Disease Poor Prognosis Research Articles

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors.

Simple SummaryThis is a retrospective cohort study of metastatic uveal melanoma patients. This study undertook to identify clinical characteristics that were predictive and prognostics of benefit to immune checkpoint inhibitors in patients with metastatic uveal melanoma. We developed a Metastatic Uveal Melanoma Prognostic risk Score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). Our findings demonstrated that the Metastatic Uveal Melanoma Prognostic risk Score was associated with a statistically significant association with overall survival outcomes in patients with metastatic uveal melanoma treated with ICI. There was a significant predictive association with disease control to ICI for patients with a ‘good risk’ Metastatic Uveal Melanoma Prognostic risk score. This is one of the larger analysis of clinical outcomes in metastatic uveal melanoma patients to date and could inform clinical decision-making.Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.

Extended T-Cell Epitope Landscape in Merkel Cell Polyomavirus Large T and Small T Oncoproteins Identified Uniquely in Patients with Cancer

Merkel cell carcinoma (MCC) is a rare, aggressive human skin cancer with a poor prognosis for advanced disease (Harms et al., 2016). The oncovirus Merkel cell polyomavirus (MCPyV) is associated with at least 80% of MCC cases (Feng et al., 2008) with persistent expression of the viral T antigens (T-Ags) (large T antigen and small T antigen) driving oncogenesis (Shuda et al., 2008).

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.

Prognostic Value of Coronary Artery Calcium Score in Hospitalized COVID-19 Patients.

Background: The association of known cardiovascular risk factors with poor prognosis of coronavirus disease 2019 (COVID-19) has been recently emphasized. Coronary artery calcium (CAC) score is considered a risk modifier in the primary prevention of cardiovascular disease. We hypothesized that the absence of CAC might have an additional predictive value for an improved cardiovascular outcome of hospitalized COVID-19 patients.Materials and methods: We prospectively included 310 consecutive hospitalized patients with COVID-19. Thirty patients with history of coronary artery disease were excluded. Chest computed tomography (CT) was performed in all patients. Demographics, medical history, clinical characteristics, laboratory findings, imaging data, in-hospital treatment, and outcomes were retrospectively analyzed. A composite endpoint of major adverse cardiovascular events (MACE) was defined.Results: Two hundred eighty patients (63.2 ± 16.7 years old, 57.5% male) were included in the analysis. 46.7% patients had a CAC score of 0. MACE rate was 21.8% (61 patients). The absence of CAC was inversely associated with MACE (OR 0.209, 95% CI 0.052–0.833, p = 0.027), with a negative predictive value of 84.5%.Conclusion: The absence of CAC had a high negative predictive value for MACE in patients hospitalized with COVID-19, even in the presence of cardiac risk factors. A semi-qualitative assessment of CAC is a simple, reproducible, and non-invasive measure that may be useful to identify COVID-19 patients at a low risk for developing cardiovascular complications.

Cytotoxic Activity of Eurycoma Longifolia Jack Root Extract Against Nasopharyngeal Carcinoma Cell Line

Background: Eurycoma longifolia (E. longifolia) or Tongkat Ali is a tree that grows in southeast Asia, the roots of which contain bioactive components that exhibit cytotoxic properties against various cancer cell lines. However, no study has been conducted to relate the cytotoxic properties against nasopharyngeal carcinoma (NPC), a type of cancer that shows poor prognosis for metastatic disease. The purpose of this study was to determine whether the E. longifolia root extract exerts cytotoxic activity against nasopharyngeal carcinoma (ORL-115) cell lines. Materials and Method: E. longifolia root extracts were obtained through Soxhlet extraction method and by using two different solvents; ethanol and dicholoromethane. MTS assay was used to evaluate the cytotoxic effect of the root extracts against ORL-115 cell line for three different incubation time which were 24-hour, 48-hour and 72-hour. Results: Ethanol extract was significantly more potent compared to DCM extract. Ethanol extract exhibited lower IC50 value compared to DCM extract. The IC50 of ethanol extract were 232.1 μg/ml, 66.86 μg/ml and 42.6 μg/ml. Meanwhile the IC50 of DCM extract were 678.87 μg/ml, 136.71 μg/ml, 73.72 μg/ml for 24-hour, 48-hour and 72-hour incubation period respectively. The cytotoxic activity of both extracts increased as the incubation time prolonged. The cytotoxic activity of ethanol extract at each incubation time was significantly different from DCM extract except at 72 hours. Conclusion: E. longifolia root extracts exerted cytotoxic activity against the nasopharyngeal carcinoma (ORL-115) cell line. Ethanol extract exhibited lower IC50 value compared to DCM extract. The cytotoxic activity of both extracts were dose dependent and time dependent. Key words: E. longifolia, Cytotoxic activity, Nasopharyngeal carcinoma.

