Clinical Use and Therapeutic Potential of IVIG/SCIG, Plasma-Derived IgA or IgM, and Other Alternative Immunoglobulin Preparations

Intravenous and subcutaneous immunoglobulin preparations, consisting of IgG class antibodies, are increasingly used to treat a broad range of pathological conditions, including humoral immune deficiencies, as well as acute and chronic inflammatory or autoimmune disorders. A plethora of Fab- or Fc-mediated immune regulatory mechanisms has been described that might act separately or in concert, depending on pathogenesis or stage of clinical condition. Attempts have been undertaken to improve the efficacy of polyclonal IgG preparations, including the identification of relevant subfractions, mild chemical modification of molecules, or modification of carbohydrate side chains. Furthermore, plasma-derived IgA or IgM preparations may exhibit characteristics that might be exploited therapeutically. The need for improved treatment strategies without increase in plasma demand is a goal and might be achieved by more optimal use of plasma-derived proteins, including the IgA and the IgM fractions. This article provides an overview on the current knowledge and future strategies to improve the efficacy of regular IgG preparations and discusses the potential of human plasma-derived IgA, IgM, and preparations composed of mixtures of IgG, IgA, and IgM

Transforming growth factor β-1 stimulates VEGF gene transcription in human cholangiocellular carcinoma cells

Deckblatt Einleitung Material und Methoden Ergebnisse Diskussion Zusammenfassung Abbildungsverzeichnis Literaturverzeichnis Publikationsverzeichnis Danksagung Eidesstattliche ErklärungDie molekularen Mechanismen der Tumorangiogenese im humanen cholangiozellulären Karzinom (CCC) sind bisher unzureichend verstanden. Die vorgelegte Arbeit beschreibt das CCC als stark vaskularisierten Tumor und identifiziert durch den Nachweis der Koexpression von VEGF, TGFß-1 und den jeweiligen Rezeptoren, diese als mögliche Faktoren für die Induktion der Tumorangiogenese im CCC. Es konnte gezeigt werden, dass TGFß-1 die VEGF Gentranskription in malignen Gallengangszellen auf prätranslationaler Ebenen in Abhängigkeit des Transkriptionsfaktors Sp1 stimuliert. Dieser Mechanismus kann zum angiogenic switch und zur malignen Transformation des CCCs führen. Es wurde erstmalig gezeigt, dass TGFß-1 außer den klassischen TGFß-1 Zielgenen (p15, p21) den proangiogenen Faktor VEGF, Sp1 abhängig, regulieren kann. Des weiteren konnte nachgewiesen werden, dass Antagonisierung von endogenem TGFß-1 durch einen neutralisierenden TGFß-1 Antikörper die VEGF Expression inhibiert. Hierdurch wurde erstmalig eine autokrine und parakrine Regulation der TGFß-1 vermittelten VEGF Expression beschrieben.The expression pattern and functional interaction of proangiogenic factors in human cholangiocellular carcinoma (CCC) have not been fully defined. We therefore investigated the expression of VEGF and TGFß-1 as well as their respective receptors in human CCC tumor samples and further analysed their functional interaction in vitro. Expression of VEGF, TGFß-1 and their receptors was examined by immunohistochemistry, in situ hybridization, quantitative competitive (QC) RT-PCR and ELISA. VEGF promoter analysis and identification of transcription factors involved in promoter regulation was investigated using transient transfection and electrophoretic mobility shift assays. We observed strong expression of VEGF in CCC tumor cells and localisation of VEGF-receptors I and II in endothelial cells; in addition, coexpression of TGFß-1 and its receptors in tumor cells suggests a possible functional interaction between both cytokines. In vitro studies confirmed a paracrine/autocrine stimulation of VEGF by TGFß-1 at a transcriptional level. Further molecular studies using 5´-deletion and mutational analysis of the human VEGF promoter revealed that TGFß-1 stimulates VEGF through Sp1-dependent transcriptional activation. These data suggest that overexpression and functional interaction of TGFß-1 and VEGF might contribute to the angiogenic switch and the malignant phenotype in human CCC

