MALAT1 functions as a transcriptional promoter of MALAT1::GLI1 fusion for truncated GLI1 protein expression in cancer.

BACKGROUND: The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a cancer biomarker. Furthermore, fusion of the MALAT1 gene with glioma-associated oncogene 1 (GLI1) is a diagnostic marker of plexiform fibromyxoma and gastroblastoma; however, the function of this fusion gene remains unexplored. METHOD: In this study, we elucidate the structure and function of the MALAT1::GLI1 fusion gene. To this end, we determined a transcriptional start site (TSS) and promoter region for truncated GLI1 expression using rapid amplification of the 5' cDNA end and a luciferase reporter assay in cultured cells transfected with a plasmid harboring the MALAT1::GLI1 fusion gene. RESULTS: We found that the TATA box, ETS1 motif, and TSS were located in MALAT1 and that MALAT1 exhibited transcriptional activity and induced expression of GLI1 from the MALAT1::GLI1 fusion gene. Truncated GLI1, lacking SUMOylation and SUFU binding sites and located in the nucleus, upregulated mRNA expression of GLI1 target genes in the hedgehog signaling pathway. CONCLUSIONS: We demonstrate a distinct and alternative function of MALAT1 as a transcriptional promoter for expression of the MALAT1::GLI1 fusion gene. Our findings will aid future research on MALAT1 and its fusion gene partners.

Pancreatic hamartoma: detection of harbouring NAB2::STAT6 fusion gene.

Hamartomas in the pancreas are rare and are often histologically and morphologically similar to solitary fibrous tumours (SFTs). We examined the differences between hamartomas and SFTs at the molecular level. METHODS AND RESULTS: Thirteen patients histopathologically diagnosed with pancreatic hamartoma were included in the study. We also performed STAT6 immunohistochemistry (IHC), which is used in the diagnosis of SFT. Furthermore, for the three cases in which RNA was extracted, reverse transcription polymerase chain reaction to search for NAB2::STAT6 fusions was used. Macroscopically, 13 patients had well-demarcated tumour lesions. Histologically, no islets of Langerhans were observed in the lesions, acinar tissue and ducts were unevenly distributed and elastic fibres were not observed around the ducts by Elastica van Gieson staining. One case contained a lipomatous hamartoma composed mainly of adipose tissue. Seven of the 13 cases demonstrated expression of STAT6 in the nuclei of intervening spindle cells. NAB2::STAT6 fusions were observed in two of the three cases in which RNA was extracted. These two cases also demonstrated STAT6 expression in spindle cells using STAT6 IHC. In one case of lipomatous hamartoma, we did not confirm NAB2::STAT6 fusion or STAT6 expression in STAT6 IHC. CONCLUSION: Of the 13 patients histopathologically diagnosed with hamartoma, two demonstrated NAB2::STAT6 fusions, suggesting the existence of pancreatic hamartomas with molecular-level components identical to those of SFT.

Pulmonary infarction caused by sarcoidosis vascular involvement: A case report.

Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.

Overexpression of transmembrane protein 2 (TMEM2), a novel hyaluronidase, predicts poor prognosis in pancreatic ductal adenocarcinoma.

BACKGROUND: Abnormal metabolism of hyaluronan (HA), a major component of extracellular matrix, is a hallmark of cancer. Our previous studies have shown the importance of enzymes responsible for HA degradation in the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). In the present study, we investigated the expression and function of transmembrane protein 2 (TMEM2), a recently identified HA-degrading enzyme, in PDAC. MATERIALS & METHODS: We used immunohistochemistry to investigate expression patterns of TMEM2 in archival tissues obtained from 100 patients with PDAC who underwent surgical resection from 1982 to 2012. The correlations between TMEM2 expression and clinicopathological variables, including survival, were determined using univariate and multivariate analyses. The effect of TMEM2 on proliferation and migratory ability (measured using transwell cell migration assay) of PDAC cells was determined by TMEM2 knockdown with small-interfering RNA (siRNA). RESULTS: Immunohistochemical analysis revealed high expression of TMEM2 in 22 (22%) of 100 patients. The overall survival was significantly shorter in patients with high TMEM2 expression than in those with low expression (P = 0.013). Multivariate analysis identified high TMEM2 expression as an independent factor predicting poor prognosis (P = 0.011). Unexpectedly, knockdown of TMEM2 resulted in increased migratory ability of PDAC cells, which was associated with increased expression of KIAA1199, a potent HA-degrading enzyme shown to enhance cell migration. CONCLUSION: TMEM2 overexpression is associated with poor prognosis in PDAC patients. Targeted disruption of this molecule, however, could enhance the aggressiveness of PDAC cells through a possible interaction with KIAA1199.

The pathological challenge of establishing a precise diagnosis for pulmonary tumour thrombotic microangiopathy: identification of new diagnostic criteria.

AIMS: Pulmonary tumour thrombotic microangiopathy (PTTM) is a fatal disease of patients with cancer that causes progressive pulmonary hypertension (PH). Its pathology is characterised by fibrocellular intimal proliferation and thrombosis caused by tumour emboli in microscopic pulmonary arteries. However, such PTTM-like lesions often appear incidentally. We sought to identify features that distinguished PTTM from incidental pulmonary tumour emboli, and to gain an overall picture of PTTM morphology in terms of its pathogenesis. METHODS AND RESULTS: Twenty-five PTTM cases were classified into two groups: (i) a definite group (n = 14), clinically diagnosed with PH; and (ii) a suspicious group (n = 11) with respiratory symptoms but without a clinical evidence of PH. As a control group, autopsy cases with PTTM-like lesions lacking progressive respiratory symptoms were selected (n = 7). PTTM-like lesions in these groups were studied and a diagnostic guide for PTTM formulated as follows: PTTM-like lesions with >17 affected vessels observed in a 1-cm2 area of lung specimen, and the absence of pulmonary metastatic nodules. PTTM due to gastric cancers was shown to have a significantly shorter course and larger arterial involvement than cases with non-gastric cancers. Serial sections revealed a PTTM lesion to be a longitudinal obstruction that accumulated in microscopic pulmonary arteries and that showed a proximal extension via supernumerary arteries. CONCLUSION: We suggest novel pathological diagnostic characteristics for PTTM deduced from a study of 25 autopsy cases. This includes PTTM-like lesions with >17 affected vessels in a 1-cm2 area of lung specimen and the absence of pulmonary metastatic nodules.

Macrophage CCL22 expression in the tumor microenvironment and implications for survival in patients with squamous cell carcinoma of the tongue.

BACKGROUND: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines. CCR4, the receptor for CCL22, is expressed in regulatory T cells (Tregs) and Th2 cells. The Yamamoto-Kohama (YK) mode of invasion has been associated with tumor prognosis. Herein, we investigated the role of CCL22 in the tumor microenvironment and its effect on the overall survival rate in patients with tongue squamous cell carcinoma (SCC). METHODS: Tumor sections obtained from 92 patients with tongue SCC were graded based on the mode of invasion according to the YK classification. The expressions of several markers (CCL22, CD8, and Ki-67 by immunohistochemistry; CCR4 and FoxP3 by immunofluorescent staining) were evaluated. Student's t test and chi-square tests were used to compare differences between numerical variables and groups, respectively. Survival curves were plotted according to the Kaplan-Meier method and compared using a log-rank test. Hazard ratios and 95% confidence intervals were estimated using univariate or multivariate Cox proportional hazard models. RESULTS: The expression of CCL22 was significantly correlated with YK classification, overall survival rate (P < 0.001), a decrease in the number of CD8-positive cells, and an increase in the tumor Ki-67 index. In addition, CCR4-positive cells were observed around CCL22-positive macrophages. CONCLUSION: These findings indicate that the expression of CCL22 in the tumor microenvironment led to a deterioration in the prognosis of patients with tongue SCC by influencing the balance of M1- and M2-like macrophages.

The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear. METHODS: Serum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration. RESULTS: Serum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice. CONCLUSIONS: PRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

Impact of examining additional deeper sections on the pathological diagnosis of endoscopically resected early gastric cancer.

OBJECTIVES: The pathological diagnosis of endoscopically resected early gastric cancer (EGC) is performed by evaluating a few representative sections from the specimen. We aimed to determine whether evaluating twice as many sections as usual by essentially cutting the original sections in half could improve the pathological diagnosis of EGC. METHODS: We retrospectively investigated 85 EGC in 82 patients who had undergone endoscopic resection at our hospital from August 2008 to October 2012. EGC without indications of curative resection were excluded. We re-examined the original paraffin blocks after shaving away approximately half their original thickness, and evaluated whether the pathological diagnoses were affected. This technique essentially doubled the number of sections examined. RESULTS: Ten pathological diagnoses of 68 EGC (14.7%) were changed from curative resection to non-curative resection when we evaluated twice as many sections as in the standard method. The median tumor size was 25 mm in the changed diagnosis group versus 14.5 mm in the no change group (P = 0.03). The univariate analysis also showed that tumor size was a significant predictor of changed diagnosis (P = 0.015). Both the changed diagnosis group and no change group had no recurrence during follow up. CONCLUSIONS: Histological evaluation of twice as many sections as usual changed the initial pathological diagnosis of EGC, although the clinical implication of an additional deeper section was controversial because there was no recurrence. Our analysis also emphasized the importance of detailed histological evaluation to confirm a radical cure in endoscopic resection, especially in the case of larger EGC.

Clinical Significance of Squamous Differentiation in Urothelial Carcinoma of the Bladder.

The prognostic value of squamous differentiation (SD) in urothelial carcinoma (UC) of the bladder is unclear. The aim of this study was to identify the clinical significance of SD in UC in terms of oncological outcomes in patients undergoing radical cystectomy (RC). We evaluated consecutive patients with muscle-invasive bladder cancer (MIBC; clinical T2-4aN0M0) treated with RC at our institution from March 2003 to March 2017. We enrolled 20 and 81 patients with UC with SD (UCSD) and pure UC, respectively. Postoperative survival outcomes were compared between the patients with UCSD and pure UC using the Kaplan-Meier method. Pre- and postcystectomy factors that influenced the overall survival (OS) and recurrence-free survival (RFS) were investigated in these patients. Multivariate Cox regression models were used to identify the predictors of OS and RFS. With a median follow-up time of 31 months, the 5-year OS rate of the UCSD and pure UC groups was 41.1% and 69.7% ( P = .002) and the 5-year RFS rate was 51.8% and 59.5% ( P = .027), respectively. The shape of the Kaplan-Meier curves for UCSD suggested a more rapid course of the disease within the first 2 years than observed in pure UC. Multivariate analyses suggested that SD in UC was significantly associated with OS (hazard ratio [HR]: 4.22; 95% confidence interval [CI]: 1.20-14.8; P = .024) and close to significance for a lower RFS (HR: 2.13, 95% CI: 0.74-6.15, P = .064). Our results indicate that SD may be an independent predictor of OS and RFS in UC of MIBC in patients undergoing RC.

PD-L1 expression in papillary renal cell carcinoma.

BACKGROUND: The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2). METHODS: In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC). RESULT: We found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases (p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD-L1 expression and all clinicopathological factors in pRCC. CONCLUSION: High expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis.

Strong expression of polypeptide N-acetylgalactosaminyltransferase 3 independently predicts shortened disease-free survival in patients with early stage oral squamous cell carcinoma.

The polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts) family of enzymes regulates the critical initial steps of mucin-type O-glycosylation. Among GalNAc-Ts that may significantly influence cancer biology, thus affecting cell differentiation, adhesion, invasion, and/or metastasis, GalNAc-T3 exhibits a high expression in several human cancers, closely associated with tumor progression and a poor prognosis. However, the expression pattern of GalNAc-T3 in oral squamous cell carcinoma (OSCC) remains obscure. Since postoperative recurrence of even early stage OSCC (ESOSCC) occurs at an early phase, significantly affecting their clinical course and worse outcome, the identification of clinically significant accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical GalNAc-T3 expression and various clinicopathological characteristics and recurrence using 110 paraffin-embedded tumor samples obtained from patients with surgically resected ESOSCC (T1-2N0). Recurrence was recognized in 37 of 110 (33.6 %) patients. The GalNAc-T3 expression was considered to be strongly positive when 20 % or more of the cancer cells showed positive cytoplasmic staining. Consequently, a strong expression of GalNAc-T3 was observed in 40 patients (36.4 %), showing a close relationship to poor differentiation, the presence of lymphatic and vascular invasion, and recurrence. Univariate and multivariate analyses further demonstrated that the patients with a strong GalNAc-T3+ status had markedly lower disease-free survival (DFS) rates, especially within the first 2 years postoperatively. Therefore, GalNAc-T3 might play a role in the pathogenesis of ESOSCC recurrence, and its immunohistochemical detection potentially predicts a shorter DFS and may be a useful parameter for providing clinical management against ESOSCC in the early postoperative phase.

Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necroinflammation and subsequent peribiliary fibrosis.

Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bile duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK1-deficient (ASK1(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK1(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK1(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK1(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribiliary fibrogenic cells and peribiliary fibrosis. These observations indicate that ASK1-mediated hepatic necroinflammation and proliferation, but not apoptosis, are closely linked to liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.

Apoptosis signal-regulating kinase 1 deficiency attenuates vascular injury-induced neointimal hyperplasia by suppressing apoptosis in smooth muscle cells.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-α-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model.

The combination of a nuclear HMGB1-positive and HMGB2-negative expression is potentially associated with a shortened survival in patients with pancreatic ductal adenocarcinoma.

High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2- status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2- expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase.

Impact of pancreatic ductal occlusion on postoperative outcomes in pancreatic head cancer patients undergoing neoadjuvant therapy.

BACKGROUND: Pancreatic ductal occlusion can accompany pancreatic head cancer, leading to pancreatic exocrine insufficiency (PEI) and adverse effects on nutritional status and postoperative outcomes. We investigated its impact on nutritional status, body composition, and postoperative outcomes in patients with pancreatic head cancer undergoing neoadjuvant therapy (NAT). METHODS: We analyzed 136 patients with pancreatic head cancer who underwent NAT prior to intended pancreaticoduodenectomy (PD) between 2015 and 2022. Nutritional and anthropometric indices (body mass index [BMI], albumin, prognostic nutritional index [PNI], Glasgow prognostic score, psoas muscle index, subcutaneous adipose tissue index [SATI], and visceral adipose tissue index) and postoperative outcomes were compared between the occlusion (n = 78) and non-occlusion (n = 58) groups, in which 61 and 44 patients, respectively, ultimately underwent PD. RESULTS: The occlusion group showed significantly lower post-NAT BMI, PNI, and SATI (p = 0.011, 0.005, and 0.015, respectively) in the PD cohort. The occlusion group showed significantly larger main pancreatic duct, smaller pancreatic parenchyma, and greater duct-parenchymal ratio (p < 0.001), and these morphological parameters significantly correlating with post-NAT nutritional and anthropometric indices. Postoperative 3-year survival and recurrence-free survival (RFS) rates were significantly poorer (p = 0.004 and 0.013) with pancreatic ductal occlusion, also identified as an independent postoperative risk factor for overall survival (hazard ratio [HR]: 2.31, 95% confidence interval [CI] 1.08-4.94, p = 0.030) and RFS (HR: 2.03, 95% CI 1.10-3.72, p = 0.023), in multivariate analysis. CONCLUSIONS: Pancreatic ductal occlusion may be linked to poorer postoperative outcomes due to PEI-related malnutrition.

Cervical Cytology Preserves Histologically Detected Surface Epithelial Slackening, Unique to the POLE Mutation-subtype in Endometrial Cancer.

BACKGROUND/AIM: Among the four genomic subtypes of endometrial cancer, distinguishing between the DNA polymerase epsilon mutation (POLEmut) and no specific molecular profile (NSMP) subtypes requires genomic profiling owing to the lack of surrogate immunohistochemical markers. We have previously found that, histologically, the POLEmut-subtype exhibits surface epithelial slackening (SES). Therefore, to improve subtype identification, we aimed to extract cytological features corresponding to SES in POLEmut-subtype cervical cytology specimens. MATERIALS AND METHODS: We analyzed 104 endometrial cancer cervical cytology specimens, with integrative diagnosis confirmation via histology, immunohistochemistry, and genomic profiling. Cytological features were evaluated for the presence of atypical glandular cells, atypical cell appearance in single cells and clusters, and cytological SES and the presence of tumor-infiltrating inflammatory cells in clusters. RESULTS: Based on cervical cytology, the POLEmut- and p53mut-subtypes exhibited more frequent atypical cells in smaller clusters, giant tumor cells, and cytological SES patterns than the NSMP-subtype. Tumor-infiltrating lymphocytes were frequent in the POLEmut- and mismatch repair-deficient subtypes. CONCLUSION: Histologically-detected SES as well as other endometrial cancer features may be preserved in the atypical cell clusters observed in cervical cytology specimens. Cytological detection of SES and of smaller clusters of atypical cells and inflammatory cells with moderate atypia are suggestive of POLEmut-subtype. Integrative diagnosis including genomic profiling remains critical for diagnostic confirmation.

Malignant phyllodes tumor with EGFR variant III mutation: A rare case report with immunohistochemical and genomic studies.

A female in her 60's presented with a left-sided breast mass. A core needle biopsy specimen showed diffuse proliferation of a round cell tumor, which was positive for vimentin, NKX2.2, BCOR, and focal CD99 on immunohistochemistry (IHC). No fusion genes of the Ewing family sarcomas were detected. With a tentative diagnosis of primary breast sarcoma (PBS), total mastectomy was performed after chemotherapy. The resected tissues showed proliferation of round or spindle-shaped tumor cells with a high nuclear-to-cytoplasmic ratio, exhibiting solid and fascicular arrangements but no epithelial component or organoid pattern. While IHC indicated no particular histological diagnosis, genomic examination revealed gene alterations in MED12 p.G44D, MLL2 (KMT2D) p.T1496fs*27, and EGFR variant III (vIII). Moreover, a retrospective IHC study showed overexpression of EGFRvIII. A malignant phyllodes tumor (PT) with extensive sarcomatous overgrowth was indicated as an integrative diagnosis. This is a rare case of a malignant PT harboring EGFRvIII. The present case provides an importance of accurate diagnosis and genomic analysis of rare breast tumors, as malignant PT and PBS are different in its treatment strategy and prognosis.

Association of troponin I and macrophages in cardiac tamponade with Stanford type A aortic dissection.

Background: Acute aortic dissection has a high mortality rate, especially for Stanford type A with a dissected ascending aorta. Cardiac tamponade is one of the most common complications of acute type A aortic dissection (ATAAD) and can cause death. However, the pathogenesis is often unclear. We aimed to examine laboratory findings at the onset of disease and macrophage involvement. Methods: Hematological and biochemical parameters, and D-dimer, brain natriuretic peptide (BNP), and high-sensitivity troponin I (hs-cTnI) levels in 70 patients with ATAAD at our hospital were investigated. Additionally, the myocardium and aorta after autopsy of an ATAAD case with cardiac tamponade were pathologically examined. Results: Forty-four ATAAD cases were complicated by cardiac tamponade. The mean age of patients with cardiac tamponade and proportion of patients over 70 years of age were both significantly higher than for those without cardiac tamponade. Evaluable D-dimer values were higher than 0.5 µg/mL in all patients. Significantly elevated laboratory parameters in patients with cardiac tamponade included: lactate dehydrogenase, aspartate aminotransferase, C-reactive protein, lactate, BNP, and hs-cTnI. However, multivariate analysis showed only hs-cTnI was significantly associated with cardiac tamponade. Histological examination revealed numerous M2-like macrophages infiltrating the myocardium and dissecting aorta, expressing CC chemokine ligand (CCL)2 together with vascular endothelial growth factor-C and matrix metalloproteinase-9. The peripheral monocyte-to-neutrophil ratio (MNR) was also significantly higher in cardiac tamponade. Conclusions: In ATAAD patients with cardiac tamponade, hs-cTnI was significantly elevated and CCL2 expression was observed, which may be involved in the expression of M2-like macrophages via an increased MNR.

Receptor for Hyaluronic Acid-mediated Motility (RHAMM) Is Associated With Prostate Cancer Migration and Poor Prognosis.

BACKGROUND/AIM: Hyaluronic acid (HA) is a large glycosaminoglycan composed of an extracellular matrix. The HA-rich microenvironment and receptors of HA have been suggested to play roles in cancer progression. The biological and clinical significance of receptor for HA-mediated motility (RHAMM), known as CD168 in prostate cancer (PC) remains unknown. This study aimed to investigate the expression of RHAMM, as well as its functional and clinical relevance in PC. MATERIALS AND METHODS: HA concentration and RHAMM mRNA expression were examined in 3 PC cell lines (LNCaP, PC3 and DU145). We investigated the effect of HA and RHAMM on the migratory ability of PC cells using a transwell migration assay. Immunohistochemistry was also used to evaluate the RHAMM expression pattern in pre-treatment tissue samples from 99 patients with metastatic hormone-sensitive PC (HSPC) who received androgen deprivation therapy (ADT). RESULTS: HA was secreted in all cultured PC cell lines. Among the total HA, low-molecular-weight HA (LMW-HA) (<100 kDa) was detected all examined cell lines. The number of migration cells was significantly increased by adding LMW-HA. RHAMM mRNA expression was increased in DU145 cells. Knockdown of RHAMM using small-interfering RNA resulted in decreased cell migration. Immunohistochemical analysis revealed strong RHAMM expression in 31 (31.3%) patients with metastatic HSPC. A strong RHAMM expression was significantly associated with short ADT duration and poor survival in univariate and multivariate analyses. CONCLUSION: The size of HA is important in terms of PC progression. LMW-HA and RHAMM enhanced PC cell migration. RHAMM could be used as a novel prognostic marker in patients with metastatic HSPC.