Abstract 2258: Germline variants associated with poorer disease prognosis in nasopharyngeal carcinoma

Abstract Nasopharyngeal carcinoma (NPC) is an endemic disease prevalent in East Asia and germline variants that confer risk for NPC have previously been identified. However, NPC patients have contrasting phenotypes at presentation that are associated with disparate risks of relapse. We hypothesize that there exist germline variants that are associated with poorer NPC disease trajectories. We performed whole exome sequencing (100x; Illumina NovaSeq) on a cohort of 795 NPC patients and probed the germline genomic landscape in a predominantly Chinese population (N=723; 90.9%). We performed univariable and multivariable - adjusting for known prognostic clinical parameters - Cox regression analyses to discover germline variants that were associated with disease-free survival (DFS). We performed joint genotyping of germline variants following GATK's best practices workflow. We next filtered out common (≥5% allele frequency in East Asian population, or ≥1% in others) and benign variants, retaining only variants classified as pathogenic (P)/likely pathogenic (LP)/variant of unknown significance (VUS) in ClinVar or are predicted to be pathogenic by Combined Annotation Dependent Depletion or Rare Exome Variant Ensemble Learner. For improved statistical power, statistical analyses (uni- and multi-variable Cox regression) were conducted at the gene level, so that contributions across all variants were aggregated for each gene. To reduce false discovery, we focused our analysis only on genes of interest: hallmark-of-cancer genes (COSMIC gene census), DNA damage and mismatch repair genes, as well as genes known to be associated with NPC risk. Genes with variants in fewer than 20 unique patients were also excluded from analysis. We observed germline variants in hallmark-of-cancer genes (FAT1 [N=133; 16.7%] and NOTCH1 [N=39; 4.9%]) and DNA repair genes (SRSF6 [N=32; 4.0%] and POLD1 [N=32; 4.0%]). Additionally, 230 (28.9%) and 180 (22.6%) patients had at least one P/LP/VUS variants in HLA-A and HLA-DRB1, consistent with known literature that variants in HLA genes confer increased NPC risk. Likewise, we observed variants in genes associated with NPC risk such as KMT2C (N=207; 26.0%), SYNE1 (N=151; 19.0%), ARID1A (N=52; 6.5%) and MST1R (N=34; 4.3%). Univariable tests of association identified variants in MMP19 (HR 2.24 with 95% confidence interval [1.30-3.87], P=0.004), MST1R (HR 2.01 [1.14-3.54], P=0.016), TGFBR2 (HR 1.85 [1.09-3.14], P=0.023), NEIL3 (HR 2.08 [1.09-3.94], P=0.025), ETV6 (HR 2.13 [1.09-4.16], P=0.028), FANCD2 (HR 2.11 [1.09-4.13], P=0.030), DDX6 (HD 2.26 [1.06-4.82], P=0.035) POLD1 (HR 1.91 [1.04-3.53], P=0.038) and RECQL4 (HR 1.92 [1.04-3.54], P=0.037) that were significantly associated with inferior DFS. Among them, MMP19, TGFBR2, FANCD2 and RECQL4 remained significant in a clinico-molecular multivariable model that comprised of age, sex, cTN-categories, EBV DNA titer and treatment (C-index = 0.71). Citation Format: Adelene Y.L. Sim, Enya H.w. Ong, Luo Huang, Kar Perng Low, Dewi Susanti, Terence W.k. Tan, Kam Weng Fong, Yoke Lim Soong, Gek San Tan, Tony K.H. Lim, Joseph T.s. Wee, Darren W.t. Lim, N. Gopalakrishna Iyer, Jacqueline S.G. Hwang, Mohamed E. Abazeed, Jin-Xin Bei, Melvin L.k. Chua. Germline variants associated with poorer disease prognosis in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2258.

Abstract 167: Multiomics profiling of BAP1 loss in uveal melanoma

Abstract BRCA1 Associated Protein 1 (BAP1) is a tumor suppressor gene with identified mutations in various cancers including uveal melanoma (UM), malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. The protein forms multicomplexes with various transcription factors and cell cycle regulators. It also functions as a deubiquitylating enzyme primarily located in the nucleus and acts on histone 2A, leading to altered gene transcription. Recently, it was shown to play a role in apoptotic signaling, homologous-directed repair, and ferroptosis regulation. Over 90% of metastatic UM cases report loss-of-function BAP1 mutations. There is a strong association between loss-of-function BAP1 mutations, metastasis, and poor disease prognosis, the mechanisms for which remain unclear. Understanding the role of BAP1 in metastasis may help uncover therapeutic approaches and improve overall survival outcomes for metastatic UM patients. Here we used a multi-omics approach to investigate changes in gene expression in UM with BAP1 loss. Bioinformatics analysis using multiple UM patient and cell line data sets revealed upregulation of key cell-cell adhesion genes, CDH1, CADM1, and SDC2 with loss of BAP1. These adhesion proteins may be involved with facilitating collective migration or enable metastatic seeding. Together, these data prompt further investigation into the specific roles of BAP1 during the metastatic cascade in UM, from primary dissemination in the eye to seeding in the liver. Citation Format: Usman Baqai, Timothy Purwin, Nelisa Bechtel, Vivian Chua, Anna Han, Andrew E. Aplin. Multiomics profiling of BAP1 loss in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 167.

