Neoplastic Progression Research Articles

CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC.Graphical

S431 Associations of Dietary Fiber and Fat Intake with Barrett’s Esophagus and Stages of Progression to Esophageal Adenocarcinoma

Introduction: The incidence of esophageal adenocarcinoma (EAC) has increased dramatically over the past half century. Changes in dietary patterns over this time may partially account for this trend. Prior studies have found inverse associations between fiber intake and both Barrett’s esophagus (BE) and EAC, and studies of fat intake have reported increased risk or no association. However, it is unknown whether fiber or fat intake contribute to neoplastic progression in BE patients. Methods: We performed a multi-center case-control study of patients with and without BE. We collected demographic, anthropometric, and clinical data and categorized BE by worst degree of histology ever. Subjects completed the NCI DHQII, a validated food frequency questionnaire assessing dietary intake over the preceding 12 months. We used multivariable logistic regression analyses to assess associations of energy adjusted fat and fiber intake with BE and with advanced neoplasia (high grade dysplasia or EAC vs. no dysplasia/indefinite/low grade dysplasia). Four models were developed: 1) fat and fiber intake; 2) Model 1 and EAC risk factors (age, sex, BMI, smoking history, family history); 3) Model 2 and aspirin and statin use; 4) reduced parsimonious model (final model: age, sex, family history). Results: We enrolled 162 subjects; 108 subjects (37 non-BE, 71 BE; 21 with advanced neoplasia) completed the questionnaire and were analyzed. Compared to controls, BE patients were older and more likely (p< 0.01) to be male, aspirin users, statin users, and ever smokers. BE patients had significantly higher energy-adjusted fiber intake but no difference in fat intake compared to controls. (Figure A-B) Adjusted for fat intake, increased fiber intake was associated with reduced odds of BE (per g/1000 kcal, OR 0.81, 95%CI 0.70-0.93), with similar associations in all the models (Table). There was no association between fat intake and BE. There was no significant association between fat or fiber intake and stages of progression to EAC (Figure C-D), and neither fat nor fiber intake was associated with advanced neoplasia in multivariable analyses. (Table) Conclusion: Fiber intake was inversely associated with BE but not with stages of progression to EAC. There was no association between fat intake and BE or dysplasia or EAC, but this may reflect our small sample size. Future larger studies are warranted to elucidate the mechanisms by which fiber may protect against the development of BE.Figure 1.: Comparisons of energy-adjusted intake of A) fat and B) fiber between BE and non-BE subjects. Comparisons of energy-adjusted intake of C) fat and D) fiber across stages of progression to EAC. Table 1. - Multivariable logistic regression models for associations between energy-adjusted fat (% kcal) and fiber (g/1000 kcal) intake with BE (vs. no BE) and with advanced neoplasia (HGD/EAC vs. ND/IND/LGD). (ORs per unit increase) Model 1 Model 2 Model 3 Model 4 BE Fat 1.01 (0.95- 1.08 1.03 (0.95- 1.08) 1.03 (0.94- 1.11) 1.03 (0.95- 1.11) Fiber 0.81 (0.70- 0.93) 0.82 90.67- 0.99) 0.82 (0.67-1.00) 0.80 (0.66- 0.97) Advanced neoplasia Fat 1.00 (0.93- 1.08 1.00 (0.92- 1.09) 1.02 (0.93- 1.12) 1.01 (0.98- 1.09) Fiber 0.94 (0.75- 1.18) 0.85 (0.65- 1.1) 0.87 (0.65- 1.16) 0.96 (0.75- 1.24)

Long Term Results of Elective Nodal Salvage Radiotherapy in Oligometastatic Prostate Cancer : A Mono-Institutional Series

Background The development of new metabolic diagnostic imaging PET is changing the history of metastatic prostate cancer (pCa), identifying situations of progression with a low disease burden; radiation treatment of metabolically active oligometastatic sites has been shown to be effective to prolong patient survival. In the scenario of oligometastatic disease to pelvic lymph nodes there is no uniform consensus on treatment volumes and radiotherapy doses to use. Methods We retrospectively assessed a series of 50 patients treated from 2015 to 2021 at our center who presented with recurrent pelvic lymph node pCa disease with 1-3 lymph-nodes lateralized to one side of the pelvis. Patients were treated with intensity modulated Rapid Arc radiotherapy (IMRT), limiting the treatment volume to the chain of the affected side only. During the follow-up, the patients who presented a biochemical recurrence of the disease were evaluated by PET. Results The biochemical progression-free survival and the metastatic progression-free survival were respectively 36% and 49% at 5 years. 22/50 patients presented a documented recurrence on PET. Only one patient presented a relapse within the irradiated volume and no patient presented a relapse on the contralateral pelvic lymph node chain. No patient had gastrointestinal toxicity &gt; grade 1 RTOG. Conclusion Treatment of patients with oligorecurrent (1-3 lesions) pelvic pCa, limiting the volume of irradiation to only one side of the affected lymph node chain, results in good biochemical disease control and presents a low risk of neoplastic contralateral progression.

