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Considering the cost and invasiveness of monitoring postoperative minimal residual disease (MRD) of colorectal cancer (CRC) after adjuvant chemoradiotherapy (ACT), we developed a favorable approach based on methylated circulating tumor DNA to detect MRD after radical resection. Analyzing the public database, we identified the methylated promoter regions of the genes FGD5, GPC6, and MSC. Using digital polymerase chain reaction (dPCR), we termed the "amplicon of methylated sites using a specific enzyme" assay as "AMUSE." We examined 180 and 114 pre‐ and postoperative serial plasma samples from 28 recurrent and 19 recurrence‐free pathological stage III CRC patients, respectively. The results showed 22 AMUSE‐positive of 28 recurrent patients (sensitivity, 78.6%) and 17 AMUSE‐negative of 19 recurrence‐free patients (specificity, 89.5%). AMUSE predicted recurrence 208 days before conventional diagnosis using radiological imaging. Regarding ACT evaluation by the reactive response, 19 AMUSE‐positive patients during their second or third blood samples showed a significantly poorer prognosis than the other patients (p = 9E‐04). The AMUSE assay stratified four groups by the altered patterns of tumor burden postoperatively. Interestingly, only 34.8% of cases tested AMUSE‐negative during ACT treatment, indicating eligibility for ACT. The AMUSE assay addresses the clinical need for accurate MRD monitoring with universal applicability, minimal invasiveness, and cost‐effectiveness, thereby enabling the timely detection of recurrences. This assay can effectively evaluate the efficacy of ACT in patients with stage III CRC following curative resection. Our study strongly recommends reevaluating the clinical application of ACT using the AMUSE assay. [ABSTRACT FROM AUTHOR]

Purpose: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. Methods: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. Results: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. Conclusion: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward. [ABSTRACT FROM AUTHOR]

Background: Nodular regenerative hyperplasia (NRH) is a rare disease that presents pathologically as diffuse hepatic nodules without fibrous septa. It is believed to be caused by vasculopathy against a background of various systemic diseases, such as hematologic, autoimmune, and drug-induced diseases, with various symptoms. In spite of the recent imaging advances, various atypical cases of nodular lesions are observed in daily clinical practice. Cases that do not completely meet these criteria are referred to as -like or -similar lesions in clinical situations, making it difficult to understand their pathogenesis. We present a case in which two hepatic nodular lesions were noted and difficult to differentiate from malignancy preoperatively. The lesions were laparoscopically resected and a pathological diagnosis with non-neoplastic liver regenerative nodules resembling NRH was made. Case presentation: A 49-year-old man with no alcohol or drug intake and no past medical history was identified as having liver tumors on screening examination without any symptoms. Contrast-enhanced computed tomography (CT) showed two hepatic tumors; approximately 2-cm tumors at S7 and S8. Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed fat inclusions in their contents. Ethoxybenzyl (EOB) uptake was also observed during the hepatobiliary phase. Based on preoperative examinations, we suspected well-differentiated hepatocellular carcinoma (HCC) and performed laparoscopic S7/8 partial resection for these lesions. Macroscopically, the resected specimens showed a non-cirrhotic yellowish-cut surface containing brownish, ill-defined lesions with irregular borders. Microscopically, these lesions showed zonal necrosis, congestion, and aggregation of hemosiderin-laden macrophages around the central vein. In these areas, the fatty deposition of hepatocytes was lower than that in the surrounding background hepatocytes. Histopathologically, neither neoplastic nor hyperplastic lesions were observed, and he was diagnosed as regenerative hepatic change with centrilobular necrosis. Conclusions: Considering the pathological results, these lesions were thought to be a type of NRH-like lesion with possible hepatic vessel disorder. However, the lesion's cause and classification was difficult to determine. The accumulation of these regenerative changes accompanying fatty liver is needed to clarify the mechanism and its clinical significance. [ABSTRACT FROM AUTHOR]

Background: Nodular regenerative hyperplasia (NRH) is a rare disease that presents pathologically as diffuse hepatic nodules without fibrous septa. It is believed to be caused by vasculopathy against a background of various systemic diseases, such as hematologic, autoimmune, and drug-induced diseases, with various symptoms. In spite of the recent imaging advances, various atypical cases of nodular lesions are observed in daily clinical practice. Cases that do not completely meet these criteria are referred to as -like or -similar lesions in clinical situations, making it difficult to understand their pathogenesis. We present a case in which two hepatic nodular lesions were noted and difficult to differentiate from malignancy preoperatively. The lesions were laparoscopically resected and a pathological diagnosis with non-neoplastic liver regenerative nodules resembling NRH was made. Case presentation: A 49-year-old man with no alcohol or drug intake and no past medical history was identified as having liver tumors on screening examination without any symptoms. Contrast-enhanced computed tomography (CT) showed two hepatic tumors; approximately 2-cm tumors at S7 and S8. Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed fat inclusions in their contents. Ethoxybenzyl (EOB) uptake was also observed during the hepatobiliary phase. Based on preoperative examinations, we suspected well-differentiated hepatocellular carcinoma (HCC) and performed laparoscopic S7/8 partial resection for these lesions. Macroscopically, the resected specimens showed a non-cirrhotic yellowish-cut surface containing brownish, ill-defined lesions with irregular borders. Microscopically, these lesions showed zonal necrosis, congestion, and aggregation of hemosiderin-laden macrophages around the central vein. In these areas, the fatty deposition of hepatocytes was lower than that in the surrounding background hepatocytes. Histopathologically, neither neoplastic nor hyperplastic lesions were observed, and he was diagnosed as regenerative hepatic change with centrilobular necrosis. Conclusions: Considering the pathological results, these lesions were thought to be a type of NRH-like lesion with possible hepatic vessel disorder. However, the lesion's cause and classification was difficult to determine. The accumulation of these regenerative changes accompanying fatty liver is needed to clarify the mechanism and its clinical significance. [ABSTRACT FROM AUTHOR]

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and health‐care providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients. [ABSTRACT FROM AUTHOR]

