Search

Background: Preoperative low skeletal muscle mass and density are associated with increased postoperative morbidity in patients undergoing curative colorectal cancer (CRC) surgery. However, the long-term effects of low skeletal muscle mass and density remain uncertain., Methods: Patients with stage I-III CRC undergoing surgery, enrolled in a prospective observational cohort study, were included. Skeletal muscle mass and density were measured on CT. Patients with high and low skeletal muscle mass and density were compared regarding postoperative complications, disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS)., Results: In total, 816 patients (53.9% males, median age 70) were included; 50.4% had low skeletal muscle mass and 64.1% low density. The severe postoperative complication rate was significantly higher in patients with low versus high skeletal muscle and density (20.9% versus 13.6%, p = 0.006; 20.0% versus 11.8%, p = 0.003). Low skeletal muscle mass (OR 1.91, p = 0.018) and density (OR 1.87, p = 0.045) were independently associated with severe postoperative complications. Ninety-day mortality was higher in patients with low skeletal muscle mass and density compared with patients with high skeletal muscle mass and density (3.6% versus 1.7%, p = 0.091; 3.4% versus 1.0%, p = 0.038). No differences in DFS were observed. After adjustment for covariates such as age and comorbidity, univariate differences in OS and CSS diminished., Conclusions: Low skeletal muscle mass and density are associated with short-term, but not long-term, outcome in patients undergoing CRC surgery. These findings recommend putting more emphasis on preoperative management of patients at risk for surgical complications, but do not support benefit for long-term outcome., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Current normalization methods for RNA-sequencing data allow either for intersample comparison to identify differentially expressed (DE) genes or for intrasample comparison for the discovery and validation of gene signatures. Most studies on optimization of normalization methods typically use simulated data to validate methodologies. We describe a new method, GeTMM, which allows for both inter- and intrasample analyses with the same normalized data set. We used actual (i.e. not simulated) RNA-seq data from 263 colon cancers (no biological replicates) and used the same read count data to compare GeTMM with the most commonly used normalization methods (i.e. TMM (used by edgeR), RLE (used by DESeq2) and TPM) with respect to distributions, effect of RNA quality, subtype-classification, recurrence score, recall of DE genes and correlation to RT-qPCR data., Results: We observed a clear benefit for GeTMM and TPM with regard to intrasample comparison while GeTMM performed similar to TMM and RLE normalized data in intersample comparisons. Regarding DE genes, recall was found comparable among the normalization methods, while GeTMM showed the lowest number of false-positive DE genes. Remarkably, we observed limited detrimental effects in samples with low RNA quality., Conclusions: We show that GeTMM outperforms established methods with regard to intrasample comparison while performing equivalent with regard to intersample normalization using the same normalized data. These combined properties enhance the general usefulness of RNA-seq but also the comparability to the many array-based gene expression data in the public domain.

The identification of patients with high-risk stage II colon cancer who may benefit from adjuvant therapy may allow the clinical approach to be tailored for these patients based on an understanding of tumour biology. MicroRNAs have been proposed as markers of the prognosis or treatment response in colorectal cancer. Recently, a 2-microRNA signature (let-7i and miR-10b) was proposed to identify colorectal cancer patients at risk of developing distant metastasis. We assessed the prognostic value of this signature and additional candidate microRNAs in an independent, clinically well-defined, prospectively collected cohort of primary colon cancer patients including stage I-II colon cancer without and stage III colon cancer with adjuvant treatment. The 2-microRNA signature specifically predicted hepatic recurrence in the stage I-II group, but not the overall ability to develop distant metastasis. The addition of miR-30b to the 2-microRNA signature allowed the prediction of both distant metastasis and hepatic recurrence in patients with stage I-II colon cancer who did not receive adjuvant chemotherapy. Available gene expression data allowed us to associate miR-30b expression with axon guidance and let-7i expression with cell adhesion, migration, and motility.

