Efficacy of fine needle aspiration cytology in diagnosing Secretory Carcinoma of salivary gland: A systematic review and meta-analysis.

BACKGROUND: The diagnosis of salivary gland secretory carcinoma (SC) in fine needle aspiration specimens is challenging, because it's low-grade nature makes it difficult to differentiate it from various benign or malignant salivary gland neoplasms. Currently, the gold standard is demonstration of ETV6-NTRK3 fusion gene. However, the decision for ordering this costly molecular testing can be facilitated by the correct recognition of its cytomorphological features. OBJECTIVES: The primary objective is to determine the accuracy of fine-needle aspiration cytology (FNAC) in diagnosis of salivary gland SC. The secondary objective is to recognize varied cytomorphological patterns, characteristic features of SC and differentiate it from other neoplasms. METHOD: PubMed/MEDLINE, Science Direct, Embase, Cochrane review and PROSPERO databases were searched for studies having all the following key search terms: ("secretory carcinoma of salivary gland" OR "mammary analogue secretory carcinoma of salivary gland") AND ("Cytology"OR "Cytological features" OR "aspirate" OR "cytodiagnosis") published in the time frame of 2010 to June 2023. Studies reporting cytological features of the salivary gland tumors which were confirmed/diagnosed as secretory carcinoma on molecular investigation, were included in the systematic review. Finally, seventeen studies reporting a total of 45 cases were included in the metanalysis. RESULTS: The sensitivity of the FNAC in diagnosing SC in salivary gland is 27.7% (95% CI16.6-42.5%). The LR+ (positive likelihood ratio) was 0.654 (0.344-1.245), LR- (negative likelihood ratio) was 1.023 (0.538- 1.946) and diagnostic odds ratio was 0.421(0.129-1.374). The molecular testing and/or immunohistochemistry performed on cell block increased the diagnostic accuracy. CONCLUSION: Recognition of subtle cytomorphological patterns, i.e., papillary formation, clusters and singly dispersed cells along with presence of fine intracytoplasmic vacuolations were the characteristic findings in majority of cases, confirmed with diagnostic molecular profiling. This may be helpful in identification of this rare entity with limited published literature and help in increasing diagnostic accuracy.

Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach.

Peripheral T-cell lymphoma (PTCL) is a clinically heterogeneous group that represents 10%-15% of all lymphomas. Despite improved genetic and molecular understanding, treatment outcomes for PTCL have not shown significant improvement. Although Janus kinase-2 (JAK2) plays an important role in myeloproliferative neoplasms, the critical role of JAK isoforms in mediating prosurvival signaling in PTCL cells is not well defined. Immunohistochemical analysis of PTCL tumors (n = 96) revealed high levels of constitutively active JAK3 (pJAK3) that significantly (p < 0.04) correlated with the activation state of its canonical substrate STAT3. Furthermore, constitutive activation of JAK3 and STAT3 positively correlated, at least in part, with an oncogenic tyrosine phosphatase PTPN11. Pharmacological inhibition of JAK3 but not JAK1/JAK2 significantly (p < 0.001) decreased PTCL proliferation, survival and STAT3 activation. A sharp contrast was observed in the pJAK3 positivity between ALK+ (85.7%) versus ALK-negative (10.0%) in human PTCL tumors and PTCL cell lines. Moreover, JAK3 and ALK reciprocally interacted in PTCL cells, forming a complex to possibly regulate STAT3 signaling. Finally, combined inhibition of JAK3 (by WHI-P154) and ALK (by crizotinib or alectinib) significantly (p < 0.01) decreased the survival of PTCL cells as compared to either agent alone by inhibiting STAT3 downstream signaling. Collectively, our findings establish that JAK3 is a therapeutic target for a subset of PTCL, and provide rationale for the clinical evaluation of JAK3 inhibitors combined with ALK-targeted therapy in PTCL.

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase.

