Christoph Kettelhack

Fast-Track Surgery – Conditions and Challenges in Postsurgical Treatment: A Review of Elements of Translational Research in Enhanced Recovery after Surgery

Background: Enhanced recovery after surgery (ERAS) or fast-track surgery is a perioperative and postoperative care concept initiated in the early 1990s aiming to reduce the length of hospital stays following elective abdominal surgery. Twenty treatment items defined in the Consensus Guidelines established in 2009 were included in this concept. The success of ERAS depends highly on multidisciplinary teamwork and patient compliance. Several ERAS items and their impact on perioperative and postoperative care have recently been discussed. In this connection, translational research topics triggered increasing interest in ERAS and new impulses aimed at improving the ERAS concept. We thus reviewed the surgical literature to highlight the role of translational research items in ERAS. Methods: A literature search of Medline®, PubMed® and the Cochrane Database was performed. Two investigators independently reviewed the abstracts and appropriate articles were included in this review. Results: Articles have been selected. The advantages of the ERAS concept over conventional postoperative care were established by four meta-analyses and several reviews. But, due to the lack of standardization of the protocols, the level of evidence is still low. The implementation of ERAS into clinical practice is furthermore hampered by the poor compliance with ERAS protocols and remains a challenge for the future. Moreover, recent trials challenge the role of some ERAS items, e.g. epidural anesthesia. Translational research trials investigating stress, immune and inflammatory response after surgery, new analgesic concepts, goal-directed fluid therapy and new drugs and substances to improve the outcome of ERAS provide first promising data but still need to be integrated in the ERAS concept. Conclusion: The Consensus Guidelines for ERAS are subject to the constant evolution of treatment strategies and implementation of translational research findings. Improvement of the compliance with ERAS protocols in surgical clinics and updating of ERAS items taking into account recent findings in translational research may improve the outcomes of ERAS but remain a long-term challenge in surgery for the next years.

Early versus delayed cholecystectomy in patients with biliary acute pancreatitis

BACKGROUND In patients with biliary acute pancreatitis (AP), cholecystectomy is mandatory to prevent further biliary events, but timing of cholecystectomy remains a subject of ongoing debate. The objective of the present, retrospective study was to compare the outcomes of early (within 2 weeks after onset of disease) versus delayed cholecystectomy in patients with biliary AP. METHODS Between January 2000 and December 2005, 112 patients underwent cholecystectomy because of biliary AP. Thirteen patients were excluded from analysis because of necrotizing pancreatitis on the initial computed tomography. Thirty-two were operated within 14 days (group A) and 67 after a longer time period (group B). The primary end point of the study was the rate of biliary complications before cholecystectomy. RESULTS There were no differences regarding conversion rates to open surgery (6% vs 3%; P = .59), local (3% vs 4%; P = 1.00), or systemic complications (0% vs 3%; P = 1.00), and mean postoperative stay (4.7 vs 5.7 days; P = .40). Nevertheless, a greater rate of recurrent biliary pancreatitis was found in the group undergoing cholecystectomy later (0% vs 13%; P < .03). CONCLUSION The timing of cholecystectomy seems to have no clinically relevant effect on local or systemic complications, but delaying cholecystectomy is associated with an increase of biliary complications in patients with non-necrotizing biliary AP.

Major vascular resection and prosthetic replacement for retroperitoneal tumors.

IntroductionInvolvement of major vascular structures has been considered a limiting factor for resecting advanced tumors. The objective of this study was to evaluate the outcome after concomitant retroperitoneal tumor and vascular resection with prosthetic replacement of the aorta/vena cava.MethodsThe authors reviewed a 5-year series of eight patients with a median age of 50 years (range 11–68 years) who had undergone resection of a retroperitoneal tumor and concomitant resection and replacement of the abdominal aorta, inferior vena cava, or both. The histologic diagnoses were sarcoma (five patients), teratoma (one), transitional cell carcinoma (one), and ganglioneuroma (one). The main outcome measures were early (< 30 days) and late (≥ 30 days) surgical morbidity and mortality. Secondary endpoints were vascular graft patency and tumor-free survival. Two patients underwent combined graft replacement of the aorta and vena cava. Single aortic and vena cava graft replacement were each done in three patients.ResultsTwo patients showed early surgical morbidity necessitating reoperation for a thrombotic graft occlusion. No patient died during the early course of the follow-up. During a median follow-up of 14 months (range 1–56 months), two patients had late surgical morbidity. The median tumor-free survival for patients with malignancy was 14 months (range 1–54 months). One patient developed locoregional tumor recurrence, and two developed distant metastases. The median survival for patients with malignancy was 14 months (range 1–60 months).ConclusionsAn aggressive surgical approach for otherwise unresectable retroperitoneal tumors with vascular resection and prosthetic vascular replacement is justified in selected cases and has acceptable morbidity and mortality.