Background/aims: The 5-year postoperative follow-up for patients undergoing curative treatment for colorectal cancer (CRC) is labour intensive. We assessed the added value of a dedicated nonphysician clinician (NPC) in the follow-up of patients after resection for CRC., Methods: Patients were divided into 2 groups as defined by the number of follow-up visits in the first year, including intensive (≥3×) and minimal (≤2×). Involvement of an NPC, diagnosis of disease recurrence and the course of the disease were determined., Results: Of the 681 patients, 79.9% belonged to the "intensive" and 21.1% to the "minimal" group. Involvement of an NPC resulted in a higher adherence to follow-up (84.3 vs. 73.9%, p = 0.001). Overall, patients in regular follow-up less often had multifocal recurrence (47.1 vs. 73.7%, p = 0.04), and a better survival after recurrence (SAR; hazard ratio [HR] 3.604, p < 0.001). The "intensive" group had a significantly better overall survival compared to the "minimal" group (HR 1.71, p = 0.013)., Conclusion: Adherence to surveillance programs after resection for CRC is better in hospitals with a dedicated NPC. Overall, patients' adherence to follow-up resulted in less multifocal disease recurrence at the time of diagnosis as compared to patients presenting with symptoms and a better 3-year SAR., (© 2017 S. Karger AG, Basel.)

Objective: Overall and splice specific expression of Spleen Tyrosine Kinase (SYK) has been posed as a marker predicting both poor and favorable outcome in various epithelial malignancies. However, its role in colorectal cancer is largely unknown. The aim of this study was to explore the prognostic role of SYK in three cohorts of colon cancer patients., Methods: Total messenger RNA (mRNA) expression of SYK, SYK(T), and mRNA expression of its two splice variants SYK short (S) and SYK long (L) were measured using quantitative reverse transcriptase (RT-qPCR) in 240 primary colon cancer patients (n = 160 patients with chemonaive lymph node negative [LNN] and n = 80 patients with adjuvant treated lymph node positive [LNP] colon cancer) and related to microsatellite instability (MSI), known colorectal cancer mutations, and disease-free (DFS), hepatic metastasis-free (HFS) and overall survival (OS). Two independent cohorts of patients with respectively 48 and 118 chemonaive LNN colon cancer were used for validation., Results: Expression of SYK and its splice variants was significantly lower in tumors with MSI, and in KRAS wild type, BRAF mutant and PTEN mutant tumors. In a multivariate Cox regression analysis, as a continuous variable, increasing SYK(S) mRNA expression was associated with worse HFS (Hazard Ratio[HR] = 1.83; 95% Confidence Interval[CI] = 1.08-3.12; p = 0.026) in the LNN group, indicating a prognostic role for SYK(S) mRNA in patients with chemonaive LNN colon cancer. However, only a non-significant trend between SYK(S) and HFS in one of the two validation cohorts was observed (HR = 4.68; 95%CI = 0.75-29.15; p = 0.098)., Conclusion: In our cohort, we discovered SYK(S) as a significant prognostic marker for HFS for patients with untreated LNN colon cancer. This association could however not be confirmed in two independent smaller cohorts, suggesting that further extensive validation is needed to confirm the prognostic value of SYK(S) expression in chemonaive LNN colon cancer.

The growing interest in the molecular subclassification of colorectal cancers is increasingly facilitated by large multicenter biobanking initiatives. The quality of tissue sampling is pivotal for successful translational research. This study shows the quality of fresh frozen tissue sampling within a multicenter cohort study for colorectal cancer (CRC) patients. Each of the seven participating hospitals randomly contributed ten tissue samples, which were collected following Standard Operating Procedures (SOP) using established techniques. To indicate if the amount of intact RNA is sufficient for molecular discovery research and prove SOP compliance, the RNA integrity number (RIN) was determined. Samples with a RIN < 6 were measured a second time and when consistently low a third time. The highest RIN was used for further analysis. 91% of the tissue samples had a RIN ≥ 6 (91%). The remaining six samples had a RIN between 5 and 6 (4.5%) or lower than 5 (4.5%). The median overall RIN was 7.3 (range 2.9-9.0). The median RIN of samples in the university hospital homing the biobank was 7.7 and the median RIN for the teaching hospitals was 7.3, ranging from 6.5 to 7.8. No differences were found in the outcome of different hospitals (p = 0.39). This study shows that the collection of high quality fresh frozen samples of colorectal cancers is feasible in a multicenter design with complete SOP adherence. Thus, using basic sampling techniques large patient cohorts can be organized for predictive and prognostic (bio)marker research for CRC.

Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3 , and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X-ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node-negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy. Cancer Res; 77(14); 3814-22. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Introduction: The completeness of the pathological examination of resected colon cancer specimens is important for further clinical management. We reviewed the pathological reports of 356 patients regarding the five factors (pT-stage, tumor differentiation grade, lymphovascular invasion, tumor perforation and lymph node metastasis status) that are used to identify high-risk stage II colon cancers, as well as their impact on overall survival (OS)., Methods: All patients with stage II colon cancer who were included in the first five years of the MATCH study (1 July 2007 to 1 July 2012) were selected (n = 356). The hazard ratios of relevant risk factors were calculated using Cox Proportional Hazards analyses., Results: In as many as 69.1% of the pathology reports, the desired information on one or more risk factors was considered incomplete. In multivariable analysis, age (HR: 1.07, 95%CI 1.04-1.10, p < .001), moderately- (HR: 0.35, 95%CI 0.18-0.70, p = .003) and well (HR 0.11, 95%CI 0.01-0.89, p = .038) differentiated tumors were significantly associated with OS., Conclusions: Pathology reports should better describe the five high-risk factors, in order to enable proper patient selection for further treatment. Chemotherapy may be offered to stage II patients only in select instances, yet a definitive indication is still unavailable.

The clinical efficacy of carcinoembryonic antigen (CEA) as a marker of colorectal liver metastasis is limited, motivating a search for new biomarkers. Recently, urine proteomic analysis revealed AGPP(-OH)GEAGKP(-OH)GEQGVP(-OH)GDLGAP(-OH)GP (AGP), a promising peptide for this application. This study aimed to determine whether combining urine AGP testing with serum CEA analyses improves the sensitivity of detecting colorectal liver metastases. Urine samples from 100 patients with CRLM were collected prospectively and compared to three control groups: healthy kidney donors, patients who were relapse-free for 24 months after curative CRLM surgery, and primary colorectal cancer patients. A stable isotope labeled peptide standard was used to quantify the abundance of AGP in urine samples by selective reaction monitoring. Combined testing of urine AGP levels and serum CEA levels revealed a significantly increased sensitivity compared to CEA alone (85% vs. 68%, P<0.001; specificity 84% and 91%, respectively). No correlation was found between CEA and AGP-positive test results within individual patients (r(2) = 0.08). Urine AGP testing was negative in the three control groups. These results indicate that collagen-derived urine AGP peptide with a specific hydroxylation pattern combined with serum CEA levels may significantly improve the detection of colorectal liver metastases in patients at risk.

Background: Despite good outcomes for many, a substantial group of patients undergoing metastasectomy for isolated liver metastases from colorectal cancer (CRC) experience early recurrence. We have investigated whether circulating tumour cell (CTC) detection can identify patients developing disease recurrence within 1 year after liver metastasectomy., Methods: In CRC patients undergoing liver metastasectomy, 30 ml peripheral blood was withdrawn preoperatively. CTCs were detected by the CellSearch system after a density-gradient-based enrichment step., Results: One hundred and seventy-three samples from 151 individual patients were analysed. In 75 samples (43%), CTCs were detected, 16% had ⩾3 CTCs/7.5 ml of blood. Eighty-two patients (47%) experienced early disease recurrence (<1 year). The 1-year recurrence rate between patients with or without detectable CTCs were similar (47% vs 48%) or with a low or high CTC count (<3 or ⩾3 CTCs/7.5 ml of blood) (50% vs 47%). Also disease-free and overall survival were similar between patients with or without CTCs., Conclusions: The presence of CTCs in preoperative peripheral blood samples does not identify patients at risk for early disease recurrence after curative resection of colorectal liver metastases. Other parameters are needed to better identify patients at high risk to relapse after liver metastasectomy for CRC.

