Prognostic value of disease-free interval in colorectal cancer: Is it time?

BACKGROUND: Previous studies have outlined that the onset of synchronous colorectal cancer (CRC) metastases is associated with poor overall survival (OS) compared to patients with metachronous disease. The aim of this study was to evaluate the association of disease-free interval with newly diagnosed CRC scheduled for primary tumor resection. METHODS: Patients who underwent primary CRC resection over an 18-year period were identified from a prospective database at a tertiary-care hospital. In this observational study, the cohort was stratified for the onset of metastases, i.e. synchronous, early-onset and late-onset metachronous disease. The OS was compared using Kaplan-Meier estimators and stratified Cox hazard regression analysis. RESULTS: Of 360 patients, 204 (57%) had synchronous, 61 (17%) had early metachronous, and 95 (26%) had late metachronous metastases, respectively. The onset of synchronous metastases was not associated with worse OS compared to early and late metachronous disease. ASA level > II (P = 0.011), right-sided compared to left-sided cancer (P = 0.032) or rectal cancer (P < 0.001), and high-grade tumors (P = 0.022) were identified as independent predictors of poor OS, whereas the only favorable prognostic factor was surgical resection of metastases (P = 0.047). Additionally, ASA level < III (P = 0.003) and low-grade tumors (P = 0.032) were found to predict resection of metastases. CONCLUSION: Individual patients' and tumor characteristics rather than the timing of metastases are associated with OS in newly diagnosed CRC. These data support curative treatment strategies even in patients with synchronous metastases.

MTL, a composite measure for objectively profiling hospitals on surgical performance in colorectal cancer surgery.

PURPOSE: MTL is a composite outcome measure based on routine administrative data defined as (a) postoperative mortality and/or (b) postoperative transfer to another hospital and/or (c) length of hospital stay ≥ the prespecified time period. Aim of the present study was to investigate MTL for profiling hospitals on surgical performance in colorectal cancer surgery, using data from the national registers of the German Society of General and Visceral Surgery (DGAV) and to determine the time interval for length of stay with the highest accuracy regarding major complications (Clavien-Dindo grade ≥ 3). METHODS: All patients undergoing colorectal cancer resection between January 2010 and February 2017 were included. MTL rates were calculated and compared to well-established single outcome measures using multivariate regression analysis. For each outcome measure, postoperative complications were tested regarding their predictability. RESULTS: Data from 14,978 patients were analyzed. Length of stay was significantly prolonged if postoperative complications occurred (p < 0.0001). Thirty-day mortality and the indication for a transfer to another hospital mainly resulted from cardiopulmonary complications. MTL occurs significantly more often than any of the single-outcome parameters. The time interval of 22 days demonstrated the highest accuracy regarding severe complications (Clavien-Dindo grade ≥ 3). CONCLUSIONS: MTL reflects the complete spectrum of postoperative complications. Compared to individual surgical outcome parameters, MTL may have a better discriminatory power and is therefore suitable to mirror surgical quality. Because of its high accuracy regarding surgical major morbidity, 22 days is the best cut-off for length of stay within the German healthcare system.

Transplanted fibroblasts proliferate in host bronchial tissue and enhance bronchial anastomotic healing in a rodent model.

