Melanie Langheinrich

Tumor-associated fibroblasts isolated from colorectal cancer tissues exhibit increased ICAM-1 expression and affinity for monocytes.

Progression of colorectal cancer (CRC) is strongly associated with inflammation and other desmoplastic reactions in the tumor cell-surrounding tissue. We successfully isolated fibroblasts from the desmoplastic stroma of human CRC specimens and uninvolved colon tissue of patients treated surgically for CRC and investigated potential functional capacities. All of the isolated fibroblasts were vimentin-positive and CK-20/CD45-negative confirming the fibroblast phenotype. Differential expression patterns were detected between tumor-associated fibroblasts (TAFs) and normal tissue-associated fibroblasts (NAFs) regarding intercellular adhesion molecule-1 (ICAM-1) expression. In 11 of 12 TAF cultures, basal ICAM-1 expression was increased as compared to corresponding NAF cultures (p=0.001). After stimulation of the cultures with interleukin-1β, 8 of the 12 TAF cultures presented higher ICAM-1 levels when compared with the level in the corresponding NAF cultures (p=0.001). Moreover, the adhesive capacity of these cultures for U937 was increased in 8 out of 10 unstimulated and in 10 out of 10 stimulated cultures when TAFs and NAFs were compared. In corresponding tumor tissue sections from the same patients, the amount of ICAM-1-positive fibroblasts was significantly higher than that in the corresponding normal colon mucosa, indicating a tumor-specific effect that was maintained in the isolated cultures. These results indicate that fibroblasts from CRC tissue exhibit an increased affinity for monocytic cells. This increased intercellular interaction may contribute to elongated residence times of monocytes in CRC tissue. Therefore, these isolated fibroblasts are a useful tool for further functional investigation of desmoplastic tissue reactions in CRC.

Therapieergebnisse von Operation und konservativer Therapie enterokutaner Fisteln. Gibt es eine Indikation zur konservativen Behandlung

INTRODUCTION The manifestation of enterocutaneous fistulas is varied. They can range from controlled secretion via the abdominal wall to septic disease. The disease is categorised into low-, moderate- and high-output fistulas. Often the only option is surgical treatment. Occasionally, there is spontaneous healing under conservative treatment. The aim of this study was to work out a possible subgroup of patients who benefit from conservative treatment. Material und Methods: Ninety-nine patients were treated for enterocutaneous fistulas from 1 January 1995 to 31 December 2005. Seventy patients underwent surgery, 29 patients were treated conservatively. All data was collected prospectively using an admission form and was analysed retrospectively. Conservative treatment consisted of fasting with parenteral nutrition, while fistulas in the surgical group were treated by suture repair or resection. Additive treatments such as vacuum dressings or TNF-α medication for patients with Crohns disease were not performed. RESULTS In our study we achieved a total cure rate of 69%, with an average hospital stay of 38 days. Surgical treatment led to significantly better results compared with conservative treatment (83 vs. 34%). Mortality in the surgical group was distinctly, but not significantly reduced at 7%, compared with 14% in the conservative group. The fistulas that healed after conservative treatment were low-output fistulas only. CONCLUSION Enterocutaneous fistulas are diseases associated with long hospital stays and, therefore, expensive treatment. Low-output fistulas may heal spontaneously. The best results are achieved by surgical treatment. More recent treatments such as vacuum therapy and TNF-α medication for patients with Crohns disease are promising approaches. In the future, many of these will have to be combined with surgical treatment.

Long-term outcome of liver transplantation as treatment modality in patients with hepatocellular carcinoma in cirrhosis: a single-center experience.

BACKGROUND Hepatocellular carcinoma (HCC) is among the most frequent malignant diseases worldwide. In the vast majority of cases, it is associated with liver cirrhosis. Liver transplantation (OLT) is potentially the gold standard treatment for patients suffering HCC in cirrhosis, because of synchronous eradication of HCC and of the underlying hepatic disease. The aim of this study was to evaluate long-term outcomes of OLT in HCC patients. MATERIAL AND METHODS Between January 2000 and December 2011, 43 patients who were diagnosed with HCC in liver cirrhosis and underwent OLT in our department, were identified from a prospective database. All patients received their grafts from deceased donors. We analyzed demographic data, laboratory values, number and size of lesions, primary liver disease, diagnostic methods, bridging therapy modalities, and postoperative outcomes, including complications, recurrences, and their treatment. RESULTS Patient follow-up as of January 2012 or to death ranged from 0 to 138 months (median, 59; mean, 63). None of the patients were lost to follow-up. The gender bias was 85%:15% (male:female) and the median age, 57.8 years (range, 44-69). The most common underlying diseases for cirrhosis and HCC were alcoholic (n = 12) and hepatitis C (n = 16). Thirty-one subjects underwent bridging therapy through transarterial chemoembolization (TACE), and/or radiofrequency ablation. All patients underwent OLT within the Milan criteria according to the preoperative evaluation and histopathologic examination of the explanted liver. Twenty-one of them suffered postoperative complications (48.8%). HCC recurrence, which occurred in 5 (10.4%), was treated by surgery (n = 3), systemic chemotherapy with sorafenib (n = 1), or TACE (n = 1). CONCLUSIONS OLT for HCC in cirrhosis, displays a relatively high complication rate. It shows good survivals with and low recurrence.

Das kolorektale Karzinom (KRK) beim jungen Patienten – ist das Alter ein prognostischer Faktor?

INTRODUCTION Concerning younger patients with colorectal carcinoma (CRC) controversies still exist regarding outcome. The aim of this study was to evaluate possible differences between patients suffering from CRC at a younger age (< 40 years) and at an age over 40 years. PATIENTS AND METHODS Data of 51 younger patients (< 40 years) and 2122 older patients (≥ 40 years) were prospectively collected and retrospectively evaluated according to clinical parameters, treatment and prognosis. Patients with a CRC arising from familial adenomatous polyposis, ulcerative colitis or Crohns disease have been excluded. RESULTS The younger patients presented significantly more often with mucinous adenocarcinomas (p = 0.033). There were no differences between the groups concerning gender, localisation, elective and emergency surgery, UICC (Union internationale contre le cancer) stages and residual tumour classification. Postoperative therapy - in adjuvant, therapeutic or palliative intent - was applied significantly more often in younger patients, especially in those with colon carcinoma (p = 0.001). After curative resection of colon carcinoma a significantly better observed (5 year rate 94 vs. 76 %; p = 0.024) and disease-free (88 vs. 69 %; p = 0.013) survival were found. This trend was similar in patients with rectal carcinoma (84 vs. 75 % and 72 vs. 65 %) without reaching the level of significance (p = 0.155 and 0.269). Taking into account differences in life expectancy, just minor differences were detected in relative survival (colon carcinoma, 5 year rate 94 vs. 89 %; rectal carcinoma, 84 % both). CONCLUSIONS The general assumption of a poorer prognosis in younger patients with CRC could not be confirmed. Younger patients have a poorer histological subtype of carcinoma. But this is compensated by the better overall condition, less comorbidities, faster postoperative recovery and an optimally organised post-operative (adjuvant, therapeutic or palliative) therapy. In summary, younger patients have a better observed survival but - considering differences in life expectancy - a similar relative survival.

Isolation of Human Endothelial Cells from Normal Colon and Colorectal Carcinoma - An Improved Protocol

Primary cells isolated from human carcinomas are valuable tools to identify pathogenic mechanisms contributing to disease development and progression. In particular, endothelial cells (EC) constituting the inner surface of vessels, directly participate in oxygen delivery, nutrient supply, and removal of waste products to and from tumors, and are thereby prominently involved in the constitution of the tumor microenvironment (TME). Tumor endothelial cells (TECs) can be used as cellular biosensors of the intratumoral microenvironment established by communication between tumor and stromal cells. TECs also serve as targets of therapy. Accordingly, in culture these cells allow studies on mechanisms of response or resistance to anti-angiogenic treatment. Recently, it was found that TECs isolated from human colorectal carcinoma (CRC) exhibit memory-like effects based on the specific TME they were derived from. Moreover, these TECs actively contribute to the establishment of a specific TME by the secretion of different factors. For example, TECs in a prognostically favorable Th1-TME secrete the anti-angiogenic tumor-suppressive factor secreted protein, acidic and rich in cysteine-like 1 (SPARCL1). SPARCL1 regulates vessel homeostasis and inhibits tumor cell proliferation and migration. Hence, cultures of pure, viable TECs isolated from human solid tumors are a valuable tool for functional studies on the role of the vascular system in tumorigenesis. Here, a new up-to-date protocol for the isolation of primary EC from the normal colon as well as CRC is described. The technique is based on mechanical and enzymatic tissue digestion, immunolabeling, and fluorescence activated cell sorting (FACS)-sorting of triple-positive cells (CD31, VE-cadherin, CD105). With this protocol, viable TEC or normal endothelial cell (NEC) cultures could be isolated from colon tissues with a success rate of 62.12% when subjected to FACS-sorting (41 pure EC cultures from 66 tissue samples). Accordingly, this protocol provides a robust approach to isolate human EC cultures from normal colon and CRC.

Reduced circulating B cells and plasma IgM levels are associated with decreased survival in sepsis - A meta-analysis

Background: B cell function and antibody production are crucial factors in host protection during inflammation. We aimed to synthesize the available evidence on the association between the reduction of circulating B cells and plasma immunoglobulin (IgM) levels and decreased survival during sepsis. Methods: We performed a systematic search in PubMed, Embase, ISI Web of Knowledge, Cochrane Central Register of Controlled Trials, BioMed Central, and Science Direct. We selected studies with data on circulating B cells and plasma IgM levels within the initial 24h after sepsis onset. Results: In total nine studies (n=992 patients) were identified. Circulating B cells were reduced in septic patients as compared to non‐septic patients (mean difference [MD] −88.2cells/&mgr;l; 95% confidence interval [CI] −148.6–−27.9). Sepsis non‐survivors showed a significant reduction of circulating B cells and IgM levels compared to sepsis survivors (MD −77.1cells/&mgr;l; 95% CI −111.4–−42.7 and MD −20.9mg/dl; 95% CI −33.8–−8.0, respectively). Conclusions: Our results suggest that a reduction of circulating B cells and IgM levels at sepsis onset are associated with decreased sepsis survival. However, due to methodological limitations and the risk of bias, we need further prospective studies to confirm this association. Registration: The protocol was registered (PROSPERO 2016:CRD42016053184). HIGHLIGHTSAmounts of circulating B cells are decreased in septic compared to non‐septic patients.Within the first 24 hours of sepsis, sepsis non‐survivors have reduced circulating B cells compared to sepsis survivors.Within the first 24 hours of sepsis, sepsis non‐survivors have reduced plasma IgM levels compared to sepsis survivors.Measuring circulating B cells or plasma IgM levels during sepsis onset as a prognostic factor should be further investigated.