Prognostic Factor For Poor Outcome Research Articles

Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma: Radiologic and Clinical Factors Predictive of Survival.

OBJECTIVE. The goal of this study was to evaluate radiologic and clinical factors associated with overall survival of advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy (HAIC). MATERIALS AND METHODS. This single-center retrospective study included 180 patients with advanced hepatocellular carcinoma who underwent HAIC with a 5-fluorouracil (250-500 mg/m2 for 5 hours) plus cisplatin (10-20 mg/m2 for 1-2 hours) regimen via an implantable port system. Survival curves were generated by the Kaplan-Meier method and compared by log-rank tests. Factors associated with overall survival were evaluated with Cox proportional hazard models. RESULTS. The median overall survival time was 7.6 months (95% CI, 6.1-9.1), and the objective response rate was 15%. In multivariate analysis, infiltrative tumor growth (hazard ratio [HR], 1.002; p = .03) and rimlike arterial enhancement (HR, 3.040; p < .001) were pretreatment radiologic factors associated with reduced overall survival. No early response to treatment (HR, 2.064-6.491) and higher Child-Pugh class (HR, 2.010-2.815) were strong prognostic factors of poor outcome. Treatment with three or more HAIC cycles (HR, 0.371; p = .001) and high-dose HAIC (HR, 0.447; p < .001) were favorable for increased overall survival. CONCLUSION. Infiltrative tumor growth and rimlike arterial enhancement in pre-treatment imaging studies were associated with poor prognosis, and better early radiologic response and preserved liver function reserve were strong indicators of prolonged survival. Recognizing these radiologic and clinical predictors may help optimize care of patients with hepatocellular carcinoma.

Do early patient reported outcome measures post total knee arthroplasty predict poor outcomes (the early PROMPT study)?

INTRODUCTION: Approximately 20% of patients are not satisfied following Total knee arthroplasty (TKA). The ability to identify patients at risk of poor outcomes in the early-postoperative period following TKA could inform the development of targeted treatments with the ability to improve outcomes for these patients. This prospective cohort study aimed to identify early post-operative, prognostic factors for patients experiencing dissatisfaction and poor outcomes at 12-months post TKA. METHODS: Patients (n = 185) were recruited from TKA waiting lists at a single site, completed measures of pain intensity, neuropathic pain, anxiety, depression, generic and disease specific health related quality of life (HRQoL), satisfaction and expectations, at discharge from hospital; three weeks post-surgery and again at 1 year. ROC curve analysis identified which variables best predicted patients experiencing dissatisfaction (VAS &lt; 5/10) and poor outcomes (Western Ontario and McMaster Universities Arthritis Index (WOMAC)&lt;40) at 12-months. RESULTS: The strongest prognostic factors for dissatisfaction were low HRQoL (EQ5D3L) at both day of discharge (AUC = 0.812) and three weeks post-surgery (AUC = 0.810), and high pain levels (WOMAC pain sub-scale) at 3-weeks post-TKA (AUC = 0.796). The strongest prognostic factors for poor outcomes were poor function (WOMAC function sub-scale) at three weeks post TKA (AUC = 0.815); low HRQoL (EQ5D3L) at three weeks post-TKA (AUC = 0.783) and high levels of pain (WOMAC pain sub-scale) at 3 weeks post-TKA (AUC = 0782). Anxiety and depression at 3-weeks were also prognostic factors for dissatisfaction (AUC = 0.629 &amp; AUC = 0.686) and poor outcomes (AUC = 0.632 &amp; 0.713) at 12-months. CONCLUSION: This single site cohort study suggests that patients with low HRQoL, high pain levels, poor function, anxiety, and depression in the first three weeks following TKA are at risk of dissatisfaction and poor outcomes at one-year post-surgery.