Evaluation of immunohistochemically expression of GLUT-1 in benign proliferative, hyperplastic endometrium and endometriosis adenocarcinoma

Objectives: The aim of this study is to evaluate the GLUT-1 expression in benign proliferative, hyperplastic, and malignant endometrial tissues, to evaluate the usefulness of GLUT-1 expression in endometrial hyperplasia, and to determine its role in the neoplastic progression to endometrioid type adenocarcinoma. We also aimed to analyze some prognostic clinical parameters (age, stage, grade).&#x0D; Methods: This cross sectional study was carried out on paraffin embedded surgical specimens of endometrial tissue. Applying the immune histochemical techniques by using the GLUT-1 as a primary antibody, statistical analysis was done and the correlation with different clinical and pathological parameters were assessed.&#x0D; Results: 98 cases of endomertial tissue, 17.4% disordered proliferative endometrium, 22.4% endometrial hyperplasia without atypia, 18.4% endometrial hyperplasia with atypia, 41.8% endometrioid adenocarcinoma, 56.1% were GLUT-1 positive. Significant correlation was found between GLUT-1 expression and increasing degree of atypia as it was negative in benign proliferative and hyperplasia without atypia meanwhile positive in hyperplasia with atypia and endometrioid carcinoma. Significant correlation with grade of carcinoma, patient age, no correlation was found with ovarian and cervical metastasis, no significant correlation was found with tumor stage.&#x0D; Conclusions: GLUT-1 immunostaining may be useful in distinguishing hyperplasia without atypia from hyperplasia with atypia; GLUT-1 overexpression is a consistent feature of endometrioid adenocarcinoma.

The utility of a genetic progression risk test for Barrett esophagus.

This study sought to characterize the utility of a gene methylation-based biomarker test that has been validated to predict progression towards esophageal adenocarcinoma. Barrett esophagus (BE) is a precursor condition for esophageal adenocarcinoma (EAC) with somewhat variable approaches among gastroenterologists toward managing neoplastic progression risk. Capsulomics has developed a validated multigene DNA methylation-based biomarker assay performed on BE biopsies designed to address this variability by classifying BE patients into progression risk groups. In the current study, a survey was administered to practicing gastroenterologists in order to assess the potential impact of this assay on clinical practice. In this context, 89% (95% Cl: 85.4-92.6%) of surveyed physicians felt strongly that the multigene Barrett Esophagus test helped resolve uncertainties and optimize care of patients with BE by impacting their decisions on surveillance intervals and use of active treatments, such as ablation. The assay significantly impacted surveillance intervals for both high-risk (22.0 no assay vs 12.3 months with assay; P = 1.7E-8) and low-risk (7.9 no assay vs 11.4 months with assay, P = 8.8E-4) stratified case results. Finally, the assay also significantly impacted decisions to pursue active ablation treatments in both high-risk (5% recommending ablation without assay vs 42% with assay; P = 3.7E-11) and low-risk (42% recommending ablation without assay vs 29% with assay; P = .049) stratified case results. Results demonstrated a strong effect of the assay on clinical decision making, even in conjunction with established clinical guidelines.

Diagnostic and prognostic role of protein and ultrastructural alterations at cell–extracellular matrix junctions in neoplastic progression of human oral malignancy

ABSTRACT Despite advancements in technology and increase in favorable outcomes associated with oral cancer, early detection remains the most significant factor in limiting mortality. The current study aimed to develop early diagnostic and prognostic markers for oral tumorigenesis. Protein and ultrastructural alterations at cell-extracellular matrix (ECM) adhesion junctions were examined concurrently using immunohistochemistry (IHC) and transmission electron microscopy (TEM) on progressive grade of oral carcinomas (n = 285). The expression of hemidesmosome (HD) proteins-integrin β4, BP180, and laminin-5 increased in hyperplasia as compared to normal, and significantly increased further, as the disease progressed. TEM analysis in parallel tissues revealed a significant decrease in HD number and increase in the length of basal lamina (BL) in hyperplasia. With cancer progression, the severity of ultrastructural alterations increased gradually and significantly. Overexpression of HD proteins, decrease in HD number and increase in BL length significantly correlated with nodal metastasis, local recurrence, and recurrence-free survival of patients. Concurrent use of IHC and TEM can add value to early recognition of neoplastic changes in primary carcinomas of oral cavity. In this regard, altered expression of integrin β4 and laminin-5, loss of HDs, and increased BL length could offer criteria for early diagnosis and prognosis of oral malignancy.

