Critical appraisal of Perez et al: Jugular venous oxygen saturation or arteriovenous difference of lactate content and outcome in children with severe traumatic brain injury.

OBJECTIVE: To review the findings and discuss the implications of jugular venous bulb oxygenation monitoring in children with severe traumatic brain injury. DESIGN: A critical appraisal of Perez et al, Jugular venous oxygen saturation or arteriovenous difference of lactate content and outcome in children with severe traumatic brain injury. FINDINGS: Two episodes of jugular venous bulb desaturation and abnormal values of arteriovenous difference in lactate content are associated with poor neurologic outcome in children with severe traumatic brain injury-risk ratio 6.6 (95% confidence interval, 1.5-29.7) and risk ratio 17.6 (95% confidence interval, 2.5-122.5), respectively. This confirms the findings of previously reported adult studies. CONCLUSIONS: This study is the first to demonstrate that jugular venous monitoring may aid in predicting the neurologic outcome of children with severe traumatic brain injury. More studies need to be performed (particularly on safety) before adopting jugular venous bulb oxygenation monitoring as a prediction tool or, ultimately, as a therapeutic intervention to help manage and improve outcome for children with severe traumatic brain injury.     

Photodynamic therapy with verteporfin for retinal angiomatous proliferation

Purpose The aim of this study was to evaluate the results of photodynamic therapy (PDT), using verteporfin, for subfoveal neovascular age-related macular degeneration (ARMD) with retinal angiomatous proliferation (RAP) with pigment epithelial detachment (PED) and/or choroidal neovascularization (CNV).Methods In this non-comparative, consecutive, interventional, case series, the data on 21 eyes (19 with stage 2 and two with stage 3 RAP) of 20 patients were reviewed. Serous PED occupied more than 50% of the lesion in 19 eyes. PDT was performed as per TAP protocol. Biomicroscopy and fluorescein and indocyanine-green angiography were performed to evaluate anatomical results and need for retreatment. Changes from baseline in best-corrected visual acuity (BCVA), and complications, were assessed.Results A mean of 3.5±0.9 treatments was performed. After 13.7±2.2 months, mean BCVA decreased from 20/80 to 20/174 (P=0.0063). In six eyes (28.6%) BCVA remained stable, whereas in 15 eyes (71.5%) it decreased. Occlusion of RAP and flattening of PED was observed in three (14.2%) eyes, conversion to disciform lesion in one (4.7%), and persistence of PED in 11 eyes (52.3%). One eye (4.7%) evolved to haemorrhagic PED, and one (4.7%) toward stage 3 RAP. A tear in the retinal pigment epithelium (RPE) was observed in four eyes (19%). Eleven (52.3%) showed progression of leakage, six moderate leakage (28.6%), and three (14.2%) absence of leakage.Conclusions Timely PDT with verteporfin in the early stages in eyes with smaller lesions has the potential for a beneficial effect on vision, whereas it might worsen the natural course of larger lesions, with most eyes undergoing enlargement, disciform transformation or RPE tear.Presented in part as a paper at the American Academy of Ophthalmology Annual Meeting, Anaheim, California, 15–18 November 2003The authors have no financial interest in this study     

Effect of montelukast on exhaled NO in asthmatic children exposed to relevant allergens

The level of exhaled nitric oxide (FENO) is increased in house dust mite (HDM)-sensitized asthmatic children after exposure to HDM antigen, and inhaled steroids can prevent this increase. The aim of this study was to evaluate whether montelukast could prevent an increase in FENO levels in allergic asthmatic children after a brief period of exposure to relevant allergens. Sixteen children were evaluated at the residential house 'Istituto Pio XII' (Misurina, Bellunio, Italy) in the Italian Alps, a dust mite-free environment. FENO levels were evaluated before ( t ₀) and immediately after ( t ₁) the children were exposed to HDM allergens for 2 weeks in their homes at sea level. No significant difference in FENO was observed in the fluticasone-treated group of children after 2 weeks at sea level. In the group treated with montelukast, an increase in FENO was observed between t ₀ and t ₁, which failed to reach statistical significance. These preliminary data suggest that oral montelukast could be effective in preventing the relapse in airway inflammation in allergic asthmatic children who are occasionally exposed to relevant allergens for a short period of time.     

The modification of human tumour blood flow using pentoxifylline, nicotinamide and carbogen.

AIM: To assess the effect of combining oral nicotinamide, oral pentoxifylline and carbogen gas (2% CO2, 98% O2) breathing on human tumour red cell flux. METHODS AND MATERIALS: Microregional red blood cell flux was measured in accessible tumour nodules using laser Doppler microprobes in 11 patients with histologically proven malignancy. Patients received single oral doses of nicotinamide 40 mgkg-1 and pentoxifylline 1200 mg 2h before a 10-min period of carbogen gas breathing, corresponding to peak plasma concentrations of these drugs. Red cell flux in up to six microregions in each tumour was measured for 30 min, recording pre-, during and post-carbogen breathing for 10 min each.RESULTS: Data from ten of the 11 patients could be assessed. The red cell flux in 48 microregions was analysed and the mean red cell flux was calculated. A mean relative increase in red cell flux of 1.18 (+/-0.09, 95% confidence interval (CI)) was observed after 6 min of carbogen breathing, 2h after the administration of nicotinamide and pentoxifylline. This compares to relative increases of 1.4 (+/-0.39, 95%CI) after nicotinamide with carbogen and 1.15 (+/-0.10, 95%CI) after pentoxifylline with carbogen. These differences are not statistically significant (P>0.05). The increased red cell flux persisted after the cessation of carbogen gas breathing. CONCLUSIONS: A combination of pentoxifylline, nicotinamide and carbogen produces an increase in human tumour red cell flux, similar to that observed when each of the drugs are used alone with carbogen breathing.     

Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.

PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.     

Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative.

PURPOSE: We previously reported that paclitaxel, a microtubule-stabilizing drug, inhibited angiogenesis, mainly by inhibiting endothelial cell motility (D. Belotti et al., Clin. Cancer Res., 2: 1843-1849, 1996). The aim of this study was to select a taxane with little cytotoxicity but with antimotility and hence antiangiogenic activity. EXPERIMENTAL DESIGN: Different taxanes, seco derivatives, and 14-beta-hydroxy-10-deacetyl baccatin III derivatives were tested for their effects on the proliferation and motility of human umbilical vein endothelial cells. The antiangiogenic and antineoplastic activities of the compound selected from this screening were further investigated in experimental models in vitro and in vivo. RESULTS: From the screening of different taxanes, we selected IDN 5390, a seco derivative that showed potent antimotility activity and less cytotoxicity than paclitaxel. In comparable experimental conditions, IDN 5390 inhibited endothelial cell migration without affecting proliferation. This compound dose-dependently inhibited the capacity of human umbilical vein endothelial cells plated on Matrigel to organize into a network of cords. In vivo, IDN 5390 significantly inhibited fibroblast growth factor-2-induced angiogenesis in Matrigel implants. Daily treatment with IDN 5390 in mice bearing established lung micrometastases from the B16BL6 murine melanoma caused a reduction in the size of metastases. Finally, IDN 5390 slowed the s.c. growth of the paclitaxel-resistant human ovarian carcinoma, 1A9/PTX22, xenografted in nude mice. CONCLUSIONS: The seco derivative IDN 5390 might represent the prototype of a new class of taxane derivatives with antiangiogenic properties.     

Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer.

PURPOSE: The transforming growth factor alpha-epidermal growth factor receptor (EGFR) autocrine pathway has been implicated in prostate cancer cell growth. Amplification and/or overexpression of c-erbB-2, a receptor closely related to the EGFR, has been recently involved in prostate cancer progression. We investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in advanced androgen-independent prostate cancer and their potential role as markers of disease progression. EXPERIMENTAL DESIGN: EGFR and c-erbB-2 expression were evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer patients with the following characteristics: 29 patients (group 1) treated with radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone-releasing hormone analogues and antiandrogen therapy followed by radical prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all patients we evaluated: association between EGFR and/or c-erbB-2 expression and clinicopathological parameters; and disease-free survival according to EGFR and c-erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and in multivariate analysis (Cox proportional hazards regression model). RESULTS: EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29 (75.9%) group 2 patients (P < 0.0005), and in 16 of 16 (100%) metastatic patients (P < 0.005), whereas c-erbB-2 expression was found in 11 of 29 (37.9%) group 1, in 10 of 29 (34.5%) group 2 patients, and in 9 of 16 (56.3%) metastatic patients. A significant association was found between EGFR expression and a high Gleason score (P < 0.01) and between EGFR expression and higher serum prostate-specific antigen values (P < 0.02) in all groups of patients. Among the 58 patients treated with radical prostatectomy, 23 of 34 EGFR-positive patients (67.6%) relapsed, whereas only 2 of 24 EGFR-negative patients (8.3%) relapsed (P < 0.00004). c-erbB-2 expression did not significantly correlate with disease relapse (P = 0.07). In a Cox multivariate analysis, the only parameter with an independent prognostic effect on disease-free survival was EGFR expression (relative hazard, 11.23; P = 0.0014). CONCLUSIONS: EGFR expression increases during the natural history of prostate cancer. Correlation with disease progression and hormone-refractory disease suggests that EGFR-targeted drugs could be of therapeutic relevance in prostate cancer.     

Role of monocytes in the early phase of acute myocardial infarction

BACKGROUND: In acute myocardial infarction peripheral leucocytosis occurs early and fibrinogen levels increase in response to the tissue injury, expressed by the enhanced enzyme plasma levels. The aim of the present study has been to investigate if a unifying link between these modifications might be found. METHODS: In 325 patients, 246 men and 79 women, 61.46 +/- 11.00 and 70.03 +/- 11.30 years mean age respectively, at admission for myocardial infarction and before treatment, we simultaneously measured plasma fibrinogen (FBG), hemochromocytometric parameters and plasma enzyme aspartate and alanine transaminase (AST and ALT), lactate dehydrogenase (LDH) and creatine phosphokinase (CPK). The statistical analysis was performed by using standard multiple regression for dependent variable FBG and for the variables white blood cells (WBC), monocyte number, large unstained cells (LUC) and CPK. RESULTS: The results showed that FBG was significantly correlated with monocyte (p < 0.001) and LUC (p < 0.05) counts; assumed as dependent variable, further on with FBG, monocyte number was correlated with WBC count, LUC and CPK; further on with monocyte number, WBC with neutrophile and lymphocyte counts, LUC with CPK, CPK with LDH. CONCLUSIONS: The study seems to show that monocyte modifications occur already in the early phase of myocardial infarction. These modifications are directly related to damage extension, as deducible from CPK levels, and seem to mainly modulate FBG and WBC, since the cytokines and hematopoietic growth factors production by activated monocytes.