In triple-negative breast cancer (TNBC) that relies on catabolism of amino acid glutamine, glutaminase (GLS) converts glutamine to glutamate, which facilitates glutathione synthesis by mediating the enrichment of intracellular cystine via xCT antiporter activity. To overcome chemo resistant TNBC, we have tested a strategy of disrupting cellular redox balance by inhibition of GLS and xCT by CB839 and Erastin, respectively. Key findings of our study include: 1. Dual metabolic inhibition (CB839+Erastin) led to significant increases of cellular superoxide level in both parent and chemo resistant TNBC cells, but superoxide level was distinctly lower in resistant cells. 2. Dual metabolic inhibition combined with doxorubicin or cisplatin induced significant apoptosis in TNBC cells and is associated with high degrees of GSH depletion. In vivo , dual metabolic inhibition plus cisplatin led to significant growth delay of chemo resistant human TNBC xenografts. 3. Ferroptosis is induced by doxorubicin (DOX) but not by cisplatin or paclitaxel. Addition of dual metabolic inhibition to DOX chemotherapy significantly enhanced ferroptotic cell death. 4. Significant changes in cellular metabolites concentration preceded transcriptome changes revealed by single cell RNA sequencing, underscoring the potential of capturing early changes in metabolites as pharmacodynamic markers of metabolic inhibitors. Here we demonstrated that 4-(3-[ 18 F]fluoropropyl)-L-glutamic acid ([ 18 F]FSPG) PET detected xCT blockade by Erastin or its analog in mice bearing human TNBC xenografts. In summary, our study provides compelling evidence for the therapeutic benefit and feasibility of non-invasive monitoring of dual metabolic blockade as a translational strategy to sensitize chemo resistant TNBC to cytotoxic chemotherapy.

Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma, including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven-IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in vivo targeting of CCR1 with CCR1 antagonist BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.

18F-Fluciclovine PET Imaging of Glutaminase Inhibition in Breast Cancer Models.

Aggressive cancers such as triple-negative breast cancer (TNBC) avidly metabolize glutamine as a feature of their malignant phenotype. The conversion of glutamine to glutamate by the glutaminase enzyme represents the first and rate-limiting step of this pathway and a target for drug development. Indeed, a novel glutaminase inhibitor (GLSi) has been developed and tested in clinical trials but with limited success, suggesting the potential for a biomarker to select patients who could benefit from this novel therapy. Here, we studied a nonmetabolized amino acid analog, 18F-fluciclovine, as a PET imaging biomarker for detecting the pharmacodynamic response to GLSi. Methods: Uptake of 18F-fluciclovine into human breast cancer cells was studied in the presence and absence of inhibitors of glutamine transporters and GLSi. To allow 18F-fluciclovine PET to be performed on mice, citrate in the tracer formulation is replaced by phosphate-buffered saline. Mice bearing triple-negative breast cancer (TNBC) xenografts (HCC38, HCC1806, and MBA-MD-231) and estrogen receptor-positive breast cancer xenografts (MCF-7) were imaged with dynamic PET at baseline and after a 2-d treatment of GLSi (CB839) or vehicle. Kinetic analysis suggested reversible uptake of the tracer, and the distribution volume (VD) of 18F-fluciclovine was estimated by Logan plot analysis. Results: Our data showed that cellular uptake of 18F-fluciclovine is mediated by glutamine transporters. A significant increase in VD was observed after CB839 treatment in TNBC models exhibiting high glutaminase activity (HCC38 and HCC1806) but not in TNBC or MCF-7 exhibiting low glutaminase. Changes in VD were corroborated with changes in GLS activity measured in tumors treated with CB839 versus vehicle, as well as with changes in VD of 18F-(2S,R4)-fluoroglutamine, which we previously validated as a measure of cellular glutamine pool size. A moderate, albeit significant, decrease in 18F-FDG PET signal was observed in HCC1806 tumors after CB839 treatment. Conclusion: 18F-fluciclovine PET has potential to serve as a clinically translatable pharmacodynamic biomarker of GLSi.

