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Cold Sintering was applied to densify a Potassium-Sodium Niobate solid solution composition, 0.5KNbO3-0.5NaNbO3 (KNN); the process uses a transient chemical sintering aid, moderate pressure (400 MPa), and temperatures between 230–300 °C to obtain ceramics of ∼92 to 96 % theoretical density. Typically, sintering temperatures between ∼1000−1050 °C are required to density KNN using conventional methods. In this paper, the densification was investigated during heating, particularly the shrinkage in the first 60 min of the cold sintering process. The low-field dielectric and electrical properties of the resulting ceramics were found to be comparable to conventionally sintered KNN. Electric fields up to 80 kV/cm could be applied, however the ceramics showed pinched hysteresis loops, even after poling over a wide range of temperatures and electric fields. A Rayleigh analysis was used to investigate domain dynamics and high reversible permittivity. The irreversible behavior was an order of magnitude lower than in conventionally sintered KNN, likely associated with defect pinning of ferroelectric domains. A Transmission Electron Microscopy (TEM) study revealed a high density of line defects in most grains; dislocations in the grains limit poling and domain wall movement, thus suppressing both the piezoelectric properties and the hysteresis. Furthermore, TEM observations indicated crystalline grain boundaries that were faceted with terrace kink ledges. These observations point to the importance of the initial powder optimization and grain boundary diffusion when using cold sintering to prepare ceramics that are intended to show bulk cooperative properties such as ferroelectricity. The impact of limited high temperature homogenization of bulk diffusional processes is discussed.

Background Microsatellite instability-high is a known biomarker for anti-PD-1/PD-L1 immune checkpoint therapy. It is also a known tumour feature of Lynch syndrome, detected most frequently in endometrial cancer. However, it remains unclear how microsatellite instability testing is carried out in the clinical field. Methods Ninety-nine patients with gynaecological malignant tumours who underwent microsatellite instability testing as a companion diagnosis for pembrolizumab and 16 patients who previously underwent microsatellite instability testing as a screening for Lynch syndrome were recruited. Clinical information, microsatellite instability status, outcomes, genetic assessments and information about cancer tissue were retrospectively analysed. Results Ninety-nine patients had 101 gynaecologic malignant tumours including 26 endometrial, 38 ovarian and 28 cervical cancers, 9 with other tumours including 2 synchronous endometrial and ovarian cancers. All tissue samples were successfully tested, even though some were ≥10-year-old samples. Three cases (3.0%, 3/99) showed microsatellite instability-high; all cases were endometrial cancers with one case of synchronous endometrial and ovarian cancer [11.5% (3/26) in endometrial cancer, 2.6% (1/38) in ovarian cancer], and there was no microsatellite instability-high in cervical and other cancers. One of the endometrial cancer patients received pembrolizumab treatment, but finally died of cancer. Two other cases underwent genetic testing; both were diagnosed as Lynch syndrome. Six cases (37.5%) showed microsatellite instability-high in screening for Lynch syndrome. Conclusions Microsatellite instability-high was less commonly detected as a companion diagnosis for pembrolizumab in unselected gynaecologic patients. Genetic counselling should be always provided along with treatment selection.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous-generation EGFR-TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a gamma-secretase inhibitor (GSI), a Notch inhibitor, impairs drug-tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho-ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR-TKI treatment in half of human EGFR-mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR-mutated NSCLC.

Cold sintering process (CSP) offers a promising strategy for the fabrication of innovative and advanced high permittivity dielectric nanocomposite materials. Here, we introduce Ba(OH)2∙8H2O hydrated flux as a new transient chemistry that enables the densification of BaTiO3 in a single step at a temperature as low as 150 °C. This remarkably low temperature is near its Curie transition of 125 °C, associated with a displacive phase transition. The cold sintered BaTiO3 shows a relative density of 95 % and a room temperature relative permittivity over 1000. This new hydrated flux permits the fabrication of a unique dense BaTiO3-polymer nanocomposite with a high volume fraction of ceramics ((1-x) BaTiO3 – x PTFE, with x = 0.05). The composite exhibits a relative permittivity of approximately 800, at least an order of magnitude higher than previous reports on polymer composites with BaTiO3 nanoparticle fillers that are typically well below 100. Unique high permittivity dielectric nanocomposites with enhanced resistivities can now be designed using polymers to engineer grain boundaries and CSP as a processing method opening up new possibilities in dielectric materials design.

