Expression of pH-Sensitive GPCRs in Peritoneal Carcinomatosis of Colorectal Cancer-First Results.

Solid tumors have an altered metabolism with a so-called inside-out pH gradient (decreased pHe < increased pHi). This also signals back to tumor cells via proton-sensitive ion channels or G protein-coupled receptors (pH-GPCRs) to alter migration and proliferation. Nothing, however, is known about the expression of pH-GPCRs in the rare form of peritoneal carcinomatosis. Paraffin-embedded tissue samples of a series of 10 patients with peritoneal carcinomatosis of colorectal (including appendix) origin were used for immunohistochemistry to study the expression of GPR4, GPR65, GPR68, GPR132, and GPR151. GPR4 was just expressed weakly in 30% of samples and expression was significantly reduced as compared to GPR56, GPR132, and GPR151. Furthermore, GPR68 was only expressed in 60% of tumors and showed significantly reduced expression as compared to GPR65 and GPR151. This is the first study on pH-GPCRs in peritoneal carcinomatosis, which shows lower expression of GPR4 and GPR68 as compared to other pH-GPCRs in this type of cancer. It may give rise to future therapies targeting either the TME or these GPCRs directly.

Safety of rectum anastomosis after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND AND OBJECTIVES: In highly selected patients with peritoneal carcinomatosis, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can be an aggressive but worthwhile treatment regimen. Resection of the rectosigmoid is frequently performed with CRS. The aim of the study was to assess the safety of the rectal anastomosis in this setting. METHODS: Between 2005 and 2016, 436 patients underwent CRS/HIPEC. Clinical data were analyzed with respect to the morbidity associated with a rectum resection. RESULTS: In 436 patients, 174 rectum resections (40%) were performed with CRS, including 149 anterior resections of the rectosigmoid, 23 low anterior rectum resections, and 2 abdominoperineal rectum excisions. A total of 141 rectum anastomoses were performed; 33 patients received a permanent ostomy, and 48 patients received a protective ileostomy. After changing the operation technique of the rectum anastomosis, the number of protective ileostomies decreased from 65% to 20%. The overall postoperative morbidity was 31%. Rectal anastomotic leakages were seen in only 5% of cases. CONCLUSIONS: Anastomotic leakages of the rectum are rarely seen after CRS/HIPEC. HIPEC performed immediately after surgery seems to have no negative effect on the rectum anastomosis. Performing rectum anastomoses after CRS/ HIPEC appears to be a safe procedure.

Laparoscopy as a useful selection tool for patients with prior surgery and peritoneal metastases suitable for multimodality treatment strategies.

BACKGROUND: Complete macroscopic cytoreduction in patients with peritoneal carcinomatosis (PC) is the basic requirement for long-term survival. Diagnostic laparoscopy (DL) can be difficult and of limited clinical value secondary to postoperative or tumor-induced adhesions. The aim of this study was to evaluate the role of DL in patients with prior surgery and PC. METHODS: The database of the surgical department of the University Medical Center of Regensburg was reviewed (9/2010-10/2014) selecting for DL in patients with PC. The operative report had a standardized format allowing for the determination of the extent of the intra-abdominal visible area and the extent of tumor on the surface of the small intestine. For the classification we used our own developed score. RESULTS: DL was performed in 102 patients. The complete abdominal cavity was evaluable in 48%. At least two quadrants and the largest part of the small intestine could be assessed in 70%. 37% of the patients had massive tumor manifestation on the small intestine or its mesentery. PCI (Peritoneal Cancer Index) could not be calculated in 71% of the patients due to incomplete visualization of the abdominal cavity and/or multiple tumor manifestations on the small intestine. 54% of patients were classified as non-resectable and 85% who seemed suitable for cytoreductive surgery underwent a CCR-0 resection and HIPEC. CONCLUSIONS: In spite of prior surgery and PC, DL is frequently possible and a useful tool to define the extent of tumor spread. Lots of patients can be prevented from needless open laparotomy. The extent of tumor involvement of the small intestine seems to be more relevant than calculation of the PCI to determine the potential for complete resection. Therefore, in the presence of adhesions, inspection of the complete abdominal cavity does not offer added clinical benefit and further adhesiolysis can be avoided.

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.

