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Introduction Acute funisitis, a granulocyte-related inflammation of the umbilical cord, is associated with chorioamnionitis and perinatal adverse events. However, there is no efficient procedure for detecting clinically relevant umbilical cord inflammation. The objective of this study was to identify such inflammation, based on immunohistochemical assessment of umbilical cord vasculitis patterns. Methods Accordingly, 261 cases were retrieved from a single medical institute. Using the well-established granulocyte marker CD15, we developed a five-tier umbilical cord inflammation-scoring system. Additionally, previous morphological assessments from pathological reports were compared to the immunohistochemical findings. Results Analysis of results based on our new scoring system revealed that severe umbilical phlebitis (score 3) was significantly associated with maternal inflammatory response and that severe umbilical arteriophlebitis (score 4) was correlated with low umbilical arterial blood pH, a feature linked to fetal mortality and morbidity. These results corresponded with and were validated by the morphology-based assessments. Additionally, immunohistochemical analysis revealed the clinical and pathological relevance of vitelline vasculitis, a recently proposed condition. We found that analyzing three umbilical cord sections enabled superior detection of severe umbilical vasculitis than analyzing two sections. However, whether these sections were sampled from multiple distant sites or a single localized site did not significantly affect the detection of clinically relevant inflammation. Discussion CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation. CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation.

Background There has been no study that has reported magnetic resonance imaging (MRI) findings of extrauterine high-grade serous carcinomas (HGSCs) that have been histologically determined by the new criteria. Purpose To assess MRI findings of extrauterine HGSCs based on new pathologic criteria. Material and Methods Fifty patients with histopathologically proven extrauterine HGSCs, who underwent pretreatment gadolinium-enhanced MRI, were included in this study. After surgery, the primary sites were histopathologically determined based on new criteria for primary site assignment in extrauterine HGSCs as follows: fallopian tube (n = 34); ovary (n = 9); primary peritoneal HGSC (n = 1); and tubo-ovarian (n = 6). We retrospectively reviewed MR images and compared the MR findings between tubal and ovarian primaries. Results MRI patterns with tubal primaries were classified as ovarian cancer (62%), peritoneal cancer (35%), and fallopian tube cancer (3%). MRI patterns with ovarian primaries were classified as ovarian cancer (78%) and peritoneal cancer (22%). The frequency of the involvement of the fallopian tube, ovary, peritoneum, uterus, and lymph node was not significantly different between the two pathologies. There was no significant difference in the abnormal amount of ascites, hemorrhagic ascites, or characteristics of the ovarian lesions between the two pathologies. Conclusion On MR images, tubal primaries almost always exhibited ovarian or peritoneal cancer pattern, but rarely exhibited fallopian tube cancer pattern. MR findings could not accurately differentiate between tubal and ovarian primaries; therefore, histopathologic investigation is essential for determination of the primary site of extrauterine HGSCs.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16INK4a and p14ARF (p19ARF in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16INK4a and p14ARF alterations independently exhibit differential roles, and p16INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16INK4a-specific loss in oral squamous cell carcinogenesis remains unclear. The authors assessed chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced multistep oral squamous cell carcinogenesis in mice carrying p16INK4a-specific loss with retention of the p19ARF gene (p16INK4a-/-). 4NQO-treated p16-/- mice exhibited a higher incidence and multiplicity of oral squamous cell carcinoma (OSCC) development relative to 4NQO-treated wild-type mice. 4NQO-treated p16INK4a-/- OSCC cells exhibited higher proliferation and up-regulation of Arf, transcription factor E2f1, tumor protein p63 (tp63), and oncogenic ΔNp63, an isoform p63, compared with observations in 4NQO-treated wild-type OSCC cells. Furthermore, the overexpression of oncogenic ΔNp63 was associated with human OSCC. In conclusion, these results in mice indicate the biological significance of p16INK4a-specific loss with retention of p19ARF in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds to thousands of polyps that unless removed by prophylactic colectomy will progress to CRC at an early age. Non-steroidal anti-inflammatory drugs (NSAIDs) and ω-3 marine fish oils, such as eicosapentaenoic acid (EPA), have been evaluated for their chemopreventive potential in delaying the onset of CRC in high-risk patients. In this study, we determined whether the NSAID, naproxen, alone or in combination with a chemically-stable form of EPA (TP-252), affects tumor formation in the ApcPirc rat model. Rats fed a combination of naproxen and TP-252 exhibited a 95% reduction in tumor formation and a 98% reduction in tumor volume, respectively. To elucidate potential mechanisms of tumor protection, a comprehensive lipidomic analysis was performed on colonic mucosa to determine changes in eicosanoid metabolism. Animals receiving TP-252 alone or in combination with naproxen had significantly reduced mucosal levels of pro-inflammatory ω-6 eicosanoids (PGE2, 5-HETE, and 14,15-DiHETrE), along with a simultaneous increase in anti-inflammatory EPA-derived ω-3 eicosanoids. Our colonic mucosal lipidomic analysis also uncovered several potential pharmacodynamic (PD) lipid biomarkers, including resolvin E2, 9-HEPE, 12-HEPE and 18-HEPE, that were increased in both the tissue and plasma of rats receiving TP-252 and were significantly correlated with tumor protection. Further studies with this drug combination should be focused on dose optimization and the role of EPA-derived lipid mediators in CRC initiation and progression. Citation Format: Ryan Beach, Yuichiro Hatano, Yong Qiao, James Grady, Shizuko Sei, Altaf Mohammed, Daniel W. Rosenberg. Combination of naproxen and a novel chemically-stable eicosapentaenoic acid analogue provide synergistic tumor protection in Pirc rats [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA002.

