Experience with chemotherapy for postoperative metastases of adenosquamous carcinoma of the esophagogastric junction and pathological study of its development.

We report here a case of postoperative recurrent adenosquamous carcinoma (ASC) of the esophagogastric junction (EGJ) treated with S-1 therapy. A 79-year-old woman was diagnosed with carcinoma of the EGJ. Thoracoscopic subtotal esophagectomy was performed, and pathological examination revealed advanced ASC with lymph node metastasis. Five months after surgery, multiple lung metastases and multiple lymph node metastases were observed, and the patient was treated with S-1 monotherapy, which showed partial response and may be effective for advanced ASC of the EGJ. On the other hand, immunohistological analysis of the tumors showed a relatively wide range of areas that could differentiate into both adenocarcinoma and squamous cell carcinoma, suggesting that tumor cells with multidifferentiation potential, or at least the ability to differentiate into both adeno-epithelial and squamous epithelial cells, were the likely source of the tumors.

[A Case of Advanced Esophagogastric Junction Adenocarcinoma with Enlarged Lymph Node Metastases of the Middle Mediastinum and Intraperitoneal That Exhibited pCR by Preoperative SOX Therapy].

A 79-year-old man was diagnosed with esophagogastric junction adenocarcinoma, cT3N3M0, cStage Ⅲ, including enlarged lymph node metastases(Bulky N)in the middle mediastinum and intraperitoneal. A total of 2 cycles of S-1 plus oxaliplatin(SOX)was administered. After neoadjuvant chemotherapy, the primary tumor and enlarged lymph nodes had greatly decreased in size. Subsequently, thoracoscopic subtotal esophagectomy and reconstruction with a gastric tube were performed. Histopathological examinations showed no residual cancer cells in the primary lesion and dissected lymph nodes (pathological complete response). Preoperative chemotherapy containing SOX could be a useful treatment strategy for patients with esophagogastric junction adenocarcinoma with enlarged lymph node metastasis.

[Primary Carcinoid Tumor of the Urinary Bladder : A Case Report].

An 81-year-old male was referred to our department with a tumor in the left wall of the urinary bladder, which was detected by contrast-enhanced abdominal computed tomographic scan (CT), incidentally. Cystoscopy revealed a smooth non-papillary tumor. The patient underwent transurethral resection (TUR) of tumor. An immunohistochemical study showed the tumor cells positively stained for chromogranin A, synaptophysin, CD56, and Ki67. The Ki67 index of the tumor was ＞0.5%, which confirmed the diagnosis of a pure carcinoid tumor. There was no recurrence of bladder tumor and no metastasis after the primary treatment.

Immunochemical analysis of iron transporters and M2 macrophages in ovarian endometrioma and clear cell adenocarcinoma.

The association between iron ions and endometriosis-associated ovarian cancer (EAOC) has been previously investigated to elucidate EAOC carcinogenesis; however, the dynamics of iron deposition in the endometrial epithelium and endometrial stroma of ovarian endometrioma (OE) remains unknown. The present study aimed to determine the expression of iron transporters on the cell surface and the distribution of tumor-associated macrophages (TAMs) englobed with iron in the endometrial stroma. The current retrospective study investigated 20 OE and 18 ovarian clear cell adenocarcinoma (CCC) samples, using Perls Prussian blue staining and immunohistochemistry of iron transporters, including divalent metal transporter 1 (DMT1), transferrin receptor (TfR) and ferroportin (FPN). Additionally, samples were stained for CD68, CD11c, CD163 and CD206, and double-immunostained for iron and CD163 to define the distribution of macrophages. Iron transporters were identified on the endometrial epithelium of OE and CCC tumor cells, and TAMs were englobed with iron in the endometrial stroma of OE and CCC. Histological findings revealed DMT1 upregulation in OE and CCC, whereas lower TfR and FPN expression was observed in OE than in CCC. M2 macrophages were englobed with iron ions in the deep layers of the OE and CCC stroma. The endometrial epithelium located in the endometrial stroma of one patient with OE and the endometrial epithelium adjacent to CCC in two patients with CCC stained positive for the tumor proliferation marker Ki67. Epithelium infiltrating the stroma of OE may become the origin of cancer under the influence of M2 macrophages englobed with iron. These findings provide new perspectives on the malignant transformation of OE into EAOC and its possibility as a precancerous index.

Inhibition of extracellular matrix integrity attenuates the early phase of aortic medial calcification in a rodent model.

BACKGROUND AND AIMS: The mechanism of vascular calcification (VC) resembles that of bone metabolism, and a correlation has frequently been reported between calcification and vascular extracellular matrix (ECM) regulating its integrity; however, the detailed mechanisms remain unclear. In this study, we examined how the vascular ECM, especially collagen metabolism, is involved in the process of VC. METHODS: VC was modeled using 5-week-old male Sprague-Dawley rats fed a diet containing warfarin and vitamin K1 (WVK). Additionally, ß-aminopropionitrile (BAPN) was administered to inhibit lysyl oxidase (LOX), which is an enzyme that mediates collagen cross-linking. Harvested aortic samples were analyzed by staining with alizarin red (AR), immunohistochemistry (IHC), transmission electron microscopy (TEM), and ex vivo microcomputed tomography (µCT). RESULTS: Rats fed WVK developed increasing numbers of aortic medial calcifications (AMCs) over time. TEM images indicated punctate calcification within collagen fibers in the early phase of AMC. AR staining of translucent samples revealed the distribution and severity of calcification, and these lesions were significantly decreased in the BAPN group. Three-dimensional reconstructed µCT images that allowed the quantification of calcified volumes revealed that BAPN significantly reduced the bulk of calcification. Moreover, IHC showed that both LOX and collagen I were present around the sites of AMC, and thus the IHC-positive area was reduced in the BAPN group compared to the WVK group. CONCLUSIONS: The results indicated that inhibition of LOX by BAPN attenuated AMC, and that collagen metabolism plays a significant role in the early pathogenesis of VC.

UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes.

Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. In this study, UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of COMPASS-like and SWI/SNF complexes, played an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in hematopoietic stem cells declined with age, and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation analyses coupled with RNA-seq data indicated that UTX contributed to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging via demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged induced neurons showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.

Pleural changes in patients with pneumothoraces and Marfan syndrome.

BACKGROUND: Patients with Marfan syndrome (MFS) often develop pneumothorax, but the features of pneumothorax in the context of MFS have not been well described in the literature. We clarified the clinical and histopathological characteristics of this condition in these patients. METHODS: Patients with MFS were selected from among all patients who underwent surgery for pneumothorax, between December 1991 and January 2015, in our hospital. We studied the histopathological characteristics of the resected lungs as well as the clinical features of the selected patients, including surgical findings and postoperative recurrence status. RESULTS: There were 966 operations underwent pneumothorax-related surgeries in our hospital. A total of 16 operations (1.66%) were performed on patients with MFS in 11 cases. In this study, 9 patients (6 men, 3 women) were included. Clinically, 7 patients (77.8%) had bilateral pneumothoraces and 4 (44.4%) exhibited postoperative recurrent pneumothoraces. Pathologically, the resected pulmonary bullae exhibited blood vessel cystic medial degeneration (55.6% of cases), calcification (55.6% of cases), and demonstrated elastic fiber fragmentation and degeneration (all cases). CONCLUSIONS: As in few previous reports, many patients with MFS develop bilateral or postoperative recurrent pneumothoraces. In many patients, characteristic changes in the pulmonary bullae, possibly caused by degenerated elastic fibers, were observed.

Histological features of endomyocardial biopsies in patients undergoing hemodialysis: Comparison with dilated cardiomyopathy and hypertensive heart disease.