Objective To optimize prediction for intestinal invasion of epithelial ovarian cancer. It is important to achieve debulking surgery to improve prognosis in ovarian cancer; intestinal resection is adopted if the cancer is invaded and resectable, but the preoperative evaluation method of intestinal invasion is still controversial. Methods Patients (n = 174) who underwent primary debulking surgery for epithelial ovarian cancer were recruited for retrospective study; 28 and 146 patients were classified into the invasion and non‐invasion groups, whether they needed intestinal resection or not. We collected clinical data including evaluation of computed tomography (CT), magnetic resonance imaging (MRI), and barium contrast radiography, and analyzed their accuracy. Results The sensitivity and specificity for intestinal invasion were 33.3% and 98.6%, 42.9% and 98.6%, and 66.7% and 93.9% in CT, MRI, and barium contrast radiography, respectively. CT and MRI combined showed a sensitivity of 58.3% and specificity of 96.9%; all three methods combined was the most sensitive combination, showing a sensitivity of 79.2% and specificity of 90.8%. Conclusion Combination of CT, MRI, and barium contrast radiography predicts intestinal invasion with the highest sensitivity. These three modalities, however, could not predict all intestinal invasion. Patients should be informed of the possibility of unexpected extensive resection., Synopsis Combination of CT, MRI, and barium contrast radiography give the best prediction of intestinal invasion in ovarian cancer.

Although cold sintering remains an emerging processing technique, it is noteworthy to consider recent progress in materials that are of interest to electrochemical systems with elevated service temperatures. Here we discuss a broad number of materials ranging from alkali electrolytes for solid state batteries, to oxygen ion conductors for gas sensing. We also discuss the opportunity to co-fire mixed ionic conductors into multilayered devices. Given the low-temperature sintering temperatures with the cold sintering process (CSP), we will discuss some insights into operating ceramics at temperatures near or above their processing temperature.

To examine the diagnostic accuracy of hysteroscopic photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5ALA) in patients with endometrial cancer and premalignant atypical endometrial hyperplasia.A single-center, open-label, exploratory intervention study.University Hospital in Japan.Thirty-four patients who underwent hysteroscopic resection in the Department of Obstetrics and Gynecology at Keio University Hospital.Patients were given 5ALA orally approximately 3 hours before surgery and underwent observation of the uterine cavity and endometrial biopsy using 5ALA-PDD during hysteroscopic resection. Specimens were diagnosed histopathologically and the diagnostic sensitivity and specificity of hysteroscopic 5ALA-PDD for malignancy in the uterine cavity was determined. Red (R), blue (B), and green (G) intensity values were determined from PDD images, and the relationships of histopathological diagnosis with these values were used to develop a model for objective diagnosis of uterine malignancy.Three patients were excluded from the study because of failure of the endoscope system. A total of 113 specimens were collected endoscopically. The sensitivity and specificity of 5ALA-PDD for diagnosis of malignancy in the uterine cavity were 93.8% and 51.9%, respectively. The R/B ratio in imaging analysis was highest in malignant lesions, followed by benign lesions and normal uterine tissue, with significant differences among these groups (p.05). The R/B and G/B ratios were used in a formula for prediction of malignancy based on logistic regression and the area under the receiver operating characteristic curve for this formula was 0.838. At a formula cutoff value of 0.220, the sensitivity and specificity for diagnosis of malignant disease were 90.6% and 65.4%, respectively.To our knowledge, this is the first study of the diagnostic accuracy of 5ALA-PDD for malignancies in the uterine cavity. Hysteroscopic 5ALA-PDD had higher sensitivity and identifiability of lesions. These findings suggest that hysteroscopic 5ALA-PDD may be useful for diagnosis of minute lesions.

The use of low-temperature and energy-efficient techniques to fabricate composites with tailored interfaces is currently a topic of growing interest. This study reports the proof of concept of a process to fabricate functional multilayer varistor (MLV) devices below 150 °C. In this MLV device, a small volume fraction of polyetherimide polymer is used to engineer ZnO grain boundaries, and the multilayer composite is cofired with base metal internal electrodes via the cold sintering cofired ceramic (CSCC). The resulting dense nanocomposite MLV and controlled nonlinear current–voltage response of the device confirmed the potential of CSCC. This work also opens up the possibility to fabricate multilayer devices for other types of applications.