Although ovarian serous carcinoma is a well-studied human gynecologic malignancy, this high-grade tumor remains fatal. The main purpose of this review is to summarize the accumulated evidence on serous malignant tumors and to clarify the unresolved issues. We discuss the 8 dichotomies of serous carcinoma: high grade versus low grade, ovarian versus extraovarian primary, extrauterine versus uterine primary, sporadic versus hereditary, orthodox versus alternative histology, p53 overexpression versus complete absence of immunophenotype, TP53-mutated versus intact precursor, and therapy responsive versus refractory. In addition, we summarize the molecular classification of high-grade serous carcinoma. This review would lead readers to rapid and parallel developments in understanding high-grade serous carcinoma.

OBJECTIVES Measurement of the macroscopic visible core (MVC) length during macroscopic on-site quality evaluation (MOSE) may allow estimation of sample adequacy for next-generation sequencing (NGS), and prediction of correct diagnosis in endoscopic ultrasound-guided tissue acquisition (EUS-TA) of pancreatic masses. METHODS This multicenter prospective study included consecutive patients who underwent EUS-TA for pancreatic masses using a 22-G Franseen needle. MVC length and pathological samples obtained from two needle passes were analyzed on a per-pass basis. Outcome measures included respective correlations of MVC length with histological sample quantity and diagnostic yields. RESULTS The analysis included 204 passes from 102 EUS-TAs. MVC length correlated positively with histological sample quantity (P

A 34-year-old woman underwent total hysterectomy for management of uterine leiomyoma. At the same time, a paraurethral tumor (2 cm in size) was diagnosed based on magnetic resonance imaging (MRI). However, the patient was not treated for the tumor considering its small size. Eight years later, the patient was referred to our institution with a chief complaint of urethral bleeding. Computed tomography revealed a paraurethral mass at the same location, which was 13 cm in size. A percutaneous needle biopsy was performed and the tumor was diagnosed as leiomyoma. Tumor extirpation was performed and immunohistochemical analysis of the specimen demonstrated positive estrogen and progesterone receptors. Recurrence was not observed on MRI taken 6 months after the surgery. Paraurethral leiomyoma is rare, but relatively common in young women.

To assess the magnetic resonance imaging (MRI) findings of endometrial cancers and to reveal the differences between endometrioid carcinoma (EC), serous carcinoma (SC), and clear cell carcinoma (CCC).In this study, 274 consecutive patients with histopathologically confirmed endometrial cancer (231 ECs, 25 SCs, and 18 CCCs) who underwent MRI before hysterectomy were enrolled. MRI images were retrospectively reviewed and compared between the three pathologies.The maximum diameters (55.6 ± 34.7 vs. 39.3 ± 21.6 vs. 39.4 ± 26.8 mm) (p 0.05) and apparent diffusion coefficient (ADC) values (1.11 ± 0.21 vs. 0.84 ± 0.17 vs. 0.86 ± 0.16 × 10SCs frequently exhibited a heterogeneous signal with peritoneal dissemination and abnormal ascites. Alternatively, CCCs tended to have a larger tumor size and higher ADC values with an infiltrative growth pattern, heterogeneous signal, and abnormal ascites.• SCs tend to have a heterogeneous signal intensity with peritoneal dissemination and abnormal ascites compared to ECs. • CCCs tend to have a heterogeneous signal intensity with an infiltrative growth pattern and abnormal ascites compared to ECs. • CCCs have a larger tumor size and higher ADC values compared to ECs and SCs.

