Kosuke Ichida

Risk factors for intra-abdominal infection after pancreaticoduodenectomy - a retrospective analysis to evaluate the significance of preoperative biliary drainage and postoperative pancreatic fistula.

BACKGROUND/AIMS Intra-abdominal infection (IAI) after pancreaticoduodenectomy (PD) is a common cause of prolongation of postoperative hospital stay and readmission to the hospital following discharge. METHODOLOGY Two hundred and six patients undergoing PD were reviewed to investigate the risk factors for IAI after PD. Patients were separated into two groups: those who developed IAI after PD (Group A; n=44), and those who had not developed IAI after PD (Group B; n=162), the two groups were then compared to identify the risk factors for IAI after PD. A hundred and six patients (51.5%) underwent preoperative biliary drainage (PBD). RESULTS Multivariate analysis revealed that pancreatic fistula (PF) was an independent risk factor for IAI after PD (p<0.001; odds ratio=9.58; 95% confidence interval=4.37-21.0), but PBD was not a significant risk factor. CONCLUSIONS We demonstrated that the adequate PBD might not affect IAI after PD. On the other hand, PF was an independent risk factor for IAI after PD. A large randomized controlled trial, which would prove the effect of early removal of a prophylactic placed drain to prevent IAI, should be planned.

En bloc pancreaticoduodenectomy and right hemicolectomy for locally advanced right-sided colon cancer

AIM To assess the usefulness of en bloc right hemicolectomy with pancreaticoduodenectomy (RHCPD) for locally advanced right-sided colon cancer (LARCC). METHODS We retrospectively reviewed the database of Saitama Medical Center, Jichi Medical University, between January 2009 and December 2016. During this time, 299 patients underwent radical right hemicolectomy for right-sided colon cancer. Among them, 5 underwent RHCPD for LARCC with tumor infiltration to adjacent organs. Preoperative computed tomography (CT) was routinely performed to evaluate local tumor infiltration into adjacent organs. During the operation, we evaluated the resectability and the amount of infiltration into the adjacent organs without dissecting the adherent organs from the cancer. When we confirmed that radical resection was feasible and could lead to R0 resection, we performed RHCPD. The clinical data were carefully reviewed, and the demographic variables, intraoperative data, and postoperative parameters were recorded. RESULTS The median age of the 5 patients who underwent RHCPD for LARCC was 70 years. The tumors were located in the ascending colon (three patients) and transverse colon (two patients). Preoperative CT revealed infiltration of the tumor into the duodenum in all patients, the pancreas in four patients, the superior mesenteric vein (SMV) in two patients, and tumor thrombosis in the SMV in one patient. We performed RHCPD plus SMV resection in three patients. Major postoperative complications occurred in 3 patients (60%) as pancreatic fistula (grade B and grade C, according to International Study Group on Pancreatic Fistula Definition) and delayed gastric empty. None of the patients died during their hospital stay. A histological examination confirmed malignant infiltration into the duodenum and/or pancreas in 4 patients (80%), and no patients showed any malignant infiltration into the SMV. Two patients were histologically confirmed to have tumor thrombosis in the SMV. All of the tumors had clear resection margins (R0). The median follow-up time was 77 mo. During this period, two patients with tumor thrombosis died from liver metastasis. The overall survival rates were 80% at 1 year and 60% at 5 years. All patients with node-negative status (n = 2) survived for more than seven years. CONCLUSION This study showed that the long-term survival is possible for patients with LARCC if RHCPD is performed successfully, particularly in those with node-negative status.

Clinical and molecular assessment of regorafenib monotherapy.

Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies. Some patients, however, exhibit severe adverse events (AEs) resulting in treatment discontinuation. Therefore, the selection of patients likely to benefit from regorafenib is crucial. Twenty patients were treated with regorafenib for metastatic colorectal cancer; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA (ctDNA) in the blood. The treatment response, AEs, overall survival (OS), progression-free survival (PFS) and tumor morphologic changes on CT images were evaluated. KRAS mutant ctDNA was determined using digital PCR. Median PFS and OS were 2.5 and 5.9 months, respectively. Treatment was discontinued because of disease progression (PD) in 10 patients, and AEs in another 10 patients. AEs included hyperbilirubinemia, severe fatigue and skin rash. Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases, and severe fatigue in another 2 patients with poor performance status (PS). These severe AEs resulted in treatment discontinuation. Ten patients had a median PFS of 2.1 months with AE related discontinuation; PD occurred at 3.5 months (p=0.00334). Four patients exhibited a morphologic response, achieving better PFS times of 3.5, 5.3, 5.6 and 14.2 months. Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors; it was detectable in the blood prior to radiographic detection of PD. Moreover, the KRAS mutation declined in two patients during regorafenib monotherapy. These patients were re-challenged with anti-EGFR antibody. Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib. Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs. KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy.

Monitoring circulating tumor DNA revealed dynamic changes in KRAS status in patients with metastatic colorectal cancer

KRAS mutated circulating tumor DNA (MctDNA) can be monitored in the blood of patients with metastatic colorectal cancer (mCRC), but dynamic changes have not been determined. Four hundred and fifty-seven plasma samples were collected prospectively from 85 mCRC patients who underwent chemotherapy. MctDNA in plasma was detected by droplet digital PCR, and the percentage of MctDNA in total circulating cell-free DNA was calculated. KRAS assessment in tumor tissues showed 29 patients with the mutant-type (MT) and 56 patients with the wild-type (WT). Twenty-three of 29 MT patients (79.3%) and 28 of 56 WT patients (50.0%) showed MctDNA. Emergence of MctDNA was recognized during treatments with various drugs. Regardless of KRAS status in tumor tissues, patients with MctDNA in blood showed poor progression-free survival with first-line treatment. Median percentage of MctDNA accounted for 10.10% in MT patients and 0.22% in WT patients. These differences between MT and WT likely affected patterns of changes in MctDNA. KRAS monitoring identified dynamic changes in MctDNA, such as continuous, intermittent, and transient changes (quick elevation and disappearance). Emergence of MctDNA involved drug resistance, except for transient changes, which were seen in WT patients and likely corresponded with the drug response. Transient changes could be involved in recovery of sensitivity to anti-EGFR antibody in WT patients. Monitoring MctDNA during various treatments showed dynamic changes in KRAS status and could provide useful information for determining treatments for patients with mCRC.

Morphological response contributes to patient selection for rescue liver resection in chemotherapy patients with initially un-resectable colorectal liver metastasis

Morphological response is considered an improved surrogate to the Response Evaluation Criteria in Solid Tumors (RECIST) model with regard to predicting the prognosis for patients with colorectal liver metastases. However, its use as a decision-making tool for surgical intervention has not been examined. The present study assessed the morphological response in 50 patients who underwent chemotherapy with or without bevacizumab for initially un-resectable colorectal liver metastases. Changes in tumor morphology between heterogeneous with uncertain borders and homogeneous with clear borders were defined as an optimal response (OR). Patients were also assessed as having an incomplete response (IR), and an absence of marked changes was assessed as no response (NR). No significant difference was observed in progression-free survival (PFS) between complete response/partial response (CR/PR) and stable disease/progressive disease (SD/PD), according to RECIST. By contrast, PFS for OR/IR patients was significantly improved compared with that for NR patients (13.2 vs. 8.7 months; P=0.0426). Exclusion of PD enhanced the difference in PFS between OR/IR and NR patients (15.1 vs. 9.3 months; P<0.0001), whereas no difference was observed between CR/PR and SD. The rate of OR and IR in patients treated with bevacizumab was 47.4% (9/19), but only 19.4% (6/31) for patients that were not administered bevacizumab. Comparison of the survival curves between OR/IR and NR patients revealed similar survival rates at 6 months after chemotherapy, but the groups exhibited different survival rates subsequent to this period of time. Patients showing OR/IR within 6 months appeared to be oncologically stable and could be considered as candidates for surgical intervention, including rescue liver resection. Comparing the pathological and morphological features of the tumor with representative optimal response, living tumor cells were revealed to be distributed within the area of vascular reconstruction induced by bevacizumab, resulting in a predictive value for prognosis in the patients treated with bevacizumab. The present findings provided the evidence for physicians to consider patients with previously un-resectable metastatic colorectal cancer as candidates for surgical treatment. Morphological response is a useful decision-making tool for evaluating these patients for rescue liver resection following chemotherapy.