How Azanucleosides Affect Myeloid Cell Fate

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies.

Mer Tyrosine Kinase (MERTK) modulates liver fibrosis progression and hepatocellular carcinoma development.

BackgroundMerTK is a tyrosine kinase receptor that belongs to the TAM (Tyro3/Axl/Mer) receptor family. It is involved in different processes including cellular proliferation/survival, cellular adhesion/migration, and release of the inflammatory/anti-inflammatory cytokines. Although it is reported that MERTK polymorphisms affect the severity of viral and metabolic liver diseases, being able to influence fibrosis progression and hepatocellular carcinoma development, the mechanisms remain unknown. Methods: using a microarray approach, we evaluated the liver expression of genes involved in fibrogenesis and hepatocarcinogenesis in patient with chronic hepatitis C (CHC), stratified for MERTK genotype and MERTK expression. Results: we found that the rs 4374383 AA homozygosity is associated with lower MERTK expression in CHC patients and that, depending on MERTK genotype, Matrix Metallopeptidase 9 (MMP9), Matrix Metallopeptidase 7 (MMP7), Secreted Frizzled Related Protein 1 (SFRP1) and WNT gene family 11(WNT11) show differential expression in patients with CHC with or without neoplastic progression. Conclusions: our results confirm that MERTK represents a genetic biomarker for progression of liver disease and are suggestive of translational relevance for the study of downstream pathways involved in fibrogenesis and hepatocarcinogenesis.

Genome-wide analysis of colorectal cancer based on gene-based somatic copy number alterations during neoplastic progression within the same tumor.

The objective of this study was to elucidate the association between neoplastic progression and somatic copy number alterations (SCNAs) occurring within the same colorectal cancer (CRC) tumor. We investigated SCNAs to identify the progression from a high-grade intramucosal lesion (HGIL) to an invasive front lesion (IFL), via an invasive submucosal lesion (ISL), within the same tumor using a crypt isolation method combined with a SNP array. Immunohistochemistry was also performed. We identified 51 amplified genes that potentially promote progression from HGIL to ISL and 6 amplified genes involved in the progression from ISL to IFL. Of the 51 genes involved in HGIL to ISL progression, TORC1, MSLN, and STUB1, which are closely associated with CRC, were identified as candidate markers of submucosal invasion. However, no candidate genes were identified among the six genes associated with ISL to IFL progression. In addition, the number of total SCNAs and the number of gains were correlated with cancer progression (from HGIL to IFL). Finally, immunohistochemistry revealed higher expression of TORC1, MSLN, and STUB1 in ISL than in HGIL. These results suggest that specific SCNAs are required for acquisition of invasive ability in CRC, and the affected genes are potential markers of invasion.

Improving the Endoscopic Detection and Management of Gastric Intestinal Metaplasia Through Training: A Practical Guide

Improving the Endoscopic Detection and Management of Gastric Intestinal Metaplasia Through Training: A Practical Guide

Impact of SARS-CoV-2 Pandemic on the Management of Patients with Hepatocellular Carcinoma.

Worldwide, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) significantly increases mortality and morbidity. The Coronavirus Disease 2019 (COVID-19) outbreak has had a considerable impact on healthcare systems all around the world, having a significant effect on planned patient activity and established care pathways, in order to meet the difficult task of the global pandemic. Patients with hepatocellular carcinoma (HCC) are considered a particularly susceptible population and conceivably at increased risk for severe COVID-19 because of two combined risk factors: chronic advanced liver disease and HCC itself. In these challenging times, it is mandatory to reshape clinical practice in a prompt way to preserve the highest standards of patient care and safety. However, due to the stay-at-home measures instituted to stop the spread of COVID-19, HCC surveillance has incurred a dramatic drop, and care for HCC patients has been rearranged by refining the algorithm for HCC treatment to the COVID-19 pandemic, permitting these patients to be safely managed by identifying those most at risk of neoplastic disease progression.