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and healthcare providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology (JSCO) and the Japanese Society of Medical Oncology (JSMO), reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey demonstrated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients. [ABSTRACT FROM AUTHOR]

Background: In telementoring, differences in teaching methods affect local surgeons' comprehension. Because the object to be operated on is a three-dimensional (3D) structure, voice or 2D annotation may not be sufficient to convey the instructor's intention. In this study, we examined the usefulness of telementoring using 3D drawing annotations in robotic surgery. Methods: Kyushu University and Beppu Hospital are located 140 km apart, and the study was conducted using a Saroa™ surgical robot by RIVERFIELD Inc. using a commercial guarantee network on optical fiber. Twenty medical students performed vertical mattress suturing using a swine intestinal tract under surgical guidance at the Center for Advanced Medical Innovation Kyushu University. Surgical guidance was provided by Beppu Hospital using voice, 2D, and 3D drawing annotations. All robot operations were performed using 3D images, and only the annotations were independently switched between voice and 2D and 3D images. The operation time, needle movement, and performance were also evaluated. Results: The 3D annotation group tended to have a shorter working time than the control group (25.6 ± 63.2 vs. − 36.7 ± 65.4 min, P = 0.06). The 3D annotation group had fewer retries than the control group (1.3 ± 1.7 vs. − 1.1 ± 0.7, P = 0.006), and there was a tendency for fewer needle drops (0.4 ± 0.7 vs. − 0.5 ± 0.9, P = 0.06). The 3D annotation group scored significantly higher than the control group on the Global Evaluate Assessment of Robot Skills (16.8 ± 2.0 vs. 22.8 ± 2.4, P = 0.04). The 3D annotation group also scored higher than the voice (13.4 ± 1.2) and 2D annotation (16.2 ± 1.8) groups (3D vs. voice: P = 0.03, 3D vs. 2D: P = 0.03). Conclusion: Telementoring using 3D drawing annotation was shown to provide good comprehension and a smooth operation for local surgeons. [ABSTRACT FROM AUTHOR]

Background: Endoplasmic reticulum (ER) stress has a close relation with cancer progression. Blocking the adaptive pathway of ER stress could be an anticancer strategy. Here, we identified an ER stress-related gene, Transducin beta-like 2 (TBL2), an ER-localized type I transmembrane protein, on increased chromosome 7q as a candidate driver gene of lung adenocarcinoma (LUAD). Methods: The association between TBL2 mRNA expression and prognostic outcomes and clinicopathological factors was analyzed using The Cancer Genome Atlas (TCGA) datasets of LUAD and lung squamous cell carcinoma (LUSC). Localization of TBL2 in tumor tissues was observed by immunohistochemical staining. Gene set enrichment analysis (GSEA) was conducted using TCGA dataset. In vitro cell proliferation assays were performed using TBL2 knockdown LUAD cells, LUSC cells, and LUAD cells overexpressing TBL2. Apoptosis and ATF4 expression (ER stress marker) were evaluated by western blotting. Results: TBL2 was overexpressed in LUAD and LUSC cells. Multivariate analysis indicated high TBL2 mRNA expression was an independent poor prognostic factor of LUAD. GSEA revealed high TBL2 expression was positively correlated to the ER stress response in LUAD. TBL2 knockdown attenuated LUAD cell proliferation under ER stress. TBL2 inhibited apoptosis in LUAD cells under ER stress. TBL2 knockdown reduced ATF4 expression under ER stress. Conclusions: TBL2 may be a novel driver gene that facilitates cell proliferation, possibly by upregulating ATF4 expression followed by adaptation to ER stress, and it is a poor prognostic biomarker of LUAD. [ABSTRACT FROM AUTHOR]

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was first proposed by Wothley et al. in 2012 as a rare familial gastric cancer syndrome associated with an autosomal dominant form of inheritance. GAPPS is characterized by gastric basal gland polyposis from the hilum to the body of the stomach. Li et al. in 2016 showed that the cause of the disease is a point mutation in the promotor 1B region of the APC gene, and genetic testing was used to confirm the diagnosis. If the patient has already developed gastric cancer, treatment should be based on the usual treatment for gastric cancer. If no distant metastases exist, a good prognosis can be expected by performing a total gastrectomy. On the other hand, patients with distant metastasis have a poor prognosis. In the case of dysplasia, prophylactic total gastrectomy is recommended, but because it is highly invasive and postoperative postgastrectomy syndrome must be considered, the decision should be made with careful consideration of the patient's background. Therefore, there are no guidelines for screening for GAPPS, the timing of prophylactic total gastrectomy, or methods of endoscopic surveillance. Because GAPPS is a rare disease, its natural history is still unclear. Further case series are needed to elucidate the molecular biology and clinicopathological features of GAPPS and to establish clinical management, including diagnosis, treatment, and surveillance. In this review, we provide an overview of GAPPS, its clinical management, and its problems, which will be useful for the treatment of GAPPS. [ABSTRACT FROM AUTHOR]

Background: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. Methods: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. Results: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. Conclusion: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery. [ABSTRACT FROM AUTHOR]

The detection and sequencing of the mutated ctDNA is one of the irreplaceable clinical measures in the postoperative management of colorectal cancer (CRC) cases. However, we are curious to comprehend the essential traits of mutated genes comprising metastatic sites out of whole mutated genes in primary sites. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes on the panel showed abundant expression but no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors. [ABSTRACT FROM AUTHOR]

