Acute effects of intracranial hypertension and ARDS on pulmonary and neuronal damage: a randomized experimental study in pigs

Abstract PURPOSE: To determine reciprocal and synergistic effects of acute intracranial hypertension and ARDS on neuronal and pulmonary damage and to define possible mechanisms. METHODS: Twenty-eight mechanically ventilated pigs were randomized to four groups of seven each: control; acute intracranial hypertension (AICH); acute respiratory distress syndrome (ARDS); acute respiratory distress syndrome in combination with acute intracranial hypertension (ARDS + AICH). AICH was induced with an intracranial balloon catheter and the inflation volume was adjusted to keep intracranial pressure (ICP) at 30-40 cmH2O. ARDS was induced by oleic acid infusion. Respiratory function, hemodynamics, extravascular lung water index (ELWI), lung and brain computed tomography (CT) scans, as well as inflammatory mediators, S100B, and neuronal serum enolase (NSE) were measured over a 4-h period. Lung and brain tissue were collected and examined at the end of the experiment. RESULTS: In both healthy and injured lungs, AICH caused increases in NSE and TNF-alpha plasma concentrations, extravascular lung water, and lung density in CT, the extent of poorly aerated (dystelectatic) and atelectatic lung regions, and an increase in the brain tissue water content. ARDS and AICH in combination induced damage in the hippocampus and decreased density in brain CT. CONCLUSIONS: AICH induces lung injury and also exacerbates pre-existing damage. Increased extravascular lung water is an early marker. ARDS has a detrimental effect on the brain and acts synergistically with intracranial hypertension to cause histological hippocampal damage

The lymphangiogenesis inhibitor esVEGFR-2 in human embryos: expression in sympatho-adrenal tissues and differentiation-induced up-regulation in neuroblastoma

Tumour-induced hem- and lymph-angiogenesis are frequently associated with tumour progression. Vascular Endothelial Growth Factor-C (VEGF-C) is a potent inducer of lymphangiogenesis, while the endogenous soluble splice-variant of VEGF receptor-2, esVEGFR-2, acts as a natural inhibitor. Previously we have shown down-regulation of esVEGFR-2 mRNA in progressed stages of neuro-blastoma (NB), a tumour derived from sympatho-adrenal precursor cells. Here we studied the immunolocalization of esVEGFR-2 in human embryos, infantile adrenal gland and primary NB. We also quantified esVEGFR-2 mRNA in NB cell lines after differentiation-induction by all-trans retinoic acid (ATRA). By immunoperoxidase staining we observed expression of esVEGFR-2 in both the sympathetic trunk and the adrenal medulla. Additionally, esVEGFR-2 was found in spinal ganglia, floor plate of the neural tube, choroid plexus, notochord, arterial endothelium, skeletal muscle, epidermis and gut epithelium. Developing and circulating leukocytes showed the strongest signal. In NB, esVEGFR-2 was considerably stronger in differentiating low grade tumours with neuronal phenotype than in undifferentiated lesions. Differentiation-induction of the NB cell line SMS-Kan with 5-10 µM ATRA resulted in a significant increase of esVEGFR-2 mRNA after 6, 9 and 12 days. We show that esVEGFR-2 is widely expressed in embryonic tissues. Especially, the adrenal medulla and circulating leukocytes seem to be potent inhibitors of lymphangiogenesis. We provide additional evidence for a role of esVEGFR-2 in NB. Thereby, high levels of esVEGFR-2 correlate with a more differentiated phenotype, and may inhibit tumour progression by inhibition of lymphangiogenesis

Effects of acute intracranial hypertension on extracerebral organs: a randomized experimental study in pigs.