Results of an international Delphi consensus in epilepsy with myoclonic atonic seizures/ Doose syndrome

ObjectiveTo establish a standard framework for early phenotypic diagnosis, investigations, expected findings from investigations, evolution, effective therapies and prognosis in the syndrome of Epilepsy with myoclonic atonic seizures (EMAS) / Doose syndrome. MethodsA core study group (CSG) interested in EMAS was convened. CSG then identified and nominated 15 experts in the field of EMAS. This expert panel (EP) from English speaking nations was invited to participate in anonymous questionnaires. A literature review was provided to them (supplement 1). Three rounds of questionnaires were sent to identify areas of consensus, strength of consensus and areas of contention. ResultsStrong consensus was obtained regarding the clinical phenotype of EMAS: myoclonic atonic seizure was identified among others as a mandatory seizure type with typical onset of afebrile seizures between one and six years. A new term “stormy phase” (SP) was designated to delineate a characteristic phenotypic evolution in EMAS patients associated with seizure worsening. Strong consensus regarding the existence and time of onset of the SP, mandatory investigations to be performed early and later in the clinical course of EMAS, first and second tier treatment and prognostic factors for poor outcome were identified. Areas of lack of consensus included some seizure types that are necessary to diagnose EMAS, interictal EEG findings that prognosticate the course of EMAS, overall duration of SP, time to complete remission, and best approach to treat drug resistant EMAS. SignificanceExpert consensus on core diagnostic criteria of EMAS necessary for natural history studies, phenotype-genotype correlations, and clinical trials including comparative studies was demonstrated. Areas of disagreements (especially prognostic features; treatment options) need further research.

Mortality rate and prognostic factors for poor outcome in HIV-infected Bulgarian patients with Pneumocystis pneumonia over a 3-year period

Background: In spite of the use of combination antiretroviral therapy and specific prophylaxis, Pneumocystis pneumonia remains one of the most common AIDS-defining disease with high mortality rate. The aim of this study is to analyze the cases of pneumocystis pneumonia over a three-year period by means of assessing the mortality rate and the prognostic factors for the outcome of the disease. Material and methods: Epidemiological, clinical, laboratory and demographic data were analyzed for 13 HIV-infected patients with proved pneumocystis pneumonia, hospitalized at the AIDS Department over the period January 2017–December 2019. For data processing we used different methods of descriptive statistics. Results: All presented patients have extremely severe immune deficiency and other opportunistic infections or AIDS-related diseases. The diagnosis of pneumocystis pneumonia was confirmed with PCR in 76.9% of the patients and with Giemsa staining for cysts and trophozoites in 23,1% of the patients. Most of our patients are male (84,6%) and the leading mechanism of HIV infection is unprotected homosexual contact. The mean age of the patients presented is 37.4 ± 10.27. Our results showed high PJP mortality (46.3 %), despite the applied etiological therapy. Conclusions: Pneumocystis jirovecii pneumonia (PJP) continues to be a life-threatening infection in HIV-infected patients with severe immune suppression. PJP mortality continues to be high, and there is a statistically significant dependence on age, male sex, low CD 4 T+ cell count, high viral load of HIV, low blood albumin, and the number and severity of comorbidities.

Prognostic factors for long-term results after condylar head fractures: A comparative study of non-surgical treatment versus open reduction and osteosynthesis

This longitudinal study compared functional, anatomical, and quality of life (QoL) outcomes after closed reduction (CR) versus open reduction and internal fixation (ORIF) of condylar head fractures (CHFs). The aim was to determine predictability of results and to establish prognostic factors for poor outcomes, thus allowing therapeutic decision making between CR and ORIF.All fractures of the non-surgical group were treated by CR with maxillomandibular fixation (CR-MMF) according to an managed analogically. Morphological and functional results were acquired using axiography and clinical functional diagnostics, as well as MRI in problematic cases. Outcomes were compared with those of a collective of patients treated by ORIF with small fragment screws (SFS), according to a uniform standard.A total of 26 patients with 29 unilateral and bilateral CHFs of the non-surgical group were examined over a period of 28.5 months after completion of therapy and compared with a collective of 54 patients with 73 CHFs treated by ORIF. Statistically significant differences were found between both groups in protrusion and mediotrusion on the fracture side, in favour of ORIF. Significantly more patients in the ORIF group were symptom free in terms of the Helkimo dysfunction index and the RDC TMD compared with conservatively treated patients. Associations between Angle class and Helkimo dysfunction index, and between occlusion or number of teeth and pain after CT, could be confirmed.Given their respective indications, both treatment options demonstrated acceptable results in the majority of cases. However, for therapeutic decision making, it is crucial that the long-term results after CR are significantly less predictable. Our study showed only few positive prognostic factors for a stable functional outcome after CR such as isolated CHFs with stable occlusal conditions in younger patients (<25 years).