Association between Cervical Microbiota and HPV: Could This Be the Key to Complete Cervical Cancer Eradication?

Simple SummaryThe microbiota can modulate immune responses and modify the physiology of the human organism, thereby increasing infective risks and a neoplastic predisposition. In this review, we focus on the composition of the cervical microbiota, to identify the risk of developing Cervical Intraepithelial Neoplasia and better understand the interaction between cervico-vaginal microbiota and human papillomavirus as a means of promoting the identification of new therapeutic strategies. In fact, no therapy for HPV is yet available. A better understanding of the cervical micro-environment could be a key element allowing complete viral clearance to be achieved in largely affected populations.The heterogeneity of the cervico-vaginal microbiota can be appreciated in various conditions, both pathological and non-pathological, and can vary according to biological and environmental factors. Attempts are still in course to define the interaction and role of the various factors that constitute this community of commensals in immune protection, inflammatory processes, and the onset of precancerous lesions of the cervical epithelium. Despite the many studies on the relationship between microbiota, immunity, and HPV-related cervical tumors, further aspects still need to be probed. In this review article, we will examine the principal characteristics of microorganisms commonly found in cervico-vaginal specimens (i) the factors that notoriously condition the diversity and composition of microbiota, (ii) the role that some families of organisms may play in the onset of HPV-dysplastic lesions and in neoplastic progression, and (iii) possible diagnostic-therapeutic approaches.

Efficacy of Topically Administered Dihydroartemisinin in Treating Papillomavirus-Induced Anogenital Dysplasia in Preclinical Mouse Models.

The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: K14E6/E7 transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with Mus musculus papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age (K14E6/E7) or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated K14E6/E7 mice.

Cancer and Evolution: An Ancient Relation Explored Recently

Cancer is a consequence of multi-cellularity and is a striking example of multilevel selection. The theory of cancer initiation and progression has its root deep within the evolutionary and ecological concepts. Cancer develops through somatic evolution, with genetic and epigenetic precariousness, generating fitness variation among the cells in the body. Epidemiological, genetic, and molecular biological research have cumulatively provided us with a brimming source of data that affirms our current understanding of the etiology and molecular pathogenesis of cancer. But this aspect only focuses on immediate mechanisms and does not competently explain the pervasiveness of tumors and cancer in animal species or what seems to be the exceptional vulnerability of Homo sapiens. At a practical level, analyses suggest that, for evolutionary reasons, as a species, we are inherently more likely to develop cancer (than we might like to admit). Though we cannot reverse our genetic legacies and predilection to cancer, emphasizing inherent vulnerability in an ‘evolutionary’ way strongly ratifies our current attempts to combat cancer. In actuality, neoplasms are microcosms of evolution. Within a neoplasm, a mosaic of mutant cells competes for space and resources, evades predation by the immune system, and can even cooperate to disperse and colonize new organs (metastasis). The evolution of neoplastic cells can explain both why we get cancer and why it has been so difficult to find a cure. Although the idea of cancer as an evolutionary problem is not new at least historically little attention has been delivered to applications of evolutionary biological principles in understanding and controlling neoplastic progression. Already, we have reached the high time when this should be changed. Ernst Mayr aptly said that “No biological problem is solved until both the proximate and the evolutionary causation has been elucidated” Keywords: [Cancer, adaptation, evolution].

Autoimmune Atrophic Gastritis: The Role of miRNA in Relation to Helicobacter Pylori Infection.

