We report a case of pembrolizumab therapy as the fourth-line therapy for colorectal cancer and multiple lymph node recurrence with high-frequency microsatellite instability(MSI-High). The patient was a 75-year-old woman diagnosed with ascending colon cancer(pT4aN2bM0, Stage Ⅲc)and underwent laparoscopic right hemicolectomy, D3 dissection, and functional end-to-end anastomosis after inserting a self-expandable metallic stent. Postoperative adjuvant chemotherapy was performed, and the patient was followed. Postoperative 1 year 8 months, lymph node recurrence was indicated, and FOLFOX plus panitumumab therapy was introduced. FOLFIRI plus ramucirumab therapy and FTD/TPI were introduced as the second-line and third-line treatments, respectively; however, recurrent lymph nodes were further exacerbated and showed treatment resistance. Lymph node biopsy confirmed MSI-High, and pembrolizumab therapy was initiated as the fourth-line treatment. After the therapy, the lymph nodes reduced markedly. The patient remains undergoing chemotherapy without any adverse events.

A 74-year-old man presented with a metastatic brain tumor in the right parietal lobe observed through an MRI scan. Lower gastrointestinal endoscopy revealed that the tumor was located in the rectum. He was diagnosed with Stage Ⅳb rectal cancer(cT4aN1bM1b[BRA, SKN]). After prior stereotactic radiotherapy for brain metastases, the patient underwent rectal amputation and D3 dissection as management for the primary tumor. His postoperative course was uneventful, and he was discharged from the hospital 33 days postoperatively. He displayed partial response with capecitabine plus L-OHP therapy, and chemotherapy was terminated due to the development of renal dysfunction. On follow-up, elevated tumor markers, enlarged left mediastinal lymph nodes, and FDG accumulation on PET-CT were observed. Despite initiating UFT/UZEL therapy, the patient was judged to have progressive disease. The patient was then administered 5-FU plus l-LV plus CPT-11. However, this was later discontinued due to the development of hyperammonemia. The patient was placed on follow-up observation due to the decrease in his tumor markers and the disappearance of his enlarged lymph nodes. He is still alive seven years after his initial diagnosis. We report a case of a patient with rectal cancer that metastasized to the brain and the skin. He was successfully managed with multidisciplinary therapy. A relevant literature discussion is also included.

Deficient mismatch repair (dMMR)/microsatellite instability (MSI)-H colorectal cancer (CRC) has high immunogenicity. Although the cyclic GMP-AMP synthase( cGAS)-stimulator of interferon genes( STING) pathway activation has considerably contributed to the high number of CD8+ tumor-infiltrating lymphocytes (TILs), its role in dMMR/MSI-H CRC is largely unknown. In this study, we investigated the association between cGAS-STING expression and CD8+ TILs in CRC. Data analysis using the TCGA dataset CRC cohort showed that cGAS, STING, and CD8 gene expression levels were significantly higher in the MSI group. Immunohistochemistry examination of resected clinical CRC samples showed that cGAS-STING expression in tumor cells was high in the MSI CRC, and CD8+ TILs was also significantly infiltrated in the MSI group. Moreover, significant CD8+ TILs infiltration was observed in CRC with high cGAS and STING expression levels. The results suggest that dMMR/MSI -H CRC has maintained a high cGAS-STING expression, which may contribute to abundant CD8+ TILs.

