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Abstract Objectives Ionized calcium binding adaptor molecule 1 (IBA1), a marker of microglia/macrophages, has not been investigated in human hematopathologic contexts. We evaluated its expression in mature and immature neoplasms of monocytic/histiocytic and dendritic cell (DC) origin. Methods Immunohistochemistry for IBA1, CD14, CD68, and CD163 was performed on a total of 114 cases, including a spectrum of monocytic/histiocytic and DC neoplasms (20 tissue based and 59 bone marrow based) and several nonhistiocytic/monocytic/DC neoplasms as control groups (15 tissue based and 20 bone marrow based). Results IBA1 expression was observed in all types of mature tissue-based histiocytic/DC neoplasms (20/20) but not in the corresponding control group (0/15). In bone marrow–based cases, IBA1 was expressed in most acute myeloid leukemias (AMLs) with monocytic differentiation (48/53), both blastic plasmacytoid dendritic cell neoplasms (2/2), and all chronic myelomonocytic leukemias (4/4), while it was positive in only one nonmonocytic AML (1/15) and none of the acute lymphoblastic leukemias (0/5). Collectively, IBA1 showed much higher sensitivity and specificity (93.7%, 97.1%) compared with CD14 (65.4%, 88.2%), CD68 (74.4%, 74.2%), and CD163 (52.6%, 90.6%). Conclusions IBA1 is a novel, highly sensitive, and specific marker for diagnosing neoplasms of monocytic/histiocytic and DC origin.

Recent work has highlighted the tumor microenvironment as a central player in cancer. In particular, interactions between tumor and immune cells may help drive the development of brain tumors such as glioblastoma multiforme (GBM). Despite significant research into the molecular classification of glioblastoma, few studies have characterized in a comprehensive manner the immune infiltrate in situ and within different GBM subtypes. In this study, we use an unbiased, automated immunohistochemistry-based approach to determine the immune phenotype of the four GBM subtypes (classical, mesenchymal, neural and proneural) in a cohort of 98 patients. Tissue Micro Arrays (TMA) were stained for CD20 (B lymphocytes), CD5, CD3, CD4, CD8 (T lymphocytes), CD68 (microglia), and CD163 (bone marrow derived macrophages) antibodies. Using automated image analysis, the percentage of each immune population was calculated with respect to the total tumor cells. Mesenchymal GBMs displayed the highest percentage of microglia, macrophage, and lymphocyte infiltration. CD68 + and CD163 + cells were the most abundant cell populations in all four GBM subtypes, and a higher percentage of CD163 + cells was associated with a worse prognosis. We also compared our results to the relative composition of immune cell type infiltration (using RNA-seq data) across TCGA GBM tumors and validated our results obtained with immunohistochemistry with an external cohort and a different method. The results of this study offer a comprehensive analysis of the distribution and the infiltration of the immune components across the four commonly described GBM subgroups, setting the basis for a more detailed patient classification and new insights that may be used to better apply or design immunotherapies for GBM.

One of the major challenges in the head and neck oncology clinic is the need to identify biomarkers and/or gene expression signatures that complement, strengthen and increase the sensitivity and specificity of the current clinicopathologic analyses. Microarray analysis of head and neck tumors has demonstrated that the combined influence of many genes or biomarkers can make superior identifiers and/or predictors of tumor behavior and patient outcome. Here, an update of the recent literature on the prognostic and predictive value of microarrays for patients with head and neck squamous cell carcinomas is presented. Microarray technology has the potential for improved decision-making and corroboration within the clinical setting. However, further integration, standardization, validation and research are required before the use of microarray analysis is ready for routine clinical management of head and neck squamous cell carcinomas.

