CXCR4 Expression and Cancer-associated Fibroblasts May Play an Important Role in the Invasion of Low-grade Endometrioid Carcinoma.

Well-differentiated endometrioid carcinoma (EC) is a low-grade cancer with relatively indolent behavior. However, even with well-differentiated histology, it sometimes tends to invade extensively and shows metastatic potential, suggesting that this is a group of cancers with heterogeneous behavior. In contrast, due to its tendency for younger onset, the treatment strategy for EC frequently considers fertility preservation, highlighting the need for a more accurate evaluation of myometrial invasion through biopsy and imaging diagnostics. We previously reported the involvement of the CXCR4-CXCL12 and CXCL14 axes in EC invasion. Accordingly, we investigated whether CXCR4 expression could reflect invasive potential and explored its interaction with cancer-associated fibroblasts that produce chemokines in the tumor microenvironment. Immunohistochemical expression of CXCR4 was assessed in 71 cases of EC (14 of EC confined to the endometrium and 57 of myoinvasive EC), 6 cases of endometrial intraepithelial neoplasia, and 42 cases of noncarcinomatous conditions. CXCR4 expression was significantly higher in myoinvasive EC than in noncancerous conditions, endometrial intraepithelial neoplasia, and endometrium-confined EC. By univariate and multivariate analysis, CXCR4 expression significantly reflected myometrial invasion. CXCR4 expression in the biopsied and resected specimens correlated weakly positively. Invasion and wound-healing assays were performed culturing an EC cell line in a cancer-associated fibroblast-conditioned medium. The invasion and wound-healing potentials were dependent on CXCR4 and cancer-associated fibroblast. Our study demonstrated that CXCR4 expression is an independent factor in myometrial invasion and can support diagnostic evaluation before treatment in the biopsy sample.

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking. OBJECTIVES: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC. METHODS: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS. RESULTS: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival. CONCLUSIONS: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.

Endotheliopathy of liver sinusoidal endothelial cells in liver disease.

Liver is the largest solid organ in the abdominal cavity, with sinusoid occupying about half of its volume. Under liver disease, hemodynamics in the liver tissue dynamically change, resulting in injury to liver sinusoidal endothelial cells (LSECs). We discuss the injury of LSECs in liver diseases in this article. Generally, in noninflamed tissues, vascular endothelial cells maintain quiescence of circulating leukocytes, and unnecessary blood clotting is inhibited by multiple antithrombotic factors produced by the endothelial cells. In the setting of inflammation, injured endothelial cells lose these functions, defined as inflammatory endotheliopathy. In chronic hepatitis C, inflammatory endotheliopathy in LSECs contributes to platelet accumulation in the liver tissue, and the improvement of thrombocytopenia by splenectomy is attenuated in cases with severe hepatic inflammation. In COVID-19, LSEC endotheliopathy induced by interleukin (IL)-6 trans-signaling promotes neutrophil accumulation and platelet microthrombosis in the liver sinusoids, resulting in liver injury. IL-6 trans-signaling promotes the expression of intercellular adhesion molecule-1, chemokine (C-X-C motif) ligand (CXCL1), and CXCL2, which are the neutrophil chemotactic mediators, and P-selectin, E-selectin, and von Willebrand factor, which are involved in platelet adhesion to endothelial cells, in LSECs. Restoring LSECs function is important for ameliorating liver injury. Prevention of endotheliopathy is a potential therapeutic strategy in liver disease.

Prediction Model with HLA-A*33:03 Reveals Number of Days to Develop Liver Cancer from Blood Test.