Malignant pleural effusion (MPE) can accompany advanced lung adenocarcinoma. Recent studies suggest that MPE could contain a heterogeneous subpopulation of cells with stem-like properties, such as tumorigenicity and self-renewal, indicating that they could be the source of metastasis. Although previous studies analyzed the correlation between cancer stem cell (CSC) marker expression and clinical outcomes using lung cancer tissues, investigations regarding the association of MPE with CSC marker expression are limited. We performed immunohistochemistry to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and Sal-like 4 (SALL4) in 46 cell block samples of MPE from patients with lung adenocarcinoma. ALDH1-positive and SALL4-positive cancer cells in MPE were detected in 30 (65.2%) and 21 samples (45.7%), respectively. Cluster formation was detected in 26 samples (56.5%). The number of clusters was significantly higher in ALDH1-positive/SALL4-negative samples. SALL4 expression was inversely correlated with the cluster ratio (r = −0.356) and positively associated with the Ki-67 index (r = 0.326), suggesting that MPE cells with high SALL4 expression comprised the proliferative subpopulation. In conclusion, we demonstrated that MPE contains an ALDH1-positive/SALL4-negative subpopulation exhibiting cluster formation and a SALL4-positive proliferative subpopulation.

Summary Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.

Background Gliomas typically escape surgical resection and recur due to their “diffuse invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the “diffuse invasion” phenotype, designated the Scherer’s secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. Methods We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. Results Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. Conclusions Targeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.

Background Intestinal-type adenocarcinoma is widely detected in the gastrointestinal tract, head and neck, lower respiratory and urinary systems. Determining the nature (monoclonal or multicentric) of the intestinal adenocarcinoma is sometimes a diagnostic challenge owing to its occurrence at various locations of the body, especially in the lower gastrointestinal tract. Herein, we successfully diagnosed metastatic colon cancer in the small intestine using tumor protein 53 gene (TP53) mutation analysis. Case presentation An 83-year-old woman presented with severe abdominal pain and nausea at the emergency department of the hospital. Her history included surgery and adjuvant chemotherapy for colon and breast cancers. Abdominal computed tomography revealed small intestinal dilation, which was associated with the mural nodule detected on fluorodeoxyglucose positron emission tomography. Laparoscopy-assisted small bowel resection was performed based on the diagnosis of small bowel obstruction, probably due to recurrence of the colon or breast cancer. Macroscopically, an ulcerated tumor was present in the resected small intestine. Histologically, the cancer cells showed infiltrative growth of colonic dysplastic glands, whose non-specific finding made it difficult to determine the relationship with past colon cancers. Retrospective pathological examination confirmed that the previous breast and colon carcinomas were primary cancers. Immunohistochemical analysis revealed that the small intestinal and colon cancer cells showed diffuse positive tumor protein 53 (p53) expression. However, the breast cancer cells showed only weakly positive p53 expression. In addition, TP53 mutational analysis detected an identical missense mutation (p.T211I) between the two intestinal cancers. Moreover, further molecular genetic work-up revealed that both small intestinal and colon adenocarcinomas harbored an identical missense mutation (p.G12D) of KRAS gene. In conclusion, the small intestinal cancer in this case was identified as a metastatic adenocarcinoma arising from a past colon cancer. Conclusions Genetic analyses help in clarifying the identity of the cells in multiple cancer cases. In morphologically indeterminate cases, molecular analysis of common cancer-related genes can be useful for a precise and reproducible diagnosis.

The use of molecular biomarkers for the early detection of heart disease, before their onset of symptoms, is an attractive novel approach. Ideal molecular biomarkers, those that are both sensitive and specific to heart disease, are likely to provide a much earlier diagnosis, thereby providing better treatment outcomes. Galectin-3 is expressed by various immune cells, including mast cells, histiocytes and macrophages, and plays an important role in diverse physiological functions. Since galectin-3 is readily expressed on the cell surface, and is readily secreted by injured and inflammatory cells, it has been suggested that cardiac galectin-3 could be a marker for cardiac disorders such as cardiac inflammation and fibrosis, depending on the specific pathogenesis. Thus, galectin-3 may be a novel candidate biomarker for the diagnosis, analysis and prognosis of various cardiac diseases, including heart failure. The goals of heart disease treatment are to prevent acute onset and to predict their occurrence by using the ideal molecular biomarkers. In this review, we discuss and summarize recent developments of galectin-3 as a next-generation molecular biomarker of heart disease. Furthermore, we describe how galectin-3 may be useful as a diagnostic marker for detecting the early stages of various heart diseases, which may contribute to improved early therapeutic interventions.

Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models.

