Deep learning-based assay for programmed death ligand 1 immunohistochemistry scoring in non-small cell lung carcinoma: Does it help pathologists score?

Several studies have developed various artificial intelligence (AI) models for immunohistochemical analysis of programmed death ligand 1 (PD-L1) in patients with non-small cell lung carcinoma; however, none have focused on specific ways by which AI-assisted systems could help pathologists determine the tumor proportion score (TPS). Herein, we developed an AI model to calculate the TPS of the PD-L1 22C3 assay and evaluated whether and how this AI-assisted system could help pathologists determine the TPS and analyze how AI-assisted systems could affect pathologists' assessment accuracy. We assessed the four methods of the AI-assisted system: 1) and 2) pathologists first assessed and then referred to automated AI scoring results (1, positive tumor cell percentage; 2, positive tumor cell percentage and visualized overlay image) for a final confirmation, and 3) and 4) pathologists referred to the automated AI scoring results (3, positive tumor cell percentage; 4, positive tumor cell percentage and visualized overlay image) while determining TPS. Mixed model analysis was used to calculate the odds ratios (ORs) with 95% confidence intervals for AI-assisted TPS 1) to 4) compared with pathologists' scoring. For all 584 samples of tissue microarray, the OR for AI-assisted TPS 1) to 4) was 0.94-1.07 and not statistically significant. Of them, we found 332 cases of discordant cases, on which the pathologists' judgments were inconsistent; the ORs for AI-assisted TPS 1), 2), 3), and 4) were 1.28 (1.06-1.54, p = 0.012), 1.29 (1.06-1.55, p = 0.010), 1.28 (1.06-1.54, p = 0.012), and 1.29 (1.06-1.55, p = 0.010), respectively, which were statistically significant. For discordant cases, the OR for each AI-assisted TPS compared with the others was 0.99-1.01 and not statistically significant. This study emphasized the usefulness of the AI-assisted system for cases wherein pathologists had difficulty determining the PD-L1 TPS.

Endogenous Microbacteria Can Contribute to Ovarian Carcinogenesis by Reducing Iron Concentration in Cysts: A Pilot Study.

Among epithelial ovarian cancer, clear cell carcinoma is common for chemo-resistance and high mortality. This cancer arises from benign ovarian endometrioma (OE), which is a high oxidative stress environment due to the cystic retention of menstrual blood produced during menstruation and the "iron" liberated from the cyst. There has been strong evidence that the iron concentration in OE decreases when they become cancerous. A decrease in iron concentration is a necessary condition for the formation of cancer. However, the mechanism of carcinogenesis is not yet clear. In the current study, the bacterial flora in endometriosis-associated ovarian cancer (EAOC), including clear cell carcinoma, and their origin, OE, were investigated using next-generation sequencing. The Shannon index in the genus level was significantly higher in EAOC than in OE fluids. Among several bacterial flora that were more abundant than benign chocolate cysts, a number of bacterial species that correlate very well with iron concentrations in the cysts were identified. These bacterial species are likely to be associated with decreased iron concentrations and cancer development.

Non-small cell lung carcinoma with focal coexpression of thyroid transcription factor-1 and Δ Np63/p40: A case report.

Most lung carcinomas are subtyped by their morphologies; however, immunohistochemistry is usually performed when it is difficult to determine. The most reliable antibodies for distinguishing lung adenocarcinoma from squamous cell carcinoma are thyroid transcription factor-1 (TTF-1) and p40 (ΔNp63). In general, these markers are mutually exclusive in their expression of lung primary carcinoma; however, a few cases of non-small cell lung carcinoma (NSCLC) with coexpression of both markers have been reported. Examining a tissue microarray of 229 squamous cell carcinomas and 346 adenocarcinomas, we found one case of NSCLC with coexpression of TTF-1 and p40. Herein, we present a 71-year-old man, who had a mass lesion in the left lung apex. A transbronchial lung biopsy was performed, revealing NSCLC. He underwent left upper segmentectomy and lymph node dissection. Macroscopically, the mass showed a white-to-tan solid tumor on the cut surface. Microscopically, the tumor was composed of polygonal tumor cells which had round and vesicular nuclei with prominent nucleoli. They had an abundant amount of cytoplasm, which was slightly eosinophilic or amphophilic. Multinucleated cells with atypical nuclear features were observed to be scattered in some areas. Multifocal necrosis and hemorrhage were also noted. Distinct squamous features and obvious glandular features were absent. Immunohistochemically, the most tumor cells were coexpressed positive for both TTF-1 and p40. In our study, NSCLC with TTF-1 and p40 coexpression is rare; therefore, it is necessary to obtain further data and examine similar cases to establish more precise definitions and clinicopathological features.

