Role of liver augmentation prior to hepatic resection - a survey on standards, procedures, and indications in Germany, Switzerland, and Austria.

PURPOSE: For primary and secondary liver tumors oncological resection remains a chance of cure. Augmentation of functional liver tissue may be necessary to preserve sufficient future liver remnant (FLR). Clinical decision-making on liver augmentation techniques and indications may differ internationally. Thus, this study aims to identify standards of liver augmentation in hepato-pancreatico-biliary (HPB) centers in Germany, Switzerland, and Austria. METHODS: Using a web-based survey, 48 hospitals in Germany, Switzerland, and Austria were invited to report their surgical indication, standard procedures, and results of liver augmentation. RESULTS: Forty (83.3%) of the hospitals invited participated. Most of the hospitals were certified liver centers (55%), performing complex surgeries such as liver transplantation (57.5%) and ALPPS (80%). The standard liver augmentation technique in all countries was portal vein embolization (PVE; 56%), followed by ALPPS (32.1%) in Germany or PVE with hepatic vein embolization (33.3%) in Switzerland and Austria. Standard procedure for liver augmentation did not correlate with certification as liver center, performance of liver transplantation or ALPPS. Surgical indication for PVE varied depending on tumor entity. Most hospitals rated the importance of PVE before resection of cholangiocarcinoma or colorectal metastases as high, while PVE for hepatocellular carcinoma was rated as low. CONCLUSION: The survey gives an overview of the clinical routine in HPB centers in Germany, Austria, and Switzerland. PVE seems to dominate as standard technique to increase the FLR. However, there is a variety in the main indication for liver augmentation. Further studies are necessary evaluating the differing PVE techniques for liver augmentation.

High CIB1 expression in colorectal cancer liver metastases correlates with worse survival and the replacement histopathological growth pattern.

To date, nearly one-quarter of colorectal cancer (CRC) patients develop liver metastases (CRCLM), and its aggressiveness can be correlated to defined histopathological growth patterns (HGP). From the three main HGPs within CRCLM, the replacement HGP emerges as particularly aggressive, characterized by heightened tumor cell motility and vessel co-option. Here, we investigated the correlation between the expression of calcium- and integrin-binding protein 1 (CIB1), a ubiquitously expressed gene involved in various cellular processes including migration and adhesion, and disease-free (DFS) and overall survival (OS) in primary CRC patients. Additionally, we explored the correlation between CIB1 expression and different HGPs of CRCLM. Proteomic analysis was used to evaluate CIB1 expression in a cohort of 697 primary CRC patients. Additionally, single-cell and spatial RNA-sequencing datasets, along with publicly available bulk sequencing data were used to evaluate CIB1 expression in CRCLM. In silico data were further validated by formalin-fixed paraffin-embedded immunohistochemical stainings. We observed that high CIB1 expression is independently associated with worse DFS and OS, regardless of Union Internationale Contre le Cancer stage, gender, or age. Furthermore, the aggressive replacement CRCLM HGP is significantly associated with high CIB1 expression. Our findings show a correlation between CIB1 levels and the clinical aggressiveness of CRC. Moreover, CIB1 may be a novel marker to stratify HGP CRCLM.

[Management of Injuries to the Parenchymal Abdominal Organs]. / Management von Verletzungen parenchymatöser Abdominalorgane.

The most common organs affected by abdominal trauma are the spleen and the liver, often in combination. Pancreatic injuries are rare. In the case of blunt abdominal trauma, which is much more common, a clinical and laboratory examination as well as sonography should be performed. In the initial assessment, the circulatory situation must be screened. If there is haemodynamic instability and presentation of free fluid, an emergency laparotomy is indicated. If the situation is stable or stabilised and a pathological sonography is present, it is essential to perform triphasic contrast enhanced computed tomography, which is also mandatory in polytraumatised patients. If a renal injury is suspected, a late venous phase should be attached. In addition to the classification of the injury, attention should be paid to possible vascular injury or active bleeding. In this case, angiography with the possibility of intervention should be performed. Endoscopic treatment is possible for injuries of the pancreatic duct. If the imaging does not reveal any intervention target and a circulation is stable, a conservative approach is possible with continuous monitoring using clinical, laboratory and sonographic controls. Most injuries can be successfully treated by non-operative management (NOM).There are various surgical options for treating the injury, such as local and resecting procedures. There is also the option of "damage control surgery" with acute bleeding control and second look. Complex surgical procedures should be performed at centres. Postoperative complications arise out of elective surgery.In the less common case of penetrating abdominal trauma, the actual extent of the injury cannot be estimated from the visible wound. Here again, the circulatory situation determines the next steps. An emergency laparotomy should be carried out in case of instability. If the condition is stable, further diagnostics should be performed using contrast enhanced computed tomography. If penetration through the peritoneum cannot be clearly excluded, diagnostic laparoscopy should be performed.