Introduction: For both patients and the outpatient clinic the frequent follow-up visits after a resection of colorectal cancer (CRC) are time consuming and due to large patient numbers expensive. Therefore it is important to develop an effective non-invasive test for the detection of colorectal liver metastasis (CRLM) which could be used outside the hospital. The urine proteome is known to provide detailed information for monitoring changes in the physiology of humans. Urine collection is non-invasive and urine naturally occurring peptides (NOPs) have the advantage of being easily accessible without labour-intensive sample preparation. These advantages make it potentially useful for a quick and reliable application in clinical settings. In this study, we will focus on the identification and validation of urine NOPs to discriminate patients with CRLM from healthy controls., Materials and Methods: Urine samples were collected from 24 patients with CRLM and 25 healthy controls. In the first part of the study, samples were measured with a nano liquid chromatography (LC) system (Thermo Fisher Scientific, Germaring, Germany) coupled on-line to a hybrid linear ion trap/Orbitrap mass spectrometer (LTQ-Orbitrap-XL, Thermo Fisher Scientific, Bremen, Germany). A discovery set was used to construct the model and consecutively the validation set, being independent from the discovery set, to check the acquired model. From the peptides which were selected, multiple reaction monitoring (MRM's) were developed on a UPLC-MS/MS system., Results: Seven peptides were selected and applied in a discriminant analysis a sensitivity of 84.6% and a specificity of 92.3% were established (Canonical correlation:0.797, Eigenvalue:1.744, F:4.49, p:0.005). The peptides AGPP(-OH)GEAGKP(-OH)GEQGVP(-OH)GDLGA P(-OH)GP and KGNSGEP(-OH)GAPGSKGDTGAKGEP(-OH)GPVG were selected for further quantitative analysis which showed a sensitivity of 88% and a specificity of 88%., Conclusion: Urine proteomic analysis revealed two very promising peptides, both part from collagen type 1, AGPP(-OH)GEAGKP(-OH)GEQGVP(-OH)GDLGAP(-OH)GP and KGNSGEP(-OH)GAPGSKGDTGAKGEP(-OH)GPVG which could detect CRLM in a non-invasive manner.

Background: Data from patients with colorectal liver metastases (CRLM) who received neoadjuvant chemotherapy before resection were reviewed and evaluated to see whether neoadjuvant chemotherapy influences the predictive outcome of R1 resections (margin is 0 mm) in patients with CRLM., Methods: Between January 2000 and December 2008, all consecutive patients undergoing liver resection for CRLM were analyzed. Patients were divided into those who did and did not receive neoadjuvant chemotherapy. The outcome after R0 (tumor-free margin >0 mm) and R1 (tumor-free margin 0 mm) resection was compared., Results: A total of 264 were eligible for analysis. Median follow-up was 34 months. Patients without chemotherapy showed a significant difference in median disease-free survival (DFS) after R0 or R1 resection: 17 [95% confidence interval (CI) 10-24] months versus 8 (95% CI 4-12) months (P < 0.001), whereas in patients with neoadjuvant chemotherapy the difference in DFS between R0 and R1 resection was not significant: 18 (95% CI 10-26) months versus 9 (95% CI 0-20) months (P = 0.303). Patients without chemotherapy showed a significant difference in median overall survival (OS) after R0 or R1 resection: 53 (95% CI 40-66) months versus 30 (95% CI 13-47) months (P < 0.001). In patients with neoadjuvant chemotherapy, the median OS showed no significant difference: 65 (95% CI 39-92) months for the R0 group versus the R1 group, in whom the median OS was not reached (P = 0.645)., Conclusions: In patients treated with neoadjuvant chemotherapy, R1 resection was of no predictive value for DFS and OS.