Purpose We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells. Methods Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines. Results All five CR cell lines highly expressed one or both of the immunoproteasome subunit genes, PSMB8 and PSMB9, while no clear trend was observed in the expression of constitutive proteasome subunits. The CR cells expressed significantly higher levels of PSMB8 and PSMB9 proteins, as well. The CR variants of the H1299 and SBC3 cell lines were more sensitive to immunoproteasome inhibitors, and had significantly more proteasomal proteolytic activity than their parental counterparts. Conclusions The immunoproteasome may be an effective therapeutic target in a subset of CR lung cancers. Proteasomal proteolytic activity may be a predictive marker for the efficacy of immunoproteasome inhibitors in cisplatin-resistant SCLC and NSCLC.

A modified cold sintering process is described, which permits the densification of the prototypical sodium-ion electrolyte, Na3Zr2Si2PO12, to greater than 90% relative density at a process temperat...

International audience; This study reports the sintering of zinc oxide (ZnO) through the comparison between the hydrothermal sintering (HS) and the cold sintering process (CSP) operating in closed and open conditions, respectively. Sintering was performed at 155 ± 5 °C applying a pressure of 320 MPa, and during different holding times (0 min, 20 min, 40 min and 80 min). Whatever the low sintering process used, ceramics characteristics are almost similar in terms of relative densities and ZnO structure. However, several differences such as the nature of stabilized phases, grain sizes and quantities of residual molecules in the densified pellets, were characterized and explained. The formation of zinc acetate “bridges” was observed ex situ in hydrothermally sintered samples. A detailed ReaxFF molecular dynamics simulation was performed to help understand the formation mechanisms of zinc acetate “bridges” and compare the chemical activities between HS and CSP.

Dense nanocrystalline BaTiO3 ceramics are prepared in a single step by the Cold Sintering Process at 300 °C, under a uniaxial pressure of 520 MPa for 12 h using a molten hydroxide flux. Transmission electron microscopy reveals a dense microstructure with sharp grain boundaries. The average grain sizes are 75−150 nm depending on the flux amount. The dielectric permittivity is 700–1800 at room temperature at 106 Hz, with a dielectric loss, tan δ ∼ 0.04. The difference in permittivity and phase transition behavior are explained in terms of the intrinsic size effect of the BaTiO3. The nanocrystalline BaTiO3 ceramics still shows a macroscopic ferroelectric switching via a hysteresis loop. This work demonstrates that cold-sintering process could enable the densification of ferroelectric oxides in a single step. Futhermore, comparable dielectric properties to reported values for nanocrystalline grains are obtained, but at this time, with the lowest processing temperatures ever used.

Densification of ZnO-PTFE (polytetrafluoroethylene) composites is permitted by the Cold Sintering Process, having no effect on the stability of both materials. Highly dense samples can be obtained by this technique at extremely low temperatures in just a few minutes. Interestingly, the obtained samples show an anisotropy impacting: crystalline, microstructural and electrical properties. While the Wurztite ZnO crystals show a preferential growth along (00l) direction, microstructure observations show a grain growth along the in-plane (perpendicular to pressure application direction) up to 240%. Electrical conductivity is also influenced and is related to microstructure. In this situation, the addition of PTFE insulating phase allows to increase the conductivity in plane compared to the pure cold sintered ZnO sample. A mechanism is proposed to explain this phenomenon which involves PTFE transient distribution competing with the transient liquid driving densification and grain growth associated with cold sintering. This is further confirmed by the observation of a curvature of microstructure direction while approaching die edges. These observations offer a large variety of designs for further orientation driven properties.

This study reports the sintering mechanisms of SiO2 and the relationship between structure, dielectric properties and processing of 1 - x S i O 2 - x P T F E composites with volume fractions up to x = 0.25, prepared by the cold sintering process (270 °C, 430 MPa, 60 min). The importance of transient liquids was evaluated by using TEOS and 5 M NaOH and the densification behavior was investigated by using a semiautomated uniaxial press equipped with a dilatometer. The shrinkage behavior observed when 5 M NaOH was used highlighted the kinetics of nucleation and growth during the phase transition from amorphous silica to α-quartz. Dielectric properties (e’ and tan δ) of cold sintered composites were studied at frequencies between 10−1 Hz and 107 Hz. For composites cold sintered with 5 M NaOH, investigations allowed to confirm the presence of PTFE polymer at the interface between two α-quartz grains by STEM EDS analysis and the presence of a dielectric relaxation at 103-104 Hz.

Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials.

Small regulatory RNAs (sRNAs) are involved in anti-viral defense and gene regulation. Although RNA-dependent RNA Polymerases (RdRPs) are known to produce sRNA in nematodes, plants and fungi, whether they play roles in sRNA biogenesis in other animals remains controversial. In this study, we study sRNAs in the ISE6 cell line, which is derived from the black-legged tick, an important vector of human and animal pathogens. We identify abundant classes of ~22nt sRNAs that require specific combinations of RdRPs and sRNA effector proteins (Argonautes or AGOs). RdRP-dependent sRNAs are mainly derived from sense and antisense strands of RNA polymerase III-transcribed genes and repetitive elements. Unlike C. elegans sRNA pathways, 5’-tri-phosphorylated sRNAs are not detected, suggesting that the tick pathways are distinct from the pathways known in worms. Knockdown of one of the RdRPs unexpectedly results in downregulation of a subset of viral transcripts, in contrast to their upregulation by AGO knockdown. Furthermore, we show that knockdown of AGO/RdRP causes misregulation of protein-coding genes including RNAi-related genes, suggesting feedback regulation. Luciferase assays demonstrate that one of the RdRP-regulated genes, the MEK1 ortholog IscDsor1 is regulated through its 3’UTR, where a putative sRNA target site resides. These results provide evidence that arachnid RdRPs are important sRNA biogenesis factors, and the discovery of novel pathways underscores the importance of characterizing sRNA biogenesis in various organisms to understand virus-vector interactions and to exploit RNAi for pest control. Significance statement RNA-dependent RNA Polymerases (RdRPs) are essential for biogenesis of small regulatory RNAs (sRNAs) in many organisms such as plants and fungi, but its general importance in animals besides nematodes remains controversial because experimental evidence is lacking. By using a tick cell line, we demonstrate that RdRP-dependent sRNAs are abundantly expressed and tick RdRPs regulate gene expression. These results indicate that ticks have unexpectedly complex sRNA biogenesis pathways that are essential for proper gene regulation. Because ticks are important vectors of human and animal pathogens, and their sRNA pathways control tick-borne viruses, studying the novel tick sRNA pathways may provide important information for a better understanding of vector-virus interactions and for developing RNA-based pesticides by utilizing tick’s RNA silencing mechanisms.

Primary malignant melanomas (MM) originating from the gynecological tract are rare. They respond poorly to immunotherapy when compared with cutaneous MM. This study reports two cases. The first is of a 54-year-old woman with a cervical amelanotic polypoid mass who was diagnosed as having stage IB1 cervical melanoma according to the International Federation of Gynecology and Obstetrics system. At 17 months post-surgery, a computed tomography examination revealed recurrence of a 68 mm pelvic tumor. The second case is of a 37-year-old woman with a 7 cm hemorrhagic mass on the vaginal wall. The patient was diagnosed as having stage IV vaginal melanoma according to the American Joint Committee on Cancer definition. Both patients received nivolumab therapy, programmed cell death receptor 1 monoclonal antibodies, and the tumors almost disappeared. These cases may add the possibility of using colposcopy with narrow-band imaging and positron-emission tomography to diagnose and evaluate primary MM.

Pelvic inflammatory disease (PID) sometimes develops after intrauterine insemination (IUI). We herein present a case of PID which developed after IUI performed after abdominal modified radical trachelectomy (AmRT) and was treated with laparoscopic surgery. To our knowledge, this is the first case report of laparoscopic surgery for PID that occurred after AmRT in Japan. A 39-year-old woman who was diagnosed with cervical cancer stage IA1 with lymphovascular invasion underwent AmRT and pelvic lymphadenectomy. At 3 years and 6 months after the surgery, she had fever and pain in her left lower abdomen 10 days after IUI. She was diagnosed with PID with left ovarian cyst infection and underwent laparoscopic left ovarian cystectomy. Before surgery, bilateral ureteral catheters were inserted because of possible difficulty identifying the ureters. During surgery, severe adhesion was seen in the pelvic cavity. By moving the catheters manually back and forth from outside the body, we were able to identify the ureters visually. A uterine manipulator was inserted during surgery, rather than before surgery, to avoid the risk of uterine perforation. Laparoscopic surgery with ureteral catheters and a uterine manipulator can be applied safely for such cases after AmRT even when severe intraperitoneal adhesion is present.