Prognostic utility of preoperative neutrophil–lymphocyte ratio in cats with malignant mammary tumors

Although studies have determined the neutrophil–lymphocyte ratio (NLR) to be a useful prognostic predictor in various human cancers, little is known regarding its preoperative prognostic significance in feline mammary tumors (FMTs). Thus, the present study aimed to determine the prognostic utility of preoperative peripheral blood NLR in malignant FMTs. Accordingly, medical records of 34 cats that had undergone mastectomy were searched, after which those histopathologically confirmed to have malignant FMTs were included. Univariate analysis was used to determine the effect of each variable on one-year survival time. Factors determined to be significant during univariate analysis were subsequently included for multivariate analysis. Receiver operating characteristic analysis was used to assess the accuracy of the tests for predicting one-year survival. Univariate analysis showed that a high NLR and large tumor size were significantly associated with shorter survival times (P < 0.01, for both). No significant differences in other factors were observed. Multivariate analysis showed that a high NLR (hazard ratio, 25.03; 95% confidence interval, 2.98–210.40; P < 0.01), but not tumor size and age, was an independent prognostic factor for poor outcomes. The sensitivity and specificity of the NLR (cut-off, 5.67) for predicting one-year survival were 93.8% and 88.9%, respectively. This study suggests that the NLR could potentially be used as a preoperative prognostic factor in FMTs. Preoperative NLR may help to establish therapeutic modalities by allowing prognostic evaluation among cats with mammary tumors.

Mouse double minute 2 amplification in oesophageal squamous cell carcinoma is associated with better outcome.

This study aimed to determine the frequency of mouse double minute 2 (MDM2) amplification in oesophageal squamous cell carcinomas (ESCC) and to clarify its prognostic significance. We investigated MDM2 amplification on tissue microarrays using fluorescence in-situ hybridisation and analysed its correlations with clinicopathological features and outcomes in 515 Chinese ESCC patients. MDM2 amplifications were found in 37 of 515 ESCC patients (7.2%). They were significantly negatively correlated with tumour size (P=0.045), disease progression (P=0.002) and death (P=0.003). Univariate analysis showed that the following clinicopathological factors were associated with disease-free survival (DFS) and overall survival (OS): differentiation (P=0.025 for DFS and P=0.061 for OS), vessel invasion (P=0.001 and P=0.002), nerve invasion (P=0.009 and P=0.001), clinical stage (P<0.001 and P<0.001) and MDM2 amplification (P=0.012 and P=0.014). Multivariate Cox regression analysis showed that MDM2 amplification was an independent prognostic factor for improved outcomes (P=0.023 for DFS, P=0.027 for OS) and the clinical stage was an independent prognostic factor for poor outcomes (P<0.001). When survival analyses were conducted at different clinical stages, MDM2 amplification was associated with longer DFS and OS in stages I-II ESCC (P=0.003 for DFS and P=0.003 for OS), but there was no significant survival difference in stages III-IVa ESCC. MDM2 amplification was significantly correlated with an improved patient outcome, especially in stage I and II disease, and was verified as an independent prognostic factor in our patients. Therefore, MDM2 amplification may be a potential biomarker for risk stratification of the lower stages of ESCC.

Caspase Recruitment Domain-Containing Protein 9 Expression is a Novel Prognostic Factor for Lung Adenocarcinoma.

PurposeCaspase recruitment domain-containing protein 9 (CARD9) is expressed at high levels in bone marrow cells and has a crucial role in innate immunity. Current studies indicate that CARD9 also plays a key role in tumor progression, but there are few reports on the role of CARD9 in lung cancer. The aim of this study was to clarify the role of CARD9 in lung adenocarcinoma.Patients and MethodsLung adenocarcinoma tumor samples from 74 patients who underwent complete resection at Kobe University Hospital from January 2014 to December 2014 were analyzed by immunohistochemistry. The role of CARD9 in cancer cells was analyzed using lung cancer cell lines treated with CARD9 siRNA.ResultsHigh expression of CARD9 was observed in 32.4% of tumors, and compared to low expression of CARD9, high expression was associated with poorer overall survival (P = 0.0365). Univariate and multivariate analyses showed that high expression of CARD9 was an independent prognostic factor. Knockdown of CARD9 in lung adenocarcinoma cells inhibited proliferation but did not increase apoptosis. In addition, CARD9 activated the NF-κB pathway in a lung adenocarcinoma cell line.ConclusionCARD9 was shown to be an independent prognostic factor of poor outcome for lung cancer and may represent a molecular target for treatment.

Kidney transplant patients with SARS-CoV-2 infection: The Brescia Renal COVID task force experience.

The outcome of kidney transplant patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is still unclear. Here we describe the clinical characteristics, disease outcome, and risk factors for acute respiratory distress syndrome (ARDS) and death of a cohort of 53 kidney transplant patients with coronavirus disease 2019 (COVID‐19). Eight of 53 have been handled as outpatients because of mild disease, on average with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin; no patients required admission, developed ARDS, or died. Because of severe symptoms, 45/53 required admission: this cohort has been managed with immunosuppression withdrawal, methylprednisolone 16 mg/d, hydroxychloroquine, and antiviral drugs. Dexamethasone and tocilizumab were considered in case of ARDS. About 33% of the patients developed acute kidney injury, 60% ARDS, and 33% died. In this group, thrombocytopenia was associated to ARDS whereas lymphopenia at the baseline, higher D‐dimer, and lack of C‐reactive protein reduction were associated with risk of death. In the overall population, dyspnea was associated with the risk of ARDS and age older than 60 years and dyspnea were associated with the risk of death with only a trend toward an increased risk of death for patients on tacrolimus. In conclusion, SARS‐CoV‐2 infection may have a variable outcome in renal transplant patients, with higher risk of ARDS and death in the ones requiring admission.

SPAG5 promotes osteosarcoma metastasis via activation of FOXM1/MMP2 axis.

Osteosarcoma (OS) is a primary malignancy of bone with a tendency to metastasize early. An understanding of the pathways that regulate OS metastasis is required for the design of novel treatment approaches. Sperm-associated antigen 5 (SPAG5) is upregulated and functions as a potential tumor promoter in diverse human cancers, but has yet to be investigated in the OS. In the present study, results showed that SPAG5 expression is upregulated in OS tissues, and SPAG5 overexpression is obviously associated with the malignant phenotype and poor survival in patients with OS. Multivariate analyses also revealed that SPAG5 overexpression is an independent prognostic factor for poor outcome of patients with OS. The functional assay indicated that SPAG5 silencing significantly inhibits the invasion and migration of OS cells in vitro. Additionally, knockdown of SPAG5 in OS cells suppresses lung metastasis in vivo. Further, we also found that SPAG5 silencing inhibits the epithelial-mesenchymal transition (EMT) process of OS cells. Moreover, our results indicated that SPAG5 promotes OS metastasis by increasing matrix metalloproteinase-2 (MMP2) expression, and demonstrated that MMP2 is crucial for the pro-metastasis role of SPAG5 in OS cells. Mechanistically, we identified that SPAG5 regulates MMP2 expression by modulating FOXM1 (Forkhead box M1) degradation to enhance the protein stability of FOXM1. Collectively, these findings describe the effects of SPAG5-FOXM1-MMP2 axis in the regulation of OS cell migration and metastasis formation. We provide a novel evidence that SPAG5 may serve as a prognostic indicator and potential therapeutic target for patients with osteosarcoma.