The necessity of histological analysis is increasing. A 19-gauge histology needle (PC19) in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has recently been developed and has shown high yields of tissue acquisition and histological diagnosis. To compare the histological diagnostic yield in single-pass EUS-FNA for solid lesions using PC19 and a standard 19-gauge needle (EC19). Consecutive patients with solid lesions were enrolled and underwent one pass with each of PC19 and EC19 for EUS-FNA with the randomized order of the needles. The primary endpoint was the histological diagnostic accuracy. The secondary endpoints were the feasibility, yield of histological core, cytological and overall diagnostic accuracies, and adverse events. Subgroup analysis was performed for the optimal situation with PC19. Of the 115 patients, 110 underwent EUS-FNA and five were excluded. EUS-FNA was performed from the esophagus in four, stomach in 80, or duodenum in 26. The final diagnosis was malignancy in 100 and benign in 10. The feasibility was 98.2 and 97.3% with PC19 and EC19, respectively (p = 1.00). The rate of presence of a histological core and the histological, cytological, and overall diagnostic accuracies for PC19 versus EC19 were 84.6 versus 80.9% (p = 0.593), 83.6 versus 73.6% (p = 0.099), 63.6 versus 56.4% (p = 0.335), and 90.0 versus 79.1% (p = 0.039), respectively. PC19 was favored in the trans-esophageal/gastric approaches to obtain a histological diagnosis (p = 0.013). Adverse events were observed in four patients. Single-pass EUS-FNA with PC19 was feasible and showed significantly higher overall diagnostic accuracy and an increased tendency towards histological diagnostic accuracy, especially with trans-esophageal/gastric FNA.

// Ayumi Niwa 1, * , Seiya Kuwano 1, * , Hiroyuki Tomita 1 , Keita Kimura 1 , Yukiya Orihara 1 , Tomohiro Kanayama 1 , Kei Noguchi 1 , Kenji Hisamatsu 1 , Takayuki Nakashima 1 , Yuichiro Hatano 1 , Akihiro Hirata 2 , Tatsuhiko Miyazaki 3 , Kazuhiro Kaneko 4 , Takuji Tanaka 5 and Akira Hara 1 1 Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan 2 Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu, Japan 3 Division of Pathology, Gifu University Hospital, Gifu, Japan 4 Department of Gastroenterology, Endoscopy Division, National Cancer Center Hospital East, Kashiwa, Japan 5 Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu, Japan * These authors have contributed equally to this work Correspondence to: Hiroyuki Tomita, email: h_tomita@gifu-u.ac.jp Keywords: duodenal neoplasms, beta-catenin Received: October 24, 2016 Accepted: February 27, 2017 Published: April 12, 2017 ABSTRACT Non-ampullary duodenal adenoma with activation of Wnt/β-catenin signalling is common in familial adenomatous polyposis (FAP) patients, whereas sporadic non-ampullary adenoma is uncommon. The adenoma-carcinoma sequence similar to colon cancer is associated with duodenal tumors in FAP, but not always in sporadic tumors. We obtained 37 non-ampullary duodenal tumors, including 25 adenomas and 12 adenocarcinomas, were obtained from biopsies and endoscopic resections. We performed immunohistochemistry for β-catenin, the hallmark of Wnt activation, and aldehyde dehydrogenase 1 (ALDH1), a putative cancer stem cell marker. In non-ampullary lesions, abnormal nuclear localization of β-catenin was observed in 21 (84.0%) of 25 adenomas and 4 (33.3%) of 12 adenocarcinomas. In the proximal duodenum, nuclear β-catenin was less frequent in both adenomas and adenocarcinomas. Gastric duodenal metaplasia (GDM) was observed only in the proximal duodenum. All adenomas with GDM were the gastric foveolar and pyloric gland types, and showed only membranous β-catenin. The intestinal-type adenomas had nuclear β-catenin in the proximal and distal duodenum. ALDH1-positive cells were more frequent in adenocarcinomas than adenomas. Nuclear β-catenin accumulation frequently occurred in ALDH1-positive cells in adenoma, but not in adenocarcinoma. In the non-ampullary proximal duodenum, Wnt/β-catenin pathway activation was more closely associated with adenomas than adenocarcinomas, and while it might cooperate with ALDH1 in adenoma, it does not in adenocarcinoma. The pathogenesis thus may differ between sporadic adenoma and adenocarcinoma of non-ampullary duodenal lesions, especially in the proximal and distal duodenum.