Abstract 2872: Methods of assessment of polysialyltransferase inhibitors for treatment of tumor cell dissemination

Abstract Polysialic acid (polySia) decorates the surface of NCAM (neuronal cell adhesion molecule) on neuroendocrine tumors, notably neuroblastoma and small cell lung cancer, and is strongly associated with poor prognosis and aggressive disease in patients in the clinic [1]. PolySia modulates tumor cell-cell and cell-matrix adhesion, migration, invasion and metastasis. SiRNA knockdown of polysialyltransferase (polyST) ST8SiaII, the enzyme primarily responsible for polySia synthesis in tumors, abrogates tumor cell migration and invasion. PolyST is a selective and largely unexplored therapeutic target for neuroblastoma dissemination [1]. While assays are available to assess polyST enzyme activity, there is no methodology available specifically optimized for identification of novel polyST inhibitors. We describe the development of cell-free and cell-based assays that enable assessment of polysialyltransferase inhibition. Development of the HPLC-fluorescence-based enzyme assay includes a comprehensive optimization of assay conditions, including evaluation of metal ion composition, enzyme concentration, substrate and acceptor concentration, temperature, pH and tolerance to DMSO, followed by validation using known polyST inhibitors. Thorough analysis of each of the assay components provided a set of optimized conditions. Under these optimized conditions, the experimentally observed Ki value for CMP, a competitive polyST inhibitor, was strongly correlated with the predicted Ki value, based on the classical Cheng-Prusoff equation [average fold error (AFE) = 1.043]. These results indicate that this assay can provide medium-throughput analysis for enzyme inhibitors with high accuracy. We additionally report optimized HPLC-based and ELISA-based methodologies for assessment of polyST inhibition in neuroblastoma cells, using endoneuraminidase N as control, and assessment of ICT3176 (a polysialylation inhibitor) as a test agent. In conclusion, in vitro cell-free and cell-based assays for accurate measurement of polysialyltransferase (polyST) inhibition are described, specifically designed for routine identification of potential polyST inhibitors, generation of kinetics data and assessment of mode of inhibition, and assessment of effects on cellular polysialylation. Given the considerable and growing interest in the polySTs as important anti-metastatic targets in cancer drug discovery, these are vital tools to enable preclinical identification and evaluation of novel polyST inhibitors for neuroblastoma therapy. [1] Falconer, R.A. et al., Curr. Cancer Drug Targets, 2012, 12, 925-939. Citation Format: Xiaoxiao Guo, Jodie R. Malcolm, Anjana Patel, Marrwa M. Ali, Goreti Ribeiro Morais, Steven D. Shnyder, Paul M. Loadman, Laurence H. Patterson, Robert A. Falconer. Methods of assessment of polysialyltransferase inhibitors for treatment of tumor cell dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2872.

Targeted Therapy in FLT3-ITD Positive Myeloid Sarcoma: Proof of Principle

INTRODUCTIONAcute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation is a poor prognosis disease, with a high rate of relapse and poor OS, even after allogeneic hematopoietic cell transplantation (alloHCT).In recent years FLT3 inhibitors have emerged in the treatment of FLT3-ITD AML both as monotherapy and in combination with standard chemotherapy; they were used both during induction therapy and in relapsed or refractory disease. They have also been used as maintenance therapy after transplantation.FLT3 inhibitors act by blocking the proliferative boost due to FLT3-ITD.Some of these drugs are approved for the treatment of solid cancers such as hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma.We report the case of a patient with FLT3-ITD-positive AML whose disease relapsed after alloHCT as a myeloid sarcoma and who was successfully treated with Sorafenib.CASE REPORTA 54-year old male was diagnosed with AML with a normal karyotype and FLT3-ITD and NPM1 mutations. A molecular complete response (CR) was observed after “3+7” induction therapy. A consolidation therapy with Citarabine was administered and then alloHCT was performed. Conditioning was tBu-Flu and donor was an HLA-identical sibling. Cyclosporine and short term Methotrexate were used as Graft Versus Host Disease (GVHD) prophylaxis.No sign of acute GVHD occurred, molecular CR was confirmed at bone marrow evaluation at day +100, thereafter CSPA was tapered.Nine months after alloHCT a left pectoral subcutaneous nodule appeared. The biopsy consisted with myeloid sarcoma; molecular analysis revealed that sarcoma was FLT3-ITD positive. Meanwhile many sarcomas quickly appeared in different areas of the body and patient referred tingle in his right leg. A CT-PET scan showed pathological uptake in cervical lymph nodes, in subcutaneous and muscular lesions at left upper limb, right hip, thighs, and at right tibia bone. At the same time bone marrow exam confirmed molecular CR and full donor chimerism.Immunosuppression was stopped and he was admistered Sorafenib 200 mg twice for day in off-label use 11 months after alloHCT. Superficial lesions and right leg tingle decreased within 7 days and no lesion was detected by physical examination after 10 weeks of therapy; CT-PET scan after 8 weeks showed partial remission.Sorafenib was increased to 400 mg twice for day and the expected side effects occurred, namely diarrhoea and palmar-plantar erythrodysesthesia.After four months of therapy with Sorafenib, he was treated with donor lymphocyte infusion (DLI), the drug was continued and no clinical manifestation of GVHD appeared. He received a second dose of DLI after seven weeks from the first dose.After 23 weeks of Sorafenib treatment and two dose of DLI, sarcomas localization continued to slowly decrease, bone marrow exam confirmed molecular CR and full donor chimerism, and patient was in good physical condition, with limited oral chronic GVHD.CONCLUSIONOur observation is the proof of Sorafenib activity even in FLT3-ITD myeloid sarcoma, and of his ability to reach extramedullary tissue and to be effective against sarcoma myeloblasts. This experience suggest to look for FLT3 mutation in myeloid sarcoma tissue and to consider therapy with FLT3-inhibitors, alone or in association with chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Lymphoma Microenvironment Signature Predicts Clinical Outcomes in Diffuse Large B-Cell Lymphoma Patients