TRAIL receptors are differentially regulated and clinically significant in gallbladder cancer

Deregulation of the receptors of TNF-related apoptosis inducing ligand (TRAIL) has been reported in various cancers. In an effort to define the role of these receptors we profiled their expression in gallbladder cancer (GBC) and explored their clinical significance. Expression of TRAIL receptors' mRNA in GBC was analysed through reverse transcriptase polymerase chain reaction (RT-PCR), and protein through western blotting, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). mRNA data show frequent higher expression of TRAIL receptors in GBC samples. Death receptors DR4 and DR5 showed significant negative correlation with tumour stage, T stage and tumour grade; DcR1 transcript showed positive correlation with tumour stage, N stage, M stage and tumour grade. Similarly, IHC showed frequent positive staining for DR4, DR5 and DcR1in GBC samples. Cytoplasmic and nuclear DR4 protein showed negative correlation with T stage and tumour grade, whereas cytoplasmic DcR1 protein showed positive correlation with tumour stage and N stage. Nuclear DcR1 showed positive correlation with N stage. ELISA results showed significantly higher expression of secretory DcR1 in GBC patients. Kaplan-Meier analysis demonstrated significantly decreased mean survival of patients with positive staining of cytoplasmic DcR1. High level of death receptors identified the patients with early gallbladder cancer, whereas high DcR1 expression served as a prognostic factor for poor outcome.

Prognosis and Risk Factors of Radiation-Induced Lymphopenia in Early-Stage Lung Cancer Treated With Stereotactic Body Radiation Therapy.

Background: To investigate the role of stereotactic body RT (SBRT) in decreased total peripheral lymphocyte count (TLC) in patients with early-stage lung cancer and to explore possible risk factors for RT-induced lymphopenia.Materials and Methods: We analyzed the TLCs and lymphocyte subsets of 76 patients in our prospective clinical database who received SBRT for early-stage lung cancer treatment. Relationships between clinical factors or dosimetric parameters and TLC were evaluated using Spearman's correlation analysis and Chi-square tests for continuous and categorical variables, respectively. Multivariate linear regression analysis was used to control for confounding factors. Kaplan–Meier analysis with a log-rank test and a multivariate Cox regression model were used for survival analysis.Results: Most patients (64/76, 84.2%) experienced decreased absolute lymphocyte counts following SBRT, as well as shifts in lymphocyte subset distributions. Spearman's correlation coefficients between post-SBRT TLC and the percentage of the lung and heart receiving 5 to 50 Gy (in 5 Gy increments) shown that most lung DVH parameters [V(10)-V(50)] were significantly negatively correlated with post-SBRT TLC, while only heart V(5), V(20), V(25), V(30), and V(45) were significant. Univariate analyses revealed that a lower Pre-SBRT TLC level, higher mean lung dose, longer treatment duration, and longer TBT were significantly associated with a lower Post-SBRT TLC level (all P < 0.05). Stepwise multivariate linear regression, which incorporated all of the significantly clinical variables and SBRT-related parameters in univariate analysis, revealed that lower pre -SBRT TLC (P < 0.001), higher heart V5 (P = 0.002), and longer total beam-on time (TBT) (P = 0.001) were the independent risk factors for decrease in post-SBRT TLC. Patients with lower post-SBRT TLC and longer TBT exhibited significantly inferior progression-free survival (PFS) (P < 0.001 and P = 0.013) and overall survival (P = 0.006 and P = 0.043).Conclusions: G2 and more severe lymphopenia after SBRT might be an independent prognostic factor for poorer outcome in early-stage lung cancer. Lowering heart V5 and TBT when designing SBRT plans may spare circulating lymphocytes and have the potential to further improve survival outcomes.

High Preoperative Controlling Nutritional Status Score Predicts a Poor Prognosis in Patients with Localized Upper Tract Urothelial Cancer: A Propensity Score Matching Study in a Large Chinese Center.