Background: Serum microRNAs (miRNAs) have been recognized as potential stable biomarkers for various types of cancer. Considering the clinical applications, there are certain critical requirements, such as minimizing the number of miRNAs, reproducibility in a longitudinal clinical course, and superiority to conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9. This study aimed to identify serum miRNAs that indicate the recurrence of colorectal cancer (CRC), surpassing inter-tumor heterogeneity. Methods: We conducted an analysis of 434 serum samples from 91 patients with CRC and 71 healthy subjects. miRNAs were obtained from Toray Co., Ltd, and miRNA profiles were analyzed using a three-step approach. miRNAs that were highly expressed in patients with CRC than in the healthy controls in the screening phase, and those that were highly expressed in the preoperative samples than in the 1-month postoperative samples in the discovery phase, were extracted. In the validation phase, the extracted miRNAs were evaluated in 323 perioperative samples, in chronological order. Results: A total of 12 miRNAs (miR-25-3p, miR-451a, miR-1246, miR-1268b, miR-2392, miR-4480, miR-4648, miR-4732-5p, miR-4736, miR-6131, miR-6776-5p, and miR-6851-5p) were significantly concordant with the clinical findings of tumor recurrence, however their ability to function as biomarkers was comparable with CEA. In contrast, the combination of miR-1246, miR-1268b, and miR-4648 demonstrated a higher area under the curve (AUC) than CEA. These three miRNAs were upregulated in primary CRC tissues. Conclusion: We identified ideal combinatorial miRNAs to predict CRC recurrence. [ABSTRACT FROM AUTHOR]

Here, we present a 69-year-old female with advanced neuroendocrine carcinoma (NEC) of colon with multiple liver, bone, and kidney metastases who developed Trousseau's syndrome. The patient received etoposide plus cisplatin (EP) as the first-line therapy; however, after single administration of EP, she developed the severe lower-limb edema and EP was considered to be intolerable. Etoposide plus carboplatin was administered as the second-line therapy and after 3 cycles of administration, the progressive disease (PD) was confirmed and 5-fluorouracil + leucovorin + irinotecan (FOLFIRI) plus ramucirumab was administered as the third-line therapy. However, PD was confirmed after 3 cycles of the therapy, and she was to receive the best supportive care and was hospitalized in our hospital. Four weeks after hospitalization, mild impaired consciousness and dysarthria were observed. Blood tests showed coagulation abnormalities including elevation of plasma fibrin/fibrinogen degradation products (FDPs) and D-dimer levels, and the diffusion-weighted image of magnetic resonance imaging (MRI) of the head showed multiple cerebral infarcts. She was diagnosed with Trousseau's syndrome due to the progression of NEC and intravenous unfractionated heparin was administered as anticoagulant therapy. After the administration of heparin, plasma FDP and D-dimer levels decreased; however, due to the progression of NEC, the patient died 6 weeks after hospitalization. This is the first report of NEC of the colon that developed Trousseau's syndrome. [ABSTRACT FROM AUTHOR]

Aim: Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. Methods: Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura–Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C‐1 and C‐2), grade 2 (C‐3 and O‐1), and grade 3 (O‐2 and O‐3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. Results: miR‐196b‐3p was significantly upregulated, and miR‐92a‐2‐5p was downregulated (P <.05 and q < 0.2). TCGA data showed a high expression of miR‐196b‐3p in gastric cancer cases (P <.001). Comparing grade 3 and the others, the area under the receiver operating characteristic curve using the detected miRNAs was as high as about 0.7. Furthermore, the combination of miRNAs resulted in higher accuracy. In terms of the significance of the combinatory mRNAs, the combination of three miRNAs (miR‐196b‐3p, miR‐92a‐2‐5p, and miR‐6791‐3p) revealed high sensitivity and specificity, with the area under the curve exceeding 0.8. Conclusion: The identified combinatory miRNAs may represent promising biomarkers of precancerous lesions in gastric cancer. [ABSTRACT FROM AUTHOR]

Background and Aim: The risk of hepatocellular carcinoma (HCC) persists in a condition of sustained virologic response (SVR) after hepatitis C virus (HCV) eradication. Comprehensive molecular analyses were performed to test the hypothesis that epigenetic abnormalities present after an SVR play a role in hepatocarcinogenesis. Methods: Whole‐genome methylome and RNA sequencing were performed on HCV, SVR, and healthy liver tissue. Integrated analysis of the sequencing data focused on expression changes in transcription factors and their target genes, commonly found in HCV and SVR. Identified expression changes were validated in demethylated cultured HCC cell lines and an independent validation cohort. Results: The coincidence rates of the differentially methylated regions between the HCV and SVR groups were 91% in the hypomethylated and 71% in the hypermethylated regions in tumorous tissues, and 37% in the hypomethylated and 36% in the hypermethylated regions in non‐tumorous tissues. These results indicate that many epigenomic abnormalities persist even after an SVR was achieved. Integrated analysis identified 61 transcription factors and 379 other genes that had methylation abnormalities and gene expression changes in both groups. Validation cohort specified gene expression changes for 14 genes, and gene ontology pathway analysis revealed apoptotic signaling and inflammatory response were associated with these genes. Conclusion: This study demonstrates that DNA methylation abnormalities, retained after HCV eradication, affect the expression of transcription factors and their target genes. These findings suggest that DNA methylation in SVR patients may be functionally important in carcinogenesis, and could serve as biomarkers to predict HCC occurrence. [ABSTRACT FROM AUTHOR]

Drugs are expected to recover the cell system away from the impaired state to normalcy through disease treatment. However, the understanding of gene regulatory machinery underlying drug activity or disease pathogenesis is far from complete. Here, we perform large-scale regulome analysis for various diseases in terms of gene regulatory machinery. Transcriptome signatures were converted into regulome signatures of transcription factors by integrating publicly available ChIP-seq data. Regulome-based correlations between diseases and their approved drugs were much clearer than the transcriptome-based correlations. For example, an inverse correlation was observed for cancers, whereas a positive correlation was observed for immune system diseases. After demonstrating the usefulness of the regulome-based drug discovery method in terms of accuracy and applicability, we predicted new drugs for nonsmall cell lung cancer and validated the anticancer activity in vitro. The proposed method is useful for understanding disease–disease relationships and drug discovery. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) can be classified into four consensus molecular subtypes (CMS) according to genomic aberrations and gene expression profiles. CMS is expected to be useful in predicting prognosis and selecting chemotherapy regimens. However, there are still no reports on the relationship between the morphology and CMS. Methods: This retrospective study included 55 subjects with T2 CRC undergoing surgical resection, of whom 30 had the depressed type and 25 the protruded type. In the classification of the CMS, we first defined cases with deficient mismatch repair as CMS1. And then, CMS2/3 and CMS4 were classified using an online classifier developed by Trinh et al. The staining intensity of CDX2, HTR2B, FRMD6, ZEB1, and KER and the percentage contents of CDX2, FRMD6, and KER are input into the classifier to obtain automatic output classifying the specimen as CMS2/3 or CMS4. Results: According to the results yielded by the online classifier, of the 30 depressed-type cases, 15 (50%) were classified as CMS2/3 and 15 (50%) as CMS4. Of the 25 protruded-type cases, 3 (12%) were classified as CMS1 and 22 (88%) as CMS2/3. All of the T2 CRCs classified as CMS4 were depressed CRCs. More malignant pathological findings such as lymphatic invasion were associated with the depressed rather than protruded T2 CRC cases. Conclusions: Depressed-type T2 CRC had a significant association with CMS4, showing more malignant pathological findings such as lymphatic invasion than the protruded-type, which could explain the reported association between CMS4 CRC and poor prognosis. [ABSTRACT FROM AUTHOR]

This article provides a comprehensive summary of the impact of the COVID era on various gastrointestinal cancers. It includes reports on the relationship between the treatment of gastrointestinal diseases and the pandemic. The findings indicate that the COVID era had negative effects on cancer care, with decreases in the number of patients, delays in diagnosis, and potential increases in cancer-related deaths in the future. However, the perioperative management of gastrointestinal cancers in Japan was generally excellent, with no difference in safety before and after the pandemic. [Extracted from the article]

Background: Combined hepatocellular and cholangiocarcinoma is a rare primary liver cancer with histological features of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Little is known about the prognostic features and molecular mechanism of cHCC-iCCA. Acylphosphatase 1 is a cytosolic enzyme that produces acetic acid from acetyl phosphate and plays an important role in cancer progression. Aims: We evaluated the clinical significance of ACYP1 expression in cHCC-iCCA, HCC, and iCCA. Methods: ACYP1 immunohistochemistry was performed in 39 cases diagnosed with cHCC-iCCA. The prognosis was evaluated in three different cohorts (cHCC-iCCA, HCC, and iCCA). The relationships between ACYP1 expression and cell viability, migration, invasiveness, and apoptosis were examined using siRNA methods in vitro. In vivo subcutaneous tumor volumes and cell apoptosis were evaluated after downregulation of ACYP1 expression. Results: Almost half of the patients with cHCC-iCCA were diagnosed with high ACYP1 expression. In all three cohorts, the cases with high ACYP1 expression had significantly lower overall survival, and high ACYP1 expression was identified as an independent prognostic factor. Downregulation of ACYP1 reduced the proliferative capacity, migration, and invasiveness of both HCC and iCCA cells. Moreover, knockdown of ACYP1 increased the ratio of apoptotic cells and decreased the expression of anti-apoptosis proteins. In vivo tumor growth was significantly inhibited by the transfection of ACYP1 siRNA, and the number of apoptotic cells increased. Conclusion: High ACYP1 expression could influence the prognosis of cHCC-iCCA, HCC, and iCCA patients. In vitro ACYP1 expression influences the tumor growth and cell viability in both HCC and iCCA by regulating anti-apoptosis proteins. [ABSTRACT FROM AUTHOR]

Breast-conserving surgery has become the preferred treatment method for breast cancer. Surgical margin assessment is performed during surgery, as it can reduce local recurrence in the preserved breast. Development of reliable and lower-cost ex vivo cancer detection methods would offer several benefits for patient care. Here, a practical and quantitative evaluation method for the ex vivo fluorescent diagnosis of breast lesions was developed and confirmed through a three-step clinical study. Gamma-glutamyl-hydroxymethyl rhodamine green (gGlu-HMRG) has been reported to generate fluorescence in breast lesions. Using this probe, we constructed a reliable and reproducible procedure for the quantitative evaluation of fluorescence levels. We evaluated the reliability of the method by considering reproducibility, temperature sensitivity, and the effects of other clinicopathological factors. The results suggest that the fluorescence increase of gGlu-HMRG is a good indicator of the malignancy of breast lesions. However, the distributions overlapped. A 5 min reaction with this probe could be used to distinguish at least part of the normal breast tissue. This method did not affect the final pathological examination. In summary, our results indicate that the methods developed in this study may serve as a feasible intraoperative negative-margin assessment tool during breast-conserving surgery. [ABSTRACT FROM AUTHOR]

Introduction: Fanconi anemia complementation group E (FANCE) is a Fanconi anemia (FA) pathway gene that regulates DNA repair. We evaluated the clinical relevance of FANCE expression in hepatocellular carcinoma (HCC). Methods: First, the associations between the expression of FA pathway genes including FANCE and clinical outcomes in HCC patients were analyzed in 2 independent cohorts: The Cancer Genome Atlas (TCGA, n = 373) and our patient cohort (n = 53). Localization of FANCE expression in HCC tissues was observed by immunohistochemical staining. Gene set enrichment analysis (GSEA) and gene network analysis (SiGN_BN) were conducted using the TCGA dataset. Next, an in vitro proliferation assay was performed using FANCE-knockdown HCC cell lines (HuH7 and HepG2). The association between mRNA expression of FANCE and that of DNA damage response genes in HCC was analyzed using TCGA and Cancer Cell Line Encyclopedia datasets. Finally, the association between FANCE mRNA expression and overall survival (OS) in various digestive carcinomas was analyzed using TCGA data. Results: FANCE was highly expressed in HCC cells. Multivariate analysis indicated that high FANCE mRNA expression was an independent factor predicting poor OS. GSEA revealed a positive relationship between enhanced FANCE expression and E2F and MYC target gene expression in HCC tissues. FANCE knockdown attenuated the proliferation of HCC cells, as well as reduced cdc25A expression and elevated histone H3 pSer10 expression. SiGN_BN revealed that FANCE mRNA expression was positively correlated with DNA damage response genes (H2A histone family member X and checkpoint kinase 1) in HCC tissues. Significant effects of high FANCE expression on OS were observed in hepatobiliary pancreatic carcinomas, including HCC. Conclusions: FANCE may provide a potential therapeutic target and biomarker of poor prognosis in HCC, possibly by facilitating tumor proliferation, which is mediated partly by cell cycle signaling activation. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common types of cancer and a significant cause of cancer mortality worldwide. Further improvements of CRC therapeutic approaches are needed. BCL2‐associated athanogene 6 (BAG6), a multifunctional scaffold protein, plays an important role in tumor progression. However, regulation of BAG6 in malignancies remains unclear. This study showed that guided entry of tail‐anchored proteins factor 4 (GET4), a component of the BAG6 complex, regulates the intercellular localization of BAG6 in CRC. Furthermore, GET4 was identified as a candidate driver gene on the short arm of chromosome 7, which is often amplified in CRC, by our bioinformatics approach using the CRC dataset from The Cancer Genome Atlas. Clinicopathologic and prognostic analyses using CRC datasets showed that GET4 was overexpressed in tumor cells due to an increased DNA copy number. High GET4 expression was an independent poor prognostic factor in CRC, whereas BAG6 was mainly overexpressed in the cytoplasm of tumor cells without gene alteration. The biological significance of GET4 was examined using GET4 KO CRC cells generated with CRISPR‐Cas9 technology or transfected CRC cells. In vitro and in vivo analyses showed that GET4 promoted tumor growth. It appears to facilitate cell cycle progression by cytoplasmic enrichment of BAG6‐mediated p53 acetylation followed by reduced p21 expression. In conclusion, we showed that GET4 is a novel driver gene and a prognostic biomarker that promotes CRC progression by inducing the cytoplasmic transport of BAG6. GET4 could be a promising therapeutic molecular target in CRC. [ABSTRACT FROM AUTHOR]

Purpose: There is currently no adequate biomarker for predicting colorectal cancer (CRC) recurrence. Chemokine (C–C motif) ligand 2 (CCL2) induces macrophages and fibroblasts to occupy metastatic niches in distant organs. The purpose of this study was to examine CCL2 as a potential predictive biomarker for CRC recurrence. Methods: Plasma samples (n = 402) were collected from 80 stage II/III/IV CRC cases and the relationship between CCL2 profiles and recurrence was investigated. The tumor immune response genes associated with CCL2 mRNA expression in a subgroup of 8 stage I/II CRC cases with 12 recurrent sites and The Cancer Genome Atlas database were also analyzed retrospectively. Results: Sixteen stage II/III/IV postoperative recurrent CRC cases experienced a significant increase in plasma CCL2 levels 6 months after surgery and continuously increased even after R0-1 resection. The 6-month postoperative CCL2 levels in recurrent cases of ≥ 1 year were significantly higher than in non-recurrent cases and recurrent cases of < 1 year. The CCL2 level in the primary tumor cases significantly correlated with the cytolytic activity, thus indicating a tumor immune response from the CD163-expressing macrophages. Conclusion: Plasma CCL2 was found to be a predictive biomarker of postoperative CRC recurrence. CCL2 in metastatic sites derives from metastatic niches that surpass the host immune response. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients. [ABSTRACT FROM AUTHOR]

Background: Intra-tumor heterogeneity (ITH) encompasses cellular differences in tumors and is related to clinical outcomes such as drug resistance. However, little is known about the dynamics of ITH, owing to the lack of time-series analysis at the single-cell level. Mouse models that recapitulate cancer development are useful for controlled serial time sampling. Results: We performed single-cell exome and transcriptome sequencing of 200 cells to investigate how ITH is generated in a mouse colorectal cancer model. In the model, a single normal intestinal cell is grown into organoids that mimic the intestinal crypt structure. Upon RNAi-mediated downregulation of a tumor suppressor gene APC, the transduced organoids were serially transplanted into mice to allow exposure to in vivo microenvironments, which play relevant roles in cancer development. The ITH of the transcriptome increased after the transplantation, while that of the exome decreased. Mutations generated during organoid culture did not greatly change at the bulk-cell level upon the transplantation. The RNA ITH increase was due to the emergence of new transcriptional subpopulations. In contrast to the initial cells expressing mesenchymal-marker genes, new subpopulations repressed these genes after the transplantation. Analyses of colorectal cancer data from The Cancer Genome Atlas revealed a high proportion of metastatic cases in human subjects with expression patterns similar to the new cell subpopulations in mouse. These results suggest that the birth of transcriptional subpopulations may be a key for adaptation to drastic micro-environmental changes when cancer cells have sufficient genetic alterations at later tumor stages. Conclusions: This study revealed an evolutionary dynamics of single-cell RNA and DNA heterogeneity in tumor progression, giving insights into the mesenchymal-epithelial transformation of tumor cells at metastasis in colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: Most small renal cell carcinomas (small RCCs) will remain indolent after detection, but some stage I RCCs still metastasize. There are no risk-stratification imaging factors that could be used to identify poor-prognosis patients based on genomic profiling. Here, we evaluated the relationships between imaging parameters and RNA expressions in small RCC and attempted to identify imaging factors that could be used as effective biomarkers. Methods: We acquired biopsy specimens of 18 clear cell carcinomas that had undergone perfusion CT (pCT) and MRI between April 2018 and March 2019. We performed RNA sequencing, assessed RNA expressions, and calculated each tumor's cell-cycle progression (CCP) score, which has prognostic value in predicting metastatic progression. We classified the tumors into two groups: clear cell type A (ccA) and type B (ccB). CcA has better survival compared to ccB. We evaluated the following characteristics of each tumor: tumor size, presence of pseudocapsule, and fat. We used the pCT and MRI to measure each tumor's volume transfer constant (Ktrans), rate constant (Kep), extracellular extravascular volume fraction (VE), fractional plasma volume (VP), and apparent diffusion coefficient (ADC). The correlations between these small RCC imaging parameters and the tumor size and RNA expressions were determined. Results: The tumor size was significantly correlated with Kep and inversely correlated with VE, VP, ADC, and hallmark angiogenesis. The CCP score was significantly inversely correlated with Ktrans and Kep. The ccA tumors tended to show a pseudocapsule on MRI. Conclusion: Tumor size was correlated with low perfusion, but not with prognostic factors based on genomic profiling. Imaging parameters (e.g., Ktrans and Kep) and tumor characteristics (e.g., pseudocapsule) may enable gene-based risk stratification in small RCC. [ABSTRACT FROM AUTHOR]

