Dynamic contrast-enhanced magnetic resonance imaging is a poor measure of rectal cancer angiogenesis

BACKGROUND: The aim of this study was to investigate the use of magnetic resonance imaging (MRI) for non-invasive measurement of rectal cancer angiogenesis and hypoxia. METHODS: Fifteen patients with rectal adenocarcinoma underwent preoperative dynamic contrast-enhanced (DCE) and blood oxygenation level-dependent (BOLD) MRI. Microvessel density (CD31 level), and expression of vascular endothelial growth factor (VEGF) and carbonic anhydrase (CA) 9 were measured immunohistochemically in histological tumour sections from 12 patients. Serum VEGF levels were also measured in 14 patients. Correlations between quantitative imaging indices and immunohistochemical variables were examined. RESULTS: There was good correlation between circulating VEGF and CD31 expression (r(S) = 0.88, P < 0.001). CD31 expression did not correlate with any dynamic MRI parameter, except transfer constant, with which it correlated inversely (r(S) = -0.65, P = 0.022). Tissue and circulating VEGF levels did not correlate, and neither correlated with any tumour DCE MRI parameter. No relationship was seen between BOLD MRI and CA-9 expression. CONCLUSION: The negative correlation between transfer constant (reflecting tumour blood flow and microvessel permeability) with CD31 expression is paradoxical. DCE MRI methods for assessing tissue vascularity correlate poorly with histological markers of angiogenesis and hypoxia, suggesting that DCE MRI does not simply reflect static histological vascular properties in patients with rectal cancer.     

Vessel transformation in chronic wounds under topical negative pressure therapy: an immunohistochemical analysis

The underlying physiological mechanism of topical negative pressure (TNP) therapy is not yet completely understood. This prospective clinical study aims to clarify a potential influence of TNP therapy on vessel proliferation and hypoxia in chronic wounds. TNP was applied on chronic wounds of 16 patients (?125 mmHg) to prepare them for a plastic‐surgical reconstruction using free or pedicled flaps. Tissue biopsies were taken from the wound edge and wound bed at different time points. All samples were stained with haematoxylin and eosin, hypoxia‐induced factor‐1α and endothelial cell markers (CD31 and CD34) for the immunohistological analysis of inflammation, hypoxia and vessel proliferation. Between day 5 and day 8 of treatment, a considerable increase in blood vessel density could be observed, reaching a maximum of approximately 200% in contrast to the vessel density prior to treatment. In addition, the number of hypoxic and inflammatory cells was found to be increased at particular time points. This study demonstrates a stimulating effect on vessel proliferation under TNP treatment. TNP appears to support (neo‐) angiogenesis and transformation of chronic non‐healing wounds in a physiological wound healing process when combined with surgical debridement. This effect underlines the positive influence of TNP in the treatment of chronic wounds as shown by various clinical reports.     

Failure of sputum eosinophilia after eotaxin inhalation in asthma

BACKGROUND: Eotaxin is a chemokine specific for eosinophils and may play an important role in eosinophil recruitment in asthma. The effects of eotaxin inhalation on sputum and blood eosinophils, exhaled nitric oxide (NO), and bronchial responsiveness were determined. METHODS: Eotaxin was administered by nebulisation to asthma patients in three studies: (1) an open dose finding study with eotaxin (5, 10 and 20 microg) to two asthmatic subjects; (2) a randomised placebo controlled study with 20 microg eotaxin to five asthmatic subjects and five normal volunteers; and (3) a randomised placebo controlled study with 40 microg eotaxin to nine asthmatics. Forced expiratory volume in 1 second (FEV(1)), exhaled NO, and blood eosinophils were measured before and hourly for 5 hours after nebulisation and at 24 and 72 hours. Methacholine bronchial challenge and sputum induction were performed before and at 5, 24, and 72 hours after nebulisation. RESULTS: In the two placebo controlled studies there was no change in sputum eosinophil count and sputum eosinophilic cationic protein concentration after eotaxin inhalation compared with placebo. FEV(1), exhaled NO, and methacholine PC(20) did not change. However, high dose eotaxin (40 microg) induced an increase in sputum neutrophil count compared with placebo (p<0.05). CONCLUSIONS: Inhaled eotaxin up to 40 microg induced no changes in sputum eosinophil count but at 40 microg it increased the sputum neutrophil count. The significance of this finding is unknown.     

Pseudoaneurysm of pulmonary artery in mucormycosis. Radiographic characteristics and management.

Pulmonary mucormycosis is a rare and almost invariably fatal complication that can occur in the context of severe deficits in host defenses. Antemortem diagnosis is difficult and requires a high index of suspicion together with invasive diagnostic techniques. Mucor species exhibit a pronounced affinity to invade vessels; mucormycosis involving the pulmonary vasculature has rarely been documented antemortem, and survival in this context has been rare. In this report, we describe a patient with chronic renal failure and systemic lupus erythematosus who developed extensive invasion of the left main pulmonary artery by mucormycosis. Chest computed tomographic (CT) scans and pulmonary arteriogram demonstrated a massive pseudoaneurysm of the left pulmonary artery; these radiographic findings have not previously been described in mucormycosis. Aggressive combination therapy, employing preoperative amphotericin B (AmB) followed by surgical resection (pneumonectomy) and a full course of AmB, was curative. This favorable outcome supports the role of surgery as adjunctive therapy, and it underscores the need for early diagnosis and aggressive treatment.     

Cerebral Embolism as a Cause of Stroke and Transient Ischemic Attack

The most frequent cause of stroke and transient ischemic attacks is cerebral embolism. Cardiogenic cerebral embolization is common among patients with any cause of atrial fibrillation (AF) but particularly in AF resulting from rheumatic and arteriosclerotic heart disease. Rare causes of cerebral embolism include fat entering the bloodstream after trauma, tumor cells arising from atrial myxomata, and gas embolism. Cerebral embolic infarctions and their sources of origin can now be confirmed during life by many invasive (I) and noninvasive (NI) procedures including computerized tomography (CT) scanning (NI), magnetic resonance imaging (MR) (NI), contrast angiography (I), digital subtraction angiography (I), magnetic resonance angiography (NI), carotid Doppler and transcranial Doppler (NI), and echocardiography (NI) without and with contrast. These tests visualize the following: embolic occlusions of small and large cerebral arteries, resultant cerebral infarctions in appropriate vascular territories, plaques within the aorta, subclavian, vertebral, and carotid arteries, and mural thrombi located within the heart and aortocephalic arteries. Transcranial Doppler monitoring of the middle cerebral artery detects both small (asymptomatic) and large (symptomatic) cerebral emboli, as well as transseptal cardiac shunting, which is a cause of paradoxical embolization. Holter monitoring detects episodic cardiac dysrhythmias not apparent during routine ECG. CT or MRI identify cerebral infarctions resulting from virtually all large cerebral emboli. Early recognition and identification of types of cerebral embolism are important because of the availability of effective prophylactic therapies.     

The origin of IgG production and homogeneous IgG components after allogeneic bone marrow transplantation

Pediatric recipients (n = 25) of an allogeneic bone marrow (BM) graft were selected on the basis of informative IgG allotype (Gm) differences between the BM donor and the recipient. To investigate the kinetics of the appearance of IgG of donor origin and the disappearance of IgG of recipient origin, G1m and G2m allotype levels were quantified in sera obtained at regular intervals between 3 months and 5 years after BM transplantation (BMT). For this quantification, a dot immunobinding assay (DIBA) has been developed. In 19 of 22 informative recipients, the Gm allotype distribution had reached the range of values expected on the basis of the Gm phenotype of the donor within 6 months after BMT. Remarkably, IgG of recipient origin persisted in 15 of 18 informative recipients until last follow up, ie, for several years after BMT. In addition to the origin of total IgG production, the origin of homogeneous IgG components (H-IgG) appearing after BMT was investigated. H-IgG of donor origin could be detected as early as 3 weeks after BMT, but also H-IgG of recipient origin were present in 8 of 13 informative recipients for a period of up to 1 year after BMT. We conclude that host-type IgG-producing cells were not eradicated by the (myeloablative) conditioning regimen and persisted in a high number of graft recipients. It is our hypothesis that lack of graft-versus-host disease (GVHD) in the majority of these recipients results in the persistence of IgG-producing cells of host origin. These observations may be relevant for the evaluation of patients who received allogeneic BMT for the treatment of multiple myeloma.     

Phenotypic and functional characterization of long-term culture- initiating cells present in peripheral blood progenitor collections of normal donors treated with granulocyte colony-stimulating factor

Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood progenitor cells (PBPC) have successfully been used as stem cells for both autologous and allogeneic transplants. However, little is known concerning the absolute number and phenotype of primitive progenitors, such as long-term culture-initiating cells (LTC-IC) in mobilized PBPC. The aim of our study was to evaluate the capacity of G- CSF to mobilize LTC-IC in the PB of normal individuals and to evaluate the phenotypic and functional characteristics of G-CSF mobilized LTC- IC. G-CSF was administered to 29 healthy volunteers at 7.5 micrograms or 10 micrograms/kg/d subcutaneously (SC) for 5 consecutive days and PBPC were harvested on day 6. Mobilization with G-CSF increased the absolute number of week 5 LTC-IC in PB 60-fold, while the number of CD34+ cells and committed colony forming cells (CFC) was increased sevenfold to 12-fold. The frequency of CFC and week 5 LTC-IC in CD34+ cells selected by fluorescence-activated cell sorter (FACS) from mobilized PBPC was 2 +/- 0.3-fold and 9 +/- 2.2-fold higher respectively than in CD34+ cells selected from unmobilized PBMNC. CFC were enriched in the CD34+ CD38+ and CD34+ HLA-DR+ populations. The absolute number of LTC-IC present in CD34+ CD38- and CD34+ HLA-DR- cells selected by FACS from either mobilized PBPC, unmobilized PBMNC or steady state bone marrow (BM) was similar (0.5% to 2%). In contrast to unmobilized PBMNC or steady state BM CD34+ CD38+ and CD34+ HLA-DR+ cells, which contain less than 0.1% LTC-IC, CD34+ CD38+ and CD34+ HLA- DR+ cells sorted from mobilized PBPC contained 0.5% to 5% of cells capable of sustaining hematopoiesis in long-term cultures for 5 weeks. However, 90% to 95% of LTC-IC present in mobilized CD34+ CD38+ and CD34+ HLA-DR+ cells were not able to sustain hematopoiesis for 8 weeks, while 30% of CD34+ CD38- and CD34+ HLA-DR- LTC-IC present in mobilized PBPC could sustain hematopoiesis for at least 8 weeks. This suggests that the majority of CD34+ CD38+ and CD34+ HLA-DR+ week 5 LTC-IC represent progenitors at an intermediate state of differentiation. We conclude that G-CSF effectively mobilizes LTC-IC in the blood of normal individuals. Although a fraction of these cells has functional characteristics similar to those of steady state PBMNC or BM LTC-IC, more than 85% of mobilized PBPC LTC-IC are CD34+ CD38+ and CD34+ HLA- DR+, capable of sustaining hematopoiesis for 5 weeks, but not for 8 weeks. The functional and phenotypic characterization of primitive and more mature populations of LTC-IC in mobilized PBPC should prove extremely useful in future studies examining the role of these progenitors in engraftment following transplantation.     

Fluconazole compared with endoscopy for human immunodeficiency virus- infected patients with esophageal symptoms

BACKGROUND & AIMS: The best initial treatment of human immunodeficiency virus (HIV)-infected patients with esophageal symptoms is unknown. The outcome, including safety and cost-effectiveness, of fluconazole compared with endoscopy as a treatment strategy for HIV-infected patients with new-onset esophageal symptoms was evaluated. METHODS: During a 53-month period, 134 HIV-infected patients with esophageal symptoms were randomized prospectively to groups receiving either standard doses of fluconazole or endoscopy. RESULTS: Among the 68 patients in the fluconazole group, a complete symptomatic response was observed in 56 patients (82%), usually within 1 week. The most common endoscopic findings in the 66 patients in the endoscopy group included Candida esophagitis alone in 42 patients (64%) and ulcerative esophagitis in 10 patients (15%). Patients responding to empirical antifungal therapy or who had Candida esophagitis alone at endoscopy were less like to have severe symptoms (P = 0.027) or odynophagia as the only symptom (P < 0.001) but more frequently had odynophagia and dysphagia (P = 0.007) and thrush (P = 0.002). Empirical fluconazole was cost-effective, saving $738.16 per patient. CONCLUSIONS: Empirical oral antifungal therapy with fluconazole is highly efficacious, safe, and cost-effective for HIV-infected patients with new-onset esophageal symptoms. (Gastroenterology 1996 Jun;110(6):1803-9)     

Intravascular hemolysis and renal insufficiency after bone marrow transplantation

Renal disease has not been considered a major late complication of bone marrow transplantation. Of 31 evaluable pediatric patients undergoing allogeneic or autologous bone marrow transplantation for neuroblastoma or acute lymphoblastic leukemia, 14 developed a hemolytic anemia, microscopic hematuria, and renal insufficiency at a median of 5 months (range, 3 to 7 months) posttransplant. Renal biopsies were performed in two patients at the onset of kidney disease and showed mesangiolysis with intraglomerular capillary aneurysm formation, mesangial proliferation, and focal thickening and splitting of the glomerular basement membranes. The clinical presentation, time to onset of renal disease, and biopsy material are consistent with a diagnosis of radiation nephritis, a previously uncommon finding in this patient group. The high incidence of this syndrome in the current report may have been due to the combination of intensive chemotherapy and total- body irradiation in the conditioning regimens.