To assess MR imaging findings of low-grade serous carcinoma (LGSC) of the ovary compared with those of serous borderline tumor (SBT). Twenty-four patients with histopathologically proven 7 LGSCs and 25 SBTs who underwent preoperative MR imaging were included. We retrospectively reviewed MR images and compared MR findings between the two pathologies. The predominantly solid lesions were marginally more frequent in LGSCs than in SBTs (43% vs. 8%, p = 0.057). All predominantly cystic LGSCs were multilocular cystic lesions with mural nodules. Predominantly solid LGSCs exhibited pure solid masses in 2 of 3 and solid masses with intratumoral cysts in 1 of 3. Papillary growth pattern with internal branching was observed only in 18 of 25 SBTs. Signal intensity ratio on T2-weighted images (4.48 ± 1.55 vs. 8.40 ± 3.53, p

We report a case of an elderly woman with no history of diabetes mellitus who experienced emphysematous cholecystitis after the successful treatment of a heat stroke. Emergency cholecystectomy was performed on day 2., Background During a heat stroke, microvascular injury may occur as a result of thermal damage and systemic hypoperfusion. We present a case of an older woman who experienced emphysematous cholecystitis during a treatment of heat stroke. Case presentation A 91‐year‐old woman presented unconscious with a blood pressure, pulse, and core temperature of 73/48 mmHg, 135 bpm, and 39.8°C, respectively. The patient was diagnosed with heat stroke. Twenty‐two hours after arrival, the patient fell into septic shock. We diagnosed emphysematous cholecystitis and performed an emergency cholecystectomy. As the bile culture was positive for Clostridium perfringens, meropenem was administered. The patient was transferred for rehabilitation 32 days after admission. Conclusions Emphysematous cholecystitis can present during a treatment of heat stroke. An abdominal X‐ray examination should be performed during treatment of heat stroke in the acute phase regardless of the physical assessment.

Every cancer carries genomic mutations. Although almost all these mutations arise after fertilization, a minimal count of cancer predisposition mutations are already present at the time of genesis of germ cells. Of the cancer predisposition genes identified to date, BRCA1 and BRCA2 have been determined to be associated with hereditary breast and ovarian cancer syndrome. Such cancer predisposition genes have recently been attracting attention owing to the emergence of molecular genetics, thus, affecting the strategy of cancer prevention, diagnostics, and therapeutics. In this review, we summarize the molecular significance of these two BRCA genes. First, we provide a brief history of BRCA1 and BRCA2, including their identification as cancer predisposition genes and recognition as members in the Fanconi anemia pathway. Next, we describe the molecular function and interaction of BRCA proteins, and thereafter, describe the patterns of BRCA dysfunction. Subsequently, we present emerging evidence on mutational signatures to determine the effects of BRCA disorders on the mutational process in cancer cells. Currently, BRCA genes serve as principal targets for clinical molecular oncology, be they germline or sporadic mutations. Moreover, comprehensive cancer genome analyses enable us to not only recognize the current status of the known cancer driver gene mutations but also divulge the past mutational processes and predict the future biological behavior of cancer through the molecular trajectory of genomic alterations.

Spur cell anemia is an acquired hemolytic anemia associated with liver cirrhosis and is characterized by the presence of increased large red blood cells, which are covered with spike-like projections that vary in width, length, and distribution. A 26-year-old man was referred to our hospital presenting with jaundice, lower limb edema, and dyspnea. The patient was subsequently diagnosed with spur cell anemia related to alcoholic liver cirrhosis. Spur cell anemia is an independent predictor of mortality in liver cirrhosis and has been associated with extremely poor prognosis. The most effective treatment for spur cell anemia is liver transplantation. As seen in the literature, the treatment of spur cell anemia without liver transplantation is quite challenging. This report highlights the importance of management and treatment strategies, including control of fluid retention, blood transfusion, plasma diafiltration, and administration of diuretics. Our treatment strategies might be useful in patients who are not candidate of liver transplantation or patients waiting for liver transplantation.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16

Colorectal cancer (CRC) remains the fourth leading cause of cancer death worldwide. Cancer stem cells (CSCs) have attracted a great deal of interest because of their potential clinical implications in a range of cancers, including CRC. CSCs were initially considered to be cell populations with well-defined phenotypic and molecular characteristics. However, accumulating evidence suggests that CSCs represent a phenotypically and functionally heterogeneous population. Recent studies also demonstrate colorectal CSCs to be dynamic rather than static populations that are continuously altered by various extrinsic factors in addition to intrinsic cellular factors such as genetic and epigenetic alterations. Thus, CSCs do not represent a fixed target population any longer, and their heterogeneous and dynamic nature present a serious problem in establishing specific therapeutic strategies. This chapter summarizes past and current literature related to CSC population heterogeneity and dynamics in CRC tissues, including evidence of the presence of distinct CSC subpopulations and signaling pathways and intra- and extra-tumoral factors involved in the regulation of CSCs in cancer tissues.