Despite improvements in systemic medical therapy (ST), liver metastases (LMs) are a poor prognostic factor in metastatic breast cancer (MBC) patients. We describe a MBC patient with predominant LMs treated with hepatic arterial infusion chemotherapy (HAIC) who declined ST. Moreover, we assessed general health status during treatment using C-reactive protein (CRP)/albumin ratio (CAR) and peripheral platelet count × CRP multiplier (P-CRP), well-known indicators of systemic inflammatory response. A 64-year-old woman who underwent a total mastectomy with axillary lymph node dissection for an HR-positive, HER2-negative infiltrating ductal BC developed multiple liver, lung, lymph node, and bone metastases. She received ST including paclitaxel plus the anti-vascular endothelial growth factor antibody, bevacizumab, hormone therapy with high-dose toremifene, the oral 5-fluorouracil derivative, S-1, and eribulin. She then declined ST because of the toxicity or decreased treatment motivation thereof, and opted for HAIC with 5FU plus epirubicin followed by Taxane for 1 year and 1 month. Computed tomography revealed a partial response or stable disease in the liver and slow progression in other sites without symptoms or side effects and decreased CEA and CA15-3 levels. The CAR and P-CRP remained low. She survived for 1 year and 3 months after the start of HAIC. This case reveals that HAIC may be an option for advanced BC patients with LMs who cannot receive ST. [ABSTRACT FROM AUTHOR]

Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue‐based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer‐related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user%5fdata/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions. [ABSTRACT FROM AUTHOR]

Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti–apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC. [ABSTRACT FROM AUTHOR]

Background: A simple measure of immune cytolytic activity (CYT) base on mRNA expression levels of two genes, GZMA and PRF1, was recently reported. Here, we aimed to evaluate the CYT score's potential as a measure of antitumor immunity and predictor of clinical outcome in gastric cancer (GC) patients. Materials and Methods: We evaluated the correlations between tumor‐infiltrating immune cells and the CYT score in 238 GC samples from The Cancer Genome Atlas (TCGA). Next, we investigated CYT score associations with molecular subtypes, somatic mutation load, and immune checkpoint molecules in GC samples from TCGA and Asian Cancer Research Group (ACRG). Moreover, we evaluated the clinical significance of the CYT score calculated by reverse transcription (RT)‐quantitative PCR (qPCR) data in 123 GC samples and the association of the CYT score with the response to anti‐PD‐1 therapy in 7 GC samples from Kyushu University Hospital. Results: The CYT score positively correlated with the proportions of tumor‐infiltrating CD8+ T cells and macrophages and negatively correlated with the proportion of regulatory T cells in GC tissues. A high CYT score was associated with common immune checkpoint molecules, a high mutation, the Epstein–Barr virus subtype, and the microsatellite instability subtype in GC. Moreover, a low CYT score was a poor prognosis factor in patients with GC. Finally, the CYT score was higher in a responder to anti‐PD‐1 therapy compared to nonresponders. Conclusion: The CYT score reflects antitumor immunity and predicts clinical outcome in GC patients. [ABSTRACT FROM AUTHOR]

Targeting mutated oncogenes is an effective approach for treating cancer. The 4 main driver genes of pancreatic ductal adenocarcinoma (PDAC) are KRAS, TP53, CDKN2A, and SMAD4, collectively called the "big 4" of PDAC, however they remain challenging therapeutic targets. In this study, ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (ASAP2), one of the ArfGAP family, was identified as a novel driver gene in PDAC. Clinical analysis with PDAC datasets showed that ASAP2 was overexpressed in PDAC cells based on increased DNA copy numbers, and high ASAP2 expression contributed to a poor prognosis in PDAC. The biological roles of ASAP2 were investigated using ASAP2‐knockout PDAC cells generated with CRISPR‐Cas9 technology or transfected PDAC cells. In vitro and in vivo analyses showed that ASAP2 promoted tumor growth by facilitating cell cycle progression through phosphorylation of epidermal growth factor receptor (EGFR). A repositioned drug targeting the ASAP2 pathway was identified using a bioinformatics approach. The gene perturbation correlation method showed that niclosamide, an antiparasitic drug, suppressed PDAC growth by inhibition of ASAP2 expression. These data show that ASAP2 is a novel druggable driver gene that activates the EGFR signaling pathway. Furthermore, niclosamide was identified as a repositioned therapeutic agent for PDAC possibly targeting ASAP2. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 27-year-old woman underwent partial mastectomy with axillary lymph node dissection. It mentions that patient received adjuvant chemotherapy, hormone therapy with luteinizing hormone-releasing hormone (LHRH) analog and tamoxifen in addition to irradiation of the affected breast and infraclavicular nodes.

