Macrophages mediate colon carcinoma cell adhesion in the rat liver after exposure to lipopolysaccharide

The surgical resection of primary colorectal cancer is associated with an enhanced risk of liver metastases. Moreover, bacterial translocation or anastomic leakage during resection has been shown to correlate with a poor long-term surgical outcome, suggesting that bacterial products may contributeto the formation of metastases. Driven by these premises, we investigated the role of the bacterial product lipopolysaccharide (LPS) in the generation of liver metastases. Intraperitoneal injection of LPS led to enhanced tumor-cell adhesion to the rat liver as early as 1.5 h post-administration. Furthermore, a rapid loss of the expression of the tight junction protein zonula occludens-1 (ZO-1) was observed, suggesting that LPS disrupts the integrity of the microvasculature. LPS addition to endothelial-macrophage co-cultures damaged endothelial monolayers and caused the formation of intercellular gaps, which was accompanied by increased tumor-cell adhesion. These results suggest that macrophages areinvolved in the endothelial damage resulting from exposure to LPS. Interestingly, the expression levels of of ZO-1 were not affected by LPS treatment in rats in which liver macrophages had been depletedas well as in rats that had been treated with a reactive oxygen species (ROS) scavenger. In both settings, decreased tumor-cell adhesion was observed. Taken together, our findings indicate that LPS induces ROS release by macrophages, resulting in the damage of the vascular lining of the liver and henceallowing increased tumorcell adherence. Thus, peri-operative treatments that prevent the activation of macrophages and-as a consequence- limit endothelial damage and tumor-cell adhesion may significantly improve the long-term outcome of cancer patients undergoing surgical tumor resection

Radiographic rib fracture nonunion and association with fracture classification in adults with multiple rib fractures without flail segment:A multicenter prospective cohort study

Background: Rib fracture nonunion is a probable cause of chronic pain following chest trauma, although its prevalence remains unknown. The aims of this study were to determine rib fracture nonunion prevalence following nonoperative management and to determine if presence of nonunion was associated with the number of rib fractures, or the rib fracture classification of anatomical location, type, and displacement. Methods: This multicenter prospective cohort study included trauma patients with three or more fractured ribs but without a flail segment, who participated in the nonoperative management group of the FixCon trial between January 2019 and June 2022. The number and classification of rib fractures were assessed on trauma chest CT. Chest CTs conducted six months post-trauma were evaluated for the presence of nonunion. Radiological characteristics of nonunions were compared with normally healed rib fractures using the Mann-Whitney U, χ2 test, and Fisher's exact test as appropriate. A generalized linear model adjusted for multiple observations per patient when assessing the associations between nonunion and fracture characteristics. Results: A total of 68 patients were included with 561 post-traumatic fractures in 429 ribs. Chest CT after six months revealed nonunions in 67 (12 %) rib fractures in 29 (43 %) patients with a median of 2 (P25-P75 1–3) nonunions per patient. Nonunion was most commonly observed in ribs seven to 10 (20–23 %, p &lt; 0.001, adjusted p = 0.006). Nonunion occurred in 14 (5 %) undisplaced, 22 (19 %) offset, and 20 (23 %) displaced rib fractures (p &lt; 0.001). No statistically significant association between rib fracture type and nonunion was found. Conclusions: Forty-three percent of patients with multiple rib fractures had radiographic nonunion six months after trauma. Fractures in ribs seven to 10 and dislocated fractures had an increased risk of rib fracture nonunion.</p

Radiographic rib fracture nonunion and association with fracture classification in adults with multiple rib fractures without flail segment:A multicenter prospective cohort study

Background: Rib fracture nonunion is a probable cause of chronic pain following chest trauma, although its prevalence remains unknown. The aims of this study were to determine rib fracture nonunion prevalence following nonoperative management and to determine if presence of nonunion was associated with the number of rib fractures, or the rib fracture classification of anatomical location, type, and displacement. Methods: This multicenter prospective cohort study included trauma patients with three or more fractured ribs but without a flail segment, who participated in the nonoperative management group of the FixCon trial between January 2019 and June 2022. The number and classification of rib fractures were assessed on trauma chest CT. Chest CTs conducted six months post-trauma were evaluated for the presence of nonunion. Radiological characteristics of nonunions were compared with normally healed rib fractures using the Mann-Whitney U, χ2 test, and Fisher's exact test as appropriate. A generalized linear model adjusted for multiple observations per patient when assessing the associations between nonunion and fracture characteristics. Results: A total of 68 patients were included with 561 post-traumatic fractures in 429 ribs. Chest CT after six months revealed nonunions in 67 (12 %) rib fractures in 29 (43 %) patients with a median of 2 (P25-P75 1–3) nonunions per patient. Nonunion was most commonly observed in ribs seven to 10 (20–23 %, p &lt; 0.001, adjusted p = 0.006). Nonunion occurred in 14 (5 %) undisplaced, 22 (19 %) offset, and 20 (23 %) displaced rib fractures (p &lt; 0.001). No statistically significant association between rib fracture type and nonunion was found. Conclusions: Forty-three percent of patients with multiple rib fractures had radiographic nonunion six months after trauma. Fractures in ribs seven to 10 and dislocated fractures had an increased risk of rib fracture nonunion.</p