Study of morphology with assessment of expression of proliferation marker Ki67 antigen and P53 protein in lesions of gall bladder.

OBJECTIVE: To study the spectrum and distribution of histopathological changes and evaluate immunohistochemistry markers p53 protein and Ki67 antigen in various lesions of gall bladder. MATERIALS AND METHODS: A total of 804 consecutive gall bladder specimens were evaluated. Forty cases were selected for immunohistochemical analysis to evaluate expression of p53 and ki67 proliferation index, including 20 carcinoma gall bladder cases and 20 cases of inflammatory pathology associated with metaplasia, atypia, hyperplasia, dysplasia, and adenoma. p53 immunostaining was categorized as wild type and mutant type. ki67 of >20% was considered high expression. RESULTS: The majority of the gall bladder lesions were inflammatory in origin, most common being chronic cholecystitis. In the group of 20 gall bladder carcinoma cases, 65% were p53 mutant and the remaining 35% cases had a p53 wild-type immunophenotype. 55% cases showed high expression for ki67 labeling. However, significant correlation (P < 0.05) was seen with lympho-vascular invasion. Among non-malignant lesions, normal/wild-type p53 expression was seen with increasing intensity and positivity in lesions with atypia and intra-epithelial neoplasms. Ki67 index also showed the same trend in all cases. CONCLUSIONS: p53 and ki-67 expression increases in inflammation, and further increment occurs in premalignant and malignant lesions of the gall bladder epithelium and can be used as a marker of aggression of histopathological lesions. The results emphasize the potential of Ki-67 and p53 as biomarkers of carcinogenesis in gall bladder carcinoma.

Dynamic Contrast-Enhanced MRI in the Abdomen of Mice with High Temporal and Spatial Resolution Using Stack-of-Stars Sampling and KWIC Reconstruction.

Application of quantitative dynamic contrast-enhanced (DCE) MRI in mouse models of abdominal cancer is challenging due to the effects of RF inhomogeneity, image corruption from rapid respiratory motion and the need for high spatial and temporal resolutions. Here we demonstrate a DCE protocol optimized for such applications. The method consists of three acquisitions: (1) actual flip-angle B1 mapping, (2) variable flip-angle T1 mapping and (3) acquisition of the DCE series using a motion-robust radial strategy with k-space weighted image contrast (KWIC) reconstruction. All three acquisitions employ spoiled radial imaging with stack-of-stars sampling (SoS) and golden-angle increments between the views. This scheme is shown to minimize artifacts due to respiratory motion while simultaneously facilitating view-sharing image reconstruction for the dynamic series. The method is demonstrated in a genetically engineered mouse model of pancreatic ductal adenocarcinoma and yielded mean perfusion parameters of Ktrans = 0.23 ± 0.14 min-1 and ve = 0.31 ± 0.17 (n = 22) over a wide range of tumor sizes. The SoS-sampled DCE method is shown to produce artifact-free images with good SNR leading to robust estimation of DCE parameters.

DWI Metrics Differentiating Benign Intraductal Papillary Mucinous Neoplasms from Invasive Pancreatic Cancer: A Study in GEM Models.

KPC (KrasG12D:Trp53R172H:Pdx1-Cre) and CKS (KrasG12D:Smad4L/L:Ptf1a-Cre) mice are genetically engineered mouse (GEM) models that capture features of human pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN), respectively. We compared these autochthonous tumors using quantitative imaging metrics from diffusion-weighted MRI (DW-MRI) and dynamic contrast enhanced (DCE)-MRI in reference to quantitative histological metrics including cell density, fibrosis, and microvasculature density. Our results revealed distinct DW-MRI metrics between the KPC vs. CKS model (mimicking human PDAC vs. IPMN lesion): the apparent diffusion coefficient (ADC) of CKS tumors is significantly higher than that of KPC, with little overlap (mean ± SD 2.24±0.2 vs. 1.66±0.2, p<10−10) despite intratumor and intertumor variability. Kurtosis index (KI) is also distinctively separated in the two models. DW imaging metrics are consistent with growth pattern, cell density, and the cystic nature of the CKS tumors. Coregistration of ex vivo ADC maps with H&E-stained sections allowed for regional comparison and showed a correlation between local cell density and ADC value. In conclusion, studies in GEM models demonstrate the potential utility of diffusion-weighted MRI metrics for distinguishing pancreatic cancer from benign pancreatic cysts such as IPMN.

