IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies.

The transplantation model provides the opportunity to assess the relevance of a molecule of interest for tumor cell extravasation by using a respective genetically modified donor animal. Here, we present a protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. We describe steps for animal preparation, lung transplantation, and tumor cell injection. We then detail procedures for the direct comparison of tumor cell spreading between the genetically modified left lung and the naive right lung parenchyma. For complete details on the use and execution of this protocol, please refer to Giannou et al. (2023).1.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Prognostic factors for intraoperative detection of necrotizing fasciitis in severe soft tissue infections.

BACKGROUND: Necrotizing fasciitis (NF) is a rare but lethal soft-tissue infection. There is still a paucity of information regarding the diagnostic tools and therapeutic strategies for the treatment of this devastating disease. This study aims to identify important perioperative parameters related to necrotizing fasciitis and to assess their relevance in terms of identifying NF. METHODS AND MATERIAL: We retrospectively analyzed patients who underwent surgical exploration for suspected necrotizing fasciitis at a tertiary referral center, to explore the clinical features and factors related to the presence of necrotizing fasciitis and mortality. RESULTS: Between 2010 and 2017, 88 patients underwent surgical exploration for suspected NF. The infection occurred in the lower extremities in 48 patients, in the thoracocervical region in 18 patients, and the perineum and abdomen in 22 patients. Histological evidence of NF was present in 59 of 88 patients. NF was associated with a longer hospital stay and ICU stay (p = 0.05 and 0.019 respectively) compared to patients without NF. ROC analysis showed that only macroscopic fascial appearance could discriminate patients with histological evidence of NF. Moreover, multivariate logistic regression revealed, that liver failure (p = 0.019), sepsis (p = 0.011), positive Gram stain (p = 0.032), and macroscopic fascial appearance (p <0.001) were independent prognostic parameters for histological evidence of NF. CONCLUSION: Intraoperative tissue evaluation by an experienced surgeon is the most important diagnostic tool in identifying necrotizing fasciitis. An intraoperative Gram stain is an independent prognostic tool and therefore its use can be recommended especially in case of clinical uncertainty.

Quantification of gastric tube perfusion following esophagectomy using fluorescence imaging with indocyanine green.

INTRODUCTION: Anastomotic leakage (AL) remains a prevalent and life-threatening complication after esophagectomy. Gastric tube perfusion assessment using indocyanine green fluorescence imaging (ICG-FI) has been published in several studies and appears to be a promising tool to reduce AL rates by changing the surgical approach, namely by an intraoperative evaluation of the anastomosis localization. METHODS: In this study, gastric tube perfusion was quantified by using ICG-FI in 20 high-risk patients undergoing esophagectomy. From a time-dependent fluorescence intensity curve, the following three parameters were evaluated: slope of fluorescence intensity (SFI), background subtracted peak fluorescence intensity (BSFI), and time to slope (TTS). RESULTS: The values between pyloric region and tip showed a similar downward trend and SFI and BSFI significantly correlated with the distance to the pyloric region. SFI and BSFI were significantly decreased at the tip of the gastric tube. The placement of anastomosis in an area with homogenous fluorescence pattern was correlated with no AL in 92.9% of cases. An inhomogeneous fluorescence pattern at anastomotic site was a risk factor for the occurrence of an AL (p < 0.05). Reduction of perfusion up to 32% using SFI and up to 23% using BSFI was not associated with AL. CONCLUSION: ICG-FI can be used to quantify the gastric tube perfusion by calculating SFI, BSFI, and TTS. The anastomosis should be created in areas with homogeneous fluorescence pattern. A reduction in blood flow of up to 32% can be accepted without causing an increased rate of insufficiency.

Surgical correction of a percutaneous dilatational tracheostomy: A case report.

