IntroductionGravimetric validation of single-indicator extravascular lung water (EVLW) and normal EVLW values has not been well studied in humans thus far. The aims of this study were (1) to validate the accuracy of EVLW measurement by single transpulmonary thermodilution with postmortem lung weight measurement in humans and (2) to define the statistically normal EVLW values.MethodsWe evaluated the correlation between pre-mortem EVLW value by single transpulmonary thermodilution and post-mortem lung weight from 30 consecutive autopsies completed within 48 hours following the final thermodilution measurement. A linear regression equation for the correlation was calculated. In order to clarify the normal lung weight value by statistical analysis, we conducted a literature search and obtained the normal reference ranges for post-mortem lung weight. These values were substituted into the equation for the correlation between EVLW and lung weight to estimate the normal EVLW values.ResultsEVLW determined using transpulmonary single thermodilution correlated closely with post-mortem lung weight (r = 0.904, P < 0.001). A linear regression equation was calculated: EVLW (mL) = 0.56 × lung weight (g) - 58.0. The normal EVLW values indexed by predicted body weight were approximately 7.4 ± 3.3 mL/kg (7.5 ± 3.3 mL/kg for males and 7.3 ± 3.3 mL/kg for females).ConclusionsA definite correlation exists between EVLW measured by the single-indicator transpulmonary thermodilution technique and post-mortem lung weight in humans. The normal EVLW value is approximately 7.4 ± 3.3 mL/kg.Trial registrationUMIN000002780.

It is generally believed that active invasion by cancer cells is essential to the metastatic process. In this report, we describe a murine mammary tumor (MCH66) model of metastasis that does not require invasion into the vascular wall of both the primary tumor and the target organ, in this case, the lung. The process involves intravasation of tumor nests surrounded by sinusoidal blood vessels, followed by intravascular tumor growth in the lung, without penetration of the vascular wall during the process. Comparative studies using a nonmetastatic MCH66 clone (MCH66C8) and another highly invasive metastatic cell line (MCH416) suggested that high angiogenic activity and sinusoidal remodeling of tumor blood vessels were prerequisites for MCH66 metastasis. Differential cDNA analysis identified several genes that were overexpressed by MCH66, including genes for the angiogenesis factor pleiotrophin, and extracellular matrix-associated molecules that may modulate the microenvironment toward neovascularization. Our analyses suggest that tumor angiogenesis plays a role in the induction of invasion-independent metastasis. This model should prove useful in screening and development of new therapeutic agents for cancer metastasis.

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P ¼ 0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flowcytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation.

cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)-poly(aspartic acid) (PEG-P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP-incorporated polymeric micelles (CDDP/m) were evaluated in comparison with those of CDDP. In vitro, CDDP/m exhibited 10-17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP/m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP/m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP/m treatment caused much less renal damage than CDDP. These results indicate that CDDP/m treatment can reduce CDDP-induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.Key words: Polymeric micelles -Cisplatin -Nephrotoxicity -EPR effect -DDS cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), the most commonly used anticancer agent, consists of a central platinum atom surrounded by four ligands, two ammonias and two chlorides.1) A high antitumor activity results when the two chloride ligands in CDDP are bi-aquated in aqueous physiological environments; CDDP can then interact directly with DNA and display cytotoxic activity.2, 3) The clinical utility of CDDP is limited by significant general organ toxicity including myelosuppression, 4) ototoxicity, 5) gastrointestinal disturbance, 5, 6) and especially acute nephrotoxicity.7) CDDP, a low-molecularweight compound, is distributed readily into almost all tissues and intracellular compartments. CDDP traverses plasma membranes rapidly via passive diffusion or active transport, and is also rapidly cleared from blood by glomerular excretion, limiting its therapeutic availability. Injection of the maximum permissible amount of this lowmolecular-weight drug to raise its therapeutic concentration and AUC (area under the curve) results in severe toxicity without significantly greater antitumor efficacy. Therefore, several novel forms of controlled release drug delivery have been designed to improve distribution and to prolong the exposure of the tumor to an effective drug concentration.It is known that solid tumors generally possess the following pathophysiological characteristics: hypervascularity, incomplete vascular architecture, secretion of vascular permeability factors, and also the absence of effective lymphatic drainage, preventing the efficient clearance of accumulated macromolecules. These characteristics, unique to solid tumors, are believed to be the basis of the so-called EPR effect (enhanced permeability and retention ef...

This study may provide the first validated quantitative bedside diagnostic tool for diffuse alveolar damage. Extravascular lung water may allow the detection of diffuse alveolar damage and may support the clinical diagnosis of acute respiratory distress syndrome. The best extravascular lung water cut-off value to discriminate between normal lungs and lungs with diffuse alveolar damage is around 10 mL/kg.