Nuh N. Rahbari

Glypican-1 identifies cancer exosomes and detects early pancreatic cancer

Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1+ circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1+ crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1+ crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1+ crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1+ crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.

Meta‐analysis of standard, restrictive and supplemental fluid administration in colorectal surgery

Optimal fluid therapy for colorectal surgery remains uncertain.

Arterial Resection During Pancreatectomy for Pancreatic Cancer: A Systematic Review and Meta-Analysis

Background:The majority of pancreatic cancers are diagnosed at an advanced stage. As surgical resection remains the only hope for cure, more aggressive surgical approaches have been advocated to increase resection rates. Institutions have begun to release data on their experience with pancreatectomy and simultaneous arterial resection (AR), which has traditionally been considered a general contraindication to resection. The aim of the present meta-analysis was to evaluate the perioperative and long-term outcomes of patients with AR during pancreatectomy for pancreatic cancer. Methods:The Medline, Embase, and Cochrane Library and J-East databases were systematically searched to identify studies reporting outcome of patients who underwent pancreatectomy with AR for pancreatic cancer. Studies that reported perioperative and/or long-term results after pancreatectomy with AR were eligible for inclusion. Meta-analyses included comparative studies providing data on patients with and without AR and were performed using a random effects model. Results:The literature search identified 26 studies including 366 and 2243 patients who underwent pancreatectomy with and without AR. All studies were retrospective cohort studies and the methodological quality was moderate to low. Meta-analyses revealed AR to be associated with a significantly increased risk for perioperative mortality [Odds ratio (OR) = 5.04; 95% confidence interval (CI), 2.69–9.45; P < 0.0001; I2 = 24%], poor survival at 1 year (OR = 0.49; 95% CI, 0.31–0.78; P = 0.002; I2 = 35%) and 3 years (OR = 0.39; 95% CI, 0.17–0.86; P = 0.02; I2 = 49%) compared with patients without AR. The increased perioperative mortality (OR = 8.87; 95% CI, 3.40–23.13; P < 0.0001; I2 = 5%) and lower survival rate at 1 year (OR = 0.50; 95% CI, 0.31–0.82; P = 0.006; I2 = 40%) was confirmed in the comparison to patients undergoing venous resection. Despite substantial perioperative mortality, pancreatectomy with AR was associated with more favorable survival compared with patients who did not undergo resection for locally advanced disease. Conclusions:AR in patients undergoing pancreatectomy for pancreatic cancer is associated with a poor short and long-term outcome. Pancreatectomy with AR may, however, be justified in highly selected patients owing to the potential survival benefit compared with patients without resection. These patients should be treated within the bounds of clinical trials to assess outcomes after AR in the era of modern pancreatic surgery and multimodal therapy.

Meta-analysis Shows That Detection of Circulating Tumor Cells Indicates Poor Prognosis in Patients With Colorectal Cancer

BACKGROUND & AIMS The prognostic significance of circulating (CTCs) and disseminated tumor cells in patients with colorectal cancer (CRC) is controversial. We performed a meta-analysis of available studies to assess whether the detection of tumor cells in the blood and bone marrow (BM) of patients diagnosed with primary CRC can be used as a prognostic factor. METHODS We searched the Medline, Biosis, Science Citation Index, and Embase databases and reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB), mesenteric/portal blood (MPB), or BM of patients with CRC. Meta-analyses were performed using a random effects model, with hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. RESULTS A total of 36 studies, including 3094 patients, were eligible for final analyses. Pooled analyses that combined all sampling sites (PB, MPB, and BM) associated the detection of tumor cells with poor recurrence-free survival (RFS) (HR = 3.24 [95% CI: 2.06-5.10], n = 26, I(2) = 77%) and overall survival (OS) (2.28 [1.55-3.38], n = 21, I(2) = 66%). Stratification by sampling site showed that detection of tumor cells in the PB compartment was a statistically significant prognostic factor (RFS: 3.06 [1.74-5.38], n = 19, I(2) = 78%; OS: 2.70 [1.74-4.20], n = 16, I(2) = 59%) but not in the MPB (RFS: 4.12 [1.01-16.83], n = 8, I(2) = 75%; OS: 4.80 [0.81-28.32], n = 5, I(2) = 82%) or in the BM (RFS: 2.17 [0.94-5.03], n = 4, I(2) = 78%; OS: 1.50 [0.52-4.32], n = 3, I(2) = 84%). CONCLUSION Detection of CTCs in the PB indicates poor prognosis in patients with primary CRC.

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Spontaneous antitumor T cell responses in cancer patients are strongly controlled by Tregs, and increased numbers of tumor-infiltrating Tregs correlate with reduced survival. However, the tumor antigens recognized by Tregs in cancer patients and the impact of these cells on tumor-specific T cell responses have not been systematically characterized. Here we used a broad panel of long synthetic peptides of defined tumor antigens and normal tissue antigens to exploit a newly developed method to identify and compare ex vivo the antigen specificities of Tregs with those of effector/memory T cells in peripheral blood of colorectal cancer patients and healthy subjects. Tregs in tumor patients were highly specific for a distinct set of only a few tumor antigens, suggesting that Tregs exert T cell suppression in an antigen-selective manner. Tumor-specific effector T cells were detectable in the majority of colorectal cancer patients but not in healthy individuals. We detected differences in the repertoires of antigens recognized by Tregs and effector/memory T cells in the majority of colorectal cancer patients. In addition, only effector/memory T cell responses against antigens recognized by Tregs strongly increased after Treg depletion. The selection of antigens according to preexisting T cell responses may improve the efficacy of future immunotherapies for cancer and autoimmune disease.

Natural Killer Cells are Scarce in Colorectal Carcinoma Tissue Despite High Levels of Chemokines and Cytokines

Purpose: Tumor infiltrating T lymphocytes in colorectal cancer (CRC) have prognostic impact, but the role of natural killer (NK) cells in CRC tissue is unclear. The contribution of intratumoral cytokines and chemokines in shaping the composition of the inflammatory lymphocytic infiltrate is also unclear. Experimental Design: In this study, localization and densities of NK and T cells within primary CRC, CRC liver metastases, adenomas, and normal tissues were analyzed on whole tissue sections from 112 patients. In a subset of these patients, the most important 50 cytokines and chemokines were quantified in paired serum, primary CRC and adjacent mucosa samples and in CRC liver metastases and correlated with NK and T-cell infiltration, respectively. Results: The various compartments displayed characteristic differences like significantly higher chemokine concentrations in CRC tissue. Most importantly, despite high local chemokine levels, NK cells were generally scarce within CRC tumor tissues, independent of human leukocyte antigen (HLA) class I expression. Adjacent normal mucosa contained normal levels of NK cells. In contrast, corresponding T-cell numbers varied substantially and were positively correlated with higher chemokine levels. Conclusions: Our findings indicate a distinct regulation of NK cells versus T cells in the CRC tumor microenvironment. NK-cell migration into CRC tumor tissue is obviously impaired early during tumor development by mechanisms that do not affect T-cell infiltration. Clin Cancer Res; 17(4); 678–89. ©2011 AACR.

Systematic review and meta‐analysis of the effect of portal triad clamping on outcome after hepatic resection

The effect of portal triad clamping (PTC) on outcome after hepatic resection is uncertain.

Duodenum-preserving pancreatic head resection versus pancreatoduodenectomy for surgical treatment of chronic pancreatitis: a systematic review and meta-analysis.

Objective:The optimal choice of technique for the surgical treatment of pancreatic head lesions in chronic pancreatitis is still under debate. This systematic review and meta-analysis aims to compare the effectiveness and safety of duodenum-preserving pancreatic head resection (DPPHR) versus pancreatoduodenectomy (PD) by means of parameters of mortality and morbidity and functional outcomes and quality of life. Methods:A systematic literature search (Medline, Embase, Biosis, The Cochrane Library, and Science Citation Index) was performed to identify randomized controlled trials (RCTs) comparing DPPHR and PD. Included literature was assessed and extracted by 2 independent reviewers. A meta-analysis of pain relief (primary end point), several parameters of short- and long-term measures and quality of life, was done using the random effects-model. Results:In total, 1284 citations were checked for eligibility and 4 RCTs were included. The critical appraisal revealed a heterogeneous methodological quality of included trials. Comparing DPPHR versus PD, postoperative pain relief, overall mortality, and morbidity showed no significant difference. Intraoperative blood replacement, hospital stay, weight gain, exocrine insufficiency, occupational rehabilitation, and quality of life were significantly improved in the DPPHR group. Conclusion:DPPHR and PD seem to be equally effective in terms of postoperative pain relief, overall morbidity, and incidence of postoperative endocrine insufficiency. However, the presented findings suggest superiority of DPPHR in the treatment of chronic pancreatitis with regard to several peri and postoperative outcome parameters and quality of life. Further RCTs are eagerly awaited to prove these findings.

