Prognostic value of GRIM-19, NF-κB and IKK2 in patients with high-grade serous ovarian cancer

Publication date: Available online 6 December 2017
Source:Pathology - Research and Practice
Author(s): Felipe Ilelis, Nayra Soares do Amaral, Mariana Rezende Alves, Alexandre André Balieiro Anastácio da Costa, Vinícius Fernando Calsavara, Leonardo Lordello, Louise De Brot, Fernando Augusto Soares, Iara Sant'Ana Rodrigues, Rafael Malagoli Rocha
AimsHigh grade serous carcinoma (HGSC) is an aggressive tumour, and most patients relapse after treatment, acquiring resistance to platinum-based chemotherapy. One of the resistance mechanisms proposed is apoptosis evasion triggered by drug-related cytotoxic effect in the cell. In this context, this study aims to evaluate the protein expression of GRIM-19, NF-κB and IKK2, their association with chemotherapy response and to determine their prognostic values in HGSC.MethodsGRIM-19, NF-κB and IKK2 expression was evaluated by immunohistochemistry (IHC) in 71 patients with HGSC selected between 2003 and 2013, whose underwent primary debulking surgery with complete cytoreduction. Protein expression was analyzed in relation to platinum response groups, tumour progression, clinicopathological data and survival.ResultsPositive IKK2 expression was related to resistance (p=0.011), shorter disease-free survival (p=0.001) and overall survival (p=0.026) and was also a risk factor for relapse (p=0.002) and death (p=0.032). The association between IKK2 and NF-κB positivity predicted a subgroup with shorter overall survival (p=0.004), disease-free survival (p=0.003) and resistance to platinum-based chemotherapy (p=0.036). NF-κB positivity was associated with worse overall survival (p=0.005) and disease-free survival (p=0.027) and was a positive predictor for relapse (p=0.032) and death (p=0.008). Higher expression of GRIM-19 was associated with higher disease-free survival (p=0.039) and was a negative predictor for relapse (p=0.046).ConclusionsGRIM-19 is a potential predictor of prognosis and disease recurrence in HGSC. IKK2 and NF-κB are related to poor prognosis and are potential predictors of response to platinum-based chemotherapy in HGSC. IHC analyses of GRIM19, IKK2 and NF-κB may be important in the attempt to provide prognostic values for relapse and response to treatment in patients with HGSC.



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Clinicopathologic features of adult EBV-associated B-cell lymphoproliferative disease

Publication date: Available online 2 December 2017
Source:Pathology - Research and Practice
Author(s): Sonja Wörner, Hans-Konrad Mueller-Hermelink, Hans-Ullrich Voelker
In the present study, 21 cases of adult/late-onset EBV-associated lymphoproliferative disease (AELPD) with an uncertain malignant potential were investigated with regard to their histomorphology, immunophenotype, clonal rearrangement of the heavy chain (IgH) and T-cell receptor (TCR) genes and clinical course.The cases were histomorphologically reevaluated and assigned to one of three morphological groups: mononucleosis-like, Hodgkin-like, or polymorphous. In addition, cases with or without detectable necrosis were investigated for differences in clinical outcome.Overall survival was highest in the group with Hodgkin-like morphology (4/4 patients), followed by patients with mononucleosis-like phenotype (4/5 patients surviving). Cases with polymorphous morphology showed the poorest survival rates with 7/12 patients dead of disease (58%). 4/6 patients with histologically detectable necrosis died (66%), but only 4/15 patients without necrosis (27%). 11/21 cases with AELPD showed clonal rearrangement for IgH (n=4), TCR (n=5) or IgH+TCR (n=2). 5/11 patients with clonal rearrangement died (45%), and this percentage was similar in all of the three subgroups.In conclusion, the present study shows that polymorphous morphology and detection of necrosis in AELPD are frequently linked to a fatal clinical course, whereas Hodgkin-like morphology seems to be associated with a more favourable prognosis. Clonal rearrangement of IgH or TCR is frequent in AELPD, but prognosis is unpredictable from this feature.