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to systemic treatment, including new immunotherapeutic approaches. Biomarkers are urgently needed for early disease detection, patient stratification for treatment, and response prediction. The role of soluble CD40 (sCD40) is unknown in PDAC. In this study, we performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum samples from patients with various stages of PDAC in a discovery study (n = 107) and analyzed sCD40 by ELISA in a validation study (n = 317). Youden's J statistic was used for diagnostic cut-off optimization. A Cox proportional hazards regression model was applied in an empiric approach for prognostic threshold optimization. Kaplan-Meier estimator and multivariable Cox regression analyses were used for survival analysis. sCD40 was significantly increased in the serum of patients with PDAC compared to healthy cohorts and patients with IPMN. In the validation cohort, the area under the receiver operating characteristic (ROC) c-statistic was 0.8, and combining sCD40 with CA19-9 yielded a c-statistic of 0.95. sCD40 levels were independent of the tumor stage. However, patients who received neoadjuvant chemotherapy had significantly lower sCD40 levels than those who underwent upfront surgery. Patients with a sCD40 level above the empirical threshold of 0.83 ng/ml had a significantly reduced overall survival with a hazard ratio of 1.4. This observation was pronounced in patients after neoadjuvant chemotherapy. Collectively, soluble CD40 may be considered as both a diagnostic and prognostic non-invasive biomarker in PDAC.

[Treatment recommendation and care in traumatic rupture of the spleen]. / Therapieempfehlung und Versorgung bei traumatischer Milzruptur.

The spleen is the most frequently affected organ in blunt abdominal trauma. Initial diagnostics include the physical examination, laboratory blood controls and ultrasound. Furthermore, a triphasic dynamic contrast-enhanced computed tomography (CT) scan is indicated. Apart from the imaging-based classification of the injury with consideration of vascular alterations and active bleeding, the hemodynamic condition of the patient is a crucial factor. For patients who are hemodynamically stable or can be stabilized, a nonoperative management with a minimum of 24 h of continuous monitoring, regular blood controls of the hemoglobin level as well as ultrasound follow-up should be given precedence. In cases of active bleeding or pathological vascular alterations, a radiological intervention in the sense of an embolization should be initiated. A hemodynamically unstable patient must immediately undergo surgical treatment, during which a spleen-preserving approach via splenorrhaphy should principally be favored over splenectomy. This also applies to patients where the intervention has failed. To prevent severe infections after splenectomy it is advised to vaccinate against Pneumococcus, Haemophilus influenzae type B and Meningococcus as well as the annual seasonal influenza vaccination according to the Standing Committee on Vaccination (STIKO) recommendations.

Immuno-histochemical correlation of fibrosis-related markers with the desmoplastic reaction of the mesentery in small intestine neuroendocrine neoplasms.

INTRODUCTION: Small intestine neuroendocrine neoplasms (siNENs) will attain more importance due to their increasing incidence. Moreover, siNENs might lead to a desmoplastic reaction (DR) of the mesentery causing severe complications and deteriorating prognosis. The expression of fibrosis-related proteins appears to be the key mechanisms for the development of this desmoplastic reaction. Therefore, this study aimed to investigate the association of the desmoplastic mesentery with specific fibrosis-related protein expression levels. MATERIALS AND METHODS: By immunohistochemistry, the protein expression levels of four fibrosis-related markers (APLP2, BNIP3L, CD59, DKK3) were investigated in primary tumors of 128 siNENs. The expression levels were correlated with the presence of a desmoplastic reaction and clinico-pathological parameters. RESULTS: In the primary tumor, APLP2, BNIP3L, CD59 and DKK3 were highly expressed in 29.7% (n = 38), 64.9% (n = 83), 92.2% (n = 118) and 80.5% (n = 103), respectively. There was no significant correlation of a single marker or the complete marker panel to the manifestation of a desmoplastic mesentery. The desmoplastic mesentery was significantly associated with clinical symptoms, such as flushing and diarrhea. However, neither the fibrosis-related marker panel nor single marker expressions were associated with clinical symptoms. DISCUSSION: The expression rates of four fibrosis-related markers in the primary tumor display a distinct pattern. However, the expression patterns are not associated with desmoplastic altered mesenteric lymph node metastases and the expression patterns did not correlate with prognosis. These findings suggest alternative mechanisms being responsible for the desmoplastic reaction.

EMT-Related Genes Have No Prognostic Relevance in Metastatic Colorectal Cancer as Opposed to Stage II/III: Analysis of the Randomised, Phase III Trial FIRE-3 (AIO KRK 0306; FIRE-3).

INTRODUCTION: There is no standard treatment after resection of colorectal liver metastases and the role of systemic therapy remains controversial. To avoid over- or undertreatment, proper risk stratification with regard to postoperative treatment strategy is highly needed. We recently demonstrated the prognostic relevance of EMT-related (epithelial-mesenchymal transition) genes in stage II/III CRC. As EMT is a major step in CRC progression, we now aimed to analyse the prognostic relevance of EMT-related genes in stage IV CRC using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of patients with metastatic CRC. METHODS: Overall and progression free survival were considered as endpoints (n = 350). To investigate the prognostic relevance of EMT-related genes on either endpoint, we compared predictive performance of different models using clinical data only to models using gene data in addition to clinical data, expecting better predictive performance if EMT-related genes have prognostic value. In addition to baseline models (Kaplan Meier (KM), (regularised) Cox), Random Survival Forest (RSF), and gradient boosted trees (GBT) were fit to the data. Repeated, nested five-fold cross-validation was used for hyperparameter optimisation and performance evaluation. Predictive performance was measured by the integrated Brier score (IBS). RESULTS: The baseline KM model showed the best performance (OS: 0.250, PFS: 0.251). None of the other models were able to outperform the KM when using clinical data only according to the IBS scores (OS: 0.253 (Cox), 0.256 (RSF), 0.284 (GBT); PFS: 0.254 (Cox), 0.256 (RSF), 0.276 (GBT)). When adding gene data, performance of GBT improved slightly (OS: 0.262 vs. 0.284; PFS: 0.268 vs. 0.276), however, none of the models performed better than the KM baseline. CONCLUSION: Overall, the results suggest that the prognostic relevance of EMT-related genes may be stage-dependent and that EMT-related genes have no prognostic relevance in stage IV CRC.

Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes.

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.

Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics.

Introduction: In patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples. Material and methods: The study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms >20 weeks with still significant elevated Kyn-levels. Results: Mean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values < 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values <0.001) and CRP (r=0.488, p-values<0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range. Conclusion: Serum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy.

Identification of an EMT-related Gene Signature Predicting Recurrence in Stage II/III Colorectal Cancer: A Retrospective Study in 1780 Patients.

OBJECTIVE: To identify a prognostic significant gene signature for predicting colorectal cancer (CRC) recurrence. BACKGROUND: Traditional prognostic risk assessment in stage II/III CRC patients remains controversial. Epithelial-mesenchymal transition is thought to be closely related to the malignant progression of tumors. Thus, it is promising to establish a prognostic model based on epithelial-mesenchymal transition-related gene (ERG) signature. MATERIALS AND METHODS: We retrospectively analyzed transcriptome profiles and clinical information of 1780 stage II/III CRC patients from 15 public datasets. Coefficient variant analysis was used to select reference genes for normalizing gene expression levels. Univariate, LASSO, and multivariate Cox regression analyses were combined to develop the ERG signature predicting disease-free survival (DFS). The patients were divided into high-risk and low-risk based on the ERG signature recurrence risk score. The survival analysis was performed in different CRC cohorts. RESULTS: The proposed ERG signature contained 7 cancer-related ERGs and 3 reference genes. The ERG signature recurrence risk score was prognostically relevant in all cohorts ( P <0.05) and proved as an independent prognostic factor in the training cohort. In the pooled cohort, high-risk CRC patients exhibited worse DFS ( P <0.0001) and overall survival ( P =0.0058) than low-risk patients. The predictive performance of the ERG signature was superior to Oncotype DX colon cancer. An integrated decision tree and nomogram were developed to improve prognosis evaluation. CONCLUSIONS: The identified ERG signature is a promising and powerful biomarker predicting recurrence in CRC patients. Moreover, the presented ERG signature might help to stratify patients according to their tumor biology and contribute to personalized treatment.

[Personalised Surgical Therapy for Neuroendocrine Neoplasia of the Pancreas]. / Personalisierte Resektionsverfahren bei neuroendokrinen Neoplasien des Pankreas.

Neuroendocrine neoplasia of the pancreas (pNEN) has an increasing incidence and is therefore becoming increasingly clinically relevant. In addition to hormonally inactive pNEN, there are hormone-producing tumours and both inactive and active pNEN can be either sporadic or hereditary. Treatment is not only based on tumour-associated factors, but also on the individual patient's own circumstances. Treatment must be based on individual, tailor-made concepts that consider the respective factors and circumstances.

Molecular subtyping of gastric cancer according to ACRG using immunohistochemistry - Correlation with clinical parameters.

BACKGROUND: Gastric cancer (GC) is a very heterogenous disease necessitating further stratification for prognostic and therapeutic aspects. Based on the recommendation of The Asisan Cancer Research Group (ACRG) recently established four molecular subtypes (MSI, MSS/EMT, MSS/TP53+, MSS/TP53-) which require molecular expression analysis. The technology required for comprehensive molecular analysis is expensive and not applicable for routine diagnostics. Thus, in this study we established a classification system utilizing immunohistochemistry and morphology-based analyses as surrogate markers in order to reproduce the ACRG molecular subtypes of gastric cancer. To clarify the clinical relevance of the novel classification system, we performed a correlation with established clinical parameters. METHODS: The study cohort consisted of 189 patients with GC (UICC III and IV). Using immunohistochemistry, the following markers were analysed: MLH1, MSH2, MSH6, PMS2 (as a surrogate for microsatellite status), p53, SOX9. We assessed tumor budding as a surrogate for EMT to distinguish between MSS/EMT and MSS/non-EMT groups. RESULTS: Immunohistochemical and morphologic subtyping classified cases as follows: 10% MSI, 35% MSS/EMT, 16% MSS/TP53 + and 39% MSS/TP53-. Subtypes significantly correlated with the Lauren classification, tumor stage, venous invasion and SOX9 expression (p < .05). There was no significant correlation between molecular subtype and lymph node growth pattern. CONCLUSION: We propose a simple algorithm for molecular subtyping of GC using universally available immunohistochemistry, which correlates with clinical parameters and is cost-effective and applicable in diagnostic routine. This classification might prospectively help to determine patient prognosis, optimize patient care and homogenize patient cohorts for clinical trials.

A novel immune-related gene signature predicting survival in sarcoma patients.

Sarcomas are a heterogeneous group of rare mesenchymal tumors. The migration of immune cells into these tumors and the prognostic impact of tumor-specific factors determining their interaction with these tumors remain poorly understood. The current risk stratification system is insufficient to provide a precise survival prediction and treatment response. Thus, valid prognostic models are needed to guide treatment. This study analyzed the gene expression and outcome of 980 sarcoma patients from seven public datasets. The abundance of immune cells and the response to immunotherapy was calculated. Immune-related genes (IRGs) were screened through a weighted gene co-expression network analysis (WGCNA). A least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish a powerful IRG signature predicting prognosis. The identified IRG signature incorporated 14 genes and identified high-risk patients in sarcoma cohorts. The 14-IRG signature was identified as an independent risk factor for overall and disease-free survival. Moreover, the IRG signature acted as a potential indicator for immunotherapy. The nomogram based on the risk score was built to provide a more accurate survival prediction. The decision tree with IRG risk score discriminated risk subgroups powerfully. This proposed IRG signature is a robust biomarker to predict outcomes and treatment responses in sarcoma patients.

[Indications for the surgical management of pancreatic neoplasms]. / Operationsindikationen bei Tumoren der Bauchspeicheldrüse.

