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Yanagisawa, K.; Konno, M.; Liu, H.; Irie, S.; Mizushima, T.; Mori, M.; Doki, Y.; Eguchi, H.; Matsusaki, M.; Ishii, H. A Four-Dimensional Organoid System to Visualize Cancer Cell Vascular Invasion. Biology 2020, 9, 361., Vascular invasion of cancer is a critical step in cancer progression, but no drug has been developed to inhibit vascular invasion. To achieve the eradication of cancer metastasis, elucidation of the mechanism for vascular invasion and the development of innovative treatment methods are required. Here, a simple and reproducible vascular invasion model is established using a vascular organoid culture in a fibrin gel with collagen microfibers. Using this model, it was possible to observe and evaluate the cell dynamics and histological positional relationship of invasive cancer cells in four dimensions. Cancer-derived exosomes promoted the vascular invasion of cancer cells and loosened tight junctions in the vascular endothelium. As a new evaluation method, research using this vascular invasion mimic model will be advanced, and applications to the evaluation of the vascular invasion suppression e_ect of a drug are expected.

Introduction: Intramural metastasis (IM) is common in esophageal cancer, and it is an important factor in determining the resection area and tumor malignancy. However, IM is rare in rectal cancer; therefore, little is known about IM in rectal cancer, and the clinical significance remains unclear. Case Presentation: We describe a case of rectal cancer with distally spreading IM. A 58-year-old man consulted a primary care physician, with a chief complaint of constipation; tests revealed a high carcinoembryonic antigen value. A colonoscopy revealed a type 2, advanced rectal tumor, which covered two-thirds of the circumference of the upper rectum. In addition, 3 protruding lesions were observed under the normal mucosa on the anal side of the primary tumor. A laparoscopic low anterior resection was performed. Pathologic findings showed that the primary tumor was a moderate-to-well-differentiated adenocarcinoma with a cribriform structure. The 3 lesions on the anal side found under normal mucosa were separate from the primary tumor, but morphologically similar to the primary adenocarcinoma; therefore, these were diagnosed as IMs. Based on a review of previous case reports, rectal carcinomas were often accompanied by vascular invasions and lymph-node metastases. Moreover, in rectal cancer, tumors with IMs often show vascular invasion. Therefore, we assumed that IM could be a marker of poor prognosis. Conclusion: This study revealed that, in surgery, detection of a distally spreading IM is an important finding for determining the optimal surgical resection margin.

It is known that single or isolated tumor cells enter cancer patients&rsquo, circulatory systems. These circulating tumor cells (CTCs) are thought to be an effective tool for diagnosing cancer malignancy. However, handling CTC samples and evaluating CTC sequence analysis results are challenging. Recently, the convolutional neural network (CNN) model, a type of deep learning model, has been increasingly adopted for medical image analyses. However, it is controversial whether cell characteristics can be identified at the single-cell level by using machine learning methods. This study intends to verify whether an AI system could classify the sensitivity of anticancer drugs, based on cell morphology during culture. We constructed a CNN based on the VGG16 model that could predict the efficiency of antitumor drugs at the single-cell level. The machine learning revealed that our model could identify the effects of antitumor drugs with ~0.80 accuracies. Our results show that, in the future, realizing precision medicine to identify effective antitumor drugs for individual patients may be possible by extracting CTCs from blood and performing classification by using an AI system.

Recently, self-expanding metallic stent (SEMS) have been found to be useful for treatment of intestinal obstruction by colorectal cancer, either as a bridge to surgery or terminal treatment. When SEMS are used for patients in the terminal stage with obstruction due to colorectal cancer, re-obstruction is a severe problem. We report 2 cases of re-insertion of SEMS for obstruction of colon cancer after the first insertion of SEMS. No major problems occurred in either the 2 cases. In the first case, the patient suffered from re-obstruction of colon cancer 6 months after the first SEMS treatment and died 9 months after the second SEMS treatment. In the second case, the patient suffered from re-obstruction of colon cancer 5 months after the first SEMS treatment and died 7 months after the second SEMS treatment. Re-insertion of SEMS for a second obstruction due to colorectal cancer after SEMS treatment is useful for terminal treatment for maintaining QOL.