IntroductionMicroRNAs (miRNAs) have been proposed as diagnostic markers, biomarkers of neoplastic progression, and possible therapeutic targets in several immune-mediated diseases. We aimed to analyze the expression profile of selected miRNAs (miR21, miR142, miR223, miR155) in patients with autoimmune atrophic gastritis (AAG), patients with non-autoimmune multifocal atrophic gastritis (MAG), and healthy control subjects (HC).Materials and methodsA total of 103 patients with AAG were consecutively recruited for this study among those attending our gastroenterology outpatient clinic. Participating patients were divided into two groups: primary, not Helicobacter pylori (HP)-associated related AAG (n=57, P-AAG) and HP-associated AAG (n=46, HP-AAG); this subgroup included HP-positive patients, patients with previously reported HP infection, and patients harboring antral atrophy, considered as a stigma of HP infection. We also included 20 sex-age-matched MAG patients and 10 HC. Upper endoscopy with gastric biopsies were performed on each AAG and MAG patient. Circulating levels of miR21-5p, miR142-3p, miR223-3p, and miR155-5p were measured by RT-PCR in all groups.ResultsMiR-21 was over-expressed in P-AAG (p=0.02), HP-AAG (p = 0.04), and MAG (p=0.03) compared with HC. By contrast, miR-142 was more expressed in HC than in HP-AAG (p=0.04) and MAG (p=0.03). MiR-155 showed no significant differences among the four subgroups, while, unexpectedly, miR-223 was overexpressed in HC compared to P-AAG (p=0.01), HP-AAG (p=0.003), and MAG (p<0.001), and was higher in P-AAG than in MAG (p=0.05).ConclusionsMiR-21 was over-expressed in patients with gastric precancerous conditions irrespective of etiology, while in the same subgroups miR-142 and miR-223 were under-expressed compared to healthy controls. Controlling miRNAs up- or downregulation could lead to a breakthrough in treating chronic autoimmune diseases and potentially interfere with the progression to cancer.

Genome-Wide Analysis of microRNA and mRNA Expression in Colorectal Intramucosal Neoplasia and Colorectal Cancer With a Microsatellite-Stable Phenotype Based on Adenoma-Carcinoma Sequences.

BackgroundAlthough MicroRNAs (miRNAs) play important roles in various biological processes, the biological functions of miRNAs are achieved through mRNAs. The aim of this study is to identify dysregulated miRNA/mRNA expression patterns in colorectal tumors.MethodsWe examined 42 colorectal tumors [15 adenomas, 8 intramucosal cancers (IMCs), and 19 invasive colorectal cancers (CRCs)] with the microsatellite stable (MSS) phenotype (first cohort). The first cohort was used for genome-wide miRNA and mRNA expression arrays, whereas the second cohort (37 colorectal neoplasias) was used for validation analyses. Finally, we used 15 cases of “adenoma in/with carcinoma” to identify network patterns of miRNAs/mRNAs that were directly associated with neoplastic progression. In addition, simple regression analysis for array-based and RT-PCR analyses was performed to select candidate miRNA–mRNA pairs. Transfection of miRNA mimics was also performed to confirm whether target mRNA expression is affected by specific miRNAs.ResultsSpecific paired miRNA/mRNA networks, including hsa-miR-34a-5p/SLC12A2, hsa-miR-15b-5p/SLC12A2, hsa-miR-195-5p/SLC12A2, hsa-miRNA-502-3p/OLFM4, hsa-miRNA-6807-5p/ZG16, and hsa-miRNA 3064-5p/SH3BGRL3, were identified in samples of adenoma, IMC, and CRC with the MSS phenotype. In adenomatous lesions obtained from the same tumor with a carcinomatous lesion, we identified pairs of miRNA-130a-3p/HSPA8 and miRNA-22-3p/RP53 that were linked to multiple pathways. On the other hand, 2 pairs of miRNA/mRNA (miRNA-660-5p and miRNA-664a-5p/APP) were found in isolated carcinomatous glands. Ectopic expression of miRNA 3064-5p suppressed SH3BGRL3 expression.ConclusionsWe found that networks based on specific pairs of miRNAs/mRNAs contribute to progression from adenomatous and carcinomatous lesions. Our results provide insights into the molecular tumorigenesis of colorectal tumors.

Sex Differences in Neoplastic Progression in Barrett's Esophagus: A Multicenter Prospective Cohort Study.

Simple SummaryBarrett’s esophagus (BE) is the only known precursor lesion of esophageal adenocarcinoma (EAC). Endoscopic surveillance plays an important role in the timely detection of neoplastic progression. However, the cost-effectiveness of current surveillance strategies is debatable. Previous studies have shown that male Barrett’s patients have lower neoplastic progression risk than females. However, these studies do not provide a more practical translation of these sex disparities into different surveillance intervals. The current multicenter prospective cohort study aimed to evaluate sex differences in 868 BE patients; not only with respect to neoplastic progression risk, but also concerning the difference in time to detection of high-grade dysplasia (HGD)/EAC: time to neoplastic progression was estimated to be almost twice as low in males than in females. In contrast, the stage of neoplasia appeared to be higher in females. Our results can guide future discussions for sex-specific guidelines, supporting the implementation of neoplastic risk stratification per individual patient in BE surveillance.Recommendations in Barrett’s esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11–4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33–10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29–0.95) and HGD (AR 0.40, 95% CI 0.19–0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models.

