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Tumor mutational burden (TMB) is gaining attention as a biomarker for responses to immune checkpoint inhibitors in cancer patients. In this study, we evaluated the status of TMB in primary and liver metastatic lesions in patients with colorectal cancer (CRC). In addition, the status of TMB in primary and liver metastatic lesions was inferred by radiogenomics on the basis of computed tomography (CT) images. The study population included 24 CRC patients with liver metastases. DNA was extracted from primary and liver metastatic lesions obtained from the patients and TMB values were evaluated by next‐generation sequencing. The TMB value was considered high when it equaled to or exceeded 10/100 Mb. Radiogenomic analysis of TMB was performed by machine learning using CT images and the construction of prediction models. In 7 out of 24 patients (29.2%), the TMB status differed between the primary and liver metastatic lesions. Radiogenomic analysis was performed to predict whether TMB status was high or low. The maximum values for the area under the receiver operating characteristic curve were 0.732 and 0.812 for primary CRC and CRC with liver metastasis, respectively. The sensitivity, specificity, and accuracy of the constructed models for TMB status discordance were 0.857, 0.600, and 0.682, respectively. Our results suggested that accurate inference of the TMB status is possible using radiogenomics. Therefore, radiogenomics could facilitate the diagnosis, treatment, and prognosis of patients with CRC in the clinical setting., This study evaluated the status of tumor mutation burden (TMB) in primary and liver metastatic lesions in patients with colorectal cancer using radiogenomics. In 7 out of 24 patients (29.2%), the TMB status differed between the primary and liver metastatic lesion. Radiogenomic analysis was used to accurately predict whether TMB status was high or low.

Radiogenomics has attracted attention for predicting the molecular biological characteristics of tumors from clinical images, which are originally a collection of numerical values, such as computed tomography (CT) scans. A prediction model using genetic information is constructed using thousands of image features extracted and calculated from these numerical values. In the present study, RNA sequencing of pancreatic ductal adenocarcinoma (PDAC) tissues from 12 patients was performed to identify genes useful in evaluating clinical pathology, and 107 PDAC samples were immunostained to verify the obtained findings. In addition, radiogenomics analysis of gene expression was performed by machine learning using CT images and constructed prediction models. Bioinformatics analysis of RNA sequencing data identified integrin αV (ITGAV) as being important for clinicopathological factors, such as metastasis and prognosis, and the results of sequencing and immunostaining demonstrated a significant correlation (r=0.625, P=0.039). Notably, the ITGAV high‑expression group was associated with a significantly worse prognosis (P=0.005) and recurrence rate (P=0.003) compared with the low‑expression group. The ITGAV prediction model showed some detectability (AUC=0.697), and the predicted ITGAV high‑expression group was also associated with a worse prognosis (P=0.048). In conclusion, radiogenomics predicted the expression of ITGAV in pancreatic cancer, as well as the prognosis.

Background Radiogenomics is an emerging field that integrates “Radiomics” and “Genomics”. In the current study, we aimed to predict the genetic information of pancreatic tumours in a simple, inexpensive, and non-invasive manner, using cancer imaging analysis and radiogenomics. We focused on p53 mutations, which are highly implicated in pancreatic ductal adenocarcinoma (PDAC), and PD-L1, a biomarker for immune checkpoint inhibitor-based therapies. Methods Overall, 107 patients diagnosed with PDAC were retrospectively examined. The relationship between p53 mutations as well as PD-L1 abnormal expression and clinicopathological factors was investigated using immunohistochemistry. Imaging features (IFs) were extracted from CT scans and were used to create prediction models of p53 and PD-L1 status. Results We found that p53 and PD-L1 are significant independent prognostic factors (P = 0.008, 0.013, respectively). The area under the curve for p53 and PD-L1 predictive models was 0.795 and 0.683, respectively. Radiogenomics-predicted p53 mutations were significantly associated with poor prognosis (P = 0.015), whereas the predicted abnormal expression of PD-L1 was not significant (P = 0.096). Conclusions Radiogenomics could predict p53 mutations and in turn the prognosis of PDAC patients. Hence, prediction of genetic information using radiogenomic analysis may aid in the development of precision medicine.