Ionized calcium binding adaptor molecule 1 (IBA1), a marker of microglia/macrophages, has not been investigated in human hematopathologic contexts. We evaluated its expression in mature and immature neoplasms of monocytic/histiocytic and dendritic cell (DC) origin. Immunohistochemistry for IBA1, CD14, CD68, and CD163 was performed on a total of 114 cases, including a spectrum of monocytic/histiocytic and DC neoplasms (20 tissue based and 59 bone marrow based) and several nonhistiocytic/monocytic/DC neoplasms as control groups (15 tissue based and 20 bone marrow based). IBA1 expression was observed in all types of mature tissue-based histiocytic/DC neoplasms (20/20) but not in the corresponding control group (0/15). In bone marrow-based cases, IBA1 was expressed in most acute myeloid leukemias (AMLs) with monocytic differentiation (48/53), both blastic plasmacytoid dendritic cell neoplasms (2/2), and all chronic myelomonocytic leukemias (4/4), while it was positive in only one nonmonocytic AML (1/15) and none of the acute lymphoblastic leukemias (0/5). Collectively, IBA1 showed much higher sensitivity and specificity (93.7%, 97.1%) compared with CD14 (65.4%, 88.2%), CD68 (74.4%, 74.2%), and CD163 (52.6%, 90.6%). IBA1 is a novel, highly sensitive, and specific marker for diagnosing neoplasms of monocytic/histiocytic and DC origin.

Abstract Objectives Grading cervical intraepithelial neoplasia is important for appropriate patient management. The management of CIN1 and CIN3 is well characterized; however, the management of CIN2 is controversial as the behavior is less predictable. HPV mRNA expression patterns within these lesions have been described; however, the predictive power of these staining patterns has not been studied. The ASCCP recommends that women <24 years with CIN2 are observed due to high likelihood of regression. In this study, we evaluated the staining patterns of CIN2 to determine whether they can be further stratified to predict regression or progression. Methods A retrospective database search was performed from 2013 to 2017, identifying 26 patients <28 years old with CIN2. Exclusion criteria included patients who underwent surgical excision. The mean follow-up time was 10.5 months. HPV E6/E7 mRNA expression patterns were evaluated by RNAscope chromogenic in situ hybridization (CISH). The mRNA expression patterns were graded as pattern 1, superficial diffuse nuclear staining; pattern 2, superficial diffuse nuclear staining and scattered dot-like nuclear and granular cytoplasmic staining; and pattern 3, scattered dot-like nuclear and granular cytoplasmic staining. Results Thirteen cases had pattern 2 and 13 had pattern 3 staining. Seven of the pattern 2 cases regressed on follow-up Pap smear or biopsy, while six persisted or progressed. Eight of the pattern 3 cases regressed while five persisted or progressed. Therefore, pattern 2 staining was not predictive of regression (P > .9). Conclusion HPV mRNA expression pattern was hypothesized to be predictive of CIN2 biologic behavior (ie, pattern 2 more likely to regress, pattern 3 likely to persist/progress); however, this small cohort with limited follow-up failed to confirm this hypothesis. This ongoing study will continue to review additional cases with follow-up to gain a larger statistical power and better understand the biologic potential of these lesions.

As we show in this study, NAMPT, the key rate-limiting enzyme in the salvage pathway, one of the three known pathways involved in NAD synthesis, is selectively over-expressed in anaplastic T-cell lymphoma carrying oncogenic kinase NPM1::ALK (ALK + ALCL). NPM1::ALK induces expression of the NAMPT-encoding gene with STAT3 acting as transcriptional activator of the gene. Inhibition of NAMPT affects ALK + ALCL cells expression of numerous genes, many from the cell-signaling, metabolic, and apoptotic pathways. NAMPT inhibition also functionally impairs the key metabolic and signaling pathways, strikingly including enzymatic activity and, hence, oncogenic function of NPM1::ALK itself. Consequently, NAMPT inhibition induces cell death in vitro and suppresses ALK + ALCL tumor growth in vivo. These results indicate that NAMPT is a novel therapeutic target in ALK + ALCL and, possibly, other similar malignancies. Targeting metabolic pathways selectively activated by oncogenic kinases to which malignant cells become “addicted” may become a novel therapeutic approach to cancer, alternative or, more likely, complementary to direct inhibition of the kinase enzymatic domain. This potential therapy to simultaneously inhibit and metabolically “starve” oncogenic kinases may not only lead to higher response rates but also delay, or even prevent, development of drug resistance, frequently seen when kinase inhibitors are used as single agents.

