Selenolactams as Synthetic Intermediates for the Synthesis of Polycyclic Amines via Seleno-Claisen Rearrangements.

A highly diastereoselective α-allylation of selenolactams with allyl halides is reported. DFT analyses and experimental observations suggested that this reaction proceeds via a Se-allylation of the eneselenolates of the lactams followed by a seleno-Claisen rearrangement. The thus-obtained products could be efficiently transformed into polycyclic amines using a previously developed sequential addition of organometallic reagents and ring-closing metathesis.

All-Dielectric Dual-Color Pixel with Subwavelength Resolution.

An all-dielectric optical antenna supporting Mie resonances enables light confinement below the free-space diffraction limit. The Mie scattering wavelengths of the antenna depend on the structural geometry, which allows the antennas to be used for colored imprint images. However, there is still room for improving the spatial resolution, and new polarization-dependent color functionalities are highly desirable for realizing a wider color-tuning range. Here, we show all-dielectric color printing by means of dual-color pixels with a subwavelength-scale resolution. The simple nanostructures fabricated with monocrystalline silicon exhibit various brilliant reflection color by tuning the physical dimensions of each antenna. The designed nanostructures possess polarization-dependent properties that make it possible to create overlaid color images. The pixels will generate individual color even if operating as a single element, resulting in the achievement of subwavelength-resolution encoding without color mixing. This printing strategy could be used to further extend the degree of freedom in structural color design.

Immunohistochemical Analysis of Debris Captured by Filter-Type Distal Embolic Protection Devices for Carotid Artery Stenting.

BACKGROUND: Little is known about the micro-debris captured in filter-type distal embolic protection devices (EPD) used for carotid stenting (CAS). This study aimed to determine the histological and immunohistochemical characteristics of such debris by using a new liquid-based cytology (LBC) technique. METHODS: Fifteen patients who underwent CAS using a filter-type distal EPD (FilterWire EZ; Boston Scientific, Marlborough, MA, USA) were included in the study. After gross inspection of each recovered filter device, micro-debris were collected using a new LBC technique (SurePath; TriPath Imaging, Inc., Burlington, NC). Histological and immunohistochemical analysis of the recovered debris was performed. The pre- and postoperative brain magnetic resonance imaging and neurological status of each patient were also reviewed. RESULTS: No patient developed ipsilateral symptomatic stroke due to a thromboembolic event. All 15 patients (100%) had microscopically identifiable debris in the filters, whereas gross inspection detected visible debris only in 5 patients (33.3%). Histological analysis revealed various types of structural components in an advanced atheromatous plaque, including fragments of fibrous cap, calcified plaque, smooth muscle cells, and necrotic tissue fragment infiltrated with monocytes and macrophages. CONCLUSIONS: Filter-type EPDs may contribute to reducing the risk of CAS-related embolic events by capturing micro-debris even when gross inspection of the recovered filter shows no visible debris in the device.

[A Case of Metastatic Tubulocystic Carcinoma of the Kidney Treated with Molecularly Targeted Therapy].

A 51-year-old man who presented with gross hematuria and back pain was found to have a right renal mass accompanied with lung and osseous metastases. The patient underwent transabdominal right nephrectomy. The histopathological examination revealed the tumor to be tubulocystic carcinoma of the kidney. After the patient received sunitinib therapy, contrast enhanced computed tomography revealed that the metastatic tumor size was stable in the bone and decreased in the lung. Unfortunately, 9 months after nephrectomy, bone scintigraphy revealed an increase in the size of the metastatic tumor in the bone. The patient's condition worsened gradually, and he died 15 months after the surgery.

Combined hepatocellular-cholangiocarcinoma producing parathyroid hormone-related protein: report of a case.

Combined hepatocellular-cholangiocarcinoma (CHCC) is an uncommon form of primary liver cancer. A 57-year-old man was readmitted to our hospital for treatment of recurrent CHCC, 12 months after central bisegmentectomy and 4 months after limited hepatic resection. Magnetic resonance imaging (MRI) revealed multiple hepatic nodules. Laboratory data showed increased serum levels of α-fetoprotein (AFP), calcium, and parathyroid hormone-related protein (PTH-rP), to 5,571 ng/mL, 17.0 mg/dL, and 16.1 pmol/L, respectively. Palliative mass reduction surgery was indicated by the fact that the hypercalcemia was difficult to manage medically. Thus, we performed lateral segmentectomy with partial resection of segment 7 and the caudate lobe, and microwave coagulation therapy for multiple recurrent CHCC. Thereafter, the serum PTH-rP and AFP levels decreased remarkably and the hypercalcemia was controlled for the next 3 months. He died of disease progression 9 months after the last hepatic surgery. To our knowledge, this is only the second reported case of CHCC producing PTH-rP in the English-language literature.