Molecular Detection of Tumor Cells in Regional Lymph Nodes Is Associated With Disease Recurrence and Poor Survival in Node-Negative Colorectal Cancer: A Systematic Review and Meta-Analysis

PURPOSE Up to 25% of patients with node-negative colorectal cancer (CRC) on conventional histopathologic analysis ultimately die of recurrent disease. We performed a systematic review with meta-analyses to clarify whether molecular detection of isolated tumor cells or micrometastases in regional lymph nodes indicates high risk of disease recurrence and poor survival in node-negative CRC. METHODS The following databases were searched in August 2011 to identify studies on the prognostic significance of molecular tumor-cell detection in regional lymph nodes of node-negative CRC: MEDLINE, BIOSIS, Science Citation Index, EMBASE, CCMed, and publisher databases. We extracted hazard ratios (HRs) and associated 95% CIs from the identified studies and performed random-effects model meta-analyses on overall survival, disease-specific survival, and disease-free survival. RESULTS A total of 39 studies with a cumulative sample size of 4,087 patients were included. Immunohistochemistry, reverse transcriptase polymerase chain reaction, and both techniques were applied in 30, seven, and two studies, respectively. Thirteen studies were graded with low risk of bias. Meta-analyses revealed that molecular tumor-cell detection in regional lymph nodes was associated with poor overall survival (HR, 2.20; 95% CI, 1.43 to 3.40), disease-specific survival (HR, 3.37; 95% CI, 2.31 to 4.93), and disease-free survival (HR, 2.24; 95% CI, 1.57-3.20). Subgroup analyses showed the prognostic significance of molecular tumor-cell detection of being independent of the applied detection method, molecular target, and number of retrieved lymph nodes. CONCLUSION Molecular detection of occult disease in regional lymph nodes is associated with an increased risk of disease recurrence and poor survival in patients with node-negative CRC.

Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer

The prognosis of colorectal cancer is closely linked to the occurrence of distant metastases. Systemic dissemination is most likely caused by circulating tumor cells (CTC). Despite the fundamental role of CTC within the metastatic cascade, technical obstacles have so far prevented detailed genomic and, in particular, phenotypic analyses of CTC, which may provide molecular targets to delay or prevent distant metastases. We show here a detailed genomic analysis of single colorectal cancer-derived CTC by array comparative genomic hybridization (aCGH), mutational profiling, and microsatellite instability (MSI) analysis. Furthermore, we report the first gene expression analysis of manually selected colorectal cancer-derived CTC by quantitative real-time PCR (qRT-PCR) to investigate transcriptional changes, enabling CTC to survive in circulation and form distant metastases. aCGH confirmed the tumor cell identity of CellSearch-isolated colorectal cancer-derived CTC. Mutational and MSI analyses revealed mutational profiles of CTC to be similar, but not identical to the corresponding tumor tissue. Several CTC exhibited mutations in key genes such as KRAS or TP53 that could not be detected in the tumor. Gene expression analyses revealed both a pronounced upregulation of CD47 as a potential immune-escape mechanism and a significant downregulation of several other pathways, suggesting a dormant state of viable CTC. Our results suggest mutational heterogeneity between tumor tissue and CTC that should be considered in future trials on targeted therapy and monitoring of response. The finding of upregulated immune-escape pathways, which may be responsible for survival of CTC in circulation, could provide a promising target to disrupt the metastatic cascade in colorectal cancer. Cancer Res; 74(6); 1694-704. ©2014 AACR.