Tumor Vascular Microenvironment of Colorectal Hepatic Metastasis and Chemotherapy Response.

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.

[Investigation of Lateral Lymph Node Dissection for Rectal Cancer in Our Department].

No clear policy has been established in Japan for proper lymph node dissection for rectal cancer. In our department, we examined the frequency of lateral lymph node metastasis, its treatment outcomes, and whether lateral dissection can narrow down necessary cases. In 10 years from 2003 to 2013, 98 cases of lower rectal cancer surgically treated in our department were examined. The clinicopathological factors in these cases were examined, and the risk factors were examined based on their correlation with the presence or absence of lateral lymph node metastasis. Based on the postoperative prognostic analysis, the dissection effect index(metastasis positive rate×5-year survival rate in cases with positive metastases)was also examined. Forty-three lateral lymph node dissections were performed. Cases involving a circumferential resection margin (CRM)of 1mm or less had significantly more lateral lymph node metastases. In the prognostic analysis, the 5-year survival rate of lateral lymph node metastasis-positive cases was 19%, and the dissection effect index was 3.5. It was suggested that CRM-positive patients had a higher risk of lateral lymph node metastasis before surgery. However, considering the results of this study and the results of JCOG0212, the presence or absence of lateral lymph node metastasis may be a prognostic predictor, although the prognostic improvement effect by dissection is considered to be limited.

Long-term outcomes after surgical resection in patients with stage IV colorectal cancer: a retrospective study of 129 patients at a single institution.

BACKGROUND AND PURPOSE: Approximately 20% of all patients with colorectal cancer (CRC) are diagnosed at more advanced stages with synchronous distant metastasis, and the prognosis in these patients is usually poor. The aim of this study was to determine the factors that can identify subgroup(s) of patients with stage IV CRC who could benefit from curative (R0) resection of both primary and metastatic lesions. PATIENTS AND METHODS: A total of 126 patients with stage IV CRC who underwent surgical resection of primary tumor were retrospectively analyzed. Among these patients, 26 cases of R0 resection were further examined subsequently. Information on various clinicopathological factors of the patients were obtained from hospital records. Overall survival was estimated using the Kaplan-Meier method, and log-rank tests were used to compare survival distribution. All the factors with P < 0.05 in univariate analysis were analyzed in the Cox proportional hazards model. RESULTS: CEA negativity, left-sided tumor, R0 resection, differentiated histology, and nodal staging less than N1 were independent factors that predicted better prognosis in all the 126 patients with stage IV CRC. Tumor depth of T3 or less was significantly correlated with better survival in patients who had undergone R0 resection. CONCLUSION: Our findings demonstrate that it is possible to select patients in whom surgical resection would yield better prognosis, from a variety of patient subgroups with stage IV CRC.

Clinical Impact of Histological Heterogeneity in the Metastatic Lymph Nodes of Patients with Colorectal Cancer.

AIM: The purpose of this study was to evaluate the clinical impact of histological heterogeneity in patients with node-positive colorectal cancer (CRC). PATIENTS AND METHODS: One hundred and twenty-nine patients who underwent curative surgical resection for histological node-positive CRC were enrolled. Patients were divided according to the histological heterogeneity in the primary lesion into p-hetero and p-homo groups. The p-hetero group was further divided according to histological heterogeneity in the metastatic lymph nodes into n-hetero and n-homo groups. RESULTS: There were no significant differences between p-homo and p-hetero groups and between n-homo and n-hetero groups in prognosis. However, the recurrence-free survival rate of the n-homo group was significantly lower than that of the n-hetero group in the N2 category. CONCLUSION: Histological heterogeneity in metastatic lymph nodes may be useful for predicting prognosis, and prognosis in those with histological heterogeneity in a metastatic lymph node is not necessarily poor, even in those of the N2 category.

Evaluation of anaerobic biodegradability of forage rice straw fertilized with livestock waste.

Fertilizing livestock waste for forage rice production can remove nitrogen and reduce the need for chemical fertilizers. Furthermore, rice straw can be used for biogas production. Here, the growth characteristics of different forage rice varieties in Japanese paddy fields fertilized with liquid cattle waste were investigated. Six experimental plots were established in a paddy field planted with three varieties of forage rice developed for livestock feed. Methane production potential assays were then conducted to investigate the anaerobic digestion characteristics of the stems and leaves of these three varieties. The total methane production potential of the Leafstar variety was higher than that of other varieties, while its lag phase was significantly shorter. Co-digestion of ethanol fermentation residue with Leafstar straw revealed that the NH(4)(+)-N concentration decreased as the C/N ratio increased. Additionally, the methane production potential of the mixed substrate was higher than that of ethanol fermentation residue or forage rice straw applied alone. Hence, Leafstar forage rice is a promising variety for establishment of agricultural resource recycling systems in which higher straw biomass can be achieved by applying liquid cattle waste and more biogas can be produced due to the potential for increased methane production.