INTRODUCTION AND IMPORTANCE: Percutaneous dilatational tracheostomy (PDT) has become a routine procedure in intensive care, because of its multiple advantages over surgical tracheostomy (ST). CASE PRESENTATION: We present the case of a 72-year-old patient with SARS-CoV-2 pneumonia, who received a PDT in the 6th tracheal ring with a lateral puncture of the trachea. This atypical placement of tracheostomy was due to a massive left-pronounced goiter, causing a tracheal shift to the right. To avoid dislocation of the tracheal cannula and prevent recurrent bleeding, surgical revision was decided. After left hemithyroidectomy, oral intubation was temporarily necessary, in order to remove the old tracheostomy. Then suturing of the left lateral tracheal defect and standard ST in the 2nd tracheal cartilage was performed. The patient was successfully weaned and decannulated and his swallowing function remained intact. CLINICAL DISCUSSION: In our case left hemithyroidectomy was necessary, in order to enable an optimal surgical tracheostomy in the 2nd tracheal cartilage. Because mechanical ventilation was carried out proximal to the large tracheal defect after PCT, a secondary closing approach was not an option. The endotracheal cuff was placed above the defect, in order to prevent acute or chronic intraluminal pressure trauma. Postoperative x-ray and bronchoscopy insured the sufficient sealing of the tracheal suturing. CONCLUSION: We describe an unusual placement of percutaneous dilatational tracheostomy through a thyroid goiter and our approach to perform a correction surgical tracheostomy.

Hypocalcemia as an important differential diagnosis in patients suffering from stridor following thyroidectomy.

It is essential to consider hypocalcemia as a cause of stridor, especially following postoperative thyroidectomy, as hypocalcemia secondary to hypoparathyroidism is an important differential diagnosis. Advances in intraoperative technology to optimize the vascularization of the parathyroid glands can help to predict and prevent patients from a postoperative hypoparathyroidism.

Morphologic Factors Predict Pain Relief Following Pancreatic Head Resection in Chronic Pancreatitis Description of the Chronic Pancreatitis Pain Relief (CPPR) Score.

OBJECTIVE: This study analyzes the clinicopathologic findings and their impact on outcome of patients so as to identify which patients benefit most from surgical treatment in chronic pancreatitis, especially in regard to pain relief. SUMMARY BACKGROUND DATA: The predominant symptom of chronic pancreatitis is chronic pain resulting in reduced quality of life. It is well known that the main reason for development of the disease is abuse of alcohol and nicotine, but only little data on factors influencing outcome are available. METHODS: One thousand one hundred forty-six consecutive patients who underwent surgery for chronic pancreatitis were included. Clinicopathologic data, including morphology of the pancreas in preoperative diagnostics and the histopathologic results, were evaluated. A long-term follow-up including Quality of Life and pain scores was performed. Additionally, we describe the novel Chronic Pancreatitis Pain Relief Score (CPPR-Score) as a tool for prediction of pain relief. RESULTS: Overall the rate of pain relief was 79.8% after surgery. The presence of an inflammatory mass in the pancreatic head larger than 4 cm (P < 0.001), presence of a dilated main pancreatic duct of over 4 mm (P < 0.001), histopathologically detected severe calcifications (P = 0.001) and severe fibrosis (P < 0.001) as well as ethanol induced disease (P < 0.001) found to be strong independent prognostic factors for pain relief. The CPPR-Score (0-5 points) proved to be a very good predictive score for pain-relief (P < 0.001). CONCLUSIONS: The rate of pain relief after surgical treatment in chronic pancreatitis is high and the commonly used procedures can be performed with acceptable morbidity and mortality. The Chronic Pancreatitis Pain Relief Score allows identifying patients who will benefit most from surgery.

Antibiotic sensitivity in correlation to the origin of secondary peritonitis: a single center analysis.