Experience since MELD implementation: How does the new system deliver

Because of increasing waiting-list mortality, the MELD (Model for End-Stage Liver Disease) allocation system was implemented within most countries of the Eurotransplant area on December 16, 2006. Five years have now passed, and we review in this paper the effects of the MELD-based allocation upon the waiting list for liver transplantation, on peri-operative management and on postoperative outcome. Giving priority to sicker patients on the waiting list has resulted in a significant increase in mean MELD score at the time of organ allocation. Consequently, there has also been a significant reduction in waiting-list mortality. However, in Germany a worsening in postoperative outcome, mainly in the group of high-MELD recipients (≥30 points), has been reported. This paper presents comprehensive results following liver transplantation within the MELD era. Especially for the group of highrisk recipients, risk factors for impaired survival are presented and discussed

Single-Incision Laparoscopic Surgery (SILS) Assisted Sigma Resection Via Pfannenstiel Incision for Complicated Diverticulitis

Background: Single-incision laparoscopic surgery (SILS) is frequently used for indications such as appendectomy, cholecystectomy or sigmoid surgery. Usually, an umbilical incision is used as access and for specimen retrieval. However, the umbilical access for SILS is linked with technical limitations in the pelvic area. Here we use a Pfannenstiel incision for SILS sigma or anterior rectum resection for complicated diverticulitis. Methods: An SILS sigma or anterior resection was performed using a Pfannenstiel access to the abdominal cavity. A Gelport (Applied Medical) with three trocars was used. In one patient, an elective resection after initially conservative treatment for a covered perforation was performed, two patients underwent resection due to an abscess and fistula (into the urinary bladder or vagina), and in two patients an early resection was performed due to abdominal abscesses. All patients suffered from sigmoid diverticulitis, which was stage IIb according to Hansen and Stock. Results: The operation time ranged from 89 to 280 min. There were no conversions, and no additional trocars were used. The postoperative hospital stay ranged from 5 to 14 days. All patients were discharged without any intraoperative or postoperative complications. Conclusions: SILS sigma or anterior rectum resection for complicated diverticulitis can be performed via a Pfannenstiel incision. This approach provides direct visualization and access into the pelvis as well as the option to benefit from open surgery devices. The Pfannenstiel incision may generally be recommended for the favorable cosmetic effect and the very low rate of incisional hernias, as reported in the literature. [Arch Clin Exp Surg 2014; 3(1.000): 10-15

Protocol of the PANCALYZE trial: a multicenter, prospective study investigating the tumor biomarkers CXCR4, SMAD4, SOX9 and IFIT3 in patients with resected pancreatic adenocarcinoma to predict the pattern of recurrence of the disease

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies today with an urgent need for novel therapeutic strategies. Biomarker analysis helps to better understand tumor biology and might emerge as a tool to develop personalized therapies. The aim of the study is to investigate four promising biomarkers to predict the clinical course and particularly the pattern of tumor recurrence after surgical resection. Design: Patients undergoing surgery for PDAC can be enrolled into the PANCALYZE trial. Biomarker expression of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. Immunohistochemistry expression pattern of all four biomarkers will be combined into a single score. Beginning with the hospital stay clinical data from enrolled patients will be collected and followed. Different adjuvant chemotherapy protocols will be used to create subgroups. The combined biomarker expression score will be correlated with the further clinical course of the patients to test the hypothesis if CXCR4 positive, SMAD4 negative, SOX9 positive, IFIT3 positive tumors will predominantly develop metastatic spread. Discussion: Pancreatic cancer is associated with different patterns of progression requiring personalized therapeutic strategies. Biomarker expression analysis might be a tool to predict the pattern of tumor recurrence and discriminate patients that develop systemic metastatic disease from those with tumors that rather develop local recurrence over time. This data might lead to personalized adjuvant treatment decisions as patients with tumors that stay localized might benefit from adjuvant local therapies like radiochemotherapy as compared to those with systemic recurrence who would benefit exclusively from chemotherapy. Moreover, the pattern of propagation might be a predefined characteristic of pancreatic cancer determined by the genetic signature of the tumor. In the future, biomarker expression analysis could be performed on tumor biopsies to develop personalized therapeutic pathways right after diagnosis of cancer