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Role of miR-1 expression in clear cell renal cell carcinoma (ccRCC): a bioinformatics study based on GEO, ArrayExpress microarrays and TCGA database

Publication date: Available online 2 December 2017
Source:Pathology - Research and Practice
Author(s): Hai-biao Yan, Jia-cheng Huang, You-rong Chen, Jian-ni Yao, Wei-ning Cen, Jia-yi Li, Yi-fan Jiang, Gang Chen, Sheng-hua Li
PurposeTo investigate the clinical value and potential molecular mechanisms of miR-1 in clear cell renal cell carcinoma (ccRCC).MethodsWe searched the Gene Expression Omnibus (GEO), ArrayExpress, several online publication databases and the Cancer Genome Atlas (TCGA). Continuous variable meta-analysis and diagnostic meta-analysis were conducted, both in Stata 14, to show the expression of miR-1 in ccRCC. Furthermore, we acquired the potential targets of miR-1 from datasets that transfected miR-1 into ccRCC cells, online prediction databases, differentially expressed genes from TCGA and literature. Subsequently bioinformatics analysis based on aforementioned selected target genes was conducted.ResultsThe combined effect was −0.92 with the 95% confidence interval (CI) of −1.08 to −0.77 based on fixed effect model (I2=81.3%, P<0.001). No publication bias was found in our investigation. Sensitivity analysis showed that GSE47582 and 2 TCGA studies might cause heterogeneity. After eliminating them, the combined effect was −0.47 (95%CI: −0.78, −0.16) with I2=18.3%. As for the diagnostic meta-analysis, the combined sensitivity and specificity were 0.90 (95%CI: 0.61, 0.98) and 0.63 (95%CI: 0.39, 0.82). The area under the curve (AUC) in the summarized receiver operating characteristic (SROC) curve was 0.83 (95%CI: 0.80, 0.86). No publication bias was found (P=0.15). We finally got 67 genes which were defined the promising target genes of miR-1 in ccRCC. The most three significant KEGG pathways based on the aforementioned genes were Complement and coagulation cascades, ECM-receptor interaction and Focal adhesion.ConclusionThe downregulation of miR-1 might play an important role in ccRCC by targeting its target genes.



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The associations between CYP24A1 polymorphisms and cancer susceptibility: A meta-analysis and trial sequential analysis

Publication date: Available online 21 November 2017
Source:Pathology - Research and Practice
Author(s): Man Zhu, Shili Qiu, Xianwei Zhang, Yingchao Wang, Tapara D.M. Souraka, Xue Wen, Chunzi Liang, Jiancheng Tu
PurposePublished data have shown that vitamin D may have a protective effect on cancer development. CYP24A1, the main enzyme responsible for the degradation of active vitamin D, plays an important role in many cancer related cellular processes. Up to now, relationships between CYP24A1 polymorphisms and cancer susceptibility have been widely investigated, whereas the results are inconsistent. The aim of present meta-analysis was to explore the associations between CYP24A1 polymorphisms and cancer susceptibility.MethodsWe searched on EMBASE, Web of Science, PubMed and China National Knowledge Infrastructure (CNKI) electronic databases (up to July 1, 2017) for relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to make the evaluation clear.ResultsTwenty-nine studies published in eight publications involving 20,593 cases and 25,458 controls were included. Five CYP24A1 gene polymorphisms were evaluated: rs2181874, rs2585428, rs4809960, rs6022999, and rs6068816. Our analyses suggested that rs2585428 and rs4809960 polymorphisms were significantly associated with overall cancer risk. Stratification analyses of ethnicity indicated that rs2585428 and rs4809960 polymorphisms decreased the risk of cancer among Caucasians. When studies were stratified by cancer type, our results indicated that rs2585428 significantly decreased the risk of pancreas cancer, while rs4809960 significantly decreased the risk of breast cancer. There were no associations of rs2181874, rs6022999, or rs6068816 with overall cancer risks.ConclusionAssociations between CYP24A1 polymorphisms and cancer risks were examined, and additional multi-center studies with large samples are necessary to validate our results.