Treatment-related morbidity and toxicity of CRS and oxaliplatin-based HIPEC compared to a mitomycin and doxorubicin-based HIPEC protocol in patients with peritoneal carcinomatosis: a matched-pair analysis.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising therapeutic option for selected patients with peritoneal carcinomatosis. The use of intraperitoneal oxaliplatin seems to further improve the efficacy of the combined treatment concept. Nevertheless, additional toxicity might be expected. PATIENTS AND METHODS: Between 03/2004 and 08/2010 307 patients underwent CRS and HIPEC at the University Medical Center Regensburg. Forty of these patients received oxaliplatin-based HIPEC. A matched-pair analysis was performed to compare IP oxaliplatin to our former standard HIPEC protocol with mitomycin C (MMC) and doxorubicin. RESULTS: The mean operating time in the OX and the MMC group was 315 and 313 min, respectively. Median hospital stay was 15.5 days in the OX group and 17 days in the MMC group. The grade 3/4 morbidity rate according to CTCAEv3.0 was 42.5% versus 37.5% (P = 0.648). Perioperative mortality was 2.5% versus 0%. CONCLUSION: Our data suggest that the use of IP oxaliplatin in the context of CRS and HIPEC does not significantly increase perioperative morbidity and/or mortality rates. Nevertheless, randomized controlled trials are required to determine the optimal intraperitoneal chemotherapeutic regimen regarding toxicity, postoperative complications, and oncological outcome.

Different approaches for complete mobilization of the splenic flexure during laparoscopic rectal cancer resection.

PURPOSE: Laparoscopic resection of rectal cancer has already become the standard procedure in many hospitals. The splenic flexure mobilization (SFM) is an important preparational step. Several methods are used for laparoscopic SFM; however, studies comparing different approaches are lacking. In the present study, three different approaches for SFM have been compared to each other. METHODS: Between January 1998 and December 2010, 415 patients with rectal adenocarcinoma underwent laparoscopic rectal resection at one center. Of these, 303 patients received complete splenic flexure mobilization. The SFM was performed using either a medial (SFM-M; n = 41), lateral (SFM-L; n = 214), or anterior (SFM-A; n = 48) approach. RESULTS: There was a significantly higher rate of intraoperative complications in the SFM-L group as compared to the SFM-M or the SFM-A group (p = 0.038). Postoperative surgical complications occurred in 5 (10.6 %) patients of the SFM-A group compared to 38 patients (17.7 %) in the SFM-L group (p = 0.002) and 5 (12.1 %) patients in the SFM-M group (p = 0.037). SFM-L was also associated with a higher frequency of overall postoperative morbidity which was mainly due to wound infection rates (p = 0.001). CONCLUSIONS: The anterior approach for SFM in laparoscopic surgery seems to be associated with lower frequency of intra- and postoperative morbidity.

Hepatobiliary procedures in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The long-term prognosis of patients with peritoneal malignancies has greatly improved since the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Nevertheless, CRS can be associated with high postoperative morbidity. In this retrospective study, we analyzed the influence of hepatobiliary surgery as part of CRS on postoperative short-term patient outcome. METHODS: Between 2005 and 2008, a total of 63 (25%) of 252 patients with peritoneal surface malignancies undergoing CRS and HIPEC required hepatobiliary surgery. Liver resection was performed in 22, resection of Glisson capsule in 39, and bile duct resection in 2 patients. The mean age of the study population was 49.3 years. Thirty-four patients (54%) were women. RESULTS: Complete macroscopic cytoreduction (CC-0/1) was reached in 59 patients (93.7%). The median hospital stay was 18 days. Twenty-two patients developed minor complications (35%), such as moderate fever, pain, or secondary wound healing. In 21 patients (33%), severe complications occurred, most commonly pancreatitis and abdominal abscess. Three patients (4.8%) developed a biliary leakage. Of these, 2 had to be reoperated. CONCLUSIONS: In our experience, hepatobiliary procedures have to be performed in up to one-third of patients and are associated with a low rate of specific complications, such as biliary leakages.

Retroperitoneoscopic adrenalectomy: lateral versus dorsal approach.

BACKGROUND: For tumours of the adrenal gland different surgical retroperitoneal approaches have been established, including the lateral and the dorsal approach. It is still unclear if the lateral or the dorsal approach should be preferred. PATIENTS AND METHODS: A retrospective comparison between 21 patients who underwent retroperitoneoscopic adrenalectomy in lateral position (LRA) and 24 patients who underwent a retroperitoneoscopic adrenalectomy in dorsal position (DRA). RESULTS: There were no significant differences with regard to the age, sex, tumour localisation, and the size of the tumour. The body-mass-index as well as the operation time was significantly higher of patients who underwent surgery in lateral position. Complications were comparable in both groups. CONCLUSION: The dorsal and the lateral retroperitoneal approach are ideal approaches for patients having had an intraabdominal surgery before. Due to the missing intraabdominal pressure the lateral approach is advantageous for patients with high body-mass-index (>35) and is indicated for patients with a tumour >6 cm due to the small retroperitoneal space.

Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.

Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.