Stromal Expression of Heat-Shock Protein 27 Is Associated with Worse Clinical Outcome in Patients with Colorectal Cancer Lung Metastases

Pulmonary metastases are common in patients with primary colorectal cancer (CRC). Heat- shock protein 27 (Hsp27) is upregulated in activated fibroblasts during wound healing and systemically elevated in various diseases. Cancer-associated fibroblasts (CAFs) are also thought to play a role as prognostic and predictive markers in various malignancies includ- ing CRC. Surprisingly, the expression of Hsp27 has never been assessed in CAFs. There- fore we aimed to investigate the expression level of Hsp27 in CAFs and its clinical implications in patients with CRC lung metastases

E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy

Background Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. Methods A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. Results Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2− to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. Conclusion These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.publishedVersio

Systemic effects of anti-angiogenic therapy

Anti-angiogenetische Tumortherapie hat in den letzten Jahren zunehmend an Bedeutung gewonnen. In diesem Zusammenhang wurde bereits 2004 Bevacizumab, ein monoklonaler Antikörper gegen Vascular Endothelial Growth Factor zugelassen. Die Kombination von Chemotherapie und Bevacizumab konnte in einigen Tumorentitäten große Erfolge erzielen, jedoch scheinen einige Patienten nicht von der Therapie zu profitieren. Weiters scheint der Effekt der anti-angiogenetischen Kombinationstherapie nur von limitierter Dauer zu sein. Das übergeordnete Thema dieser Disseration war es, systemische Effekte der Bevacizumab Therapie zu charakterisieren, um eine mögliche Erklärung für diese Diskrepanz zu liefern. Im Konkreten wurde eine Auswahl an Angiogeneseparametern im Rahmen einen klinischen Studie mit Pankreaskarzinompatienten im kurzen Intervall monitiert. Zu diesem Zweck wurde zu Beginn der Dissertation eine optimierte Plasmapräparationsmethode zur Messung von zirkulierenden Angiogenesefaktoren etabliert. Bereits im Rahmen dieser Analysen zeigte sich ein deutlicher Zusammenhang zwischen Thrombozyten und zirkulierenden Angiogeneseparametern. Diese Assoziation konnte im klinischen Setting ebenfalls beobachtet werden. Speziell der anti-angiogenetische Faktor Thrombospondin-1 (TSP-1) korrelierte mit der Thrombozytenzahl der Patienten, die aufgrund der myelosuppressiven Wirkung des Chemotherapeutikums Gemcitabine stark herabgesetzt war. Daraus resultierte die Hypothese, dass die Wahl der kombinierten Chemotherapie die Wirksamkeit von Bevacizumab herabsetzen könnte. In Zusammenschau mit der klinischen Literatur bestätigte sich, dass die Kombination einer anti-angiogenetischen Therapie mit stark myelosuppressiver Chemotherapie und der damit verbundenen Thrombopänie kaum eine Verbesserung des Überlebens der Patienten bringt. Da TSP-1 als essentieller Faktor in der Neovaskularisierung und der Wirksamkeit der anti-angiogenetischen Tumortherapie identifiziert wurde, wurde die Proteinexpression und Prozessierung von TSP-1 im Detail untersucht. Im Rahmen dieses Projektteils konnten wir zeigen, dass Thrombozyten die Hauptquelle für zirkulierendes TSP-1 darstellen. Das intakte Protein wird von Plättchen sezerniert. In Folge kommt es durch den in vivo Angiogeneseprozess zu einer proteolytischen Fragmentierung von TSP-1, die bei einer in vitro Aktivierung von Plättchen nicht zu beobachten ist. Unsere Ergebnisse deuten gesamt darauf hin, dass die anti-angiogenetische Tumortherapie intensiv durch Thrombozyten beeinflusst werden kann und sich daher nicht für eine Kombination mit stark myelosuppressiver Chemotherapie eignet. Prospektive klinische Studien werden jedoch beweisen müssen, ob dieses Wissen zu einer definitiven Therapieverbesserung beitragen kann.Anti-angiogenic cancer therapy has gained importance within the past decades. In this context, bevacizumab, a monoclonal antibody neutralizing vascular endothelial growth factor, has been approved for clinical use. The combination of chemotherapy with bevacizumab has shown a remarkable benefit in several neoplastic entities. However, a notable number of patients do not respond to this therapy. Furthermore, response to therapy seems to be short-lived. The primary topic of this PhD thesis was to characterize systemic effects of anti-angiogenic therapy to possibly identify mechanisms that could explain this heterogeneity in therapy response. To this end, a carefully selected subset of angiogenesis factors were monitored in detail in the course of a clinical study of pancreatic cancer receiving gemcitabine based anti-angiogenic therapy with bevacizumab. To enable the reliable monitoring of angiogenesis parameters, we initially defined an optimized procedure to evaluate angiogenesis factors in blood. During these investigations a remarkable association of circulating angiogenic growth factors with platelet counts and activation was observed. Strikingly, we were able to confirm this association in the clinical setting. In particular, the anti-angiogenic factor thrombospondin-1 (TSP-1) correlated with platelet counts. We further showed that the highly myelosuppressive chemotherapeutic agent gemcitabine resulted in a decrease of platelet counts and circulating TSP-1 levels. As a result, we hypothesized that the choice of chemotherapy might affect the angiogenic balance and counteract the therapeutic effect of bevacizumab. This notion was further supported by a careful evaluation of other studies reporting on the combination of bevacizumab with thrombocytopenic chemotherapies which were generally of minor therapeutic benefit for cancer patients. To further focus on TSP-1 as an essential modulator of neovascularization and anti-angiogenic therapy we investigated TSP-1 protein expression and processing in more detail. In the course of this study, we identified platelets as the major source of circulating TSP-1. While platelets release the full-length molecule, proteolytic fragmentation of TSP-1 occurs during the angiogenic process which we identified as a hallmark of in vivo as compared to in vitro platelet activation. In conclusion our results suggest that platelets which are known to produce and store angiogenesis factors may have a major impact on anti-angiogenic cancer therapy. Hence, for combined application thrombocytopenic chemotherapeutics should be avoided. However, prospective clinical trials will have to prove if this hypothesis will translate into therapeutic benefit.submitted by Patrick StarlingerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersWien, Med. Univ., Diss., 2011(VLID)171370

Shaping the future of liver surgery : Implementation of experimental insights into liver regeneration

Background While liver surgery has become a safe and feasible operation technique, the incidence of postoperative liver dysfunction still remains a central problem. Approximately 10% of patients undergoing liver resection were shown to develop liver dysfunction, which is associated with an increased risk of morbidity and mortality. Yet, to date there is no effective treatment option for postoperative liver dysfunction available. The development of postoperative liver dysfunction was linked to a disruption in the livers potential to regenerate. Thus, it is importance to elucidate the underlying mechanisms of liver regeneration and to find potential therapeutic targets for the treatment of patients with postoperative liver dysfunction. Methods A review of the literature was carried out. Results We report on potential future interventions for improvement of liver regeneration after surgical resection. Moreover, we evaluate the benefits and drawbacks of hepatic progenitor cell therapy and hematopoietic stem cell therapy. However, the most significant improvement seems to come from molecular targets. Indeed, von Willebrand factor and its pharmacologic manipulation are among the most promising therapeutic targets to date. Furthermore, using the example of platelet-based therapy, we stress the potentially adverse effects of treatments for postoperative liver dysfunction. Conclusion The present review reports on the newest advances in the field of regenerative science, but also underlines the need for more research in the field of postoperative liver regeneration, especially in regard to translational studies.(VLID)358381

Early postoperative CRP predicts major complications following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is associated with significant postoperative complications. Early detection of at-risk patients may lead to improved outcomes. The role of C-reactive protein (CRP) in predicting postoperative complications has only been recently investigated