Adhesive and invasive characteristics appear to be crucial for organ-specific metastasis formation. Using intravital microscopy we investigated the relation between the metastatic potential of colon carcinoma cells and their adhesive and invasive behavior during early steps of metastasis within microvasculatures of rat liver, lung, intestine, skin, muscle, spleen, and kidney in vivo. Colorectal carcinomas will affect ϳ6% of the population in the Western countries during their lifetime. These carcinomas are the third leading cause of cancer-related deaths among women and men and are the most important malignancies of the gut.1 Approximately 50% of the cancer patients die within 5 years because of cancerrelated problems, mostly attributable to metastatic lesions caused by the spread of cancers to near and distant sites. Even after potentially curative surgery, more than 30% of the patients with colorectal carcinomas subsequently develop metastases demonstrating that the spread from primary tumors to distant organs is usually the life-limiting aspect in colorectal carcinoma patients. 2Similar to other cancer entities, colorectal carcinomas often show organ preference of metastasis formation. The liver is the most common organ in which colorectal carcinomas establish distant metastases, and the liver is involved in more than 70% of patients with colorectal metastases. However, in 40 to 50% of these patients with liver metastases, other organs are also involved in metastatic colonization. The second most important organ for colorectal cancer metastasis is the lung, and 20 to 30% of all distant colorectal carcinoma metastases are found primarily in the lung. Isolated lung metastases with no evidence of other organ involvement are found in 5 to 10% of colorectal cancer patients. Other organs, such as the central nervous system, adrenal glands, spleen, skeleton, or skin together account for less than 10% of all colorectal metastases. 2,3The metastatic process consists of a number of sequential, interrelated steps that can all be rate limiting. 4,5 An important and early step during formation of distant metastasis appears to be the arrest of circulating tumor cells within the host organ.6,7 Approximately a century ago, two major hypotheses on the mechanisms of tumor cell arrest in metastatic host organs were proposed. Ewing 8 assumed that the random mechanical lodgment of Supported by the Innovative Medizinische Forschung Fund (University Hospital Mü nster) (Ha 1 2 01 01 to J.H.).K.S. and P.G. contributed equally to this study.

IntroductionOrgan-specific composition of extracellular matrix proteins (ECM) is a determinant of metastatic host organ involvement. The chemokine CXCL12 and its receptor CXCR4 play important roles in the colonization of human breast cancer cells to their metastatic target organs. In this study, we investigated the effects of chemokine stimulation on adhesion and migration of different human breast cancer cell lines in vivo and in vitro with particular focus on the liver as a major metastatic site in breast cancer.MethodsTime lapse microscopy, in vitro adhesion and migration assays were performed under CXCL12 stimulation. Activation of small GTPases showed chemokine receptor signalling dependence from ECM components. The initial events of hepatic colonisation of MDA-MB-231 and MDA-MB-468 cells were investigated by intravital microscopy of the liver in a rat model and under shRNA inhibition of CXCR4.ResultsIn vitro, stimulation with CXCL12 induced increased chemotactic cell motility (p<0.05). This effect was dependent on adhesive substrates (type I collagen, fibronectin and laminin) and induced different responses in small GTPases, such as RhoA and Rac-1 activation, and changes in cell morphology. In addition, binding to various ECM components caused redistribution of chemokine receptors at tumour cell surfaces. In vivo, blocking CXCR4 decreased extravasation of highly metastatic MDA-MB-231 cells (p<0.05), but initial cell adhesion within the liver sinusoids was not affected. In contrast, the less metastatic MDA-MB-468 cells showed reduced cell adhesion but similar migration within the hepatic microcirculation. Conclusion: Chemokine-induced extravasation of breast cancer cells along specific ECM components appears to be an important regulator but not a rate-limiting factor of their metastatic organ colonization.

In summary, these results demonstrate that lumen occlusion alone, as determined by in vivo microscopy, is insufficient to establish stable tumor cell arrest of colon carcinoma cells in metastatic target organs and does therefore not rule out the requirement of specific adhesive interactions for tumor cell arrest in the microcirculation.

IMPORTANCEIntraoperative handovers of anesthesia care are common. Handovers might improve care by reducing physician fatigue, but there is also an inherent risk of losing critical information. Large observational analyses report associations between handover of anesthesia care and adverse events, including higher mortality.OBJECTIVE To determine the effect of handovers of anesthesia care on postoperative morbidity and mortality. DESIGN, SETTING, AND PARTICIPANTSThis was a parallel-group, randomized clinical trial conducted in 12 German centers with patients enrolled between June 2019 and June 2021 (final follow-up, July 31, 2021). Eligible participants had an American Society of Anesthesiologists physical status 3 or 4 and were scheduled for major inpatient surgery expected to last at least 2 hours.INTERVENTIONS A total of 1817 participants were randomized to receive either a complete handover to receive anesthesia care by another clinician (n = 908) or no handover of anesthesia care (n = 909). None of the participating institutions used a standardized handover protocol. MAIN OUTCOMES AND MEASURESThe primary outcome was a 30-day composite of all-cause mortality, hospital readmission, or serious postoperative complications. There were 19 secondary outcomes, including the components of the primary composite, along with intensive care unit and hospital lengths of stay. RESULTS Among 1817 randomized patients, 1772 (98%; mean age, 66 [SD,12] years; 997 men [56%]; and 1717 [97%] with an American Society of Anesthesiologists physical status of 3) completed the trial. The median total duration of anesthesia was 267 minutes (IQR, 206-351 minutes), and the median time from start of anesthesia to first handover was 144 minutes in the handover group (IQR, 105-213 minutes). The composite primary outcome occurred in 268 of 891 patients (30%) in the handover group and in 284 of 881 (33%) in the no handover group (absolute risk difference [RD], −2.5%; 95% CI, −6.8% to 1.9%; odds ratio [OR], 0.89; 95% CI, 0.72 to 1.10; P = .27). Nineteen of 889 patients (2.1%) in the handover group and 30 of 873 (3.4%) in the no handover group experienced all-cause 30-day mortality (absolute RD, −1.3%; 95% CI, −2.8% to 0.2%; OR, 0.61; 95% CI, 0.34 to 1.10; P = .11); 115 of 888 (13%) vs 136 of 872 (16%) were readmitted to the hospital (absolute RD, −2.7%; 95% CI, −5.9% to 0.6%; OR, 0.80; 95% CI, 0.61 to 1.05; P = .12); and 195 of 890 (22%) vs 189 of 874 (22%) experienced serious postoperative complications (absolute RD, 0.3%; 95% CI, −3.6% to 4.1%; odds ratio, 1.02; 95% CI, 0.81 to 1.28; P = .91). None of the 19 prespecified secondary end points differed significantly.CONCLUSIONS AND RELEVANCE Among adults undergoing extended surgical procedures, there was no significant difference between the patients randomized to receive handover of anesthesia care from one clinician to another, compared with the no handover group, in the composite primary outcome of mortality, readmission, or serious postoperative complications within 30 days.

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