The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation.

Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is "shock and kill." This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) acts as an LRA by increasing signal transducer and activator of transcription (STAT) factor activation mediated by interleukin-15 (IL-15) in cells isolated from aviremic participants. The IL-15 superagonist N-803 is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanisms of action by promoting the activation of STATs and have shown some promise in preclinical models directed toward HIV eradication. In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in natural killer (NK) cells and the biological consequences associated with increased STAT activation in NK cell effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increases in the secretion of CXCL-10 and interferon gamma (IFN-γ) and the expression of cytotoxic proteins, including granzyme B, granzyme A, perforin, granulysin, FASL, and TRAIL. This increased cytotoxic profile results in increased cytotoxicity against HIV-infected cells and different tumor cell lines. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and thus, targeting this pathway could be further explored for HIV cure interventions. IMPORTANCE Several clinical trials targeting the HIV latent reservoir with LRAs have been completed. In spite of a lack of clinical benefit, they have been crucial to elucidate hurdles that "shock and kill" strategies have to overcome to promote an effective reduction of the latent reservoir to lead to a cure. These hurdles include low reactivation potential mediated by LRAs, the negative influence of some LRAs on the activity of natural killer and effector CD8 T cells, an increased resistance to apoptosis of latently infected cells, and an exhausted immune system due to chronic inflammation. To that end, finding therapeutic strategies that can overcome some of these challenges could improve the outcome of shock and kill strategies aimed at HIV eradication. Here, we show that the LRA HODHBt also improves IL-15-mediated NK cell effector and memory-like functions. As such, pharmacological enhancement of IL-15-mediated STAT activation can open new therapeutic avenues toward an HIV cure.

Role of intra-tumoral vasculature imaging features on susceptibility weighted imaging in differentiating primary central nervous system lymphoma from glioblastoma: a multiparametric comparison with pathological validation.

PURPOSE: Primary objective of this study was to retrospectively evaluate the potential of a range of qualitative and quantitative multiparametric features assessed on T2, post-contrast T1, DWI, DCE-MRI, and susceptibility-weighted-imaging (SWI) in differentiating evenly sampled cohort of primary-central-nervous-system-lymphoma (PCNSL) vs glioblastoma (GB) with pathological validation. METHODS: The study included MRI-data of histopathologically confirmed ninety-five GB and PCNSL patients scanned at 3.0 T MRI. A total of six qualitative features (three from T2 and post-contrast T1, three from SWI: thin-linear-uninterrupted-intra-tumoral-vasculature, broken-intra-tumoral-microvasculature, hemorrhage) were analyzed by three independent radiologists. Ten quantitative features from DWI and DCE-MRI were computed using in-house-developed algorithms. For qualitative features, Cohen's Kappa-interrater-variability-analysis was performed. Z-test and independent t-tests were performed to find significant qualitative and quantitative features respectively. Logistic-regression (LR) classifiers were implemented for evaluating performance of individual and various combinations of features in differentiating PCNSL vs GB. Performance evaluation was done via ROC-analysis. Pathological validation was performed to verify disintegration of vessel walls in GB and rim of viable neoplastic lymphoid cells with angiocentric-pattern in PCNSL. RESULTS: Three qualitative SWI features and four quantitative DCE-MRI features (rCBVcorr, Kep, Ve, and necrosis-volume-percentage) were significantly different (p < 0.05) between PCNSL and GB. Best diagnostic performance was observed with LR classifier using SWI features (AUC-0.99). The inclusion of quantitative features with SWI feature did not improve the differentiation accuracy. CONCLUSIONS: The combination of three qualitative SWI features using LR provided the highest accuracy in differentiating PCNSL and GB. Thin-linear-uninterrupted-intra-tumoral-vasculature in PCNSL and broken-intra-tumoral-microvasculature with hemorrhage in GB are the major contributors to the differentiation.

Spectrum of MRI Features of Mucin-producing Neoplasms in the Abdomen and Pelvis.

Mucin-producing neoplasms in the abdomen and pelvis are a distinct entity, separate from simple fluid-containing neoplasms and loculated fluid collections. Mucin is a thick gelatinous substance and-owing to its high water content-has imaging features that can be mistaken for those of simple fluid-containing neoplasms with multiple imaging modalities. However, mucin-producing neoplasms arise from specific organs in the abdomen and pelvis, with unique imaging appearances, knowledge of which is important to guide accurate diagnosis and management. With its large field of view and high soft-tissue resolution, MRI has advantages over other imaging modalities in characterizing these neoplasms. The authors focus on the spectrum of MRI features of such mucin-producing neoplasms and illustrate how-despite a varied organ origin-some of these neoplasms share similar MRI and histopathologic features, thereby helping narrow the differential diagnosis. One common finding in these tumors is that the presence of internal complexity and solid enhancing components increases as the degree of malignant transformation increases. Lack of internal complexity generally indicates benignity. These tumors have a varied range of prognosis; for example, a low-grade appendiceal mucinous neoplasm is indicative of a good prognosis, while a mucinous tumor of the rectum is known to manifest at an early age with aggressive behavior and poorer prognosis compared with its nonmucinous counterpart. Online supplemental material is available for this article. ©RSNA, 2022.

Radiomics signature for temporal evolution and recurrence patterns of glioblastoma using multimodal magnetic resonance imaging.

Glioblastoma is a highly infiltrative neoplasm with a high propensity of recurrence. The location of recurrence usually cannot be anticipated and depends on various factors, including the surgical resection margins. Currently, radiation planning utilizes the hyperintense signal from T2-FLAIR MRI and is delivered to a limited area defined by standardized guidelines. To this end, noninvasive early prediction and delineation of recurrence can aid in tailored targeted therapy, which may potentially delay the relapse, consequently improving overall survival. In this work, we hypothesize that radiomics-based phenotypic quantifiers may support the detection of recurrence before it is visualized on multimodal MRI. We employ retrospective longitudinal data from 29 subjects with a varying number of time points (three to 13) that includes glioblastoma recurrence. Voxelwise textural and intensity features are computed from multimodal MRI (T1-contrast enhanced [T1CE], FLAIR, and apparent diffusion coefficient), primarily to gain insights into longitudinal radiomic changes from preoperative MRI to recurrence and subsequently to predict the region of relapse from 143 ± 42 days before recurrence using machine learning. T1CE MRI first-order and gray-level co-occurrence matrix features are crucial in detecting local recurrence, while multimodal gray-level difference matrix and first-order features are highly predictive of the distant relapse, with a voxelwise test accuracy of 80.1% for distant recurrence and 71.4% for local recurrence. In summary, our work exemplifies a step forward in predicting glioblastoma recurrence using radiomics-based phenotypic changes that may potentially serve as MR-based biomarkers for customized therapeutic intervention.

Mantle cell lymphoma polarizes tumor-associated macrophages into M2-like macrophages, which in turn promote tumorigenesis.

Tumor-associated macrophages (TAMs) are recognized as a hallmark of certain solid cancers and predictors of poor prognosis; however, the functional role of TAMs in lymphoid malignancies, including B-cell lymphoma, has not been well defined. We identified infiltration of F4/80+ TAMs in a syngeneic mouse model using the recently generated murine mantle cell lymphoma (MCL) cell line FC-muMCL1. Multicolor flow cytometric analysis of syngeneic lymphoma tumors showed distinct polarization of F4/80+ TAMs into CD206+ M2 and CD80+ M1 phenotypes. Using human MCL cell lines (Mino, Granta, and JVM2), we further showed that MCL cells polarized monocyte-derived macrophages toward an M2-like phenotype, as assessed by CD163+ expression and increased interleukin-10 (IL-10) level; however, levels of the M1 markers CD80 and IL-12 remained unaffected. To show that macrophages contribute to MCL tumorigenesis, we xenografted the human MCL cell line Mino along with CD14+ monocytes and compared tumor growth between these 2 groups. Results showed that xenografted Mino along with CD14+ monocytes significantly increased the tumor growth in vivo compared with MCL cells alone (P < .001), whereas treatment with liposomal clodronate (to deplete the macrophages) reversed the effect of CD14+ monocytes on growth of MCL xenografts (P < .001). Mechanistically, IL-10 secreted by MCL-polarized M2-like macrophages was found to be responsible for increasing MCL growth by activating STAT1 signaling, whereas IL-10 neutralizing antibody or STAT1 inhibition by fludarabine or STAT1 short hairpin RNA significantly abolished MCL growth (P < .01). Collectively, our data show the existence of a tumor microenvironmental network of macrophages and MCL tumor and suggest the importance of macrophages in interventional therapeutic strategies against MCL and other lymphoid malignancies.

Comparative evaluation of intracranial oligodendroglioma and astrocytoma of similar grades using conventional and T1-weighted DCE-MRI.

PURPOSE: This retrospective study was performed on a 3T MRI to determine the unique conventional MR imaging and T1-weighted DCE-MRI features of oligodendroglioma and astrocytoma and investigate the utility of machine learning algorithms in their differentiation. METHODS: Histologically confirmed, 81 treatment-naïve patients were classified into two groups as per WHO 2016 classification: oligodendroglioma (n = 16; grade II, n = 25; grade III) and astrocytoma (n = 10; grade II, n = 30; grade III). The differences in tumor morphology characteristics were evaluated using Z-test. T1-weighted DCE-MRI data were analyzed using an in-house built MATLAB program. The mean 90th percentile of relative cerebral blood flow, relative cerebral blood volume corrected, volume transfer rate from plasma to extracellular extravascular space, and extravascular extracellular space volume values were evaluated using independent Student's t test. Support vector machine (SVM) classifier was constructed to differentiate two groups across grade II, grade III, and grade II+III based on statistically significant features. RESULTS: Z-test signified only calcification among conventional MR features to categorize oligodendroglioma and astrocytoma across grade III and grade II+III tumors. No statistical significance was found in the perfusion parameters between two groups and its subtypes. SVM trained on calcification also provided moderate accuracy to differentiate oligodendroglioma from astrocytoma. CONCLUSION: We conclude that conventional MR features except calcification and the quantitative T1-weighted DCE-MRI parameters fail to discriminate between oligodendroglioma and astrocytoma. The SVM could not further aid in their differentiation. The study also suggests that the presence of more than 50% T2-FLAIR mismatch may be considered as a more conclusive sign for differentiation of IDH mutant astrocytoma.

Diagnostic Accuracy in Assessment of Depth of Myometrial Invasion in Low-grade Endometrioid Carcinoma: A 2 Center Comparative Study by MRI and Intraoperative Assessment.

The role of lymphadenectomy in endometrial carcinomas is controversial, especially in low-grade endometrioid carcinomas. In many institutions, lymphadenectomy in the latter neoplasms is undertaken only when there is deep myometrial invasion, defined as invasion involving 50% or more of the myometrium (FIGO stage IB). There has been considerable debate as to the best modality to detect deep myometrial invasion. In Europe, preoperative magnetic resonance imaging (MRI) is the most commonly used modality while in North America, intraoperative assessment (IOA) is undertaken in most, but not all, institutions. The aim of this study was to compare the diagnostic accuracy of these 2 modalities in identifying deep myometrial invasion in low-grade endometrioid carcinomas. Two patient cohorts were studied from Belfast, UK (n=253) and Boston, USA (n=276). With respect to detecting deep myometrial invasion, MRI had a sensitivity of 72.84%, positive predictive value of 75.64% and a positive likelihood ratio of 6.59 (95% confidence interval; 4.23-10.28). IOA had a sensitivity of 78.26%, positive predictive value of 80% and a positive likelihood ratio of 20.00 (95% confidence interval; 10.35-38.63). The superior positive likelihood ratio suggests that IOA is better than MRI in determining deep myometrial invasion and the nonoverlapping 95% confidence intervals suggest this is a significant finding. However, there are significant resource implications associated with IOA and preoperative MRI carries other advantages that are discussed herein.

