Peritoneal Metastatic Gastric Cancer: Local Treatment Options and Recommendations.

Peritoneal metastasis is a common finding in patients with advanced gastric cancer. Beyond systemic chemotherapy, additive local treatments such as cytoreductive surgery and intraperitoneal chemotherapy are considered an inherent part of different multimodal treatment concepts for selected patients with peritoneal metastatic gastric cancer. This review article discusses the role of cytoreductive surgery (CRS) and intraperitoneal chemotherapy, including HIPEC, NIPS, and PIPAC, as additive therapeutic options with curative and palliative intent.

Radiologic staging of peritoneal and retroperitoneal disease. / Peritoneum und Retroperitoneum: Seltenes aber Wichtiges beim Staging.

Peritoneal and retroperitoneal tumors consist of a heterogenous group of benign and malignant lesions of different origin. Due to often complex multidisciplinary treatment concepts in patients with peritoneal surface malignancies radiological imaging plays a pivotal role regarding the therapeutic options. Moreover, tumor entity, abdominal tumor distribution and common as well as rare differential diagnoses have to be taken into account. Using different radiological modalities non-invasive pretherapeutic diagnostics might be significantly improved. KEY POINTS:: · Diagnostic CT is a valuable part of the initial diagnostic approach to peritoneal surface malignancies.. · Sensitivity might be increased by the additional use of dwMRI and PET/CT considering tumor entity and individual diagnostic issues.. · The Peritoneal Cancer Index (PCI) should be determined independent of radiologic modality.. CITATION FORMAT: · Glockzin G, Helmberger T. Radiologic staging of peritoneal and retroperitoneal disease. Fortschr Röntgenstr 2023; 195: 377 - 384.

Re-operations for early postoperative complications after CRS and HIPEC: indication, timing, procedure, and outcome.

PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have become standard of care for many peritoneal malignancies in selected patients. Nevertheless, this aggressive treatment strategy is associated with significant major morbidity. The aim of the present study is to analyze the re-operation rate and clinical outcome following CRS and HIPEC. PATIENTS AND METHODS: In the present study, prospectively documented data of 474 consecutive patients treated with CRS and HIPEC between February 2011 and December 2015 in a high-volume certified reference center for peritoneal malignancies in Germany have been retrospectively analyzed. RESULTS: The re-operation rate was 14.5%. The most frequent reasons for revisional surgery were fascial dehiscence, intraabdominal hemorrhage, and anastomotic leak. Most complications occurred between postoperative day 7 and 9. However, postoperative bleeding was more common within the first 5 days after surgery. The overall in-hospital mortality rate was 2.1% for all patients and 10% after revisional surgery. CONCLUSIONS: CRS and HIPEC are associated with an acceptable re-operation rate and low mortality rate. Most frequently, re-operations are performed on 7-9 days after initial surgery due to fascial dehiscence, pancreatitis, or anastomotic leak. Postoperative bleedings are more common within the first 5 days after surgery.

Morbidity and Mortality Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Data from the DGAV StuDoQ Registry with 2149 Consecutive Patients.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are performed for well-selected patients with peritoneal surface malignancies. This combined treatment is potentially associated with an increased rate of complications. OBJECTIVE: The aim of this paper was to analyze the morbidity and mortality of CRS and HIPEC in the German national registry. METHODS: We present a retrospective analysis of 2149 consecutive patients from 52 hospitals. The data were prospectively documented in the DGAV StuDoQ Registry between February 2011 and December 2016. RESULTS: Almost two-thirds of all patients had a colorectal malignancy; therefore, the most frequently performed resections were colectomies (54%) and rectal resections (30%). Only 36.2% of all patients had no anastomosis, and fewer than 20% of all patients were older than 70 years of age (16.4%). Enteric fistula and anastomotic leaks occurred in 10.5% of all cases. The reoperation rate was 14.6% (95% confidence interval [CI] 11.51-18.1). Major grade 3 and 4 complications (Clavien-Dindo classification) occurred in 19.3% of all patients, half of which were due to surgical complications. The overall 30-day postoperative hospital mortality was 2.3% (95% CI 1.02-3.85). Multivariate analysis showed an increased risk for morbidity associated with pancreatic resections (odds ratio [OR] 2.4), rectal resection (OR 1.5), or at least one anastomosis (OR 1.35), and mortality with reoperation (OR 8.7) or age > 70 years (OR 3.35). CONCLUSIONS: CRS and HIPEC are associated with acceptable morbidity and low mortality. These results show that CRS and HIPEC can be safely performed nationwide when close mentoring by experienced centers is provided.

