Peripheral T-lymphocyte subsets in patients treated with Rituximab-Chlorambucil combination therapy for indolent NHL.
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Antibodies, Monoclonal↗
Biomedical subjects
P Mancuso
Publications and source records attributed to P Mancuso.
The prevalence and clinical implications of c-kit expression in plasma cell myeloma.
AIM: To evaluate the clinical implications of c-kit (CD117) expression in plasma cell myeloma (PCM). METHODS AND RESULTS: We first evaluated the reliability of immunohistochemistry in assessing c-kit expression by comparing the results with those obtained by flow cytometry and gene expression arrays in 22 PCM and in 10 PCM cell lines. Immunohistochemical results showed a perfect concordance with those of flow cytometry; likewise, immunohistochemical and gene expression data were also concordant in all but one PCM and cell lines analysed. Then, we investigated the clinical implications of c-kit immunoreactivity in bone marrow biopsies of 85 PCM patients with a mean follow-up of 41 months. C-kit immunoreactivity was detected in 24 (28.2%) of the 85 cases and it was significantly associated with a high microvessel density, but not with traditional clinicopathological characteristics or with survival. CONCLUSIONS: Our findings suggest that immunohistochemistry is a reliable indicator of c-kit gene expression and reinforce the notion that approximately one-third of PCM express high levels of c-kit. The lack of association with traditional clinicopathological parameters and patient survival suggests that c-kit expression may not be an adjunct in predicting the clinical course of the disease.
Adult↗
Endothelial precursors and mature endothelial cells are increased in the peripheral blood of myelodysplastic syndromes.
Increased angiogenesis has been demonstrated to be a significant prognostic factor in many solid tumors. In the oncohematological setting, it has been associated with myelodysplastic syndromes (MDS), chronic myeloid leukemia, acute lymphoid, and myeloid leukemias. Recently, increased circulating endothelial cells (CECs) have been associated with breast cancer and non-Hodgkin lymphoma (NHL). Based on these premises we analysed total and activated CECs, and endothelial precursors (CEPs) in 50 MDS patients and 20 healthy donors. CECs and CEPs were quantified by flow cytometry. CEC levels were compared with bone marrow (BM) microvessel density (MVD). In addition, some angiogenic factors, namely vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble VEGF-Receptor2 (VEGFR2), were tested in the sera from 25 MDS patients. Total, activated CECs and CEPs were significantly increased in MDS when compared to control group (p<0.0001); whereas in the MDS cases no association was found with French--American--British (FAB), International Prognostic Scoring System (IPSS) subtypes or survival. Patients with higher CECs also showed higher MVD. Among the cytokines analysed, sVEGFR2 was significantly higher in the lower IPSS risk classes, while the levels of bFGF directly correlated with total and activated CECs. Taken together these data strengthen the hypothesis of a possible role of angiogenesis in MDS pathogenesis.
Adult↗
Spinal epidural hematoma following coronary thrombolysis. A case report.
A case of cervicothoracic spontaneous spinal epidural hematoma (SSEH) following coronary thrombolysis with r-TPA and intravenous heparin is reported. The clinical picture is discussed, as well as the importance of rapid neuroradiological diagnosis (with spinal MRI being the method of choice) and surgical treatment. Anyway, in these patients, thorough cardiac function evaluation and rapid correction of any clotting disorder is necessary prior to surgery. With the increasing use of fibrinolytic therapy this complication would be more frequent. This underlines the importance of prompt recognition and adequate treatment.
Cervical Vertebrae↗
Idarubicin containing regimen in multiple myeloma: preliminary results of a pilot study using a modified "TANDEM" transplant program.
Tandem autologous transplant actually represents a challenge in multiple myeloma treatment, but the best conditioning regimen is still under investigation. With the aim of evaluating the feasibility of a modified tandem transplant strategy, we treated 10 multiple myeloma patients after conventional first line chemotherapy with a two step conditioning regimen consisting of high-dose melphalan (200 mg/m2) followed by high-dose melphalan (180 mg/m2) together with indarubicin (15 mg/sqm2 c.i. x 3 days) both with peripheral stem cell support. At first transplant, the median age wasyears, performance status was good and disease status was CR in 2 patients and PR in the rest. At the end of the first transplant, 70% of patients achieved CR and only mild toxicity was observed. After the second transplant further improvement of the response rate was obtained with 90% CR. However, we observed three toxic early infection-related deaths from CMV and legionella pneumonia at day + 17, +26, +54 after transplantation. Although this schedule seems to be effective in terms of response rate, the 30% TRM imposes an anthracycline dose-reduction with careful patient selection. This approach could reduce the toxic effects and maintain the efficacy of therapy at the same time.
