Retroperitoneal paraganglioma with loss of heterozygosity of the von Hippel-Lindau gene: a case report and review of the literature.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease related to germline mutations in VHL. In VHL disease, pheochromocytoma develops in 10%-20% of patients because of germline mutations and loss of heterozygosity of VHL. However, the rate of paraganglioma associated with VHL is low compared with that of pheochromocytoma, and the reason is unknown. In this study, we performed germline and somatic mutation analyses of retroperitoneal paraganglioma that developed in a patient with clinically diagnosed VHL disease and investigated the tumorigenic mechanism of paraganglioma. The patient was a 25-year-old woman who was considered to have VHL disease on the basis of her family history. She was referred to our clinic to investigate a tumor at the bifurcation of the common iliac artery. The tumor was diagnosed as retroperitoneal paraganglioma by clinical evaluations. A left renal cell carcinoma was also suspected. Polymerase chain reaction direct sequencing analysis and polymorphic microsatellite analysis within the VHL locus suggested that loss of heterozygosity of VHL was associated with paraganglioma and renal cell carcinoma. Multiplex ligation-dependent probe amplification analysis showed a loss of the copy number of VHL exons in paraganglioma. These results suggest that VHL disease contributes to the development of paraganglioma. A literature review showed no reported common missense variants involved in the progression of paraganglioma. The loss of heterozygosity of VHL can be a tumorigenic mechanism of retroperitoneal paraganglioma in VHL disease. However, the low rate of paraganglioma compared with pheochromocytoma is not explained by their genetic background alone.

Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma.

AIMS: Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an unfavourable indicator in squamous cell carcinoma of the lung, but little is known about its clinical significance in early-stage lung adenocarcinoma. We evaluated the prognostic impact of podoplanin expression in patients with pathological stage (p-stage) IA lung adenocarcinoma as categorised by the 8th edition of the tumour-node-metastasis classification for lung cancer. METHODS AND RESULTS: Immunohistochemical analyses using anti-podoplanin antibody were performed on resected specimens from 158 patients with p-stage IA lung adenocarcinoma. When more than 10% of cancer cells or CAFs showed immunoreactivity with podoplanin, the specimens were classified as podoplanin-positive. Podoplanin-positive status in cancer cells (n = 8) was not correlated with clinicopathological factors or with patient prognosis. Podoplanin-positive status in CAFs (n = 41) was correlated significantly with poorer tumour differentiation (P < 0.001), the presence of lymphatic invasion (P < 0.001) and high-grade (solid and/or micropapillary) components constituting ≥1% of the entire tumour (P < 0.001). The log-rank test showed that podoplanin-positive status in CAFs was associated significantly with shorter disease-free survival (DFS) (P < 0.001) and disease-specific survival (P = 0.015). In Cox's multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DFS [hazard ratio (HR) = 4.411, P = 0.004], followed by the presence of high-grade components (HR = 3.581, P = 0.013). CONCLUSIONS: Podoplanin expression in CAFs could be an independent predictor of increased risk of recurrence in patients with p-stage IA lung adenocarcinoma.

Cytoplasmic expression of maspin predicts unfavourable prognosis in patients with squamous cell carcinoma of the lung.

AIMS: Maspin is known to be a tumour suppressor protein, and its prognostic significance in patients with several types of cancer, including lung squamous cell carcinoma (SCC), has been reported. However, its prognostic impact on lung SCC has been controversial. We explored the prognostic value of maspin expression with particular reference to its subcellular localization in patients with lung SCC. METHODS AND RESULTS: Paraffin-embedded tissue samples from 101 curatively resected patients with lung SCC were analysed immunohistochemically using an antibody for maspin. Maspin positivity was defined as strong expression in only the cytoplasm and observed in 25 patients (24.6%). It correlated significantly with the presence of lymph node metastasis (P = 0.006) and higher pathological stage (P = 0.003). The patients were followed-up for 2-119 months (median: 50 months), and the maspin-positive group had shorter disease-free survival (DFS) and disease-specific survival (DSS) by log-rank test (P = 0.002, P = 0.016, respectively). Multivariate analysis revealed that the status of maspin was the only independent prognostic factor for DFS and DSS (P = 0.017, P = 0.047, respectively). CONCLUSIONS: Cytoplasmic expression of maspin could be an independent unfavourable prognostic indicator in patients with lung SCC.

Cytoplasmic maspin expression is a predictor of poor prognosis in patients with lung adenocarcinoma measuring <3 cm.

AIMS: Maspin is known to be a tumour suppressor protein, and few studies focused upon its prognostic significance in patients with small-size lung adenocarcinoma have been reported; however, its clinical significance remains controversial. We explored the prognostic value of maspin with particular reference to its subcellular localization in patients with resected lung adenocarcinoma measuring <3 cm. METHODS AND RESULTS: Immunohistochemical analyses were performed on resected 110 specimens of lung adenocarcinoma measuring <3 cm. Maspin positivity was defined as strong expression in only the cytoplasm and was observed in 27 patients (24.5%). It correlated significantly with the presence of lymph node metastasis (P = 0.009) and micropapillary component (P < 0.001). The patients were followed-up for 6-88 months (median: 71 months), and the maspin-positive group had shorter disease-free survival (DFS) and overall survival (OS) by log-rank test (P < 0.001, P < 0.001, respectively). Using Cox's multivariate analysis, the status of maspin was an independent prognostic factor for DFS and OS (P = 0.004, P = 0.022, respectively), as well as lymph node metastasis. CONCLUSIONS: Cytoplasmic maspin expression could be an independent poor prognostic indicator of patients with lung adenocarcinoma measuring <3 cm.

MR imaging findings of mass-forming endosalpingiosis in both ovaries: a case report.

A 50-year-old postmenopausal woman, who underwent ultrasonography at a periodic medical checkup, was found to have bilateral ovarian masses. Pelvic magnetic resonance imaging (MRI) showed bilateral multilocular cystic ovarian masses. The cyst walls and septal structure demonstrated contrast enhancement. She underwent bilateral salpingo-oophorectomy. Microscopic examination revealed that the cysts were lined with cuboidal or columnar epithelial cells, and some of the cells were ciliated. The final histopathological diagnosis was endosalpingiosis. Endosalpingiosis is defined as the presence of ectopic ciliated epithelium, resembling the normal endosalpinx, without endometrial stroma. It rarely presents as a tumor-like mass on MRI.

Precancerous Pyloric Gland Metaplasia in the Biliary Epithelium Associated with Congenital Biliary Dilatation in a Three-Month-Old Infant.

Pyloric gland metaplasia in the biliary epithelium is a precancerous lesion and has been confirmed in patients with congenital biliary dilatation presenting with overt biliary tract cancer. A patient was found to have an intra-abdominal cyst on fetal ultrasonography and was born at 37 weeks of gestation with a body weight of 2,636 g. Abdominal distension and repeated vomiting appeared 2 days after birth. Congenital biliary dilatation was diagnosed by imaging, wherein the common bile duct was enlarged to 9-10 cm in size, and the surrounding organs were extensively compressed; however, there was no sign of pancreatitis or cholangitis. Biliary drainage was performed through the gallbladder at 6 days of age, but it was insufficient because of the narrow and twisted cystic duct and changed to common bile duct at 18 days to relieve the compression. Because the body weight gain was poor due to loss of large amount of bile, the dilated bile duct and gallbladder were resected and hepatic duct Roux-Y jejunostomy was performed at 115 days of age with 4,500 g of body weight. Intraoperative imaging showed a pancreaticobiliary maljunction, and the pancreatic enzyme activities of the bile in the biliary system were remarkably elevated. Histopathological examination revealed pyloric gland metaplasia in the gallbladder epithelium and cystic duct. The patient is now over 2 years old and has been doing well without any complications. Based on our experience, precancerous pyloric gland metaplasia of the biliary epithelium may already occur even in a 3-month-old infant presenting with congenital biliary dilatation.

Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma.

Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of SLC44A5, a choline transporter-like protein-coding gene, was significantly upregulated, and that of TMEM100, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein-protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.

Clinical Significance of Serglycin Expression in Human Breast Cancer Patients.

BACKGROUND/AIM: Serglycin plays a crucial role in the aggressiveness of several types of malignancies, including breast cancer. In this study, we aimed to investigate the prognostic impact of serglycin expression in breast cancer patients, which has not been previously reported. PATIENTS AND METHODS: Immunohistochemical analyses were performed on 348 resected specimens of invasive carcinomas, using antibodies against serglycin. RESULTS: Low serglycin expression was observed in 23% of specimens (80/348) and significantly correlated with high histological grade (p=0.001) and negative ER (p=0.013). The log-rank test showed that low serglycin expression correlated with shorter distant metastasis-free survival (DMFS) (p=0.016) and disease-specific survival (DSS) (p=0.037) in node-positive breast cancer patients. Cox's multivariate analysis revealed that low serglycin expression was an independent factor for shorter DMFS (p=0.017) and DSS (p=0.020) in node-positive breast cancer patients. CONCLUSION: Low serglycin expression is an independent predictor of unfavorable prognosis in node-positive breast cancer patients.

Is Adjuvant Chemotherapy Necessary in Patients with Early Endometrial Cancer?

BACKGROUND: We investigated whether there was a difference in prognosis between patients with stage IA endometrial cancer with and without lymphovascular space invasion. METHODS: We enrolled patients with stage IA (pT1aN0M0) endometrial cancer admitted to our hospital from 2009 to 2018. All patients underwent hysterectomy, bilateral salpingo-oophorectomy, and systematic pelvic lymphadenectomy. We immunopathologically evaluated the presence or absence of lymphovascular space invasion in the tumor tissue using hematoxylin and eosin, Elastica-van Gieson, and podoplanin staining. We analyzed disease-free and overall survival and calculated patients' survival distribution using the Kaplan-Meier method and log-rank test. The multivariate analysis was performed to determine the prognostic factors. RESULTS: A total of 116 patients were included. The median age of the patients was 57 (range, 30-78) years, and the histological subtype revealed 98 and 18 cases of types 1 and 2, respectively. The median follow-up period was 71.9 (range, 10.8-149) months, and the 3-year disease-free and 3-year overall survival rates were 94% and 99%, respectively. The disease-free and overall survival rates were significantly shorter in type 2 patients than in type 1 patients (type 2 vs. type 1; 77% vs. 97%, P < 0.01, 94% vs. 100%, P = 0.014, respectively). The univariate and multivariate analyses showed that there were no significant differences in disease-free survival between the lymphovascular space invasion-positive and -negative groups among type 1 cases. CONCLUSION: There was no difference in prognosis between patients with stage IA and type 1 endometrial cancer with and without lymphovascular space invasion.

Pembrolizumab-induced aseptic meningitis in a patient with non-small cell lung cancer: A case report and literature review of aseptic meningitis as an immune-related adverse event.

Aseptic meningitis is a rare immune-related adverse event (irAE), which occurs during treatment with immune checkpoint inhibitors (ICIs). This condition has non-specific symptoms and exhibits no clear signs on magnetic resonance imaging (MRI). There are only a few reports of aseptic meningitis caused by pembrolizumab treatment for non-small cell lung cancer (NSCLC). The present study includes a report of such a case and a review of the related literature. A 67-year-old Japanese man received first-line pembrolizumab treatment for NSCLC and subsequently developed severe nausea and vomiting. No significant findings were observed following a computed tomography (CT) scan, MRI of the brain and upper gastrointestinal tract, or upper gastrointestinal endoscopy. Cerebrospinal fluid analysis revealed lymphocyte infiltration and elevation of the IgG index, without indications of metastasis or infection, which suggested the presence of aseptic meningitis. The symptoms immediately improved following prednisolone treatment, and aseptic meningitis was diagnosed as an irAE related to pembrolizumab treatment. Given that aseptic meningitis can cause non-specific symptoms, including headache and nausea, the possibility of an irAE should be considered in patients with non-specific symptoms who are receiving ICIs, and a cerebrospinal fluid examination should be performed.

Magnetic resonance imaging findings of endosalpingiosis: a case report.

Endosalpingiosis is characterized by the presence of glands lined by benign tubal-type epithelium outside the fallopian tube. It is usually an incidental finding and rarely occurs as a tumor-like mass lesion. Here, we describe the magnetic resonance imaging findings of endosalpingiosis that presented as a paraovarian multicystic lesion. It exhibited iso to low intensity on T1-weighted images and inhomogeneous high intensity on T2-weighted images. The septa presented relatively iso to slight high intensity on T2-weighted images and strong contrast enhancement on dynamic contrast-enhanced imaging. Endosalpingiosis should be considered as a differential diagnosis in cases of paraovarian multicystic lesions along the uterine serosa.

CT and MR imaging findings of bilateral ovarian metastasis from renal cell carcinoma: a case report.

Secondary ovarian involvement by renal cell carcinoma rarely occurs. Here, we describe the computed tomography and magnetic resonance imaging findings of bilateral ovarian metastases from renal cell carcinoma that demonstrated heterogeneous strong contrast enhancing tumors with flow voids around and within the tumors. In addition, the apparent diffusion coefficients of the malignant tumors were high. These findings were similar to those of renal cell carcinomas at primary and other metastatic sites.