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, whose response to standard chemotherapy is variable. Stratification of DLBCL into GCB (germinal center B-cell)- or ABC (activated B-cell)-like type, so-called cell-of-origin (COO) classification, has been performed based on gene expression signatures and/or immunohistochemistry. Since COO classification may not necessarily retain prognostic power, a more accurate risk stratification model is warranted.Purpose: The goal of this study is to identify a gene expression signature(s) that accurately predicts clinical outcomes of DLBCL patients.Hypothesis: During the process of normal B-cell development in germinal center (GC), a variety of microenvironment cells, including T cells, fibroblasts, dendritic cells and macrophages, coordinately regulate clonal selection and proliferation of B-cells. Therefore, we hypothesized that the differences in the contexts of lymphoma microenvironment could affect clinical outcomes of DLBCL.Methods: Standard genome-wide gene expression analysis, including microarray and RNA-seq, can only measure abundant transcripts derived from lymphoma cells. In contrast, cells constituting lymphoma microenvironment are minor fractions in lymphoma tissues, and transcripts derived from these cells are expressed at low levels. To quantitatively measure those lowly-expressed transcripts, we employed the nCounter system, which enables an accurate measurement of rare and highly-fragmented transcripts from formalin-fixed paraffin-embedded (FFPE) tissues.Results: We first examined expression levels of 1900 genes related to immune-, cancer- and kinase-pathways using tissues from 30 DLBCL cases. We then identified a set of genes that were differentially expressed between cases exhibiting good prognosis (alive > 2 years without relapse) and those with poor prognosis (disease progression < 1 year). Strikingly, differentially-expressed genes were not B cell-related genes, but those related to microenvironment cells, including T cells, fibroblasts and macrophages. Furthermore, high levels of microenvironment-related genes dictated favorable prognosis. To identify subtypes of microenvironment cells, we next performed single-cell q-PCR assays (C1 system) and a multi-color immunofluorescence analysis of DLBCL tissues (Mantra system). We found that presence of GC microenvironment components such as follicular helper T cells, CD11c+ macrophages and FGFR1+ stromal cells was an accurate predictor for favorable prognosis. We defined the GC microenvironment signature based on the expression levels of ICOS, CD11c and FGFR1 mRNA using nCounter and established a novel scoring system. We then validated the system using an independent DLBCL cohort consisting of 170 cases. Our scoring system enabled precise prognostic stratification among patients treated with R-CHOP independently of IPI status and traditional COO-based prognostic models (Figure 1). Finally, to explore potential correlation between the microenvironment signature and mutational status of DLBCL cells, we performed target capture sequencing of 100 DLBCL cases using a clinically-validated sequencing platform (OncoPanel). Our interim analysis did not reveal a correlation between specific lymphoma mutations and the microenvironment signature, suggesting that GC microenvironment signature, which we have identified, predicts clinical outcomes independently from mutational status of DLBCL cells.Conclusions: We identified a GC microenvironment signature that accurately dictates clinical outcomes and established a novel nCounter-based scoring system, which may inform prognostic stratification and the selection of chemotherapeutic regimen of DLBCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Seven Gene Signature to Distinguish Bortezomib- and Lenalidomide-Responsive Myeloma: Rnaseq from the Padimac Study

BackgroundThe treatment of multiple myeloma has benefited from the adoption of several highly active novel therapies over the last 20 years. This has led to the challenge of how to rationally choose the best drug regimen for an individual patient. Two of the most important novel anti-myeloma drugs are the proteasome inhibitor (PI), bortezomib, and the immunomodulatory drug (IMiD), lenalidomide. However, whilst patients often respond much better to one or other of these agents, there are very few means for rationally choosing between them. The application of precision medicine to guide this choice would improve efficacy and reduce adverse drug effects. Microarray data can identify poor prognosis disease very effectively, but is agnostic to treatment and does not inform drug selection. RNA sequencing (RNAseq) offers several potential advantages over microarray profiling. However, it also poses specific challenges for deriving prediction signatures and RNAseq-based signatures have not so far been described in myeloma.MethodsIn the phase 2 PADIMAC trial, newly diagnosed transplant-eligible myeloma patients were treated with bortezomib, doxorubicin, and dexamethasone (PAD) therapy and stratified to receive autograft in partial remission or no further treatment (“watch and wait”) in very good partial remission (VGPR) or better. We extracted somatic RNA from CD138-selected cells prior to treatment and performed massively parallel RNAseq. We employed a novel combination of published techniques to transform the data and to perform training, validation, and testing.ResultsNine of 41 patients with RNAseq data achieved ≥VGPR sustained for over 12 months with no further treatment. We used these RNAseq data as a training/validation set to develop a signature for predicting good responses to bortezomib-based therapy in the absence of an IMiD. We developed several signatures, cross-validated within the PADIMAC dataset, and tested performance in identifying good responders to bortezomib-based therapy from an independent test set of 109 patients from the CoMMpass study. The signatures performed extremely well in testing (p=2.3x10-14, p=0.001, p<2.2x10-16, and p<2.2x10-16 for sensitivity, specificity, F-measure, and accuracy, respectively).Based on cross-validation performance, we identified a single seven-gene signature, trained it on the PADIMAC data, and applied it to the 109 bortezomib-treated patients within CoMMpass. Predicted good responders had superior survival to the remaining patients (p=0.016; Figure 1A). To investigate whether the signature identified generic good risk disease or whether it was treatment-specific, we tested it on 31 patients treated with lenalidomide-based therapies (without PI) within the CoMMpass study. To our surprise, when applied to lenalidomide-treated patients, the signature performed significantly worse than expected by chance, as did several other signatures trained on the PADIMAC data (p=3.2x10-9, p=3.6x10-6, p=3.8x10-12, and p=1.7x10-13 for sensitivity, specificity, F-measure, and accuracy, respectively). This implied that expectation of a good response to bortezomib was associated with a poor response when the patient received lenalidomide and vice - versa . We could not assess survival in lenalidomide-treated patients because of small numbers, so we instead trained our seven-gene signature on lenalidomide-treated patients and tested it on bortezomib-treated patients. This confirmed the reciprocal relationship; patients expected to respond well to lenalidomide, but receiving bortezomib, had an inferior survival to other bortezomib-treated patients (p=0.008; figure 1B). This reciprocity across independent datasets implies that our signature could select between bortezomib-based or lenalidomide-based therapies for individual patients.ConclusionsWe have identified a seven-gene RNAseq signature that can predict if newly diagnosed myeloma patients would benefit from initial bortezomib-based or lenalidomide-based therapy, both in terms of response and survival. This is, to our knowledge, the first example of such a signature in MM and could be employed for precision medicine in the future. [Display omitted] DisclosuresChapman:Takeda: Other: Travel sponsorship; Janssen: Honoraria; Celgene: Other: Travel sponsorship; Celgene: Honoraria. Popat:Janssen: Honoraria, Other: Travel support for meetings; Celgene: Honoraria, Other: Travel support for meetings; Amgen: Honoraria; Takeda: Honoraria, Other: Travel support for meetings. Cavenagh:Novartis: Consultancy; Janssen: Honoraria; Celgene: Consultancy; Takeda: Consultancy. Owen:Janssen: Consultancy, Other: Travel support; Takeda: Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding. D'Sa:Janssen Cilag: Consultancy, Honoraria, Other: Education grant, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cook:Janssen: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Jazz Pharmaceuticals: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees. Yong:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Prevalence and influencing factors of chronic post-traumatic stress disorder in patients with myocardial infarction, transient ischemic attack (TIA) and stroke \u2013 an exploratory, descriptive study

BackgroundCardio- and cerebrovascular events such as myocardial infarction (MI), stroke and transient ischemic attack (TIA) are leading causes of death and disability and have also been associated with poor mental outcomes. In addition, cardio- and cerebrovascular events may pose the risk of experiencing a sudden traumatic occurrence of symptoms during ictus and thus contribute to high rates of PTSD as well as high rates of subsequent depression and anxiety. Moreover, MI, TIA and stroke survivors with PTSD, depressive and anxiety symptoms may have poorer health-related quality of life (HRQoL) and poorer disease prognosis than patients who do not develop psychiatric symptoms after ictus. However, data on the prevalence of PTSD, anxiety and depression, as well as the HRQoL, coping strategies and potential risk factors for development of PTSD in these patients, are rare.MethodsIn an exploratory, descriptive study we interviewed 112 patients (54 MI, 18 TIA, 40 stroke; mean age: 69.5 years, 55.4% males) from three general physician practices and used psychometric self-assessment tools to determine the occurrence of PTSD and psychosomatic comorbidity, anxiety and depression and to assess HRQoL and coping strategies. We evaluated disease severity and compared the patient groups to each other. Moreover, we assessed psychological outcome differences between patients with or without PTSD after ictus.ResultsThe prevalence of PTSD after MI, TIA and stroke was 23.2%. The patients who developed PTSD had higher rates of depression, anxiety and maladaptive coping as well as reduced HRQoL. Adaptive coping was positively related to better mental HRQoL and negatively related to anxiety and depression. Disease severity of MI, TIA and stroke was not related to PTSD, depression, anxiety or physical HRQoL.ConclusionsExperiencing MI, TIA or stroke means confronting a life-threatening event for those affected and, therefore, these can be regarded as traumatic events. Cerebral and cardiovascular events increase the risk of developing chronic PTSD with subsequent increased depression and anxiety and reduced HRQoL. These findings emphasize the need for early screening and diagnosis of PTSD in somatically ill patients, which should be followed by specialized treatment, as PTSD hampers overall (somatic) disease prognosis.Trial registrationGerman Clinical Trials Register, DRKS00021730, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021730, registered 05/19/2020 - Retrospectively registered.