Insulin-like Growth Factor II mRNA-binding Protein 3 is a Highly Sensitive Marker for Intravascular Large B-cell Lymphoma: Immunohistochemical Analysis of 152 Pathology Specimens From 88 Patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive extranodal large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of blood vessels, particularly capillaries. IVLBCL lacks mass formation, and its diagnosis can be challenging. We analyzed the utility of insulin-like growth factor II mRNA-binding protein 3 (IMP3) immunohistochemistry for IVLBCL diagnosis in various organs. Double staining with paired box 5 (PAX5) was performed for validation. Overall, 152 pathological specimens (111 positive and 41 negative for IVLBCL) obtained from 88 patients with a diagnosis of IVLBCL were stained for IMP3 and IMP3/PAX5. As negative controls, 40 pathology specimens from 38 patients with no history of IVLBCL or other B-cell lymphomas were stained for IMP3, which comprised 31 benign pathological specimens from 29 patients in whom malignancy was suspected, 7 cases of appendicitis with intravascular and/or intralymphatic lymphoid proliferations, and 2 cases of intravascular natural killer/T-cell lymphoma. All mononuclear cells with cytoplasmic staining were considered positive for IMP3 expression, but expression restricted to germinal center B cells was excluded from evaluation. All 111 IVLBCL pathological specimens were positive for IMP3 and IMP3/PAX5. In addition, 11 of the 41 specimens originally diagnosed as IVLBCL-negative showed IMP3/PAX5 double-positive cells, raising the suspicion of IVLBCL. However, of the 40 negative control samples, IMP3-positive non-germinal center B cells were detected in only 2 samples (P= 0.0131) and no intravascular IMP3-positive B cells suspicious for IVLBCL were identified. Altogether, IMP3 immunohistochemistry is a highly sensitive marker of IVLBCL and can be a helpful adjunct for IVLBCL diagnosis.

Fibrotic progression from acute cellular rejection is dependent on secondary lymphoid organs in a mouse model of chronic lung allograft dysfunction.

Chronic lung allograft dysfunction (CLAD) remains one of the major limitations to long-term survival after lung transplantation. We modified a murine model of CLAD and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 which, by day 30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis, reminiscent of changes observed in restrictive allograft syndrome. Lung transplantation into splenectomized B6 alymphoplastic (aly/aly) or splenectomized B6 lymphotoxin-ß receptor-deficient mice demonstrated that recipient secondary lymphoid organs, such as spleen and lymph nodes, are necessary for progression from acute cellular rejection to allograft fibrosis in this model. Our work uncovered a critical role for recipient secondary lymphoid organs in the development of CLAD after pulmonary transplantation and may provide mechanistic insights into the pathogenesis of this complication.

The impact of vascular division sequence and epithelial-mesenchymal transition status on postoperative recurrence in lung adenocarcinoma.

BACKGROUND: The vascular division sequence in video-assisted thoracic surgery (VATS) lung resection is usually determined by the handling difficulty due to the limited surgical view through the scope. However, upfront pulmonary vein division is theoretically desirable to avoid tumor cells spreading by surgical manipulation. Epithelial-mesenchymal transition (EMT) is associated with poor prognosis and an increased number of circulating tumor cells. The purpose of this study is to evaluate the effect of vascular division sequence and EMT on postoperative recurrence. METHODS: We retrospectively investigated tissue microarrays of 282 lung adenocarcinomas surgically resected between 2001 and 2007. We excluded the cases with segmentectomy, wedge resection, dissemination, insufficient material for staining, or lack of medical records. The effect of vascular division sequence and clinicopathologic factors on recurrence was evaluated in 195 cases. RESULTS: The upfront pulmonary vein division (V-first) was performed in 60 patients, and the upfront pulmonary artery division (A-first) was performed in 135 patients. The recurrence was observed in 67 patients (13 in V-first and 54 in A-first). Epithelial-mesenchymal transition activation was observed in 104 patients. Multivariable analysis with 195 patients revealed that lymph node metastasis and pleural invasion were risk factors for the recurrence. The stratified multivariable analysis showed that vascular division sequence (A-first) was a risk factor only in the EMT-negative group (91 patients). In the EMT-negative subset, the 5-year relapse-free survival rate was significantly lower in the A-first group than the V-first group (72.6% vs. 92.2%, p = 0.0136). CONCLUSIONS: The upfront pulmonary artery division might be a risk factor in patients without EMT activation.

Histopathological significance of connective tissue disease-associated interstitial lung disease in transbronchial lung cryobiopsy specimens.

Differentiating between idiopathic interstitial pneumonia (IIP) and secondary interstitial pneumonia, particularly connective tissue disease-associated interstitial lung disease (CTD-ILD), can be challenging histopathologically, and there may be discrepancies among pathologists. While surgical lung biopsy has traditionally been considered the gold standard for diagnosing interstitial pneumonia, the usefulness of transbronchial lung cryobiopsy (TBLC) has been reported. If TBLC could effectively distinguish between primary and secondary diseases, it would provide a less invasive option for patients. The aim of this study was to identify specific pathologic findings in TBLC specimens that could assist in distinguishing CTD-ILD from IIP. A total of 93 underwent TBLC at Tenri Hospital between 2018 and 2022. We retrospectively reviewed cases of CTD-ILD exhibiting a nonspecific interstitial pneumonia (NSIP) pattern (CTD-NSIP) and cases of NSIP with an unknown etiology (NSIP-UE), as determined through multidisciplinary discussion. Nineteen patients with CTD-NSIP and 26 patients with NSIP-UE were included in the study for clinicopathological analysis. The CTD-NSIP group had a significantly higher proportion of female patients compared to the NSIP-UE group (79% vs. 31%; p = 0.002). The presence of both fresh and old intraluminal fibrosis within the same TBLC specimen was significantly more frequent in CTD-NSIP group than in the NSIP-UE group (p = 0.023). The presence of an NSIP pattern with co-existing fresh and old intraluminal fibrosis in TBLC specimens raised suspicion for CTD-ILD.

Formalin-Fixed Paraffin-Embedded Proteomics of Malignant Mesothelioma and New Candidate Biomarkers Thioredoxin and Superoxide Dismutase 2 for Immunohistochemistry.

The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species. We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens using liquid chromatography-mass spectrometry. We extracted proteins from formalin-fixed paraffin-embedded sections of MM tissues (n = 7) and compared their profiles with those of benign mesothelial tissues (n = 4) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in MM and lung cancer tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to hydrogen peroxide and other reactive oxygen species. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, lung cancer, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets.

Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis.

BACKGROUND: We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. METHODS: We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. RESULTS: Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. CONCLUSIONS: Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.

Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis.

Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.

Combination therapy with EGFR tyrosine kinase inhibitors and TEAD inhibitor increases tumor suppression effects in EGFR mutation-positive lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line therapies for EGFR mutation-positive lung cancer. EGFR-TKIs have favorable therapeutic effects. However, a large proportion of patients with EGFR mutation-positive lung cancer subsequently relapse. Some cancer cells survive the initial treatment with EGFR-TKIs, and this initial survival may be associated with subsequent recurrence. Therefore, we aimed to overcome the initial survival against EGFR-TKIs. We hypothesized that yes-associated protein 1 (YAP1) is involved in the initial survival against EGFR-TKIs, and we confirmed the combined effect of EGFR-TKIs and a YAP1-TEAD pathway inhibitor. The KTOR27 (EGFR kinase domain duplication [KDD]) lung cancer cell lines established from a patient with EGFR mutation-positive lung cancer and commercially available PC-9 and HCC827 (EGFR exon 19 deletions) lung cancer cell lines were used. These cells were used to evaluate the in vitro and in vivo effects of VT104, a TEAD inhibitor. Additionally, YAP1 involvement was investigated in pathological specimens. YAP1 was activated by short-term EGFR-TKI treatment in EGFR mutation-positive lung cancer cells. In addition, inhibiting YAP1 function using small interfering RNA increased the sensitivity to EGFR-TKIs. Combination therapy with VT104 and EGFR-TKIs showed better tumor-suppressive effects than EGFR-TKIs alone, in vitro and in vivo. Moreover, the combined effect of VT104 and EGFR-TKIs was observed regardless of the localization status of YAP1 before EGFR-TKI exposure. These results suggest that combination therapy with the TEAD inhibitor and EGFR-TKIs may improve the prognosis of patients with EGFR mutation-positive lung cancer.

M2-like tumor-associated macrophages promote epithelial-mesenchymal transition through the transforming growth factor ß/Smad/zinc finger e-box binding homeobox pathway with increased metastatic potential and tumor cell proliferation in lung squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.

Novel intrathoracic irrigation using ultrafine ozone bubbles in a rat empyema model.

Dissolved ozone is generally used for sanitization, but it has not been used for thoracic cavity sanitization because of its short half-life (< 20 min) and possible toxicity. We developed a novel solution containing ultrafine ozone bubbles (ozone-UFB) with a fivefold longer half-life than non-UFB ozone. Using an in vitro model, Staphylococcus aureus colonies were counted after exposure to ozone-UFB or non-UFB ozone at the same ozone concentration (0.4 mg/L). The colony count was significantly lower in the ozone-UFB group than in the non-UFB ozone group (p = 0.034). The effect of repeated pleural irrigation using ozone-UFB and saline was compared in a rat empyema model of S. aureus infection. The bacterial count in the pleural effusion was decreased by at least fivefold following intrathoracic lavage with ozone-UFB (3 mg/L). To examine the safety of ozone-UFB for intrathoracic use, ozone-UFB with a higher ozone concentration (10 mg/L) was injected into the thoracic cavities of normal rats. The treatment did not result in any specific pleural damage or elevated serum interleukin-6 concentrations. The findings highlighted the efficacy and safety of ozone-UFB for intrathoracic sanitization, but further studies are needed to determine the optimal therapeutic ozone concentration with appropriate safety margins.

Deep Learning for Predicting Effect of Neoadjuvant Therapies in Non-Small Cell Lung Carcinomas With Histologic Images.

Neoadjuvant therapies are used for locally advanced non-small cell lung carcinomas, whereby pathologists histologically evaluate the effect using resected specimens. Major pathological response (MPR) has recently been used for treatment evaluation and as an economical survival surrogate; however, interobserver variability and poor reproducibility are often noted. The aim of this study was to develop a deep learning (DL) model to predict MPR from hematoxylin and eosin-stained tissue images and to validate its utility for clinical use. We collected data on 125 primary non-small cell lung carcinoma cases that were resected after neoadjuvant therapy. The cases were randomly divided into 55 for training/validation and 70 for testing. A total of 261 hematoxylin and eosin-stained slides were obtained from the maximum tumor beds, and whole slide images were prepared. We used a multiscale patch model that can adaptively weight multiple convolutional neural networks trained with different field-of-view images. We performed 3-fold cross-validation to evaluate the model. During testing, we compared the percentages of viable tumor evaluated by annotator pathologists (reviewed data), those evaluated by nonannotator pathologists (primary data), and those predicted by the DL-based model using 2-class confusion matrices and receiver operating characteristic curves and performed a survival analysis between MPR-achieved and non-MPR cases. In cross-validation, accuracy and mean F1 score were 0.859 and 0.805, respectively. During testing, accuracy and mean F1 score with reviewed data and those with primary data were 0.986, 0.985, 0.943, and 0.943, respectively. The areas under the receiver operating characteristic curve with reviewed and primary data were 0.999 and 0.978, respectively. The disease-free survival of MPR-achieved cases with reviewed and primary data was significantly better than that of the non-MPR cases (P<.001 and P=.001), and that predicted by the DL-based model was almost identical (P=.005). The DL model may support pathologist evaluations and can offer accurate determinations of MPR in patients.

Resolution of Eosinophilic Pneumonia after Coronavirus Disease 2019 without Systemic Corticosteroids.

Pulmonary and extrapulmonary complications after coronavirus disease 2019 (COVID-19) have been major public health concerns during the COVID-19 pandemic. Although post-COVID-19 pulmonary manifestations cover a wide spectrum, eosinophilic pneumonia (EP) has rarely been reported. To date, only four cases of EP potentially triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, all of which required systemic corticosteroid therapy. We herein report the first case of post-COVID-19 EP resolution without systemic corticosteroid therapy. We also review the literature regarding EP associated with SARS-CoV-2 infection and vaccination.

Artificial intelligence for evaluating the risk of gastric cancer: reliable detection and scoring of intestinal metaplasia with deep learning algorithms.

BACKGROUND AND AIMS: Gastric cancer (GC) is associated with chronic gastritis. To evaluate the risk, the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) system was constructed and showed a higher GC risk in stage III or IV patients, determined by the degree of intestinal metaplasia (IM). Although the OLGIM system is useful, evaluating the degree of IM requires substantial experience to produce precise scoring. Whole-slide imaging is becoming routine, but most artificial intelligence (AI) systems in pathology are focused on neoplastic lesions. METHODS: Hematoxylin and eosin-stained slides were scanned. Images were divided into each gastric biopsy tissue sample and labeled with an IM score. IM was scored as follows: 0 (no IM), 1 (mild IM), 2 (moderate IM), and 3 (severe IM). Overall, 5753 images were prepared. A deep convolutional neural network (DCNN) model, ResNet50, was used for classification. RESULTS: ResNet50 classified images with and without IM with a sensitivity of 97.7% and specificity of 94.6%. IM scores 2 and 3, involved as criteria of stage III or IV in the OLGIM system, were classified by ResNet50 in 18%. The respective sensitivity and specificity values of classifying IM between scores 0 and 1 and 2 and 3 were 98.5% and 94.9%, respectively. The IM scores classified by pathologists and the AI system were different in only 438 images (7.6%), and we found that ResNet50 tended to miss small foci of IM but successfully identified minimal IM areas that pathologists missed during the review. CONCLUSIONS: Our findings suggested that this AI system would contribute to evaluating the risk of GC accuracy, reliability, and repeatability with worldwide standardization.

Acinar cystic transformation in the pancreatic tail.

Pancreatic acinar cystic transformation (ACT) is a rare non-neoplastic cystic lesion that is predominantly located at the pancreatic head in females. Preoperative definitive diagnosis of ACT remains challenging despite advances in radiologic imaging methods. A 25-year-old male patient presented with abdominal discomfort and a 50-mm cystic lesion in the pancreatic tail. The patient underwent laparoscopic distal pancreatectomy, because branch duct intraductal papillary mucinous neoplasm cannot be ruled out and the presence of abdominal symptoms. The resected specimen revealed a collection of small and large cysts lined by a single cuboidal epithelium layer with scattered pancreatic tissue exhibiting fibrosis in the septal wall. The cystic lesion was epithelial, trypsin-positive, B cell lymphoma 10-positive, cytokeratin 19-positive, mucin 1-positive, and MUC6-negative with a differentiated lobular central conduit causing to an adeno-cystic cell, thereby supporting the ACT diagnosis. Distinguishing ACT from other pancreatic cystic tumors remains a diagnostic challenge despite improvements in radiologic imaging methods. Surgical resection may be justified when other cystic neoplasms cannot be excluded because of its heterogeneous nature, although the ACT is a non-neoplastic lesion, and cases of malignant transformation have never been reported to date.

