL have hyperdiploidy, which is usually related to gains of C, F, and /or G chromosomes, and that the abnormalities of +8 and of +19, +22 in DS children may be associated with acute leukemia (AL) in an early stage of myeloid differentiation.