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DOWNREGULATION OF MIR-10B* IS CORRELATED WITH ALTERED EXPRESSION OF MITOTIC KINASES IN OSTEOSARCOMA

Publication date: Available online 2 December 2017
Source:Pathology - Research and Practice
Author(s): Gabriela Molinari Roberto, Edgard Eduard Engel, Carlos Alberto Scrideli, Luiz Gonzaga Tone, María Sol Brassesco
Dysregulated mitotic kinases have frequently been associated with cancer. Changes in their expression might result from diverse mechanisms including avoidance of the tight regulation exerted by miRNAs. Herein we show that miR-10b* is downregulated in osteosarcoma samples and demonstrate its correlation with PLK1, PLK4, BUB1, and BUBR1, which are strongly intercorrelated. The selection of miRNAs that coordinately target and regulate multiple members of cancer-related pathways are particularly advantageous to tumors. Thus, even though no associations with clinical parameters were found, our data place miR-10b* as a tumor suppressor that might contribute to guarantee genomic stability, deserving further functional confirmation.



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Accentuated p53 Staining in Usual Type Vulvar Dysplasia – A Potential Diagnostic Pitfall

Publication date: Available online 16 November 2017
Source:Pathology - Research and Practice
Author(s): Matthew Jeffreys, Susanne K. Jeffus, Michael Herfs, Charles Matthew Quick
Evaluation of vulvar intraepithelial neoplasia (VIN) may be difficult due to overlapping histologic features seen in both usual (UVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). DVIN represents a diagnostic challenge; poor inter-observer agreement is well documented. P53 has been described as a potentially helpful adjunct in some cases; however, intricacies in its interpretation remain. This study evaluated 41 consecutive cases which consisted of 23 keratinizing dysplasias that were morphologically suggestive of DVIN and 18 UVINs. All cases were stained with p16 and p53. Our results revealed that 22 of 41 (54%) VINs showed novel accentuated wild type (WT) staining with non-linear basal staining for p53, including 12 (52%) cases histologically suggestive of DVIN and 10 (56%) described as UVIN. P16 was positive in 100% of the accentuated wild type cases, consistent with a diagnosis of UVIN. Positive p53 and negative p16 staining was seen in 4 (17%) cases histologically suggestive of DVIN. Of these, 75% progressed to carcinoma, whereas only 1 of 35 (3%) patients with UVIN progressed to carcinoma. In conclusion, DVIN is difficult to diagnose due to potential histologic overlap with UVIN, especially the warty, or keratinizing, subtype. Accentuated WT p53 in absence of concurrent p16 staining may lead to misdiagnosis of DVIN, especially in small biopsy samples. P16/p53 staining should be performed in tandem with strict adherence to patterns considered positive, as patients with UVIN have significantly less risk of progression.



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Ultrastructural Change of the Subchondral Bone Increases the Severity of Cartilage Damage in Osteoporotic Osteoarthritis of the Knee in Rabbits

Publication date: Available online 2 December 2017
Source:Pathology - Research and Practice
Author(s): Jiahui Zhang, Sainan Chen, Wenlie Chen, Yunmei Huang, Ruhui Lin, Meiya Huang, Yinsheng Wu, Liangpu Zheng, Zuanfang Li, Naishun Liao, Jinxia Ye, Xianxiang Liu
Osteoporotic osteoarthritis is a phenotype of osteoarthritis (OA) manifested as fragile and osteoporotic subchondral bone. However, the ultrastructural features of subchondral bone in osteoporosis OA have not been determined. The study was aimed to investigate the ultrastructural dynamic changes of subchondral bone in osteoporotic OA model and how the ultrastructural damage in the subchondral bone caused by osteoporosis deteriorated the cartilage damage in OA. Eighteen rabbits were equally randomized to three groups, including the control, the OA and the osteoporotic OA groups. The structural changes of cartilage were evaluated by HE and safranin-O fast green staining, the Mankin's grading system was used to assess the stage of OA progression. And microstructural or ultrastructural changes in subchondral bone were assessed by micro-computed tomography or by scanning electron microscopy. According to the changes of cartilage histopathology, the OA group was in the early pathological stage of OA while the osteoporotic OA group was in the middle stage of OA based on Mankin's grading system. In addition, the damage of cartilage surface, reduction in the number of chondrocytes and the matrix staining were more increased in the osteoporotic OA group compared to the OA group. Compared to the OA group, the subchondral bone in the microstructure and ultrastructure in the osteoporotic OA group showed more microfracture changes in trabecular bone with more destructions of the tree-like mesh. Moreover, the collagen fibers were random rough with a fewer amount of bone lacunae in subchondral cortical plate in the osteoporotic OA group compared to the OA group. These findings indicated that the subchondral bone ultrastructure in the osteoporotic OA model was characterized by the destruction of the network structure and collagen fibers. The subchondral bone ultrastructural damage caused by osteoporosis may change mechanical properties of the upper cartilage and aggravate OA cartilage. Therefore, early diagnosis and treatment of osteoporosis is of great significance to prevent early OA from further developing osteoporotic OA.



