Goblet Cell Adenocarcinoma in the Stomach: A Case Report.

Goblet cell adenocarcinoma (GCA) is known as an amphicrine tumor often seen in the appendix. Here, we report a rare case of GCA in the stomach. An 80-year-old man underwent gastroscopy due to epigastric pain and was diagnosed with gastric cancer. He received total gastrectomy and histology showed a mixture of a moderately-differentiated tubular adenocarcinoma, a mucinous adenocarcinoma, and a tumor composed of goblet-like mucinous cells with neuroendocrine differentiation. The tumor volume ratio was about 4:1:5, respectively, and a final diagnosis of GCA was made. The metastasis of the regional lymph node was occupied by only the component of goblet-like cells. GCA should be recognized as a rare histologic subtype of gastric cancer.

An autopsy case of disseminated carcinomatosis of the bone marrow from esophageal adenocarcinoma.

Key Clinical Message: Disseminated carcinomatosis of the bone marrow is rare. We present such a case, which is useful for raising awareness about the importance of early diagnosis and treatment of carcinomas complicated by disseminated carcinomatosis of the bone marrow. Abstract: This is the first autopsy report of disseminated carcinomatosis of the bone marrow (DCBM) in esophageal adenocarcinoma. Advanced poorly differentiated adenocarcinoma with signet ring cell carcinoma arising in Barrett's esophagus caused disseminated intravascular coagulation (DIC) with extensive bone marrow metastasis, resulting in death from cerebral hemorrhage. Although DCBM due to malignancy is rare with poor prognosis, it should be considered in malignancies associated with DIC, and prompt initiation of chemotherapy is the only way to improve the patient's prognosis.

Autocrine TGF-ß-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.

The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-ß plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-ß-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets.

Identifying a Lung Stem Cell Subpopulation by Combining Single-Cell Morphometrics, Organoid Culture, and Transcriptomics.

Single-cell RNA sequencing is a valuable tool for dissecting cellular heterogeneity in complex systems. However, it is still challenging to estimate the proliferation and differentiation potentials of subpopulations within dormant tissue stem cells. Here, we established a new single-cell analysis method for profiling the organoid-forming capacity and differentiation potential of tissue stem cells to disclose stem cell subpopulations by integrating single-cell morphometrics, organoid-forming assay, and RNA sequencing, a method named scMORN. To explore lung epithelial stem cells, we initially developed feeder-free culture system, which could expand all major lung stem cells, including basal, club, and alveolar type 2 (AT2) cells, and found that club cells contained a subpopulation, which showed better survival rate and high proliferation capacity and could differentiate into alveolar cells. Using the scMORN method, we discovered a club cell subpopulation named Muc5b+ and large club (ML-club) cells that efficiently formed organoids than other club or AT2 cells in our feeder-free organoid culture and differentiated into alveolar cells in vitro. Single-cell transcriptome profiling and immunohistochemical analysis revealed that ML-club cells localized at the intrapulmonary proximal airway and distinct from known subpopulations of club cells such as BASCs. Furthermore, we identified CD14 as a cell surface antigen of ML-club cells and showed that purified CD14+ club cells engrafted into injured mouse lungs had better engraftment rate and expansion than other major lung stem cells, reflecting the observations in organoid culture systems. The scMORN method could be adapted to different stem cell tissues to discover useful stem-cell subpopulations.

Accurate deep learning model using semi-supervised learning and Noisy Student for cervical cancer screening in low magnification images.

