Roles of omental and bone marrow adipocytes in tumor biology

Accumulating evidence highlights the importance of interactions between tumour cells and stromal cells for tumour initiation, progression, and metastasis. In tumours that contain adipocyte in their stroma, adipocytes contribute to modification of tumour microenvironment and affect metabolism of tumour and tumour progression by production of cytokines and adipokines from the lipids. The omentum and bone marrow (BM) are highly adipocyte-rich and are also common metastatic and primary tumour developmental sites. Omental adipocytes exhibit metabolic cross-talk, immune modulation, and angiogenesis. BM adipocytes secrete adipokines, and participate in solid tumour metastasis through regulation of the CCL2/CCR2 axis and metabolic interactions. BM adipocytes also contribute to the progression of hematopoietic neoplasms. Here, we here provide an overview of research progress on the cross-talks between omental/BM adipocytes and tumour cells, which may be pivotal modulators of tumour biology, thus highlighting novel therapeutic targets. Abbreviations: MCP-1, monocyte chemoattractant protein 1IL, interleukinSTAT3, signal transducer and activator of transcription 3FABP4, fatty acid binding protein 4PI3K/AKT, phosphoinositide 3-kinase/protein kinase BPPAR, peroxisome proliferator-activated receptorPUFA, polyunsaturated fatty acidTAM, tumour-associated macrophagesVEGF, vascular endothelial growth factorVEGFR, vascular endothelial growth factor receptorBM, bone marrowBMA, bone marrow adipocytesrBMA, regulated BMAcBMA, constitutive BMAUCP-1, uncoupling protein-1TNF-α, tumour necrosis factor-alphaRANKL, receptor activator of nuclear factor kappa-Β ligandVCAM-1, vascular cell adhesion molecule 1JAK2, Janus kinase 2CXCL (C-X-C motif) ligandPGE2, prostaglandin E2COX-2, cyclooxygenase-2CCL2, C-C motif chemokine ligand 2NF-κB, nuclear factor-kappa BMM, multiple myelomaALL, acute lymphoblastic leukemiaAML, acute myeloid leukemiaGDF15, growth differentiation factor 15AMPK, AMP-activated protein kinaseMAPK, mitogen-activated protein kinaseAPL, acute promyelocytic leukemiaCCR2, C-C motif chemokine receptor 2SDF-1α, stromal cell-derived factor-1 alphaFFA, free fatty acidsLPrA, leptin peptide receptor antagonistMCD, malonyl-CoA decarboxylase.ope

Clinical significance of tumor-infiltrating lymphocytes and neutrophil-to-lymphocyte ratio in patients with stage III colon cancer who underwent surgery followed by FOLFOX chemotherapy

Local tumor immune response and host immunity have been suggested as important prognosticators respectively in colorectal cancer. However, the utility of combination of these parameters remains inconclusive. The aim of this study was to investigate the combinational impact of local and host tumor immune response, as determined by tumor-infiltrating lymphocytes (TILs) and neutrophil-to-lymphocyte ratio (NLR), in patients with stage III colon cancer. Patients with stage III colon cancer homogeneously treated with surgery followed by FOLFOX chemotherapy between Jan 2007 and Aug 2013 were included retrospectively. Hematoxylin and eosin (H&E) stained tumor sections of local inflammatory infiltrate (TILs) were classified as 0-3 by the Klintrup-Mäkinen grading method. NLR was measured within 1 month of surgery. The association of NLR and TILs with survival, alone or combined, were measured using multivariate Cox proportional hazard regression analysis. Among 137 patients, 75 (54.7%) were identified as the high TIL group (TILs 2 and 3) and 97 (70.8%) as the low NLR group (NLR < 3). Of the patients with high TILs, 51 (68%) had a low NLR. In univariate analysis, operation time, complications, lymph node ratio (LNR), stage, TILs, and high TILs with low NLR were significantly associated with overall survival(OS). Multivariate Cox regression identified operation time, stage, and TILs as independent risk factors for OS. When high TILs with low NLR vs. others was entered into multivariate analysis, this also proved to be a significant predictor of OS (HR 4.1, 95% CI 1.1-14.2, P = 0.025), with an increased C-index and lower AIC value compared to TILs. Measuring TILs using H&E stained sections could stratify the prognosis of stage III colon cancer. Considering host immunity, using the combination of TILs and NLR, allowed the prognosis to be stratified in more detail.ope

Correlation of PD-L1 Expression Tested by 22C3 and SP263 in Non-Small Cell Lung Cancer and Its Prognostic Effect on EGFR Mutation-Positive Lung Adenocarcinoma

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is tested by immunohistochemistry (IHC)-22C3, SP263, and SP142. The aim of this study is to evaluate the correlation among the three methods of PD-L1 IHC in non-small cell lung cancer (NSCLC) and clinical significance of PD-L1 expression in lung adenocarcinoma with an epidermal growth factor receptor (EGFR)-tyrosine kinase domain mutation. METHODS: The results of 230 patients who were pathologically confirmed as having NSCLC; tested using PD-L1 IHC 22C3, SP263, and SP142 methods; and evaluated via the peptide nucleic acid clamping method to confirm EGFR mutation, were analyzed in this study. RESULTS: 164 patients underwent both the SP263 and 22C3 tests. There was a significant positive correlation between the outcomes of the two tests (Spearman correlation coefficient=0.912, p<0.001), with a derived regression equation as follows: 22C3=15.2+0.884×SP263 (R²=0.792, p<0.001). There was no relationship between the expression of PD-L1 and clinical parameters, including EGFR-tyrosine kinase inhibitor (TKI) mutation. The PD-L1 expression in patients treated with EGFR-TKI yielded a 2-month-shorter progression period than that in the PD-L1-negative group. However, this did not reach statistical significance (PD-L1<1% vs. PD-L1≥1%, 10 months vs. 8 months). CONCLUSION: The results of the 22C3 and those of SP263 methods were in good correlation with one another. Since the PD-L1 expression is not influenced by the EGFR mutation, it is necessary to perform a PD-L1 test to set the treatment direction in the patients with EGFR-mutant NSCLC.ope

A Multi-institutional Study of Prevalence and Clinicopathologic Features of Non-invasive Follicular Thyroid Neoplasm With Papillary-like Nuclear Features (NIFTP) in Korea

Background: In the present multi-institutional study, the prevalence and clinicopathologic characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were evaluated among Korean patients who underwent thyroidectomy for papillary thyroid carcinoma (PTC). Methods: Data from 18,819 patients with PTC from eight university hospitals between January 2012 and February 2018 were retrospectively evaluated. Pathology reports of all PTCs and slides of potential NIFTP cases were reviewed. The strict criterion of no papillae was applied for the diagnosis of NIFTP. Due to assumptions regarding misclassification of NIFTP as non-PTC tumors, the lower boundary of NIFTP prevalence among PTCs was estimated. Mutational analysis for BRAF and three RAS isoforms was performed in 27 randomly selected NIFTP cases. Results: The prevalence of NIFTP was 1.3% (238/18,819) of all PTCs when the same histologic criteria were applied for NIFTP regardless of the tumor size but decreased to 0.8% (152/18,819) when tumors ≥1 cm in size were included. The mean follow-up was 37.7 months and no patient with NIFTP had evidence of lymph node metastasis, distant metastasis, or disease recurrence during the follow-up period. A difference in prevalence of NIFTP before and after NIFTP introduction was not observed. BRAFV600E mutation was not found in NIFTP. The mutation rate for the three RAS genes was 55.6% (15/27). Conclusions: The low prevalence and indolent clinical outcome of NIFTP in Korea was confirmed using the largest number of cases to date. The introduction of NIFTP may have a small overall impact in Korean practice.ope

Liver stiffness and perfusion changes for hepatic sinusoidal obstruction syndrome in rabbit model

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) is caused by damage to hepatic sinusoidal endothelial cells that results in fibrous obliteration of intrahepatic venules and necrosis of hepatocytes. Currently the diagnosis is primarily based on nonspecific clinical features and invasive liver biopsy. Therefore, noninvasive imaging methods are required for the early diagnosis and severity assessment of hepatic SOS. AIM: To determine the effectiveness of supersonic shear wave imaging (SSI) and dual energy computed tomography (DECT) for diagnosing hepatic SOS using a rabbit model. METHODS: Among nine New Zealand white rabbits (3-4 kg, male), three in control group ingested normal saline for 20 d and six in the SOS group ingested 6-thioguanine (5 mg/kg/d) for 20 d. Liver stiffness was measured using SSI on days 0, 3, 10, and 20. On the same days, liver perfusion was evaluated from virtual monochromatic images of 55 keV and iodine map using DECT. Morphologic changes in the liver were assessed using CT. Final pathology scores were compared between the two groups. Liver stiffness and perfusion parameters were compared according to the groups, days, and pathology scores. RESULTS: Final pathology scores were significantly higher in the SOS than the control group (median 22 vs 2, P = 0.024). No gross morphologic changes were seen in livers. Liver stiffness, Hounsfield Unit values, and iodine concentrations were higher in the SOS compared to the control group on days 10 and 20 (all, P ≤ 0.007). Compared to day 0, liver stiffness and perfusion parameters were higher on day 20 in the SOS group (all, P ≤ 0.001). Correlation coefficients for liver stiffness (r = 0.635), Hounsfield Unit values (r = 0.587), and iodine concentration (r = 0.611) with final pathology scores were positive without significance (all, P > 0.05). CONCLUSION: Liver stiffness and perfusion parameters were significantly increased in the livers of a rabbit SOS model. SSI and DECT might aid in early diagnosis of hepatic SOS.ope