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Editorial Board

Publication date: December 2017
Source:Pathology - Research and Practice, Volume 213, Issue 12





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Corrigendum to “Characterization of common and rare mutations in EGFR and associated clinicopathological features in a large population of Chinese patients with lung cancer” [Pathology – Research and Practice 213 (2017) 749–758]

Publication date: December 2017
Source:Pathology - Research and Practice, Volume 213, Issue 12
Author(s): Bing Wei, Pengfei Ren, Chengjuan Zhang, Zhizhong Wang, Bing Dong, Ke Yang, Jiuzhou Zhao, Shichun Tu, Jie Ma, Yongjun Guo




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TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice

Publication date: Available online 26 November 2017
Source:Pathology - Research and Practice
Author(s): Hui Li, Jia Song, Guochao Niu, Hong Zhang, Jinbo Guo, David Q. Shih, Stephan R. Targan, Xiaolan Zhang
Tumor necrosis factor like cytokine 1A (TL1A) is a member of the TNF superfamily. Accumulating evidence demonstrated the importance of TL1A in the pathogenesis of inflammatory bowel disease (IBD) and suggested a potential role of TL1A blocking in IBD therapy. Here we aimed to explore whether the anti-TL1A antibody could ameliorate intestinal inflammation and fibrosis in IBD. A T cell transfer model of chronic colitis was induced by intraperitoneal injection of CD4⁺CD45RB^high naive T cells isolated from either C57BL/6 wild type (WT) mice or LCK-CD2-Tl1a-GFP transgenic (L-Tg) mice into recombinase activating gene-1-deficient (RAG^−/−) mice. The colitis model mice were treated prophylactically or therapeutically with anti-Tl1a antibody or IgG isotype control. Haematoxylin and eosin staining (H&E staining), Masson's trichrome staining (MT staining) and sirius red staining were used to detect histopathological changes in colonic tissue, immunohistochemical staining was used to detect the expressions of collagen I, collagen III, TIMP1, Vimentin, α-SMA and TGF-β1/Smad3. Results showed that anti-TL1A antibody could reduce intestinal inflammation and fibrosis by inhibiting the activation of intestinal fibroblasts and reducing the collagen synthesis in the T cell transfer model of chronic colitis. The mechanism may be related to the inhibition of TGF-1/Smad3 signaling pathway.



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IMPACT OF DNA REPAIR, FOLATE AND GLUTATHIONE GENE POLYMORPHISMS ON RISK OF NON-SMALL CELL LUNG CANCER.

Publication date: Available online 21 November 2017
Source:Pathology - Research and Practice
Author(s): Cristina Pérez-Ramírez, Marisa Cañadas-Garre, Ahmed Alnatsha, Eduardo Villar, Juan Ramón Delgado, Miguel Ángel Calleja-Hernández, María José Faus-Dáder
Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC.No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.



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High expression of GRK3 is associated with favorable prognosis in pancreatic ductal adenocarcinoma

Publication date: Available online 20 November 2017
Source:Pathology - Research and Practice
Author(s): Wen-Jing Liu, Li Zhou, Zhi-Yong Liang, Wei-Xun Zhou, Lei You, Tai-Ping Zhang, Yu-Pei Zhao
BackgroundIt was found that G-protein-coupled receptor kinase 3 (GRK3) played key biological roles in some cancers. However, its associations with clinicopathologic features and prognosis in pancreatic ductal adenocarcinoma (PDAC) remain unknown.Methods and methodsExpression of GRK3 was detected, using tissue microarray-based immunohistochemistry, in paired formalin-fixed paraffin-embedded tumor and non-tumor samples from 165 patients with PDAC after curative resection, and was further correlated with clinicopathologic parameters and cancer-specific survival (CSS).ResultsIt was shown that GRK3 expression was much lower in tumor than in non-tumor tissues. Moreover, expression of GRK3 in tumor tissues was significantly associated with gender and T stage. Univariately, high GRK3 expression was predictive for favorable CSS, along with some conventional clinicopathologic variables. In multivariate Cox regression test, GRK3 expression remained to be a significant prognostic marker for PDAC. Finally, combination of GRK3 with some clinicopathologic variables, especially N stage, obtained more precise prediction for CSS.ConclusionsOur data suggested that expression of GRK3 was down-regulated in PDAC and was an independent prognostic factor.