Deep learning technology has been used in the medical field to produce devices for clinical practice. Deep learning methods in cytology offer the potential to enhance cancer screening while also providing quantitative, objective, and highly reproducible testing. However, constructing high-accuracy deep learning models necessitates a significant amount of manually labeled data, which takes time. To address this issue, we used the Noisy Student Training technique to create a binary classification deep learning model for cervical cytology screening, which reduces the quantity of labeled data necessary. We used 140 whole-slide images from liquid-based cytology specimens, 50 of which were low-grade squamous intraepithelial lesions, 50 were high-grade squamous intraepithelial lesions, and 40 were negative samples. We extracted 56,996 images from the slides and then used them to train and test the model. We trained the EfficientNet using 2,600 manually labeled images to generate additional pseudo labels for the unlabeled data and then self-trained it within a student-teacher framework. Based on the presence or absence of abnormal cells, the created model was used to classify the images as normal or abnormal. The Grad-CAM approach was used to visualize the image components that contributed to the classification. The model achieved an area under the curve of 0.908, accuracy of 0.873, and F1-score of 0.833 with our test data. We also explored the optimal confidence threshold score and optimal augmentation approaches for low-magnification images. Our model efficiently classified normal and abnormal images at low magnification with high reliability, making it a promising screening tool for cervical cytology.

An autopsy case of ovarian mucinous cystic tumor complicated by ovarian abscess and a review of the English literature.

Ovarian tumors are rarely associated with abscesses. Herein, an autopsy case of an ovarian mucinous cystic tumor complicated by an abscess, along with a review of previous cases, suggests the necessity of considering ovarian abscess as a cause of inflammation in patients with the ovarian tumors.

Chemotherapy for patients with advanced lung cancer with interstitial lung disease: a prospective observational study.

Introduction: Although recent advances in chemotherapy for lung cancer are remarkable, most clinical trials have excluded patients with interstitial lung disease (ILD) due to the concern of developing acute exacerbation (AE) of ILD. Hence, accumulating original evidence of cancer treatment for this population is important. Methods: Between 2016 and 2020, a prospective observational study was conducted across 11 Japanese hospitals. Patients with chemotherapy-naïve, inoperable, advanced lung cancer with ILD were included. The primary outcome was the frequency of AE-ILD after registration; the secondary outcomes were the risk factor of AE-ILD and the efficacy of chemotherapy. Results: Among 124 patients enrolled, 109 patients who received chemotherapy were analyzed. The median age was 72 years, and the majority showed usual interstitial pneumonia (UIP)/probable UIP pattern upon chest computed tomography. The median percent-predicted forced vital capacity (%FVC) was 81% (interquartile range: 66-95%). After registration, 23 patients (21.1%; 95% confidence interval [CI]: 14.4-29.7%) developed AE-ILD. The logistic analysis revealed that lower %FVC slightly but significantly increased the risk of AE-ILD (odds ratio per 10% decrease: 1.27; 95% CI: > 1.00-1.62). Overall response rates/median overall survival times in non-small-cell lung cancer and small-cell lung cancer for the first-line chemotherapy were 41% (95% CI: 31-53)/8.9 months (95% CI: 7.6-11.8) and 91% (95% CI: 76-98)/12.2 months (95% CI: 9.2-14.5), respectively. Conclusion: AE-ILD during chemotherapy is a frequent complication among patients with lung cancer with ILD, particularly those with lower %FVC. Conversely, even in this population, passable treatment response can be expected.

Metformin reduces pleural fibroelastosis by inhibition of extracellular matrix production induced by CD90-positive myofibroblasts.

Metformin, an AMP-activated protein kinase activator used to treat diabetes mellitus, has recently attracted attention as a promising anti-fibrotic agent. However, its anti-fibrotic effects on pleural fibroelastosis remain unknown. We induced mouse pleural fibroelastosis by intra-pleural coadministration of bleomycin and carbon and evaluated its validity as a preclinical model for human pleural fibrosis. We assessed the expression of the myofibroblast surface marker CD90 in the fibrotic pleura and the effects of metformin in vivo and in vitro. Finally, we evaluated the effects of metformin on human pleural mesothelial cells stimulated by transforming growth factor ß1 (TGFß1). The fibrotic pleura in mice had collagen and elastin fiber deposition similar to that seen in human fibrotic pleura. Moreover, CD90-positive myofibroblasts were detected in and successfully isolated from the fibrotic pleura. Metformin significantly suppressed the deposition of collagen and elastic fibers in the fibrotic pleura and decreased the expression of extracellular matrix (ECM)-related genes, including Col1a1, Col3a1, Fn1, and Eln, in pleural CD90-positive myofibroblasts. In human pleural mesothelial cells, metformin decreased TGFß1-induced upregulation of ECM-related genes and SNAI1. Overall, metformin suppresses pleural fibroelastosis by inhibition of ECM production by pleural myofibroblasts, suggesting that this drug has therapeutic potential against human pleural fibrosis, including pleuroparenchymal fibroelastosis.

