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Supplemental Digital Content is available in the text Objective: This multicenter randomized controlled trial was designed to test the hypothesis that early drain removal (EDR) could decrease the incidence of grade 2 to 4 complications for patients undoing pancreaticoduodenectomy (PD) with low or intermediate risk of postoperative pancreatic fistula (POPF). Background: The safety and effects of EDR on postoperative complications after PD are still controversial. Methods: A multicenter randomized controlled trial at 6 tertiary referral hospitals was carried out (NCT03055676). Patients who met the inclusion criteria, including drain amylase level less than 5000 U/L on postoperative day (POD) 1 and POD 3, and drain output less than 300 mL per day within 3 days after surgery, were enrolled. Patients were then randomized to the EDR group or the routine drain removal (RDR) group. In the EDR group, all drainage tubes were removed on POD3. In the RDR group, drainage tubes were removed on POD 5 or beyond. Primary outcome was the incidence of Clavien-Dindo grade 2 to 4 complications. Secondary outcomes were comprehensive complication index, grade B/C POPF, total medical expenses and postoperative in-hospital stay etc, within 90 days after surgery. Results: A total of 692 patients were screened, and 312 patients were eligible for randomization. Baseline characteristics were well balanced between the 2 groups and 96.8% of these 312 patients had low or intermediate risk of POPF, according to the 10-point fistula risk score. A total of 20.5% of the patients in the EDR group suffered at least 1 grade 2 to 4 complication, versus 26.3% in the RDR group (P = 0.229). Multi-variate analysis showed older age (>65 years old) and blood transfusion were independent risk factors for grade 2 to 4 complications. The rate of grade B/C POPF was low in either group (3.8% vs 6.4%, P = 0.305). The comprehensive complication index of the 2 groups was also comparable (20.9 vs 20.9, P = 0.253). Total medical expenses were not significantly different. Postoperative in-hospital stay was clinically similar (15 days vs 16 days, P = 0.010). Conclusions: Nearly half of the patients undergoing PD met the inclusion criteria, predicting low incidence of grade B/C POPF and major complications. EDR was safe in these patients but did not significantly decrease major complications. [ABSTRACT FROM AUTHOR]

The mechanisms of distant metastasis of malignancies largely remain unknown. Circulating tumor cells (CTC) derived from the primary cancer initiate distant metastasis by entering and traversing the bloodstream. Current methods to detect CTC are based on the notion that CTC do not express the common leukocyte antigen CD45. However, these methods neglect the fact that CTC can directly adhere to platelets and immune cells and therefore appear to be CD45-positive. The potential effects of interactions between CTC and adhesive immune cells have been largely overlooked, despite the fact that most CTC are killed by immune effector cells and only those that evade immune surveillance result in clonal expansion and metastatic lesions. It is crucial to define the characteristics that allow a select CTC population to escape immune surveillance; particularly, it must be determined whether interactions between CTC and adhesive immune cells provide a protective effect on CTC survival. If interactions between CTC and adhesive immune cells offer a selective advantage to those CTC cells, the next consideration is which characteristics of a CTC-immune cell population allow sufficient protection to facilitate immune evasion. Myeloid-derived suppressor cells (MDSC) are a large heterogeneous population of immature myeloid cells that accumulate during cancer progression to induce extensively systemic and local immunosuppression, a phenomenon that has been demonstrated to facilitate cancer distant metastasis. We hypothesize, therefore, that CTC populations interacting with adhesive immune cells will have different biological behavior than CTC populations alone. Further, we hypothesize that CTC can create a defensive shield consisting of adhesive MDSC, which allows evasion of immune surveillance and therefore facilitates distant metastatic lesions. This possibility highlights the importance of direct interactions between CTC and adhesive immune cells and suggests the potential target that the CTC-MDSC cluster represents for prevention and treatment of distant metastasis of malignancies. [ABSTRACT FROM AUTHOR]

Abstract: Viral cirrhotic primary liver cancer (VCPLC) is characterized by intra-hepatic metastasis (IHM) at early stage. By contrast, simple primary liver cancer without cirrhosis (SPLC) has high extra-hepatic metastasis (EHM) rate. Historically, studies on mechanism of metastasis of PLC mainly focused on biological behaviors of cancer cells, however tumor microenvironment is always neglected, especially blood flow dynamics and Kupffer cells. In SPLC, few damages of hepatic lobules occur, to the contrary, VCPLC is characterized by obvious hepatic fibrosis which results in varieties of blood flow disturbances, such as central lobular vein obstruction, hepatic artery-portal vein fistula (HAPVF), and portal vein countercurrent (PVC). Traditionally, Kupffer cells in liver are regarded as powerful defenses against PLC and metastasis lesions in liver, however, recent studies show under long term ischemic–hypoxic stress, Kupffer cells can secrete varieties of pro-inflammatory mediators to promote fibrosis or even cancerogenesis. Tumor associated macrophages (TAMs) are a group of macrophages living in ischemic tumor lesions which can promote tumor progression and metastasis. Based on the totally different metastasis routes and significantly different tumor microenvironment of VCPLC and SPLC, we hypothesize: (1) unlike the normal Kupffer cells in non-cirrhosis liver, Kupffer cells of VCPLC, a group of dominant hepatic resident macrophages living in extremely cirrhotic ischemic–hypoxic sinusoids, might not act as fighters against cancer cells, what is worse, ischemic–hypoxic situation might incite Kupffer cells to secrete cytokines and chemokines, just like TAMs, to promote tumor growth and metastasis; (2) the blood flow disturbances, not the behaviors of cancer cells, are the main force to determine the different metastasis preferences. In VCPLC, central lobular vein is mechanically compressed by cirrhosis nodes, so cancer cells cannot go extra-hepatically, instead, the hepatic artery-portal vein fistula (HAPVF) and portal vein countercurrent (PVC) load cancer cells intra-hepatically. In SPLC, cancer cells can run directly extra-hepatically through central lobular vein fluently. In short, the different blood flow dynamics between these two PLC is the predominant factor to determine the preferences of metastasis route. In VCPLC, the Kupffer cells should not be the powerful defenses against tumor and metastasis lesions, instead, they should be tamed to be some TAMs by long term ischemic–hypoxic stress and tumor derived factors to play important roles in tumorigenesis or even metastasis, so Kupffer cells can be a new target for preventing hepatocancerogenesis and metastasis. [Copyright &y& Elsevier]

Breast cancer is the most common malignant tumor in women around the world. Most breast cancer-related deaths are from CTC (circulating tumor cells) metastasis. CTC is associated with the breast cancer patients' prognosis. But recently, circulating clusters were found and its metastasis and tumor formation ability is 23-50 times as CTC. However, its mechanism has not been clarified. These days, researchers have successfully completed CTC cluster separation, CTC cell culture, and PD-L1 was found to be related with histological grading of tumor. Meanwhile, the high expression of PD-L1 in CTC surface has also been reported. Since PD-L1 can mediate Treg to play the role of immunosuppression, we propose that CTC with positive PD-L1 is easier to connect PD-L1, immune cells (Treg regulatory T cells, MDSC bone marrow inhibitory cells) and CK cytokines etc. On one hand, Treg cells can protect CTC from being attacked by the immune system through the immunosuppression, on the other hand, they can weaken CTL killing ability and trigger more MDSC. Finally, CTC formed the metastatic lesion. [ABSTRACT FROM AUTHOR]