Katsura Emoto

Presence of primary cilia in cancer cells correlates with prognosis of pancreatic ductal adenocarcinoma

Primary cilia are microtubule-based organelles that protrude from basal bodies and are involved in cell differentiation, sensory functions, and planar cell polarity. Although there are many studies examining the roles of primary cilia in the fields of embryology and physiology, few such studies have been carried out in the field of oncology, and the role of primary cilia in cancer cells is poorly understood. In this study, we identified primary cilia by immunofluorescence analysis in which primary cilia were visualized as green rods labeled with anti-acetylated α-tubulin adjacent to basal bodies detected as red dots labeled with anti-γ-tubulin. Primary cilia were found in human pancreatic cancer cell lines and in cancer cells in 25 of 100 pancreatic ductal carcinoma patients. In the clinical samples, most primary cilia in cancer tissue were observed in areas showing well-differentiated glandular structures. Patients whose cancers were primary cilia positive had a higher frequency of lymph node metastasis than those whose cancers were primary cilia negative (P = .016). Univariate analysis demonstrated that tumor size (P = .009), tumor grade (P = .001), lymph node metastasis (P = .008), and the presence of primary cilia (P = .002) correlated with overall survival. Multivariate analysis found that tumor grade (P < .001) and the presence of primary cilia (P = .001) were independent prognostic indicators. In conclusion, we showed that pancreatic cancer cells can form primary cilia and that the presence of primary cilia is significantly associated with the prognosis of pancreatic ductal adenocarcinoma.

Prognostic Factors Based on Clinicopathological Data Among the Patients with Resected Peripheral Squamous Cell Carcinomas of the Lung

Introduction: Although the incidence of peripheral squamous cell carcinomas (p-SqCCs) of the lung has increased over recent years, clinicopathological factors influencing prognosis of resected p-SqCCs remain unclear. Methods: We examined 280 patients who underwent complete resection of SqCCs and analyzed the clinicopathological features in relation to their overall survival (OS) and recurrence-free survival (RFS) according to the primary location. Results: Multivariate analysis of all stages of p-SqCCs patients revealed that high serum squamous cell carcinoma antigen (SCC) level (OS; p < 0.01, RFS; p < 0.01), vascular invasion (OS; p < 0.01, RFS; p < 0.01), pleural invasion (OS; p = 0.03, RFS; p = 0.01), nodal metastasis (OS; p = 0.02) and complication with lung disease (OS; p < 0.01) were independently unfavorable prognostic factors. Among stage I p-SqCCs patients, high serum SCC level (OS; p < 0.01, RFS; p < 0.01), vascular invasion (RFS; p < 0.01) and pleural invasion (RFS; p = 0.01) were also strongly correlated with poor prognosis independently. When we reevaluated the survival rate, T1 p-SqCCs with high serum SCC level or vascular invasion can be upgraded to T2a. Patients with stage IB had a significantly poorer prognosis than stage IA (5-year RFS; 61.4 % versus 76.6 %, p < 0.05). Conclusion: High serum SCC level, pleural and vascular invasions were independent poor prognostic factors for completely resected p-SqCCs. T1 p-SqCCs with high serum SCC level or vascular invasion should be upgraded to T2a, which accurately reflect survival status among patients with p-SqCCs.

Surgical technique for allogeneic uterus transplantation in macaques

No study has reported an animal model of uterus transplantation (UTx) using cynomolgus macaques. We aimed to establish a surgical technique of allogeneic UTx assuming the recovery of a uterus from a deceased donor in cynomolgus macaques. Four allogeneic UTxs were performed in female cynomolgus macaques. Donor surgeries comprised en bloc recovery of organs with iliac vessels on both sides, and/or abdominal aorta/vena cava after sufficient perfusion from one femoral artery or external iliac artery. Before perfusion, 150 mL of whole blood was obtained from the donor for subsequent blood transfusion to the recipient. Four uterine grafts were orthotopically transplanted to recipients. End-to-side anastomosis was performed to the iliac vessels on one side in case 1 and iliac vessels on both sides in case 2; aorto-aorto/cavo-caval anastomosis was performed in cases 3 and 4. Arterial blood flow of the uterine grafts was determined by intraoperative indocyanine green (ICG) angiography. ICG angiography results showed sufficient blood flow to all uterine grafts, and anaemia did not progress. Under appropriate immune suppression, all recipients survived for more than 90 days post-transplantation, without any surgical complications. We describe a surgical technique for allogeneic UTx in cynomolgus macaques.

