Obesity and its influence on liver dysfunction, morbidity and mortality after liver resection.

Background: Obesity and associated steatosis is an increasing health problem worldwide. Its influence on post-hepatectomy liver failure (PHLF) and after liver resection (LR) is still unclear. Methods: Patients who underwent LR were investigated and divided into three groups [normal weight: body mass index (BMI) 18.5-24.9 kg/m2, overweight: BMI 25.0-29.9 kg/m2, obese: BMI ≥30 kg/m2] in this retrospective study. Primary aim of this study was to assess the influence of BMI and nonalcoholic steatohepatitis (NASH) on PHLF and morbidity. Results: Of 888 included patients, 361 (40.7%) had normal weight, 360 (40.5%) were overweight, 167 (18.8%) were obese. Median age was 62.5 years (IQR, 54-69 years). The primary indication for LR was colorectal liver metastases (CLM) (n=366, 41.2%). NASH was present in 58 (16.1%) of normal weight, 84 (23.3%) of overweight and 69 (41.3%) of obese patients (P<0.001). PHLF occurred in 16.3% in normal weight, 15.3% in overweight and 11.4% in obese patients (P=0.32). NASH was not associated with PHLF. There was no association between patients' weight and the occurrence of postoperative complications (P=0.45). At multivariable analysis, solely major LR [odds ratio (OR): 2.7, 95% confidence interval (CI): 1.83-4.04; P<0.001] remained a significant predictor for PHLF. Conclusions: Postoperative complications and PHLF are comparable in normal weight, overweight and obese patients and LRs using modern techniques can be safely performed in these patients.

Evaluation of Eosinophilic Cationic Protein as a Marker of Alveolar and Cystic Echinococcosis.

Echinococcosis is a neglected zoonotic disease and a worldwide public health problem caused by infection with the larval stages of taeniid cestodes of the genus Echinococcus. In vitro studies have demonstrated a protoscolecidal effect of eosinophilic cationic protein (ECP), a granule protein of eosinophilic granulocytes, against E. granulosus. Therefore, the main objective of this study was to evaluate ECP as a biomarker in the treatment of alveolar echinococcosis (AE) and cystic echinococcosis (CE). Data were collected retrospectively from the Vienna Echinococcosis Cohort over 7 years until December 2020. Altogether, 32 patients (16 AE and 16 CE) were included. In the selected patients, serum ECP values were compared before and after the beginning of an operative and/or benzimidazole (BMZ) therapy. Mean ECP serum levels before intervention were significantly (p < 0.05) elevated at 34.0 ± 22.9 µg/L in AE patients and at 38.6 ± 19.9 µg/L in CE patients compared to the control group. After the intervention, mean ECP levels decreased significantly (p < 0.05) to 20.4 ± 14.6 µg/L in AE patients and to 22.4 ± 8.3 µg/L in CE patients. Furthermore, ECP showed a significant (p < 0.05) correlation of k = 0.56 with PET-CTI. Based on the significant decrease after operative and/or BMZ treatment and the correlation with clinical markers such as PET-CTI, it is recommended to investigate ECP more intensively as a marker of AE and CE in prospective studies with larger cohorts.

Immune checkpoints and liver resection after neoadjuvant chemotherapy including bevacizumab in patients with microsatellite-stable colorectal liver metastases.

BACKGROUND: The clinical value of immune checkpoint expression as prognostic biomarker in bevacizumab-pretreated patients with resected microsatellite-stable (MMS) colorectal liver metastases is unclear and was retrospectively investigated in this study. METHODS: Expression analyses of IDO-1, PD-L1, and CTLA-4 were performed by immunohistochemistry in resected bevacizumab-pretreated colorectal liver metastases. Association of immune checkpoint expression in tumor cells and immune cells with response and clinical outcome was investigated. Expression profiles were compared with those of patients with anti-EGFR-targeted therapy and lung metastases, respectively. RESULTS: One hundred thirty-six patients with MMS disease were investigated (79 (58.1%) male/57 (41.9%) female, median age 62.9 years (range 31.0-80.4)). High expression of IDO-1 in immune cells was associated with longer OS (not reached versus 44.8 months, HR 0.23 (95% CI 0.09, 0.55), P = 0.001). Low expression of CTLA-4 in tumor cells was associated with better histological response (26 major, 19 partial, 18 none versus 14 major, 23 partial, 30 none, P = 0.032). Expression profiles differed compared to patients with anti-EGFR-targeted therapy and patients with lung metastases. CONCLUSION: Immune checkpoint expression was associated with response and survival. IDO-1 may serve as a novel prognostic and/or predictive biomarker in patients with MMS colorectal liver metastases.

Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.

BACKGROUND: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. METHODS: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. RESULTS: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). CONCLUSION: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases.

BACKGROUND: Patients with desmoplastic (angiogenic) histopathological growth pattern (HGP) colorectal liver metastases (CLM) might derive more benefit from bevacizumab-based chemotherapy than those with replacement (non-angiogenic) HGP. This study investigated the association of HGP with the immune phenotype (IP) and clinical outcome after liver resection. METHODS: CLM of patients treated with perioperative bevacizumab-based chemotherapy and liver resection were investigated. Association of HGP and IP with response, recurrence-free survival (RFS) and overall survival (OS) was investigated. RESULTS: One hundred and eighteen patients (M/F 66/52, median age 62.3 (31.0-80.4) years, median follow-up 32.2 (5.0-92.7) months) were enrolled. The inflamed IP was associated with the desmoplastic HGP. The desmoplastic HGP was associated with better radiological and histological response compared to the replacement HGP, respectively. The replacement HGP was associated with shorter RFS (8.7 versus 16.3 months, HR 2.60, P = 0.001) and OS (36.6 months versus not reached, HR 2.32, P = 0.027), respectively. The non-inflamed IP was associated with shorter RFS (10.8 versus 16.5 months, HR 1.85, P = 0.029). The HGP but not the IP remained significant in multivariable analysis for RFS. CONCLUSIONS: The desmoplastic HGP is associated with the inflamed IP and HGP may be a potential biomarker for adjuvant treatment that includes targeting the immune contexture.

The value of indocyanine green clearance assessment to predict postoperative liver dysfunction in patients undergoing liver resection.

Postoperative liver dysfunction remains a major concern following hepatic resection. In order to identify patients who are at risk of developing liver dysfunction, indocyanine green (ICG) clearance has been proposed to predict postoperative liver function. All patients who underwent liver resection at the Medical University Vienna, Austria between 2006 and 2015 with preoperative ICG clearance testing (PDR, R15) were analyzed in this study. Postoperative liver dysfunction was analyzed as defined by the International Study Group of Liver Surgery. Overall, 698 patients (male: 394 (56.4%); female: 304 (43.6%)) with a mean age of 61.3 years (SD: 12.9) were included in this study, including 313 minor liver resections (44.8%) and 385 major liver resections (55.2%). One hundred and seven patients developed postoperative liver dysfunction after liver resection (15.3%). Factors associated with liver dysfunction were: male sex (p = 0.043), major liver resection (p < 0.0001), and preoperative ICG clearance (PDR (p = 0.002) and R15 (p < 0.0001)). Notably ICG clearance was significantly associated with liver dysfunction in minor and major liver resections respectively and remained a predictor upon multivariable analysis. An optimal cut-off for preoperative ICG clearance to accurately predict liver dysfunction was PDR < 19.5%/min and R15 > 5.6%. To the best of our knowledge, this is the largest study analyzing the predictive value of preoperative ICG clearance assessment in patients undergoing liver resection. ICG clearance is useful to identify patients at risk of postoperative liver dysfunction.

Clinical outcome after resection of early-stage hilar cholangiocarcinoma.