Dedifferentiated liposarcoma lung metastases with different FDG-PET/CT findings.

BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is a rare tumor and generally shows poor prognosis with the lung frequent metastatic site. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is used for staging or metastatic evaluation of this disease. We report a case of bilateral lung metastases of DDLPS showing uncommon imaging on FDG-PET/CT with completely different FDG uptake, which made preoperative diagnosis difficult. CASE PRESENTATION: The patient was a male in his 60 s and bilateral lung nodules were noted after proton beam therapy for retroperitoneal DDLPS. FDG-PET/CT showed high FDG uptake in the left S3 15-mm nodule but no uptake in the right S8 10-mm nodule. Thoracoscopic wedge resection for the left nodule was performed, and the pathology revealed metastasis of dedifferentiated liposarcoma. After resection of the left nodule, the right S8 nodule enlarged without FDG uptake. Thoracoscopic right S8 segmentectomy was performed, and metastasis of dedifferentiated liposarcoma was diagnosed. The 2 tumors showed completely different appearances on FDG-PET/CT with similar histopathological findings. CONCLUSIONS: We encountered a case of multiple pulmonary metastases of DDLPS which did not follow the same imaging appearance on FDG-PET/CT. Appropriate timing of surgical resection for pathological diagnosis should be determined carefully.

An exploratory study for tuft cells in the breast and their relevance in triple-negative breast cancer: the possible relationship of SOX9.

BACKGROUND: Breast cancer is highly heterogeneous, suggesting that small but relevant subsets have been under-recognized. Rare and mainly triple-negative breast cancers (TNBCs) were recently found to exhibit tuft cell-like expression profiles, including POU2F3, the tuft cell master regulator. In addition, immunohistochemistry (IHC) has identified POU2F3-positive cells in the normal human breast, suggesting the presence of tuft cells in this organ. METHODS: Here, we (i) reviewed previously identified POU2F3-positive invasive breast cancers (n = 4) for POU2F3 expression in intraductal cancer components, (ii) investigated a new cohort of invasive breast cancers (n = 1853) by POU2F3-IHC, (iii) explored POU2F3-expressing cells in non-neoplastic breast tissues obtained from women with or without BRCA1 mutations (n = 15), and (iv) reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from normal breast cells. RESULTS: Two TNBCs of the four previously reported invasive POU2F3-positive breast cancers contained POU2F3-positive ductal carcinoma in situ (DCIS). In the new cohort of invasive breast cancers, IHC revealed four POU2F3-positive cases, two of which were triple-negative, one luminal-type, and one triple-positive. In addition, another new POU2F3-positive tumor with a triple-negative phenotype was found in daily practice. All non-neoplastic breast tissues contained POU2F3-positive cells, irrespective of BRCA1 status. The scRNA-seq reanalysis confirmed POU2F3-expressing epithelial cells (3.3% of all epithelial cells) and the 17% that co-expressed the other two tuft cell-related markers (SOX9/AVIL or SOX9/GFI1B), which suggested they were bona fide tuft cells. Of note, SOX9 is also known as the "master regulator" of TNBCs. CONCLUSIONS: POU2F3 expression defines small subsets in various breast cancer subtypes, which can be accompanied by DCIS. The mechanistic relationship between POU2F3 and SOX9 in the breast warrants further analysis to enhance our understanding of normal breast physiology and to clarify the significance of the tuft cell-like phenotype for TNBCs.