Dynamic Contrast-Enhanced Computed Tomography: A New Diagnostic Tool to Assess Renal Perfusion After Ischemia-Reperfusion Injury in Mice: Correlation of Perfusion Deficit to Histopathologic Damage.

OBJECTIVE: The aim of this study was to investigate the value of dynamic contrast-enhanced computed tomography (CT) in the assessment of renal perfusion parameters after ischemia-reperfusion (I/R) injury in an experimental murine model. MATERIALS AND METHODS: Balb/cJ wildtype mice were subjected to 45 minutes (AKI45) or 60 minutes (AKI60) of unilateral warm I/R injury by clamping the pedicle of the right kidney. Two, 7, and 18 days after right I/R injury, renal blood flow (RBF), renal volume of distribution (RVD), and mean transit time were quantitatively assessed in the cortex of both kidneys by dynamic contrast-enhanced CT. Acute tubular injury (ATI) was assessed by histologic analysis using a semiquantitative sum score (score, 0-18) and correlated with RBF, RVD, and mean transit time. RESULTS: Histologic signs of ATI could be detected in the clamped kidneys in both groups already at day 2. Pathologic features of ATI worsened in AKI60 until day 18 (score, 7 ± 0), whereas mice in AKI45 group showed amelioration over time (score, 4 ± 2). Renal blood flow was significantly reduced in ischemic kidneys in AKI45 (287 ± 32 mL/100 mL per minute; P < 0.01) and AKI60 group (249 ± 73 mL/100 mL per minute; P < 0.01) as compared with that in healthy kidneys (402 ± 49 mL/100 mL per minute) on day 2. It decreased further at day 7 in both groups (AKI45: 165 ± 44 mL/100 mL per minute, P < 0.01; AKI60: 151 ± 72 mL/100 mL per minute, P < 0.05) and improved at day 18 in AKI45 (261 ± 11 mL/100 mL per minute, P < 0.05) and to a lesser degree in AKI60 (197 ± 52 mL/100 mL per minute, P > 0.05). Values of RVD paralleled RBF at all time points. Renal blood flow (r = -0.79; P < 0.01) and RVD (r = -0.8; P < 0.01) significantly correlated with the histological damage score (Spearman rank correlation). CONCLUSIONS: Dynamic contrast-enhanced CT is a noninvasive method to determine renal perfusion changes in acute kidney injury. It might be a valuable diagnostic tool to predict outcome or monitor treatment effects of renal I/R injury.

Decompression of inflammatory edema along with endothelial cell therapy expedites regeneration after renal ischemia-reperfusion injury.

Increased pressure due to postischemic edema aggravates renal ischemia-reperfusion injury (IRI). Prophylactic surgical decompression using microcapsulotomy improves kidney dysfunction after IRI. Supportive cell therapy in combination with microcapsulotomy might act synergistically protecting kidney function against IRI. The effects of therapeutic endothelial cell application alone and in combination with microcapsulotomy were investigated in a xenogenic murine model of 45-min warm renal ischemia. Renal function and perfusion were determined before as well as 2 and 18 days postischemia by (99m)Tc-MAG3 imaging and laser Doppler. Histological analysis included H&E stains and immunohistology for endothelial marker MECA-32, cell proliferation marker Ki-67, and macrophage marker F4/80. Histomorphological changes were quantified using a tubular injury score. Ischemia of 45 min led to severe tissue damage and a significant decrease in renal function and perfusion. Microcapsulotomy and cell therapy alone had no significant effect on renal function, while only surgical decompression significantly increased blood flow in ischemic kidneys. However, the combination of both microcapsulotomy and cell therapy significantly improved kidney function and perfusion. Combination therapy significantly reduced morphological injury of ischemic kidneys as determined by a tubular injury score and MECA-32 staining. Macrophage infiltration evidenced by F4/80 staining was significantly reduced. The Ki-67 proliferation index was increased, suggesting a regenerative environment. While microcapsulotomy and cell therapy alone have limited effect on renal recovery after IRI, combination therapy showed synergistic improvement of renal function, perfusion, and structural damage. Microcapsulotomy may create a permissive environment for cell therapy to work.

Active-specific immunotherapy for non-small cell lung cancer.

Non-small cell lung cancer constitutes about 85% of all newly diagnosed cases of lung cancer and continues to be the leading cause of cancer-related deaths worldwide. Standard treatment for this devastating disease, such as systemic chemotherapy, has reached a plateau in effectiveness and comes with considerable toxicities. For all stages of disease fewer than 20% of patients are alive 5 years after diagnosis; for metastatic disease the median survival is less than one year. Until now, the success of active-specific immunotherapy for all tumor types has been sporadic and unpredictable. However, the active-specific stimulation of the host's own immune system still holds great promise for achieving non-toxic and durable antitumor responses. Recently, sipuleucel-T (Provenge(®); Dendreon Corp., Seattle, WA) was the first therapeutic cancer vaccine to receive market approval, in this case for advanced prostate cancer. Other phase III clinical trials using time-dependent endpoints, e.g. in melanoma and follicular lymphoma, have recently turned out positive. More sophisticated specific vaccines have now also been developed for lung cancer, which, for long, was not considered an immune-sensitive malignancy. This may explain why advances in active-specific immunotherapy for lung cancer lag behind similar efforts in renal cell cancer, melanoma or prostate cancer. However, various vaccines are now being evaluated in controlled phase III clinical trials, raising hopes that active-specific immunotherapy may become an additional effective therapy for patients with lung cancer. This article reviews the most prominent active-specific immunotherapeutic approaches using protein/peptide, whole tumor cells, and dendritic cells as vaccines for lung cancer.