BACKGROUND: Liver transplantation in patients with unresectable early-stage (<3 cm, node negative) hilar cholangiocarcinoma has been recently reported to be associated with longer survival compared to liver resection and therefore suggested as potential treatment option also in resectable disease. Here, we investigated the outcome of resection in early-stage tumours as the standard of care in an experienced European centre. METHODS: Patients with de novo resectable hilar cholangiocarcinomas who underwent liver resection between mid-2009 and December 2017 were classified as early-stage (<3 cm and node negative) or later-stage tumours (≥3 cm and/or node positive), and were investigated with respect to clinical outcome. RESULTS: Fifty-six patients were analyzed of whom 17 had early-stage tumours and 39 had later-stage tumours. The sex ratio (m:f) was 30:26. The median age was 65 years (range 33-80). The median follow-up was 17.0 months (range 0.7-92.4). 5-year overall survival (OS) rates were 82% in patients with early-stage tumours and 23% in patients with later-stage tumours, respectively. Median OS was 89.9 months and 27.6 months, respectively (HR 0.25 (95% CI 0.08-0.84), P = 0.024). CONCLUSIONS: In an experienced European centre, 5-year survival rates after liver resection for early-stage hilar cholangiocarcinoma are comparable with reported outcomes after transplantation. The results of this study question the value of liver transplantation in this setting, especially with respect to the shortage of transplantable organs worldwide.

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

BACKGROUND: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. PATIENTS AND METHODS: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. RESULTS: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. CONCLUSION: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.

DNA damage predicts prognosis and treatment response in colorectal liver metastases superior to immunogenic cell death and T cells.

Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear. Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33). DNA damage (γH2AX), RNA and DNA sensors (RIG-I, DDX41, cGAS, STING), ER stress response (p-PKR, p-eIF2α, CALR), type I and type II IFN- induced proteins (MxA, GBP1), mature dendritic cells (CD208), and cytotoxic and memory T cells (CD3, CD8, CD45RO) were investigated by an immunohistochemistry whole-slide tissue scanning approach and further correlated with recurrence-free survival (RFS), overall survival (OS), radiographic and pathologic therapy response. Results: γH2AX is a negative prognostic marker for RFS (HR 1.32, 95% CI 1.04-1.69, p=0.023) and OS (HR 1.61, 95% CI 1.23-2.11, p<0.001). A model comprising of DDX41, STING and p-PKR predicts radiographic therapy response (AUC=0.785, p=0.002). γH2AX predicts prognosis superior to the prognostic value of CD8. CALR positively correlates with GBP1, CD8 and cGAS. A model consisting of γH2AX, p-eIF2α, DDX41, cGAS, CD208 and CD45RO predicts pathological therapy response (AUC=0.944, p<0.001). Conclusion: In contrast to preclinical models, DNA damage inversely correlated with ICD and its associated T cell infiltrate and potentially serves as a therapeutic target in CLM.

Microscopic biliary and perineural invasion and clinical outcome after neoadjuvant bevacizumab-based chemotherapy and liver resection in patients with colorectal liver metastases.

BACKGROUND: The value of microscopic biliary and perineural invasion as prognostic biomarkers in patients with resectable colorectal liver metastases (CLM) who undergo neoadjuvant chemotherapy and liver resection is still unclear. This retrospective study was performed to elucidate this issue. METHODS: Histologic slides of resected CLM of patients who underwent neoadjuvant bevacizumab-based chemotherapy and liver resection were investigated with respect to biliary and perineural invasion. Presence of invasion was correlated with radiologic and histologic response, recurrence-free survival (RFS) and overall survival (OS). RESULTS: One hundred forty-one patients were enrolled. There was a significant association between biliary and perineural invasion, respectively (P = 0.001). Moreover, both biliary and perineural invasion were associated with bilobar metastatic spread and higher number of metastases, while perineural invasion was also associated with a higher Fong score. No significant association was found with response. In univariable analysis, biliary and perineural invasion were associated with shorter RFS (median 10.1 vs. 13.5 months, HR 2.09, P = 0.010 and 7.6 vs. 14.0, HR 2.23, P = 0.001, respectively). Biliary invasion was also associated with shorter OS (median 32.8 months vs. not reached, HR 2.78, P = 0.010), however these results did not remain significant in multivariable analysis. CONCLUSIONS: In patients with resectable colorectal liver metastases undergoing neoadjuvant bevacizumab-based chemotherapy and liver resection, biliary and perineural invasion are associated with higher tumor load but may not be prognostic biomarkers.

Perioperative Non-Invasive Indocyanine Green-Clearance Testing to Predict Postoperative Outcome after Liver Resection.