Aged↗
Short- and long-term safety of the 2 x 10(6) CD34+ cells/kg threshold for hematopoietic reconstitution after high-dose chemotherapy and peripheral blood progenitor cell support.
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Antigens, CD34↗
Resting and activated endothelial cells are increased in the peripheral blood of cancer patients.
Circulating endothelial cells (CECs) were enumerated in 20 healthy controls and 76 newly diagnosed cancer patients by means of 4-color flow cytometry. In breast cancer (n = 46) and lymphoma (n = 30) patients, both resting and activated CECs were increased by 5-fold (P <.0008 vs control). CECs significantly correlated with plasma levels of vascular cell adhesion molecule-1 and vascular endothelial growth factor. Resting and activated CECs were similar to healthy controls in 7 lymphoma patients achieving complete remission after chemotherapy, and activated CECs were found to decrease in 13 breast cancer patients evaluated before and 24 hours after quadrantectomy. (Blood. 2001;97:3658-3661)
Breast Neoplasms↗
Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma.
Circulating endothelial cells (CECs) were evaluated by flow cytometry in immunodeficient mice bearing human lymphoma. A trend toward higher CEC values was observed on days 7 and 14 after transplant, and differences versus controls were highly significant on day 21 (P = 0.0061). A strong correlation was found between CEC and tumor volume (r, 0.942; P = 0.004) and between CEC and tumor-generated VEGF (r, 0.669; P = 0.02). In mice given cyclophosphamide, most of the circulating apoptotic cells were hematopoietic and not endothelial. Conversely, in mice given endostatin, all of the increase in apoptotic cells was in the endothelial cell compartment. CEC evaluation is promising as a noninvasive, surrogate angiogenesis marker.
Angiogenesis Inhibitors↗
Evaluation of phagocytosis and arachidonate metabolism by alveolar macrophages and recruited neutrophils from F344xBN rats of different ages.
The incidence of infectious respiratory diseases increases with aging. Resident alveolar macrophages (AMs) and recruited leukocytes (PMNL) mediate cellular defense against bacterial infections in the lung, and phagocytosis and lipid mediator synthesis are important components of their antimicrobial capacity. The objective of this study was to determine if either phagocytic capacity or lipid mediator generation declines with normal aging, in either AMs or PMNL recruited to a site of inflammation. The F344xBN rat hybrid has a lower incidence of pathologies associated with aging, particularly up to 20 months; animals aged 6,12 and 18 months were chosen to evaluate changes associated with normal aging. As previously reported for peripheral blood leukocytes, phagocytosis by recruited PMNL declined with aging: recruited PMNL from 18 months rats showed a significantly decreased capacity to phagocytose live Klebsiella pneumoniae bacteria, compared to PMNL from 6 months rats. Surprisingly, however, the phagocytic capacity of AMs increased with aging: the phagocytic index of AMs from 18 months rats was more than three times that of AMs from 6 months rats. The capacity of AMs and recruited PMNL to release arachidonic acid or synthesize leukotrienes or prostaglandins did not change with aging. This study demonstrates that, although phagocytosis by recruited PMNL declines with aging, other aspects of immune function do not decline, and may actually increase, with normal aging. These results suggest that impaired phagocytosis by recruited PMNL may be an important component of the increased susceptibility to infectious respiratory diseases during normal aging.
Age Factors↗
Thalidomide in multiple myeloma, myelodysplastic syndromes and histiocytosis. Analysis of clinical results and of surrogate angiogenesis markers.
BACKGROUND: Thalidomide, as a single agent, has been recently found to induce a clinical response in one third of refractory or relapsed myeloma patients. Although it has been reported that thalidomide significantly inhibits angiogenesis. it is still unclear whether its clinical effect is mediated, at least in part, by its anti-angiogenic properties. PATIENTS AND METHODS: We evaluated thalidomide as a single agent in myeloma, myelodysplastic syndromes (MDS) and histiocytosis, i.e. hematological diseases characterized by increased angiogenesis, and measured prospectively a number of surrogate angiogenesis markers. RESULTS: Clinical responses were observed in 7 of 17 myeloma and 2 of 5 MDS patients. The histiocytosis patient had a partial response. At the time of the best clinical response, plasma levels of angiogenic growth factors, vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF), were significantly decreased, and flow cytometry indicated a decrease of activated endothelial cells in the bone marrow of responding MDS patients. CONCLUSIONS: These observations confirm thalidomide efficacy in myeloma, suggest a possible use in MDS and histiocytosis and may contribute to the prediction of clinical response and to understanding the mechanism of thalidomide's action.
Aged↗
Macrophage inflammatory protein 1alpha/CCL3 is required for clearance of an acute Klebsiella pneumoniae pulmonary infection.
