Peritoneal carcinomatosis: patients selection, perioperative complications and quality of life related to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

<p>Abstract</p> <p>Background</p> <p>Peritoneal tumor dissemination arising from colorectal cancer, appendiceal cancer, gastric cancer, gynecologic malignancies or peritoneal mesothelioma is a common sign of advanced tumor stage or disease recurrence and mostly associated with poor prognosis.</p> <p>Methods and results</p> <p>In the present review article preoperative workup, surgical technique, postoperative morbidity and mortality rates, oncological outcome and quality of life after CRS and HIPEC are reported regarding the different tumor entities.</p> <p>Conclusion</p> <p>Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising combined treatment strategy for selected patients with peritoneal carcinomatosis that can improve patient survival and quality of life. The extent of intraperitoneal tumor dissemination and the completeness of cytoreduction are the leading predictors of postoperative patient outcome. Thus, consistent preoperative diagnostics and patient selection are crucial to obtain a complete macroscopic cytoreduction (CCR-0/1).</p

Identifizierung und Charakterisierung von potentiellen Interaktionspartnern der Ubiquitin-Protein-Ligase E6-AP

Die menschliche Ubiquitin-Protein-Ligase E6-AP gehört zur Familie der HECT-Ligasen und ubiquitiniert im Komplex mit dem E6-Onkoprotein Krebs-assoziierter humaner Papillomviren (HPV) den Tumorsuppressor p53 und markiert ihn damit für den proteasomalen Abbau. In normalen (HPV-negativen) Zellen ist aber über Substrate und Interaktionspartner von E6-AP nur wenig bekannt. Mutationen im E6-AP-kodierenden Gen UBE3A führen zu einer schweren neurologischen Erbkrankheit, dem Angelman-Syndrom. In dieser Arbeit wurden Interaktionspartner von E6-AP im Yeast Two Hybrid -System identifiziert und nachfolgend charakterisiert. Dabei konnten Hinweise auf das HECT-Domänen Protein HERC2 als physiologisch relevantes Substrat von E6-AP erhalten werden. Weiterhin konnte gezeigt werden, dass das E6-AP-interagierende Protein HHR23A einen Einfluss auf das Ubiquitin- Proteasom-System hat und in vitro über seine Ubiquitin-assoziierte (Uba) Domäne an polyubiquitinierte Proteine bindet und sie vor Deubiquitinierung schützt. Für die Ubiquitinähnlichen (Ubl= ubiquitin like) Domänen von HHR23A und CHAP1 konnten spezifische Wechselwirkungen mit Ubiquitin-interagierenden Motiven (UIMs) verschiedener Proteine demonstriert werden. Somit sind UIMs neben Ubiquitin- auch spezifische Ubl-Domänen- Interaktionsmotive. Schließlich konnte nachgewiesen werden, dass UIMs, zumindest in vitro, Ubiquitinierungssignale darstellen, die transferabel sind und von verschiedenen Ubiquitin- Protein-Ligasen erkannt werden

Therapeutic options for peritoneal metastasis arising from colorectal cancer

Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer (pmCRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standardization of oncologic treatment regimens for pmCRC. The addition of further therapeutic options such as neoadjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investigated to optimize therapeutic regimens and further improve the oncological outcome

Adeno-associated virus-mediated heme oxygenase-1 gene transfer suppresses the progression of micronodular cirrhosis in rats

Aim: To test the hypothesis that enhancement of the activity of heme oxygenase can interfere with processes of fibrogenesis associated with recurrent liver injury, we investigated the therapeutic potential of over-expression of heme oxygense-1 in a CCI 4-induced micronodular cirrhosis model. Methods: Recombinant adeno-associated viruses carrying rat HO-1 or GFP gene were generated. 1×10 12 vg of adeno-associated viruses were administered through portal injection at the time of the induction of liver fibrosis. Results: Conditioning the rat liver with over-expression of HO-1 by rAAV/HO-1 significantly increased the HO enzymatic activities in a stable manner. The development of micronodular cirrhosis was significantly inhibited in rAAV/HO-1-transduced animals as compared to controls. Portal hypertension was markedly diminished in rAAV/ HO-1-transduced animals as compared to controls, whereas there are no significant changes in systolic blood pressure. This finding was accompanied with improved liver biochemistry, less infiltrating macrophages and less activated hepatic stellate cells (HSCs) in rAAV/ HO-1-transduced livers. Conclusions: Enhancement of HO activity in the livers suppresses the development of cirrhosis. © 2006 The WJG Press. All rights reserved.published_or_final_versio

Surgical Approach Including Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients with Peritoneal Metastasis

Background: Peritoneal metastasis arising from colorectal cancer, appendiceal cancer, gastric cancer and gynecologic malignancies, or primary peritoneal surface malignancies such as peritoneal mesothelioma and primary peritoneal adenocarcinoma may be efficiently treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in selected patients. Method: CRS is based on the technique of parietal and visceral peritonectomy and consists of multiple surgical procedures. HIPEC combines high local doses of cytostatics with the additional cytotoxic effects of hyperthermia. Results: The goal of CRS is to achieve a complete macroscopic cytoreduction (CC-0/1) as a precondition for consecutive HIPEC that should destroy residual tumor cells within the abdominal cavity. Conclusion: CRS and HIPEC can be performed with acceptable morbidity and low mortality in specialized centers. However, due to long learning curves, consistent surgical training is strongly recommended

Autofluorescent Imaging in Patients With Peritoneal Carcinomatosis

Background and objectives. Autofluorescence imaging (AFI) is mainly used to detect (pre)cancerous colorectal and pulmonal lesions. This is the first report establishing the feasibility of AFI in patients with peritoneal carcinomatosis (PC). Methods. This is a prospective analysis of 10 patients undergoing conventional white-light laparoscopy (WL) and AFI for PC of different gastrointestinal tumors and 1 ovarian cancer. Before taking biopsies, suspicious peritoneal lesions were first detected by WL and then investigated by AFI. The intraoperative findings were photographed and then correlated with histological results. Results. Conventional WL and AFI evaluation was successful in all patients. A total of 38 biopsies were taken. The neoplasm detection rate under WL was 66% and increased to 86% when using AFI. The positive tumor detection rate was slightly higher in low AF lesions (83 vs 88%) and higher in tumor nodules (94%) than in flat peritoneal lesions (75%). For tumor nodules, the sensitivity was 94%, and the specificity was 100%. For flat lesions, the sensitivity was 75% and specificity 50%. Conclusions. We demonstrate the feasibility and effectiveness of AFI in patients with PC

Post-operative critical care management of patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC)

<p>Abstract</p> <p>Background</p> <p>Cytoreductive surgery (CRS) and Heated Intraperitoneal Chemotherapy (HIPEC) results in a number of physiological changes with effects on the cardiovascular system, oxygen consumption and coagulation. The Critical Care interventions required by this cohort of patients have not yet been quantified.</p> <p>Methods</p> <p>This retrospective audit examines the experience of a Specialist Tertiary Centre in England over an 18 month period (January 2009-June 2010) during which 69 patients underwent CRS and HIPEC. All patients were extubated in the operating theatre and transferred to the Critical Care Unit (CCU) for initial post-operative management.</p> <p>Results</p> <p>Patients needed to remain on the CCU for 2.4 days (0.8-7.8). There were no 30 day mortalities. The majority of patients (70.1%) did not require post-operative organ support. 2 patients who developed pneumonia post-operatively required respiratory support. 18 (26.1%) patients required vasopressor support with norepinephrine with a mean duration of 13.94 hours (5-51 hours) and mean dose of 0.04 mcg/kg/min. Post-operative coagulopathy peaked at 24 hours. A significant drop in serum albumin was observed.</p> <p>Conclusion</p> <p>The degree of organ support required post-operatively is minimal. Early extubation is efficacious with the aid of epidural analgesia. Critical Care monitoring for 48 hours is desirable in view of the post-operative challenges.</p

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate