A 51-year-old woman who had previously undergone left mastectomy for left breast cancer accompanied by multiple metastasis experienced worsening dyspnea. Physical and imaging assessments of the ...hemodynamics suggested cardiac tamponade, and emergency pericardiocentesis was successfully performed. However, immediately after the procedure, the patient's condition deteriorated rapidly and showed pulseless electrical activity. Contrast-enhanced computed tomography with continuous mechanical support demonstrated massive thrombi in both pulmonary arteries. An abrupt decrease in the central venous pressure and an increase in the venous return following pericardiocentesis might result in the migration of a deep venous thrombus and fatal acute pulmonary thromboembolism.
Summary Background The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral ...diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. Methods This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. Findings Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 38·0%; 95% CI 26·7–49·3 of 71 patients, placebo group 35 56·5%; 95% CI 44·1–68·8 of 62; p=0·034, risk ratio RR 0·67 95% CI 0·47–0·97; adenomas: metformin group 22 30·6%; 95% CI 19·9–41·2 of 71 patients, placebo group 32 51·6%; 95% CI 39·2–64·1 of 62; p=0·016, RR 0·60 95% CI 0·39–0·92). The median number of polyps was zero (IQR 0–1) in the metformin group and one (0–1) in the placebo group (p=0·041). The median number of adenomas was zero (0–1) in the metformin group and zero (0–1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. Interpretation The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. Funding Ministry of Health, Labour and Welfare, Japan.
This review shows the highlights of a 4-year-long research project supported by the Japanese Government to explore new superconducting materials and relevant functional materials. The project found ...several tens of new superconductors by examining ∼1000 materials, each of which was chosen by Japanese experts with a background in solid state chemistry. This review summarizes the major achievements of the project in newly found superconducting materials, and the fabrication wires and tapes of iron-based superconductors; it incorporates a list of ∼700 unsuccessful materials examined for superconductivity in the project. In addition, described are new functional materials and functionalities discovered during the project.
High activity in tight spaces: Polyoxometalate H3PW12O40 surrounded by hydrophobic alkyl groups in the channels of mesoporous silica (see picture) showed exceptionally high catalytic activity for ...ester hydrolysis in water. The nanostructure based on mesoporous silica allows the aqueous reaction mixture to easily reach the active sites, despite their being surrounded by hydrophobic moieties.
Single crystals of sodium containing silicon clathrate compounds Na8Si46 (type I) and Na x Si136 (type II) were prepared from the mixtures of NaSi and Si under high-pressure and high-temperature ...conditions of 5 GPa at 600–1000 °C. The type II crystals were obtained at relatively low-temperature conditions of 700–800 °C, which were found to have a Na excess composition Na30.5Si136 in comparison with the compounds Na x Si136 (x ≤ 24) obtained by a thermal decomposition of NaSi under vacuum. The single crystal study revealed that the Na excess type II compound crystallizes in space group Fd3̅m with a lattice parameter of a = 14.796(1) Å, slightly larger than that of the ambient phase (Na24Si136), and the large silicon hexakaidecahedral cages (@Si28) are occupied by two sodium atoms disordered in the two 32e sites around the center of the @Si28 cages. At temperatures <90 K, the crystal symmetry of the compound changes from the face-centered to the primitive cell with space group P213, and the Na atoms in the @Si28 cages are aligned as Na2 pairs. The temperature dependence of the magnetic susceptibility of Na30.5Si136 suggests that the two Na ions (2 Na+) in the cage are changed to a Na2 molecule. The Na atoms of Na30.5Si136 can be deintercalated from the cages topochemically by evacuation at elevated temperatures. The single crystal study of the deintercalated phases Na x Si136 (x = 25.5 and 5.5) revealed that only excess Na atoms have disordered arrangements.
Background
The role of hepatic iron overload (HIO) in nonalcoholic fatty liver disease (NAFLD) pathogenesis has not been fully elucidated.
Purpose
This study aimed to investigate the effect of HIO ...and examine the diagnostic usefulness of magnetic resonance imaging (MRI)‐based R2* quantification in evaluating hepatic iron content (HIC) and pathological findings in NAFLD.
Study Type
Prospective and retrospective.
Population
A prospective study of 168 patients (age, 57.2 ± 15.0; male/female, 80/88) and a retrospective validation study of 202 patients (age, 57.0 ± 14.4; male/female, 113/89) with liver‐biopsy‐confirmed NAFLD were performed.
Field Strength/Sequence
3 T; chemical‐shift encoded multi‐echo gradient echo.
Assessment
Using liver tissues obtained by liver biopsy, HIC was prospectively evaluated in 168 patients by atomic absorption spectrometry. Diagnostic accuracies of HIC and R2* for grading hepatic inflammation plus ballooning (HIB) as an indicator of NAFLD activity were assessed.
Statistical Tests
Student's t‐test and analysis of variance (ANOVA) with Scheffe's multiple testing correction for univariate comparisons; multivariate logistic analysis. P‐value less than 0.05 is statistically significant.
Results
HIC was significantly correlated with HIB grades (r = 0.407). R2* was significantly correlated with HIC (r = 0.557) and HIB grades (r = 0.569). R2* mapped an area under the receiver operating characteristic (AUROC; 0.774) for HIC ≥808 ng/mL (median value) with cutoff value of 62.5 s−1. In addition, R2* mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s−1. When R2* was <62.5 s−1, R2* correlated weakly with HIC (r = 0.372) as it was affected by fat deposition and did not correlate with HIB grades (P = 0.052). Conversely, when R2* was ≥62.5 s−1, a significant correlation of R2* with HIC (r = 0.556) and with HIB grades was observed (P < 0.0001) with being less affected by fat deposition.
Data Conclusion
R2* ≥ 62.5 s−1 is a promising modality for non‐invasive diagnosis of clinically important high grades (≥3) of HIB associated with increased HIC.
Level of Evidence
1
Technical Efficacy Stage
2
Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) ...pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA–binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43–negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43–positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43–positive NCIs.
Biphenotypic sinonasal sarcoma is a newly established tumor entity that is associated with distinct clinicopathological findings. Biphenotypic sinonasal sarcoma is a rare, low-grade spindle cell ...sarcoma that arises in middle-aged females, exclusively in the sinonasal tract. A fusion gene involving PAX3 is detected in most biphenotypic sinonasal sarcomas, which aids in its diagnosis. Here, we report a case of biphenotypic sinonasal sarcoma with its cytological findings. The patient was a 73-year-old woman who presented with purulent nasal discharge and dull pain in the left cheek area. Computed tomography showed a mass extending from the left nasal cavity to the left ethmoid sinus, the left frontal sinus, and the frontal skull base. She underwent a combined transcranial and endoscopic approach for en bloc resection with a safety margin. Histologically, spindle-shaped tumor cells have been thought to proliferate mainly in the subepithelial stroma. Here, nasal mucosal epithelial hyperplasia was noted, and the tumor had invaded the bone tissue accompanying the epithelial cells. Fluorescence in situ hybridization (FISH) analysis showed a PAX3 rearrangement, and next-generation sequencing identified a PAX3::MAML3 fusion. Based on FISH, split signals were observed not in respiratory cells but in stromal cells. This indicated that respiratory cells were non-neoplastic. In the diagnosis of biphenotypic sinonasal sarcoma, the inverted growth of the respiratory epithelium can be a diagnostic pitfall. FISH analysis using a PAX3 break-apart probe is helpful not only for an accurate diagnosis but also for detecting the true neoplastic cells.
To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. ...To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient‐derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient‐derived or PDX‐derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX‐derived organoid cells were evaluated for the presence of MYB‐mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC‐derived organoids were successfully generated in three‐dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short‐term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short‐term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC‐derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC.
What's new?
The biological underpinnings of salivary adenoid cystic carcinoma (ACC) remain largely unknown, owing to a lack of preclinical model systems. In this study, the authors describe the successful generation of human salivary ACC cell lines from organoid culture and the subsequent development of an in vivo salivary ACC mouse model. The orthotopic xenograft mouse model was established efficiently from ACC organoid cells from patient‐derived xenografts (PDX). Short‐term cultures of PDX‐derived ACC organoid cells further were amenable for in vitro drug‐sensitive studies with several agents. This novel approach could be useful for investigating personalized therapies for patients with salivary ACC.
Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low‐grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, ...and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF‐1 when using the clone SPT24, but negative for HNF‐4α. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki‐67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746‐T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors.
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