Mesothelin is a potential therapeutic target and prognostic marker in breast cancer. However, results on its prognostic value in breast cancer have been equivocal and warranted further evaluation. We analyzed clinical data from two breast cancer patient cohorts comprising of 141 patients treated at our institution (discovery cohort) and 844 patients from The Cancer Genome Atlas (TCGA) (validation cohort). Mesothelin expression was quantified by immunohistochemistry or by RNA transcript levels as measured by whole-transcriptome sequencing in the discovery and validation cohorts respectively. Univariate analyses of data from the discovery cohort demonstrated that tumor size [hazard ratio (HR) = 1.30, 95 % confidence interval (CI) 1.11–1.51], positive (+) axillary lymph nodes (HR = 3.34; 95 % CI 1.51–7.39), and mesothelin expression (HR = 2.03; 95 % CI 1.10–3.74) were associated with disease-specific survival. Multivariate analyses demonstrated that mesothelin expression was significantly associated with worse survival (HR = 3.06, 95 % CI 1.40–6.68) after adjusting for (+) axillary lymph nodes and tumor size. Using TCGA cohort as validation dataset, mesothelin-expressing tumors were indeed significantly associated with worse overall survival with HR = 1.46; 95 % CI 1.05–2.03 and HR = 1.69; 95 % CI 1.17–2.42 in univariate and multivariate analyses respectively. Our results suggest that mesothelin is a prognostic breast tumor marker whose expression is highly enriched in triple negative breast cancer (TNBC) tumors. As there is no existing targeted therapy for TNBC, mesothelin may be a promising drug target for TNBC. Future work is needed to evaluate the efficacy of mesothelin directed targeted therapy in the treatment of breast cancer.

Background H. pylori ( Hp ) infection is a major risk factor in gastric carcinogenesis leading to epithelial mutagenesis, and may affect gastric epithelial stem cells. Aims To characterize the expression of Lgr5, a marker of epithelial stem cells in human gastric mucosa, to determine whether Hp infection affects Lgr5-positive epithelial cells (LPECs) and whether LPECs are susceptible to DNA damage associated with Hp infection. Methods Lgr5 expression was characterized in non-neoplastic gastric mucosa from 52 patients (34 with and 18 without gastric cancer (GC); 21 Hp -positive ( Hp +) and 31 Hp -negative ( Hp −)) by immunohistochemical and immunofluorescence staining. To determine the extent of DNA damage in LPECs, nuclear 8-hydroxydeoxyguanosine (8OHdG), a marker of DNA damage associated with oxidative stress, was measured by quantitative spectral image analysis. Results LPECs were primarily present in gastric antrum. Higher numbers of LPECs were seen in Hp + than in Hp − non-neoplastic mucosa of GC patients, P  = .006, but not in patients without GC. 8OHdG levels in LPECs were significantly higher than in Lgr5-negative epithelial cells in Hp + GC patients ( P  = .012) but not in Hp − cases ( P  = .414), whereas no difference was seen between Hp + and Hp − mucosa of patients without GC. Conclusions The Lgr5-positive epithelial stem cell pool is expanded in Hp -associated gastritis in the antrum of patients with GC. In GC patients with active Hp infection, LPECs may be more susceptible to DNA damage than Lgr5-negative epithelial cells, suggesting that Hp infection may contribute to GC risk by affecting epithelial stem cells in the human stomach.

Microsatellite instability (MSI) contributes to the tumorigenesis of upper urinary tract urothelial carcinomas (UUT-UCs). In this study, we first used MLH1 and MSH2 immunohistochemistry to identify patients with loss of expression of either or both of these proteins in 132 UUT-UCs. We found a total loss of MSH2 expression in 4 patients. MSI was evaluated using 5 markers in these 4 cases. All of the tumors had high MSI (MSI-H) status. Trans-activation responsive RNA-binding protein 2, an integral component of DICER1-containing complex, was a putative target of DNA mismatch repair deficiency. Truncating mutation has been identified in gastrointestinal cancers with MSI. No previous study has evaluated the mutation status of this gene in MSI UUT-UCs. In this study, we analyze the mutation of TARBP2 in MSI-H UUT-UCs with reverse transcription polymerase chain reaction. No truncating mutations were identified in the MSI-H UUT-UCs.