Heterogeneous expression of zinc-finger E-box-binding homeobox 1 plays a pivotal role in metastasis via regulation of miR-200c in epithelial-mesenchymal transition.

Although epithelial-mesenchymal transition (EMT) has been implicated as the pivotal event in metastasis, there is insufficient evidence related to EMT in clinical settings. Intratumor heterogeneity may lead to underestimation of gene expression representing EMT. In the present study, we investigated the expression of EMT-associated genes and microRNAs in primary colorectal cancer while considering intratumor heterogeneity. One-hundred and thirty-three multiple spatially separated samples were obtained from 8 patients with metastatic colorectal cancers and 8 with non-metastatic colorectal cancers, from the tumor center (TC), invasive front (IF) and metastasis. Differences in gene and microRNA expression were investigated by microarray and quantitative reverse-transcription PCR. Gene expression microarray analysis detected 7920 sites showing differing levels of gene expression among the TC, IF and metastasis. Expression of the EMT-associated gene zinc-finger E-box-binding homeobox 1 (ZEB1) significantly increased in the IF (p<0.01). To exclude individual differences, the expression ratio between TC and IF in each tumor was applied to analysis. This approach enabled recognition of the activation of the VEGF and Wnt signaling pathways, which were involved in metastasis via promotion of EMT. While no activation of these pathways was seen at the TC, regardless of whether tumors were metastatic or non-metastatic, they were preferentially activated at the IF in metastatic tumors, where high ZEB1 expression was seen in connection with decreased miR-200c expression. Multiple sampling in a tumor revealed that heterogeneous ZEB1 expression induced by EMT-associated signaling pathways played a pivotal role in metastasis via regulation of miR-200c.

Effect of triclosan-coated sutures on the incidence of surgical site infection after abdominal wall closure in gastroenterological surgery: a double-blind, randomized controlled trial in a single center

Background: Surgical site infection is one of the most common postoperative complications after gastroenterologic surgery. This study investigated the effect of triclosan‐coated sutures in decreasing the incidence of surgical site infections after abdominal wall closure in gastroenterologic surgery. Methods: A prospective, double‐blind, randomized, controlled parallel adaptive group‐sequential superiority trial was conducted from March 2014 to March 2017 in a single center. Eligible patients were those who underwent gastroenterologic surgery. Patients were allocated randomly to receive either abdominal wall closure with triclosan‐coated sutures (the study group) or sutures without triclosan (the control group). The primary end point was the incidence of superficial or deep surgical site infections within 30 days after operation. This study was registered with the University Hospital Medical Information Network‐Clinical Trials Registry (http://www.umin.ac.jp/ctr/), identification number UMIN000013054. Results: A total of 1,013 patients (study group, 508 patients; control group, 505 patients) were analyzed by a modified intention‐to‐treat approach. The wounds in 990 (97.7%) of the 1,013 patients were classified as clean‐contaminated. The primary end point (incidence of superficial or deep surgical site infections) was 35 (6.9%) of 508 patients in the study group and 30 (5.9%) of 505 in the control group. The incidence of surgical site infections did not differ markedly between the 2 groups (95% confidence interval: 0.686–2.010, P = .609). Of the 65 infections, 42 (64.6%) were superficial surgical site infections, with similar frequencies in the 2 groups, and 23 (35.4%) were deep surgical site infections, again with similar frequencies in the 2 groups. Conclusion: Triclosan‐coated sutures did not decrease the incidence of surgical site infections after abdominal wall closure in gastroenterologic surgery.