The development of liver cancer in patients with hepatitis B is a major problem, and several models have been reported to predict the development of liver cancer. However, no predictive model involving human genetic factors has been reported to date. For the items incorporated in the prediction model reported so far, we selected items that were significant in predicting liver carcinogenesis in Japanese patients with hepatitis B and constructed a prediction model of liver carcinogenesis by the Cox proportional hazard model with the addition of Human Leukocyte Antigen (HLA) genotypes. The model, which included four items-sex, age at the time of examination, alpha-fetoprotein level (log10AFP) and presence or absence of HLA-A*33:03-revealed an area under the receiver operating characteristic curve (AUROC) of 0.862 for HCC prediction within 1 year and an AUROC of 0.863 within 3 years. A 1000 repeated validation test resulted in a C-index of 0.75 or higher, or sensitivity of 0.70 or higher, indicating that this predictive model can distinguish those at high risk of developing liver cancer within a few years with high accuracy. The prediction model constructed in this study, which can distinguish between chronic hepatitis B patients who develop hepatocellular carcinoma (HCC) early and those who develop HCC late or not, is clinically meaningful.

Intraductal papilloma with atypical ductal hyperplasia and neuroendocrine differentiation as a possible precursor lesion of solid papillary carcinoma.

Breast papillary neoplasms include a wide range of tumor types, and their pathological diagnosis is sometimes difficult. Furthermore, the etiology of these lesions is still not fully understood. We report the case of a 72-years-old woman referred to our hospital with bloody discharge from the right nipple. An imaging study detected a cystic lesion, including a solid component contiguous with the mammary duct, in the subareolar region. The lesion was then removed by segmental mastectomy. Pathological examination of the resected specimen revealed an intraductal papilloma with atypical ductal hyperplasia. Moreover, the atypical ductal epithelial cells expressed neuroendocrine markers. The presence of an intraductal papillary lesion with neuroendocrine differentiation suggests solid papillary carcinoma. Thus, this case suggests that intraductal papilloma could be a precursor of solid papillary carcinoma.

[Minimally Invasive Conversion Hepatectomy for Advanced Hepatocellular Carcinoma].

Some cases of advanced hepatocellular carcinoma(HCC)diagnosed as unresectable(UR)have been reported to undergo conversion surgery following systemic therapy. Furthermore, the combination of atezolizumab plus bevacizumab(Atez/Bev) shows potential therapeutic effects in conversion surgery for UR-HCC. At our hospital, neoadjuvant chemotherapy(NAC) using New-FP therapy(hepatic arterial infusion chemotherapy: HAIC)has been performed for borderline resectable HCC. New-FP therapy for advanced HCC with macrovascular invasion has a high response rate of 70%. For hepatectomy after NAC, a high response rate is required as a pretreatment, and New-FP therapy may be useful as the initial treatment. Limited reports exist of the laparoscopic approach in conversion surgery for advanced HCC. However, 14 cases of minimally invasive liver resection, including 10 cases after New-FP therapy and 4 cases after Atez/Bev therapy, have been safely performed conversion surgery for advanced HCC. In selected patients with advanced HCC, minimally invasive liver resection may be safely performed if the tumor shows shrinkage with various treatments.

Squamous cell carcinoma of the tongue: subtypes and morphological features affecting prognosis.

Squamous cell carcinoma (SCC) is the most common histological type of mobile tongue carcinoma. The incidence of mobile tongue carcinoma is decreasing in some countries owing to decreasing exposure to risk factors, but it has been reported to be increasing in younger people. The majority of mobile tongue cancers are conventional SCCs. Pathological diagnosis of conventional SCC is relatively easy. However, mobile tongue SCCs involve several subtypes that have distinct pathological features and biological behaviors. Some subtypes are relatively rare, and the pathological subtype influences treatment decision-making. Therefore, the recognition of SCC subtypes is crucial for proper treatment. In this review, we summarize nine SCC subtypes, including conventional SCC and highlight their pathological characteristics. We also report some morphological factors, such as the pattern of invasion, budding, desmoplastic reaction, lymphovascular invasion, and perineural invasion, which could be predictive of prognosis. As some morphological factors are closely associated with prognosis, pathologists may need to evaluate additional factors in pathological reports of near features. In summary, we highlight the basic knowledge of mobile tongue SCC with an emphasis on pathological subtypes, morphological features, and their relationship. We provide information to further elucidate SCC in the oral region.

Utility of sonic hedgehog and keratin 8/18 immunohistochemistry for detecting ballooned hepatocytes.

AIMS: Ballooned hepatocytes represent liver cell degeneration and are histological hallmarks in the diagnosis of non-alcoholic steatohepatitis, a severe form of non-alcoholic fatty liver disease. However, the identification of ballooned hepatocytes is often difficult, especially in the clinical setting of patients with other chronic liver diseases. In this study, we investigated the utility of immunostaining for positive sonic hedgehog (SHh) protein and negative Keratin 8/18 (K8/18) expression on ballooned hepatocytes. METHODS AND RESULTS: Immunohistochemistry for SHh and K8/18 was evaluated independently by two experienced liver pathologists in non-tumorous liver tissue from 100 cases of resected hepatocellular carcinoma of various aetiology. The degree of hepatocyte ballooning was scored as follows: 0, none; 1, few; 2, many ballooned hepatocytes. These evaluations were performed using routine haematoxylin and eosin (H&E) staining, followed by immunostaining for SHh or K8/18. Using SHh or K8/18 immunostaining combined with H&E staining, the score of ballooned hepatocytes was upgraded in 20 and 19 cases, and downgraded in none and 2 cases, respectively. The percentage of observed agreement for ballooned hepatocytes scoring was 85% and 92%, and the weighted kappa value was 0.806 and 0.893 with SHh or K8/18 immunohistochemistry. Considering the immunohistochemistry results, background liver disease diagnosis was changed in 15 out of 100 cases (15%) evaluated. CONCLUSIONS: SHh and K8/18 immunohistochemistry are useful in detecting ballooned hepatocytes, regardless of background liver disease, and improving pathological diagnosis accuracy.

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.

Expression and significance of laminin receptor in squamous cell carcinoma of the tongue.

BACKGROUND: Laminin receptor is a non-integrin cell-surface receptor that binds laminin present on the basement membrane. It has been reported to be associated with infiltration and metastasis of various malignant tumors. However, no studies regarding tongue cancer have been reported. This study aimed to clarify the role of laminin receptor in squamous cell carcinoma of the tongue. METHODS: We performed immunohistochemical staining of specimens from 66 patients with squamous cell carcinoma of the tongue and assessed laminin receptor expression and clinicopathological factors. As epithelial-mesenchymal transition has been shown to be associated with infiltration and metastasis of malignant tumors, staining for E-cadherin, vimentin, and N-cadherin were also performed. RESULTS: Of 20 patients with postoperative recurrence, 14 exhibited high laminin receptor expression (p = 0.0025). Kaplan-Meier analysis revealed a significantly shorter time to postoperative recurrence for the high laminin receptor expression group than that for the low laminin receptor expression group (p = 0.0008). Based on multivariate analyses for postoperative recurrence, high laminin receptor expression was associated with poor prognosis (high expression vs. low expression; HR =3.19, 95% CI =0.92-11.08; p = 0.0682). There was a correlation between laminin receptor and N-cadherin (p = 0.0089) but not between laminin receptor and E-cadherin (p = 0.369) or vimentin (p = 0.4221). CONCLUSION: These results suggest that high laminin receptor expression is a useful prognostic factor for postoperative recurrence and may be a target for molecular therapy to treat squamous cell carcinoma of the tongue.

Diagnosis of hepatic steatosis based on ultrasound attenuation imaging is not influenced by liver fibrosis.

AIM: Recently, a new technique using attenuation imaging (ATI) was developed to diagnose hepatic steatosis. The aim of this study was to investigate whether ATI for the evaluation of hepatic steatosis is influenced by liver fibrosis. METHODS: A total of 328 patients with chronic liver disease were enrolled to study the associations between histological hepatic steatosis or liver fibrosis and ATI findings. The interaction between liver fibrosis and ATI was also analyzed. RESULTS: Median ATI values according to steatosis grade and fibrosis stage increased in line with the progression of liver steatosis (p < 0.001) and fibrosis (p < 0.05). However, in each steatosis grade, ATI values according to fibrosis stage were not significantly increased. In multiple regression analyses for assessment of the effect of their interaction, the p values for fibrosis stage, steatosis grade, and fibrosis stage × steatosis grade were 0.096, <0.001, and 0.077, respectively. Variance inflation factor values for fibrosis stage, steatosis grade, and fibrosis stage × steatosis grade were 1.079, 1.094, and 1.074, respectively. CONCLUSION: Attenuation imaging values are not influenced by liver fibrosis.

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma.

We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi-institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small-sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa-fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06-2.19], P = 0.023), disease-free survival (HR: 1.66 [1.21-2.27], P = 0.002), and overall survival (HR: 2.26 [1.37-3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (ß-catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.

Severity of liver fibrosis using shear wave elastography is influenced by hepatic necroinflammation in chronic hepatitis patients, but not in cirrhotic patients.

AIM: Shear wave elastography (SWE) in patients with chronic liver diseases is a noninvasive useful method for the diagnosis of liver fibrosis severity, which can be an alternative to liver biopsy. However, the liver stiffness measurement using SWE can be affected by various factors including hepatic inflammation, extrahepatic cholestasis, heart failure, and underlying liver diseases. The aim of this study is to clarify the correlation between liver stiffness using SWE and hepatic necroinflammation serologically and pathologically. METHODS: A total of 843 patients with chronic liver disease who received liver biopsy were analyzed. Liver stiffness measurement using transient elastography (TE) and virtual touch quantification (VTQ) were carried out on the same day as the liver biopsy. The correlation between SWE and hepatic inflammation was analyzed serologically and pathologically. RESULTS: The liver stiffness values increased significantly with the progression of liver fibrosis and inflammation (overall p < 0.001). In patients with F0-1, F2, and F3, TE and VTQ values of A2 or A3 were significantly higher than those of A0 or A1 (p value, all <0.05), but not in patients with F4. The median alanine aminotransferase (ALT) values increased significantly with the progression of liver inflammation (p < 0.001). Moreover, TE and VTQ in patients with ALT ≥70 IU/L were significantly higher than those in patients with ALT <70 IU/L (p < 0.01), but not in patients with F4. CONCLUSION: Shear wave elastography can be affected by hepatic necroinflammation in F0-F3 fibrosis, but not in F4.

Laparoscopic left hepatectomy for a patient with intrahepatic cholangiocarcinoma metastasis in the falciform ligament: a case report.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is primary cancer of the liver with poor prognosis because of its high potential for recurrence and metastasis. We experienced a rare case of ICC with hematogenous metastasis to the falciform ligament. We aimed to clarify the route of metastasis to the mesentery by increasing the accuracy of preoperative imaging and establish a hepatectomy to control cancer. CASE PRESENTATION: An 85-year-old woman was referred to our hospital for a detailed study of progressively increasing liver tumors. She had no subjective symptoms. Her medical history showed hypertension, aneurysm clipping for cerebral hemorrhage, and gallstones. A detailed physical examination and laboratory data evaluation included tumor markers but did not demonstrate any abnormalities. On computed tomography scan, contrast-enhanced ultrasound, and magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid, the tumor appeared to be located in liver segment IV, protruding outside the liver. It appeared to contain two distinct components; we suspected ICC in the intrahepatic tumor component. Laparoscopic observation revealed that the extrahepatic lesion was an intra-falciform ligament mass; laparoscopic left hepatectomy was performed. Microscopically, the main tumor in segment IV was 15 mm in diameter and was diagnosed as moderately and poorly differentiated ICC. The tumor of the intra-falciform ligament was not continuous with the main intrahepatic nodule and was also diagnosed as ICC with extensive necrosis. There were no infiltrates in the round ligament of the liver, and several tumor thrombi were found in the small veins of the falciform ligament. CONCLUSIONS: To date, there have been a few reports of metastases of primary liver cancer to the falciform ligament. At the time of preoperative imaging and pathological diagnosis, this case was suggestive of considering that the malignant liver tumor might be suspected of metastasizing to the falciform ligament. Our case improves awareness of this pathology, which can be useful in the future when encountered by hepatic specialists and surgeons.

Neoadjuvant Hyperthermia and Chemoradiotherapy for Borderline Resectable Pancreatic Cancer.

Pancreatic cancer(PC)is associated with poor prognosis and low resectability rates. Currently, only 15-20% of all patients are candidates for upfront surgery at the time of diagnosis, which offers the chance of long-term survival. In recent years, patients with borderline resectable PC(BR-PC)have been treated with surgery following neoadjuvant chemoradiotherapy or intensive multi-agent chemotherapy. In PC, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of chemo(radio)therapy. An 84-year-old man with fatty stool was diagnosed with pancreatic head cancer according to the result of contrast computed tomography(CT), which showed a 37 mm irregular low-density area at the pancreatic head infiltrating nearly half of the superior mesenteric artery(SMA)plexus. There were no findings of lymph node metastasis or distant metastasis. The pretreatment diagnosis was BR-PC, cT3, N0, M0, cStage Ⅱ A. The patient was treated with hyperthermia plus S-1 and radiotherapy. The size of the tumor had reduced from 37 mm to 15 mm after the neoadjuvant therapy, and the infiltration into the SMA plexus had also reduced. Therefore, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy(SSPPD)concomitant resection of the PV, SMV, SV confluence. The histopathological findings were invasive ductal carcinoma with R0 radical resection. There has been no recurrence 18 months after the surgery. Based on the above-mentioned findings, hyperthermia and chemoradiotherapy can be an effective option of neoadjuvant treatment for BR-PC.

Androgen receptor expression is useful to predict the therapeutic effect in HER2-positive breast carcinoma.

PURPOSE: Although HER2-positive (HER2+) invasive breast carcinomas (BC) have a different clinical therapeutic responsiveness according to estrogen and progesterone receptor expression, the relationship with androgen receptors (AR), which are the same family of steroid hormones, is poorly understood. We investigated the relationship between AR expression in HER2 BCs and therapeutic responsiveness and prognosis in this study. METHODS: We evaluated patients with HER2 (H) + invasive BC undergoing surgery after neoadjuvant chemotherapy (± HER2-targeted therapies) from 2007-2017, classified as hormone receptor-positive (Allred score: 2-8) (luminal B: LH) and receptor-negative groups (Allred: score 0) (non-luminal: NLH). AR expression was assessed by immunostaining pre-neoadjuvant chemotherapy biopsy specimens, positive with Allred score ≥ 4. The pathological complete response, disease-free survival, and overall survival rates were compared between AR-positive and AR-negative groups. RESULTS: We classified 82 patients with HER2 + invasive BC into LH (n = 45, 54.9%) and NLH groups (n = 37, 45.1%), and AR + was observed in 43 patients (52.4%) (LH: 23, 51.1%; NLH: 20, 54.1%; p = 0.79). Quasi-pathological complete response was observed in 40 patients (48.8%) (LH: 18, 40%; NLH: 22, 59.5%; p = 0.08) overall, and in 31 AR + patients (72.1%) (LH: 15, 34.9%; NLH: 16, 37.2%), significantly higher than in the AR - group for both subgroups (p < 0.001). Regarding prognosis, disease-free survival was relatively better in the AR + group in all HER2 + BCs (p = 0.085), and overall survival was significantly better in the AR + group for NLH (p = 0.029). CONCLUSIONS: High AR expression may be a useful predictor of therapeutic effects and prognosis in both subgroups of HER2 + BCs.

Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in Lipopolysaccharide-Induced Experimental Endotoxemia.

Neutrophil elastase (NE) is necessary for effective sterilization of phagocytosed bacterial and fungal pathogens; however, NE increases alveolocapillary permeability and induces proinflammatory cytokine production in sepsis-induced acute respiratory distress syndrome. Under septic conditions, the pulmonary endothelial glycocalyx covering on the healthy endothelium surface is injured, but the contribution of NE to this injury remains unknown. Our aim was to examine whether NE-induced pulmonary endothelial injury is associated with endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 9- to 12-week-old granulocyte colony-stimulating factor knockout (G-CSFKO) mice, which harbor few neutrophils, and littermate control mice; in a second assay, mice were injected with the NE-inhibitor sivelestat (0.2 mg/kg) at 3, 6, 9, and 12 hours after LPS administration. Subsequently, vascular endothelial injury was evaluated through ultrastructural analysis. At 48 hours after LPS injection, survival rate was more than threefold higher among G-CSFKO than control mice, and degradation of both thrombomodulin and syndecan-1 was markedly attenuated in G-CSFKO compared with control mice. Ultrastructural analysis revealed attenuated vascular endothelial injury and clear preservation of the endothelial glycocalyx in G-CSFKO mice. Moreover, after LPS exposure, survival rate was approximately ninefold higher among sivelestat-injected mice than control mice, and sivelestat treatment potently preserved vascular endothelial structures and the endothelial glycocalyx. In conclusion, NE is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions.