Background: Peritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC. Materials and methods: We identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells. Results: In silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells. Conclusions: LOXL1 is associated with PD in GC, possibly through the induction of EMT. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death 1 (PD-1) inhibitors have shown significant therapeutic promise in various cancers. However, the clinical significance of PD-1 expression remains not fully understood. In this study, we evaluated the clinical and prognostic relevance of PD-1 expression in breast cancer (BC). Methods: First, we analyzed PD-1 mRNA expression in BC tissues and performed a survival analysis using a dataset from The Cancer Genome Atlas. Next, we measured PD-1 mRNA expression in peripheral blood (PB) in BC patients by quantitative reverse-transcription polymerase chain reaction. We performed a survival analysis and evaluated the association between PD-1 mRNA expression in PB and the clinicopathological features of 372 BC patients who underwent curative resection. Flow cytometry (FCM) analysis was performed to identify PD-1-expressing cells in PB. Finally, we determined whether there was a correlation of PD-1 mRNA expression in PB and tumor tissue. Results: PD-1 mRNA expression was significantly higher in tumor tissues compared with normal tissues. Decreased PD-1 mRNA expression in tumor tissue was associated with poor overall survival (OS). PD-1 mRNA expression in PB of BC patients was higher than that of healthy volunteers, and increased PD-1 mRNA expression in PB was associated with poor OS. FCM revealed that PD-1 was mostly expressed on T cells in PB, predominantly in CD4+ T cells. PD-1 mRNA expression in PB was negatively correlated with PD-1 mRNA expression in tumor tissue. Conclusion: High expression of PD-1 mRNA in preoperative PB could serve as an effective biomarker that indicates poor prognosis in BC. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) is usually initiated by infection with high‐risk types of human papillomavirus (HPV). The HPV E6 and E7 proteins target p53 and RB, respectively, but other cellular targets likely exist. We generated uterus‐specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Mutant cervical epithelial cells showed YAP1‐dependent hyperproliferation, altered self‐renewal, impaired contact inhibition, and chromosomal instability. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion. In human CC, strong YAP1 activation was observed from the precancerous stage. Human cells overexpressing HPV16 E6/E7 showed inactivation of not only p53 and RB but also PTPN14, boosting YAP1 activation. Estrogen, cigarette smoke condensate, and PI3K hyperactivation all increased YAP1 activity in human cervical epithelial cells, and PTPN14 depletion along with PI3K activation or estrogen treatment further enhanced YAP1. Thus, immediate CC onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo‐YAP1 signaling a major CC driver. [ABSTRACT FROM AUTHOR]

External auditory canal squamous cell carcinoma (EACSCC) is an extremely rare and aggressive malignancy. Due to its rarity, the molecular and genetic characteristics of EACSCC have not yet been elucidated. To reveal the genetic alterations of EACSCC, we performed whole exome sequencing (WES) on 11 primary tumors, 1 relapsed tumor and 10 noncancerous tissues from 10 patients with EACSCC, including 1 with a rare case of synchronous bilateral EACSCC of both ears. WES of the primary tumor samples showed that the most frequently mutated gene is TP53 (63.6%). In addition, recurrent mutations in CDKN2A, NOTCH1, NOTCH2, FAT1 and FAT3 were detected in multiple samples. The mutational signature analysis of primary tumors indicated that the mutational processes associated with the activation of apolipoprotein B mRNA‐editing enzyme catalytic polypeptide‐like (APOBEC) deaminases are the most common in EACSCC, suggesting its similarity to SCC from other primary sites. Analysis of arm‐level copy number alterations detected notable amplification of chromosomes 3q, 5p and 8q as well as deletion of 3p across multiple samples. Focal chromosomal aberrations included amplifications of 5p15.33 (ZDHHC11B) and 7p14.1 (TARP) as well as deletion of 9p21.3 (CDKN2A/B). The protein expression levels of ZDHHC11B and TARP in EACSCC tissues were validated by immunohistochemistry. Moreover, WES of the primary and relapsed tumors from a case of synchronous bilateral EACSCC showed the intrapatient genetic heterogeneity of EACSCC. In summary, this study provides the first evidence for genetic alterations of EACSCC. Our findings suggest that EACSCC mostly resembles other SCC. [ABSTRACT FROM AUTHOR]

Introduction: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. Methods:PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. Results:PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10–4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12–6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. Conclusions:PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan. [ABSTRACT FROM AUTHOR]

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow‐derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid‐derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7‐deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose‐escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Twelve patients were enrolled in the study. Dose‐limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)‐6, in agreement with our previous mouse model. Also, IL‐6 was downregulated in a PG dose‐dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494. [ABSTRACT FROM AUTHOR]

Chromosome 7q (Ch.7q) is clonally amplified in colorectal cancer (CRC). We aimed to identify oncogenes on Ch.7q that are overexpressed through DNA copy number amplification and determine the biological and clinical significance of these oncogenes in CRC. We identified general transcription factor 2I repeat domain‐containing protein 1 (GTF2IRD1) as a potential oncogene using a CRC dataset from The Cancer Genome Atlas with a bioinformatics approach. We measured the expression of GTF2IRD1 in 98 patients with CRC using immunohistochemistry and RT‐quantitative PCR (RT‐qPCR). The biological effects of GTF2IRD1 expression were explored by gene set enrichment analysis (GSEA). Next, we undertook in vitro cell proliferation and cell cycle assays using siGTF2IRD1‐transfected CRC cells. We further investigated the oncogenic mechanisms through which GTF2IRD1 promoted CRC progression. Finally, we assessed the clinical significance of GTF2IRD1 expression by RT‐qPCR. GTF2IRD1 was overexpressed in tumor cells and liver metastatic lesions. The GSEA revealed a positive correlation between GTF2IRD1 expression and cell cycle progression‐related genes. GTF2IRD1 knockdown inhibited cell proliferation and induced cell cycle arrest in Smad4‐mutated CRC. GTF2IRD1 downregulated the expression of the gene encoding transforming growth factor β receptor 2 (TGFβR2), a tumor‐suppressor gene in Smad4‐mutated CRC. On multivariate analysis, high GTF2IRD1 expression was an independent poor prognostic factor. Clinicopathological analysis showed that GTF2IRD1 expression was positively correlated with liver metastasis. In conclusion, GTF2IRD1 promoted CRC progression by downregulating TGFβR2 and could be a prognostic biomarker on Ch.7q in CRC. GTF2IRD1 could also be a novel oncogene in CRC. [ABSTRACT FROM AUTHOR]