Global histone modification of histone H3 in colorectal cancer and its precursor lesions.

Chromatin remodeling through histone modification is an important mechanism of epigenetic gene dysregulation in human cancers. However, little is known about global alteration of histone status during tumorigenesis and cancer progression. Histone H3 status was examined in benign and malignant colorectal tumors by immunohistochemistry and Western blotting. For immunohistochemical evaluation, 4 anti-histone H3 antibodies, specific to dimethylation at lysine 4 (H3K4me2), acetylation at lysine 9 (H3K9ac), dimethylation at lysine 9 (H3K9me2), and trimethylation at lysine 27 (H3K27me3), were used. On immunohistochemistry, H3K4me2, H3K9ac, and H3K27me3 showed no significant changes between normal and colorectal tumors. On the other hand, the global level of H3K9me2 was distinctly higher in neoplastic cells (adenoma and adenocarcinoma) than in normal glandular cells. In addition, it was significantly higher in adenocarcinoma than in adenoma. Correspondingly, Western blotting confirmed that H3K9me2 expression was significantly higher in adenocarcinomas than in normal colorectal mucosa. No alteration of H3K9me2 was observed with tumor differentiation and with the histological subtypes of colorectal cancers. These results suggest that aberration of the global H3K9me2 level is an important epigenetic event in colorectal tumorigenesis and carcinogenesis involved with gene regulation in neoplastic cells through chromatin remodeling.

Diagnosis of colorectal hepatic metastases: comparison of contrast-enhanced CT, contrast-enhanced US, superparamagnetic iron oxide-enhanced MRI, and gadoxetic acid-enhanced MRI.

PURPOSE: To compare the diagnostic accuracy of contrast-enhanced computed tomography (CE-CT), contrast-enhanced ultrasonography (CE-US), superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI), and gadoxetic acid-enhanced MRI (Gd-EOB-MRI) in the evaluation of colorectal hepatic metastases. MATERIALS AND METHODS: In all, 111 patients with colorectal cancers were enrolled in this study. Of the 112 metastases identified in 46 patients, 31 in 18 patients were confirmed histologically and the remaining 81 in 28 patients were confirmed by follow-up imaging. CE-CT, CE-US, SPIO-MRI, and Gd-EOB-MRI were evaluated. Mean (of three readers, except for CE-US) area under the receiver operating characteristic curve (A(z) ), sensitivities, and positive predictive values (PPV) were calculated. Each value was compared to the others by variance z-test or chi-square test with Bonferroni correction. RESULTS: For all lesions, mean A(z) and sensitivity of Gd-EOB-MRI (0.992, 95% [56/59]) were significantly greater than those of CE-CT (0.847, 63% [71/112]) and CE-US (0.844, 73% [77/106]). For lesions ≤1 cm, mean A(z) and sensitivity of Gd-EOB-MRI (0.999, 92% [22/24]) were significantly greater than those of CE-CT (0.685, 26% [13/50]) and CE-US (0.7, 41% [18/44]). Mean A(z) (95% CI) of SPIO-MRI for all lesions (0.966 [0.929-0.987]) and lesions ≤ 1 cm (0.961 [0.911-0.988]) were significantly greater than those of CE-CT and CE-US. Mean sensitivity of SPIO-MRI for lesions ≤1 cm (63%, 26/41) was significantly greater than that of CE-CT. CONCLUSION: Gd-EOB-MRI and SPIO-MRI were more accurate than CE-CT and CE-US for evaluation of liver metastasis in patients with colorectal carcinoma.

Diagnosis of colorectal hepatic metastases: Contrast-enhanced ultrasonography versus contrast-enhanced computed tomography versus superparamagnetic iron oxide-enhanced magnetic resonance imaging with diffusion-weighted imaging.

PURPOSE: To compare the diagnostic accuracy of contrast-enhanced ultrasonography (CE-US), contrast-enhanced CT (CE-CT), and superparamagnetic iron oxide-enhanced MRI (SPIO-MRI) with diffusion-weighted imaging (DWI) in the evaluation of colorectal hepatic metastases. MATERIALS AND METHODS: Thirty-six patients with colorectal cancers were prospectively enrolled and retrospectively evaluated. Of the 86 metastases identified, 16 were confirmed histologically and the remaining 70 were confirmed by follow-up imaging. CE-CT and SPIO-MRI + DWI were independently evaluated by two readers, whereas CE-US was evaluated by consensus reading of two different readers. Area under receiver operating characteristic curve (A(z)), sensitivities, and positive predictive values (PPVs) were calculated and compared. RESULTS: For both readers, SPIO-MRI+DWI had significantly greater A(z) (0.879 and 0.904) and sensitivity (78% and 87%) for all lesions compared with CE-CT (0.779 and 0.793; 59% and 59%) and CE-US (0.811; 69%), and significantly greater A(z) (0.783 and 0.837) and sensitivity (56% and 73%) for lesions ≤1 cm compared with CE-CT (0.562 and 0.601; 20% and 22%) and CE-US (0.66; 37%). For lesions >1 cm, there was no significant difference in A(z), sensitivity and PPV between all the image sets. CONCLUSION: SPIO-MRI with DWI was the most reliable modality for evaluation of liver metastases particularly for lesions ≤1 cm.