INTRODUCTION: Healing of airway anastomoses after preoperative irradiation can be a significant clinical problem. The augmentation of bronchial anastomoses with a fibroblast-seeded human acellular dermis (hAD) was shown to be beneficial, although the underlying mechanism remained unclear. Therefore, in this study we investigated the fate of the fibroblasts transplanted to the scaffold covering the anastomosis. MATERIAL AND METHODS: 32 Fisher rats underwent surgical anastomosis of the left main bronchus. In a 2 × 2 factorial design, they were randomized to receive preoperative irradiation of 20 Gy and augmentation of the anastomosis with a fibroblast-seeded transplant. Fibroblasts from subcutaneous fat of Fischer-344 rat were transduced retrovirally with tdTomato for cell tracking. After 7 and 14 days, animals were sacrificed and cell concentration of transplanted and nontransplanted fibroblasts in the hAD as well as in the bronchial tissue was measured using RT-PCR. RESULTS: Migration of transplanted fibroblasts from dermis to bronchus were demonstrated in both groups, irradiated and nonirradiated. In the irradiated groups, there was a cell count of 7 × 104 ± 1 × 104 tomato+-fibroblasts in the bronchial tissue at day 7, rising to 1 × 105 ± 1 × 104 on day 14 (p <0.0001). Tomato+-cell concentration in hAD increased from 6 × 103 ± 1 × 103 at day 7 to 6 × 104 ± 1 × 104 at day 14 (p <0.0001). In the nonirradiated groups, tomato+-cell concentration in bronchus was 4 × 103 ± 1 × 103 on day 7 and 4 × 103 ± 1 × 103 at day 14. In the hAD tomato+ cell concentration rising from 1 × 104 ± 1 × 103 at day 7 to 2 × 104 ± 3 × 103 cells at day 14 (p = 0.0028). CONCLUSIONS: Transplanted fibroblasts in the irradiated groups proliferate and migrate into the irradiated host bronchial tissue, but not in the nonirradiated groups.

mMRI at 3.0 T as an Evaluation Tool of Therapeutic Response to Neoadjuvant CRT in Patients with Advanced-stage Rectal Cancer.

AIM: To assess whether multiparametric MRI (mMRI) can serve as a tool for evaluating response to chemoradiation therapy (CRT) in advanced-stage rectal cancer. PATIENTS AND METHODS: Twenty-one patients underwent a mMRI protocol at 3T before and after CRT. Two experienced radiologists evaluated the MRI measurements and inter-reader correlation was assessed. Changes in functional parameters in relation to regression, as well as pT stage were analyzed. The perfusion parameters plasma flow (PF) and mean transit time (MTT) were calculated offline using the established UMM Perfusion tool. RESULTS: Apparent diffusion coefficient values were significantly different among the different tumor RGs before CRT (p=0.041). Changes of dynamic contrast enhanced (DCE) MRI values did not reflect treatment response (PF: p=0.5; MTT: p=0.74). CONCLUSION: The results of our study population indicate that a high initial apparent diffusion coefficient value may be predictive of response to therapy following CRT.

Clinical relevance of morphologic MRI criteria for the assessment of lymph nodes in patients with rectal cancer.

AIM: The aim of this study is the evaluation of lymph node staging by magnetic resonance imaging (MRI) within clinical routine in patients with rectal cancer. METHOD: Routine MRI reports (3 T) of 65 consecutive patients with rectal cancer were retrospectively categorized in lymph node tumor positive or negative (mriN+; mriN0) and compared to the final histopathological results (pN+; pN0). Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy were calculated. The original MRI readings were then reanalyzed in order to identify the longest short-axis lymph node diameter for each patient. A receiver operating characteristic (ROC) curve was used to calculate a possible cutoff value for the short-axis lymph node diameter. RESULTS: Overall sensitivity was 94 %, specificity 13 %, NPV 86 %, PPV 28 %, and accuracy 34 %. The best accuracy could be calculated for a short-diameter cutoff of ≤5 mm (83 %); pN+ and pN0 groups were then significantly different (p < 0.0001). CONCLUSION: In clinical routine, lymph node assessment in patients with rectal cancer through MRI tends to overstage malignant lymphadenopathy. A ≤5-mm cutoff value for the short-axis lymph node diameter of benign nodes is able to improve the accuracy and has potential to lower the risk of overstaging.

Radioimmunoimaging of liver metastases with PET using a 64Cu-labeled CEA antibody in transgenic mice.