Vesnarinone suppresses TNFα mRNA expression by inhibiting valosin-containing protein.

Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IκBα to activate nuclear factor (NF)κB. We show that vesnarinone impairs the degradation of IκBα, and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression.

Macrophage activation syndrome triggered by methotrexate-related lymphoproliferative disease in a patient with rheumatoid arthritis.

A 56-year-old woman was treated for rheumatoid arthritis for 17 years with methotrexate (MTX). Night sweats, fever and weight loss made her visit our hospital. Although levofloxacin failed to resolve her fever, she was suspected of having sepsis because of pancytopenia, elevated procalcitonin and a nodular lesion in the lung. After urgent hospitalization, she was diagnosed finally with the methotrexate-related lymphoproliferative disorder (MTX-LPD) associated with macrophage activation syndrome (MAS). Her general condition was improved with MTX withdrawal and 5-day high-dose glucocorticoid administration. Thus, even when the patient was critically ill with MAS, no cytotoxic agents were required to control MTX-LPD.

Long-term peritoneal dialysate exposure modulates expression of membrane complement regulators in human peritoneal mesothelial cells.

The membrane complement regulators (CRegs) CD46, CD55, and CD59 are highly expressed on human peritoneal mesothelial cells. However, how mesothelial CRegs change according to the peritoneal dialysis (PD) history of patients has remained unclear. We therefore examined longitudinal changes in CRegs in primary cultured mesothelial cells from PD patients (human peritoneal mesothelial cells; HPMCs) and examined which components of PD fluid (PDF) affect CRegs in vitro. We measured levels of soluble C5b-9 in overnight-dwelling PDF in PD patients and also evaluated changes in CRegs expression on HPMCs collected from PDF using flow cytometry and polymerase chain reaction at a 1-year interval of PD therapy. We also evaluated changes in CReg expressions with stimulation by each component of PDF (glucose, lactic acid and pH) using the Met5A human mesothelial cell line. Levels of sC5b-9 in PDF decreased significantly during 1 year, while expressions of CD46 and CD59 proteins and mRNAs increased significantly in HPMCs during 1 year. Analyzing Met-5A cells, we observed that expressions of the three CRegs were increased by glucose and lactic acid in a concentration-dependent manner, but conversely that expressions of CRegs were decreased by lower pH stimulation. History of PD might influence expression of CRegs by HPMCs through properties of PDF such as glucose, lactic acid, and pH. These results suggest that mesothelial cells may alter expression of CRegs for the purpose of protecting the peritoneum and the presence of PDF might affect peritoneal homeostasis associated with the complement system.

Strong impact of pathological node-negative on long-term overall survival of patients with triple-negative breast cancer receiving neoadjuvant chemotherapy.

Triple-negative breast cancer (TNBC) has a high pathological complete response (pCR) rate; however patients without a high pCR are reported to have a poor prognosis. The current study investigated the long-term overall survival of patients with TNBC who received neoadjuvant chemotherapy (NAC) and analyzed various prognostic factors including basal marker and claudin expressions. Between November 2005 and March 2012, the current study retrospectively reviewed the records of 323 patients with breast cancer who received anthracycline followed by taxane as NAC at the Jikei University Hospital Basal marker and claudin expression was determined via immunohistochemistry. The median age of the patients was 53.0 years. Of the 323 patients, 26 (8%) achieved a pCR, including 13 patients (19.7%) with TNBC and 13 (5.1%) with non-TNBC (P<0.001). Of the 66 patients with TNBC, 13 (19.7%) demonstrated recurrence and 8 (12.1%) died after a median follow-up time of 111.5 months [10-year disease-free survival (DFS), 80.3%; 95% confidence interval (CI), 0.68-0.88; 10-year overall survival (OS), 84.8%; 95% CI, 0.72-0.92]. Of the 257 patients with non-TNBC, 45 (17.5%) patients demonstrated recurrence and 26 (10.1%) died (10-year DFS, 82.1%; 95% CI, 0.76-0.87; 10-year OS, 88.6%; 95% CI, 0.83-0.92). There was no statistical difference between the patients with and without TNBC. In the TNBC group, patients with pathological node-negative status survived without distant recurrence. Additionally, negative lymphovascular infiltration was another favorable prognostic factor. Patients with TNBC who received NAC demonstrated comparably high prognoses to non-TNBC patients. Overall, pathological node status after NAC had a strong impact on the prognosis of patients with TNBC.