Sleep quality and adherence to medical therapy among hemodialysis patients with depression: a cross-sectional study from a developing country

AimsDepression is a fairly common finding among end-stage renal disease (ESRD) patients on hemodialysis and is an independent risk factor for morbidity and mortality. The psychiatric manifestations of the disease may affect their compliance to medications and alter sleep quality that is often overlooked by nephrologists. This translates into poor quality of life and poorer disease prognosis. Thus, Our study aims to assess the prevalence of depression and its association with compliance to medical therapy and sleep quality among ESRD patients on hemodialysis.MethodIn this cross-sectional study, a total of 288 hemodialysis patients with a confirmed diagnosis of ESRD were evaluated for depression using Patient Health Questionnaire-9 (PHQ-9) scale. Only the patients with moderate to severe depressive symptoms on PHQ-9 were further evaluated for sleep quality and compliance to medications using the Pittsburgh Sleep Quality Index (PSQI) and Drug Attitude Inventory-10 (DAI-10) respectively. The characteristics of ESRD patients with depression were also assessed. Median PHQ-9, DAI-10, and PSQI scores were calculated and the correlation between study variables was assessed using spearman's correlation.ResultOf the 288 included participants, 188 (65.27%) had depression as evaluated via PHQ-9. Of these 188 patients, 114 were males while 74 were females. A total of 113 (60.01%) of the depressed patients had poor compliance with medication while 137 (72.87%) patients had poor sleep quality. Higher PHQ-9 scores were positively correlated with disease duration, dialysis years, and time between diagnosis and therapy (r = 0.41, 0.39, and 0.43 respectively) and negatively with marital and employment status (r = −0.32 and −0.49 respectively). Spearman's correlation matrix showed that PHQ-9 scores were negatively correlated with DAI-10 but positively correlated with PSQI scores.ConclusionThe study indicates a high prevalence of depression among ESRD patients on hemodialysis. Poor sleep quality and non-adherence to medications are extremely common among ESRD patients with depression. These psychiatric components must be considered to optimize medical treatment and improve the quality of life in this subset of patients.

Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature.

Simple SummaryWe define the transcriptome and secretome of primary LSECs during the progression of cirrhosis, revealing specific molecular signatures, novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced chronic liver disease.The poor prognosis of chronic liver disease (CLD) generates the need to investigate the evolving mechanisms of disease progression, thus disclosing therapeutic targets before development of clinical complications. Considering the central role of liver sinusoidal endothelial cells (LSECs) in pre-neoplastic advanced CLD, the present study aimed at investigating the progression of CLD from an endothelial holistic perspective. RNAseq defined the transcriptome of primary LSECs isolated from three pre-clinical models of advanced CLD, during the progression of the disease, and from fresh human cirrhotic tissue. At each stage of the disease, the effects of LSECs secretome on neighboring cells and proteomic analysis of LSECs-derived extracellular vesicles (EVs) were also determined. CLD was associated with deep common modifications in the transcriptome of LSECs in the pre-clinical models. Pathway enrichment analysis showed predominance of genes related with pro-oncogenic, cellular communication processes, and EVs biogenesis during CLD progression. Crosstalk experiments revealed endothelial EVs as potent angiocrine effectors. The proteome of LSECs EVs showed stage-specific signatures, including over-expression of tropomyosin-1. Proof-of-principle experiments treating cirrhotic HSCs with recombinant tropomyosin-1 suggested de-activating effects. Our data provide the basis for discovering novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced CLD.

Expanding the molecular taxonomy of NUT midline carcinomas with multiomic analyses.

e21008 Background: NUT midline carcinoma (NMC) is an aggressive squamous cell carcinoma molecularly defined by a chromosomal rearrangement of nuclear protein in testis (NUTM1) with bromodomain-containing protein 3 or 4 (BRD3/4). While NMCs are characterized by this rare canonical gene rearrangement little is known about the transcriptome and proteosome of this rare disease. As such, we set out to comprehensively characterize five NMC cases in which we attained targeted DNA sequencing, full-transcriptome RNA sequencing, and targeted proteomics. We further examine and integrate these results in order to better understand the relationship between gene expression and protein abundance within the context of NMC. Methods: All cases were analyzed for genomic and transcriptomic alterations against a custom panel via the Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth and full-transcriptome RNA sequencing) for germline and/or somatic mutations. The xT assay detects single nucleotide variants, specific insertion/deletions, amplifications and gene fusions, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. Proteomic data were obtained utilizing digital spatial profiling through Nanostring immune, MAPK and PI3/AKT, and pan tumor nCounter GeoMix panels. Results: Clinical characteristics, histology, and genomic/proteomic alterations for 5 NMC cases are presented. Cases were defined by pathological assessment and the identification of the canonical NUTM1 fusion, further broken down by fusion partner with three patients having NUTM1-BRD4 fusions, one NUT-BRD3, and one NUT-ZMYND8. TMBs ranged for 0.8-.6 mutations/megabases (n=5). All patients were MSI stable (5/5). Of three patients with available PD-L1 IHC result, one had elevated PD-L1 tumor staining at 70%. Results will be presented from full-transcriptome RNA expression analysis indicating overexpression of BRAF, MYC, mTOR, and EGFR, among others. Targeted proteomics were performed to assess relative abundance at the protein level (results to be presented). Clinical follow up for the five patients revealed that two have survived beyond 7 months. A lung primary patient treated with surgical resection and post op radiation (XRT) is NED at 63 months. A sinus primary patient is NED at 16 months after a partial response (PR) to taxotere/5FU/Cisplatin followed by resection and XRT/cis platin. One patient had a brief PR from ifosphamide/etoposide/vorinostat. One patient's tumor grew through XRT/cisplatin. Conclusions: Multi-omic analysis has the potential to further elucidate the mechanisms of tumor growth in NMC and identify new targets for the treatment of this aggressive and poor prognosis disease.

