Mesenteric granulomas independently predict long-term risk of surgical recurrence in Crohn's disease.

AIM: The risk factors that predict surgical recurrence in Crohn's disease (CD) remain controversial. Postoperative anti-tumour necrosis factor (anti-TNF) therapy might lower recurrence rates whilst the presence of mesenteric granulomas has been postulated to increase the risk. We hypothesized that mesenteric granulomas indicate disease severity and might predict the risk of surgical recurrence, irrespective of immunosuppressive therapy. METHOD: We performed a retrospective review of all consecutive patients undergoing operations for CD between January 2000 and December 2014 at a single tertiary referral centre and assessed the perioperative factors and histological findings at the time of surgery. Surgical recurrence rates and the immunosuppressive regimen were assessed through retrospective chart review and telephone interviews. RESULTS: A total of 274 patients were eligible for analysis. Median follow-up was 8.54 (5.48-14.42) years. A total of 63 patients (23.0%) underwent surgery for recurrent CD after a median of 4.75 (2.10-7.96) years. In final histology, 35 (12.8%) patients had mesenteric granulomas. TNF inhibitors were administered postoperatively in 104 (38.0%) and thiopurines in 137 (50.0%) patients. In univariate analysis, only the presence of mesenteric granulomas [hazard ratio (HR) 1.95; 95% CI 1.05-3.62; P = 0.035] significantly increased the risk for recurrent surgery while postoperative anti-TNF (HR 0.85; 95% CI 0.49-1.50; P = 0.581) or thiopurine therapy (HR 1.03; 95% CI 0.61-1.73; P = 0.916) did not. In multivariate analysis, only the presence of mesenteric granulomas significantly influenced the risk of surgical recurrence (HR 1.94, 95% CI 1.04-3.60; P = 0.037). CONCLUSION: Intestinal and mesenteric granulomas should be differentiated in pathology reports, because mesenteric, but not intestinal, granulomas may be associated with an increased risk of surgical recurrence.

The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NeoCTx) is performed for most patients with colorectal cancer liver metastases (CRCLM). However, chemotherapy-associated liver injury (CALI) has been associated with poor postoperative outcome. To date, however, no clinically applicable and noninvasive tool exists to assess CALI before liver resection. METHODS: Routine blood parameters were assessed in 339 patients before and after completion of NeoCTx and before surgery. The study assessed the prognostic potential of the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), the albumin-bilirubin grade (ALBI), and their combinations. Furthermore, an independent multi-center validation cohort (n = 161) was included to confirm the findings concerning the prediction of postoperative outcome. RESULTS: Higher ALBI, APRI, and APRI + ALBI were found in patients with postoperative morbidity (P = 0.001, P = 0.064, P = 0.001, respectively), liver dysfunction (LD) (P = 0.009, P = 0.012, P < 0.001), or mortality (P = 0.037, P = 0.045, P = 0.016), and APRI + ALBI had the highest predictive potential for LD (area under the curve [AUC], 0.695). An increase in APRI + ALBI was observed during NeoCTx (P < 0.001). Patients with longer periods between NeoCTx and surgery showed a greater decrease in APRI + ALBI (P = 0.006) and a trend for decreased CALI at surgery. A cutoff for APRI + ALBI at - 2.46 before surgery was found to identify patients with CALI (P = 0.002) and patients at risk for a prolonged hospital stay (P = 0.001), intensive care (P < 0.001), morbidity (P < 0.001), LD (P < 0.001), and mortality (P = 0.021). Importantly, the study was able to confirm the predictive potential of APRI + ALBI for postoperative LD and mortality in a multicenter validation cohort. CONCLUSION: Determination of APRI + ALBI before surgery enables identification of high-risk patients for liver resection. The combined score seems to dynamically reflect CALI. Thus, APRI + ALBI could be a clinically relevant tool for optimizing timing of surgery in CRCLM patients after NeoCTx.

Viral dominance patterns in chronic hepatitis delta determine early response to interferon alpha therapy.

Chronic hepatitis D is caused by coinfection of hepatitis B and hepatitis D virus. While HDV is the dominant virus over HBV in the majority of cases, mechanisms and consequences of viral dominance are largely unknown. We aimed to investigate associations between viral dominance patterns and patients' characteristics and inflammatory features; 109 HDV-infected patients treated with PEG-IFNa-2α within the international multicentre, prospective HIDIT-2 trial were studied. Patients were classified as D- or B-dominant if the viral load of one virus exceeded that of the other virus by more than 1log10 . Otherwise, no viral dominance (ND) was described. We used Luminex-based multiplex technology to study 50 soluble immune mediators (SIM) in pretreatment samples of 105 HDV RNA-positive patients. Dominance of HDV was evident in the majority (75%) of cases. While only 7% displayed B-dominance, 17% showed nondominance. D-dominance was associated with downregulation of 4 interleukins (IL-2ra, IL-13, IL-16 and IL-18) and 5 chemokines/cytokines (CTACK (CCL27), MCP-1 (CCL2), M-CSF, TRAIL and ICAM-1) while no analyte was increased. In addition, D-dominance could be linked to a delayed HDV RNA response to pegylated interferon as patients with B-dominance or nondominance showed higher early HDV RNA responses (61% at week 12) than D-dominant patients (11%; P < .001). In conclusion, this study revealed unexpected effects of viral dominance on clinical and immunological features in chronic hepatitis delta patients. Individualizing PEG-IFNa-2α treatment duration should consider viral dominance. Overall, our findings suggest an activated but exhausted IFN system in D-dominant patients.

Effect of pathologist's dedication on lymph node detection rate and postoperative survival in colorectal cancer.