Podoplanin expression in cancer-associated fibroblasts predicts unfavorable prognosis in node-negative breast cancer patients with hormone receptor-positive/HER2 - negative subtype.

BACKGROUND: Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an indicator for poor prognosis in patients with invasive breast carcinomas, but little is known about its clinical significance in node-negative breast cancer patients with hormone receptor (HR) + /HER2 - subtype, who are expected to have a favorable prognosis. METHODS: Immunohistochemical analyses were performed on 169 resected specimens of node-negative invasive carcinoma of no special type with HR + /HER2 - subtype using antibodies for podoplanin. When more than 10% of CAFs showed immunoreactivity with podoplanin as strong as that of internal positive controls, the specimens were judged as podoplanin-positive. RESULTS: Podoplanin-positive status in CAFs was observed in 16.0% (27 of 169 cases) and it associated with high Ki67 labeling index (LI) (> 30%) (p = 0.03), higher stromal tumor-infiltrating lymphocytes (p < 0.001) and progesterone receptor-negative status (p = 0.045). Log-rank test showed that podoplanin-positive status in CAFs correlated with shorter disease-free survival (DFS) (p = 0.007) and disease-specific survival (DSS) (p < 0.001). Univariate analysis showed a significant correlation between shorter DFS and podoplanin-positive status in CAFs (hazard ratio [HR] = 3.380; p = 0.012), the presence of lymphatic invasion (HR = 5.621; p < 0.001), high Ki67 LI (HR = 5.217; p < 0.001), and histological grade III (HR = 3.748; p = 0.008). According to Cox multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DSS (HR = 37.759; p = 0.003) followed by high Ki67LI (HR = 27.664; p = 0.007). CONCLUSION: Podoplanin expression in CAFs could be an independent predictor for poor prognosis in node-negative breast cancer patients with HR + /HER2 - subtype.

Is Preoperative Magnetic Resonance Imaging in a Daily Clinical Setting Useful to Evaluate Tumor Invasion Beyond the Pseudocapsule in Renal Cell Carcinoma?

BACKGROUND: We wanted to clarify whether preoperative magnetic resonance imaging (MRI) in the clinical setting can evaluate the pathologic pseudocapsule (PC) morphology with high accuracy in renal cell carcinoma (RCC). METHODS: We retrospectively analyzed 34 consecutive patients who underwent MRI (1.5 or 3.0T, 5 mm slices) prior to partial nephrectomy (PN) for RCC at our institution between January 2010 and December 2019. First, the correlation between PC morphology (complete or incomplete) and tumor infiltration to the renal parenchyma was examined as pathologic validation. Second, the concordance rate of PC morphology between pathologic tissue and preoperative MRI was evaluated as radiologic validation. Third, risk factor for renal parenchymal invasion in RCC was analyzed. RESULTS: In the pathologic validation, parenchymal invasion rates were 11% and 28% in the "complete PC" and "incomplete PC" groups, respectively. In the radiologic validation, pathological PC morphology could be diagnosed on preoperative MRI in 17 patients (50.0%). "None PC" on MRI had the lowest positive predictive value (PPV) (0%), "partial PC" on MRI had a good PPV (76.5%), "complete PC" on MRI had a relatively low PPV (33.3%). Unfortunately, these data were insufficient for diagnostic accuracy. As risk factor for renal parenchymal invasion in RCC, only pathologic subtype (non-clear cell) was found to have significant differences in the multivariate analysis. CONCLUSION: The results of this study suggest that renal tumors with pathologically incomplete PC have a high possibility of renal parenchymal invasion. However, it is currently difficult to accurately evaluate pathologic PC morphology by preoperative MRI in the clinical setting.

AMIGO2 as a novel indicator of liver metastasis in patients with colorectal cancer.

Our previous study showed that adhesion molecule with immunoglobulin like domain 2 (AMIGO2) is a pivotal driver gene of liver metastasis via regulating tumor cell adhesion to liver endothelial cells in mouse models. The aim of the present study was to clarify the role of AMIGO2 in liver metastasis in patients the colorectal cancer (CRC). Two human CRC cell lines, Caco-2 (AMIGO2-low) and HCT116 (AMIGO2-high), were used in this study. AMIGO2-overexpressing Caco-2 and AMIGO2-knockdown HCT116 cells were generated by transfection with an AMIGO2 expression vector or AMIGO2 small interfering RNA, respectively. Cell proliferation, invasion and adhesion to human liver endothelial cells were examined in in vitro studies. Immunohistochemical analysis was also performed to evaluate the association between AMIGO2 expression and liver metastasis in patients with CRC. In vitro studies revealed that cell proliferation, invasion and adhesion to liver endothelial cells were accelerated by upregulation of AMIGO2 expression, but suppressed by downregulation of AMIGO2 expression in human CRC cells. Immunohistochemical analysis using clinical CRC specimens revealed that AMIGO2 expression was associated with the frequency of liver metastasis (P<0.01), but not that of pulmonary metastasis (P=0.611) and peritoneal dissemination (P=0.909). In addition, AMIGO2 expression levels in tumor cells were significantly higher in liver metastatic foci than primary lesions (P=0.012). In conclusion, the present results indicated that AMIGO2 expression may contribute to the formation of liver metastasis in CRC.

Geminin, Ki67, and minichromosome maintenance 2 in gastric hyperplastic polyps, adenomas, and intestinal-type carcinomas: pathobiological significance.

BACKGROUND: Geminin negatively regulates Cdt1 and induces the formation of prereplicative complexes by loading mini-chromosome maintenance proteins (Mcm) onto chromatin and limiting DNA replication to once per cell cycle. Recent studies have suggested that geminin expression is a marker of the S/G2/M phase of the cell cycle and is associated with a poor prognosis in various human malignancies. This study aimed to clarify the pathobiological role of geminin in intestinal-type gastric carcinoma, and its relationships with minichromosome maintenance 2 (Mcm2) and Ki67 expression. METHODS: We performed western blot analysis of seven human gastric cancer cell lines, and immunohistochemical analysis of 72 gastric mucosal lesions and 128 surgically removed advanced intestinal-type gastric carcinomas. Double-labeling immuno-fluorescence was performed to identify the coexpression of geminin and Ki67. RESULTS: Geminin was detected in all cell lines. Geminin labeling indices (LIs) in hyperplastic polyps, low-grade adenomas, high-grade adenomas, and intestinal-type adenocarcinomas were 3.9%, 10.5%, 18.6%, and 27.2%, respectively. The equivalent LIs for Ki67 and Mcm2 were 17.7%, 42.2%, 52.6%, and 59.7%; and 26.7%, 70.0%, 67.8%, and 77.8%, respectively. Double-labeling immunofluorescence revealed coexpression of geminin and Ki67 in both normal and tumor cells. The LI for geminin was significantly correlated with N stage, International Union Against Cancer (UICC) stage, Mcm2 LI, and Ki67 LI. Patients in stages I-IV and stage III with higher LIs for geminin (>25%) had significantly worse prognoses (P < 0.05 and P < 0.04, respectively). Univariate Cox regression analysis indicated that the overall survival of stage I-IV tumors was significantly correlated with high geminin LIs (relative risk [RR] = 1.94; P = 0.04). CONCLUSIONS: Geminin expression might reflect the biological nature of gastric intramucosal neoplasms and could be a possible prognostic marker in advanced intestinal-type gastric carcinomas.

Minichromosome maintenance-7 and geminin are reliable prognostic markers in patients with oral squamous cell carcinoma: immunohistochemical study.

BACKGROUND: Minichromosome maintenance (MCM) proteins act as the origin licensing machinery that regulates initiation of DNA replication. Geminin is a licensing repressor and prevents reinitiation of DNA replication by blocking reloading of MCM proteins at replication origins. Recent studies have proposed that MCM7 and geminin may be sensitive proliferative and prognostic markers of various malignant tumors. This study aimed to analyze the expression of MCM7 and geminin to clarify pathobiological significance in human oral squamous cell carcinomas (OSCCs). METHODS: We performed immunohistochemical analysis on 10 specimens of normal oral epithelia, 50 lesions with dysplasia and 113 OSCCs. Labeling indices (LIs) for MCM7, geminin and Ki-67 were evaluated, comparing with clinicopathological profiles. RESULTS: The mean LIs for MCM7 were 29.2% for normal epithelia, 32.2% for dysplasias, and 51.1% for OSCCs; the value was significantly higher in the last than in the former two (P < 0.01). The mean LIs for geminin were 6.8% for normal epithelia, 9.2% for dysplasias, and 21.3% for OSCCs; the value was significantly higher in the OSCCs (P < 0.01). The MCM7 LIs were correlated with the histological grade of OSCCs, in which the highest LIs were noted in the poorly differentiated type (P < 0.01). The survival rate was significantly lower in patients with a higher MCM7 LI (>49.5%) than in those with a lower LI (P < 0.05) at stage III-IV. However, the survival rate in the patients with a higher geminin LI (>19.5%) was significantly higher than in those with a lower LI (P < 0.05) at stage IV.

Gene expression profiling by targeted RNA sequencing in pathological stage I lung adenocarcinoma with a solid component.

OBJECTIVES: Solid predominant adenocarcinoma is considered an independent predictor of an unfavorable prognosis in patients with stage I lung adenocarcinoma (LUAD). Furthermore, solid minor components are related to poor prognosis in patients with stage I LUAD. Therefore, it is imperative to elucidate the molecular determinants of the malignant potential of solid components (SC). Several studies reported the gene expression profiling specific for lepidic predominant adenocarcinoma or solid predominant adenocarcinoma, however; there is no report identifying the differentially expressed genes (DEGs) between SC and acinar component (AC) within the same tumor tissue in pathological (p)-stage I LUAD patients. MATERIALS AND METHODS: LUAD tissue samples containing both SC and AC were obtained from 8 patients with p-stage I LUAD and each component was microdissected. Targeted RNA sequencing was performed by a high-throughput chip-based approach. RESULTS: In total, 1272 DEGs were identified, including 677 upregulated genes and 595 downregulated genes in SC compared with AC. The most highly upregulated gene was TATA binding protein associated factor 7 (TAF7) and the most highly downregulated gene was homeobox B3 (HOXB3), which acts as a metastasis suppressor. A protein-protein interaction (PPI) network analysis of upregulated genes in SC identified ribosomal protein S27a (RPS27a) as a hub gene with the highest degree. First neighbors of RPS27a included PSMA6, which is a highly promising target for lung cancer. The subnetwork of PD-L1 had 10 first neighbors, including CMTM6, which enhances the ability of PD-L1-expressing tumor cells to inhibit T cells. The staining score for PD-L1 in SC was significantly higher than that in AC by immunohistochemistry (p = 0.001). CONCLUSION: Our results revealed several new DEGs and key PPI network in SC compared to AC, contributing to understanding the biological features of SC and providing therapeutic targets for early-stage LUAD with SC in the future.

Upregulation of glucose and amino acid transporters in micropapillary carcinoma.

Micropapillary carcinoma (MPC), a relatively rare histologic carcinoma observed in various organs, is associated with vascular invasion, nodal metastasis, and poor prognosis. MPC is different from papillary carcinoma as it has no fibrovascular core and is thus considered essentially hypovascular. MPCs are known to upregulate glucose transporter 1 (GLUT1) via the activation of a transcription factor, hypoxia-inducible factor (HIF)-1. Here we evaluated the expression of nutrient transporters in MPCs to gain a better understanding of the system used by MPCs to compensate for their intrinsic poor vascularity. We immunohistochemically evaluated 29 MPCs including breast (n=14), lung (n=8), gastrointestinal tract (n=5), and urinary tract cancers (n=2), and compared them with non-micropapillary control cancers (n=32) regarding the expression of amino acid (ASCT1, ASCT2, LAT1, and SNAT1) and glucose (GLUT1, GLUT2) transporters. Each section was scored by the staining intensity (0-3) multiplied by the occupying area (0-10), with a possible range 0-30. The average scores of the MPC and control groups were compared by Student's or Welch's t-test according to the homoscedasticity. The MPC group showed significantly higher scores for ASCT1 (p=0.007), ASCT2 (p=0.001), GLUT1 (p<0.001), and GLUT2 (p<0.001), whereas no significant scores were noted for LAT1 and SNAT1. In conclusion, MPC could be associated with the upregulation of several nutrient transporters, which may contribute to the malignant potential by supporting the survival of cancer cells.

Recurrent Erythema Nodosum in a Child with a SHOC2 Gene Mutation.

We report the case of a 6-year-old male who developed recurrent erythema nodosum (EN) at the age of 3 years. The patient exhibited hypertelorism, low-set ears, micrognathia, moderate intellectual disability, thin long fingers, loose anagen hair, and prominent palmoplantar wrinkles. A heterozygous single nucleotide variant in the SHOC2 gene (c.4 A > G, p.S2G) was identified. Patients with a SHOC2 mutation exhibit a unique combination of ectodermal abnormalities including darkly pigmented skin and loose anagen hair. This report is the first to describe EN in a patient with SHOC2 mutation, and to examine the patient's hair using scanning electron microscopy. We hypothesize that the RAS/MAPK pathway is associated with the pathogenesis of cutaneous lesions in patients with SHOC2 mutations via autoinflammation and disturbance of epithelial stem cells.