BACKGROUND: Heart failure is a frequently occurring complication in patients on maintenance hemodialysis (HD). However, the histological features of right ventricular endomyocardial biopsy (RVEMB) samples remain unclear. METHODS: The clinical characteristics and histological findings of consecutive patients undergoing HD with available RVEMB samples (HD group; n=28) were retrospectively compared with those of patients with dilated cardiomyopathy (n=56) and hypertensive heart disease (n=15). RESULTS: The mean myocyte diameter was significantly larger in the HD group than in the other groups (P<.001), whereas the mean percent area of fibrosis did not differ among the three groups. Immunohistochemical analysis revealed that the capillary density was significantly lower in the HD group compared with the other groups (P<.001), and it was positively associated with left ventricular ejection fraction (P=.014). The number of CD68-positive macrophages, which was significantly higher in the HD group compared with the other two groups (P<.001), was associated with cardiovascular mortality (P=.020; log-rank test). CONCLUSIONS: Myocyte hypertrophy, macrophage infiltration, and reduced capillary density were characteristic histological features of the RVEMB samples in patients undergoing HD, which may be related to the pathogenesis of cardiac dysfunction.

EMT-inducing transcription factor ZEB1-associated resistance to the BCL-2/BCL-XL inhibitor is overcome by BIM upregulation in ovarian clear cell carcinoma cells.

Ovarian clear cell carcinoma (OCCC) is an aggressive subtype of epithelial ovarian cancer, which generally exhibits chemoresistance. Effective therapy for OCCC is currently unavailable, requiring the development of new therapeutic strategies. ABT-263 (navitoclax), an inhibitor of the anti-apoptotic BCL-2/BCL-XL, has a potent ability of inducing death in cancer cells; however, the therapeutic effect of ABT-263 in OCCC remains unclear. Epithelial cells undergo epithelial-mesenchymal transition (EMT) to acquire a mesenchymal phenotype, which is known to contribute to the development of resistance against therapeutic agents. In this study, we revealed that the sensitivity of OCCC cells to ABT-263 was associated with the epithelial/mesenchymal status of the cells. While the OCCC cells with an epithelial phenotype were ABT-263-sensitive, those with a mesenchymal phenotype were ABT-263-resistant, which was accompanied by an insufficient expression of the pro-apoptotic BH3 protein BIM. Mechanistically, the EMT-inducing transcription factor, ZEB1 down-regulated BIM transcription by binding to BIM promoter, resulting in resistance to ABT-263. It is noteworthy that ZEB1-associated ABT-263 resistance was overcome by an HDAC inhibitor, FK228 (romidepsin), through the up-regulation of BIM. In summary, our study provides evidence for a mechanism for ABT-263 resistance in OCCC cells as well as a potential therapeutic strategy to overcome it.

Recurrent pericardial effusion with pericardial amyloid deposition: a case report and literature review.

Pericardial amyloidosis is a rare cause of pericardial effusion. Here, we report a case of recurrent pericardial effusion because of pericardial amyloid deposition. The patient was a man in his 40s admitted for pulmonary embolism. During hospitalization, arterial fibrillation and cardiac tamponade were observed, and an initial pericardial puncture was performed. Thereafter, pericardial puncture was repeated nine times over the next two years. Cytological examination of the pericardial effusion suggested malignant mesothelioma. Afterward, pericardial fenestration and partial resection were performed. Intraoperatively, a thickened pericardium and hemorrhagic pericardial effusion were noted. Histologically, the surface of the pericardium was covered by an eosinophilic amorphous material. Congo red and DYLON stains, electron microscopy, and immunohistochemical findings revealed localized amyloidosis composed of an immunoglobulin lambda light chain. Although the patient did not receive further treatment for 5 years postoperatively, his renal and cardiac functions remained within normal limits. Based on these findings, the patient was diagnosed with localized amyloidosis. So far, hemorrhagic pericardial effusion has been reported in few cases with systemic amyloidosis. Because localized immunoglobulin light-chain-derived (AL) amyloidosis may progress to systemic disease (although it is a very rare occurrence), long-term follow-up is necessary to detect recurrence or progression to a systemic form.

Practical Issues and Future Perspectives for Inflammation in Areas of Interstitial Fibrosis and Tubular Atrophy in Chronic Active T cell-Mediated Rejection: Three Case Reports with Commentary.