Imaging of small hepatic metastases of colorectal carcinoma: how to use superparamagnetic iron oxide-enhanced magnetic resonance imaging in the multidetector-row computed tomography age?

PURPOSE: To compare the accuracy of dynamic contrast-enhanced multidetector-row computed tomography (CT) and superparamagnetic iron oxide-enhanced magnetic resonance imaging (MRI) in the evaluation of small hepatic metastases of colorectal carcinoma. MATERIALS AND METHODS: Of 94 patients with colorectal carcinoma analyzed, 76 hepatic metastases (<2 cm) were diagnosed in 17 patients. Superparamagnetic iron oxide (SPIO)-magnetic resonance (precontrast and postcontrast MRI) and dynamic contrast-enhanced multidetector-row CT (dynamic CT [precontrast, arterial, portal-venous, and delayed phase]) were evaluated. The alternative free-response receiver operating characteristic analysis was performed, and the sensitivities and positive predictive values were analyzed. RESULTS: The Az values and sensitivities of portal-venous phase CT, dynamic CT, and SPIO-MRI (0.62/59%, 0.69/61%, and 0.67/61%) were identical. The mean positive predictive value of dynamic CT (82%) was inferior to that of SPIO-MRI (91%). CONCLUSIONS: The diagnostic ability of dynamic CT is identical to that of SPIO-MRI in Az value and sensitivity. Superparamagnetic iron oxide-MRI should be recommended only if an equivocal lesion is detected by dynamic CT.

High-b value diffusion-weighted MRI for detecting pancreatic adenocarcinoma: preliminary results.

OBJECTIVE: The objective of our study was to evaluate the usefulness of high-b value diffusion-weighted MRI (DWI) in the detection of pancreatic adenocarcinoma. SUBJECTS AND METHODS: Twenty-six patients with pancreatic adenocarcinoma were included in the study. Twenty-three other patients who were being followed up due to pancreatic diseases other than adenocarcinoma were included as control subjects. All patients and subjects underwent DWI, and the images were evaluated by three blinded radiologists. RESULTS: Receiver operating characteristic (ROC) curve analysis yielded A(z) values (i.e., area under the ROC curve) of 0.998, 0.998, and 0.995 for the three radiologists. The mean sensitivity and specificity for the detection of pancreatic adenocarcinoma were 96.2% and 98.6%, respectively. The kappa values indicating interobserver agreement between different pairs of radiologists were in the category of excellent. CONCLUSION: High-b value DWI allows the detection of pancreatic adenocarcinoma with a high sensitivity and specificity.

High-B-value diffusion-weighted MRI in colorectal cancer.

OBJECTIVE: The purpose of this article is to evaluate the usefulness of high-b-value diffusion-weighted MRI (DW-MRI) in the detection of colorectal adenocarcinoma. CONCLUSION: High-b-value DW-MRI allows detection of colorectal adenocarcinoma with a high sensitivity and specificity.

Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study.

Overexpression of HER-2 and the epidermal growth factor receptor (EGFR) has been observed in many cancers, sometimes accompanied by gene amplification. To assess whether novel chemotherapies targeting these overexpressed proteins may be effective for the treatment of colorectal cancers, we examined the exact frequency of HER-2 and EGFR overexpression, the relationship between gene amplification and protein expression, and the heterogeneity of gene amplification within and between primary and metastatic tumors. We evaluated 244 colorectal cancers immunohistochemically. All tumors found to overexpress HER-2 or EGFR were further analyzed for gene amplification by fluorescent in situ DNA hybridization. Overexpression of HER-2 and EGFR was found in 8 (3%) and 19 (8%) of the 244 colorectal carcinomas, respectively. Gene amplification was observed in 100 and 58% of the tumors exhibiting HER-2 and EGFR overexpression, respectively. HER-2 amplification in cancer cells was characterized by clusters of hybridization signals, suggesting amplicons in homogeneously staining regions that were predominant in most primary and metastatic tumors. EGFR amplification, observed as scattered signals reminiscent of amplicons in double minute chromosomes, or coamplification of EGFR with the centromeric regions was observed as a minor population within primary tumors, and found in variety of populations in metastatic tumors. Overexpression of HER-2 and EGFR were observed in only a small fraction of colorectal carcinomas, but were frequently accompanied by gene amplification.