Advanced colorectal cancer resulting in acute bowel obstruction during pregnancy; a case report

Introduction: Abdominal pain is frequently found in the pregnant population; however life-threatening pathology such as colorectal cancer does occur rarely. As such, intestinal obstructions are usually attributed to pregnancy-related issues. We present the case of a young woman with an acute bowel obstruction caused by advanced colorectal carcinoma. Presentation of Case: A 34-year old pregnant woman was referred to our emergency department with complaints of severe upper abdominal pain. Initial investigations did not show abdominal pathology and conservative treatment for obstipation was commenced. However, complaints persisted and a near blowout of the colon was diagnosed, prompting a caesarean section and diagnostic laparotomy. An obstructing tumour was found and a left-sided hemi-colectomy was performed. Unfortunately, skeletal, lymphatic and additional hepatogenic metastasis were discovered during chemotherapy and treatment was discontinued. Discussion and conclusion: The mainstay of abdominal complaints during pregnancy can be attributed to normal physiological alterations associated with gravidity. Nonetheless serious pathology should be considered, especially when conservative treatment fails. On this note, diagnostic imaging during pregnancy should be used promptly upon suspicion of serious abdominal pathology

The Role of Macrophages in Tumor Development

Macrophages constitute a large proportion of the immune cell infiltrate, which is present in many tumors. Activation state of macrophages is greatly influenced by their environment, leading to different macrophage subsets with diverse functions. Although previously regarded as potent immune cells that are capable of destroying tumor cells, recent literature focuses on the ability of macrophages to promote tumor development due to secretion of mediators, like growth and angiogenic factors. It is now becoming increasingly clear that a complicated synergistic relationship exists between macrophages and malignant cells whereby tumor cells can affect macrophage phenotype, and vice versa. As such, macrophages and their contribution in cancer development are currently subject of debate

Experimental Antibody Therapy of Liver Metastases Reveals Functional Redundancy between Fc gamma RI and Fc gamma RIV

Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery-although mandatory-paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR gamma-chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory Fc gamma R was necessary for successful therapy. TA99-treatment was still effective in Fc gamma RI-/-, Fc gamma RIII-/-, Fc gamma RI/III-/-, and Fc gamma RI/II/III-/- mice, suggesting an important role for Fc gamma RIV. However, wildtype mice that were treated with TA99 Abs and an Fc gamma RIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both Fc gamma RI and Fc gamma RIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis. The Journal of Immunology, 2008, 181: 6829-6836

Macrophages mediate colon carcinoma cell adhesion in the rat liver after exposure to lipopolysaccharide

The surgical resection of primary colorectal cancer is associated with an enhanced risk of liver metastases. Moreover, bacterial translocation or anastomic leakage during resection has been shown to correlate with a poor long-term surgical outcome, suggesting that bacterial products may contribute to the formation of metastases. Driven by these premises, we investigated the role of the bacterial product lipopolysaccharide (LPS) in the generation of liver metastases. Intraperitoneal injection of LPS led to enhanced tumor-cell adhesion to the rat liver as early as 1.5 h post-administration. Furthermore, a rapid loss of the expression of the tight junction protein zonula occludens-1 (ZO-1) was observed, suggesting that LPS disrupts the integrity of the microvasculature. LPS addition to endothelial-macrophage co-cultures damaged endothelial monolayers and caused the formation of intercellular gaps, which was accompanied by increased tumor-cell adhesion. These results suggest that macrophages are involved in the endothelial damage resulting from exposure to LPS. Interestingly, the expression levels of of ZO-1 were not affected by LPS treatment in rats in which liver macrophages had been depleted as well as in rats that had been treated with a reactive oxygen species (ROS) scavenger. In both settings, decreased tumor-cell adhesion was observed. Taken together, our findings indicate that LPS induces ROS release by macrophages, resulting in the damage of the vascular lining of the liver and hence allowing increased tumor-cell adherence. Thus, peri-operative treatments that prevent the activation of macrophages and-as a consequence-limit endothelial damage and tumor-cell adhesion may significantly improve the long-term outcome of cancer patients undergoing surgical tumor resectio

Prolonged maturation and enhanced transduction of dendritic cells migrated from human skin explants after in situ delivery of CD40-targeted adenoviral vectors

Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumor-associated Ags, critically depends on the in vivo transduction of dendritic cells (DC). Transfection of predominantly nonprofessional APC and only small numbers of DC may hamper proper T cell activation. Aim of this study was, therefore, the targeted, selective, and enhanced in situ transduction of DC. A human skin explant model was used to explore targeted transduction of cutaneous DC after intradermal injection of a bispecific Ab conjugate to link adenoviral (Ad) vectors directly to CD40 on the DC surface. A significantly enhanced transduction efficiency and selectivity, and an increased activation state of migrating DC were thus achieved. Moreover, DC transduced by CD40-targeted Ad maintained their Ag-specific CTL-stimulatory ability for up to 1 wk after the start of migration, in contrast to DC transduced by untargeted Ad, which had lost this capacity by that time. Because DC targeting in vivo might obviate the need for the in vitro culture of autologous DC for adoptive transfer, CD40-targeted Ad vectors constitute a promising new vaccine modality for tumor immunotherapy