First results from a randomized phase II study of cabazitaxel (CBZ) versus an androgen receptor targeted agent (ARTA) in patients with poor-prognosis castration-resistant prostate cancer (mCRPC).

5059 Background: In the OSTRICh trial, poor-prognosis mCRPC patients were randomized between CBZ and ARTA, following progression on docetaxel (DOC) treatment. Methods: The OSTRICh trial is an open label, multicenter, phase IIb study. Patients with poor-prognosis mCRPC (visceral metastases AND/OR &lt; 12 months responsive to androgen deprivation AND/OR progressing during or within 6 months after DOC completion), were randomized 1:1 between CBZ (25 mg/m2 IV Q3W and prednisone 2 d 5 mg PO) and ARTA (daily abiraterone 1000 mg and prednisone 2 d 5 mg PO OR enzalutamide 160 mg PO). Life prolonging therapy between DOC and randomization was not allowed. Primary endpoint was to establish the Clinical Benefit Rate (no radiotherapy, no ECOG PS increase ≥2, no change of therapy AND no radiological progression) at 12 weeks (CBR) in the study arms, while formal comparison of the CBR was a secondary endpoint. A Fisher Exact test was used to assess differences in rates and a log rank test to assess differences in progression free and overall survival. All time to event endpoints were estimated with the Kaplan-Meier method and censored at last follow-up. Results: A total of 106 patients were randomized, 53 in each arm. Baseline median age was 70 (IQR 67-75) years and PSA 79.4 (IQR 29.0 - 160) ng/ml. ECOG PS score was 0/1 in 99 (93%) and 2 in 7 (7%) patients. Al patients fulfilled the criteria for poor-prognosis disease. Thirty-six (34%) patients received DOC in the metastatic hormone sensitive stage, while 41 (39%) previously received ARTA. Twenty-six of 43 evaluable patients in the CBZ arm had clinical benefit at 12 weeks (CBR: 60%, 95% CI: 44%-75%) and 20 of 39 (CBR: 51%, 95% CI: 35%-68%) in the ARTA arm (p = 0.50). At 12 weeks, 30 of 34 (88%, 95% CI: 73% - 97%) patients in the CBZ arm and 24 of 36 (67%, 95% CI: 49% - 81%) patients in the ARTA arm had no radiological progression (p = 0.046). After a median follow-up of 16.4 months (95% CI: 13.6–27.8), a serum PSA decrease ≥50% from baseline was established in 12 (23%, 95% CI: 12% - 36%) and 26 (49%, 95% CI: 35% - 63%)(p = 0.008) patients treated with CBZ and ARTA, respectively. Median radiological progression free survival (rPFS) was 6.0 months (95%CI: 4.11-14.5) in the CBZ arm and 5.8 months (95% CI: 5.22-10.2) months in the ARTA arm (p = 0.5), while median overall survival (OS) was 15.3 months (95%CI 9.49-22.4) and 13.8 months (95%CI 11.7-16.4) in CBZ and ARTA treated patients, respectively (p = 0.8). Grade ≥3 adverse events (AEs) occurred in 15 (29%) and 8 (15%) of patients treated with CBZ and ARTA, respectively. Conclusions: No significant difference in CBR was established between CBZ and ARTA treated patients. However, at 12 weeks significantly more CBZ treated patients had no radiological progression, while ≥50% PSA response rates were higher in ARTA treated patients. Clinical trial information: NCT03295565.

Hypocalcemia in Setting of Malignancy of Unknown Origin: A Case Report

Background: Hypercalcemia is a common finding well-recognized in up to 30% of cases of malignancy, associated with poor prognosis and advanced disease state. Hypocalcemia, while uncommon, can also be found in cases of malignancy facilitated by its own unique mechanism and etiologies. We present a case of severe hypocalcemia in the setting of malignancy of unknown origin. Clinical Case: 72-year-old female with a history of metastatic carcinoma of unknown origin, followed actively by Oncology, presented acutely with shortness of breath, chest pain, stiff hands and clenched fist. Patient had reported a 20 lbs weight loss over three months with a “knot” in the epigastric area affecting appetite and interfering with eating. Prior CT showed diffuse adenopathy with diffuse permeative bone destruction highly suspicious for malignancy. Follow up PET-CT showed mixed lytic lesion and sclerotic changes throughout the entire skeleton from the skull to mid thighs compatible with osseous metastatic. Initial tests show severe hypocalcemia with appropriately PTH elevation and normal vitamin D25 (calcium 5.5 mg/dL, albumin 3.9 g/dL, phosphorus (PO4) 2.3 mg/dL, magnesium (Mg) 1.5 mg/dL, PTH 243 pg/mL, vitamin D25 31.44 ng/mL). Further workup shows normal creatinine levels (0.88 mmol/L) and elevated alkaline phosphatase (1140 IU/L). Physical exam revealed bilaterally clenched fist and positive Chvostek sign. After two doses of 2 grams calcium gluconate, calcium had improved up to 7.2 mg/dL (corrected 7.76 mg/dL, albumin 3.3 g/dL) with plans to replete Mg and PO4. Patient was started on Calcium-Vitamin-D 500-200 mg-units (Oscal) two tabs trice daily. However, calcium continues to drop the next day with levels at 5.7 mg/dL (corrected 6.42 mg/dL, albumin 3.1 g/dL). A calcium infusion of 10 grams was then given over 16 hours. Calcitriol 0.25 mg twice daily was started. 24-hour urine study showed low calcium excretion (<0.8 mg/dL), normal Mg excretion (6.5 mg/dL) with an adequate creatinine collected (0.6 grams) showing no deficiencies in kidney resorption. Prior to discharge, patient’s calcium had stabilized (corrected 8.2 mg/dL, albumin 3.4 g/dL) and her associated symptoms had resolved. She was discharged on Oscal 2 tabs 4 times daily and Calcitriol 1 mcg twice daily. Conclusion: Given these biochemical results and imaging evidence of bone metastases, this case highlights the uncommon findings of hypocalcemia in the setting of malignancy. With the combination of low 24-hour urine calcium, elevated PTH, normal vitamin D25, low PO4, normal kidney function and increased alkaline phosphatase, these findings most likely indicate hypocalcemia secondary to osteoblastic bone metastasis, resulting from deposition of calcium in osteoblastic lesions.