Due to its rising incidence, pancreatic neoplasia, which mainly include adenocarcinomas, neuroendocrine and cystic neoplasia of the pancreas, is becoming increasingly relevant in everyday clinical practice.Based on a systematic literature search, a working group of pancreatic experts developed evidence-based recommendations for surgical indications in pancreatic neoplasia to improve the quality.There is a clear surgical indication for primary or secondary resectable pancreatic carcinomas without metastasis, for functionally active, symptomatic and functionally inactive neuroendocrine neoplasia of more than 2 cm in size and for cystic neoplasm with symptoms or signs of malignancy including all intraductal papillary-mucinous neoplasia (IPMN) of the main duct and mixed type, all mucinous-cystic neoplasia (MCN) > 4 cm and all solid pseudopapillary neoplasia (SPN). Surgery can be indicated for pancreatic carcinomas with isolated arterial vascular infiltration or for long periods of stable oligometastasis, regarding neuroendocrine neoplasias for metastasis or debulking surgery as well as for branch-duct IPMN with risk criteria and MCN <4 cm. There is no primary indication for surgery in locally advanced and metastatic pancreatic cancer or asymptomatic serous-cystic neoplasia (SCN).The indication for surgery should always be individualized taking into account age, comorbidities and patient wishes.

EMT-related genes are unlikely to be involved in extracapsular growth of lymph node metastases in gastric cancer.

BACKGROUND: In gastric cancer (GC), extracapsular growth (ECG) pattern of lymph node metastases is associated with decreased overall survival rates compared to intracapsular lymph node metastases (ICG). Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in hematogenous metastatic spread. Aim of the present study was to analyze if EMT related genes are involved in the growth pattern of lymph node metastases in GC. METHODS: Out of our prospective database with 529 patients who underwent surgical resection for GC between 2002 and 2014 forty lymph node positive patients were identified (20 ECG, 20 ICG). The expression of 84 EMT-associated genes were analyzed by RT2 Profiler PCR Array (n = 20). Results were validated by Real-Time PCR (n = 20). RESULTS: GC with ECG showed differently expressed EMT related genes. GC leading to ECG showed an upregulation of three and downregulation of eleven genes. Those differences, however, could not be confirmed in PCR analysis. CONCLUSIONS: This study demonstrates that EMT related genes are not responsible for the different growth patterns of lymph node metastases in GC. Further studies are required to evaluate the underlying mechanisms of ECG in GC as it might provide a potential therapeutic target for this subgroup of more aggressive tumors in the future.

Current State of Multidisciplinary Treatment in Cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly aggressive malignancy, and its incidence seems to be increasing over the last years. Given the high rate of irresectability at the time of initial diagnosis, new treatment approaches are important to achieve better patient outcomes. Our review provides an overview of current multimodal therapy options across different specialties of gastroenterology/oncology, surgery, and interventional radiology. SUMMARY: CCA is subdivided into clinically and molecularly distinct phenotypes. Surgical treatment currently is the only potentially curative therapy, but unfortunately, the majority of all patients are not eligible for resection at the time of initial diagnosis due to anatomic location, inadequate hepatic reserve, metastatic disease, or limiting comorbidities. However, multimodal treatment options are available to prolong survival, relieve symptoms, and maintain life quality. KEY MESSAGES: The treatment of CCA is complex and requires close interdisciplinary collaboration and individualized treatment planning to ensure optimal patient care at specialized centers. Molecular profiling of patients and inclusion into clinical trials is highly recommended.

Expression of CIB1 correlates with colorectal liver metastases but not with peritoneal carcinomatosis.