The objective of these studies was to determine the role of macrophage inflammatory protein 1alpha/CCL3 in pulmonary host defense during Klebsiella pneumoniae infection. Following intratracheal inoculation, 7-day survival of CCL3(-/-) mice was less than 10%, compared to 60% for CCL3(+/+) mice. Survival of CCR5(-/-) mice was equivalent to that of controls, indicating that the enhanced susceptibility of CCL3(-/-) mice to K. pneumoniae is mediated via another CCL3 receptor, presumably CCR1. At day 3, CFU burden in the lungs of CCL3(-/-) mice was 800-fold higher than in CCL3(+/+) mice, demonstrating that CCL3 is critical for control of bacterial growth in the lung. Surprisingly, CCL3(-/-) mice had no differences in the recruitment of monocytes/macrophages and even showed enhanced neutrophil recruitment at days 1, 2, and 3 postinfection, compared to CCL3(+/+) mice. Therefore, the defect in clearance was not due to insufficient recruitment of leukocytes. No significant differences in cytokine levels of monocyte chemoattractant protein 1 (MCP-1), interleukin 12, gamma interferon, or tumor necrosis factor alpha in lung lavages were found between CCL3(+/+) and CCL3(-/-) mice. CCL3(-/-) alveolar macrophages were found to have significantly lower phagocytic activity toward K. pneumoniae than CCL3(+/+) alveolar macrophages. These findings demonstrate that CCL3 production is critical for activation of alveolar macrophages to control the pulmonary growth of the gram-negative bacterium K. pneumoniae.
Acute Disease↗
Leukotriene B4 augments neutrophil phagocytosis of Klebsiella pneumoniae.
Neutrophils play a critical role in the clearance of bacteria from the lung and other organs by their capacity for phagocytosis and killing. Previously, we identified an important role for the leukotrienes in rat alveolar macrophage phagocytosis of Klebsiella pneumoniae. In this report, we explored the possibility that the leukotrienes play an important role in phagocytosis by neutrophils as well. Inhibition of endogenous leukotriene synthesis by 5-lipoxygenase knockout in mice or by pharmacologic means in human peripheral blood neutrophils attenuated phagocytosis of opsonized K. pneumoniae. Reduced phagocytosis was also observed in human neutrophils pretreated with a leukotriene B4 receptor but not a cysteinyl-leukotriene receptor antagonist. While leukotriene B4 reconstituted defective phagocytosis in leukotriene-deficient neutrophils and enhanced phagocytosis in neutrophils capable of leukotriene synthesis, leukotriene C4, leukotriene D4, 5-hydroperoxyeicosatetraenoic acid, and 5-oxo-eicosatetraenoic acid were ineffective. To determine the opsonin dependence of the leukotriene B4 augmentation of phagocytosis, we assessed the ability of leukotriene B4 to modulate neutrophil phagocytosis and the adherence of sheep erythrocytes opsonized with immunoglobulin G or the complement fragment C3bi. While leukotriene B4 augmented both Fc receptor- and complement receptor-mediated phagocytosis, increased adherence to leukotriene B4-treated neutrophils was limited to complement opsonized targets. In conclusion, we have identified a novel role for leukotriene B4 in the augmentation of neutrophil phagocytosis mediated by either the Fc or complement receptor.
Animals↗
Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis.
Prostaglandins of the E series are believed to act as important mediators of several pathophysiological events that occur in sepsis. Studies were performed to evaluate the effect of cyclooxygenase (COX)-2-specific inhibition on the outcome in murine endotoxemia and cecal ligation and puncture (CLP). We observed a significant time-dependent upregulation of PGE(2) production in both blood and lung homogenates of mice administered lipopolysaccharide intraperitoneally, which was nearly completely suppressed by the administration of the COX-2 inhibitor NS-398. Treatment with NS-398 significantly improved early but not late survival in lipopolysaccharide-challenged mice. On the contrary, elevated PGE(2) levels were found in bronchoalveolar lavage fluid but not in plasma of mice subjected to CLP (21 gauge). Pretreatment with NS-398 failed to significantly improve survival in CLP mice. No significant differences were noted in plasma or lung homogenate proinflammatory cytokine levels or lung neutrophil sequestration between the NS-398-treated and control groups. These results demonstrate that selective COX-2 inhibition confers early but not long-term benefits without affecting the expression of proinflammatory cytokines or the development of lung inflammation.
Animals↗
Intramural leiomyoma during pregnancy becoming pedunculated postpartally. A case report.
