Introduction:Calcifying fibrous tumor (CFT) is a rare benign lesion that occasionally arises in the gastrointestinal tract. Gastric CFT is extremely uncommon and often mimics gastrointestinal stromal tumor (GIST), making preoperative diagnosis challenging. Presentation of Case:We report a 46-year-old man with a gastric submucosal tumor detected during a medical checkup. During 3 years of follow-up, the tumor increased in size from 20 mm to 30 mm. Endoscopic ultrasonography revealed a hyperechoic lesion located medial to the muscularis propria, and abdominal computed tomography showed a calcified submucosal mass with contrast enhancement. Fine-needle aspiration biopsy failed to provide a definitive diagnosis, and malignant potential, including GIST, could not be excluded. Therefore, laparoscopic partial gastrectomy was performed. Histopathological examination revealed dense collagen, psammomatous calcification, spindle cells, and lymphoplasmacytic infiltrates, consistent with CFT. The final pathological tumor size was 15 mm. Immunohistochemistry showed positivity for vimentin and negativity for c-kit, DOG1, SMA, and CD34. The postoperative course was uneventful, and there has been no recurrence observed during 2.5 years of follow-up. Discussion:Gastric CFT is rare, with only 22 cases reported worldwide since 2014. Most cases of gastric CFT were managed by endoscopic resection, while laparoscopic surgery has rarely been reported. Radiologic and endoscopic findings may help differentiate CFT from GIST, but definitive diagnosis requires histopathology. Conclusion:Laparoscopic resection is a safe and effective treatment option when gastric CFT cannot be preoperatively distinguished from GIST. Awareness of this rare entity may prevent overtreatment and guide optimal surgical decision-making.

Aim: The Yes-associated protein (YAP) family of transcriptional coactivators has emerged as a potent promoter of cell proliferation in many types of stem/progenitor cells and cancers. Skin is a squamous epithelium that is continuously regenerated by stem/progenitor cells in the basal layer and is capable of wound healing, and YAP also plays an important role in maintaining skin homeostasis and cellular proliferation. Therefore, we focused on YAP and investigated the importance of YAP regulation in allergic contact dermatitis from the perspective of wound healing and regeneration. Methods: We investigated the expression and pathological characteristics of Transmembrane protein 207 (TMEM207), focusing on YAP-mediated regulation in atopic models, as abnormal TMEM207 expression may cause various functional abnormalities or regulate the function of YAP. Results: TMEM207 was detected not only in the stomach and large intestine but also in the bulge region of the sebaceous glands and hair roots in mice expressing TMEM207. In addition, ATP binding cassette subfamily B member 1 (ABCB1) expression decreased in the sebaceous glands, and MIB E3 Ubiquitin Protein Ligase 1 (MIB-1) expression diminished in the epidermis. Furthermore, although we were unable to confirm the binding of TMEM207 to NEDD4, we confirmed the binding of TMEM207 to the Yes1-associated transcription factor (YAP) by immunoprecipitation, and a decrease in the nuclear localization of YAP was observed by immunohistochemical staining. Conclusion: Our findings indicate that abnormal expression of TMEM207 is involved in the decline of skin regeneration capacity through YAP, leading to the aggravation of Allergic contact dermatitis.

ABSTRACT Epithelial‐mesenchymal transition (EMT) plays a crucial role in carcinogenesis, including mesothelioma. D‐Meso‐Sonobe is a deciduoid‐type mesothelioma cell line with morphological features similar to those of epithelioid cells. Here, we report that D‐Meso‐Sonobe cells exhibit spindle cell mesenchymal features under continuous confluent culture conditions. The spindle cell mesenchymal D‐Meso‐Sonobe expresses zinc finger E‐box‐binding homeobox 1 (Zeb1), which is a master regulator of EMT in the nucleus. Xenoplanted D‐Meso‐Sonobe cells expressed nuclear Zeb1 and yes‐associated protein at the cancer invasion front and focally expressed integrin subunit alpha V and actin alpha 2, which are molecular phenotypes acquired by EMT in mesothelioma. Subsequent RNA sequencing revealed that lysyl oxidase like 1 (LOXL1) was more highly expressed in cultured spindle mesenchymal D‐Meso‐Sonobe cells than in epithelioid cells. LOXL1 immunoreactivity was observed at the invasive front of xenoplanted D‐Meso‐Sonobe cells. The epithelial‐mesenchymal plasticity of D‐Meso‐Sonobe cells may be applicable for the development of candidate molecular agents targeting EMT in mesothelioma.

BACKGROUND/AIM:5-Fluorouracil (5-FU) plays a major role in the treatment of gastric cancer (GC), and overcoming resistance to this drug remains a critical challenge. This study aimed to identify genes associated with resistance to 5-FU in GC. MATERIALS AND METHODS:Gene expression levels were analyzed in 5-FU-resistant MKN-45/F2R cells compared to the parental MKN-45 strain before and after 5-FU treatment (24 and 72 h). Among the consistently over-expressed genes, those with high expression were further investigated for their roles in resistance and expression patterns in GC tissues. RESULTS:NPC1L1, a protein hypothesized to influence 5-FU resistance, did not exhibit resistance-related effects in tested cells. Its expression was subsequently studied in gastric cells. NPC1L1 was detected in the stomach, jejunum, duodenum, and liver, with increased mRNA levels in several GC samples. Immunostaining of samples from 95 GC patients revealed that 39 (41.0%) exhibited ≥10% higher NPC1L1 expression. Patients with NPC1L1-positive tumors had poorer prognoses than those with negative tumors. CONCLUSION:NPC1L1 is expressed in both normal gastric tissues and GC tissues, with elevated levels at invasive sites associated with poor prognosis.

The high mortality rate of colorectal cancer (CRC) highlights the need for new treatment strategies; however, the venous invasion mechanisms in tumor endothelial cells within CRC remain unexplored. Therefore, we investigated the clinicopathological features of SRY-box transcription factor 17 (SOX17) in CRC. Immunohistochemical staining was performed on 55 CRC tissue specimens using a SOX17-specific antibody, followed by Kaplan-Meier and Cox proportional hazards regression analyses. SOX17 immunoreactivity was detected in the endothelial cells of tumor-penetrating vessels in 35/55 CRC samples. Kaplan-Meier analysis indicated that patients with SOX17 immunoreactivity had favorable overall and progression-free survival (log-rank test, P = 0.03 and 0.02, respectively). Notably, tumor endothelial SOX17 immunoreactivity was associated with a favorable prognosis in patients with stage III or IV disease (OS, P = 0.0089; PFS, P = 0.0065). Cox proportional hazard regression analysis indicated that SOX17 immunoreactivity is an independent factor for predicting favorable overall and progression-free survival in CRC (P = 0.02 and 0.01, respectively). The present findings suggest that SOX17 expression in tumor endothelial cells is a potential indicator of favorable prognosis in patients with CRC.

A 73-year-old man presented with left hypochondral pain. Dynamic computed tomography (CT) revealed abnormal vessels surrounding the pancreas, leading to a suspected diagnosis of pancreatic arteriovenous malformation (PAVM). At the time of the initial examination, dynamic CT revealed mild acute pancreatitis, and PAVM was diagnosed based on the findings of dynamic CT. Although repeated abdominal pain was observed after the improvement of pancreatitis, distal pancreatectomy was performed. At >1 year after surgery, no recurrence of PAVM was observed. Surgical resection should be considered in patients with symptomatic PAVM.

BACKGROUND:Advances in chemotherapy have increased clinical experience with conversion surgery for inoperable advanced gastric cancer. This report describes three patients with unresectable gastric cancer accompanied by multiple liver metastases. In all three patients, nivolumab resolved the liver metastases and subsequent conversion surgery achieved a pathological complete response.CASE PRESENTATION:In Case 1, a 68-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX plus nivolumab. The patient completed 13 cycles; however, only nivolumab was continued for 3 cycles because of adverse events. Distal gastrectomy and partial hepatic resection were performed because of a significant reduction in the size of the liver metastases as observed on magnetic resonance imaging (MRI). In Case 2, a 72-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX. Because of the subsequent emergence of new liver metastases, the patient transitioned to ramucirumab plus paclitaxel as second-line therapy. Third-line therapy with nivolumab was initiated because of side effects. MRI revealed necrosis within the liver metastasis, and the patient underwent proximal gastrectomy and partial hepatectomy. In Case 3, a 51-year-old woman with clinical Stage IVB gastric cancer accompanied by multiple metastases of the liver and para-aortic lymph nodes began first-line therapy with SOX plus nivolumab. The patient completed 10 cycles; however, only nivolumab was continued for 5 cycles because of adverse events. Computed tomography showed a significant decrease in the size of the para-aortic lymph nodes, while MRI indicated the presence of a singular liver metastasis. Distal gastrectomy and partial hepatic resection were subsequently performed. In all three cases, MRI revealed the presence of liver metastases; however, pathological examination showed no viable tumor cells.CONCLUSIONS:We herein present three cases in which chemotherapy, including nivolumab, elicited a response in patients with multiple unresectable liver metastases, ultimately culminating in R0 resection through conversion surgery. Although MRI showed liver metastases, pathological analysis revealed no cancer, underscoring the beneficial impact of chemotherapy.

IZUMO2 belongs to the testis-expressed IZUMO family of proteins, which are characterized by an N-terminal IZUMO domain. Based on integrated analysis of expression profiles and matched DNA methylation data from a public database, IZUMO2 represents a prognosis-related methylation-driven gene in colorectal cancer. However, it remains unclear whether IZUMO2 protein expression is suppressed or overexpressed in colorectal cancer cells. In this study, we aimed to elucidate the expression of the IZUMO2 protein in colorectal cancer, with a focus on the clinicopathological features. Sixty-four colorectal cancer tissue specimens were immunohistochemically stained using specific antibodies against IZUMO2. IZUMO2 immunoreactivity was detected at the invasion front in 30 of the 64 colorectal cancer samples. Kaplan-Meier analysis demonstrated that patients with IZUMO2 immunoreactivity had a relatively shorter overall and progression-free survival (log-rank test, P = 0.046 and 0.019, respectively). IZUMO2 immunoreactivity served as an independent factor predictive of poor progressionfree survival in colorectal cancer (P = 0.025) as determined via the Cox proportional hazard regression model. Moreover, IZUMO2 immunoreactivity represented an independent factor for poor overall survival (P = 0.035) and progression-free survival (P = 0.013) in patients with colon cancer. The present findings suggest that IZUMO2 is expressed in many colorectal cancers, especially at the cancer invasion front, and may represent an indicator of poor prognosis in colorectal cancer.

The combination of the cancer mitochondrial metabolic inhibitor CPI-613 and hydroxychloroquine has tumor-suppressive effects on clear cell sarcoma, which shares pathobiological properties with melanoma. Therefore, we intended to examine the effects of a combination of CPI-613 and hydroxychloroquine on the growth of melanoma cells in the present study. However, cell death was not induced in melanoma cells. Therefore, a monoclonal antibody, ICT, that induced apoptosis in melanoma cells in combination with CPI-613 and hydroxychloroquine was developed. Immunoprecipitation, mass spectrometry, and small interfering RNA (siRNA)-mediated gene silencing demonstrated that ICT targeted Endoplasmic Reticulum Resident Protein 57/ Protein Disulfide Isomerase Family A Member 3 (ERp57/PDIA3), which was first identified as being upregulated by metabolic depletion stress and is localized on the cell surface during immunogenic cell death. The combination of CPI-613 and hydroxychloroquine enhanced the localization of ERp57/PDIA3 to the surface of melanoma cells. siRNA-mediated downregulation of ERp57/PDIA3 did not significantly induce ICT-mediated apoptosis in melanoma cells in the presence of CPI-613 and hydroxychloroquine. Therefore, the ICT antibody acts as a tumor suppressor in melanoma cells by targeting the cell membrane ERp57/PDIA3, expression of which was enhanced by the combination of CPI-613 and hydroxychloroquine.

Recent studies have revealed that the Sry-related HMG box gene 17 (SOX17) plays an important role in ovarian carcinogenesis. Unlike other types of ovarian cancer, ovarian clear cell carcinoma (OCCC) has a distinct pathobiological phenotype, often harboring an AT-rich interaction domain 1 A (ARID1A) mutation. In the present study, to determine the SOX17 in OCCC cells, we immunohistochemically examined SOX17 expression in 47 whole-tissue specimens of OCCC. Although not statistically significant, SOX17-high immunoreactivity tended to be related to unfavorable patient outcomes. We also aimed to determine the relationship of SOX17 with ARID1A. Double immunofluorescence staining demonstrated that SOX17 immunoreactivity was not associated with ARID1A immunoreactivity. Immunoblotting revealed that SOX17 was abundantly expressed in cultured OVISE and RMG-V OCCC cells, but not in OVTOKO OCCC cells. Polyubiquitinated bands of SOX17 were observed in MG132 treated OVTOKO, but not in OVISE or RMG-V OCCC cells. Notably, si-RNA-mediated knockdown of a deubiquitinase enzyme, ubiquitin C-terminal hydrolase L1, increased polyubiquitination followed by proteasome degradation of SOX17 in OVISE. These findings indicate that SOX17 is not uniformly and heterogeneously expressed in OCCCs, independent of ARID1A deficiency. Impaired ubiquitin-mediated proteasome degradation may stabilize SOX17 in some OCCC cells.

Accurate diagnosis of the localization of prostate cancer (PCa) on magnetic resonance imaging (MRI) remains a challenge. We aimed to assess discrepancy between the location of PCa pathologically diagnosed using surgical specimens and lesions indicated as possible PCa by the Prostate Imaging Reporting and Data System on MRI. The primary endpoint was the concordance rate between the site of probable clinically significant PCa (csPCa) identified using biparametric MRI (bpMRI) and location of PCa in the surgical specimen obtained using robot-assisted total prostatectomy. Among 85 lesions identified in 30 patients; 42 (49.4%) were identified as possible PCa on MRI. The 85 PCa lesions were divided into positive and negative groups based on the bpMRI results. None of the patients had missed csPCa. Although the diagnostic accuracy of bpMRI was relatively high for PCas located in the middle of the prostate (p = 0.029), it was relatively low for PCa located at the base of the prostate, all of which were csPCas. Although current modalities can accurately diagnose PCa, the possibility that PCa is present with multiple lesions in the prostate should be considered, even if MRI does not detect PCa.

Chemotherapy-induced ovarian toxicity in patients with cancer significantly affects future fertility depending on the age of initiation of treatment. However, the mechanisms underlying the age-related depletion of the ovarian reserve are not well understood. We investigated the effects of chemotherapy on pre- and postpubertal ovarian reserves in a mouse model. Juvenile (3-week-old) and adult (8-week-old) mice were injected with vehicle or cyclophosphamide (CPA;100 mg/kg). We assessed the short-term effects at 24 h and 72 h after injection and the long-term effects at 10 and 12 weeks of age by counting the follicles. The number of primordial follicles in the juvenile group was significantly reduced by CPA treatment compared with that in the adult group. To elucidate the mechanisms of this depletion, we performed immunostaining for γH2AX, cleaved PARP1, and FOXO3 at 24 h post-treatment. CPA-treated juvenile mice had a significantly higher proportion of γH2AX-positive primordial follicles, indicating double-strand DNA breaks. By contrast, 4-hydroperoxy CPA, an activated analog of CPA, induced γH2AX-positive primordial follicles in both groups in vitro, suggesting age-dependent differences in humoral ovarian microenvironment. Moreover, the level of cleaved PARP1 was specifically elevated in CPA-treated juvenile mice. However, primordial follicle activation was unaffected in the CPA-treated groups, as assessed by FOXO3 translocation. In conclusion, our findings suggest that ovaries in juveniles are more susceptible to DNA damage and subsequent apoptosis, leading to a higher rate of primordial follicle depletion. Therefore, it is crucial to recognize that cancer treatment, especially in children, can exert a substantial influence on future fertility.

AbstractIntroductionSex‐determining region Y‐related high‐mobility group box 17 protein (SOX17), a proangiogenic transcription factor, is specifically expressed in tumor endothelial cells (TECs) of implanted Lewis lung carcinoma. However, the expression profile of SOX17 is largely unknown in human lung cancer. We aimed to elucidate SOX17 expression in cancer cells and the tumor microenvironment of lung adenocarcinoma.MethodsIn the present study, we examined SOX17 expression in whole‐tissue specimens of 83 lung adenocarcinomas by immunohistochemistry.ResultsSOX17 immunoreactivity was minimal in lung adenocarcinoma cells, except in five non‐mucinous adenocarcinomas in situ. SOX17 was also expressed in cultured A549 lung adenocarcinoma cells, which is widely used as a model of malignant alveolar type II epithelial cells. Notably, SOX17 immunoreactivity was found in endothelial cells of tumor‐penetrating vessels in 19 of 83 lung adenocarcinoma tissue specimens, with statistical significance to stromal infiltration of CD8+ T cells (p < 0.01) but was not associated with the number of tertiary lymph nodes. Although not statistically significant, SOX17 immunoreactivity was related to favorable patient outcomes.ConclusionOur findings indicate that SOX17 might play a pleiotropic role in lung adenocarcinoma in cancer cells and stromal niches. SOX17‐mediated CD8+ T‐cell‐rich tumor microenvironment might attract interest in improving the effect of cancer immunotherapy.

Background: Triple-negative breast cancer (TNBC) is characterized by the loss of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The aggressive clinicopathological features and resistance to currently available therapeutics of the disease warrant an urgent need for the development of novel alternate therapeutic options. We have previously reported adiponectin-expressing regulatory T cells (A-Tregs), which can induce apoptosis in TNBC through the cell-in-cell phenomenon. In this study, we aimed to elucidate the molecule that allows TNBC cells to engulf A-Tregs.Methods: A monoclonal antibody, which repressed the engulfment of A-Tregs by TNBC cells, was developed. Immunoprecipitation followed by mass spectrometry and small interfering RNAs-mediated gene silencing was performed to characterize the antigen.Results: We successfully generated a monoclonal antibody, designated G1D7, which abrogated the engulfment of A-Tregs by TNBC and subsequent A-Treg-mediated apoptosis. G1D7 detected the immunoglobulin-like type I membrane protein IZUMO2, a molecule related to IZUMO1 that is essential for cell-cell membrane binding and fusion of sperm to oocyte.Conclusion: The findings highlight the importance of IZUMO2 on TNBC cells in facilitating the cell-in-cell phenomenon by A-Tregs.