BACKGROUND: Molecular differences in colorectal cancer (CRC) are associated with the metastatic route. Patient survival is mainly driven by metastatic spread thus it is imperative to understand its key drivers to develop biomarkers for risk stratification, follow-up protocols and personalized therapy. Thus, this study aimed to identify genes associated with the metastatic route in CRC. MATERIAL AND METHODS: CRC patients resected at our clinic from 2005 to 2014 and with a minimum 5-year follow-up were included in this analysis and grouped into CRC with hepatic (HEP), peritoneal (PER) or without distant metastases (M0), and HEP/PER. Firstly, tumor RNA of 6 patients each was isolated by microdissection from formalin-fixed paraffin-embedded specimens and analyzed by a NanoString analysis. Subsequently, these results were validated with immunohistochemistry and correlated to clinicopathological parameters in a larger collective of CRC patients (HEP n = 51, PER n = 44, M0 n = 47, HEP/PER n = 28). RESULTS: Compared to M0, HEP tumors showed 20 differentially expressed genes associated with epithelial-mesenchymal transition (EMT) and angiogenesis. Compared to M0, PER tumors had 18 differentially expressed genes. The finding of different gene signatures was supported by the multidimensional principal component clustering analysis. Tumor perforation did not influence the metastatic route. CIB1 was homogenously and significantly overexpressed in HEP compared to M0 (p < 0.001), but not in PER. Furthermore, immunohistochemical validation demonstrated that the mean CIB1 expression in HEP was 80% higher than in M0 (p < 0.001). CONCLUSION: Gene expression analysis revealed that CIB1 is significantly overexpressed in CRC leading to liver metastases compared to M0 and PER. Thus, the present results suggest that CIB1 may play a crucial role for hematogenous spread to the liver but not for peritoneal carcinomatosis. Consequently, CIB1 seems to be a promising prognostic marker and a potential tool for future targeted therapies as well as early diagnostics and follow-up.

The association of immunosurveillance and distant metastases in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy worldwide, but the key driver to distant metastases is still unknown. This study aimed to elucidate the link between immunosurveillance and organotropism of metastases in CRC by evaluating different gene signatures and pathways. MATERIAL AND METHODS: CRC patients undergoing surgery at the Department of General, Visceral and Transplantation Surgery at the Ludwig-Maximilian University Hospital Munich (Munich, Germany) were screened and categorized into M0 (no distant metastases), HEP (liver metastases) and PER (peritoneal carcinomatosis) after a 5-year follow-up. Six patients of each group were randomly selected to conduct a NanoString analysis, which includes 770 genes. Subsequently, all genes were further analyzed by gene set enrichment analysis (GSEA) based on seven main cancer-associated databases. RESULTS: Comparing HEP vs. M0, the gene set associated with the Toll-like receptor (TLR) cascade defined by the Reactome database was significantly overrepresented in HEP. HSP90B1, MAPKAPK3, PPP2CB, PPP2R1A were identified as the core enrichment genes. The immunologic signature pathway GSE6875_TCONV_VS_FOXP3_KO_TREG_DN with FOXP3 as downstream target was significantly overexpressed in M0. RB1, TMEM 100, CFP, ZKSCAN5, DDX50 were the core enrichment genes. Comparing PER vs. M0 no significantly differentially expressed gene signatures were identified. CONCLUSION: Chronic inflammation might enhance local tumor growth. This is the first study identifying immune related gene sets differentially expressed between patients with either liver or peritoneal metastases. The present findings suggest that the formation of liver metastases might be associated with TLR-associated pathways. In M0, a high expression of FOXP3 + tumor infiltrating lymphocytes (TILs) seemed to prevent at least in part metastases. Thus, these correlative findings lay the cornerstone to further studies elucidating the underlying mechanisms of organotropism of metastases.

Patient expectations shape convalescence after major liver surgery - A prospective, randomized study.

BACKGROUND: Several studies suggest an important influence of patient expectations on outcomes. We hypothesized that patient expectations with regard to length of postoperative stay influence convalescence after liver resections. METHOD: This prospective, randomized study compared patients who were preoperatively either informed to be expected to stay 7-10 days (short arm) or 12-16 days (long arm) after major liver resections (≥4 segments). Additionally, psychological traits were assessed using questionnaires and the time to fulfillment of objective discharge criteria [oral analgesics only, first bowel movement, ability to tolerate solid food, full mobilization, no complications which need general anesthesia (>CD IIIa)] was defined as the primary endpoint. RESULTS: Patients in the short arm reached the objective discharge criteria after 8.39 days (SD 3.60), while patients in the long arm needed 12.73 days (SD 3.43) (p = 0.001). The actual length of stay in the short arm was 12.00 (IQR 8-16) and 19.3 days in the long arm (IQR 14-26) (p = 0.008). A more pronounced self-efficacy correlated with earlier fulfillment of the objective discharge criteria (p = 0.048), whereas patients placing a high value on their health needed more time (p = 0.049). CONCLUSION: The expectation of a shorter length of stay results in a quicker objective, physical patient convalescence after major liver resections.