Perioperative Systemic Chemotherapy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: Results of the Prospective Multicenter Phase 2 COMBATAC Trial.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as parts of an interdisciplinary treatment concept including systemic chemotherapy can improve survival of selected patients with peritoneal metastatic colorectal cancer (pmCRC). Nevertheless, the sequence of the therapeutic options is still a matter of debate. Thus, the COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial was conducted to evaluate a combined treatment regimen consisting of preoperative systemic polychemotherapy + cetuximab followed by CRS + HIPEC and postoperative systemic polychemotherapy + cetuximab. PATIENTS AND METHODS: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase 2 trial. Twenty-six patients with synchronous or metachronous colorectal or appendiceal peritoneal carcinomatosis were included. Enrollment was terminated prematurely by the sponsor because of slow recruitment. Progression-free survival as primary end point and overall survival were estimated by the Kaplan-Meier method. Also evaluated were morbidity according to Common Terminology Criteria for Adverse Events v4.0 and feasibility of the combined treatment concept. RESULTS: Median progression-free survival for the intention-to-treat population (n = 25) was 14.9 months. Median overall survival was not reached during the study duration. Ninety-two adverse events were documented in 16 patients, including 14 serious adverse events in 9 patients. The overall morbidity rate was 64%, and the grade 3/4 morbidity rate was 44%. Of all grade 3/4 morbidity events, 36.4% were related to systemic chemotherapy and 22.7% to surgery, whereas 40.9% were not directly related. There was no treatment-related mortality. CONCLUSION: The results of the COMBATAC trial show that the multimodal treatment concept consisting of perioperative systemic chemotherapy and CRS + HIPEC is safe and feasible. Progression-free survival in selected patients with colorectal or appendiceal peritoneal metastasis might be improved.

Total Parathyroidectomy With Routine Thymectomy and Autotransplantation Versus Total Parathyroidectomy Alone for Secondary Hyperparathyroidism: Results of a Nonconfirmatory Multicenter Prospective Randomized Controlled Pilot Trial.

OBJECTIVE: This randomized controlled multicenter pilot trial was conducted to find robust estimates for the rates of recurrence of 2 surgical strategies for secondary hyperparathyroidism (SHPT) within 36 months of follow-up. BACKGROUND: SHPT is a frequent consequence of chronic renal failure. Total parathyroidectomy with autotransplantation (TPTX+AT) and subtotal parathyroidectomy (SPTX) are the standard surgical procedures. Total parathyroidectomy alone (TPTX) might be a good alternative, as morbidity and recurrence rates are low according to small-scale retrospective studies. METHODS: The trial was performed as a nonconfirmatory randomized controlled pilot trial with 100 patients on long-term dialysis with otherwise uncontrollable SHPT to generate data on the rate of recurrent disease within a 3-year follow-up period after TPTX or TPTX+AT. Parathyroid hormone (PTH) and calcium levels, recurrent or persistent hyperparathyroidism, parathyroid reoperations, morbidity, and mortality were evaluated during a 3-year follow-up. RESULTS: A total of 52 patients underwent TPTX and 48 TPTX+AT. Patient characteristics, preoperative baseline data, duration of surgery (02:29 vs 02:47 hrs, P = 0.17) and mean hospital stay (10 ± 7.1 vs 8 ± 3.7 days, P = 0.11) did not differ significantly. Persistent SHPT developed in 1 TPTX and 2 TPTX+AT patients. None of the TPTX patients required delayed parathyroid AT to treat permanent hypoparathyroidism. Serum-calcium values were similar (2.1 ± 0.3 vs 2.1 ± 0.2, P = 0.95) whereas PTH rose by time in the TPTX+AT group and was significantly higher at the end of follow-up when compared with the TPTX group (31.7 ± 43.6 vs 98.2 ± 156.8, P = 0.02). Recurrent SHPT developed in 4 TPTX+AT and none of the TPTX patients. CONCLUSIONS: TPTX+AT and TPTX seem to be safe and equally effective for the treatment of otherwise uncontrollable SHPT. TPTX seems to suppress PTH more effectively and showed no recurrences after 3 years. The hypothesis that TPTX is superior to TPTX+AT referring to the rate of recurrent SHPT has to be tested in a large-scale confirmatory trial. Nevertheless, TPTX seems to be a feasible alternative therapeutic option for the surgical treatment of SHPT.