Alternative splicing, regulated by DEAD‐Box Helicase (DDX) families, plays an important role in cancer. However, the relationship between the DDX family and cancer has not been fully elucidated. In the present study, we identified a candidate oncogene DDX56 on Ch.7p by a bioinformatics approach using The Cancer Genome Atlas (TCGA) dataset of colorectal cancer (CRC). DDX56 expression was measured by RT‐qPCR and immunochemical staining in 108 CRC patients. Clinicopathological and survival analyses were carried out using three CRC datasets. Biological roles of DDX56 were explored by gene set enrichment analysis (GSEA), and cell proliferation in vitro and in vivo, cell cycle assays, and using DDX56‐knockdown or overexpressed CRC cells. RNA sequencing was carried out to elucidate the effect of DDX56 on mRNA splicing. We found that DDX56 expression was positively correlated with the amplification of DDX56 and was upregulated in CRC cells. High DDX56 expression was associated with lymphatic invasion and distant metastasis and was an independent poor prognostic factor. In vitro analysis, in vivo analysis and GSEA showed that DDX56 promoted proliferation ability through regulating the cell cycle. DDX56 knockdown reduced intron retention and tumor suppressor WEE1 expression, which functions as a G2‐M DNA damage checkpoint. We have identified DDX56 as a novel oncogene and prognostic biomarker of CRC that promotes alternative splicing of WEE1. [ABSTRACT FROM AUTHOR]

Purpose: Recent developments in molecular-targeted therapies have improved the clinical outcome of cancer patients; however, the issue of adverse effects due to treatments has often gone unconsidered. We herein report the results of a clinical trial of dual genomic analyses for healthy longevity in a postoperative cancer patient. Methods: We performed dual genomic analyses for a representative 79-year-old rectal cancer patient who relapsed with liver metastasis. First, we determined single-nucleotide polymorphisms according to the constitution and disease risk in the genomic DNA from the patient's saliva by referring to the data of 10,000 Japanese patients obtained from Yahoo Japan Corporation. Second, we conducted whole-exome sequencing to detect druggable mutations in the primary tumour. Results: Forty of 59 determinable characters related to the constitution were consistent with the clinical phenotype. Several diseases classified as 'high risk' diseases actually occurred during the patient's clinical course. Of the 129 significant mutations, we identified somatic mutations in BRAF, PIK3CA, and SMAD4 as targets. Conclusion: The dual genomic examination will improve the follow-up observation system to support primary care doctors in the social community for taking care of postoperative cancer patients. [ABSTRACT FROM AUTHOR]

Inflammation plays an essential role in the development and progression of most cancers. Chemokine C‐C motif chemokine 2 (CCL2) and its receptor C‐C chemokine receptor type 2 (CCR2) constitute a key signaling axis in inflammation that has recently attracted much interest on the basis of evidence showing its association with cancer progression. Propagermanium (3‐oxygermylpropionic acid polymer) is an organogermanium compound that is given for the treatment of hepatitis B in Japan and which inhibits the CCL2‐CCR2 signaling pathway. Herein, we review the importance of the CCL2‐CCR2 axis as a target in cancer treatment as shown by studies in mice and humans with pharmacological agents including propagermanium. [ABSTRACT FROM AUTHOR]

The plastin3 (PLS3) gene, which encodes an actin bundling protein known to inhibit cofilin-mediated depolymerization of actin fiber, has been previously reported to serve an important role in the epithelial-mesenchymal transition (EMT) in cancer. The aim of the present study was to determine the clinical significance of PLS3 and its role in regulating EMT, as well as in promoting cell invasion and migration in gastric cancer. The expression of plastin3 mRNA was measured in 163 resected gastric cancer specimens, in order to determine the clinicopathological significance. Furthermore, in vitro invasion and migration assays were performed on gastric cancer cells, which revealed that PLS3 expression was suppressed. The high PLS3 expression group had a higher incidence of advanced tumour stage, cancer differentiation, tumour invasion depth and distant metastases compared with the low PLS3 expression group (P<0.05). In addition, the high PLS3 expression group had a significantly poorer prognosis than the low expression group (P=0.012). Multivariate analysis indicated that high PLS3 expression was an independent prognostic factor for survival. The present study also identified that suppression of PLS3 in gastric cancer cells was associated with decreased cell invasion and migration. The findings from the present study indicate that high expression of PLS3 in gastric cancer is independently associated with a poor prognosis, and that PL3 serves an important role in EMT. [ABSTRACT FROM AUTHOR]

Background: Anti-PD-1 therapy has shown a promising clinical outcome in gastric cancer (GC). We evaluated the clinical significance of systemic immune-related gene expression in GC patients who underwent surgery.Methods: The correlation between the preoperative PD-1, PD-L1, and CD8 mRNA levels in peripheral blood (PB) and clinicopathological factors, including survival, in 372 GC patients was evaluated using quantitative RT-PCR. PD-1- and PD-L1-expressing cells were identified by flow cytometric analysis.Results: The PD-1, PD-L1, and CD8 mRNA levels in GC patients were significantly higher than those in normal controls, respectively (all P < 0.0001). The levels of each gene were positively correlated with those of the other two genes (all P < 0.0001). GC patients with low PD-1, high PD-L1, and low CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, low PD-L1, and high CD8 mRNA levels, respectively (P < 0.01, P < 0.05, and P < 0.05, respectively). Multivariate analysis showed that low PD-1 and high PD-L1 mRNA levels were independent poor prognostic factors for OS (PD-1: HR 2.38, 95% CI 1.27-4.78, P < 0.01; PD-L1: HR 1.81, 95% CI 1.15-2.78, P < 0.05). PD-1 and PD-L1 expression occurred on T cells (> 90%) and T cells or monocytes (> 70%), respectively.Conclusions: The PD-1, PD-L1, and CD8 mRNA levels in preoperative PB reflected the anti-tumour immune response, and the low PD-1 and high PD-L1 mRNA levels in PB were independent poor prognostic markers in GC patients who underwent surgery. [ABSTRACT FROM AUTHOR]