A 77-year-old-woman underwent distal gastrectomy D2 lymph node dissection and cholecystectomy followed by Roux- en-Y reconstruction for Stage ⅢC gastric neuroendocrine cell carcinoma in January 2017. In July of the same year, an abdominal computed tomography scan revealed liver metastasis in segment 4. For treatment of recurrence, SP therapy(S-1 and cisplatin), ramucirumab plus weekly paclitaxel therapy, and nivolumab were administered in that order. TAS-102 was started as the fourth-line agent for multiple liver metastases, para-aortic lymph node metastases, and cancerous peritonitis. Although Grade 2 anemia, Grade 1 oral mucositis and general fatigue were observed during the treatment, both liver metastases and para-aortic lymph node metastases showed improvement after three courses, and the patient was able to continue 11 courses in 1 year. She died 1 year and 5 months after the first administration of TAS-102. TAS-102 can be effective after immune checkpoint inhibitor as a late treatment for gastric cancer and NEC. The appropriate timing for switching drug therapy may be important in the future. We report a favorable therapeutic effect of TAS-102 after immune checkpoint inhibitor treatment along with a review of the literature.

A 46-year-old man visited our hospital complaining of dysphagia. He was diagnosed with unresectable esophageal cancer with multiple lung metastases(cStage Ⅳb)and gastric cancer(L, Gre, T3N+M0, cStage Ⅲ). The esophageal lesion and the lung metastatic lesions showed shrinkage initially with 5-FU, CDDP(FP)therapy but then re-grew; therefore, the therapy was changed to nivolumab therapy. After three courses of nivolumab therapy, the patient visited our hospital with a high fever. He was admitted as an emergency patient with a diagnosis of esophageal perforation and mediastinal abscess. CT- guided drainage was performed, and a self-expanding metal stent(SEMS)was placed. He was discharged on the 31st day of hospitalization and nivolumab therapy was resumed. We report the first case of esophageal perforation during immunotherapy with nivolumab therapy for esophageal cancer.

In this study, a 76-year-old man initially diagnosed with branch-duct pancreatic intraductal papillary mucinous tumor is presented. During follow-up, stenosis was discovered in the main pancreatic duct of the tail. A nodular lesion was found in the pancreatic duct consistent with the stenosis. Distal pancreatectomy was performed since it was suspected to be malignant. Histopathology revealed polymorphic mononuclear cells proliferated with osteoclast-like giant cells in the nodule. The patient was finally diagnosed with anaplastic pancreatic cancer with osteoclast-like giant cells, a relatively rare tumor. It is reported herein with a review of the literature.

A 53-year-old woman who had undergone excision of KIT-positive extra-gastrointestinal stromal tumor (EGIST) of the vulva 6 years ago presented to our hospital due to a positive fecal occult blood test. Colonoscopy revealed a submucosal tumor in the rectum ventral side. In addition, computed tomography and magnetic resonance imaging revealed a tumor in the rectovaginal septum. For diagnostic and therapeutic purposes, the tumor was resected via the perineal approach. The resected specimen analysis revealed a KIT-positive gastrointestinal stromal tumor (GIST). Following immunopathological and genetic mutation identifications, GIST of the rectovaginal septum from vulva EGIST metastasis was diagnosed. It is important to consider primary GIST and metastatic GIST as differential diagnoses in the case of a rectal submucosal tumor detected by endoscopy.

Intratumoral HER2 heterogeneity is a well-described gastric cancer feature and may explain many false-negative results related to this oncogene. An 81-year-old man was diagnosed at our hospital with stage IV gastric cancer with multiple lymph node metastases. Immunohistochemistry (IHC) analysis indicated that the primary tumor was HER2-negative. After a chemotherapy course, we submitted a pretreatment biopsy specimen for comprehensive cancer genome profiling (CGP) to determine the last-line therapy. This revealed HER2 amplification. The specimen was reevaluated using fluorescence in situ hybridization and IHC with deeper-cut specimens, which confirmed that the tumor was indeed HER2-positive. Therefore, the patient was treated with chemotherapy plus trastuzumab, which elicited tumor shrinkage and conferred long-term survival. Our current data underscore the CGP importance, which can provide more accurate tumor profilings and inform subsequent treatment decisions.