Chordomas: Histopathological Study in View of Anatomical Location

BACKGROUND: Chordomas are aggressive bone tumors that have a predilection for the axial skeleton including the skull base and spinal/sacral bones. However, the histopathological and clinical differences between skull base chordoma (SBC) and sacral/spinal chordoma (SC) are unclear as previous studies have been focused on patient prognosis and treatment outcome. This study aimed to evaluate the clinicopathologic features and prognosis of chordoma according to its location. METHODS: Patients with chordomas were enrolled, and the histopathologic features were compared according to the tumor location. RESULTS: A total of 52 patients were enrolled. SBCs had more abundant chondroid matrix and diffuse growth pattern, while SCs had non-chondroid, myxoid matrix and a lobulating pattern, typical of chordoma. Old age and residual tumors were risk factors for shorter overall survival in SBCs. The chondroid matrix was an independent risk factor for shorter disease-free survival in the overall population. CONCLUSION: Chordomas have different histopathologic features depending on the anatomical location.ope

Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer

Purpose: The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). We strove to understand the biological, genomic, and clinical characteristics associated with SP142 PD-L1 positivity in TNBC patients. Methods: Using 149 TNBC formalin-fixed paraffin-embedded tumor samples, tissue microarray (TMA) and gene expression microarrays were performed in parallel. The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides. We next generated a gene signature reflective of SP142 status and evaluated signature distribution according to TNBCtype and PAM50 subtypes. A SP142 gene expression signature was identified and was biologically and clinically evaluated on the TNBCs of TCGA, other cohorts, and on other malignancies treated with immune checkpoint inhibitors (ICI). Results: Using SP142, 28.9% of samples were PD-L1 protein positive. The SP142 PD-L1-positive TNBC had higher CD8+ T cell percentage, stromal tumor-infiltrating lymphocyte levels, and higher rate of the immunomodulatory TNBCtype compared to PD-L1-negative samples. The recurrence-free survival was prolonged in PD-L1-positive TNBC. The SP142-guided gene expression signature consisted of 94 immune-related genes. The SP142 signature was associated with a higher pathologic complete response rate and better survival in multiple TNBC cohorts. In the TNBC of TCGA, this signature was correlated with lymphocyte-infiltrating signature scores, but not with tumor mutational burden or total neoantigen count. In other malignancies treated with ICIs, the SP142 genomic signature was associated with improved response and survival. Conclusions: We provide multi-faceted evidence that SP142 PDL1-positive TNBC have immuno-genomic features characterized as highly lymphocyte-infiltrated and a relatively favorable survival.ope

Anti-adhesion agent to prevent of post-operative adhesion and fibrosis after vasectomy: a study using a rat model

Background: Post-vasectomy pain syndrome (PVPS) is difficult to treat. Direct damage to the vas deferens, inflammation, compression of nerves through fibrotic adhesions, and congestion of the epididymis are known to cause PVPS. The purpose of this study was to evaluate whether the application of anti-adhesion agents after vasectomy can reduce the degree of adhesion and fibrosis in a rat model. Methods: In the study, 11 Sprague-Dawley rats (22 vas deferens) from each group were evaluated. In the experimental group, surgery was terminated after applying the anti-adhesion agent; this was not applied in the control group. After 14 days of vasectomy, the scrotum was dissected to evaluate the degree of gross adhesion at the vasectomy site. Histological examination of the surrounding tissues, including the vas deferens and the spermatic cord, was also performed. Results: Adhesions were not observed in 72.73% (16/22) rats from the experimental group, in which the anti-adhesion agent was applied; in contrast, the incidence of adhesions in the control group was 100%. There was a statistically significant relationship between the distribution of grades for adhesion and anti-adhesion agent (chi-square, P<0.001). On classification of fibrosis and inflammation, application of the anti-adhesion agent was significantly associated with lower grade inflammation and fibrosis compared to that of the control group (chi-square, P=0.001). The rate of intact muscle structure was 90.91% (20/22) in the experimental group, and 36.36% (8/22) in the control group, and the application of the anti-adhesion agent demonstrated significant association with preservation of intact muscle structure (chi-square, P<0.001). Conclusions: The application of an anti-adhesion agent after vasectomy prevented the development of adhesion, fibrosis, and inflammation reaction and further reduced structural destruction.ope