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Cyclin D1 expression by histiocytes may mimic cyclin D1-positive proliferation centres of chronic lymphocytic leukaemia/small lymphocytic lymphoma

Publication date: Available online 16 November 2017
Source:Pathology - Research and Practice
Author(s): Jianghua Wu, Yanhui Zhang, Lin Sun, Qiongli Zhai
AimsCyclin D1, generally considered to be absent in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), has been reported in the proliferation centres (PCs) of recent CLL/SLL cases. Cyclin D1 immunostaining in CLL/SLL may lead to diagnostic confusion. The objective of this study was to identify the types of stained cells and the impact on diagnosis.MethodsCyclin D1 expression was assessed by immunostaining samples from 46 cases of CLL/SLL. CD68 and double immunostaining with CD20/CyclinD1, CD68/CyclinD1, and CD163/CyclinD1 were then performed in cases of CLL/SLL positive for cyclinD1 in the PCs.ResultsDim-positive cyclin D1 staining in randomly scattered cells in the CLL/SLLs were observed in 38/46 cases (82.6%). In five (10.9%) cases, more than 50 cyclin D1-positive cells per high-power field were detected within the PCs in CLL/SLL with weak to moderate intensity. Double immunochemical staining in these cases showed that cyclin D1 in these positive cells was mostly co-expressed with CD68 and CD163 and the cells were negative for CD20.ConclusionsThe cyclin D1-positive CLL/SLL cells in this study were mostly histiocytes. The expression of cyclin D1 by histiocytes may mimic cyclin D1+ CLL/SLL; thus, the recognition of cyclin D1 expression by non-lymphoid cells in lymphoma is important.



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Cost-effectiveness of Ovarian Cancer Screening in the United States

Using a Markov simulation model based on the United Kingdom Collaborative Trial of Ovarian Cancer Screening clinical trial, this study examines the cost-effectiveness of multimodal screening for ovarian cancer in the United States and the association of screening with mortality.

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Financial Toxicity of Cancer Care in America

This article discusses the benefits of shared decision making and having open discussions about costs in the cancer care debate.

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A Peculiar Adenocarcinoma

A man in his 60s presented with a 1-year history of a mild, dry cough; a chest radiograph revealed a 10 × 9-cm lobulated left lower lobe mass. What is your diagnosis?

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Validation Study of the AJCC Eighth Edition Prognostic Stage in Breast Cancer

This validation study compares the American Joint Committee on Cancer eighth edition prognostic stage with the anatomic stage among patients with breast cancer in a single-institution cohort and a large population database.

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A Policy That Encourages Wastage of Expensive Medications

This Viewpoint explores the legislation that allows payment for wastage of injectable medications.

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Seizure and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer

This safety study investigates seizure rates in men at increased risk for seizure who are taking enzalutamide for metastatic castration-resistant prostate cancer.

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Zoledronic Acid Dosing in Patients With Metastatic Breast Cancer

To the Editor Hortobagyi et al conducted a noninferiority study for zoledronic acid dosing every 12 weeks (12W), comparing it with its counterpart of dosing every 4 weeks (4W) in women with breast cancer metastatic to bone. The primary end point was whether the patient had at least 1 debilitating skeletal-related event (SRE) by 12 months. The SREs occurred in 44 patients (22.0%) in the 4W zoledronic acid group and 47 patients (23.2%) in the 12W zoledronic acid group. The treatment difference (12W minus 4W) is 1.2%, with the upper bound of the 1-sided 97.5% confidence interval (CI) being 9.8%, barely within the prespecified noninferiority margin of 10%. That is, potentially, 12W zoledronic acid can be 9.8% worse than 4W zoledronic acid with respect to the SRE rate. Using such a large observed noninferiority margin to claim that 12W is as good as 4W is debatable.

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