Difference in the distribution of tumor-infiltrating CD8+ T cells and FOXP3+ T cells between micronodular thymoma with lymphoid stroma and micronodular thymic carcinoma with lymphoid stroma.

Micronodular thymoma with lymphoid stroma (MNT) is a rare thymic epithelial neoplasm subtype characterized by a micronodular tumor cell growth pattern and abundant lymphoid stroma. Micronodular thymic carcinoma with lymphoid stroma (MNCA) is considered as a malignant counterpart of MNT and exhibits a growth pattern similar to that of MNT but has histologic features reminiscent of thymic squamous cell carcinoma, such as cytologic atypia and CD5 and CD117 immunoexpression. Although both MNT and MNCA are characterized by abundant lymphoid stroma, it remains unknown whether there are differences in infiltrating lymphocytes between MNT and MNCA. We analyzed the immune microenvironment profile in eight MNT and three MNCA cases. The cell density of CD8-positive T cells was significantly higher in MNT than in MNCA, whereas that of FOXP3-positive T cells was significantly higher in MNCA than in MNT. There was no significant difference in the cell density of programmed death protein 1-positive T cells and programmed death ligand 1 expression between the MNT and MNCA cases. Our findings indicated that the immune microenvironment of MNCA differed from that of MNT and, compared with the T-cell profile of MNT, that of MNCA was more suppressive to patients' antitumor immune response.

Prognostic and Clinical Value of Cluster Analysis in Idiopathic Pleuroparenchymal Fibroelastosis Phenotypes.

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a distinctive interstitial pneumonia with upper lobe predominance that shows unique morphological features among idiopathic interstitial pneumonias (IIPs). Affected patients have a variety of clinical presentations with heterogeneous clinical courses. Cluster analysis is a valuable tool for identifying distinct clinical phenotypes under heterogeneous conditions. This study aimed to identify the phenotypes of patients with idiopathic PPFE. Using cluster analysis, novel PPFE phenotypes were identified among subjects from our multicenter cohort, and outcomes were stratified according to phenotypic clusters. Among the subjects with baseline data (N = 84), four clusters were identified. Cluster 1 included younger male subjects with coexisting non-UIP-like patterns. Cluster 2 included elderly female nonsmokers with low body mass index (BMI). Cluster 3 included elderly male smokers with a coexisting IP-like pattern. Cluster 4 included younger male smokers without lower lobe lesions. Patients in cluster 3 had significantly worse survival outcomes than those in clusters 1, 2, and 4 (p < 0.001, p = 0.0041, and p = 0.0155, respectively). Among idiopathic PPFE patients, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might predict survival outcomes.

Gremlin-1 for the Differential Diagnosis of Idiopathic Pulmonary Fibrosis Versus Other Interstitial Lung Diseases: A Clinical and Pathophysiological Analysis.