Simple Summary Carcinogens, causes of cancer, are usually invisible and therefore in vivo carcinogenesis is difficult to detect. Tumor viruses, definitive carcinogens, are also usually unremarkable, particularly due to latent infection. However, recent developments in tumor virology are unraveling how a single infected cell becomes a life-threatening cell population from a molecular perspective. The recognition and characterization of virus-driven carcinogenesis is the first step in the eradication of tumor virus-associated cancer. Abstract Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era of precision oncology, carcinogens contributing to neoplastic process are still an important focus of research. Comprehensive genomic analyses have revealed various combinations of base substitutions, referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein–Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex network of data for virus-associated carcinogenesis.

Serrated lesions in the colorectum are currently predominantly classified as hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) according to their morphology. However, the histological morphology and the molecular changes in the serrated lesions are still unclear. We performed immunohistochemistry for Ki67, p16INK4a, and WNT5A in human HPs (n=22), SSA/Ps (n=41), and TSAs (n=19). The distribution of Ki67 and p16INK4a positive cells in TSAs was different from that in HPs and SSA/Ps. Co-expression of Ki67 and P16INK4a was infrequent in HPs and SSA/Ps; p16INK4a-positive cells were found in the crypt cleft and stromal WNT5A-positive stromal cells were localized near the cleft in SSA/Ps, while intraepithelial lymphocytes (IELs) in SSA/Ps were more abundant than HPs. In conclusion, our study provides evidence that HPs branch because of the increase in and patchy distribution of senescent and proliferative cells, with increased and misdistributed stromal and inflammatory cells, which might contribute to creation of L- and/or T-shaped crypts, which are of distinctive shapes in SSA/Ps. Our findings may facilitate better understanding and therapy in the serrated lesions.

A solid and cystic pancreatic lesion was incidentally found in a 62-year-old woman on abdominal computed tomography. The lesion was diagnosed as a solid pseudopapillary neoplasm by using endoscopic ultrasound-guided fine needle aspiration, and the tumor was resected. Histologically, the tumor cells had relatively small, round nuclei and papillary-like architecture in a hemorrhagic background. On immunohistochemical examination, the tumor cells were diffusely positive for nuclear β-catenin and cytoplasmic CD10. In addition, typical histological findings of IgG4-related pancreatitis (obstructive phlebitis, storiform-type fibrosis, and abundant IgG4-positive plasma cell infiltration) were found in the surrounding stroma of the solid pseudopapillary neoplasm. Postoperative workup failed to detect any other sclerotic lesions or serum IgG4 elevation, suggesting that the patient had no evidence of IgG4-related disease. To avoid misdiagnosis of a combined pancreatic neoplasm and fibro-inflammatory lesion, pathologists should consider such situations and make a definitive diagnosis after careful observation of all pancreatic lesions.

To retrospectively compare the MR findings of histological subtypes of clear cell carcinomas (CCCs) of the ovary. This single-center retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. Between April 2005 and August 2015, we found 51 consecutive patients with histopathologically proven CCCs. Among them, 44 CCCs in 37 patients who underwent preoperative MR imaging were included. CCCs were pathologically divided into three subgroups: (1) four clear cell adenofibroma-associated CCCs, (2) 21 endometriosis-associated CCCs, and (3) 19 indeterminate CCCs. The statistical tests were used to compare the frequency of qualitative assessments and value of quantitative measurements among the histological subtypes. On T2-weighted images, hypointense areas within solid components were more frequently observed in clear cell adenofibroma-associated CCCs [3/4 (75%)] than in the remaining CCCs [1/40 (3%)] (p < 0.01), and the signal intensity ratios (SIRs) of solid components were significantly lower in clear cell adenofibroma-associated CCCs (0.27 ± 0.13) than in the remaining CCCs (0.61 ± 0.18) (p < 0.01). On T1-weighted images, hyperintensities of cystic components were more frequently observed in the endometriosis-associated CCCs [17/21 (81%)] than in the remaining CCCs [5/20 (25%)] (p < 0.01), and the SIRs of cystic components were significantly higher in endometriosis-associated CCCs (2.99 ± 1.51) than in the remaining CCCs (1.82 ± 1.10) (p < 0.01). MR features may help differentiate between adenofibroma-associated and endometriosis-associated CCC.