We experienced a rare case of liposarcoma that we were able to remove laparoscopically based on a preoperative diagnosis. The patient in this case was a 67-year-old woman. Abdominal CT and pelvic MRI showed a mass of 15 cm in diameter on the left side of the pelvis. Well-differentiated liposarcoma was diagnosed based on these images. Based on imaging findings, the possibility of permeation to the neighboring organs was considered to be low, and so the operation was performed laparoscopically. The location of the tumor was similar to that seen during preoperative imaging diagnosis, and we were able to remove it laparoscopically without resecting the organ. The postoperative progress was good, and the patient left the hospital on the fourth postoperative day. This case shows how with detailed preoperative imaging, a minimally invasive approach is possible for the treatment of liposarcoma.

For patients with Stage Ⅳ colorectal cancer, primary site resection improves survival and relieves symptoms of bleeding and obstruction by the primary lesion. Laparoscopic surgery is thought to be useful for Stage Ⅳ colorectal cancer because of its low aggressiveness and the short recovery time. We examined the usefulness of laparoscopic resection of primary lesions for Stage Ⅳ colon cancer patients. Forty-one cases of Stage Ⅳ colorectal cancer treated by resection of the primary lesion were investigated, and we compared the group of patients with laparoscopic surgery (LAC) to the group of patients with open laparotomy (OP). The LAC Group was superior to the OP Group from the viewpoint of blood loss, days of hospitalization, and length of time from operation to start of chemotherapy. For Stage Ⅳ colorectal cancer, laparoscopic resection of the primary lesion is thought to be a useful method to reduce the invasiveness of treatment.

Although the stiffness of tissues likely is involved in the malignant behavior of tumors, it remains to be clarified which molecules control the nature, how it is involved in the invasiveness of tumors, or whether any marker is available for the prediction of cancer patient prognosis. In the present study, we studied the role of Myl9, a non-muscle-type, myosin light chain by the experiment in vitro, and assessed the usefulness in the stratification of patients in vivo as the precision medicine. Given that Myl9 is involved in the contraction of cell skeleton, cell hardness, and alterations of cell morphology in various tissues, we first examined whether the expression of the Myl9 is associated with the clinical status of tumors by immunohistochemistry. The results of 45 cases with colon cancer and pancreatic cancer indicated that the increased expression of Myl9 is associated significantly with a reduced provability of overall survival and disease-free survival of those cancers. Moreover, we noted the differential expression of Myl9 in epithelial cancer cells and mesenchymal fibroblasts, i.e., the accumulation of Myl9 staining in cell nuclei of fibroblasts. The experiment of 3-dimensional culture with cancer cells and fibroblasts confirmed the results. Furthermore, we investigated whether Myl9 overexpression is involved in the biologic behavior of gastrointestinal cancer cells. The results showed that the rentiviral-mediated overexpression of Myl9 resulted in an increase of cell proliferation and invasion as well as tumorigenicity in mice. The present study indicates that Myl9 protein can play a fundamental role in the malignant behaviors of gastrointestinal cancer cells. Citation Format: Masamitsu Konno, Kiminori Yanagisawa, Katsunori Matsushita, Ayumu Asai, Jun Koseki, Michiya Matsusaki, Shinji Deguchi, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Mechanosensor MYL9 regulates cancer cell malignancy in gastrointestinal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5164.

In recent years, innovative technologies that extract feature descriptions from the large volume of data on speech recognition, visual object recognition and detection as well as many other domains, such as drug discovery and DNA sequence annotations by deep learning techniques and applying them to automatic recognition etc. are drawing attention. As cancer research aiming at applying deep learning techniques to cases that are resistant to surgical therapy and drug therapy in metastatic colorectal cancer, we developed a fundamental technology that can predict the resistance of free cancer cells to fluorinated pyrimidine anticancer drugs by deep learning from the morphological image data taken from images. An experimental model was used in our investigation in order to clarify whether or not its image recognition ability can be applied to the determination of drug resistance of free cancer cells circulating in the peripheral blood. That is, a cell line established by inducing a resistance to FTD or 5 FU added to the cell culture solution was prepared over several months and the ability to recognize the tolerance of the drug was examined from a large volume of image data, and it was shown that it can be distinguished dominantly in a short-term culture system. Further, as a result of examination after separation at the single cell level, it was possible to distinguish fluorescent-labeled resistant strains dominantly. In addition, we were able to recognize the drug resistance character well by injecting resistant strains intravenously into the mice to prepare a model of free cancer cells and collecting circulating free cancer cells. Moreover, as a pre-clinical model, resistant strains were mixed with susceptible strains at various ratios and transplanted into mice and experimented. As a result, the nature of the resistance to treatment was predicted by image recognition, and death of the mice due to cancer was well correlated with the malignant trait of drug-resistant cancer cells. Then, by linking the feature expression obtained from the image and the Omics data, a detailed stratification of treatment resistance was possible. From the above, a technique in the mouse that can distinguish free cancer cells collected from the peripheral blood by deep learning of images was constructed, and a foundation to be applied to medical treatment and precision medical care in the future was established. Citation Format: Kiminori Yanagisawa, Masamitsu Konno, Masayasyu Toratani, Hirohiko Niioka, Ayumu Asai, Jun Koseki, Kenta Tsunekuni, Taroh Satoh, Kazuhiko Ogawa, Jun Miyake, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Deep learning recognizes FTD-resistant isolated cancer cells of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2859.