Despite improvements in diagnosis, intensive-care medicine and surgical technique, the mortality of patients with secondary peritonitis is still high. Early and aggressive empiric antibiotic treatment has strong impact on the outcome. This retrospective study investigates bacterial and fungal pathogens and their antibiotic sensitivity in patients with secondary peritonitis. All patients that underwent emergency laparotomy due to secondary peritonitis at the Department of Surgery, University Medical Center Hamburg-Eppendorf between 2005 and 2015 were reviewed and overall 414 patients were included. We correlated the intra-abdominal localization of the organ perforation with intraoperative microbiological findings and corresponding sensitivities to relevant antibiotics. Overall, the most common findings were Escherichia coli (39%) and other Enterobacterica (24%). Depending on the location of the perforation, Cefuroxime/Metronidazole and Cefutaxime/Metronidazole were effective (based on in vitro susceptibility testing) in only 55-73% of the patients, while Meropenem/Vancomycin was able to control the peritonitis in more than 98% of the patients; independent of the location. Besides early source control, appropriate empiric treatment plays a pivotal role in treatment of secondary peritonitis. We are able to show that the frequently used combinations of second or third generation Cephalosporins with Metronidazole are not always sufficient, which is due to the biological resistance of the bacteria. Further clinical studies are needed to determine whether calculated use of broad-spectrum antibiotics with a sensitivity rate > 99%, such as Carbapenem plus Vancomycin, can improve overall survival rates in critically ill patients with secondary peritonitis.

A single-center experience: management of patients with thymic epithelial tumors.

BACKGROUND: Thymic epithelial tumors are rare neoplasias. There are no internationally accepted standards to treat this complex oncological disease. The studies on which our knowledge is based frequently have methodological weaknesses. If the tumor is resectable, complete surgical excision is currently the first-line therapy. Thymic epithelial tumors respond to radiation. The therapeutic benefit of adjuvant radiotherapy depends on tumor stage. To validate and improve treatment, we share our current experiences with clinical management and surgical intervention. METHODS: This single-center retrospective study included 40 patients with primarily resectable thymic epithelial tumors who underwent resection with curative intent. The survival data was collected and presented according to Kaplan-Meier. Single- and multiple predictor survival analyses were carried out using the log-rank test and Cox proportional hazards model. RESULTS: Single-predictor survival analysis showed survival to be dependent on the Masaoka-Koga classification, WHO histological classification, resection status, surgical technique, and Clavien-Dindo grade for postoperative complications. Multiple predictor analysis confirms that the Masaoka-Koga stage (HR = 4.876, P = 0.032) and Clavien-Dindo grade (HR = 4.904, P = 0.011) are independent prognostic factors for survival. CONCLUSION: In addition to the Masaoka stage, the occurrence of severe postoperative complications represents an independent prognostic factor. Given the tumor's sensitivity to radiation, the use of neoadjuvant radiotherapy can be considered to downstage Masaoka-Koga stages III and higher, thus reducing surgical risks. Further prospective multicenter studies are urgently needed.

C-Reactive Protein in the Prediction of Localization of Gastrointestinal Perforation.

AIM: Information regarding the localization of the anatomic site of gastrointestinal (GI) tract perforation is essential for the following surgical procedure. The purpose of this study was to evaluate the significance of C-reactive protein (CRP) and other circulating markers for the prediction of the localization of intra-abdominal hollow organ perforation. METHODS: Measurements of serum markers were analyzed in 423 patients with GI tract perforations, who were divided according to the intraoperative diagnosis into colorectal and upper GI tract perforation groups. RESULTS: Levels of CRP were higher in patients with colorectal perforations than in upper GI tract perforations (p < 0.001). Moreover, high levels of CRP were associated with increased mortality of patients with hollow organ perforations (p = 0.009), which was largely driven by the subset of patients with perforations of the upper GI tract (p = 0.001). CONCLUSION: Increased CRP levels predict worse clinical outcome in patients with intra-abdominal hollow organ perforations and are associated with perforations in the colorectal tract. Thus, CRP might be a useful marker for preoperative risk stratification and prediction of the localization of the perforation site.