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.

Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor microenvironment inducing senescence and proliferation arrest in cancer cells.

Background : Peritoneal carcinomatosis (PC) is a terminal evolution from primary colorectal cancer (pCRC) associated with poor patient survival. Impact of the immune cell infiltrate on PC pathogenesis is unknown. Therefore, we characterized the immunological tumor microenvironment regarding proliferation, senescence and neovascularization. Methods : Formalin-fixed and paraffin-embedded (FFPE) tissue of PC and pCRC was examined by immunohistochemistry. Cells infiltrating resected tissue were isolated and analyzed by flow cytometry. PCR arrays detected the expression of genes relevant for helper T (TH) cell responses, like TH1, TH2 and TH17 response. Results : PC tumor cells demonstrate significantly lower proliferation rates than pCRC, but show significantly more senescence. PC is surrounded by significantly increased numbers of cytotoxic active Natural Killer (NK) cells, follicular helper T cells (TFH) and B cells, whereas pCRC shows more CD4+ TH cells, CD8+ cytotoxic T (TC) cells, eosinophilic granulocytes, TH17 and regulatory T (Treg) cells. PC is characterized by significantly increased interferon-γ (IFNγ), an upregulation of tumor necrosis factor (TNF) and the NK cell-regulating cytokine interleukin-15 (IL-15). An upregulation of angiogenesis-related genes, like vascular endothelial growth factor-A (VEGF-A), leads to severe neovascularization in PC. Correlations of PC results reveal that elevated numbers of interleukin-17 (IL-17) positive cells are associated with high cancer cell proliferation, whereas high numbers of IFNγ positive cells correlate with more tumor cells in senescence. Conclusion : The cellular immune reaction is modified during metastasis, inducing senescence in PC tumor cells. Immune surveillance in PC is facilitated by NK cells and high levels of IFNγ and TNF. Counteracting this effect, TFH and B cells combined with VEGF-A enhancement promote neovascularization in PC (Illustration 1). During metastasis from primary CRC to PC the immune cell infiltrate changes, accompanied by the induction of senescence in PC cancer cells (marked red): In pCRC, the antitumor immune response is facilitated by CD4+TH cells, CD8+TC cells and PRG2+ eosinophilic granulocytes. The premetastatic niche development is promoted by Treg cells and TH17 cells producing systemic factors like VEGF-A, TGF-ß and TNF. Along with TFH and B cells, as with a pro-tumor immune response, they support metastatic formation and lead to severe neovascularization in PC. This is counterbalanced by the IL-15-induced activation and proliferation of NK cells. The secreted cytokines IFNγ and TNF mediate immunosurveillance.

Long-term results after in-situ split (ISS) liver resection.

PURPOSE: In-situ split (ISS) liver resection is a novel method to induce rapid hypertrophy of the contralateral liver lobe in patients at risk for postoperative liver failure due to insufficient liver remnant. So far, no data about oncological long-term survival after ISS liver resection is available. METHODS: We retrospectively analyzed our patients treated with ISS liver resection at the Department of Surgery of the University of Regensburg, the first center worldwide to perform ISS. RESULTS: Between 2007 and 2014, ISS liver resection was performed in 16 patients. Two patients (12.5 %) were lost in early postoperative phase (90 days) and one was lost to follow-up. Thirteen patients with a follow-up period of more than 3 months were included into oncologically focused analyses. Median follow-up was 26.4 months (range 3.2-54.6). Seven patients had suffered from colorectal liver metastases (CRLM) and six from various other liver malignancies (non-CRLM). The ISS procedure had led to a median increase of 86.3 % of the left lateral liver lobe after a median of 9 days (range 4-28 days). Median disease-free survival (DFS) was 14.6 months and median overall survival (OS) was 41.7 months (26.4 months when including 90-days mortality). Three-year survival was calculated with 56.4 and 48.9 % when including perioperative mortality, respectively (CRLM 64.3 % vs. non-CRLM 50 %). CONCLUSION: ISS liver resection can provide long-term survival of selected patients with advanced liver malignancies that otherwise are not eligible for liver resection due to insufficient liver remnant.