Our purpose was to determine if MRI could be used to distinguish ovarian mucinous carcinoma (MC) from mucinous borderline tumor (MBT).This study included 63 consecutive patients with histopathologically proven ovarian mucinous neoplasms (11 MCs and 52 MBTs) who underwent preoperative contrast-enhanced MRI. MRI images were retrospectively reviewed and compared between the 2 pathologies.The maximum tumor diameters (219.7 ± 80.8 mm vs. 177.4 ± 56.5 mm, p 0.05) and maximum mural nodule (MN) diameters (41.7 ± 33.8 mm vs. 6.6 ± 8.9 mm, p 0.01) were significantly larger in MCs than in MBTs. MNs larger than 5 mm (82 % vs. 29 %, p 0.01) and abnormal ascites (45 % vs. 12 %, p 0.05) were significantly more frequent in MCs than in MBTs. Apparent diffusion coefficient (ADC) values of MN were significantly lower in MCs than in MBTs (1.20 ± 0.25 × 10MRI findings of these 2 pathologies overlapped considerably. Compared with MBTs, MCs exhibited larger tumor size, larger MN size, and lower ADC values of MN, and MCs more frequently had MNs larger than 5 mm and abnormal ascites. T2 hypointense microcysts might be a specific MRI finding in MBTs.

Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a new type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking and IPNB pathogenesis remains unclear. Here, we used a doxycycline-inducible Tet-on mice model facilitating the control of fibroblast growth factor 10 (FGF10) expression which contributes to branching and tubule formation. FGF10-induced IPNB mimicked the multifocal and divergent human IPNB phenotypes via the FGF10–FGFR2–RAS–ERK signalling pathway. A paracrine/autocrine growth factor was sufficient for the initiation and maintenance of IPNB originating from the peribiliary glands, including the biliary stem/progenitor cells. With KrasG12D, p53 and/or p16 gene alterations, Fgf10-induced IPNB showed stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes were suppressed by FGF10–FGFR2–RAS–ERK signalling inhibition, which was inhibited with a MEK inhibitor, demonstrating that the signal is a novel therapeutic target for IPNB and associated carcinoma.

Colorectal cancer (CRC) remains the fourth leading cause of cancer death worldwide. Cancer stem cells (CSCs) have attracted a great deal of interest because of their potential clinical implications in a range of cancers, including CRC. CSCs were initially considered to be cell populations with well-defined phenotypic and molecular characteristics. However, accumulating evidence suggests that CSCs represent a phenotypically and functionally heterogeneous population. Recent studies also demonstrate colorectal CSCs to be dynamic rather than static populations that are continuously altered by various extrinsic factors in addition to intrinsic cellular factors such as genetic and epigenetic alterations. Thus, CSCs do not represent a fixed target population any longer, and their heterogeneous and dynamic nature present a serious problem in establishing specific therapeutic strategies. This chapter summarizes past and current literature related to CSC population heterogeneity and dynamics in CRC tissues, including evidence of the presence of distinct CSC subpopulations and signaling pathways and intra- and extra-tumoral factors involved in the regulation of CSCs in cancer tissues.

Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain tissues, and consequent aberrant vascularization. In these characteristics of GBM, invasive properties are responsible for its recurrence after various therapies. The histomorphological patterns of glioma cell invasion have often been referred to as the “secondary structures of Scherer.” The “secondary structures of Scherer” can be classified mainly into four histological types as (i) perineuronal satellitosis, (ii) perivascular satellitosis, (iii) subpial spread, and (iv) invasion along the white matter tracts. In order to develop therapeutic interventions to mitigate glioma cell migration, it is important to understand the biological mechanism underlying the formation of these secondary structures. The main focus of this review is to examine new molecular pathways based on the histopathological evidence of GBM invasion as major prognostic factors for the high recurrence rate for GBMs. The histopathology-based pharmacological and biological targets for treatment strategies may improve the management of invasive and resistant GBMs.

Cancer stem cells (CSC) have attracted a great deal of interest for their clinical relevance in a range of cancers, including colorectal cancer. CSCs were initially considered to be cell populations with homogeneous, well-defined phenotypic and molecular characteristics. However, accumulating evidence suggests that CSCs represent phenotypically and functionally heterogeneous populations. Recent studies demonstrate colorectal CSCs to be dynamic rather than static, and continuously altered by multiple extrinsic and intrinsic factors. Thus, CSCs no longer should be viewed as a fixed target population, and we should note that their heterogeneous and dynamic nature presents a serious problem for the development and implementation of specific therapeutic strategies. This review summarizes past and current literature related to the heterogeneity and dynamics of colorectal CSC populations, focusing on evidence for distinct subpopulations, and signaling pathways, and intra- and extratumoral factors involved in their regulation in cancer tissues.