Pancreatic cancer is an aggressive tumor associated with poor survival, and early detection is important to improve patient outcomes. In the present study, we examined MIR1246 expression as a biomarker of pancreatic cancer. Total RNA was extracted from serum, urine and saliva samples from healthy subjects (n = 30) and patients with pancreatic cancer (n = 41, stage 0–IV). The MIR1246 level in each fluid was analyzed by quantitative reverse transcription-polymerase chain reaction. Significantly higher MIR1246 expression in serum and urine was observed in patients with cancer than in healthy controls. A significant positive correlation was found between serum and urine MIR1246 expression (r = 0.34). Receiver operating characteristic curves were constructed for MIR1246 in all three body fluids. The area under the curve for serum MIR1246 was 0.87 (sensitivity, 92.3%; specificity, 73.3%), and that for urine MIR1246 was 0.90 (sensitivity, 90.2%; specificity, 83.3%). With a cut-off of the control group’s mean plus twice the standard deviation, the sensitivities of MIR1246 in serum and urine for pancreatic cancer were 60.9 and 58.5%, respectively. Combining both serum and urine MIR1246 expression yielded a sensitivity of 85%. These results indicate that MIR246 may be a useful diagnostic biomarker for pancreatic cancer.

Indocyanine green (ICG) fluorescence imaging has been used to assess the blood perfusion of the gastrointestinal tract in surgery. Especially, it was used to determine the best anastomotic site. However, in previous studies, ICG fluorescence was judged subjectively based on the visual appearance. This study evaluated the usefulness of our novel method to quantitatively assess the blood perfusion of the gastric conduit in esophagectomy based on ICG fluorescence.Twenty patients who underwent esophagectomy with gastric conduit reconstruction were prospectively investigated. Using a camera in contact with the surface of the stomach, ICG images were quantitatively evaluated using "ROIs", a software program that quantified the fluorescence intensity and created a time-fluorescence intensity curve to assess the blood perfusion three times intraoperatively.No postoperative esophago-gastrostomy leakage developed. However, after preparing the gastric conduit and just before anastomosis, the maximum increase in fluorescence intensity (FImax) significantly decreased (48.8 ± 26.0 and 31.5 ± 14.9 versus 84.9 ± 28.2; P 0.001 and P 0.001, respectively), and the time to reach FImax was significantly extended (60 ± 35.4 and 58.3 ± 34.9 versus 18.9 ± 6.5; P 0.001 and P 0.002, respectively), in comparison to the control value. Just before anastomosis, 18 cases (90%) showed an identical pattern characterized by an obtuse and low arterial inflow peak and a slow rise of fluorescence intensity over time, indicating a decreased blood flow.The quantitative analysis of ICG fluorescence imaging could objectively prove a decrease in blood perfusion-which could not be determined macroscopically-in the gastric conduit before esophageal reconstruction. The results from the present and further studies may indicate its clinical value.

Esophageal squamous cell carcinoma is a malignant tumor with unfavorable prognosis. In this study, we investigated the usefulness of microRNA (miR)-1246 detection in various body fluids as a biomarker for this disease. A total of 72 patients with esophageal squamous cell carcinoma were enrolled, and their blood, urine, and saliva samples were collected prior to treatment. Reverse transcription–polymerase chain reaction of miR-1246 was performed, and pre- and postoperative and intraday fluctuations in its expression were examined. The expression of miR-1246 in the blood and urine was significantly higher in the patients with esophageal squamous cell carcinoma than in 50 healthy control subjects. Receiver operating characteristic curves showed that the area under the curve values were 0.91 (sensitivity 91.7%, specificity 76.0%), 0.82 (sensitivity 90.3%, specificity 62.0%), and 0.80 (sensitivity 83.3%, specificity 66.0%) in the serum, urine, and saliva, respectively. A relatively high diagnostic performance of miR-1246 was observed in all samples, which was better than that of the existing biomarkers squamous cell carcinoma antigen, carcinoembryonic antigen, and cytokeratin 19 fragment. No clear correlation was observed in the levels of miR-1246 expression among the three body fluids. Postoperatively, serum samples displayed significantly decreased miR-1246 levels. Although not significant, changes in the miR-1246 levels were observed at all collection times, with large fluctuations in the saliva. Meanwhile, serum miR-1246 expression was found to be associated with the disease prognosis. The results indicate that the levels of miR-1246 in the urine, saliva, and serum are a useful biomarker for esophageal squamous cell carcinoma and support the use of urine samples instead of blood samples for noninvasive diagnosis.