Challenges in the multidisciplinary management of stage IV colon and rectal cancer.

Colorectal metastases still represent a challenge to all oncologists despite progresses achieved by improved resectability, systemic chemotherapy and targeted therapies. In particular in patients with oligo-metastases, the role of surgical resections has been redefined. Resection is the most effective treatment method for liver metastases performed with curative intent; however, primary rate of resectability is low. Several methods to increase resectability have been developed: conversion chemotherapy, portal vein embolization, two-stage resections, vascular reconstruction of the liver veins, combination of resection and intraoperative ablation. Liver resections can be performed at present with low mortality. Patients with isolated peritoneal metastases, no extra-abdominal disease, low volume tumor and complete surgical cytoreduction do benefit from surgery and hyperthermic intraperitoneal chemotherapy. Several national guidelines recommend multimodality treatment for highly selected patients. The management of stage IV colorectal cancer includes several disciplines with focus on resection. A multidisciplinary evaluation of all patients is of crucial importance to define the treatment sequence and individual strategies for each patient.

Oxaliplatin-based versus irinotecan-based hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis from appendiceal and colorectal cancer: a retrospective analysis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide an effective treatment option for selected patients with colorectal peritoneal metastasis with encouraging survival results. Many different drug combinations and HIPEC regimens including bidirectional, i.e. synchronous intravenous and intraperitoneal, drug application have been used. However, there is still no standardization of the HIPEC regimen. METHODS: Between 05/2007 and 04/2010 190 patients underwent CRS and HIPEC at the University Hospital Regensburg. Thirty-two patients with peritoneal metastasis arising from colorectal or appendiceal cancer underwent complete macroscopic cytoreduction (CC-0/1) and bidirectional HIPEC and completed at least 3-year follow-up. Twenty patients received oxaliplatin-based (OX) and twelve patients received irinotecan-based HIPEC (IRI). Group-specific perioperative morbidity and 3-year survival has been determined. RESULTS: The grade 3/4 morbidity rate according to CTCAE v4 was 35.0% in the OX group vs. 33.3% in the IRI group (p = 1.000). There was no perioperative mortality in both groups. Median survival was 26.8 months (95% CI 15.7-33.1 months) in the IRI group and has not yet been reached in the OX group during a median follow-up of 39.4 months. Three-year survival rates were 65.0% in the OX group vs. 41.7% in the IRI group (p = 0.295). CONCLUSIONS: The morbidity and toxicity rates of bidirectional irinotecan-based and oxaliplatin-based HIPEC are comparable. Nevertheless, in the absence of contraindications oxaliplatin-based HIPEC might be preferred due to the positive trend regarding 3-year and median survival.

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.

A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial.

BACKGROUND: Peritoneal carcinomatosis is regarded as a common sign of advanced tumor stage, tumor progression or local recurrence of appendiceal and colorectal cancer and is generally associated with poor prognosis. Although survival of patients with advanced stage CRC has markedly improved over the last 20 years with systemic treatment, comprising combination chemotherapy +/- monoclonal antibodies, the oncological outcome-especially of the subgroup of patients with peritoneal metastases-is still unsatisfactory. In addition to systemic therapy, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are specific treatment options for a selected group of these patients and may provide an additional therapeutic benefit in the framework of an interdisciplinary treatment concept. METHODS/DESIGN: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial investigating perioperative systemic polychemotherapy including cetuximab in combination with CRS and HIPEC patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal carcinomatosis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), perioperative morbidity and treatment-associated toxicity, feasibility of the combined treatment regimen, quality of life (QoL) and histopathological regression after preoperative chemotherapy. DISCUSSION: The COMBATAC trial is designed to evaluate the feasibility and efficacy of the combined multidisciplinary treatment regimen consisting of perioperative systemic combination chemotherapy plus cetuximab and CRS plus bidirectional HIPEC with intraperitoneal oxaliplatin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01540344, EudraCT number: 2009-014040-11.

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.