A low temperature sintering method, namely cold sintering process, was used to prepare 97 vol%V2O5-3 vol% PEDOT:PSS (Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate ceramic-polymer nanocomposites. The density, phase purity, microstructure, elemental distribution and electrical properties of sintered tape-cast films were investigated. The composition with 97 vol%V2O5-3 vol% PEDOT:PSS ceramic-polymer nanocomposites can be densified (∼90%) after a cold sintering of 140 °C for 45 min under a uniaxial pressure of 300 MPa. The Transmission Electron Microscopy (TEM) microstructure shows that a ∼10 nm thick intergranular polymer of PEDOT:PSS has been distributed around the V2O5 grains after cold sintering. The resistivity decreases with temperature increasing, indicating a typical negative temperature coefficient (NTC) characteristic. The resistivity at 25 °C, temperature coefficient α at 25 °C, and B coefficient (material constant) are 6.34 Ωm, −2.4% K−1 and 2153 K, respectively. The V2O5-PEDOT:PSS nanocomposite materials are suitable for new NTC devices, with properties that are comparable to traditional NTC materials that are sintered at much higher temperatures and with much more complexed process and compositions.

Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so-called "Warburg effect" in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.

Molten hydroxides, often used for crystal growth and nanoparticle synthesis, have recently been applied for the single step densification of several inorganic materials under moderate uniaxial pressures and 1000 °C below their usual sintering temperatures. The latter approach, termed cold sintering process (CSP), is a mechanochemically driven process that enables the densification of inorganic materials through a dissolution-precipitation creep mechanism. In this study, we report the main densification mechanisms of BaTiO3 in a NaOH-KOH eutectic mixture. A chemical insight at the atomistic level, investigated by ReaxFF molecular dynamics simulations, offers plausible ionic complex formation scenarios and reactions at the BaTiO3/molten hydroxide interface, enabling the dissolution-precipitation reactions and the subsequent cold sintering of BaTiO3.

Background The number of cases of novel coronavirus disease 2019 (COVID-19) in Japan have risen since the first case was reported on January 24, 2020, and 6225 infections have been reported as of June 30, 2020. On April 8, 2020, our hospital began screening patients via pre-admission reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and chest computed tomography (CT). Although no patients exhibited apparent pneumonia, treatment delay or changes in treatment plans were required for a few patients based on the results of screening tests. During an emerging infectious disease pandemic, the likelihood of being infected, as well as the disease itself, affects clinical decision making in several ways. We summarized and presented our experience. Case presentation After the introduction of pre-admission screening, RT-PCR and CT were performed in 200 and 76 patients, respectively, as of June 30, 2020. The treatment of five patients, including two patients with cervical cancer, two patients with ovarian tumors, and one patient with ovarian cancer, was affected by the results. Two asymptomatic RT-PCR-positive patients did not develop COVID-19, but their treatment was delayed until the confirmation of negative results. The other three patients were RT-PCR-negative, but abnormal CT findings suggested the possibility of COVID-19, which delayed treatment. The patients receiving first-line preoperative chemotherapy for ovarian cancer had clinically evident exacerbations because of the treatment delay. Conclusion During the epidemic phase of an emerging infectious disease, we found that COVID-19 has several other effects besides its incidence. The postponing treatment was the most common, therefore, treatment of ovarian tumors and ovarian cancer was considered to be the most likely to be affected among gynecological diseases. Protocols that allow for easy over-diagnosis can be disadvantageous, mainly because of treatment delays, and therefore, the protocols must be developed in light of the local infection situation.