PURPOSE: The differential diagnosis of interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF) versus other non-IPF ILDs, is important for selecting the appropriate treatment. This retrospective study aimed to explore the utility of gremlin-1 for the differential diagnosis. METHODS: Serum gremlin-1 concentrations were measured using an ELISA in 50 patients with IPF, 42 patients with non-IPF ILD, and 30 healthy controls. The baseline clinical data, including pulmonary functions, prognosis, and three serum biomarkers (Krebs von den Lungen-6 [KL6], surfactant protein-D [SP-D], and lactate dehydrogenase [LDH]), were obtained through a medical record review for analyzing their associations with serum gremlin-1 concentrations. To evaluate the origin of gremlin-1, we performed immunostaining on lung sections. RESULTS: Serum gremlin-1 concentrations were significantly higher in patients with IPF (mean concentration, 14.4 ng/mL), followed by those with non-IPF ILD (8.8 ng/mL) and healthy controls (1.6 ng/mL). The area under the curve for IPF versus non-IPF ILDs was 0.759 (95% confidence interval, 0.661-0.857), which was superior to that of KL6/SP-D/LDH. The sensitivity and specificity for gremlin-1 (cutoff, 10.4 ng/mL) was 72 and 69%, respectively. By contrast, serum gremlin-1 concentrations were not associated with the pulmonary functions nor the prognosis in all patients with ILDs. In immunostaining, the gremlin-1 was broadly upregulated in IPF lungs, particularly at myofibroblasts, bronchiolar/alveolar epithelium, and CD163-positive M2-like macrophages. CONCLUSIONS: Gremlin-1 may be a useful biomarker to improve the diagnostic accuracy for IPF compared to non-IPF ILDs, suggesting a role of this molecule in the pathogenesis of IPF.

Pneumothorax in Patients with Idiopathic Pleuroparenchymal Fibroelastosis: Incidence, Clinical Features, and Risk Factors.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare form of idiopathic interstitial pneumonia that is characterized by predominantly upper lobe pleural and subpleural lung parenchymal fibrosis. Pneumothorax is one of the major respiratory complications in PPFE patients; however, its clinical features are poorly understood. OBJECTIVE: We aimed to investigate the complication of pneumothorax in patients with idiopathic PPFE. METHODS: A retrospective multicenter study involving 89 patients who had been diagnosed with idiopathic PPFE was conducted. We investigated the cumulative incidence, clinical features, and risk factors of pneumothorax after the diagnosis of idiopathic PPFE. RESULTS: Pneumothorax developed in 53 patients (59.6%) with 120 events during the observation period (41.8 ± 35.0 months). The cumulative incidence of pneumothorax was 24.8, 44.9, and 53.9% at 1, 2, and 3 years, respectively. Most events of pneumothorax were asymptomatic (n = 85; 70.8%) and small in size (n = 92; 76.7%); 30 patients (56.6%) had recurrent pneumothorax. Chest drainage was required in 23 pneumothorax events (19.2%), and a persistent air leak was observed in 13 (56.5%). Patients with pneumothorax were predominantly male and frequently had pathological diagnoses of PPFE and prior history of pneumothorax and corticosteroid use; they also had significantly poorer survival than those without pneumothorax (log-rank test; p = 0.001). Multivariate analysis revealed that a higher residual volume/total lung capacity ratio was significantly associated with the development of pneumothorax after the diagnosis. CONCLUSION: Pneumothorax is often asymptomatic and recurrent in patients with idiopathic PPFE, leading to poor outcomes in some cases.

Pneumothorax in connective tissue disease-associated interstitial lung disease.

BACKGROUND: Spontaneous pneumothorax is a complication that occurs in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD); however, few studies on the clinical implications of pneumothorax for patients with CTD-ILD have been performed. OBJECTIVES: This study aimed to investigate the incidence and prognostic significance of pneumothorax and the risk factors for its onset in patients with CTD-ILD. METHODS: This study included 140 consecutive patients with CTD-ILD. Clinical characteristics, laboratory findings, pulmonary function test results, and chest high-resolution computed tomography (HRCT) images were retrospectively evaluated. RESULTS: A total of 18 patients (12.9%) developed pneumothorax during their clinical course. The cumulative incidence of pneumothorax from the time of CTD-ILD diagnosis was 6.5%, 8.7%, and 11.3% at 1, 3, and 5 years, respectively. The 10-year survival rate was significantly lower in patients with pneumothorax (29.6%) than that in those without pneumothorax (81.3%). The development of pneumothorax was significantly associated with poor prognosis (HR 22.0; p < 0.010). Furthermore, a lower body mass index, greater extent of reticular abnormalities on HRCT, and administration of methylprednisolone pulse therapy were significantly associated with the development of pneumothorax. CONCLUSION: Pneumothorax is a serious complication in the clinical course of patients with CTD-ILD and the onset of pneumothorax predicts a poor outcome.