PURPOSE: Colorectal cancer is one of the most common forms of cancer, and the development of novel tools for detection and efficient treatment of metastases is needed. One promising approach is the use of radiolabeled antibodies for positron emission tomography (PET) imaging and radioimmunotherapy. Since carcinoembryonic antigen (CEA) is an important target in colorectal cancer, the CEA-specific M5A antibody has been extensively studied in subcutaneous xenograft models; however, the M5A antibody has not yet been tested in advanced models of liver metastases. The aim of this study was to investigate the (64)Cu-DOTA-labeled M5A antibody using PET in mice bearing CEA-positive liver metastases. PROCEDURES: Mice were injected intrasplenically with CEA-positive C15A.3 or CEA-negative MC38 cells and underwent micro-computed tomography (micro-CT) to monitor the development of liver metastases. After metastases were detected, PET/MRI scans were performed with (64)Cu-DOTA-labeled M5A antibodies. H&E staining, immunohistology, and autoradiography were performed to confirm the micro-CT and PET/MRI findings. RESULTS: PET/MRI showed that M5A uptake was highest in CEA-positive metastases. The %ID/cm(3) (16.5% ± 6.3%) was significantly increased compared to healthy liver tissue (8.6% ± 0.9%) and to CEA-negative metastases (5.5% ± 0.6%). The tumor-to-liver ratio of C15A.3 metastases and healthy liver tissue was 1.9 ± 0.7. Autoradiography and immunostaining confirmed the micro-CT and PET/MRI findings. CONCLUSION: We show here that the (64)Cu-DOTA-labeled M5A antibody imaged by PET can detect CEA positive liver metastases and is therefore a potential tool for staging cancer, stratifying the patients or radioimmunotherapy.

Influence of conversion on the perioperative and oncologic outcomes of laparoscopic resection for rectal cancer compared with primarily open resection.

BACKGROUND: This study aimed to evaluate the influence of conversion on perioperative and short- and long-term oncologic outcomes in laparoscopic resection for rectal cancer and to compare these with those for an open control group. METHODS: The data of 276 consecutive patients who underwent surgery for rectal cancer between 2006 and 2010 at a single institution were prospectively collected. Of the 276 patients, 114 underwent primarily open surgery, and 162 underwent laparoscopic surgery (on an intention-to-treat basis). Of the 162 laparoscopic patients, 38 (23.5%) underwent conversion to open surgery. The three groups of patients were compared: the conversion surgery group, the open surgery group, and the completed laparoscopy surgery group. RESULTS: The converted patients had more wound infections (18.4 vs 4.8%, p = 0.009), but the wound infection rate in the primarily open group also was significantly higher than in the laparoscopic resection group (p = 0.007). No further differences in perioperative morbidity, including anastomotic leakage, were found. The perioperative 30-day mortality rate was comparable between all the groups (0.6 vs 2.6 vs 2.6%, nonsignificant difference). The oncologic parameters such as number of harvested lymph nodes and rate of R0 resection were equal in all the groups. The completed laparoscopy group had a shorter hospital stay [12 vs 16 days in the primarily open group (p = 0.02) vs 15 days in the converted group (p = 0.03)]. The rates for survival, local recurrence (4.5 vs 3 vs 3%), and metachronous metastasis (10.1 vs 9.3 vs 9%) did not differ significantly between the three groups after a period of 3 years. CONCLUSION: Conversion to open surgery in laparoscopic rectal resection has no negative effect on perioperative or long-term oncologic outcome.

Comparison of Fenestra LC, ExiTron nano 6000, and ExiTron nano 12000 for micro-CT imaging of liver and spleen in mice.

RATIONALE AND OBJECTIVES: The purpose of this study was to compare different contrast agents for longitudinal liver and spleen imaging in a mouse model of liver metastasis. MATERIALS AND METHODS: Mice developing liver metastases underwent longitudinal micro-computed tomography imaging after injection of Fenestra LC, ExiTron nano 6000, or ExiTron nano 12000. Elimination times and contrast enhancement of liver and spleen were compared. RESULTS: For all contrast agents, liver contrast peaked at approximately 4 hours and spleen contrast at 48 hours postinjection. A single dose of 100 µL of ExiTron nano 6000 or 12000 resulted in longstanding enhancement of liver and spleen tissue for longer than 3 weeks, whereas repeated injections of 400 µL of Fenestra LC were required to retain contrast at acceptable levels and allowed imaging of the liver/spleen for up to 2 and 9 days, respectively. CONCLUSION: Both ExiTron nano agents provide longer and stronger contrast enhancement of liver and spleen compared to Fenestra LC, and they do so at a 75% lower injection volume in mice.

Micro-CT based experimental liver imaging using a nanoparticulate contrast agent: a longitudinal study in mice.