Myxoinflammatory fibroblastic sarcoma: investigations by comparative genomic hybridization of two cases and review of the literature.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma of the distal extremities characterized by a myxohyaline stroma, a dense inflammatory infiltrate and virocyte- and lipoblast-like giant cells. Up to now, only two cases have been investigated cytogenetically, showing complex and heterogeneous karyotypes, in part with supernumerary ring chromosomes. We characterized two further cases of MIFS immunohistochemically and performed comparative genomic hybridization as well as DNA image cytometry analyses. Both tumors showed the characteristic histomorphological pattern of MIFS and were positive for Vimentin and CD68. Moreover, both cases presented aberrant karyotypes including distinct DNA copy number changes involving chromosome 7 and disclosed DNA aneuploidy.

Absence of myeloperoxidase and CD8 positive cells in colorectal cancer infiltrates identifies patients with severe prognosis

Colorectal cancer (CRC) infiltration by cells expressing myeloperoxidase (MPO) or CD8 positive T lymphocytes has been shown to be independently associated with favorable prognosis. We explored the relationship occurring between CD8+ and MPO+ cell CRC infiltration, its impact on clinical-pathological features and its prognostic significance in a tissue microarray (TMA) including 1,162 CRC. We observed that CRC showing high MPO+ cell infiltration are characterized by a prognosis as favorable as that of cancers with high CD8+ T cell infiltration. However, MPO+ and CD8+ CRC infiltrating cells did not synergize in determining a more favorable outcome, as compared with cancers showing MPOhigh/CD8low or MPOlow/CD8high infiltrates. Most importantly, we identified a subgroup of CRC with MPOlow/CD8low tumor infiltration characterized by a particularly severe prognosis. Intriguingly, although MPO+ and CD8+ cells did not co-localize in CRC infiltrates, an increased expression of TIA-1 and granzyme-B was detectable in T cells infiltrating CRC with high MPO+ cell density.

The Acute Physiology and Chronic Health Evaluation II score is helpful in predicting the need of relaparotomies in patients with secondary peritonitis of colorectal origin.

BACKGROUND Secondary peritonitis of colorectal origin has considerable morbidity and mortality. Relaparotomies are frequently necessary in the course of the disease. The objective of this study was to evaluate several scores in terms of their predictive value, i.e. whether Mannheim Peritonitis Index (MPI), Acute Physiology And Chronic Health Evaluation (APACHE) II, or Colorectal Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (CR-POSSUM) scores can predict relaparotomies. METHODS Charts of 147 patients treated for secondary peritonitis of colorectal origin were retrospectively reviewed, MPI, APACHE II, and CR-POSSUM scores were calculated, and groups of patients with or without relaparotomies were compared. RESULTS Thirty-four percent of patients underwent one or more relaparotomies. Patients with relaparotomies showed a significantly higher APACHE II score than patients without relaparotomies (p = 0.004). MPI (p = 0.072) and CR-POSSUM score (p = 0.319) did not differ between the two groups. A high APACHE II score was also significantly associated with the need for a relaparotomy on demand (p <0.001), and for the combined outcome parameter relaparotomy and/or an interventional drainage (p = 0.046). Both other scores were not predictive for these outcomes. Overall in-hospital mortality was 21.8%. All three scores investigated were predictive for mortality. Sensitivity was 62.5%, 78.1%, and 75.0% for MPI, APACHE II score, and CR-POSSUM score, respectively. CONCLUSION The Acute Physiology And Chronic Health Evaluation II score might be helpful in predicting the need for relaparotomies in patients with secondary peritonitis of colorectal origin.

OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer

Background OX40 is a TNF receptor family member expressed by activated T cells. Its triggering by OX40 ligand promotes lymphocyte survival and memory generation. Anti-OX40 agonistic monoclonal antibodies (mAb) are currently being tested in cancer immunotherapy. We explored the prognostic significance of tumor infiltration by OX40+ cells in a large colorectal cancer (CRC) collective. Methods OX40 gene expression was analyzed in 50 freshly excised CRC and corresponding healthy mucosa by qRT-PCR. A tissue microarray including 657 clinically annotated CRC specimens was stained with anti-OX40, -CD8 and -FOXP3 mAbs by standard immunohistochemistry. The CRC cohort was randomly split into training and validation sets. Correlations between CRC infiltration by OX40+ cells alone, or in combination with CD8+ or FOXP3+ cells, and clinical-pathological data and overall survival were comparatively evaluated. Results OX40 gene expression in CRC significantly correlated with FOXP3 and CD8 gene expression. High CRC infiltration by OX40+ cells was significantly associated with favorable prognosis in training and validation sets in univariate, but not multivariate, Cox regression analysis. CRC with OX40high/CD8high infiltration were characterized by significantly prolonged overall survival, as compared to tumors with OX40low/CD8high, OX40high/CD8low or OX40low/CD8low infiltration in both uni- and multivariate analysis. In contrast, prognostic significance of OX40+ and FOXP3+ cell infiltration was not enhanced by a combined evaluation. Irrespective of TNM stage, CRC with OX40high/CD8high density infiltrates showed an overall survival similar to that of all stage I CRC included in the study. Conclusions OX40high/CD8high density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers.