Indoleamine 2, 3-dioxygenase (IDO), an enzyme that degrades the essential amino acid L-tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1-deficient[(−/−)] mice were crossed with Apc[Min/+] mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1-methyltryptophan (1-mT) also resulted in no significant differences in tumor size and number in Apc[Min/+] mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro-inflammatory cytokines and a significant decrease in the number of Foxp3-positive regulatory T cells in the colon tumors of Ido1[(−/−)] mice. Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is considered to be a cancer stem cell marker in several human malignancies. However, the role of ALDH1A1 in hepatocellular carcinoma (HCC) has not been well elucidated. In this study, we investigated the relationship between ALDH1A1 and clinicopathological findings and examined whether ALDH1A1 deserves to be a cancer stem cell marker in HCC. Sixty HCC samples obtained from surgical resection were collected for immunohistochemical (IHC) staining. Of these 60 samples, 47 samples of HCC tumorous and non-tumorous tissues were evaluated with qRT-PCR. There was no significant difference in the ALDH1A1-mRNA level between tumorous and non-tumorous tissues. Tumorous ALDH1A1-mRNA level had no relationship with the clinicopathological features. Immunoreactivity of ALDH1A1 was classified into two groups based on the percentage of ALDH1A1-overexpressing cells. The ALDH1A1-high group was significantly associated with low serum levels of α-fetoprotein, small tumor diameter, very little lymphovascular invasion, more differentiated pathology and good stage. The ALDH1A1-high group showed more favorable prognosis for recurrence-free survival. In double-staining IHC, ALDH1A1 was not co-expressed with BMI1, EpCAM, CD13, CD24, CD90 and CD133, which reported as cancer stem cell markers in HCC. In conclusion, ALDH1A1-overexpressing cells could appear to be differentiated cells rather than cancer stem cells in HCC.

The forced reduction of global DNA methylation suppresses tumor development in several cancer models in vivo. Nevertheless, the mechanisms underlying these suppressive effects remain unclear. In this report, we describe our findings showing that a genome-wide reduction in the DNA methylation levels induces cellular differentiation in association with decreased cell proliferation in Apc (Min/+) mouse colon tumor cells in vivo. Colon tumor-specific DNA methylation at Cdx1 is reduced in the DNA-hypomethylated tumors accompanied by Cdx1 derepression and an increased expression of intestinal differentiation-related genes. Furthermore, a histological analysis revealed that Cdx1 derepression in the DNA-hypomethylated tumors is correlated with the differentiation of colon tumor cells. Similarly, the treatment of human colon cancer cell lines with a hypomethylating agent induces differentiation-related genes, including CDX1. We herein propose that DNA demethylation exerts a tumor suppressive effect in the colon by inducing tumor cell differentiation.

Galectin-3 is a β-galactosidase-binding lectin which is important in cell proliferation and apoptotic regulation. Encephalomyocarditis virus (EMCV), which includes the Enterovirus genus, can cause not only acute myocarditis but also neuronal degeneration of central nervous system in various animals including mice. The pathophysiological role of galectin-3 in central nervous system following acute viral infection is not fully understood. The goal of this study is to determine the localization and time-course of galectin-3 expression after acute viral inoculation with EMCV. Galectin-3 is up-regulated in degenerated lesions of brain area including cerebellum, hippocampus, thalamus and cerebral hemisphere, 96 h after EMCV inoculation. At the same time, Iba-1 positive microglia was morphologically activated within and around the focus of infection. Interestingly, in cerebellum, the microlesions containing a few galectin-3 cells were detected in the immediate-early phase of infection, as early as 48 h after EMCV inoculation. Thus, our results indicate that galectin-3 expression may be a key mediator between viral infection and neuronal degeneration in central nervous system including cerebellum. Furthermore, detection of galectin-3 might be an early diagnostic method for neuronal degeneration after virus infection.

We presented a 27-year-old male diagnosed with intraosseous schwannoma of the ilium. Computed tomographic images revealed a well-demarcated, lobulated, expansile, osteolytic lesion in the right supraacetabular region of the ilium. In addition, an intratumoral punctate calcification and a sclerotic rim were observed. T2-weighted magnetic resonance (MR) images demonstrated a heterogeneously hyperintense lesion with a hypointense rim. Major parts of the lesion, excluding some central areas, were enhanced on gadolinium-enhanced MR images. Pathological examination revealed an intraosseous schwannoma. Our findings indicate that intraosseous schwannoma should be considered when images demonstrate a well-demarcated, lobulated, expansile, osteolytic lesion with a sclerotic rim.

An 83-year-old man admitted for left hand pain due to a large necrotic ulcer presented with many sites of erythema on his trunk. Computed tomography revealed multiple poorly marginated masses in the liver; however, no malignant cells were detected on a biopsy of several skin lesions. He died on the 47th hospital day, and autopsy was subsequently performed, showing multiple nodules in the liver. The histological findings revealed clusters of malignant melanoma cells that had diffusely infiltrated the liver parenchyma. No tumor cells were detected in the skin lesions or lymph nodes. Immunohistochemically, the patient was diagnosed to have metastasis from malignant melanoma of unknown origin.