A total of 100 patients were retrospectively analyzed with magnetic resonance imaging-ultrasonography (MRI-US) fusion biopsy(KOELIS, TRINITY®) at our institution between October 2019 and May 2020. The median patient age was 71 years, median prostate specific antigen (PSA) level was 7.4 ng/ml, and median PSA-density was 0.183 mg/ml. Sixty-one of the patients were positive for cancer ; 14 of them were positive by targeted biopsy only, 9 were positive by systematic biopsy only, and 38 were positive by both. Clinically significant prostate cancer (CPSC ; Gleason Score ≥3＋4 and % core ≥50%) was detected by target biopsies in 46 patients and by systematic biopsies in 33 patients. The positive core detection rate for CSPC was 32.5% for targeted biopsies and 7.0% for systematic biopsies(P＜0.0001), with a significantly higher rate for targeted biopsies. These results indicate that in MRI-US fusion biopsy, targeted biopsy has a higher detection rate for cancer and a significantly higher detection rate for clinically significant prostate cancer compared with systematic biopsy.

Epstein-Barr virus (EBV)-associated lymphomas are common in Asia and exhibit a poor prognosis. As EBV antigens LMP1 and LMP2 are often expressed in EBV-associated lymphomas, these lymphomas should be a good target for antigen-specific cytotoxic T lymphocyte (CTL) therapy. However, CTLs continuously exposed to viral or tumor antigens often become exhausted. Antigen-specific CTLs generated from induced pluripotent stem cells are functionally rejuvenated, showing a strong antitumor effect on EBV-associated lymphomas and persistence in vivo. For feasible "off-the-shelf" therapy, we generated allogeneic EBV-specific CTLs in the cell processing center and prepared them for actual use in clinical settings.

Chimeric antigen receptor (CAR)-engineered T-cell therapy against B-cell malignancies and multiple myeloma was recently introduced for clinical use. However, the efficacy of CAR-T cell therapy is not durable in most patients, warranting the development of CAR-T cells with additional genetic modification or engineering of synthetic molecules to enhance their functions. This review will provide an overview of the molecular mechanisms underlying the functional alteration of T cells, especially transcriptional networks associated with memory formation and T cell exhaustion. In addition, methods to rationally improve CAR-T cell functions based on these mechanistic insights will be discussed.

Acute myeloid leukemia (AML) is a heterogeneous cell population comprising genetically diverse sub-clones with significant differences in properties that vary from one patient to another. Since AML properties are similar to those of hematopoietic stem and myeloid cells, bone marrow as an organ responsible for the survival of AML-initiating cells has been proposed to be able to cause relapse following chemotherapy. Therefore, establishing in vivo experimental systems is critical for understanding the properties of AML cells and developing therapeutic strategies. In this review, the history, advantages, and disadvantages of mouse leukemia models wherein mouse cells are transformed by oncogenic events, including xenograft mice in which human AML cells are transplanted into immunodeficient mice, were introduced. Following which I described the development of chimeric antigen receptor cell therapy using human cytokines expressing the AML xenograft mice.

Malignant lymphomas are a group of heterogeneous lymphoid malignancies, consisting of over 70 subtypes, which are classified according to their cell of origin. Classically, disease classification has been based on cellular morphology and immunophenotype. Due to the advancement of next-generation sequencing (NGS) technology, many comprehensive genomic studies have clarified the landscape of somatic alterations in these lymphomas, which has drastically improved our understanding of their molecular pathogenesis. Consequently, a new framework has been proposed for disease classification based on such somatic alterations and/or gene expression characteristic of each lymphoma subtype. Additionally, the results from the genomic studies have also established an important basis for the development of new targeted therapies and prognostic biomarkers. In the future, NGS-based gene panels will be covered by health insurance, and cancer precision medicine is expected to become more prevalent in this field. This paper outlines the analytical methods used in genomic studies by primarily focusing on NGS technology, and describes the results of major genomic and single-cell studies for various subtypes of malignant lymphoma.

A 76-year-old man was admitted to our hospital for a thorough examination of a suspected cardiac tumor on transthoracic echocardiography. Transesophageal echocardiography demonstrated a 9.4×8.1 mm mobile stalk-like mass in the left ventricular outflow tract. A preoperative electrocardiogram revealed paroxysmal atrial fibrillation. Tumor resection and pulmonary vein isolation were performed to prevent embolism and confirm the diagnosis. The tumor was resected using an endoscope because it was difficult to evaluate the tumor under direct view from the aortic valve. Pathological diagnosis was cardiac papillary fibroelastoma. Postoperative echocardiography showed no residual tumor or aortic regurgitation. One year and eight months passed since the surgery, and no recurrence of the tumor was detected. In cases like this one, where direct observation of the tumor is difficult, we suggest that the use of an endoscope may be effective because it has the advantage of sharing information with other surgeons.

We herein report a case of a 73-year-old man with lung cancer who underwent thoracoscopic right upper lobectomy with combined resection of the superior chest wall. His tumor was 48 mm in diameter and located in the posterior right lung apex involving the chest wall between ribs 1 and 3. The anterior aspects of the ribs 2 and 3 were separated using forceps under thoracoscopic vision. The first rib could be released from the tumor by peeling off the parietal pleura. An 8 cm incision was made posteriorly between the scapula and vertebrae to obtain the posterior aspect of the ribs 2 and 3. After separating the pulmonary vessels and bronchus, en bloc resection of the superior sulcus tumor was completed. Thoracoscopic chest wall resection of the superior sulcus tumor can be an alternative to the Paulson posterolateral-paravertebral thoracotomy approach, which can cause severe postoperative pain and limited range of motion of the shoulder joint.

A 51-year-old female patient visited our department with a complaint of pain in the left breast. She was found to have Stage Ⅳ breast cancer with liver metastasis. The biopsy-based historical diagnosis was triple negative breast cancer(TNBC). Epirubicin plus cyclophosphamide therapy(EC therapy)plus weekly paclitaxel therapy(weekly PTX)was started for the unresectable advanced breast cancer, but infiltration of an armor-like tumor was observed in the chest wall. It was judged that drug resistance had occurred; hence, the treatment was switched to S-1. Subsequently, almost all the chest wall tumors disappeared after 2 months. However, we did not control the disease, and the patient died. We report about the positioning of S-1 with regard to TNBC, including a literature review.

The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer 2018 indicated that operation is the standard treatment for breast cancer in elderly patients. This study aimed to assess the safety and efficacy of surgery for elderly patients with breast cancer.

Although the indications for immune checkpoint inhibitors are expanding rapidly, the disease will eventually progress in many patients. Elucidating and overcoming the resistant mechanisms to immune checkpoint inhibitors is a major challenge. WNT/β-catenin pathway has long been known as one of the mechanisms involved in cell proliferation and epithelial-mesenchymal transition in cancer development. Recently, it has become clear that WNT/β-catenin pathway also plays a role in cancer immune escape, as reported in melanoma. We have also studied WNT/β-catenin pathway as a mechanism of immune escape in lung cancer. In this article, we review how WNT/β-catenin pathway is involved in immune escape and resistance to immune checkpoint inhibitors, mainly in non-small cell lung cancer. In addition, we discuss how to overcome the tumor immune mechanism caused by WNT/β-catenin pathway in the context of current combination therapies and therapies in development.

The relationship between the tumor microenvironment and the clinical efficacy of neoadjuvant chemotherapy is unclear in patients with cT2-4aN0M0 muscle-invasive bladder cancer. We examined the tumor microenvironment in these patients via multiplex fluorescence immunohistochemistry. This comprehensive analysis of the immune microenvironment of a muscle- invasive bladder cancer specimen revealed that preexisting tumor-infiltrating proliferating CD8+ T cells and CD204+ cells are indicators of the response to neoadjuvant chemotherapy and that CD204+ cells can be considered an unfavorable prognostic factor in these patients.