Ileus due to colon cancer often develops from a timing and the method of the operation and perioperative care, comparing with ordinary cases. The use of self-expanding metallic stent (SEMS) was first authorized by insurance and became available nationwide in Japan in 2012. Insertion of SEMS for ileus due to colorectal cancer is useful as a bridge to surgery (BTS) approach and releases stenosis as palliative care. Here we report 5 successful cases of anastomosis performed during a laparoscopic operation for ileus due to colorectal cancer after BTS using SEMS. Successful SEMS insertion for colon cancer ileus enables observation of the proximal side. Because the decompression efficiency with SEMS is high, laparoscopic surgery becomes possible. SEMS insertion as a BTS is useful for ileus due to colorectal cancer.

The neutrophil to lymphocyte ratio (N/L ratio) has been reported to be related to the prognosis of various types of cancer. In particular, a high N/L ratio has been suggested to be associated with poor outcome. We investigated the changes in N/L ratio during treatment in 12 patients who had undergone surgery for colorectal cancer and were receiving postoperative adjuvant therapy with a combination of chemotherapy and polysaccharide-K (PSK). The patients were stratified into 2 groups according to the preoperative N/L ratio (cut-off ratio was 2.5): high N/L (≥2.5) and low N/L (2.5). The changes in N/L ratio and other clinical parameters over time were investigated. In patients with a high preoperative N/L ratio, the use of postoperative PSK-chemotherapy controlled the N/L ratio at low levels. The N/L ratio tended to remain low in patients with low preoperative N/L ratios. No difference in outcome was observed between patients with high and low N/L ratios. In patients who underwent colorectal cancer surgery, postoperative adjuvant therapy with a combination of chemotherapy and PSK succeeded in controlling the N/L ratio at low levels. Further studies with more patients are required to explore the outcomes associated with changing N/L ratios.

For the prevention of influenza, immunization through vaccination appears to be the only method presently available. Following the Asian innfluenza (A2 type) epidemic in 1957, a new epidemic of influenza caused by a new type A virus (Hong Kong type) with special antigenic structure unlike the previous A2 type broke out here in July 1968. During this outbreak of Hong Kong influenza, the authors selected an area which had not been invaded by the first wave and inoculated a population with a vaccine containing A2 Hong Kong virus strain and a control group with a placebo to await the arrival of the Hong Kong influenza, During the second wave of the epidemic of Hong Kong influenza in this country, the same infection appeared in this area, so that it became possible to study the effect of the vaccine from the viewpoint of incidence and serological responses. The following results were obtained. The epidemic of Hong Kong influenza was seen in this area from December 1969 to January 1970. This corresponded to one after vaccine inoculation. The maximum effect of the vaccine was expected to be obtained around this time . In view of the rather short duration of the immunicty after inoculation of this vaccine, it is dangerous to assume an overall effect based on these values. However, the frequency of appearance of symptoms of a common cold was significantly higher in the controls than in the inoculated group. Influenza-like illness occurred 4 times more frequently in the controls than in the inoculated group, definitely indicating a protective effect of the present vaccine. Based on these facts, the present commercial vaccine appears to be of some significant preventive value if sufficient time elapses between vaccination and subsequent exposure to offending viruses. However, the effect of the present commercial vaccine appears to last only 3-4 months after inoculation. In the use of present vaccine, another inoculation towards the end of December or the beginning of January as a 3rd additional immunization is recommended, in order to prevent an epidemic from arising during November to May.