The p16 gene, which is also known as CDKN2A, INK4A, or CDK4I, and its products that are known to be cell cycle inhibitors and tumor suppressors have been reported to be altered in various human tumor types. Altered p16 has been indicated to be correlated with negative p16 expression using immunohistochemistry (IHC). However, its association with the prognosis remains controversial because the findings of previous studies are inconsistent. The current study evaluated the relationship between the expression levels of p16 and the clinicopathological features associated with prognosis in patients with primary pancreatic ductal adenocarcinomas (PDACs). From January 2013 to December 2017, tissues of 103 PDAC patients who had undergone elective pancreatic resection were obtained and assessed for p16 expression by IHC. No correlation was observed between p16 status and clinicopathological factors (P>0.05). Notably, negative p16 expression on IHC was not significantly associated with poor prognosis using the Kaplan-Meier method.

Radiogenomics is a new field that provides clinically useful prognostic predictions by linking molecular characteristics such as the genetic aberrations of malignant tumors with medical images. The abnormal expression of serum microRNA-1246 (miR-1246) has been reported as a prognostic factor of esophageal squamous cell carcinoma (ESCC). To evaluate the power of the miR-1246 level predicted with radiogenomics techniques as a predictor of the prognosis of ESCC patients. The real miR-1246 expression (miR-1246real) was measured in 92 ESCC patients. Forty-five image features (IFs) were extracted from tumor regions on contrast-enhanced computed tomography. A prediction model for miR-1246real was constructed using linear regression with selected features identified in a correlation analysis of miR-1246real and each IF. A threshold to divide the patients into two groups was defined according to a receiver operating characteristic analysis for miR-1246real. Survival analyses were performed between two groups. Six IFs were correlated with miR-1246real and were included in the prediction model. The survival curves of high and low groups of miR-1246real and miR-1246pred showed significant differences (p = 0.001 and 0.016). Both miR-1246real and miR-1246pred were independent predictors of overall survival (p = 0.030 and 0.035). miR-1246pred produced by radiogenomics had similar power to miR-1246real for predicting the prognosis of ESCC.

The prognosis of metastatic recurrent non-small cell lung cancer (NSCLC) is poor, and chemotherapy improves survival by only a few months. The concept of oligo-recurrence, defined as a small number of new lesions at a distant site theoretically curable by local therapy, has recently been proposed for several cancers. To evaluate the possible benefits of surgical resection for oligo-recurrence, we report the outcomes of seven patients who underwent hepatic resection for oligo-recurrence of NSCLC in the liver. Among the 2038 patients who underwent resection for NSCLC between January 1997 and December 2015 at the Department of Chest Surgery, Chiba Cancer Center, 7 (0.34%) with oligo-recurrence in the liver underwent hepatectomy. Perioperative data were retrospectively reviewed, including recurrence-free and overall survival. Primary tumor histopathological types included five cases of squamous cell carcinoma, one case of adenocarcinoma, and one case of large-cell carcinoma. All patients underwent complete tumor resection without complication. The median survival duration following hepatectomy was 24.0 (range 15.2–30.2) months. Four patients were alive at the end of follow-up (23.4–30.2 months), whereas three died between 15.2 and 24.5 months. There was no evidence of second recurrence in two patients. Hepatectomy may be equally effective as multidisciplinary therapy for oligo-recurrence of NSCLC in the liver.

The function of microRNAs (miRs) is associated with the development and progression of various malignancies, with miRs presenting stably in the serum. The current study assessed the role of miR-1246 and miR-106b in the serum of patients with esophageal squamous cell carcinoma (ESCC). A comprehensive microarray analysis of miR expression was performed using the serum of patients with ESCC, which were subsequently validated via reverse transcription-quantitative PCR. A total of 55 test samples were obtained from Chiba University and 101 validation samples were gained from Chiba Cancer Center. The results revealed that miR-1246 expression significantly increased and miR-106b expression significantly decreased in each cohort. Receiver operating characteristic analysis revealed that the area under the curve (AUC) value of miR-1246 was 0.816 (sensitivity, 72.7%; specificity, 69.2%) and 0.779 (sensitivity, 71.3%; specificity, 70.6%) for the test and validation cohorts, respectively. The AUC of miR-106b was 0.716 (sensitivity, 65.5%; specificity, 61.6%) and 0.815 (sensitivity, 74.3%; specificity, 73.5%), respectively. In addition, the AUC of the miR-1246/miR-106b ratio was 0.901 (sensitivity, 80.0%; specificity, 80.0%) and 0.903 (sensitivity, 82.1%; specificity, 82.3%), respectively, which indicated a higher diagnostic ability compared with that of miR-1246 or miR-106b alone. The high miR-1246/miR-106b ratio group was associated with clinicopathological factors such as depth of invasion, progression, lymph node metastasis, and poor prognosis. Therefore, effective biomarkers may be generated by combining individual miRs obtained by comprehensive analysis of ESCC patient sera.

