Tailored hormonal therapy in secretory adrenocortical cancer

Mitotane is often considered the front-line hormonal therapyof adrenocortical carcinoma (ACC). An illustrative case concerningthis issue and the rationale to ponder other alternatives isreported. A 69 year-old woman, diagnosed with ACC was admittedwith hypertensive crisis, supraventricular tachycardia, congestiveheart-failure, diarrhoea and rabdomyolisis. Two years earlier,she had undergone     

Ia antigen is a differentiation marker on human eosinophils

Evidence suggests that the "la-like" or antigen is a differentiation marker that is expressed on early human hematopoietic precursor cells, but is absent on their mature progeny. The eosinophil precursor cell (CFU-EO) is distinct from the granulocyte-monocyte colon-forming cell (CFU-C). We provide data that indicate that the ia antigen is expressed on the human eosinophil colony-forming cells and is absent on mature eosinophils. All CFU-EO were inhibited in the presence of rabbit la antiserum at a titer of 1:30. Cytotoxicity was complement-dependent. The metamyelocytic eosinophil and more mature eosinophil forms did not express the la antigen.     

Granulocyte-macrophage colony-stimulating factor: signals for its mRNA accumulation

Granulocyte-monocyte colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor. Mesenchymal cells produce abundant GM-CSF in response to tumor necrosis factor alpha (TNF). We wished to determine (1) what cellular pathways enhanced levels of GM-CSF mRNA, and (2) if TNF used any of these pathways. Modulation in levels of GM- CSF mRNA in human fibroblasts (WI-38) was studied by using Northern blot analysis. Markedly increased levels of GM-CSF mRNA occurred in these cells after exposure to sodium fluoride (NaF) and the effect of NaF was slightly enhanced by aluminum chloride; these results suggest that accumulation of GM-CSF mRNA can occur by activating a G-binding protein. Stimulators of protein kinase C dramatically increased levels of GM-CSF mRNA; however, blockade of protein kinase C activity did not attenuate accumulation of GM-CSF mRNA stimulated by TNF and NaF. Exposure to ouabain increased levels of GM-CSF mRNA and this effect was prominently enhanced in the presence of low concentrations of extracellular K+ and was almost abolished in high concentrations of extracellular K+. A monovalent ionophore (monensin) also increased levels of GM-CSF mRNA. Both ouabain and monensin can increase intracellular Ca++ concentration (Cai++) through Na+-Ca++ exchange. A calcium channel blocker (diltiazem) blocked the increased levels of GM- CSF mRNA mediated by ouabain, but could not block the stimulation mediated by TNF alpha. Ca++ ionophores also increased levels of GM-CSF mRNA and rapidly increased levels of Cai++. TNF did not increase Cai++ and, moreover, was able to stimulate accumulation of GM-CSF mRNA in the absence of extracellular Ca++. Taken together, we have found that several different cellular pathways can lead to prominent accumulation of GM-CSF mRNA in mesenchymal cells including (1) activation of protein kinase C, (2) increase in Cai++, and (3) stimulation of G-binding protein. Our studies show that TNF appears to increase levels of GM-CSF mRNA independent of protein kinase C activity or levels of Cai++.     

Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency

Homozygous or double heterozygous protein-C deficiency can present at birth with purpura fulminans or later in life with venous thrombosis. Two homozygous patients who had previously sustained thrombotic episodes were investigated at a time when they were asymptomatic and not receiving antithrombotic therapy. The plasma levels of protein-C antigen and activity in both individuals were approximately 20% of normal. We administered a highly purified plasma-derived protein C concentrate to these individuals and monitored levels of several markers of in vivo coagulation activation. Assays for protein-C activation (activated protein C and protein C activation peptide) showed a sustained increase from reduced baseline levels, whereas thrombin generation (as measured by prothrombin fragment F1 + 2) gradually decreased over about 24 hours into the normal range. These investigations provide direct evidence that protein C is converted to activated protein C in vivo, and that the protein-C anticoagulant pathway is a tonically active mechanism in the regulation of hemostatic system activation in humans.     

整合蛋白α5亚基表达与肝癌恶性表型

目的探讨整合蛋白α５亚基与原发性肝癌的关系。方法应用免疫组化技术（ＡＢＣ法）和Ｎｏｒｔｈｅｒｎｂｌｏｔ杂交检测整合蛋白α５亚基在原发性肝癌中的表达。结果发现在７９例癌与癌周组织α５阳性率分别为３２．９％和８１．０％，两者间差异有显著性（Ｐ＜０．０１）。直径≤５ｃｍ的肝癌α５阳性率高于直径＞１０ｃｍ的肝癌（５５．６％比１０．０％，Ｐ＜０．０１），分化较好的肝癌α５阳性率高于分化不良者（４０．６％比１６．０％，Ｐ＜０．０５），已发生明确肝内转移（包括肝内播散和门静脉癌栓形成）的肝癌α５阳性率低于未发生肝内转移者（２０．６％比４２．２％，Ｐ＜０．０５）。α５亚基表达与患者年龄、血清甲胎蛋白水平、乙型肝炎病毒感染、肝硬化有无等因素均无明显相关（Ｐ＞０．０５）。Ｎｏｒｔｈｅｒｎｂｌｏｔ杂交结果也同时显示，非侵袭性肝癌α５表达高于侵袭性肝癌。结论整合蛋白α５低表达与肝癌增大、分化程度低、侵袭转移发生等恶性表型相关，可能对这些恶性表型起负性调节作用。     