BACKGROUND: Postoperative liver dysfunction may lead to morbidity and mortality after liver resection. Preoperative liver function assessment is critical to identify preexisting liver dysfunction in patients prior to resection. The aim of this study was to evaluate the predictive potential of perioperative indocyanine green (ICG)-clearance testing to prevent postoperative liver dysfunction and morbidity using standardized outcome parameters in a routine Western-clinical-setting. STUDY DESIGN: 137 patients undergoing partial hepatectomy between 2011 and 2013, at the general hospital of Vienna, were included. ICG-clearance was recorded one day prior to surgery as well as on the first and fifth postoperative day. Postoperative liver dysfunction was defined according to the International Study Group of Liver Surgery and evaluation of morbidity was based on the Dindo-Clavien classification. Statistical analyses were based on non-parametric tests. RESULTS: Preoperative reduced ICG-plasma disappearance rate (PDR) as well as increased ICG-retention rate at 15 min (R15) were able to significantly predict postoperative liver dysfunction (Area under the curve = PDR: 0.716, P = 0.018; R15: 0.719, P = 0.016). Furthermore, PDR <17%/min. or R15 >8%, were able to accurately predict postoperative complications prior to surgery. In addition to this, ICG-clearance on postoperative day 1 comparably predicted postoperative liver dysfunction (Area under the curve = PDR: 0.895; R15: 0.893; both P <0.001), specifically, PDR <10%/min or R15 >20% on postoperative day 1 predicted poor postoperative outcome. CONCLUSION: PDR and R15 may represent useful parameters to distinguish preoperative high and low risk patients in a Western collective as well as on postoperative day 1, to identify patients who require closer monitoring for potential complications.

Expression of Genes Involved in Vascular Morphogenesis and Maturation Predicts Efficacy of Bevacizumab-Based Chemotherapy in Patients Undergoing Liver Resection.

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected before bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, and KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P < 0.05). High ACVRL1 levels predicted favorable 3-year OS (P = 0.041) and radiologic response (PR = 1.093, SD = 0.539, P = 0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P < 0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 months; HR = 2.83, P = 0.038). High VEGFB (46% vs. 85%; HR = 5.75, P = 0.009) and low FLT1 (55% vs. 100%; P = 0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers. Mol Cancer Ther; 15(11); 2814-21. ©2016 AACR.

Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab.

The purpose of this study was to evaluate the clinical significance of single-nucleotide polymorphisms in TLR1, TLR2, TLR6, and TAK1 in patients with metastatic colorectal cancer (mCRC). We genotyped 9 SNPs of TLR1, TLR2, TLR6, and TAK1 in mCRC patients treated with first-line FOLFIRI (combination therapy of irinotecan, 5-fluorouracil, and folinic acid) plus bevacizumab, using a discovery cohort (TRIBE trial, n = 228) and a validation cohort (FIRE-3 trial, n = 297), and analyzed for the association with response rate (RR), progression-free survival (PFS), and overall survival (OS). There was a significant association of TLR1 rs5743618 (T1805G) with the clinical outcome. In the TRIBE cohort, a homozygous wild-type genotype (T/T) associated with a significantly lower RR compared with variant T/G and G/G genotypes (43% vs. 62%, P = 0.025), and this observation was validated in the FIRE-3 cohort (46% vs. 65%, P = 0.021). In addition, those patients with the T/T genotype had significantly worse PFS (median, 8.2 vs. 10.5 months; HR, 1.57; 95% CI, 1.09-2.28, P = 0.014) and OS (median: 19.9 vs. 27.9 months; HR, 1.63; 95% CI, 1.14-2.35, P = 0.007), compared with those with other genotypes in the TRIBE cohort. These differences remained statistically significant in multivariate analysis. Our data suggest that TLR1 rs5743618 could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC. Mol Cancer Ther; 15(7); 1740-5. ©2016 AACR.

Cytokeratin-20 and Survivin-Expressing Circulating Tumor Cells Predict Survival in Metastatic Colorectal Cancer Patients by a Combined Immunomagnetic qRT-PCR Approach.

