Dynamic Contrast-Enhanced Ultrasound of Colorectal Liver Metastases as an Imaging Modality for Early Response Prediction to Chemotherapy

Our aim was to investigate whether dynamic contrast-enhanced ultrasound (DCE-US) can detect early changes in perfusion of colorectal liver metastases after initiation of chemotherapy. Newly diagnosed patients with colorectal cancer with liver metastases were enrolled in this explorative prospective study. Patients were treated with capecitabine or 5-fluorouracil-based chemotherapy with or without bevacizumab. DCE-US was performed before therapy (baseline) and again 10 days after initiation of treatment. Change in contrast-enhancement in one liver metastasis (indicator lesion) was measured. Treatment response was evaluated with a computed tomography (CT) scan after three cycles of treatment and the initially observed DCE-US change of the indicator lesion was related to the observed CT response. Eighteen patients were included. Six did not complete three series of chemotherapy and the evaluation CT scan, leaving twelve patients for analysis. Early changes in perfusion parameters using DCE-US did not correlate well with subsequent CT changes. A subgroup analysis of eight patients receiving bevacizumab, however, demonstrated a statistically significant correlation (p = 0.045) between early changes in perfusion measures of peak enhancement at DCE-US and tumor shrinkage at CT scan. The study indicates that early changes in DCE-US perfusion measures may predict subsequent treatment response of colorectal liver metastases in patients receiving bevacizumab

IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma

PURPOSE: Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the effects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine. EXPERIMENTAL DESIGN: Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 microg/kg using two planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily for five consecutive days followed by nine dose-free days (5 + 9). The following biomarkers were studied in peripheral blood mononuclear cells (PBMC) during treatment: phosphorylation of STAT3, alterations in the composition of leukocyte subsets, ex vivo cytotoxicity, expression of effector molecules in enriched CD8(+) T cells and CD56(+) NK cells by quantitative RT-PCR, and gene array profiling of CD8(+) T cells. RESULTS: Effects of IL-21 were observed at all dose levels. In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods. In both CD8(+) T cells and CD56(+) NK cells we found up-regulation of perforin and granzyme B mRNA. In addition, full transcriptome analysis of CD8(+) T cells displayed changes in several transcripts associated with increased cell cycle progression, cellular motility, and immune activation. Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo. CONCLUSIONS: IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8(+) T cell activation

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Interobserver and Intraobserver Reproducibility with Volume Dynamic Contrast Enhanced Computed Tomography (DCE-CT) in Gastroesophageal Junction Cancer

The purpose of this study was to assess inter- and intra-observer reproducibility of three different analytic methods to evaluate quantitative dynamic contrast-enhanced computed tomography (DCE-CT) measures from gastroesophageal junctional cancer. Twenty-five DCE-CT studies with gastroesophageal junction cancer were selected from a previous longitudinal study. Three radiologists independently reviewed all scans, and one repeated the analysis eight months later for intraobserver analysis. Review of the scans consisted of three analysis methods: (I) Four, fixed small sized regions of interest (2-dimensional (2D) fixed ROIs) placed in the tumor periphery, (II) 2-dimensional regions of interest (2D-ROI) along the tumor border in the tumor center, and (III) 3-dimensional volumes of interest (3D-VOI) containing the entire tumor volume. Arterial flow, blood volume and permeability (ktrans) were recorded for each observation. Inter- and intra-observer variability were assessed by Intraclass Correlation Coefficient (ICC) and Bland-Altman statistics. Interobserver ICC was excellent for arterial flow (0.88), for blood volume (0.89) and for permeability (0.91) with 3D-VOI analysis. The 95% limits of agreement were narrower for 3D analysis compared to 2D analysis. Three-dimensional volume DCE-CT analysis of gastroesophageal junction cancer provides higher inter- and intra-observer reproducibility with narrower limits of agreement between readers compared to 2D analysis

Interobserver and Intraobserver Reproducibility with Volume Dynamic Contrast Enhanced Computed Tomography (DCE-CT) in Gastroesophageal Junction Cancer

The purpose of this study was to assess inter- and intra-observer reproducibility of three different analytic methods to evaluate quantitative dynamic contrast-enhanced computed tomography (DCE-CT) measures from gastroesophageal junctional cancer. Twenty-five DCE-CT studies with gastroesophageal junction cancer were selected from a previous longitudinal study. Three radiologists independently reviewed all scans, and one repeated the analysis eight months later for intraobserver analysis. Review of the scans consisted of three analysis methods: (I) Four, fixed small sized regions of interest (2-dimensional (2D) fixed ROIs) placed in the tumor periphery, (II) 2-dimensional regions of interest (2D-ROI) along the tumor border in the tumor center, and (III) 3-dimensional volumes of interest (3D-VOI) containing the entire tumor volume. Arterial flow, blood volume and permeability (ktrans) were recorded for each observation. Inter- and intra-observer variability were assessed by Intraclass Correlation Coefficient (ICC) and Bland-Altman statistics. Interobserver ICC was excellent for arterial flow (0.88), for blood volume (0.89) and for permeability (0.91) with 3D-VOI analysis. The 95% limits of agreement were narrower for 3D analysis compared to 2D analysis. Three-dimensional volume DCE-CT analysis of gastroesophageal junction cancer provides higher inter- and intra-observer reproducibility with narrower limits of agreement between readers compared to 2D analysis