Expression of genes is controlled by histone modification, histone acetylation and methylation, but abnormalities of these modifications have been observed in carcinogenesis and cancer development. The effect of the lysine-specific histone demethylase 1 (LSD1) inhibitor, a demethylating enzyme of histones, is thought to be caused by controlling the expression of genes. The aim of the present study is to elucidate the efficacies of the LSD1 inhibitor on the gene expression of esophageal cancer cell lines using chromatin immunoprecipitation (ChIP)-Seq. A comprehensive analysis of gene expression changes in esophageal squamous cell carcinoma (ESCC) cell lines induced by the LSD1 inhibitor NCL1 was clarified via analysis using microarray. In addition, ChIP-seq analysis was conducted using a SimpleChIP plus Enzymatic Chromatin IP kit. NCL1 strongly suppressed the proliferation of T.Tn and TE2 cells, which are ESCC cell lines, and further induced apoptosis. According to the combinatory analysis of ChIP-seq and microarray, 17 genes were upregulated, and 16 genes were downregulated in both cell lines. The comprehensive gene expression study performed in the present study is considered to be useful for analyzing the mechanism of the antitumor effect of the LSD1 inhibitor in patients with ESCC.

This study aimed to survey treatment ofgastric cancer via gastrectomy or endoscopic submucosal dissection(ESD)in patients aged 85 years or older and to clarify the risks and benefits of gastrectomy in terms of postoperative complications and prognosis. The analysis included 40 patients who were treated via gastrectomy and 41 who were treated via ESD. All patients were aged 85 years or older. Although most ofthe patients who had gastrectomy had good performance status(PS), comorbidities were found in 72.5%, and limited operation was often performed. In the gastrectomy group, R0 tumor-free resection margins were achieved in 75%, and postoperative complications occurred in 45%. Despite R0 surgery, the 2-year overall survival rate was 61.7% and the 3-year overall survival was 42.9%. Seven patients(17.1%)in the ESD group were diagnosed with T1b tumors, and no patients were shifted to surgery. Treatment decisions for super-elderly gastric cancer patients are made with regard to age, PS, and comorbidities. There is a limit to survival time after radical gastrectomy. It is necessary to examine the negative effect of gastrectomy on survival time. Selected patients aged 85 years or older with T1b gastric cancer should be given the option of ESD.

We report a case of mucinous adenocarcinoma of the appendix with peritoneal dissemination diagnosed by laparoscopic abdominal exploration and appendectomy. A man in his 60's was diagnosed with peritoneal dissemination of mucinous adenocarcinoma incidentally during an operation for an inguinal hernia. Carcinoma of the appendix was suspected as the primary lesion after further examination. We performed laparoscopic abdominal exploration and appendectomy. The purpose of the operation was to detect the primary lesion, make a pathological diagnosis, and to evaluate the extent of peritoneal dissemination. Laparoscopic findings revealed wide spread peritoneal dissemination and the pathological findings confirmed mucinous adenocarcinoma of the appendix. These laparoscopic procedures lead to a precise diagnosis and allowed for adequate treatment selection.

Background We tried integrated analysis of epigenomic information (Epigenomics) and image information (Radiomics) as Ragioepigenomics for esophageal cancer. Methods 1, Expression analysis of miR, evaluation as prognostic predictor (Epigenomics), 2, Image information analysis (Radiomics): a, Normalization of contrast CT images, feature quantities by 3D gray level co-occurrence matrix extraction. b, Normalization of SUV of FDG-PET image. Extraction of feature quantity by 3D gray level co-occurrence matrix. c, Image analysis of features. 3, Integrated analysis of Epigenomics and Radiomics information: We analyzed the relationship between miR expression level and variables obtained from image analysis. Results As a result of Cox regression by the selection method using elastic net, three variables were selected from contrast CT, and the results of both were consistent. Furthermore, when the survival curve and the log rank test were performed by the Kaplan-Meier method for the cluster shade high value group and the low value group, a significant difference was observed in the 2 groups. Conclusion A multimodal approach so called Radioepigenomics, which is a system for analyzing molecular information from image analysis will be applied to future Precision Medicine. Disclosure All authors have declared no conflicts of interest.

