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Introduction BCOR-CCNB3 sarcoma (BCS) is one of the histological types classified as undifferentiated small round cell sarcoma of bone and soft tissue. This sarcoma frequently develops in males under 20 years of age. Histologically, it has been reported that a delicate capillary network is a conspicuous finding. In this study, the cytological findings of BCS were observed in 2 cases of primary lesions and 1 case of a lung metastatic lesion. The cytological findings of BCS were compared with its histological mimics, and the characteristic findings of BCS were examined. Methods Three cases of BCS were studied, and a cytological comparison was performed with 8 cases of Ewing sarcoma (ES) and 10 cases of synovial sarcoma (SS) (monophasic type SS: 7 cases, biphasic type SS: 2 cases, poorly differentiated SS: 1 case). Results In all BCS cases, small clusters with thin and delicate vascular cores and tiny vascular fragments were conspicuous. In ES and SS cases, although small clusters with vascular cores were observed, the vascular cores were thicker than in BCS, and no tiny vascular fragments appeared in most cases. Cytomorphological differences of tumor cells were also observed among BCS, ES, and SS. Predominantly rounded nuclei with fine chromatin and inconspicuous nucleoli can be cytological clues for BCS. Conclusions BCS shows characteristic cytological findings that make the diagnosis of BCS more likely than that of ES and SS. Cytological evaluation is a useful tool for appropriate differential diagnosis that leads to a more accurate final diagnosis and rapid treatment.

Thymic adenocarcinoma is an extremely rare neoplasm, and little is known about its pathogenesis and clinical characteristics. A 52‐year‐old man presented to our clinic with severe dyspnea. At initial presentation, massive carcinomatous pleuritis and pericarditis were observed, and a lobulated mass in the anterior mediastinum was found on computed tomography. Cytological examination revealed adenocarcinoma accompanied by signet ring cells; however, his tumor showed aggressive growth without any possibility of treatment, and he died as a result of cancer progression within one month of admission. An autopsy confirmed thymic adenocarcinoma showing various histological features including mucinous, signet ring cell‐like, and trabecular features. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) (AE1/AE3) but negative for TTF‐1. In addition, some tumor cells were positive for CD5 and KIT. Further examination revealed that tumor cells of the nonmucinous type were positive for CK7, and negative for CK20 and caudal‐type homeobox 2 (CDX2). The tumor cells with mucinous and signet ring‐like features were positive for CK20 and CDX2 and negative for CK7, indicating enteric differentiation. In particular, tumor cells with signet ring cell‐like features indicated widespread lymphangitic carcinomatosis and pulmonary tumor thrombotic microangiopathy (PTTM). The presence of signet ring cell‐like features with enteric differentiation is suggestive of a fulminant clinical course due to widespread lymphangiosis carcinomatosa and PTTM in patients with thymic adenocarcinoma. Key points Thymic adenocarcinoma is an extremely rare neoplasm.Histological features of thymic adenocarcinoma include mucinous, signet ring cell‐like, and trabecular features.Tumor cells with signet ring cell‐like features indicate widespread lymphangitic carcinomatosis and pulmonary tumor thrombotic microangiopathy.The presence of signet ring cell‐like features with enteric differentiation is associated with a fulminant clinical course., Thymic adenocarcinoma is an extremely rare neoplasm with various histological features including mucinous, signet ring cell‐like, and trabecular features. Tumour cells with signet ring cell‐like features indicate widespread lymphangitic carcinomatosis and pulmonary tumour thrombotic microangiopathy. The presence of signet ring cell‐like features with enteric differentiation is associated with a fulminant clinical course.

Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from 90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression.

Introduction Positive peritoneal cytology (PPC) in endometrial cancer remains a controversial topic. Cleaved caspase-3 (CC3) and Ki-67 are excellent markers of apoptotic and proliferating cells, respectively. The objective of this study was to determine the significance of CC3 and Ki-67 expression in peritoneal cytology samples as prognostic factors for endometrial cancer with PPC. Methods Sixty endometrial cancer specimens with PPC alone were divided into 51 endometrioid tumours (43 endometrioid carcinomas and eight carcinomas with squamous differentiation) and nine non-endometrioid tumours (two serous carcinomas, three clear cell carcinomas and four carcinosarcomas). CC3 and Ki-67 expression in peritoneal cytology samples were immunocytochemically assessed and correlated with disease-free survival (DFS) and overall survival (OS). Results Expression levels of CC3 and Ki-67 were not associated with any clinicopathological parameter. Patients with non-endometrioid tumours had significantly shorter DFS (P = .001) and OS (P = .001). Low CC3 expression (CC3Low ) was significantly associated with shorter OS (P = .02), but not DFS (P = .13). Multivariate analysis showed that non-endometrioid histology and CC3Low were independent prognostic factors. However, Ki-67 expression was not associated with survival. When endometrioid and non-endometrioid tumours were assessed separately, CC3Low was significantly associated with shorter DFS (P = .002) and OS (P = .002) in patients with non-endometrioid tumours. Conclusions Our results suggest that CC3Low in peritoneal cytology samples is a poor prognostic factor in patients with endometrial cancers, especially non-endometrioid tumours. Immunocytochemical analysis of CC3 expression could potentially facilitate identification of patients with high-risk endometrial cancer with PPC.

The cell surface glycoprotein mesothelin is highly expressed in several malignant diseases. Normal mesothelin expression is limited to mesothelial cells lining the pleura, peritoneum, and pericardium, making it a biomarker and an attractive target for cancer therapy. We investigated tumor mesothelin expression and serum mesothelin levels in patients with epithelial ovarian cancer or borderline tumors. In total, 161 patients selected from a previous prospective study were analyzed for tumor mesothelin expression using immunohistochemistry and serum mesothelin expression using enzyme-linked immunosorbent assay. Eighty-eight (68.8%) epithelial ovarian cancers and eight (24.2%) borderline tumors showed high mesothelin expression, which was associated with shorter progression-free and overall survival. The tumor mesothelin expression status was moderately correlated with serum mesothelin levels in epithelial ovarian cancer patients. Based on receiver operating characteristic analysis, a serum mesothelin level above 2.20 nM predicted high tumor mesothelin expression in epithelial ovarian cancer patients (area under the curve = 0.81). In 45 patients with recurrent epithelial ovarian cancer, we observed relatively lower levels of serum mesothelin, compared to the level at the primary diagnosis. We also tracked the change in the serum mesothelin level during the course of second-line chemotherapy and found a discrepancy between the clinical response and the serum mesothelin change in some patients, which suggested tumor heterogeneity among the tumor cells with or without mesothelin expression. Serum mesothelin may be a useful noninvasive biomarker surrogate for tumor mesothelin expression in future clinical trials for mesothelin-targeted therapy.

Acute exacerbation of pre-existing interstitial lung disease (ILD) associated with systemic anticancer therapy is recognized as a life-threatening adverse event of lung cancer treatment. Programmed cell death 1 (PD-1) checkpoint inhibitors, such as nivolumab, often induce pneumonitis in patients with cancer; however, the tolerance and safety of nivolumab for advanced lung cancer with ILD are unclear. We report a 72-year-old patient with lung cancer with pathologically proven idiopathic pulmonary fibrosis who was treated with nivolumab. She demonstrated pneumonitis with an organized pneumonia (OP) pattern, but no acute exacerbation of ILD featuring a diffuse alveolar damage (DAD) pattern. She was successfully treated with corticosteroid therapy, and maintained good disease control after the discontinuation of nivolumab. She also showed pseudoprogression of the primary tumor, implying infiltration of T-cells into the lung. These findings suggest that T-cell activation by nivolumab treatment might not be directly associated with acute ILD exacerbation, and that treatable OP might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients without underlying ILD.

Folate receptor alpha (FRA) is a GPI-anchored glycoprotein and encoded by the FOLR1 gene. High expression of FRA is observed in specific malignant tumors of epithelial origin, including ovarian cancer, but exhibits very limited normal tissue expression, making it as an attractive target for the ovarian cancer therapy. FRA is known to shed from the cell surface into the circulation which allows for its measurement in the serum of patients. Recently, methods to detect the soluble form of FRA have been developed and serum FRA (sFRA) is considered a highly promising biomarker for ovarian cancer. We prospectively investigated the levels of sFRA in patients clinically suspected of having malignant ovarian tumors. A total of 231 patients were enrolled in this study and analyzed for sFRA as well as tumor expression of FRA by immunohistochemistry. High sFRA was predominantly observed in epithelial ovarian cancer patients, but not in patients with benign or borderline gynecological disease or metastatic ovarian tumors from advanced colorectal cancers. Levels of sFRA were highly correlated to clinical stage, tumor grade and histological type and demonstrated superior accuracy for the detection of ovarian cancer than did serum CA125. High sFRA was significantly associated with shorter progression-free survival in both early and advanced ovarian cancer patients. Finally, tumor FRA expression status was strongly correlated with sFRA levels. Taken together, these data suggest that sFRA might be a useful noninvasive serum biomarkers for future clinical trials assessing FRA-targeted therapy.

Objective: Parathyroid carcinoma is a rare malignant neoplasm. Hypercalcemia due to parathyroid carcinoma is often resistant to medical management in the advanced stage. Here we report the usefulness of denosumab as an option for managing refractory hypercalcemia in the setting of parathyroid carcinoma.Methods: A 39-year-old Japanese female with metastatic parathyroid carcinoma was referred to our hospital due to frequent episodes of hypercalcemia. Upon admission, her respective serum calcium (Ca) and intact parathyroid hormone (PTH) levels were 13.3 mg/dL (reference range, 8.5–10.2 mg/dL) and 1,920 pg/mL (reference range, 10–65 pg/mL). Although her hypercalcemia initially responded to strengthened standard therapy, it became unmanageable as her disease progressed. A single denosumab injection dramatically decreased her hypercalcemia from 15.1 to 10.1 mg/dL within 10 days. Her Ca levels remained in the reference range for more than 1 month. Her hypercalcemia could be controlled by denosumab injected at a frequency lower than that used for the bone metastasis of malignant tumors.Results: Although her serum PTH level increased to 4,130 pg/mL, her condition has remained good for the last 14 months.Conclusions: Denosumab is a humanized monoclonal antibody that inhibits the receptor activator of nuclear factor-κB ligand (RANKL) and is a potentially important palliative treatment for refractory hypercalcemia due to parathyroid carcinoma.Abbreviations: Ca calcium PTH parathyroid hormone RANK receptor activator of nuclear factor-κB RANKL receptor activator of nuclear factor-κB ligand TRACP-5b tartrate-resistant acid phosphatase 5b

The present study presents a case of peritoneal malignant mesothelioma (PMM) following radiation therapy for cervical cancer. A 34-year-old Japanese woman, without asbestos exposure, was referred to the Department of Gynecologic Oncology, Saitama Medical University International Medical Center due to a cervical mass, and was diagnosed with cervical squamous cell carcinoma (SCC). The serum levels of tumor markers, including SCC antigen and cancer antigen 125 (CA125) were 229.0 ng/ml and 54.4 U/ml, respectively. The patient underwent concurrent chemoradiotherapy (CCRT), and a complete response was achieved. After 54 months, ascites was found at the rectouterine pouch, but peritoneal cytology suggested reactive mesothelial cell. After 62 months of CCRT, magnetic resonance imaging revealed masses in both the salpinges. The serum levels of SCC and CA125 were 0.9 ng/ml and 506.1 U/ml, respectively. Following this, left salpingectomy and peritoneal biopsy were performed laparoscopically. Histologic examination revealed atypical mesothelial cells with no continuity of background tubal epithelium. Immunohistochemistry showed positive staining for calretinin, thrombomodulin, mesothelin and glucose transporter 1. Based on these findings, the patient was diagnosed with PMM epithelioid type and underwent systemic chemotherapy; stable disease status has been obtained for 3 months. This case demonstrates the possibility of PMM occurrence within 10 years after radiotherapy, and indicates the importance of histological and immunohistochemical examination, particularly in cases of an atypical tumorigenesis pattern from the primary cancer.

The aim of this study was to investigate the impact of genetic polymorphisms in the metabolic and cellular transport pathway of methotrexate (MTX) on the clinical outcome of MTX monotherapy in Japanese rheumatoid arthritis (RA) patients. Fifty-five patients were treated with MTX monotherapy at a dose of 4-10 mg/week. The total concentration of MTX-polyglutamates (MTX-PGs) was measured at steady-state in red blood cells (RBCs) by high performance liquid chromatography. The genotype at 16 polymorphic sites in 11 genes (ABCB1, ABCG2, ABCC2, RFC1, PCFT, SLCO1B1, MTHFR, GGH, ATIC, MTR, and MTRR) was analyzed. No significant association between the total concentration of MTX-PGs in RBCs and clinical outcome was found. However, patients with the ABCB1 3435TT genotype had a significantly lower mean disease activity score (DAS) 28 than did patients with the ABCB1 3435CC genotype (p = 0.02). Similarly, patients with the ABCB1 2677AA/AT/TT genotypes had a significantly lower mean DAS28 than did patients with the ABCB1 2677GG/GA/GT genotypes (p = 0.04). The patients with the MTHFR 1298AA genotype had a significantly lower mean DAS28 than those with the MTHFR 1298AC/CC genotypes (p = 0.04). In conclusion, the ABCB1 3435C>T, ABCB1 2677G>A/T, and MTHFR 1298A>C polymorphisms influenced the efficacy of MTX monotherapy.

Objectives Cytology is well established and widely accepted method to diagnose lung tumors. However, cytological changes of malignant cells can be so subtle that cytopathologists cannot always diagnose with certainty. In such cases, some cytopathologists believe that radiological assessment is important for correct cytological diagnosis. However others deny the importance of radiological information, because they believe it could not change the cytological assessment. This study mainly aimed to clarify how radiologist's comments affect cytological diagnosis of lung tumors. Methods Of 201 patients who underwent cytological examinations, 131 and 57 patients were diagnosed with malignant and benign lung lesions, respectively. Study coordinators randomly selected 60 cytological slides each of the benign and malignant lesions. A radiologist graded their CT images by using a 5-point confidence scale. Three cytotechnologists assessed the 120 cytological slides twice on the basis of a 5-grade classification: first before and then after obtaining radiologist's grading. Receiver operating characteristic analysis was performed. The Az values, sensitivities, and specificities of the cytological diagnoses were calculated for comparing the results before and after obtaining radiologist's grading. Results The mean Az value for cytological assessment after obtaining radiologist's grading (0.88) was significantly higher than that before obtaining radiologist's grading (0.78). The mean sensitivity of cytological assessment after obtaining radiologist's grading (77%) was significantly higher than that before obtaining radiologist's grading (67%). Conclusions Radiological assessment, together with a radiologist's confidence, improves cytological diagnoses of lung diseases. Thus, the importance to positively provide radiological assessment to cytopathologists should be considered by all clinicians.

73歳男性. 珪肺, 副鼻腔炎手術, 虫垂炎手術の既往あり. 平成14年8月14日より発熱, 倦怠感出現, その後皮膚黄染が出現し, 歩行不能となり当院へ救急搬送された. 来院時より発熱, 無尿, 全身の筋の把握痛, 黄疸を認めた. 白血球11,900/mm3, CRP 37.6mg/dL, 血小板17,000/mm3, 総ビリルビン10.8mg/dL, 尿素窒素103.8mg/dL, クレアチニン4.9mg/dL. 集中治療室 (ICU) 入室後まもなく血圧低下し, 呼吸不全に陥った. 呼吸不全に対して人工呼吸管理を行い, 大量のカテコラミンを使用して循環動態の安定化を図り, 抗生剤を複数使用, 急性腎不全に対し持続血液濾過透析 (CHDF) を施行した. 臨床症候, 検査所見および農業従事歴よりレプトスピラ症も疑われたため, Streptomycin (SM) も併用した. その後全身状態は改善し, 入院後約1週間で, 透析と人工呼吸管理から離脱できた. 入院当日の抗レプトスピラ抗体は陰性であったが, 約1週間後の再検査でレプトスピラ (あきやみB) に対する抗体が640倍と陽性であったため, 秋季レプトスピラ症と診断した. 全身状態が改善し, 透析を離脱した後ではあったが, 腎の病態把握と予後推定のため腎生検を施行し, 間質性腎炎の所見を得た.

Effects of human soluble thrombomodulin on experimental glomerulonephritis. Background Coagulation and inflammation are both important processes that contribute to glomerular injury. The present study was performed to evaluate the effects of recombinant human soluble thrombomodulin (RHS-TM) in a lethal model of thrombotic glomerulonephritis and to investigate the possible mechanisms. Methods Thrombotic glomerulonephritis was induced in rats by administration of lipopolysaccharide and rabbit anti-rat glomerular basement membrane antibody. One hour later, RHS-TM or heparin was administered, and the histological findings, renal functions, and coagulation parameters were evaluated. To evaluate the contribution of carboxypeptidase R (CPR) to the results obtained in rats treated with RHS-TM, plasma CPR levels were measured. Then, carboxypeptidase inhibitor (CPI), which prevents the function of CPR, was administered. Results Massive glomerular thrombosis and lung hemorrhage developed within five hours of disease induction, and all rats died within 24 hours. RHS-TM (3 mg/kg) prevented the progression of the disease and all rats survived. Heparin (250 U/kg/h) showed similar anti-thrombotic effect, but induced massive hemorrhage in the lungs or stomach. RHS-TM attenuated leukocyte/neutrophil infiltration in the glomerulus but heparin did not, suggesting that RHS-TM has anti-inflammatory properties. CPR levels in plasma were about threefold higher in rats treated with RHS-TM compared to those in rats treated with heparin. Furthermore, the inhibitory effect of RHS-TM on leukocyte/neutrophil infiltration was significantly diminished by injection of CPI. Conclusion RHS-TM effectively attenuates the injuries of thrombotic glomerulonephritis in rats. The results indicate that RHS-TM, in addition to its anti-thrombotic action, may exert its anti-inflammatory properties by converting proCPR to CPR, which then inactivates anaphylatoxins. RHS-TM is a potential novel therapeutic tool for thrombotic glomerular injury and related disorders.

Fukuyama-type congenital muscular dystrophy (FCMD) is characterized by congenital muscular dystrophy and associated with neuropathological anomalies. However, the issue of whether the radiological findings of white-matter lesions represent delayed myelination, demyelination or other problems remains controversial. We present serial radiological findings, including MR spectroscopy (MRS), in a child with FCMD. These findings indicate a correlation between the imaging abnormalities and the choline/creatine ratio, suggesting the possible usefulness of MRS in addition to MRI for following FCMD patients.

In order to assess the effect of surfactant therapy on the neurodevelopmental outcome of infants with a birth weight of less than 1000 g, we evaluated the outcome of 169 infants in the period after introduction of the surfactant (January 1989 to May 1993) by a follow-up of 6 years on the average, and compared these results to those of 107 infants in our previous study before the surfactant period (October 1981 to March 1986) by a follow-up of 7.5 years on the average. Nursery survival rate was significantly increased from 69.3% in the presurfactant period to 80% in the surfactant period (P < 0.05). However, there were no substantial differences in the neurodevelopmental outcomes between the two periods. This enhanced survival rate without the improvement of outcome resulted in a proportionate increase in normal and impaired survivors.

We retrospectively evaluated pelvic magnetic resonance imaging including diffusion-weighted imaging (DWI) of 16 ovarian lesions (5 adenocarcinofibromas, 2 borderline adenofibromas, and 9 benign adenofibromas). All adenocarcinofibromas were detected as large solid areas of strong high signal on DWI, and seven of nine benign adenofibromas and both borderline adenofibromas demonstrated no areas of high signal or small areas of weak high signal. Solid components that appear as areas of strong high signal on DWI might represent a characteristic finding of adenocarcinofibromas.

Purpose Changes in body composition in rheumatoid arthritis (RA), including a reduction in skeletal muscle mass and the accumulation of visceral fat, have been identified, and the interaction between immune abnormality and metabolic disorders has received much attention. The effect of a high-fat (HF) diet and the role of adipose tissue in an arthritis model were investigated. Methods The effect of an HF diet on the histopathology of joints in murine type II collagen-induced arthritis (CIA) was evaluated. The morphology and adipokine production of adipose tissues were analyzed, and macrophages in the stromal vascular fraction (SVF) were counted by flow cytometry. Serum adipokine levels were measured by ELISA. Results Significant exacerbation of joint destruction and aggravated pathological conditions were observed in CIA mice that were fed an HF diet. However, the boundary length of adipose tissue tended to decrease and the levels of adipokines (leptin and adiponectin) were lowered by the induction of arthritis. In HF/CIA mice, nevertheless, the production of MCP-1 in adipose tissues and the accumulation of macrophages in the SVF were significantly higher than CON/CIA group. The serum leptin/adiponectin (L/A) ratio was positively correlated with the number of macrophages in the SVF and MCP-1 production by adipose tissue, particularly in the CIA group. Conclusion Functional alterations of adipose tissues could be originated from HF diet during developing arthritis. An abnormal activation of macrophages and an increased production of MCP-1 in adipose tissues might be both involved in joint destruction and inflammation.

We report a patient with Bloom's syndrome who developed diabetes mellitus at 21 years of age, which was complicated by a nasopharyngeal B-cell-type malignant lymphoma 9 months later. Although the tumor had been eradicated by radiation therapy, metastasis was detected in the cecum after 5 months. Chemotherapy could not be performed sufficiently due to bone marrow suppression, although powerful supportive care was provided. Hemicolectomy and radiation were also done but resulted in failure of remission. He died of abdominal bleeding at age 23 years and 9 months.

Background: The aim of the present study was to delineate the psychological status of 10 patients with the attenuated phenotype of mucopolysaccharidosis type II (MPS-II) and their parents (six fathers and five mothers) for the improvement of clinical management. Methods: Intellectual ability was evaluated using the Wechsler Intelligence Scale. Activities of daily living (ADL) was assessed using the Functional Independence Measure. The personality and psychiatric aspects were analyzed using the Yatabe–Guilford Personality test (Y-G test) and the Tree-Drawing Test. Mental health was assessed using the General Health Questionnaire 60 (GHQ-60) and State–Trait Anxiety Inventory (STAI). Results: Intellectual background, measured with full-scale, verbal and performance IQ, were 72.8, 76.1 and 79.3, respectively. Nine of 10 patients were not judged as having neurosis and a psychotic tendency with the Y-G test. In the tree-drawing test, many patients drew a tree without ground, suggesting that they have difficulties in making relationships with surrounding people and the community. The child patient with a psychosis pattern on the Y-G test, drew a bizarre tree, suggesting psychological problems. GHQ-60 and STAI survey indicated that the patients and their parents had higher levels of anxiety. A significant negative correlation between GHQ-60 score and ADL (R = −0.77) was identified, suggesting that the psychological status may worsen as ADL decreases. Conclusions: Patients with MPS-II and their parents had higher risks for mental problems. Understanding psychological status is essential when providing genetic counseling or therapeutic intervention.

Hepatosplenomegaly is one of the cardinal signs of Hunter disease; however, portal hypertension has not been described. We report portal hypertension in an adult Hunter patient with the attenuated phenotype.

Highlights • We present a case of multiple mucinous metaplasia and neoplasia of cervix, endometrium, fallopian tube, ovary, and mesenterium with external urethral meatus neoplasm. • Immunohistochemistry showed almost same pattern in each neoplasms. • PCR-direct sequencing showed no existence of both KRAS and GNAS mutations. • This report suggests a possibility of synchronous mucinous metaplasia and neoplasia “beyond” female genital tract.