Circulating tumor cells (CTC) express epithelial and stem cell-like genes, though current approved detection methods mainly use epithelial markers. We optimized a CTC isolation method that could capture their molecular heterogeneity and predict overall survival (OS) in metastatic colorectal cancer (mCRC) patients receiving various chemotherapy regimens. We combined immunomagnetic enrichment of CD45-negative, EpCAM-positive circulating cancer cells with qRT-PCR amplification of CK20 and survivin expression in 88 mCRC patients and 20 healthy controls. We then evaluated the prognostic value of baseline CTC CK20 and survivin expression in mCRC patients. The presence of elevated CTC CK20 or survivin expression distinguished mCRC patients from controls with sufficient sensitivity (79.6%) and specificity (85%). In univariate analysis, patients with high CTC-CK20 expression (9 vs. 33.2+ months, log-rank P < 0.001) or high CTC-survivin expression (10 vs. 33.2+ months, log-rank P = 0.032) had a significantly worse median OS than those with low expression of either marker. In multivariable analysis, the high CTC-CK20 group had significantly shortened OS (HR, 3.11; adjusted P = 0.01), and there was a trend toward inferior OS in the high CTC-survivin group (HR, 1.76; adjusted P = 0.099). Patients with either high CTC CK20 or survivin expression had inferior OS compared with those with low expression of both markers (HR, 4.39; 95% confidence interval, 1.56-12.35; adjusted P = 0.005). Colorectal cancer CTCs can be reliably isolated using epithelial and stem cell markers. CTC CK20 and survivin expression may effectively predict OS in mCRC patients receiving chemotherapy.

Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer.

Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.

Genetic variations in angiopoietin and pericyte pathways and clinical outcome in patients with resected colorectal liver metastases.

BACKGROUND: Genes involved in the angiopoietin and pericyte pathways may become escape mechanisms under antivascular endothelial growth factor (anti-VEGF) therapy. The authors investigated whether variations within genes in these pathways are associated with clinical outcome in patients with colorectal liver metastases who undergo liver resection and receive perioperative, bevacizumab-based chemotherapy. METHODS: Single nucleotide polymorphisms (SNPs) in 9 genes (angiopoietin-1 [ANGPT1]; ANGPT2; TEK tyrosine kinase, endothelial [TEK]; platelet-derived growth factor ß [PDGFB]; ß-type platelet-derived growth factor receptor [PDGFRB]; insulin-like growth factor 1 [IGF1]; transforming growth factor ß1 [TGFB1]; RalA binding protein 1 [RALBP1]; and regulator of G-protein signaling 5 [RGS5]) were analyzed in samples of genomic DNA from 149 patients and were evaluated for associations with clinical outcome. RESULTS: RALBP1 reference SNP 329007 (rs329007) A>G resulted in a significant difference in recurrence-free survival (A/A genotype, 14.0 months; A/G or G/G genotype, 9.2 months; hazard ratio [HR], 1.60; P = .024). PDGFB rs1800818 A>G was associated with 3-year overall survival rates (A/A genotype, 78%; A/G genotype, 69%; [HR 1.37]; G/G genotype, 53%; [HR 2.12]; P = .048). In multivariate analysis, RALBP1 rs329007 A>G remained significant (HR, 1.99; P = .002). PDGFB rs1800818 A>G and RALBP1 rs329007 A>G were correlated with radiologic response (A/A or A/G genotype, 86%; G/G genotype, 71% [P = .042]; A/A genotype, 78%; A/G or G/G genotype, 94% [P = .018], respectively). RALBP1 rs329007 A>G demonstrated significantly different rates of histologic response (A/A genotype: major histologic response, 35%; partial histologic response, 34%; no histologic response, 30%; A/G or G/G genotype: 46%, 13%, and 41%, respectively; P = .029). Recursive partitioning analysis revealed that ANGPT2 rs2442599 T>C and RALBP1 rs329007 A>G were the main SNPs that predicted histologic response and recurrence-free survival, whereas PDGFB rs1800818 A>G was the leading SNP that predicted overall survival. ANGPT2 rs2916702 C>T and rs2442631 G>A were significantly associated with the probability of achieving a cure. CONCLUSIONS: The current data suggest that variations in genes involved in the angiopoietin and pericyte pathways may be predictive and/or prognostic biomarkers in patients with resected colorectal liver metastases who receive bevacizumab-based chemotherapy.