CD248 and integrin alpha-8 are candidate markers for differentiating lung fibroblast subtypes.

BACKGROUND: Lung fibrosis is a serious life-threatening condition whose manifestation varies according to the localization and characteristics of fibroblasts, which are considered heterogeneous. Therefore, to better understand the pathology and improve diagnosis and treatment of this disease, it is necessary to elucidate the nature of this heterogeneity and identify markers for the accurate classification of human lung fibroblast subtypes. METHODS: We characterized distinct mouse lung fibroblast subpopulations isolated by fluorescence-activated cell sorting (FACS) and performed microarray analysis to identify molecular markers that could be useful for human lung fibroblast classification. Based on the expression of these markers, we evaluated the fibroblast-like cell subtype localization in normal human lung samples and lung samples from patients with idiopathic pulmonary fibrosis (IPF). RESULTS: Mouse lung fibroblasts were classified into Sca-1high fibroblasts and Sca-1low fibroblasts by in vitro biological analyses. Through microarray analysis, we demonstrated CD248 and integrin alpha-8 (ITGA8) as cell surface markers for Sca-1high fibroblasts and Sca-1low fibroblasts, respectively. In mouse lungs, Sca-1high fibroblasts and Sca-1low fibroblasts were localized in the collagen fiber-rich connective tissue and elastic fiber-rich connective tissue, respectively. In normal human lungs and IPF lungs, two corresponding major fibroblast-like cell subtypes were identified: CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells, localized in the collagen fiber-rich connective tissue and in the elastic fiber-rich connective tissue, respectively. CONCLUSION: CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells were localized in an almost exclusive manner in human lung specimens. This human lung fibroblast classification using two cell surface markers may be helpful for further detailed investigations of the functions of lung fibroblast subtypes, which can provide new insights into lung development and the pathological processes underlying fibrotic lung diseases.

Recognition of alpha-mannan by dectin 2 is essential for onset of Kawasaki disease-like murine vasculitis induced by Candida albicans cell-wall polysaccharide.

Objectives: Using a murine model of systemic Kawasaki disease (KD)-like vasculitis induced by Candida albicans cell-wall-derived mannan · ß-glucan · protein complexes, the objective was to elucidate the relationships of ß-glucan receptor dectin-1 (D1) and α-mannan receptor dectin-2 (D2) to the onset of that vasculitis.Methods: The incidence and histological severity of vasculitis were compared among mice lacking the genes for D1 or D2 (i.e. D1-/- and D2-/-) and wild-type (WT) mice.Results: The incidences of vasculitis in the three animal groups were 100% (18/18) in the WT group, 100% (18/18) in the D1-/- group, and 0% (0/18) in the D2-/- group. In the WT and D1-/- mice, severe inflammatory cell infiltration, consisting mainly of neutrophils and macrophages, was seen in the aortic root and the coronary arteries. On the other hand, in the D2-/- mice, not even mild vascular lesions such as endoarteritis were seen.Conclusion: Recognition of α-mannan by D2 played an important role in the onset of vasculitis in the studied murine model.

Nationwide cloud-based integrated database of idiopathic interstitial pneumonias for multidisciplinary discussion.

Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs.Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis.Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis.This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs.

Successful treatment of porocarcinoma with maxacalcitol and imiquimod.

This is the first report of a case of porocarcinoma that was successfully treated with maxacalcitol and imiquimod.