BACKGROUND: The natural history of uterine leiomyomas during pregnancy has been reported. CASE: A 39-year-old primigravida presented with vaginal spotting in the 10th week of pregnancy. Ultrasonic evaluation revealed a large intramural leiomyoma. Unsuccessful tocolysis at 25 weeks' gestation resulted in a cesarean section for breech presentation. At hysterotomy a 10-cm intramural leiomyoma was found in the right fundus and was left in situ. Six months later, at open laparotomy for myomectomy, the 10-cm leiomyoma was pedunculated, on a 4-cm stalk. CONCLUSION: Large intramural leiomyomas found at cesarean section may become pedunculated postpartally, thus making myomectomy easier and safer at a postpartum intervention than at the time of cesarean section. Also, prior knowledge of the possibility of myoma transformation from intramural to pedunculated postpartally may help in planning a later myomectomy. Myomectomy prior to pregnancy should be considered when it has caused a prior pregnancy complication.
Adult↗
Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-grade non-Hodgkin lymphoma.
Both chemotherapy and chimeric anti-CD20 monoclonal antibodies are effective agents against B-cell non-Hodgkin lymphoma (NHL). However, patients achieving remission are at risk of relapse. To evaluate the effect of the antiangiogenic drug endostatin used alone and after the administration of cyclophosphamide (CTX) or the anti-CD20 antibody rituximab, we generated a new model of human NHL by transplanting Namalwa cells intraperitoneally into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. First, we determined the most effective treatment schedule for the drugs assessed. When administered alone, CTX (3 courses of 75 mg/kg of body weight given intraperitoneally), rituximab (3 courses of 25 mg/kg given intraperitoneally), and endostatin (5 courses of 50 microg given subcutaneously) delayed tumor growth, and CTX was the most effective in controlling bulky disease. When given after chemotherapy or immunotherapy, endostatin effectively induced tumor stabilization. When mice given CTX or rituximab on days 3, 5, and 7 after transplantation were randomly assigned to receive endostatin or phosphate-buffered saline on days 15 to 19, tumor growth was prevented in endostatin-treated mice as long as the drug was administered. Furthermore, administration of endostatin on days 25 to 29 after tumor regrowth still induced significant tumor regression, whereas CTX and rituximab were not effective. The specific antiangiogenic action of endostatin was confirmed by in vitro and in vivo studies indicating that the drug inhibited proliferation and induced apoptosis of endothelial (but not of NHL) cells. In conclusion, sequential administration of chemotherapy and endostatin seems promising for treating bulky NHL, and the less toxic sequential administration of rituximab and endostatin is promising for treating limited disease. (
Angiogenesis Inhibitors↗
The thin red line: angiogenesis in normal and malignant hematopoiesis.
This review describes the current knowledge about cell subsets involved in vasculogenesis (i.e., differentiation of endothelial cells from mesodermal precursors) and angiogenesis (i.e., blood vessel generation from pre-existing vessels), together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma, myeloma, and myelodysplastic syndromes.
Animals↗
Idarubicinol myelotoxicity: a comparison of in vitro data with clinical outcome in patients treated with high-dose idarubicin.
We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves. We treated 16 patients with poor prognosis lymphoma in a phase I-II trial of high-dose idarubicin and melphalan and investigated if idarubicinol persisting in patients' plasma at the time of transplantation (day 0), on day +1 and +2 could result in an inhibition of infused progenitors. Colony inhibition was correlated with pharmacokinetic data and with the time of patients' engraftment. Plasma samples obtained before idarubicin treatment demonstrated a colony-stimulating effect, increasing the cloning efficiency by 72%. The inhibitory activity on colony forming unit granulocyte-macrophage (CFU-GM) of patients' plasma collected on the day of transplantation was lower than expected from dose-response curves (21% measured vs 70% expected). The time to patients' WBC and PLT recovery correlated with the amount of CD34+ cells reinfused and, to a lesser extent, with the colony-inhibiting effect of patients' plasma. The correlation between idarubicinol concentration and CFU-GM inhibition was not significant. These data suggest that plasma drug concentration on the day of stem cell reinfusion may overestimate the toxicity of residual anthracyclines to the transplanted cells.
Adult↗
Dermatologic manifestations of infectious diseases in pregnancy.
Several pathogens that have been identified as teratogenic or fetotoxic have associated dermatologic changes when active infection is present. Viral and bacterial teratogenic pathogens include herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, cytomegalovirus, human papilloma virus, human parvovirus B19, rubella, viral hepatitis, syphilis, and gonorrhea. This article focuses on the characteristic dermatologic manifestation of these diseases in pregnancy; diagnostic strategies; interpretation of maternal and fetal laboratory test results; treatment of the pregnant woman, fetus, and newborn; and congenital outcomes of treated and untreated infection. Emphasis is placed on vaccination and prevention of transmission of infection to pregnant women.
Adult↗