The 2017 Banff meeting provided specific criteria for the diagnosis of tubulointerstitial changes in chronic active T cell-mediated rejection (CATCR), with an emphasis on inflammation in areas of interstitial fibrosis and tubular atrophy, which was thought to reflect an ongoing T cell-mediated alloimmunity. CATCR is considered to occur as a consequence of persistent or recurrent acute T cell-mediated rejection. Acute T cell-mediated rejection is an acute cytotoxic T-cell reaction to HLA antigens on the donor kidneys and causes tubulitis, interstitial inflammation, and intimal arteries. However, unlike early T-cell transplant damage, CATCR can sometimes be difficult to diagnose because the subsequent chronic T-cell damage can become more complex from the accumulation of previous immune and nonimmune injuries. Furthermore, scoring inflammation in areas of interstitial fibrosis and tubular atrophy has potential problems because other diseases and not even native kidneys can have scattered inflammatory cells. Therefore, detailed insights on the pathogenesis of CATCR are indispensable for appropriate diagnosis and further treatment. In this study, the pathologic characteristics and possible factors involved in the interstitial lesions in both typical and complex cases of CATCR are discussed.

RUNX1-EVI1 induces dysplastic hematopoiesis and acute leukemia of the megakaryocytic lineage in mice.

The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia. We created another mouse model of RUNX1-EVI1 using transplantation of retrovirus-infected bone marrow cells. Some mice transplanted with RUNX1-EVI1-expressing bone marrow cells developed acute megakaryoblastic leukemia within eight months, and the other non-leukemic mice showed thrombocytosis at around a year. In the non-leukemic mice, dysplastic megakaryocytes proliferated in the bone marrow and frequently infiltrated into the spleen, which was not associated with marrow fibrosis. In the leukemic mice, their tumor cells were positive for c-kit and CD41, and negative for TER119. Although they were negative for platelet peroxidase in the electron microscopic analysis, they had multiple centrioles in the cytoplasm, which are characteristic of megakaryocytes that undergo endomitosis. The leukemic cells were serially transplantable, and gene-expression analyses using quantitative RT-PCR arrays revealed that they showed significantly elevated expression of stem cell, primitive hematopoietic cell and endothelial cell-related genes compared with normal bone marrow cells. All these data suggested that RUNX1-EVI1 caused dysplastic hematopoiesis or leukemia of the megakaryocytic lineage and endowed gene expression profiles distinctive of immature hematopoietic cells.

Effectiveness of Stereotactic Radiotherapy and Bevacizumab for Recurrent High-Grade Gliomas: A Potential Therapy for Isocitrate Dehydrogenase Wild-Type Recurrent High-Grade Gliomas.

OBJECTIVE: This study aimed to evaluate the efficacy of stereotactic radiotherapy combined with bevacizumab (SRT-Bv) compared with Bv treatment for recurrent high-grade gliomas (HGGs). METHODS: Data for patients with recurrent HGGs who received SRT and Bv (n = 29) or Bv (n = 29) between June 2014 and September 2016 were retrospectively analyzed. All patients received conventional radiotherapy (total, 60 Gy) before this study. SRT was administered at a median dose of 42 Gy in 3-7 fractions. The recurrence pattern was classified into 3 groups: in-field, marginal, and out-field. RESULTS: The median overall survival in the SRT-Bv group was significantly longer than that in the Bv group (10.4 vs. 5.6 months; P = 0.02). In patients with isocitrate dehydrogenase wild-type tumors, the SRT-Bv treatment significantly prolonged survival more than the Bv treatment (10.9 vs. 8.2 months; P = 0.01). The World Health Organization grade and presence or absence of SRT were significant prognostic factors in the univariate analysis. Besides brain edema in 2 cases and asymptomatic subdural hematoma in 1 case, no other severe adverse effect due to SRT-Bv treatment was recorded. The pattern of recurrence was as follows: in-field, 2 cases (7%); marginal, 8 cases (28%); out-field, 11 cases (38%); no recurrence on radiologic findings, 6 cases (21%); and uncertain, 2 cases (7%). CONCLUSIONS: SRT-Bv treatment significantly prolonged survival duration more than Bv treatment and provides good local control in patients with recurrent HGGs, especially those with isocitrate dehydrogenase wild-type tumors.

Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity, is an emerging risk factor for hepatocellular carcinoma (HCC). Accumulating evidence has shown that chronic inflammation represents a plausible link between obesity and HCC and that the pro-inflammatory cytokine interleukin (IL)-6 contributes to the development of obesity-related HCC. In the present study, we aimed to examine the therapeutic potential of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), which exerts anti-inflammatory effects. The results showed that the development of carcinogen-induced HCC was significantly less in mice fed a high-fat diet (HFD) supplemented with EPA than in those fed HFD only, suggesting that EPA attenuates the development of obesity-related HCC. Although EPA did not appear to affect obesity-linked inflammation, it suppressed the activation of the pro-tumorigenic IL-6 effector STAT3, contributing to the inhibition of tumor growth. These findings suggest a clinical implication of EPA as a treatment for obesity-related HCC.

Synchronous and bilateral oncocytic carcinoma of the breast: A case report and review of the literature.

Synchronous bilateral breast cancer is rare, and oncocytic carcinoma is an even rarer breast cancer histological subtype. In general, oncocytic tumors are defined as neoplasms with eosinophilic granular cytoplasm and have been reported in various organs. Oncocytic carcinoma of the breast was first documented by Gadaleanu and Craciun in 1987, and 48 cases have since been reported. The present study reports a case of synchronous bilateral breast oncocytic carcinoma. The patient was a 78-year-old woman. Although she exhibited no symptoms, chest computed tomography revealed three multinodular breast tumors: Two in the right breast and one in the left. Core needle biopsy was performed on the three tumors, and the patient was diagnosed with invasive ductal carcinoma with potential apocrine carcinoma. A bilateral modified radical mastectomy was performed. Surgical specimens of the three tumors revealed cord- or nest-forming tumor cells with eosinophilic granular cytoplasm. Immunohistochemically, the tumor cells were markedly positive for mitochondria. Electron microscopy of the tumor samples additionally revealed numerous mitochondria filling the cytoplasm. Based on these findings, the tumors were diagnosed as oncocytic carcinoma. The pathogenesis of oncocytic carcinoma remains to be fully elucidated; thus, additional clinicopathological studies are required.

Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knockin mice for Cbl that express wild-type Cbl in a steady state and inducibly express CblQ367P , a CMML-associated Cbl mutant. CblQ367P mice exhibited sustained proliferation of myelomonocytes, multilineage dysplasia, and splenomegaly, which are the hallmarks of CMML. The phosphatidylinositol 3-kinase (PI3K)-AKT and JAK-STAT pathways were constitutively activated in CblQ367P hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. Gem, a gene encoding a GTPase that is upregulated by CblQ367P , enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1, a gene encoding a transcription factor, was found to cooperate with CblQ367P and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of CblQ367P -bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant Cbl-induced CMML and propose a possible molecular targeting therapy for mutant Cbl-carrying CMML patients.

Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression.

Polycomb repressive complex 2 (PRC2) catalyzes the monomethylation, dimethylation, and trimethylation of histone H3 Lys27 (H3K27) and acts as a central epigenetic regulator that marks the repressive chromatin domain. Embryonic ectoderm development (EED), an essential component of PRC2, interacts with trimethylated H3K27 (H3K27me3) through the aromatic cage structure composed of its three aromatic amino acids, Phe97, Trp364, and Tyr365. This interaction allosterically activates the histone methyltransferase activity of PRC2 and thereby propagates repressive histone marks. In this study, we report the analysis of knock-in mice harboring the myeloid disorder-associated EED Ile363Met (I363M) mutation, analogous to the EED aromatic cage mutants. The I363M homozygotes displayed a remarkable and preferential reduction of H3K27me3 and died at midgestation. The heterozygotes increased the clonogenic capacity and bone marrow repopulating activity of hematopoietic stem/progenitor cells (HSPCs) and were susceptible to leukemia. Lgals3, a PRC2 target gene encoding a multifunctional galactose-binding lectin, was derepressed in I363M heterozygotes, which enhanced the stemness of HSPCs. Thus, our work provides in vivo evidence that the structural integrity of EED to H3K27me3 propagation is critical, especially for embryonic development and hematopoietic homeostasis, and that its perturbation increases the predisposition to hematologic malignancies.