Background: Several clinical risk scores (CRSs) for the outcome of patients with colorectal liver metastases have been validated, but not in patients undergoing neoadjuvant chemotherapy. Therefore, this study evaluates the predictive value of these CRSs in this specific group., Methods: Between January 2000 and December 2008, all patients undergoing a metastasectomy were analyzed and divided into two groups: 193 patients did not receive neoadjuvant chemotherapy (group A), and 159 patients received neoadjuvant chemotherapy (group B). In group B, the CRSs were calculated before and after administration of neoadjuvant chemotherapy. Results were evaluated by using the CRSs proposed by Nordlinger et al., Fong et al., Nagashima et al., and Konopke et al., Results: In groups A and B, the overall median survival was 43 and 47 months, respectively (P = 0.648). In group A, all CRSs used were of statistically significant predictive value. Before administration of neoadjuvant chemotherapy, only the Nordlinger score was of predictive value. After administration of neoadjuvant chemotherapy, all CRSs were of predictive value again, except for the Konopke score., Conclusions: Traditional CRSs are not a reliable prognostic tool when used in patients before treatment with neoadjuvant chemotherapy. However, CRSs assessed after the administration of neoadjuvant chemotherapy are useful to predict prognosis.

Background: The increased use of neoadjuvant chemotherapy and minimally invasive therapies for recurrence in patients with colorectal liver metastases (CLM) makes a surgical strategy to save as much liver volume as possible pivotal. In this study, we determined the difference in morbidity and mortality and the patterns of recurrence and survival in patients with CLM treated with anatomical (AR) and nonanatomical liver resection (NAR)., Methods: From January 2000 to June 2008, patients with CLM who underwent a resection were included and divided into two groups: patients who underwent AR, and patients who underwent NAR. Patients who underwent simultaneous radiofrequency ablation in addition to surgery and patients with extrahepatic metastasis were excluded. Patient, tumor, and treatment data, as well as disease-free and overall survival (OS) were compared., Results: Eighty-eight patients (44%) received AR and 113 patients (56%) underwent NAR. NAR were performed for significant smaller metastases (3 vs. 4 cm, P < 0.001). The Clinical Risk Score did not differ between the groups. After NAR, patients received significantly less blood transfusions (20% vs. 36%, P = 0.012), and the hospital stay was significantly shorter (7 vs. 8 days, P < 0.001). There were no significant differences in complications, positive resection margins, or recurrence. For the total study group, estimated 5-year disease-free and OS was 31 and 44%, respectively, with no difference between the groups., Conclusions: Our study resulted in no significant difference in morbidity, mortality, recurrence rate, or survival according to resection type. NAR can be used as a save procedure to preserve liver parenchyma.

Aim: Approximately 25% of the patients with colorectal cancer already have liver metastases at diagnosis and another 30% will develop them subsequently. The features and prognosis of patients with synchronous and metachronus colorectal liver metastases, treated with primary resection first followed by partial liver resection were analysed., Method: Curative staged resection of liver metastases was performed in 272 consecutive patients. Demographics, characteristics of the primary tumour and metastatic tumours, surgery-related data and outcome were analysed., Results: Synchronous metastases were present in 105 (39%) patients and metachronous metastases in 167 (61%). More patients in the synchronous group had an advanced primary tumour (T3/T4 and/or node positivity), more than three liver metastases and bilobar distribution. A significantly higher percentage of patients in the synchronous group received neoadjuvant chemotherapy. The 5-year survival rate in the group of 272 patients was 38%. Patients with more than three metastases had a significantly worse survival rate. There were no differences in disease-free and overall survival rates between the synchronous and metachronous group., Conclusion: Although patients with synchronous colorectal liver metastases may have poorer biological features, there was no difference in 5-year disease-free and overall survival compared with patients with metachronous metastases. This may be explained by the observation that patients in the synchronous group received significantly more neoadjuvant chemotherapy., (© 2010 The Authors. Colorectal Disease © 2010 The Association of Coloproctology of Great Britain and Ireland.)