Genetic variants within obesity-related genes are associated with tumor recurrence in patients with stages II/III colon cancer.

OBJECTIVE: Obesity is an established risk factor for colorectal cancer (CRC) incidence and it is also linked to CRC recurrence and survival. Polymorphisms located in obesity-related genes are associated with an increased risk of developing several cancer types including CRC. We evaluated whether single-nucleotide polymorphisms in obesity-related genes may predict tumor recurrence in colon cancer patients. MATERIALS AND METHODS: Genotypes were obtained from germline DNA from 207 patients with stage II or III colon cancer at the Norris Comprehensive Cancer Center. Nine polymorphisms in eight obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA, and DSCR1) were evaluated. The primary endpoint of the study was the 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients. RESULTS: In univariate analysis, for PPARrs1801282, patients with a CC genotype had significantly lower recurrence probability (29 ± 4% SE) compared with patients with a CG genotype (48 ± 8% SE) [hazard ratio (HR): 1.77; 95% confidence interval (CI), 1.01-3.10; P = 0.040]. For DSCR1rs6517239, patients with an AA genotype had higher recurrence probability than patients carrying at least one allele G (37 ± 4% SE vs. 15 ± 6% SE) (HR: 0.51; 95% CI, 0.27-0.94; P = 0.027). This association was stronger in the patients bearing a left-sided tumor (HR: 0.34; 95% CI, 0.13-0.88; P = 0.018). In the Japanese cohort, no associations were found. CONCLUSION: This hypothesis-generating study suggests a potential influence of polymorphisms within obesity-related genes in the recurrence probability of colon cancer. These interesting results should be evaluated further.

CEA change after neoadjuvant chemotherapy including bevacizumab and clinical outcome in patients undergoing liver resection for colorectal liver metastases.

BACKGROUND: Liver resection after neoadjuvant chemotherapy offers the chance of cure and long-term survival in patients with resectable colorectal liver metastases (CLM). Currently, there are no established biomarkers that could help identify patients with low risk of recurrence who may benefit most from liver resection in curative intent. To address this issue, the value of carcinoembryonic antigen (CEA) change after neoadjuvant chemotherapy was investigated to predict clinical outcome in this study. METHODS: CEA levels before (baseline) and after neoadjuvant chemotherapy including bevacizumab before liver resection were obtained in 154 patients with CLM from a prospectively maintained database. Changes of CEA in percent through neoadjuvant treatment were correlated with recurrence-free survival and overall survival (OS). Patients with normal CEA levels at all times (baseline and follow-up) were excluded from the analyses. RESULTS: After exclusion of 15 patients with normal CEA levels at all times, 139 patients were available for analysis. Receiver operating characteristic analyses revealed a CEA change (decrease) cutoff value of 50 %, which significantly separated 88 patients with respect to OS (P = 0.017). Cox regression analyses showed that the change of CEA at a cutoff value of 50 % was predictive for OS (hazard ratio 0.37, P = 0.025) independent from the baseline CEA level, but not for recurrence-free survival. Furthermore, a CEA change of >50 % was associated with a higher radiologic response rate (P = 0.016). CONCLUSIONS: CEA change induced through neoadjuvant treatment was associated with radiologic response and OS, and this measure is a promising tool to predict clinical outcome in the future.

Predictive and prognostic markers in the treatment of metastatic colorectal cancer (mCRC): personalized medicine at work.

This article clarifies prognostic and predictive markers in the treatment of colorectal cancer. Multiple chemotherapeutic drugs are approved for metastatic colorectal cancer (mCRC), but available guidelines are often not helpful in directing drug selections. It would be desirable to define patient populations before chemotherapy by biomarkers that predict outcome and toxicities. RAS mutational evaluation remains the only established biomarker analysis in the treatment of mCRC. BRAF mutant tumors are associated with poor outcome. Chemotherapeutic combination therapies still remain the most active treatments in the armamentarium, and future trials should address the need to prospectively investigate and validate biomarkers.