Sequential administration of XELOX and XELIRI is effective, feasible and well tolerated by patients with metastatic colorectal cancer

Sequential administration of the chemotherapy regimes capecitabine and oxaliplatin (XELOX) and capecitabine and irinotecan (XELIRI) in the first- to second-line treatment setting would allow patients to be managed more easily in an outpatient unit. However, a small number of studies have raised concerns of cumulative adverse events as a consequence of the continuous use of capecitabine. To investigate this, the present study conducted a retrospective review of 81 consecutive metastatic colorectal cancer (mCRC) patients treated with the oxaliplatin, fluorouracil and leucovorin-irinotecan, fluorouracil and leucovorin (FOLFOX-FOFIRI/F-F) regimen (n=40) or the XELOX-XELIRI (X-X) regimen (n=41) in first- to second-line chemotherapy in Saitama Medical Center between 2006 and 2012. The disease control rate (DCR), the progression free survival (PFS), the overall survival (OS) and the time to failure of strategy (TFS) from first to second-line chemotherapy, as well as adverse events, were assessed and compared between patients receiving X-X or F-F. A total of 10 and 20 patients were additionally treated with bevacizumab in the F-F and X-X regimens, respectively, during first or second-line chemotherapy. There was no significant difference in DCR and the median PFS between the two regimens for first or second-line chemotherapy. There was no significant difference in the median OS and TFS between the two regimens (OS=24.5 and TFS=14 months in the F-F vs. 23.2 and 12.0 months in the X-X). Regarding adverse events, 45.0% of patients (18/40) exhibited grade 3-4 neutropenia throughout treatment with F-F. Whilst, 15.0% of patients (6/41) exhibited grade 3 hypertension throughout treatment with X-X, which was effectively controlled by a single antihypertensive drug. The results show that sequential administration of X-X is as effective and feasible as F-F treatment, while additionally reducing the frequency of infusion visits and eliminating the need for a central venous access device or home infusion pump, thereby offering a more convenient treatment option to patients with mCRC.

Significance of the Difference in the Size of Liver Tumors in the Managementof Patients with Colorectal Liver Metastases

Background: The combination of chemotherapy and surgery is currently accepted for the treatment of patients with technically resectable colorectal liver metastases. It is, however, hard to determine which of these modalities should be the forward treatment. In this study, we assessed the usefulness of the difference in tumor size assessed in pretherapeutic imaging in the selection of chemotherapy in these patients. Methods: We present a retrospective review of 80 consecutive colorectal liver metastases without extrahepatic tumors. The relapse-free survival (RFS), progression-free survival (PFS) and overall survival (OS) were evaluated and compared between patients who underwent surgery (n=66) and chemotherapy (n=14) according to clinical features. In particular, we addressed pretherapeutic imaging studies including the distribution and number of metastatic liver tumors. In addition, the ratio of tumor size (largest to smallest tumor) was calculated; two groups classified as R<5 (ratio <5) and R ≥ 5 (ratio ≥ 5) were compared. Results: Univariate analysis was performed in the surgery group; significant differences in RFS were found regarding time of occurrence, the number of tumors and the ratio of tumor diameters. Multivariate analysis showed that the ratio of tumor size, R ≥ 5, was the only independent prognostic risk factor concerning both RFS and OS. We then compared the outcome of patients with prognostic risk factors between surgery and chemotherapy. Surgery achieved significantly better OS than chemotherapy, with the exception of the R ≥ 5 group. No difference in OS, in addition to RFS and PFS, was seen in the R ≥ 5 groups regardless of treatment. Conclusion: CRC patients with resectable liver metastases with R ≥ 5 showed no significant difference in outcome using surgery or chemotherapy. Chemotherapy could be used as an alternative to forward surgery to address oncological concerns such as the presence of latent metastases or poor treatment outcome in these patients.