Long-term outcomes of oligometastatic breast cancer patients treated with curative intent: an updated report.

BACKGROUND: Oligometastatic breast cancer (OMBC) is characterized by limited metastatic tumor numbers and sites. We have reported a 20-year overall survival (OS) rate and relapse-free rate (RFR) of 34.1% and 27.4%, respectively, in a retrospective analysis of OMBC patients treated with curative intent including a multidisciplinary approach. Metastatic breast cancer (MBC) is generally incurable; however, OMBC might be a potentially curable subset. The previous analysis included isolated locoregional recurrence (ILRR) cases, which differs from distant metastasis in treatment strategies. Therefore, in this study, we excluded ILRR cases and provided an update on clinical outcomes. We also performed a detailed subgroup analysis of OMBC patients by introducing new prognostic variables. METHODS: Data of 73 OMBC patients, including 10 ILRR cases, treated in our institution between 1980 and 2010 were retrospectively analyzed. OMBC was defined as the presence of metastatic lesions in 1-2 organs, < 5 lesions per metastasized organ, and lesion diameter < 5 cm. RESULTS: The median follow-up duration was 151 (range 12-350) months. Twenty-eight (44%) patients received local therapy. Excluding ILRR cases, the OS rates were 28.3% and 18.9% and RFRs were 26.7% at 20 and 25 years, respectively. In multivariate analysis, single-organ involvement and three or fewer metastatic lesions per organ were associated with a longer progression-free and relapse-free interval (RFI). CONCLUSIONS: Relapse-free interval reached a plateau after 20 years at approximately 25% probability. Patients with long-term survival without disease relapse are considered cured. Curative-intent therapy should be considered for OMBC patients, especially those with low tumor volume.

EGFR as paradoxical predictor of chemosensitivity and outcome among triple-negative breast cancer.

We retrospectively analyzed the expression of epidermal growth factor receptor (EGFR) as a prognostic marker to predict neoadjuvant chemotherapy response and survival among breast cancer subtypes. We used immunohistochemical profiles to subtype the patients. EGFR expression was determined using immunohistochemistry. All patients received an anthracycline-based regimen preoperatively. Ninety-three patients also received docetaxel. Of the 117 patients tested, 28 (24%) were triple-negative breast cancer (TNBC) and 73 (62%) were hormone receptor-positive (luminal) subtype. Among the TNBC patients, a significantly higher incidence of EGFR expression (50%) was observed (P=0.002), and EGFR expression was related to a less favorable response to chemotherapy (P=0.03) and poorer survival (P=0.17); in contrast, among the luminal subtype patients, positive EGFR expression was related to a favorable clinical response (P=0.06) and better survival (P=0.11). This retrospective analysis demonstrated that EGFR expression may represent an adverse prognostic marker in patients with TNBC and may provide a valuable tool for selecting appropriate treatment regimens for patients with TNBC.

Development of a chemical screening system using aqueorin-fused protein.

We developed a unique screening system that consists of combination of high photo-sensitivity of photoprotein aequorin (AQ) and our developed high-performance affinity purification system. In the present study, we demonstrated to detect the specific interaction between methotrexate (MTX) and its target dihydrofolate reductase (DHFR) fused with AQ. We succeeded to prepare highly purified AQ-fused DHFR, which showed high sensitive light emission. To test the screening system, we prepared the complex of MTX-immobilized magnetic nanobeads and AQ-fused DHFR. Bound AQ-fused DHFR with the beads was specifically released by addition of MTX. Thus, this methodology enables us to search a novel chemical that binds to target proteins without complicated processes. Furthermore, thank to the highly sensitive luminescence intensity of AQ, this methodology would be performed in very small scale with high responsibility, leading to development of high throughput screening systems.

Laparoscopic treatment of a solitary fibrous tumor originating in the cystic plate.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare mesenchymal tumor originating from the tissue underlying the mesothelial layer of the pleura or mediastinum. Other reported sites include the upper respiratory tract, orbit, thyroid, peritoneum, and central nervous system. CASE PRESENTATION: We describe a case of a 7 cm SFT that originated in the cystic plate. A liver tumor was an incidental finding in a 49-year-old woman during a regular radiological checkup for uterine fibroids. Imaging revealed a well-circumscribed solid mass between the gallbladder and liver. Intraoperative laparoscopy identified a soft tumor that had progressively expanded behind the gallbladder which was easily separated from the Laennec's capsule of the liver. Hematoxylin and Eosin and immunohistochemical staining of the tumor tissue found both tangled and patterned arrangements of spindle cells consistent with a SFT derived from the subserosal layer of the gallbladder. CONCLUSIONS: To the best of our knowledge, this is the first report of a SFT originating in the cystic plate.