The patient was a 59-year-old woman with advanced double cancers of the stomach and endometrium with peritoneal metastasis. Abdominal computed tomography revealed that the endometrial cancer was more advanced than the gastric cancer; therefore, the peritoneal metastasis was diagnosed as arising from the endometrial cancer. Treatment of the endometrial cancer with cytoreductive surgery followed by adjuvant chemotherapy was performed first. She underwent total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Disseminated nodules were found throughout her abdomen. The histopathological findings indicated carcinosarcoma of the uterus, pT3bNXM1, Stage Ⅳb. One month after surgery, she received 6 courses of adjuvant chemotherapy with paclitaxel plus carboplatin. After the adjuvant chemotherapy, abdominal computed tomography revealed that both the ascites and the disseminated nodules had disappeared. Therefore, a second-look surgery for the endometrial cancer and definitive surgery for the gastric cancer were planned. At the laparotomy, no disseminated nodules were found, so distal gastrectomy and D2 lymphadenectomy were performed. The histopathological findings were pT4aN1M0P0Cy0, Stage ⅢA. She received adjuvant chemotherapy with S-1 for 1 year, and has been alive with no evidence of recurrence for 2 years and 7 months after the initial surgery.

We evaluated the difference in effectiveness between preoperative radiotherapy (RT) and chemotherapy (C) as part of multimodal therapy for locally advanced rectal cancer. In the RT group, 43 patients were enrolled and preoperative radiotherapy was performed with 42.6 Gy for 4 weeks. In the C group, 16 patients were treated with preoperative chemotherapy consisting of mFOLFOX6/XELOX plus bevacizumab for 3 months. All 43 tumors in the RT group were located in the lower rectum. The C group was composed of 9 in the lower rectum and 7 in the middle or upper rectum. The C group was more advanced than the RT group in terms of depth of invasion, lymph node metastasis, and tumor diameter. The histological treatment response was better after RT (7 with little, 10 with a minor, 24 with a major, and 2 with a complete response) than after C (10 with little, 4 with a minor, 1 with a major, and 1 with a complete response). The tumor reduction ratio by colonography showed 36.5% after RT and 28.7% after C. CEA was reduced by 47.2% after RT and 45.2% after C. Though RT is more effective for local lesions than C, C is expected to be preferred as the local and systemic therapy for locally advanced rectal cancer with pelvic organ involvement or lateral lymph node metastases.

Gastric carcinoma with lymphoid stroma (GCLS) is a histological type with severe lymphocytic infiltration. GCLS is very rare and few cases have been reported. We examined the clinical features, problems of preoperative diagnosis, and treatment of 14 cases (1.8%) that were diagnosed as GCLS out of 790 gastric cancers surgically resected in our hospital. The mean age was 69 years. Six, 8, and 0 cases were located in the upper, middle, and lower fields of the stomach, respectively, and 8, 1, 4, and 1 cases were macroscopically 0-Ⅱc, 0-Ⅰ, type 2, and type 3, respectively. The depth of invasion was M, SM1, SM2, MP, and SS in 0, 0, 9, 3, and 2 cases, respectively. There were 12 cases(86%)with infection by Epstein-Barr virus, and just 1 case with lymph node metastasis. All cases have had no evidence of recurrence. There were no cases that were diagnosed as GCLS before surgery. GCLS is recognized as having a more favorable prognosis compared with other types of gastric carcinoma, so an aggressive surgery might achieve good outcomes. However, preoperative diagnosis is very difficult and there is a compelling need for new techniques or criteria for diagnosis of GCLS.

A 78-year-old man presented with a chief complaint of dysphagia. He was diagnosed with an esophageal squamous cell carcinoma and referred to our hospital. A type 3 tumor was identified in the lower thoracic esophagus on endoscopy. A CT scan revealed lymph node metastases at the No. 3 station. The clinical stage of the tumor was T3N1M0, Stage III. The patient was treated with neoadjuvant chemotherapy consisting of2 courses of5 -FU and nedaplatin. He had a partial response and underwent a radical esophagectomy. Histopathological examination revealed a complete response of the primary lesion and viable cancer cells in only one lymph node at the No. 3 station. No adjuvant chemotherapy was administered. Three months after the operation, recurrences in the upper abdominal multiple para-aortic lymph nodes were detected. Although he was treated with chemotherapy, he died 7 months after the operation. Even after a complete response of the primary lesion was achieved using neoadjuvant chemotherapy, esophageal cancer with lymph node metastasis has the potential for an early recurrence. Therefore, we should consider adjuvant therapy in such cases.