Cytomorphological pattern analysis of tubercular lymphandenopathies.

BACKGROUND: The spectrum of morphological pattern in tubercular lymphandenopathies was observed to study the various cytomorphological patterns and their correlation with acid fast bacilli. METHODS: FNAC smears of 210 cases of granulomatous lymphadenitis stained with Giemsa, Pap and haematoxylin and eosin were used to analyze cytomorphological pattern and Zeihl Neelsen stained smears for acid fast bacilli (AFB) detection. RESULTS: 193 cases with necrotising granulomatous inflammation or positive acid fast bacilli were included. Age group 21-30 years was most common (38.3%) followed by age group 11-20 years (30.05%). Females constituted 66.3% of patients and 33.7% were male. Overall the most common pattern in present study was pattern A (Epitheloid granuloma with caseous necrosis 33.7% followed by pattern B (caseous necrosis with few scattered epitheloid histiocytes and lymphocytes) 31.1% and pattern C (caseous necrosis with suppurative inflammation) 30.6%, followed by pattern D (Caseous necrosis only) (3.6%) and pattern E (non necrotising epitheloid granuloma with positive acid fast bacilli) (1.03%). Acid fast bacilli were demonstrable in 175 cases (90.7%). Amongst the acid fast bacilli positive cases highest bacillary load 3+ grade was seen in pattern C in 6/59 (10.16%) cases. CONCLUSION: FNAC is a simple useful tool and should be attempted in all cases of lymphandenopathies. It helps in establishing a diagnosis of tubercular etiology based on its morphological patterns however demonstration of acid fast bacilli on aspirated material confirms the diagnosis.

Deregulation of Polycomb Repressive Complex-2 in Mantle Cell Lymphoma Confers Growth Advantage by Epigenetic Suppression of cdkn2b.

The polycomb repressive complex 2 (PRC2) maintains the transcriptional repression of target genes through its catalytic component enhancer of zeste homolog 2 (EZH2). Through modulating critical gene expression, EZH2 also plays a role in cancer development and progression by promoting cancer cell survival and invasion. Mutations in EZH2 are prevalent in certain B-cell lymphoma subtypes such as diffuse large cell lymphoma and follicular lymphoma; while no EZH2 mutation has been reported in the mantle cell lymphoma (MCL). Here we demonstrate that the PRC2 components EZH2, EED and SUZ12 are upregulated in the MCL cells as compared to normal B-cells. Moreover, stably transfected cells with wild-type EZH2 or-EED showed increased cell growth and H3K27-trimehtylation. However, unlike wild-type EZH2, ectopic expression of a deletion construct of EZH2 (EZH2Δ550-738 lacking SET domain) had no growth advantage over control cells. Pharmacological inhibition of EZH2 suppressed H3K27me3 and had significant inhibitory effect on cell growth and colony forming capacity (p < 0.05) of MCL cells, and this effect was more or less comparable to the anti-proliferative effects of EZH2 inhibition in cells harboring EZH2-mutation. Mechanistically, EZH2 appears to downregulate expression of cdkn2b gene via enhanced H3K27me3, a well-known suppressive epigenetic mark, at the cdkn2b promoter region. Overall, these results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of cdkn2b in MCL, and in part responsible for increased cell growth, thus the EZH2 inhibitors may have therapeutic potential in the patients with MCL.