Differential clinical features of patients with clinically amyopathic dermatomyositis who have circulating anti-MDA5 autoantibodies with or without myositis-associated autoantibodies.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies have been identified as myositis-specific autoantibodies that are often associated with clinically amyopathic dermatomyositis (CADM) and a poor prognosis due to rapidly progressive interstitial lung disease (RP-ILD) in East Asian patients. Besides anti-MDA5 autoantibodies, patients with CADM may have myositis-associated autoantibodies (MAAs), which characterize other connective tissue diseases such as rheumatoid arthritis and Sjögren's syndrome. However, the clinical significance of the coexistence of anti-MDA5 autoantibodies and MAAs in patients with CADM remains unclear. METHODS: We retrospectively analyzed 24 patients with CADM who had anti-MDA5 autoantibodies. Their clinical phenotypes including laboratory test results, high-resolution lung computed tomography data, response to therapy, and prognosis were compared between those who were positive and negative for MAAs, such as antinuclear antibody (ANA), anti-cyclic citrullinated peptide (CCP), anti-SSA, and anti-SSB antibodies. RESULTS: Among 24 patients, 9 (37.5%) additionally had at least one of the MAAs examined in this study: 1 patient was positive for ANA, 5 for anti-CCP, 5 for either anti-SSA or anti-SSB, 1 for anti-cardiolipin, and 1 for anti-Scl-70. Although all anti-MDA5-positive patients with CADM had ILD, the MAA-positive patients showed a lower risk of developing RP-ILD (p = 0.03), a more favorable response to combination therapy of corticosteroids and immunosuppressive agents, and a lower mortality rate than patients with no MAAs (p = 0.03). CONCLUSIONS: Our data suggest that anti-MDA5-positive patients with CADM who also have MAAs have a better prognosis than those without MAAs; thus, anti-MDA5 autoantibodies by themselves may not be strong predictors of worse clinical outcomes in patients with CADM. Coexistent MAAs could be biomarkers for a favorable prognosis in anti-MDA5-positive patients with CADM.

Clinicopathological Features of Thymoma with Ring Calcification: Case Reports.

Thymomas with ring calcifications are very rare and quaint style. Herein, we presented our three cases of thymomas with ring calcifications and reviewed totally 10 cases including 7 cases of previous English literatures. The median age was 53 years. Myasthenia gravis was a complication in 40%. The median maximal diameter was 50 mm. They were diagnosed as pathological type B or had type B component. Based on World Health Organization (WHO) classification, 20%, 60%, and 20% cases were stage I, stage II, and stage III, respectively. Seven ring calcifications were within tumors (inner type) and two cases were outside tumors (outer type). The other had a thymoma arising in the calcic wall of a calcified thymic cyst (miscellaneous type). Four other anterior mediastinal tumors with ring calcification had been reported. We need pathological examinations for a definitive diagnosis. Surgeons should plan surgery because of the possibility of invasive thymomas, or other malignant tumors.

Dynamic high-spatial-resolution MR imaging of invasive ductal carcinoma: influence of histological scirrhous component on MR descriptors.

PURPOSE: The purpose of this study was to assess the relationship between the amount of scirrhous component in invasive ductal carcinoma and its MR characteristics. MATERIALS AND METHODS: We retrospectively reviewed 71 consecutive patients with invasive ductal carcinoma smaller than 25 mm (average, 16.6 mm) in diameter. The scirrhous component was defined as invasive foci in small clusters of cancer cells showing desmoplasia. Invasive ductal carcinoma was subclassified into 3 groups in accordance with the amount of the scirrhous component (scirrhous component degree; SCD): SCD I (scirrhous component less than 20%), SCD II (intermediate), and SCD III (more than 80%). Dynamic magnetic resonance (MR) imaging was performed using volumetric interpolated sequence. Prior to dynamic study, T2*-weighted first-pass perfusion images were obtained before, during, and after bolus injection of 0.1 mmol Gd-DTPA/kg. RESULTS: Twenty-eight lesions were classified as SCD I, 14 as SCD II, and 29 as SCD III. Mass margin and signal intensity loss in the perfusion study were significantly different among the 3 SCD groups (P<0.001). The kinetic patterns were significantly different among the 3 SCD groups (P=0.04), and between SCD I/II and SCD III (P=0.03). The presence of enhancing internal septations was significantly different between SCD I/II and SCD III carcinomas (P=0.05). Central enhancement was only observed in SCD I carcinoma (4%; 3/71). CONCLUSION: The histological predominance of the scirrhous component in invasive ductal carcinoma may be one explanation for the differences in morphologic and kinetic patterns on MR imaging.

Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors.

Monoclonal antibody therapy for immune checkpoint blockade has achieved promising results for several types of malignant tumors. For the future treatment of gastrointestinal stromal tumors (GISTs) by immune checkpoint blockade, expression of immune checkpoint-related molecules that suppress antitumor immunity in GISTs was examined. Infiltration of immune cell types into 19 GIST tissues was analyzed by immunohistochemistry, and expression of T cell immunoglobulin and mucin protein 3 (Tim-3) and programmed cell death-1 (PD-1) in the infiltrated immune cells was examined by immunofluorescence microscopy. The expression status of galectin-9 in the GIST tumor cells was also determined by immunohistochemistry. All the GIST tissues showed CD8+ T cell infiltration and 8 showed CD56+ natural killer (NK) cell infiltration, and the numbers of infiltrated CD8+ T and NK cells were strongly correlated. However, these CD8+ T and NK cells were CD69-negative inactivated cells. Tim-3 was expressed in the infiltrated NK cells in 6/8 (75%) of the GIST tissues. Expression of galectin-9, a ligand of Tim-3, was observed in 13/19 (68.4%) GIST tissues and all of the GIST tissues with Tim-3+ NK cell infiltration showed positive galectin-9 expression. No PD-1 expression in the infiltrated NK cells and neither Tim-3 nor PD-1 expression was observed in the infiltrated CD8+ T cells. Interaction between Tim-3 in infiltrated NK cells and galectin-9 in tumor cells may be involved in an immune checkpoint mechanism for suppression of antitumor immunity in GISTs. Blockade of the Tim-3/galectin-9 pathway may become a new strategy for GIST treatment.

A case of Trousseau syndrome caused by pulmonary adenocarcinoma that was controlled for one year and 10 months with thrombosis treatment using an EGFR tyrosine kinase inhibitor and chemotherapy.

A 47-year-old female with no history of previous illnesses developed cerebral infarction and was diagnosed with lung cancer, specifically EGFR mutation-positive adenocarcinoma, and Trousseau syndrome. The patient's response to anticoagulant therapy with non-fractionated heparin was very poor; however we were able to control the thrombosis with chemotherapy. She survived for one year and 10 months following treatment with gefitinib, CBDCA + PEM and erlotinib, without recurrence of thrombosis. Trousseau syndrome carries a poor prognosis and controlling thrombosis is difficult. In this case, the administration of anticancer therapy allowed use to control the patient's thrombosis. Therefore, this case highlights the importance of treating cancer in patients with Trousseau syndrome. In addition, the FDP and D-dimer levels changed in parallel with changes in the CEA level, which suggests that the activity of cancer is related to an internal thrombotic tendency. Hence, changes in the FDP and D-dimer values are associated with the efficacy of treatment with EGFR tyrosine kinase inhibitors and chemotherapy and may function as markers of recurrence.

Characterization of smooth muscle components in renal angiomyolipomas: Histological and immunohistochemical comparison with renal capsular leiomyomas.

The smooth muscle components of angiomyolipoma (AML) of the kidney have a wide histological and immunohistochemical spectrum. In the present study, 50 cases of AML and seven cases of renal capsular leiomyoma (RCL) were reviewed histologically and immunohistochemically, and the results compared with those of leiomyomas of soft parts. The AML cases were subclassified into 34 cases of common, 12 of leiomyomatous and four of lipomatous type. Even the common-type AML tissues showed a variety of histologic features, including lymphangiomyoma. The cytoplasm of leiomyomatous cells in AML was usually plump and eosinophilic, but sometimes clear with abundant glycogen, and an ovoid or irregular cleaved nucleus. AML cells, irrespective of whether they were epithelioid or leiomyomatous, stained positively for HMB45, S100 protein, and alpha-smooth muscle actin. RCL cells had histologic features identical to those of the leiomyomatous cells in AML. Moreover, the immunohistochemical profiles of the RCL cells were also identical to those of AML. These morphologic and immunohistochemical findings are different from those of smooth muscle tumors in soft parts and confirm that AML and RCL are closely related proliferative entities.