Two-year follow-up of 196 interstitial lung disease patients after ICU stay.

OBJECTIVE: Interstitial lung diseases (ILDs) are associated with poor prognosis in the intensive care unit (ICU). We aimed to assess factors associated with hospital mortality in ILD patients admitted to the ICU and to investigate long-term outcome.MATERIAL AND METHODS: This was a retrospective study in a teaching hospital specialised in ILD management. Patients with ILD who were hospitalised in the ICU between 2000 and 2014 were included. Independent predictors of hospital mortality were identified using logistic regression.RESULTS: A total of 196 ILD patients were admitted to the ICU during the study period. Overall hospital mortality was 55%. Two years after ICU admission, 70 (36%) patients were still alive. Of the 196 patients, 108 (55%) required invasive mechanical ventilation, of whom 21 (20%) were discharged alive from hospital. Acute exacerbation of ILD and multi-organ failure were highly associated with hospital mortality (OR 5.4, 95% CI 1.9-15.5 and OR 12.6, 95% CI 4.9-32.5, respectively).CONCLUSION: Hospital mortality among ILD patients hospitalised in the ICU was high, but even where invasive mechanical ventilation was required, a substantial number of patients were discharged alive from hospital. Multi-organ failure could lead to major ethical concerns.

Intracellular pH governs the subcellular distribution of hexokinase in a glioma cell line.

Hexokinase plays a key role in regulating cell energy metabolism. Hexokinase is mainly particulate, bound to the mitochondrial outer membrane in brain and tumour cells. We hypothesized that the intracellular pH (pH1) controls the intracellular distribution of hexokinase. Using the SNB-19 glioma cell line, pH1 variations were imposed by incubating cells in a high-K+ medium at different pH values containing specific ionophores (nigericin and valinomycin), without affecting cell viability. Subcellular fractions of cell homogenates were analysed for hexokinase activity. Imposed pH1 changes were verified microspectrofluorimetrically by using the pH1-sensitive probe SNARF-1-AM (seminaphtho-rhodafluor-1-acetoxymethyl ester). Imposition of an acidic pH1 for 30 min strongly decreased the particulate/total hexokinase ratio, from 63% in the control sample to 31%. Conversely, when a basic pH1, was imposed, the particulate/total hexokinase ratio increased to 80%. The glycolytic parameters, namely lactate/pyruvate ratio, glucose 6-phosphate and ATP levels, were measured concomitantly. Lactate/pyruvate ratio and ATP level were both markedly decreased by acidic pH1 and increased by basic pH1. Conversely, the glucose 6-phosphate level was increased by acidic pH1 and decreased by basic pH1. To demonstrate that the change of hexokinase distribution was not due to altered metabolite levels of glycolysis, a pH1 was imposed for a 5 min incubation time. Modification of the hexokinase distribution was similar to that noted after a 30 min incubation, whereas metabolite levels of glycolysis were not affected. These results provide evidence that the intracellular distribution of hexokinase is highly sensitive to variations of the pH1, and regulates hexokinase activity.

Mitochondria-bound hexokinase as target for therapy of malignant gliomas.

Hexokinase plays an important role in glucose-utilizing tissues like normal brain and cancers. In these tissues, hexokinase (HK) is mainly bound to mitochondria (mHK). Our objectives were to evaluate total HK (tHK) activity and mHK fraction in gliomas and to determine whether mHK binding could be targeted for therapy. Tumors were obtained from 26 patients and 13 were xenografted. HK, lactate and ATP were measured in cytosol and mitochondria extracts. The tHK expressed in mU/mg protein were 147 +/- 19 and 78 +/- 12, in fresh gliomas and xenografts, respectively, and of 489 in the normal brain. The mHK fraction was 76% in normal brain, 74 +/- 4% in fresh tumors and 53 +/- 6% in xenografts. Lactate/mHK ratios were higher in gliomas than in normal brain. The ATP was 10, 52 +/- 31 and 19 +/- 8 nmol/mg protein in normal brain, xenografts and fresh gliomas respectively. Loss of one copy of chromosome 10 which carries the HK1 gene, was evidenced in 11 of the 13 xenografted gliomas. The anti-tumor effect of lonidamine (LND), which affects glycolysis in interfering with mHK activity, was tested in nude mice bearing 4 gliomas. LND (125 mg/kg, given i.p., twice daily for 5 days) led to a growth inhibition of TG-7-RO of 72%, with 2-fold growth retardation, and had no effect for TG-8-OZ. Intermediate LND-sensitivities for TG-11-DU and TG-10-PY were noted. The LND-sensitivity was correlated with the mHK activity (R2 = 0.73) and mHK fraction (R2 = 0.88). HK binding to mitochondria is a key of glycolysis in malignant gliomas, and targetting this binding with appropriate agents could be an effective therapeutic approach.

Computed tomography of mediastinal lymph nodes in nonsmall cell lung cancer. A new approach based on the lymphatic pathway of tumor spread.

Computed tomography was used to evaluate mediastinal lymph nodes in 97 patients with nonsmall cell lung cancer. All patients had thorough surgical-pathological determination of mediastinal node status. Twenty-three patients were found to have metastatic lymph nodes. The usual lymphatic pathways of tumor spread into the mediastinum were defined using the node mapping scheme suggested by the American Thoracic Society. We considered mediastinal nodes abnormal when the short axis of the largest mediastinal node in the lymphatic drainage territory of the cancer was greater than or equal to 10 mm and the difference between this node and the largest node in the other territories is greater than 5 mm. The sensitivity was 78%, the specificity 99%, the positive predictive value 95%, the negative predictive value 94%, and the accuracy 94%. Comparing our method to those that used the size criterion alone, the number of false positives was reduced.