none7The study was conducted to determine the effects of isolated acute intracranial hypertension (AICH) on extracerebral organs. DESIGN: A total of 14 mechanically ventilated pigs were randomized to two groups of seven each: (1) control and (2) AICH. METHODS: AICH was induced by inflating an intracranial balloon catheter. The inflation volume was adjusted to keep intracranial pressure between 30 and 40 cm H2O. Hemodynamics, gas-exchange, and global oxygen delivery parameters were observed over a 4-hour period. At the end of the 4-hour period, tissue samples of heart, lungs, liver, and kidneys were collected and histologically graded for inflammation, edema, and cell damage (necrosis) using semiquantitative scores. RESULTS: Animals with AICH had increased heart rate and cardiac output, and higher scores for inflammation, edema, and necrosis in heart, lung, kidney, and liver tissues (all p < 0.05). Peripheral and mixed-venous oxygen saturations were unaffected. CONCLUSIONS: Isolated AICH induces injury to multiple extracerebral organs, even in the absence of hypoperfusion or hypoxemia. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.JF Heuer; M. Selke; TA Crozier;P. Pelosi; P. Herrmann;C. Perske; M. Quintel;Jf, Heuer; M., Selke; Ta, Crozier; Pelosi, PAOLO PASQUALINO; P., Herrmann; C., Perske; M., Quinte

Contrast Enhancement on Cone-Beam Breast-CT for Discrimination of Breast Cancer Immunohistochemical Subtypes

PURPOSE: To evaluate whether contrast enhancement on cone-beam breast-CT (CBBCT) could aid in discrimination of breast cancer subtypes and receptor status. METHODS: This study included female patients age >40 years with malignant breast lesions identified on contrast-enhanced CBBCT. Contrast enhancement of malignant breast lesions was standardized to breast fat tissue contrast enhancement. All breast lesions were approved via image-guided biopsy or surgery. Immunohistochemical staining was conducted for expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor-2 (HER2) and Ki-67 index. Contrast enhancement of breast lesions was correlated with immunohistochemical breast cancer subtypes (Luminal A, Luminal B, HER2 positive, triple negative), receptor status and Ki-67 expression. RESULTS: Highest contrast enhancement was seen for Luminal A lesions (93.6 HU) compared to Luminal B lesions (47.6 HU, P = .002), HER2 positive lesions (83.5 HU, P = .359) and triple negative lesions (45.3 HU, P = .005). Contrast enhancement of HER2 positive lesions was higher than Luminal B lesions (P = .044) and triple negative lesions (P = .039). No significant difference was evident between Luminal B and triple negative lesions (P = .439). Lesions with high Ki-67 index showed lower contrast enhancement than those with low Ki-67 index (P = .0043). ER, PR and HER2 positive lesions demonstrated higher contrast enhancement than their receptor negative counterparts, although differences did not reach statistical significance (P = .1714; P = .3603; P = .2166). CONCLUSIONS: Contrast enhancement of malignant breast lesions on CBBCT correlates with immunohistochemical subtype and proliferative potential. Thereby, CBBCT might aid in selecting individualized treatment strategies for breast cancer patients based on pre-operative imaging

Induction therapy with Erlotinib (E) and Gemcitabine/Platinum (GP) in stage III NSCLC

Background: In 2004 we started a phase II trial in non-small lung cancer (NSCLC), stage III, with erlotinib followed by a combination with a platinum-based doublet in unselected patients to identify molecular subgroups benefitting from an EGFR targeting approach. Patients and methods: Induction with erlotinib (E, 150 mg, d1-42) was followed by three cycles of gemcitabine (G, 1250 mg/m&sup2;, d1+d8, q3w) and cisplatin (P, 80 mg/m&sup2;, d1, q3w). Patients with at least stable disease after E were treated with a GP + E combination. Induction was followed by surgery and radiation. The trial was conducted as a prospective, multi-center, open label, exploratory phase II study to determine pathological response rate (pRR), as well as secondary endpoints disease free survival (DFS) and overall survival (OS). Results: Of 38 prescreened patients 16 were included in the main study. Due to slow recruitment the study had to be terminated early. Combination of E and GP was well tolerated, surgery was feasible after induction therapy in 12 of 16 patients, 7/12 (58%) patients had a major pathological response (MPR). Median overall survival for patients with MPR was 57.7 months (confidence interval (CI), 37.4 to 78.0; n = 7) and for patients without MPR 11.9 months (CI, 6.4 to 17.4; n = 5). 2/16 patients had an epidermal growth factor receptor (EGFR) mutation. Conclusion: Before discovery of distinct molecular mechanisms in NSCLC our study was an attempt to identify clinical and pathological subgroups that would benefit from E induction. Two patients with an EGFR mutation were identified. MPR was a predictor of long term disease free and overall survival