Comprehensive Immune Profiling of Lung Adenocarcinomas Reveals Four Immunosubtypes with Plasma Cell Subtype a Negative Indicator

Lung cancer is a complex disease with variable outcomes. Immune cells from 114 cases were quantified immunohistochemically, identifying four immunosubtypes of lung adenocarcinoma (CD8, mast cell, macrophage/DC, and plasma cell) that could potentially be useful for therapy selection. Neoplastic cancer cells and cancer stroma (including infiltrating immune cells) determine the biology and prognosis of cancer. Various types of adaptive and innate immune cells are known to infiltrate the cancer stroma. However, the patterns and spatial distribution of immune cell infiltration as well as its association with tumor histology remain poorly understood. To address these issues, we comprehensively analyzed the infiltrating immune cells present in lung adenocarcinoma. The principal types of both adaptive and innate infiltrating immune cells were immunohistochemically evaluated in the predominant histologic components of 111 lung adenocarcinomas. The same analysis was also carried out on 143 samples of histologic subtypes making up more than 20% of tumors. As a result, plasma cells and B cells with interfollicular distribution were almost exclusively observed in invasive histologic subtypes, while an increased number of mast cells were observed in noninvasive histologic subtypes. Cluster analysis revealed four distinct immunosubtypes (CD8, mast cell, macrophage/dendritic cell, and plasma cell subtypes) based on the infiltrating immune cell profiles. These immunosubtypes correlated with histologic subtypes, and univariate and multivariate analyses identified the plasma cell subtype as an independent negative prognostic factor. These plasma cells may be one of the major producers of the immunosuppressive cytokine IL35 in cancer stroma. Cancer Immunol Res; 4(3); 234–47. ©2016 AACR.

Evaluation of allowable time and histopathological changes in warm ischemia of the uterus in cynomolgus monkey as a model for uterus transplantation.

The objective of this study was to examine the allowable warm ischemic time and pathological changes due to ischemia and reperfusion injury in the uterus of the cynomolgus monkey as a model for uterus transplantation.

Prognostic Impact of Preoperative Tumor Marker Levels and Lymphovascular Invasion in Pathological Stage I Adenocarcinoma and Squamous Cell Carcinoma of the Lung

Introduction: Some unfavorable prognostic factors for stage I non–small-cell lung cancers have been reported; however, they are not reflected in the current Tumor–Node–Metastasis classification. Methods: We retrospectively reviewed 629 patients who underwent complete resection of pathological stage I adenocarcinomas (ADs) or squamous cell carcinomas (SQs) at two institutes between 1996 and 2011. The correlation between clinicopathological characteristics and survival rates was analyzed to identify prognostic factors. Results: Multivariate analysis indicated that among ADs, high serum carcinoembryonic antigen levels (p = 0.04 for overall survival [OS]; p < 0.01 for recurrence-free survival [RFS]; p = 0.02 for disease-specific survival [DSS]), lymphatic permeation (p < 0.01 for RFS and DSS), and vascular invasion (p < 0.01 for OS and RFS; p = 0.03 for DSS) were independent prognostic factors. Among SQs, high squamous cell carcinoma antigen (SCC) (p < 0.05 for OS), and vascular invasion (p < 0.05 for RFS and DSS) were independently prognostic. We suggest that among completely resected tumors less than or equal to 5 cm without lymph node metastasis, the current stages IA and IB AD with high serum carcinoembryonic antigen levels, lymphatic permeation, or vascular invasion should be upgraded to stage IB and IIA, respectively. The current stage IA SQ with high SCC antigen levels or vascular invasion should be upgraded to stage IB. These reclassifications accurately reflect survival status (p < 0.04 in all comparisons). Conclusions: Some important differences in prognostic factors were observed between AD and SQ. High preoperative serum tumor marker levels and lymphovascular invasion should be included as additional criteria in the forthcoming Tumor–Node–Metastasis staging.