BACKGROUND: Micro-CT imaging of liver disease in mice relies on high soft tissue contrast to detect small lesions like liver metastases. Purpose of this study was to characterize the localization and time course of contrast enhancement of a nanoparticular alkaline earth metal-based contrast agent (VISCOVER ExiTron nano) developed for small animal liver CT imaging. METHODOLOGY: ExiTron nano 6000 and ExiTron nano 12000, formulated for liver/spleen imaging and angiography, respectively, were intravenously injected in C57BL/6J-mice. The distribution and time course of contrast enhancement were analysed by repeated micro-CT up to 6 months. Finally, mice developing liver metastases after intrasplenic injection of colon carcinoma cells underwent longitudinal micro-CT imaging after a single injection of ExiTron nano. PRINCIPAL FINDINGS: After a single injection of ExiTron nano the contrast of liver and spleen peaked after 4-8 hours, lasted up to several months and was tolerated well by all mice. In addition, strong contrast enhancement of abdominal and mediastinal lymph nodes and the adrenal glands was observed. Within the first two hours after injection, particularly ExiTron nano 12000 provided pronounced contrast for imaging of vascular structures. ExiTron nano facilitated detection of liver metastases and provided sufficient contrast for longitudinal observation of tumor development over weeks. CONCLUSIONS: The nanoparticulate contrast agents ExiTron nano 6000 and 12000 provide strong contrast of the liver, spleen, lymph nodes and adrenal glands up to weeks, hereby allowing longitudinal monitoring of pathological processes of these organs in small animals, with ExiTron nano 12000 being particularly optimized for angiography due to its very high initial vessel contrast.

High-speed single-breath-hold micro-computed tomography of thoracic and abdominal structures in mice using a simplified method for intubation.

OBJECTIVES: Respiratory gating with and without controlled ventilation has been applied for in vivo micro-computed tomography (micro-CT) of thoracic and abdominal structures in mice. We describe a simplified method for intubation and demonstrate its applicability for single-breath-hold micro-CT in mice. METHODS: Mice (n = 10) were anesthetized, intubated, ventilated, and relaxed by intraperitoneal administration of rocuronium. Contrast-enhanced micro-CT of the complete thorax including the upper abdominal organs (80 kV; 37.5 µA; 190-degree rotation; 600 projections/20 seconds or 1200 projections/40 seconds; 39 × 39 × 50-µm voxel size) was performed with and without single-breath-hold technique. RESULTS: The simplified method of intubation was fast (<1 minute) and required no special hardware in all mice. Relaxation of mice allowed prolonged single-breath-hold imaging of up to 40 seconds. Diameter of smallest identifiable lung vessels was 100 µm. CONCLUSIONS: The presented simplified method for intubation in mice is fast, safe, and effective. Additional relaxation allowed high-resolution single-breath-hold micro-CT in mice.

Donor dopamine treatment in brain dead rats is associated with an improvement in renal function early after transplantation and a reduction in renal inflammation.

Brain death (BD) is associated with tissue inflammation. As dopamine treatment of BD donor rats reduces renal monocyte infiltration, we tested if this treatment affects renal function and inflammation in recipients. BD was induced in F344 rats and was maintained for 6 h in all experiments. Dopamine was given for 6 (DA6) or 3 h (DA3) from the onset of BD. Ventilated non-BD (NBD) and BD animals served as controls. Kidneys were transplanted into bilaterally nephrectomized Lewis recipients. Serum creatinine (s-crea) was measured and leukocyte infiltration was assessed 10 days after transplantation. One day after transplantation, s-crea was significantly reduced in recipients who received a renal allograft from dopamine treated BD or from NBD rats compared to BD vehicle (P < 0.05). Ten days after transplantation, the number of infiltrating monocytes was significantly lower in grafts obtained from dopamine treated and from NBD rats (P < 0.05). A reduced infiltration in these grafts was confirmed by Banff 97 classification. Cytokine-induced neutrophil-chemoattractant 1 and interleukin (IL)-6 mRNA expression were reduced in DA rats compared to BD controls. No difference for macrophage chemoattractant protein 1 and IL-10 were found. These findings may explain the salutary effect of donor dopamine treatment in renal transplantation.