Current status and future directions in gastric cancer with peritoneal dissemination.

Peritoneal carcinomatosis arising from gastric cancer is mostly associated with poor prognosis. Despite the improvement of survival with modern polychemotherapy, the results are still unsatisfactory. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy might provide an additional therapeutic option for highly selected patients with gastric cancer and peritoneal metastasis leading to improved prognosis. Considering the increased rate of perioperative morbidity and the crucial prognostic role of complete macroscopic cytoreduction, adequate preoperative diagnostics and patient selection are strongly recommended. Further prospective randomized trials are needed to determine the roles of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as part of an interdisciplinary treatment concept.

Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature.

BACKGROUND: More than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis. METHODS/DESIGN: In these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/- irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability. DISCUSSION: The CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients' characteristics in the CHARTA trial. TRIAL REGISTRATION: Clinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435.

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.

Completion thyroidectomy: effect of timing on clinical complications and oncologic outcome in patients with differentiated thyroid cancer.

BACKGROUND: Despite improved preoperative diagnostics, incidental postoperative detection of differentiated thyroid cancer in the final histology is still common. In most of these cases, completion thyroidectomy is recommended by national and international guidelines, although secondary surgery is associated with an increased operative risk. The optimal timing of completion thyroidectomy is still controversial. METHODS: Between January 1993 and December 2009, a total of 128 patients underwent completion thyroidectomy for differentiated thyroid carcinoma: papillary (n = 87) and follicular (n = 41). These patients were divided into five groups according to the time of the completion thyroidectomy after primary surgery (groups A, 1-3 days; B, 4-7 days; C, 1-7 weeks; D, 7-12 weeks; E, >3 months). Clinical complications and oncologic outcomes were analyzed. The mean follow-up was 82.5 ± 17 months. RESULTS: The overall rates of transient and persistent postoperative hypocalcemia were 7.0 and 3.1%, respectively. The rates of persistent hypocalcemia were significantly increased in groups B, C, and D in comparison to those in groups A and E (p < 0.003). The hypocalcemia rates were 7.1, 4.5, and 3.8% versus 0%, respectively. Transient or persistent vocal cord paresis was observed in eight (6.2%) and four patients (3.1%), respectively. The incidence of persistent vocal cord paresis (VCP) was significantly higher in groups B, C, and D than in groups A and E (p < 0.003). The VCP rates were 7.1, 4.5, and 3.8% versus 0%, respectively. There was no significant difference regarding survival or recurrence among the five groups. CONCLUSIONS: Considering perioperative morbidity and oncologic outcomes, completion thyroidectomy should be performed either within 3 days or beyond 3 months after primary surgery.

Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer.

Activation of receptor tyrosine kinases, such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and VEGF receptor (VEGFR), has been implicated in tumor progression and metastasis in human pancreatic cancer. In this study, we investigated the effects of TKI258, a tyrosine kinase inhibitor to FGFR, PDGFR, and VEGFR on pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa2, and L3.6pl), endothelial cells, and vascular smooth muscle cells (VSMC). Results showed that treatment with TKI258 impaired activation of signaling intermediates in pancreatic cancer cells, endothelial cells, and VSMCs, even upon stimulation with FGF-1, FGF-2, VEGF-A, and PDGF-B. Furthermore, blockade of FGFR/PDGFR/VEGFR reduced survivin expression and improved activity of gemcitabine in MiaPaCa2 pancreatic cancer cells. In addition, motility of cancer cells, endothelial cells, and VSMCs was reduced upon treatment with TKI258. In vivo, therapy with TKI258 led to dose-dependent inhibition of subcutaneous (HPAF-II) and orthotopic (L3.6pl) tumor growth. Immunohistochemical analysis revealed effects on tumor cell proliferation [bromodeoxyuridine (BrdUrd)] and tumor vascularization (CD31). Moreover, lymph node metastases were significantly reduced in the orthotopic tumor model when treatment was initiated early with TKI258 (30 mg/kg/d). In established tumors, TKI258 (30 mg/kg/d) led to significant growth delay and improved survival in subcutaneous and orthotopic models, respectively. These data provide evidence that targeting FGFR/PDFGR/VEGFR with TKI258 may be effective in human pancreatic cancer and warrants further clinical evaluation.