Prostate intraepithelial neoplasia 와 prostate cancer 에서의 microRNA 발현의 차이와 carcinogenesis 에 관여하는 연관된 전사 인자

의과대학/박사Background: Prostatic intraepithelial neoplasia (PIN), convincingly acceptable precursor lesion of prostate cancer (PCa), is characterized by obvious cytologic atypia in luminal cells with preserved basal cells. However, molecular association between PIN and PCa has been vaguely clarified. We aimed to identify miRNAs and surrogate target mRNA specific to regulate development of PIN and PCa, and to identify clinical implication of PIN as precancerous lesion of PCa. Materials and methods: Among the 388 radical prostatectomy patients, 69.3% harbored PIN, and large PIN was observed in 56 patients. Clinicopathologic analysis was performed based on the PIN status. To anlaysis miRNAs and surrogate target mRNAs, PIN clusters were obtained by macrodisseciton or laser capture microdissection from formalin-fixed paraffin embedded tissue. Using miRNA microarray screening analysis for each PIN or PCa to compare with normal prostatic tissue, top-ranked miRNAs with relatively lower expression were selected. Immunohistochemistry for FGFRL1, BACH1, ephrin-A3, STAT3, and ZEB1was performed, and expression level of the proteins in PCa, PIN, and normal prostatic tissue was analyzed. Results: Patients harbored PIN showed significant less lymphovascular invasion, less lymph node metastasis, lower tumor volume, lower Gleason score, lower death rate, longer overall survival compared to patients without PIN. Significant downregulation of miR-155, miR-210, miR-153, and miR-200c was observed. Subsequent validation step using immunohistochemistry against the candidate gene products revealed significant high expression of STAT3, ephrin-A3 and ZEB1 in PCa compared to PIN and normal prostatic tissue. Significant stepwise increase in expression of STAT3 and ZEB1 was observed from normal prostatic tissue to PCa. Conclusion: More favorable clinicopathologic parameters and longer overall survival in patients with PIN imply disease progression from PIN to PCa. Furthermore, downregulation of cancer-related miRNAs - miR-155, miR-210, miR-153, and miR-200c- in both PIN and PCa and stepwise increased expression of STAT3 and ZEB1 support that PIN is a preceding lesion of PCa and early carcinogenesis starts at the molecular level.ope

Expression of EMP1, EMP2, and EMP3 in breast phyllodes tumors

Purpose: Phyllodes tumors (PTs) are biphasic tumors accounting for 0.3-1.5% of all breast tumors. Epithelial membrane proteins (EMPs) have been reported in various malignant tumors but their expression in PTs is unclear. In this study, we aimed to evaluate the expression of EMP1, EMP2, and EMP3 in breast phyllodes tumors (PTs), and to investigate their clinical implications. Methods: In total, 185 PTs were used for constructing a tissue microarray. Immunohistochemical staining for EMP1, EMP2, and EMP3 was performed, and the results were analyzed along with the clinicopathologic parameters. Results: In total, 185 PTs were included in this study, and comprised 138 benign, 32 borderline, and 15 malignant PTs. In malignant PTs, the epithelial component showed decreased expression of EMP1 (P = 0.027), EMP2 (P = 0.004), and EMP3 (P = 0.032), compared to the benign and borderline PTs. Conversely, stromal component of borderline and malignant PTs showed higher expression of EMP1 (P = 0.027), EMP2 (P = 0.004), and EMP3 (P = 0.032) compared to benign PTs. Expression of EMP1 and EMP3 correlated positively with stromal cellularity and cellular atypia (P < 0.001). In the univariate analysis, stromal EMP3 was associated with shorter disease-free survival (P < 0.001), and shorter overall survival (P = 0.034). Conclusion: The expression of EMP1, EMP2, and EMP3 is decreased in the epithelial component and is increased in the stromal component of PT with higher histologic grade. Thus, stromal EMP3 expression may serve as an independent prognostic factor in PT.ope