Diverse histomorphology of HER2-positive breast carcinomas based on differential ER expression.

AIMS: HER2-positive (HER2+) breast carcinoma (BC) cases are often treated similarly; however, they can be classified as either luminal B (LH) or non-luminal type (NLH) BC, which have different prognoses. In this study, we investigated the clinicohistomorphological features of each HER2+ BC subgroup. METHODS AND RESULTS: We classified 166 patients with HER2+ invasive BC into LH (n = 110, 66.3%) and NLH groups (n = 56, 33.7%). We further subclassified LH into patients with carcinomas expressing high levels of hormone receptors [LH-high; Allred score, oestrogen receptor (ER) and/or progesterone receptor (PgR) 4-8, n = 89, 53.6%] or low levels (LH-low; Allred score, ER and/or PgR 2 or 3, n = 21, 12.7%) for clinicohistomorphological characterisation. Morphological review showed that NLH included a percentage of patients with comedo necrosis, while LH patients had significantly more central scarring. In terms of immune responsiveness, NLH showed significantly higher rates of tumour-infiltrating lymphocytes and healing. The LH-high and NLH groups showed distinct characteristics (by both models, P < 0.05) and the LH-low group appeared to demonstrate intermediate characteristics according to multinomial analyses using covariates reflecting tumour morphology and immune response outcomes. CONCLUSIONS: These results support the classification of HER2+ BC into two major subgroups, LH-high and NLH, based on tumour morphology and immune response; LH-high proliferates via scirrhous and/or spiculated growth with a central scar, while the primary proliferation pattern of NLH is based on in-situ carcinomas containing comedo necrosis with noticeable TILs and healing.

Distinctive clinicopathological features and KRAS and IDH1/2 mutation status of cholangiolocellular carcinoma.

AIM: Cholangiolocellular carcinoma (CLC) is classified as a subtype of combined hepatocellular cholangiocarcinoma with stem-cell features (CHC-SC) in the latest World Health Organization classification. This subclassification of CHC-SCs is controversial and the relevance of such classification is unclear. METHODS: We analyzed a series of CHC-SCs and intrahepatic cholangiocarcinoma (iCCA) to clarify the clinicopathological features and mutational status of each tumor. RESULTS: Background liver disease, fibrosis stage, microvascular invasion, nodal metastasis, and IDH1/2 mutation status were associated with their histology. Compared with the intermediate cell subtype of CHC-SC (CHCs-SC-int), CLCs were less frequently associated with chronic viral hepatitis, and showed lower levels of serum alpha-fetoprotein. Compared with iCCAs, CLCs showed lower levels of serum carbohydrate antigen 19-9 (CA19-9) and a lower frequency of expression of S100P. Patients with iCCA showed worse overall survival than those with CLC or CHC-SC-int. In patients with iCCA, CLC, or CHC-SC-int, a histology of iCCA, microvascular invasion, and serum CA19-9 value of >100 U/mL were significant poor prognostic factors for overall survival in univariate analysis. Multivariate analysis showed that a high serum CA19-9 value was an independent poor prognostic factor for overall survival. CONCLUSIONS: Patients with CLC are likely to have a different etiology and mutational background from those with CHC-SC-int. Their clinicopathological manifestations are also different from those with classic iCCA. Our results suggest that CLC might be a distinct entity among primary liver carcinomas.

cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. CONCLUSION: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).