Duplication of the digestive organs in the retroperitoneum: A case report with reference to the importance of a standardized nomenclature and definition

Duplications of the digestive organs, especially in the retroperitoneum, are rare malformations. We present the case of a 20‐year‐old man who had recurrent abdominal pain because of a solid and cystic mass located in the retroperitoneum, posterior to the pancreatic body. Preoperative diagnosis was difficult and a resection was performed. Histopathologically, intestinal mucosa, respiratory mucosa, aberrant pancreatic tissue, smooth muscle coat, and an external fibrous capsule were found. The mass was diagnosed as a duplication of the digestive organs. Findings in the pancreatic tissue indicated chronic pancreatitis and mild atypia in the pancreatic duct epithelium. Currently, many terms are used to describe these series of malformations, including duplication, foregut cyst, gastrointestinal duplication cyst, and enteric duplication cyst. Consequently, diagnosis and investigation can be difficult. In the atlas produced by the Armed Forces Institute of Pathology, duplication is used as a standardized diagnostic nomenclature with subclassification according to the site, but this has not been uniformly accepted. In addition, there are cases whose origins are unclear, especially in the retroperitoneum. In this report, we propose that the term duplication should be uniformly used for all cases in the digestive organs, and that they may then be distinguished according to their mechanisms.

Organ Perfusion for Uterus Transplantation in Non-Human Primates with Assumed Procurement of a Uterus from a Brain-Dead Donor

BACKGROUND Clinical studies of uterus transplantation have been performed to treat uterine factor infertility. Because the uterus is a pelvic visceral organ, the method of perfusion for the procurement of vital organs from a brain-dead donor should be modified for removal of the uterus. Herein, we report the results of a preliminary study in cynomolgus monkeys of a new perfusion method for uterus transplantation with assumed procurement of a uterus from a brain-dead donor. METHODS Cynomolgus monkeys were used; thoracolaparotomy was performed on the donor. A perfusion catheter was then placed into the unilateral femoral artery and/or external iliac artery. Cross-clamping was performed for the aorta under the diaphragm and the inferior vena cava was divided in the pleural space. The perfusion solution was then administered via the catheter to perfuse all organs in the abdominal cavity, including those in the pelvic cavity. After the perfusion, gross observation and histopathological examination of abdominal organs were conducted. RESULTS Gross findings showed that all abdominal organs turned white in all specimens, indicating favorable perfusion of the uterus and all other organs in the abdomen. Pathological findings showed that almost no hemocytes were observed in the vessels of each organ. CONCLUSIONS With perfusion via the femoral artery and/or external iliac artery, all organs in the abdominal cavity, including the uterus, could be perfused. It was suggested that this technique could be useful for uterus transplantation assuming the procurement of a uterus from a brain-dead donor.

Methotrexate-associated Intravascular Large B-cell Lymphoma in a Patient with Rheumatoid Arthritis

Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically aggressive lymphoma with an unfavorable prognosis. We report the case of a 50-year-old woman who was diagnosed with IVLBCL during treatment with methotrexate (MTX) and biologic agents for rheumatoid arthritis. The symptoms showed partial improvement only after the cessation of both treatments. She subsequently received chemotherapy and achieved a complete remission and has remained free of recurrence for 2 years without any further treatment. We herein describe a rare case of IVLBCL which presented with the features of an MTX-associated lymphoproliferative disorder.

Dry pleurisy complicating solitary pulmonary nodules caused by Mycobacterium avium: a case report

IntroductionMycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense 18F-fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN.Case presentationA 36-year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense 18F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium.ConclusionThis is the first report of MAC-SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation.