Anti-signal Recognition Particle Antibody-positive Necrotizing Myopathy with Secondary Cardiomyopathy: The First Myocardial Biopsy- and Multimodal Imaging-proven Case.

A 69-year-old Japanese woman was admitted to our hospital with progressive muscle weakness and dysphagia. She was taking pitavastatin for dyslipidemia. Her serum creatine kinase was 6,300 U/L. Pitavastatin was stopped, but her symptoms deteriorated, and cardiac congestion appeared. A muscle biopsy showed necrotizing myopathy (NM), and anti-signal recognition particle (SRP) antibody was positive. 18F-fluorodeoxyglucose-positron emission tomography showed an abnormal uptake, and magnetic resonance imaging showed abnormal gadolinium enhancement in the left ventricular wall. An endomyocardial biopsy revealed inflammatory cardiomyopathy. Steroid, tacrolimus, and intravenous immunoglobulins were effective against the symptoms. This is the first case of biopsy-proven secondary cardiomyopathy due to anti-SRP-positive NM.

[Intrapulmonary Thymoma Suspected of Malignancy].

A 68-year-old woman was found a nodule of the right lower lobe. Malignancy was suspected by positive positron emission tomography-computed tomography finding. Wedge resection was performed to establish the diagnosis, and the pathological diagnosis was a type AB thymoma. At 13 months after operation, no recurrence was observed.

Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors.

Activation of the phosphoinositide 3-kinase-AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3ß, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3ß and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase-AKT pathway is a key determinant of differentiation.

Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer.

Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.

Nodular fasciitis of the breast clinically resembling breast cancer in an elderly woman: a case report.

BACKGROUND: Nodular fasciitis is a benign reactive proliferative lesion of fibroblast cells, which can occur throughout the body. However, it has rarely been reported in the breast of an elderly woman. CASE PRESENTATION: Our patient was an 88-year-old Asian woman who had noticed a mass in her right breast for 1 month before presentation to our hospital. The mass was elastic-hard and 20 mm in size. No qualitative diagnosis was made by core needle biopsy. Because of potentially malignant findings on mammography and ultrasonography, she underwent an excisional biopsy. Microscopically, spindle cell proliferation with abundant elastic fibers were observed. The tumor cells were positive for α-smooth muscle actin and negative for pancytokeratin, ß-catenin, and cluster of differentiation 34. Based on these morphological and immunohistochemical features, a diagnosis of nodular fasciitis was made. All resection margins in the specimen were tumor-free. The patient has been disease-free for over 12 months. CONCLUSIONS: Nodular fasciitis shows clinical features and imaging findings similar to those of breast cancer. To avoid unnecessary surgery, nodular fasciitis should be taken into consideration when there is spindle cell proliferation found by biopsy.

Long-term outcome of amniotic membrane transplantation combined with mitomycin C for conjunctival reconstruction after ocular surface squamous neoplasia excision.

The aim of the study is to evaluate the long-term clinical results of amniotic membrane transplantation (AMT) combined with mitomycin C (MMC) for reconstruction of conjunctival defects created during the excision of ocular surface squamous neoplasia (OSSN). Eight consecutive eyes of seven patients (five males and two females; mean age, 64 ± 19 years) treated by one surgeon (KH) were included in this study. AMT was performed after excision of a mass region, along with 0.04 % MMC treatment for the exposed sclera. The tumor size, histopathological retrieval, AM graft size after tumor excision, recurrence, and postoperative complications were recorded. During a mean postoperative follow-up period of 60.9 ± 14.6 months (range 36-78 months), the ocular surfaces completely re-epithelialized in all cases. The median size of the tumor was 44.4 ± 21.2 mm2 (range 13-67 mm2). The histopathological diagnoses were five cases of squamous cell carcinoma in situ (SCC in situ) and three cases of dysplasia. The median size of the AM graft after tumor excision was 100.8 ± 32.7 mm2 (range 49-151 mm2). A case of recurrent SCC in situ with a preoperative history of using MMC eye drops developed further corneal limbal deficiency and was treated with therapeutic soft contact lenses. A case of dysplasia with a history of large pterygial excision developed symblepharon postoperatively was treated with AMT 6 months after tumor excision. The tumors recurred in two eyes with SCC in situ and were successfully treated with continuous AMT and MMC. No severe complications, such as infections, corneal or scleral thinning, or ulceration developed in all cases. The combination of AMT and MMC is effective for safe reconstruction over the long-term after the excision of OSSN with postoperative careful observation and treatment. In recurrent tumor excision cases, AMT is a suitable technique for repeated ocular surface reconstruction.

Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system.

A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2-weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV-encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV-positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis.

Non-islet cell tumor hypoglycemia caused by intrathoracic solitary fibrous tumor: a case report.

BACKGROUND: Non-islet cell tumor hypoglycemia (NICTH) is defined as a form of hypoglycemia caused by an extrapancreatic tumor. Solitary fibrous tumor (SFT) associated with hypoglycemia is rare. CASE PRESENTATION: A 76-year-old woman, who had frequently experienced hypoglycemic symptoms such as presyncope for the prior 6 months, visited our hospital to undergo detailed examinations. Her fasting glucose level was low at 49 mg/dl. The blood levels of IRI and C-peptide were also low at 0.2 µU/ml and 0.21 ng/ml, respectively. Chest computed tomography revealed a mass measuring 15 cm in the left thoracic cavity. Percutaneous needle biopsy yielded a diagnosis of intrathoracic SFT associated with NICTH. The tumor was removed by video-assisted thoracoscopic surgery. Histological examination showed a tumor composed of simple spindle-shaped cells with an irregular arrangement. Immunohistochemical staining was positive for CD34, bcl-2, and vimentin and negative for alpha SMA and mesothelin. These results confirmed the diagnosis of SFT. Her hypoglycemic symptoms resolved rapidly after surgery. The clinical course has since remained favorable with no signs of recurrence. CONCLUSION: We report a case of non-islet cell tumor hypoglycemia caused by intrathoracic SFT. The high-molecular-weight IGF-II produced by the tumor has been regarded as the cause of NICTH.

Multiple Intestinal Ulcers Associated with Primary Epstein-Barr Virus Infection in a Patient with Rheumatoid Arthritis Undergoing Methotrexate Therapy.

A 47-year-old woman with a 2-year history of rheumatoid arthritis (RA) undergoing methotrexate treatment developed a perforated ulcer in the ileum for which she underwent emergency surgery. A histological analysis of the extirpated specimen presented a possible Epstein-Barr virus (EBV) infection in the ulcerative lesion without a feature of lymphoproliferative disorder. Interestingly, the patient's serological tests with a paired serum diagnosed a primary EBV infection. The present case emphasizes the importance of being aware of severe enteritis as a possibility for patients with RA, for an accurate diagnosis.

Leiomyoma of the Trachea: a case report.

We present a surgical case of a rare primary tracheal tumor. In a 44-year-old asymptomatic man, computed tomography (CT), performed as part of health check-up, revealed a tumor measuring 1.5 cm in diameter in the mediastinal trachea. Biopsy failed to yield a definitive diagnosis, but the tumor tended to grow rapidly; therefore, surgery was performed. Five tracheal rings were resected through median sternotomy, followed by interrupted suture with 3-0 absorbable thread. The postoperative course has been favorable with no evidence of recurrence. The pathological diagnosis was leiomyoma. We report this case with literature review.

Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors.

AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs). METHODS: The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed. RESULTS: All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis. CONCLUSION: Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation.

Hepatic clearance measured with (99m)Tc-GSA single-photon emission computed tomography to estimate liver fibrosis.

AIM: To evaluate the clinical utility of hepatic clearance (HC) measured with technetium-99m-diethylenetriaminepenta-acetic acid-galactosyl human serum albumin ((99m)Tc-GSA) single-photon emission computed tomography (SPECT) to estimate the degree of liver fibrosis. METHODS: Seventy-eight consecutive patients who underwent initial hepatectomy due to hepatocellular carcinoma were enrolled in this study. Indocyanine green clearance (ICG R15), quantitative indices estimated by (99m)Tc-GSA [the receptor index (LHL15 and HH15) and HC via SPECT analysis], and conventional liver function tests were performed before hepatectomy. Correlations among the quantitative indices for liver functional reserve, conventional liver function tests, and the degree of liver fibrosis were evaluated. RESULTS: The degree of liver fibrosis was correlated with ICG R15, HH15, LHL15, and HC. HC showed the best correlation with conventional liver function tests. According to multivariate analysis, HC and LHL15 were significant independent predictors of severe fibrosis. HC was the most valuable index for predicting severe fibrosis. CONCLUSION: HC measured with (99m)Tc-GSA SPECT is a reliable index for assessing liver fibrosis before hepatectomy.

Successful curative resection of gallbladder cancer following S-1 chemotherapy: A case report and review of the literature.

The symptoms of gallbladder cancer (GBC) are vague and non-specific. Therefore, GBC is often detected at an advanced or metastatic stage. The most effective treatment for GBC is surgical resection, however the majority of GBC cases are unresectable at the time of diagnosis. Therefore, numerous GBC patients undergo chemotherapy. This study reports the case of a 60-year-old female with GBC who underwent successful surgical curative resection following a single dose of the chemotherapeutic agent, S-1, twice daily for 4 weeks followed by a 14-day rest period for 36 months. S-1 is a novel orally administered drug composed of a combination of the 5-fluorouracil (5-FU) prodrug, tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and oteracil potassium in a 1:0.4:1 molar concentration ratio. The focus of the present study was the candidate factors that affect the therapeutic efficacy of S-1-based chemotherapy. In particular, the gene expression involved in the S-1 metabolic pathway was investigated by assessing the intratumoral dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) and orotate phosphoribosyltransferase gene expression. The surgical specimen exhibited high intratumoral DPD gene expression levels compared with those observed in previously reported non S-1 responsive cases of biliary tract cancer. Due to the results obtained in the current study, we hypothesize that CDHP enhanced the antitumor efficacy of 5-FU by inhibiting the excess DPD protein produced by the tumor.

Cutaneous lesions of Kikuchi's disease: evolution of histopathological findings.

We report a 38-year-old male patient who presented with cutaneous lesions mimicking widespread discoid lupus erythematosus with high-grade fever, arthralgia and lymphadenopathy. Additional lymph node and skin biopsies, however, revealed karyorrhectic debris without neutrophils and numerous CD68-positive cells, a characteristic finding of Kikuchi's disease (KD). Comparing skin biopsies on different occasions, we could see different forms of histopathology. The histopathology of skin lesions of KD may vary during the clinical course, which may reflect the stage of the disease.

Spindle cell carcinoma of the breast as complex cystic lesion: a case report.

Spindle cell carcinoma of the breast is a rare tumor. This tumor can proliferate rapidly and cause cystic changes because of internal tissue necrosis. We evaluated a 54-year-old woman with right breast lump. Mammography showed a category four mass with a diameter of 2.5 cm. Ultrasonography (US) revealed a complex cystic lesion, and fine-needle aspiration (FNA) cytology demonstrated bloody fluid and malignant cells. Partial breast resection and sentinel lymph node biopsy were performed. Immunohistology revealed spindle cells with positive results for cytokeratin (AE1/AE3) and vimentin, partially positive results for s-100, and negative results for desmin and α-actin. The pathological stage was IIA, and biochemical characterization showed that the tumor was triple negative. Six courses of FEC-100 chemotherapy (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2)) were administered. Radiotherapy was performed. This case is discussed with reference to the literature.

A case of pathology-proven neuromyelitis optica spectrum disorder with Sjögren syndrome manifesting aphasia and apraxia due to a localized cerebral white matter lesion.

A woman with Sjögren syndrome manifesting as aphasia with a left deep cerebral white matter lesion tested positive for anti-aquaporin 4 (AQP4) antibody. Open biopsy of the lesion revealed active demyelination with edematous changes and the preservation of most axons, indicating a non-necrotic demyelinating lesion. Immunostaining for AQP4 was diffusely lost, whereas the loss of glial fibrillary acidic protein immunostaining was limited but with highly degenerated astrocytic foot processes in perivascular areas. These results suggested neuromyelitis optica spectrum disorder (NMOSD) pathology rather than Sjögren-related vasculitis. Only cerebral cortical symptoms with a cerebral white matter lesion could be observed in NMOSDs.

Histological grade as an alternative to the Ki67 labeling index is only available for luminal-type breast cancers.

BACKGROUND: The 2011 St. Gallen Consensus Statement advocated using histological grade (HG) as a proliferation marker of breast cancer (BC) if reliable Ki67 labeling index (Ki67-LI) assessment is not available. However, it has been difficult to evaluate tumor aggressiveness in case of HG2. METHODS: A total of 259 cases of BC were assessed for HG, Ki67-LI and other clinicopathological features. The cut point for Ki67-LI was interpreted as low and high using a 14% threshold. RESULTS: The average age at diagnosis was 58.2 years (range 28-86); 64.9% of the patients were postmenopausal. Of the 259 cases, 151 were stage I, 78 were stage II, 29 were stage III, and 1 was stage IV. The subtypes based on immunohistochemical staining were 60 cases of luminal A (LA) type (23.2%), 37 cases of luminal B (LB) (HER2-) type (14.3%), 91 cases of LB (HER2+) type (35.1%), 40 cases of human epidermal growth factor receptor 2 (HER2) type (15.4%) and 31 cases of triple negative (TN) type (12%). HG was 1 (89 cases, 34.4 %), 2 (117 cases, 45.2%) and 3 (53 cases, 20.5%). High Ki67-LI cases were observed in HG1 (37.1%), HG2 (56.4%) and HG3 (96.2%). Especially in cases of HG2, high Ki67-LI cases were observed in 0 % of LA type, 100% of LB (HER2-) type, 71.2% of LB (HER2+) type, 68.8% of HER2 type and 40.0% of TN type. The average Ki67-LI was 6.0 ± 3.8 (LA type), 31.4 ± 15.7 [LB (HER2-) type], 20.2 ± 14.8 [LB (HER2+) type], 32.7 ± 21.9 (HER2 type) and 55.7 ± 32.2 (TN type). All LA-type cases and 66.7% of LB (HER2+)-type cases were low Ki67-LI. CONCLUSIONS: Our study demonstrates that all LA-type cases and most HG1 of LB (HER2+)-type cases are low proliferative. However, HG was not informative enough for estimating tumor proliferation in cases of LB (HER2-), HER2 and TN types. It is necessary to add other proliferation tools such as the gene expression profiling tool and Ki67-LI except in LA and HG1 of LB (HER2+)-type cases.

Monitoring with serum SP-A, SP-D, and KL-6 in a patient with interstitial pneumonia complicated with ANCA-associated glomerulonephritis.

A 69-year-old woman was admitted to hospital, complaining of fatigue and dry cough. Her renal function deteriorated rapidly, and the laboratory findings showed elevated myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (ANCA). Renal biopsy examination revealed crescentic glomerulonephritis (pauci-immune type), and linear opacities and a honeycomb appearance in both lower lobes was evident on the chest computed tomography scan. The patient was diagnosed as having ANCA-associated glomerulonephritis complicated with mild interstitial pneumonia (IP). Treatment with methylprednisolone pulse therapy improved both her renal function and IP, but her lung lesions worsened during the course of tapering the prednisolone doses. After careful observation, her IP improved gradually without specific treatment. Worsening or improvement of her lung lesions was accompanied by changes in the serological markers of IP, namely, surfactant protein-A, surfactant protein-D, and KL-6. We found that monitoring these markers was helpful in diagnosing and managing IP in our patient with ANCA-associated vasculitis.

Esophageal schwannoma: a case report.

Most tumorous lesions of the esophagus are esophageal cancers. Benign primary tumors of the esophagus are uncommon, and account for approximately 2% of all esophageal tumors. More than 80% of benign esophageal tumors are leiomyomas, with schwannomas being rare. A 55-year-old woman visited our internal medicine department with complaints of palpitations and discomfort during swallowing. A chest computed tomography scan showed a lobulated tumor (75 × 57 × 80 mm) in the upper to middle mediastinum, with homogenous inner opacity, compressing the esophagus. Upper gastrointestinal endoscopy revealed a smooth-surfaced elevated lesion covered with normal mucosa, and a schwannoma was diagnosed based on the biopsy result. The tumor was large. It was thus considered to be difficult to repair the esophagus by direct anastomosis after tumor resection. Therefore, subtotal esophagectomy and esophagogastrostomy in the right thorax were performed. Histopathological examination revealed spindle-shaped cells in a fasciculated and disarrayed architecture and nuclei in a palisading pattern. Immunohistochemical studies revealed S100 protein positivity and the absence of staining for α smooth muscle actin (αSMA), CD34 and CD117, thereby establishing the diagnosis of benign schwannoma. Her postoperative course was uneventful and there has been no evidence of recurrence to date.