Surgical treatment of uncomplicated diverticulitis in Switzerland: comparison of population‐based data over two time periods

The standard of care for acute uncomplicated diverticulitis used to be an elective colon resection after the second or third episode. This practice was replaced by a more conservative and individualized approach. This study investigates current surgical practice in the treatment of acute uncomplicated diverticulitis in Switzerland.

Abstract 328: Original microenvironment of different cancer types is maintained upon culture of primary tissues in perfused bioreactors

The development of novel three-dimensional (3D) culture systems allowing the survival/expansion of primary tumors in vitro may help to bridge the gap between conventional bi-dimensional (2D) cultures and animal models, poorly predictive of therapeutic responses. We have investigated the suitability of a previously developed perfused bioreactor system for the in vitro culture of human primary tumor tissues. Surgical specimens of colorectal cancer (CRC, n = 15), glioblastoma (n = 3), breast cancer (n = 3), sarcoma (n = 2), and melanoma (n = 1) were used. Tumor fragments, obtained upon mechanical mincing and enzymatic digestion, were cultured on collagen scaffolds, in medium supplemented with human serum, under alternate perfusion up to 20 days. Characterization of expanded tissues was performed by histo-morphological analysis, immunofluorescence and gene expression profiling. CRC tissues were effectively expanded in perfused 3D cultures in 10 out of 15 cases, whereas no expansion was observed under static culture conditions. Gene profiles of expanded tumor tissues suggested a heterogeneous tissue composition, as indicated by the expression of EpCAM, CD90, CD8, CD16 and Foxp3 genes. Phenotypic analysis confirmed that expanded tissues included epithelial and stromal cells, as assessed by EpCAM and vimentin staining, respectively. Evidence of tumor cell proliferation was provided by Ki67 staining. Furthermore, infiltrating CD4+ and CD8+ lymphocytes were consistently identified within cultured tumor fragments. The established protocol could easily be adapted to other tumor types, including breast-cancer, glioblastoma, sarcoma and melanoma, with highly effective tissue formation. Taken together, our results indicate that culture of primary tumor fragments within perfused bioreactors can be successfully achieved over a short-time period in a reproducible manner, and results in the expansion of epithelial and interstitial cells. These ex-vivo generated tissues might mirror features of the original tumor more effectively than 2D or 3D static cultures, and of patient-derived xenografts, thus possibly representing useful tools for the evaluation of sensitivity to chemotherapies or new targeted treatments. Citation Format: Christian Hirt, Manuele G. Muraro, Valentina Mele, Francesca Amicarella, Celeste Manfredonia, Savas D. Soysal, Simone Muenst, Luigi Mariani, Christoph Kettelhack, Michael Heberer, Giulio C. Spagnoli, Ivan Martin, Giandomenica Iezzi, Adam Papadimitropoulos. Original microenvironment of different cancer types is maintained upon culture of primary tissues in perfused bioreactors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 328. doi:10.1158/1538-7445.AM2015-328

A large fibroma of the round ligament of the liver.

Fig 1. CT scan. AC, Ascending colon; DC, descending colon; DD, duodenum; IVC, inferior vena cava; LK, left kidney; RK, right kidney; TM, tumor. CASE REPORT A 46-YEAR-OLD FEMALE presented initially with severe back pain and left-sided radicular symptoms. A magnetic resonance image of the spine was performed because of a suspected discal hernia at level L5/S1. It showed the incidental finding of a large tumor of 12 3 6.5 3 11 cm suspected to originate from the retroperitoneum on the right side. A staging computed tomography 2 days later showed no evidence of local or distant metastases but revealed suspected contact of the tumor with the duodenum, the ascending colon, and the inferior vena cava (Fig 1). Laboratory results were unremarkable. Family history was negative for malignancies. Personal history revealed solely a series of suspected abdominal traumata during childhood and adolescence due to intensive gymnastics on a professional level. A core needle biopsy was performed, and it showed scar tissue without evidence of malignancy. Intraoperatively, the tumor was found to originate from the round hepatic ligament (Fig 2). The tumor had no contact with the ascending colon or the inferior vena cava. Part of the midline, including the tumor and the round hepatic ligament, was resected. The patient was discharged on postoperative day 5. The tumor had a diameter of 13.5 cm. Its profile showed white, soft fibrous tissue, which was encapsulated.Onmicroscopic examination, the lesionwas well circumscribed without infiltrative borders and was paucicellular, composed of bland spindled cells embedded in a dense collagenous background.