Strategies to Overcome High-Risk Multiple Myeloma.

Multiple myeloma (MM) patients with high-risk cytogenetics continue to have inferior outcomes despite recent advances in the treatment of MM. As defined by the International Myeloma Working Group, the presence of t(4;14), t(14;16), del(17p), t(14;20) and amplification of 1q are considered to be high-risk chromosomal abnormalities associated with poor survival. Despite the use of immunomodulatory agents, proteasome inhibitors, autologous stem cell transplantation, and anti-CD38 monoclonal antibodies, clinical trials of current therapies have not shown strong statistical evidence of being able to overcome the poor prognosis of high-risk disease. Novel treatment approaches are urgently needed to improve survival in this subset of MM patients.

A438079 affects colorectal cancer cell proliferation, migration, apoptosis, and pyroptosis by inhibiting the P2X7 receptor

BackgroundOur previous study identified elevated expression of the P2X7 receptor (P2X7R) in colorectal cancer (CRC) patients, suggesting the receptor is a target for predicting poor disease prognosis. A438079 is a highly selective P2X7R antagonist, however, no studies have identified A438079 effects and mechanisms toward the biological behavior of CRC cells, and its therapeutic in vivo potential in CRC nude mice. MethodsThe CRC cell lines, HCT-116 and SW620 were treated with 10 μM A438079, after which proliferation, migration, invasion, and apoptosis were assessed. SW620 cell xenografted BALB/c nude male mice were randomly divided into control, 5-FU, and A438079 groups. Mouse weight and tumor dimensions were also measured every two days. Furthermore, the expression of apoptosis related indicators (P2X7R, Bcl-2, Bax, caspase9, cleaved caspase9, caspase3, and cleaved caspase3) and pyroptosis related indicators (NLRP3, ASC, cleaved caspase1, and interleukin (IL)-β) were investigated in vitro and in vivo. ResultsA438079 inhibited HCT-116 and SW620 cell proliferation, invasion and migration, and inhibited the growth of CRC xenografts in nude mice. A438079 promoted apoptosis via the Bcl-2/caspase9/caspase3 pathway and inhibited pyroptosis through the NLRP3/caspase1 pathway by inhibiting P2X7R in vitro and in vivo. ConclusionsWe preliminarily confirmed the therapeutic potential of A438079 toward CRC, and we provide a sound theoretical basis for A438079 as a new drug for the clinical treatment of CRC.

Metastatic Esophageal Carcinoma: Prognostic Factors and Survival.

Worldwide, esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer-related death. At initial diagnosis, about 50% of esophageal cancer patients present with metastasis. The prognosis of metastatic esophageal cancer is poor with 5-year survival rate of less than 5%. This is a retrospective study of stage IV esophageal cancer patients registered at Clinical Oncology and Nuclear Medicine department and Oncology Center Mansoura University in the period from 2009 to 2018 inclusive. Eligibility criteria were all pathologically proven stage IV esophageal cancer patients. The medical files of patients were reviewed. Most patients were ≥ 50years (67.8%) with male predominance (76.7%). Middle third was the most common site of primary tumor (38.9%). Squamous cell carcinoma was more common with incidence of grade 3 (40%). T3-4 lesion was recorded in 61.1% and node positive in 66.7%. As regards metastasis; liver was the most common one (45.5%) followed by lung (30%). One-year survival rate was 25.6% with median survival time of 8months. Multivariate analysis indicated that age (p = 0.03), site (p = 0.04), grade of primary tumor (p = 0.049), T classification (p = 0.0038), ECOG PS (p = 0.046), site (p = 0.026), and number of metastasis (p = 0.04) significantly affect prognosis while sex (p = 0.74) and histologic type (p = 0.94) do not. Metastatic esophageal carcinoma is a disease of poor prognosis especially in patients with the following criteria: old age, lower third location, high grade and large tumors, poor performance status, multiple sites of metastasis and presence of bone secondaries.