FOXO1 overexpression and loss of pSerine256-FOXO1 expression predicts clinical outcome in esophageal adenocarcinomas.

The function of Forkhead box O 1 (FOXO1) and pSerine256-FOXO1 immunostaining in esophageal cancer is unclear. To clarify the prognostic role of nuclear FOXO1 and cytoplasmic pSerine256-FOXO1 immunostaining, a tissue microarray containing more than 600 esophageal cancers was analyzed. In non-neoplastic esophageal mucosae, FOXO1 expression was detectable in low and pSerine256-FOXO1 expression in high intensities. Increased FOXO1 and decreased pSerine256-FOXO1 expression were linked to advanced tumor stage and high UICC stage in esophageal adenocarcinomas (EACs) (tumor stage: p = 0.0209 and p < 0.0001; UICC stage: p = 0.0201 and p < 0.0001) and squamous cell carcinomas (ESCCs) (tumor stage: p = 0.0003 and p = 0.0016; UICC stage: p = 0.0026 and p = 0.0326). Additionally, overexpression of FOXO1 and loss of pSerine256-FOXO1 expression predicted shortened survival of patients with EACs (p = 0.0003 and p = 0.0133) but were unrelated to outcome in patients with ESCCs (p = 0.7785 and p = 0.8426). In summary, our study shows that overexpression of nuclear FOXO1 and loss of cytoplasmic pSerine256-FOXO1 expression are associated with poor prognosis in patients with EACs. Thus, evaluation of FOXO1 and pSerine256-FOXO1 protein expression - either alone or in combination with other markers - might be useful for prediction of clinical outcome in patients with EAC.

Omental infarction in the postpartum period: a case report and a review of the literature.

INTRODUCTION: Omental infarction is a rare and often misdiagnosed clinical event with unspecific symptoms. It affects predominantly young and middle aged women. CASE PRESENTATION: This is a case report of a 26-year-old Caucasian woman with spontaneous omental infarction two weeks after normal vaginal delivery. CONCLUSION: Omental infarction is a differential diagnosis in the postpartum acute abdomen. As some cases of omental infarction, which are caused by torsion, can be adequately diagnosed via computed tomography, a conservative treatment strategy for patients without complications should be considered in order to avoid any unnecessary surgical intervention.

Pediatric transplantation: the Hamburg experience.

BACKGROUND: Since starting our program in 1989, 455 pediatric orthotopic liver transplantations have been performed using all techniques. In April 2001, we experienced our last in-hospital death of a pediatric liver-transplant recipient. Since then, all our liver-transplant children (n=170) were able to be discharged from the hospital. The aim of this study is to analyze the actual status of pediatric liver transplantation at the University of Hamburg and to find future perspectives to improve the results after pediatric liver transplantation. METHODS: From May 4, 2001 until September 8, 2004, 22 (13%) whole organs, 18 (11%) reduced-size organs, 79 (47%) split organs, and 51 (30%) organs from living donors were transplanted into 142 patients. One hundred forty-one were primary liver transplants, 25 retransplants, 3 third, and 1 fourth liver transplants. Of the 170 orthotopic liver transplantations (OLT), 31 (18%) were highly urgent (United Network of Organ Sharing [UNOS] I). RESULTS: After 170 consecutive pediatric liver transplants, no patients died during the hospital course (100% patient survival<3 months), but overall, 5 (2.9%) recipients died during further follow-up. The 3-month and actual graft survival rates are 93% and 85%, respectively. Twenty (11.8%) children had to undergo retransplantation. However, patient survival was not sustained by longer graft survival. Analyzing our series, we see that graft survival after reduced-size liver transplantation showed a significantly lower rate versus living-donor liver transplantation. CONCLUSION: The learning curve in pediatric liver transplantation has reached a turning point where immediate patient survival is considered the rule. The challenge is to increase graft survival to the same level. The long-term management of the transplant patients, with the aim of avoiding late graft loss and achieving excellent quality of life, will become the center of the debate.