AIM: As adjuvant chemotherapy in colorectal cancer relies on the identification of lymph node metastases, the pathologist's dedication may have a considerable influence on postoperative survival. METHOD: The aim of this retrospective study was to assess the impact of the pathologist's dedication on lymph node detection rate and postoperative survival in patients operated on by a single experienced colorectal surgeon within a 5-year period. We assessed 229 patients undergoing total mesorectal excision or complete mesocolic excision by the senior author between 1 January 2009 and 31 December 2013. Pathologists were grouped as 'general pathologist' or 'dedicated pathologist' depending on their dedication/specialization. RESULTS: Dedicated pathologists found statistically significantly more lymph nodes in colorectal specimens than general pathologists [23 (interquartile range 24) vs 14 (interquartile range 11), respectively; P < 0.001]. The detection rate of ≥ 12 lymph nodes per specimen was significantly higher in the dedicated pathologist group [65/74 (87.8%) vs 105/155 (67.7%); P = 0.016]. However, postoperative survival did not differ in the respective subgroups. In the multivariable analysis by Cox proportional hazard model, International Union against Cancer Stage IV was the only factor associated with decreased disease-specific survival (hazard ratio 28.257; 95% CI 3.850-207.386; P = 0.001). CONCLUSION: In our centre, the pathologist's dedication has an impact on lymph node detection rate but does not influence postoperative disease-specific survival.

Variations in genes involved in dormancy associated with outcome in patients with resected colorectal liver metastases.

BACKGROUND: Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy. PATIENTS AND METHODS: Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns. RESULTS: NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively. CONCLUSION: Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.

Variations in genes involved in immune response checkpoints and association with outcomes in patients with resected colorectal liver metastases.

In patients with colorectal liver metastases (CLM), liver resection offers the possibility of cure and long-term survival. The liver is a highly immunogenic organ harboring ~80% of the body's tissue macrophages. Emerging data demonstrate a critical role of the immune response for cancer treatment. We investigated variations within genes involved in immune response checkpoints and their association with outcomes in patients with CLM who underwent neoadjuvant chemotherapy including bevacizumab and liver resection. Single-nucleotide polymorphisms (SNPs) in nine genes (CCL2, CCR2, LAG3, NT5E, PDCD1, CD274, IDO1, CTLA4 and CD24) were analyzed in genomic DNA from 149 patients with resected bevacizumab-pretreated CLM by direct Sanger DNA sequencing, and correlated with response, recurrence-free survival (RFS), overall survival (OS), probability of cure and recurrence patterns. IDO1 (indoleamine 2, 3-dioxygenase) rs3739319 G>A and CD24 rs8734 G>A showed a significant difference in 3-year OS rates. In addition, IDO1 rs3739319 G>A was significantly associated with extrahepatic recurrence. Recursive partitioning analyses revealed that IDO1 rs3739319 G>A was the dominant SNP predicting RFS and OS. Our data suggest that variants within genes involved in immune response checkpoints are associated with outcomes in patients with resected CLM and might lead to improved treatment strategies modulating anti-tumor immune response by targeting novel immune checkpoints.

KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab.

BACKGROUND: The prognostic value of KRAS mutation in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab before liver resection is unclear. METHODS: The KRAS and BRAF status of resected CLM was assessed in prospectively studied patients. Mutations were correlated with recurrence-free and overall survival. Only patients with remaining vital tumour cells in the resected specimen and those without disease progression were analysed; those with progressive disease did not undergo resection. RESULTS: A total of 60 patients were enrolled. Fifteen (25 per cent) had a KRAS mutation, but none of the 60 patients had a BRAF mutation. The radiological response to neoadjuvant chemotherapy including bevacizumab, assessed according to the Response Evaluation Criteria In Solid Tumours, was partial in 52 patients (87 per cent) and the remaining eight had stable disease. The partial response rate was similar in patients with a KRAS mutation and those with the wild-type gene (12 of 15 versus 40 of 45 patients; P = 0·400). KRAS mutation had a negative prognostic effect on recurrence-free survival (hazard ratio (HR) 2·48, 95 per cent confidence interval 1·26 to 4·89; P = 0·009) and overall survival (HR 3·51, 1·30 to 9·45; P = 0·013). CONCLUSION: This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM.

Histological response, pattern of tumor destruction and clinical outcome after neoadjuvant chemotherapy including bevacizumab or cetuximab in patients undergoing liver resection for colorectal liver metastases.

AIM: We investigated whether the type of antibody [bevacizumab (bev) or cetuximab (cet)] added to neoadjuvant combination chemotherapy before curative liver resection was associated with histological response, the pattern of tumor destruction and clinical outcome in patients with colorectal liver metastases (CLM). METHODS: We investigated 138 patients with KRAS wild-type status (codon 12, 13 and 61) who received neoadjuvant chemotherapy including bev (n = 101) or cet (n = 37). The primary endpoint was histological response. Secondary endpoints were necrosis and fibrosis of metastases, radiological response, recurrence-free survival (RFS) and overall survival (OS). RESULTS: Histological response was not significantly different between the two groups (P = 0.19). A significantly higher fraction of patients in the bev group showed necrosis of the metastases of ≥ 50% (P < 0.001), while a higher fraction of patients in the cet group showed fibrosis of ≥ 40% (P = 0.030). Radiological response was not significantly different (P = 0.17). Median RFS was significantly shorter in the cet group in univariable analysis (HR 1.59 (95% CI 1.00, 2.51), P = 0.049), but this difference did not remain significant in multivariable analysis (P = 0.45). The 3-year OS rate was not significantly different (P = 0.73). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy showed more necrosis but less fibrosis of metastases compared to cetuximab and a trend towards higher histological and radiological response and longer RFS. Further investigations of biological tumor characteristics are required to individualize treatment combinations.