Background: The traditional treatment for stage IV colorectal cancer has changed from palliative chemotherapy toward an aggressive multimodality approach. In the current study outcome in patients who underwent surgery for synchronous colorectal liver metastases (CLM) in a single center was evaluated., Methods: From January 1991 to May 2008 all consecutive patients with synchronous CLM who underwent curative resection of both primary and metastatic disease were included. Date of resection was divided into two groups: date of hepatic resection before and after the year 2000., Results: Fifty patients (26%) with synchronous CLM were resected before 2000 and 142 patients (74%) underwent resection after 2000. The estimated 5-year disease-free survival before and after 2000 was 9% and 27%, respectively (P = 0.379). More patients who underwent resection after 2000 were treated with local therapy or underwent resection for intra-hepatic recurrence (62% vs. 28%, P = 0.033). The estimated 5-year survival before and after 2000 was 26% and 44%, respectively (P = 0.001)., Conclusion: Survival rates in patients with synchronous CLM have been increased in the past decade. The introduction of new chemotherapeutic drugs and a more aggressive treatment approach in patients with liver recurrence were probably major factors in this progress., (J. Surg. Oncol. 2010;102:413-418. © 2010 Wiley-Liss, Inc.)

Background: This study evaluated the outcome of patients treated for rectal cancer and synchronous hepatic metastases in the era of effective induction radiotherapy and chemotherapy., Methods: All patients undergoing surgical treatment of rectal cancer and synchronous liver metastases between 2000 and 2007 were identified retrospectively from a prospectively collected database. Three approaches were followed: the classical staged, the simultaneous and the liver-first approach., Results: Of 57 patients identified, the primary tumour was resected first in 29 patients (group 1), simultaneous resection was performed in eight patients (group 2), and 20 patients underwent a liver-first approach (group 3). The overall morbidity rate was 24.6 per cent; there was no in-hospital mortality. Median in-hospital stay was significantly shorter for the simultaneous approach (9 days versus 18 and 15 days for groups 1 and 3 respectively; P < 0.001). The overall 5-year survival rate was 38 per cent, with an estimated median survival of 47 months., Conclusion: Long-term survival can be achieved using an individualized approach, with curative intent, in patients with rectal cancer and synchronous liver metastases. Simultaneous resections as well as the liver-first approach are attractive alternatives to traditional staged resections., ((c) 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Objective: The objective of the study was to identify patients who may benefit from local treatment in recurrent colorectal liver metastases., Materials and Methods: A total of 51 consecutive patients were treated for hepatic recurrence(s) after an initial partial hepatic resection. Surgery was considered as the primary treatment option for eligible patients. Patients with a small liver remnant after major hepatectomy were treated with radiofrequency ablation (RFA) or stereotactic body radiation therapy (SRx). SRx was given as an outpatient, emerging local treatment option for patients with intra-hepatic recurrences not eligible for surgery or RFA. Partial liver resection was performed in 36 patients (70%), RFA in ten patients (20%), and SRx in five patients (10%)., Results: Median hospital stay was 7 (range, 3-62) days with a morbidity of 16% without in-hospital death. None of the patients received adjuvant chemotherapy. There was no difference in recurrence or survival between the three treatment modalities. Overall 5-year survival was 35% with an estimated median survival of 37 months. Patients with a disease-free interval between first hepatectomy and hepatic recurrence less than 6 months did not survive 3 years., Conclusions: Resection, RFA, and SRx can be performed safely in patients with recurrent colorectal liver metastases and offer a survival that seems comparable to primary liver resections of colorectal liver metastases.