Synergistic effects of thrombopoietin and granulocyte colony- stimulating factor on neutrophil recovery in myelosuppressed mice

Severe suppression of the hematopoietic system is a major factor in limiting chemotherapy dose escalation. To determine whether a combination of human recombinant granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO) would alter recovery of platelets, red blood cells (RBCs), or neutrophils after myeloablative therapy, myelosuppressed mice were treated with sc injections of TPO (90 micrograms/kg), G-CSF (250 micrograms/kg). TPO plus G-CSF or vehicle and complete blood counts were measured. Marrow and spleen cells were obtained at various times and assayed for erythroid, myeloid, and megakaryocytic progenitors. The prolonged neutropenia in vehicle controls (14 days) was significantly shortened in mice treated with G- CSF or TPO for 14 days. The combination of TPO plus G-CSF further reduced the duration of neutropenia. TPO and TPO plus G-CSF treatments also significantly shortened thrombocytopenia compared to vehicle. Recovery of RBCs was also enhanced in mice treated with either G-CSF or TPO, or the combination. Furthermore, treatment with G-CSF and/or TPO hastened myeloid, erythroid, and megakaryocyte progenitor recovery compared to vehicle controls. These results show that the combination of TPO plus G-CSF acts synergistically to accelerate neutrophil recovery in myelosuppressed mice and does not compromise the platelet or RBC response to TPO therapy.     

Infrequent alterations of the RAR alpha gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes, and cell lines

Retinoids are important regulators of cell growth and differentiation in vitro and in vivo and they exert their biologic activities by binding to nuclear retinoic acid receptors (RARs; alpha, beta, and gamma) and retinoid X receptors (RXRs; alpha, beta, and gamma). All- trans retinoic acid (RA) induces complete remission in patients with acute promyelocytic leukemia (APL) presumably by binding directly to RAR alpha of APL cells. Leukemic blasts from APL patients initially responsive to RA can become resistant to the agent. HL-60 myeloblasts cultured with RA have developed mutations of the ligand-binding region of RAR alpha and have become resistant to RA. Furthermore, insertion of an RAR alpha with an alteration in the ligand-binding region into normal murine bone marrow cells can result in growth factor-dependent immortalization of the early hematopoietic cells. To determine if alterations of the ligand binding domain of RAR alpha might be involved in several malignant hematologic disorders, the mutational status of this region (exons 7, 8, and 9) was examined in 118 samples that included a variety of cell lines and fresh cells from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), including 20 APL patients, 5 of whom were resistant to RA and 1 who was refractory to RA at diagnosis, using polymerase chain reaction-single- strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing. In addition, 7 of the 20 APLs were studied for alterations of the other coding exons of the gene (exons 2 through 6). No mutations of RAR alpha were detected. Although the sensitivity of PCR-SSCP analysis is less than 100%, these findings suggest that alterations of RAR alpha gene are rare and therefore other mechanisms must be involved in the onset of resistance to retinoids and in the lack of differentiation in disorders of the myeloid lineage.     

Relapse cell population differs from acute onset clone as shown by absence of the initially activated N-ras oncogene in a patient with acute myelomonocytic leukemia

We have conducted a follow-up study of a patient with myelomonocytic leukemia exhibiting an N-ras mutation (Gln61----Lys61) using the polymerase chain reaction method and synthetic oligonucleotide hybridization probes. This method allowed us to detect as little as 3% of N-ras-mutated cells within a population. When the patient went into clinical remission, the mutation became undetectable. When a relapse occurred, the blasts did not carry the N-ras mutation. Analysis of M13 cloned amplified N-ras sequences from relapse DNA revealed exclusively the wild type allele of the N-ras gene. These findings suggest that the relapse cell population is derived from a different clone than the acute phase population. Furthermore, the data argue that N-ras mutation is not an initiating lesion in this case of acute myelomonocytic leukemia (AMML).     

Clinical diagnosis of hypersensitivity pneumonitis

The diagnosis of hypersensitivity pneumonitis (HP) is difficult and often relies on histopathology. Our objective was to identify diagnostic criteria and to develop a clinical prediction rule for this disease. Consecutive patients presenting a condition for which HP was considered in the differential diagnosis underwent a program of simple standardized diagnostic procedures. High-resolution computed tomography scan and bronchoalveolar lavage (BAL) defined the presence or absence of HP. Patients underwent surgical lung biopsy when the computed tomography scan, BAL, and other diagnostic procedures failed to yield a diagnosis. A cohort of 400 patients (116 with HP, 284 control subjects) provided data for the rule derivation. Six significant predictors of HP were identified: (1) exposure to a known offending antigen, (2) positive precipitating antibodies to the offending antigen, (3) recurrent episodes of symptoms, (4) inspiratory crackles on physical examination, (5) symptoms occurring 4 to 8 hours after exposure, (6) and weight loss. The area under the receiver operating characteristic curve was 0.93 (95% confidence interval: 0.90-0.95). The rule retained its accuracy when validated in a separate cohort of 261 patients. The diagnosis of HP can often be made or rejected with confidence, especially in areas of high or low prevalence, respectively, without BAL or biopsy.