Proliferative Verrucous Leukoplakia with Dysplastic Changes

Proliferative verrucous leukoplakia is one of the rare premalignant white lesions with highest conversion rate to malignancy. It grows gradually and irreversibly with multifocal presentation, exophytic and verrucous appearance. This lesion has been reported resistant to all therapeutic approaches including both non-surgical and surgical. Predisposing factors include female gender in the 6th decade of life. Proliferative verrucous leukoplakia has the highest tendency to neoplastic transformation and progression to oral squamous cell carcinoma and oral verrucous carcinoma in majority of the cases. The case of proliferative verrucous lesion clinically appearing benign presented here but on histopathology proven dysplasia in a patient with the history of smoking which he stopped six years back

Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM.

P747: LR-MDS IS CHARACTERIZED BY DIFFERENTIAL EXPRESSION OF INFLAMMASOME-RELATED GENES IN SPECIFIC CELL POPULATIONS

Background: Myelodysplastic Syndromes (MDS) are a group of hematopoietic neoplasms characterized by clonal expansion of hematopoietic stem and progenitor cells (HSPC) and peripheral blood cytopenia. MDS can develop from clonal hematopoiesis of indeterminate potential (CHIP) and progress through low-risk (LR) to high-risk (HR)-MDS and further to acute myeloid leukemia (AML). Recent findings emphasize the role of sterile inflammation in the bone marrow (BM) as a driver of neoplastic progression. Our previous analysis of whole BM mononuclear cells (BM-MNC) has revealed distinct expression patterns of inflammasome-related genes, including IL1B and IL18, to be associated with LR-MDS subgroups and clinical features. This raises the prospect of interrupting disease evolution at an early stage by targeted, personalized anti-inflammatory therapy. The development and stratification of such therapies will ultimately require more detailed knowledge of the variety and consequences of inflammation networks in MDS bone marrow. Aims: Our objective was to assess inflammasome-related gene expression levels in individual cell types in the BM of CHIP, LR-MDS and HR-MDS individuals as well as non-CHIP controls in order to determine a) which cell types contribute to the expression of inflammasome-related genes and b) whether specific disease states are associated with consistent patterns of cell-specific gene expression. Methods: Cryopreserved BM-MNC from 3 non-CHIP controls, 3 CHIP individuals, 14 LR-MDS and 5 HR-MDS patients were obtained from the MDS registry and the BoHemE Study (NCT02867085) at the University Hospitals in Dresden and Leipzig. Hematopoietic stem and progenitor cells (HSPC), monocytes, monocytic myeloid-derived suppressor cells (M-MDSC), polymorphonuclear MDSC (PMN-MDSC), B lymphocytes, T lymphocytes and CD45- cells (control) were sorted from thawed BM-MNC on a BD FACS Jazz. RNA was isolated and the gene expression of IL1B, IL18, S100A9, IRAK4, NLRP3, PYCARD, CASP1 and NLRC4 was assessed by RT-qPCR. Results: The majority of the inflammasome-related genes, including IL1B, NLRP3, NLRC4 and S100A9 were expressed in all disease states predominantly by monocytes and M-MDSC (p<0.001). However, IL18 was expressed at the highest level in HSPC. Consistent to our previous analysis of whole BM-MNC, we found an association between cell-specific gene expression and LR-MDS genetics, with HSPC-derived IL18 mRNA being highest in SF3B1-mutated LR-MDS, while monocytic IL1B mRNA was highest in del(5q) LR-MDS. Furthermore, an apparent progression in expression from non-CHIP through to LR-MDS was detected, with mRNA levels of IL1B and NLRP3 in monocytic cells and PYCARD and CASP1 in HSPC increasing from non-CHIP to CHIP between 1.5- and 7.9-fold. From CHIP to LR-MDS, mRNA levels of CASP1 and NLRC4 in monocytic cells and PYCARD both in HPSC and in monocytic cells increased by 1.8- to 2.1-fold. Summary/Conclusion: We identify features of inflammasome-related gene expression in individual cell populations and disease states reflecting the progression from non-CHIP through CHIP to MDS. Our analysis suggests strongly that high resolution studies of gene expression in specific populations or single cells will resolve a spectrum of MDS-related inflammation states relevant to prognosis and personalized therapy. Therefore, we are currently performing RNA-Seq from sorted cell populations in order to extend our analysis beyond the core inflammasome reported here.