Most metastatic lung tumors display well-defined, round, multiple nodular shadows, whereas the presence of diffuse ground-glass opacities on chest computed tomography generally suggests non-malignant conditions. Here, we report an unusual case of pulmonary metastasis from gastric cancer in which diffuse ground-glass opacities were observed in all lung segments. A 59-year-old man with a 3-month history of worsening chest pain and shortness of breath was referred to the pulmonary clinic. Chest computed tomography revealed low attenuation areas, suggesting emphysema, along with diffuse ground-glass opacities and interlobular septal thickening in both lungs. A transbronchial lung biopsy specimen revealed signet-ring cell carcinoma infiltrating the alveolar septa. Immunohistochemical staining of the cancer cells was positive for CDX-2, cytokeratin 7, and cytokeratin 20, and negative for surfactant apoprotein-A, TTF-1, and Napsin A. Gastrointestinal endoscopy revealed an ulcerative tumor in the stomach, and a biopsy from the tumor demonstrated malignant cells with similar morphology and immunophenotypes as those in the lungs. The final diagnosis was diffuse lung metastasis from gastric cancer. Our case shows that although multiple, well-defined nodules are typically considered to be the classic presentation of pulmonary metastasis, clinicians should also be aware of the possibility of pulmonary metastasis presenting as diffuse ground-glass opacities.

BackgroundTo date, only few large studies are available concerning the safety and diagnostic concordance rates of outpatient flexible hysteroscopy. In our institution, outpatient hysteroscopy has been routinely and educationally applied Kosuke Tsuji to intrauterine lesions; thus, we retrospectively investigated the institution’s outpatient flexible hysteroscopy cases.MethodsA total of 1591 cases of outpatient flexible hysteroscopy conducted at our institution in 2012–2016 were retrospectively analyzed in terms of their clinical background, complications and diagnostic concordance rates.ResultsA total of 1591 cases included 546 cases of benign tumors (317 endometrial polyps, 168 myomas and 61 endometrial hyperplasia), 361 cases of atypical endometrial hyperplasia, 571 cases of endometrial cancers and 113 cases of other diagnoses. No major complications, including uterine perforation, occurred. However, one patient (0.06%) was diagnosed with septic shock caused by intrauterine infection that required prolonged immunosuppressive drug administration. Meanwhile, 335 patients diagnosed with benign tumors through outpatient flexible hysteroscopy underwent operation, and the diagnostic concordance rate was 74.6% (250 cases). However, this rate included 14 cases (4.2%) diagnosed with malignant tumors postoperatively. In preoperative endometrial cancer cases, the sensitivity and specificity for cervical invasion diagnosis were 39.4 and 90.8%, respectively. In addition, only one patient manifested positive ascites cytology intraoperatively, possibly caused by outpatient hysteroscopy.ConclusionsOutpatient flexible hysteroscopy is highly safe, with a slight negligible effect on ascites cytology. However, the diagnosis should be determined by multidisciplinary approaches, as hysteroscopy alone can miss malignancy.

Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.

Case series Patients: Female, 32-year-old • Female, 43-year-old Final Diagnosis: Endometriosis Symptoms: Massive genital bleeding Medication: — Clinical Procedure: — Specialty: Obstetrics and Gynecology Objective: Rare disease Background: Endometriosis is defined as the growth of ectopic endometrial tissue beyond the uterine cavity, and endometriosis on the uterine cervix is a rare variant. Although asymptomatic patients with cervical endometriosis or those with minor symptoms are treated conservatively, there are reports of life-threatening hemorrhage due to cervical endometriosis. Here, we report 2 cases of massive genital bleeding caused by cervical endometriotic cysts and we performed a literature review. Case Reports: Case 1: A 32-year-old woman presented to our hospital due to massive genital bleeding on her 11th day of menstruation. An arterial hemorrhage in a cervical endometriotic cyst was suspected. As pressure hemostasis proved difficult, urgent uterine artery embolization (UAE) by interventional radiology was performed. Angiography during the UAE showed extravascular leakage from the branch of the left uterine artery. After embolization, hemostasis was achieved. No further genital bleeding was observed, and transvaginal ultrasound showed the cyst has continued to shrink for 9 months after the UAE with sequential dienogest, a progesterone receptor agonist, treatment. Case 2: A 43-year-old woman presented to our hospital with increasing massive genital bleeding after completing a 12-day course of 0.5 mg of norgestrel and 0.05 mg of ethinyl estradiol as a treatment for irregular intermenstrual bleeding. We suspected cervical endometriotic cyst rupture on imaging and performed an urgent laparoscopic total hysterectomy. In the excised uterine specimen, a cystic lesion that contained old, blood-like fluid was macroscopically observed in the cervix and was diagnosed pathologically as endometriosis. Conclusions: Cervical endometriotic cyst rupture is rare; however, it should be kept in mind as a differential diagnosis when treating massive genital bleeding because urgent intervention is sometimes required to control the bleeding.