PurposeThe aim of this study was to elucidate the prognostic value of the preoperative controlling nutritional status (CONUT) score, a new index based on the total lymphocyte count, serum albumin concentration and total cholesterol concentration, in patients with localized upper tract urothelial cancer (UTUC) after radical nephroureterectomy (RNU) using propensity score matching (PSM) analysis.MethodsWe retrospectively reviewed 908 consecutive patients with localized UTUC who underwent RNU between 1999 and 2015. Patients were divided into two groups according to the optimal cutoff value of the preoperative CONUT score. Relationships between the CONUT score with clinicopathological characteristics, overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) were analyzed before and after 1:1 PSM.ResultsA high preoperative CONUT score was significantly correlated with older age, low body mass index (BMI), poor American Statistical Association (ASA) score, advanced pathological T stage, and tumor squamous or glandular differentiation (all p<0.05). Kaplan-Meier curves showed poor OS, CSS, and DFS for patients with a high CONUT score before and after PSM (all p<0.001). Furthermore, multivariate analyses revealed that a high preoperative CONUT score was an independent risk factor for poor DFS (hazard ratio [HR] 1.418, 95% confidence interval [CI] 1.132–1.776, p=0.002) before PSM and an independent risk factor for poor DFS (HR 1.333, 95% CI 1.010–1.760, p=0.042) and OS (HR 1.459, 95% CI 1.010–2.107, p=0.044) after PSM.ConclusionA high preoperative CONUT score is an independent prognostic factor for poor outcomes in patients with localized UTUC after RNU.

Neurodevelopmental effect of intracranial hemorrhage observed in hypoxic ischemic brain injury in hypothermia-treated asphyxiated neonates - an MRI study

BackgroundIdentification of early signs of hypoxic ischemic encephalopathy (HIE) with magnetic resonance imaging (MRI) has proven of prognostic significance. Yet, the importance of intracranial hemorrhage (ICH), being present concomitantly had not been investigated yet, despite the known influence of hypothermia on hemostasis. We aimed to determine whether presence of ICH on MRI alongside the signs of HIE have an impact on prognosis in neonates with the clinical diagnosis of HIE.MethodsA retrospective study of consecutively sampled 108 asphyxiated term infants admitted to a tertiary neonatal intensive care unit (between 2007 and 2016), treated with whole body hypothermia and having brain MRI within 1 week of life was conducted. Presence or absence of HIE signs on MRI (basal ganglia-thalamus, watershed pattern and total brain injury) and on MR spectroscopy (lactate peak with decreased normal metabolites measured by Lac/NAA ratio) and/or of the five major types of ICH were recorded. Neurodevelopmental outcome was measured with Bayley Scales of Infant Development-II (BSID-II) test. Death or abnormal neurodevelopment (BSID-II score < 85) was defined as poor outcome in Chi-square test. Multivariate logistic regression analysis was performed on survivors.ResultsMRI and MR-spectroscopy (MRS) signs of HIE were present in 72% (n = 78). 36% (n = 39) of neonates had ICH, being mainly small in size. Chi-square test showed a relationship between neurodevelopmental outcome and initial MRI. Unadjusted logistic regression showed that neonates presenting MRI and MRS signs of HIE have 6.23 times higher odds for delayed mental development (OR = 6.2292; CI95% = [1.2642; 30.6934], p = 0.0246), than infants without imaging alterations; with no ICH effect on outcome. Adjustment for clinical and imaging parameters did not change the pattern of results, i.e. HIE remained an independent risk factor for delayed neurodevelopment (OR = 6.2496; CI95% = [1.2018; 32.4983], p = 0.0294), while ICH remained to have no significant effect.ConclusionHIE related MRI abnormalities proved to be important prognostic factors of poor outcome in cooled asphyxiated infants when present, suggesting that early MRI with MRS is beneficial for prognostication. Interestingly, ICHs present in about one third of all cases had no significant effect on neurodevelopmental outcome, despite the known hemostasis altering effects of hypothermia.

Prognostic factor of poor outcome in anti-MAG neuropathy: clinical and electrophysiological analysis of a French Cohort.

Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases. We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used. Forty-seven patients were included in the study; of these, 61% had a classical 'distal demyelinating pattern', 34.2% had a 'CIDP-like pattern', and the others had an 'axonal pattern'. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination. Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a 'red flag' for the prompt initiation of rituximab to try to delay long-term disability.

AGR2 is controlled by DNMT3a-centered signaling module and mediates tumor resistance to 5-Aza in colorectal cancer

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is upregulated in various human cancers and reportedly has oncogenic activities. However, the functional roles of AGR2 and its regulation in colorectal cancer (CRC) remain unclear. Here, we showed that AGR2 promoted CRC tumorigenesis and progression in vitro and in vivo and acted as an independent prognostic factor of poor outcome. AGR2 was negatively regulated by DNA methyltransferase 3a (DNMT3a) through directly methylating AGR2 promoter and by a DNMT3a–SPRY2–miR-194 axis. Moreover, AGR2 mediated the resistance to 5-Aza-2′-deoxycytidine (5-Aza) treatment. Knockdown of AGR2 improved the therapeutic effect of 5-Aza in human CRC xenograft tumor model. Thus, our work supports AGR2's oncogenic role in CRC, reveals DNMT3a-mediated epigenetic modulation on AGR2 promoter, and uncovers a new DNMT3a signaling module controlling expression of AGR2. Upregulated AGR2 offset 5-Aza mediated epigenetic therapy. This work might provide potential targets for clinical anti-cancer therapy.

1253P - CCND1 amplification contributes to immunosuppression in head and neck squamous cell carcinoma and the association with a poor response to immune checkpoint inhibitors

BackgroundCopy number alterations in cyclin D1 (CCND1) relevant to malignant biological behavior exist in solid tumors, including head and neck squamous cell cancer (HNSCC). The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to immune checkpoint inhibitors (ICIs) therapy is unknown. MethodsThis was a three-cohort pooled study, 6904 samples from 6540 patients from the Geneplus Insitute, 10562 samples from the TCGA and 10614 samples from the MSKCC were statistically analyzed. Next-generation sequencing assays were performed in tumor samples at the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC. Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and their correlation with the prognosis and the response to ICIs. Assessment of the CCND1 amplification frequency, overall survival (OS), gene set enrichment analysis (GSEA) and immune profile in solid tumors. ResultsIn HNSCC, 7 cases (25.00%) were identified CCND1 amplification in the Chinese cohort, 120 cases (23.21%) in the TCGA cohort, and 5 cases (9.43%) in the MSKCC cohort. Survival analysis showed that CCND1 amplification was an independent prognostic factor for poor outcome in HNSCC as well as for pan-cancer in the TCGA and MSKCC populations. Furthermore, in the MSKCC cohort, patients receiving ICIs with CCND1 amplification had a shorter OS compared with neutral patients (HR, 1.63; 95%CI, 1.09–2.43; median OS, 11.0m vs. 18.0m; P=.0024), especial in the high-TMB subgroup (HR, 2.82; 95%CI, 1.11–7.20; median OS, 10.0m vs. 41.0m; P=.0003). Comparing the transcriptome between amplification and neutral groups in six solid tumors from the TCGA cohort showed various degrees of immunosuppression in the tumor microenvironment (TME), especially in HNSCC. The GSEA suggested that multiple aggressive, immunosuppressive and angiogenic hallmarks correlate with CCND1 amplification in HNSCC. ConclusionsThese findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs. Legal entity responsible for the studyChuan Ben Chen. FundingMinistry of Health P.R.China (Grant No. WKJ2016-2-33). DisclosureAll authors have declared no conflicts of interest.

Progress in Allogeneic Hematopoietic Cell Transplantation in Adult T-Cell Leukemia-Lymphoma.

The prognosis of aggressive adult T-cell leukemia-lymphoma (ATL) remains poor because of frequent infections and drug resistance. Dose-intensified chemotherapy followed by autologous stem cell transplantation failed to improve the prognosis of patients with ATL; however, we first revealed that allogeneic hematopoietic cell transplantation (allo-HCT) might improve their prognosis. We showed that reduced-intensity stem cell transplantation using peripheral blood was feasible for elderly patients. Further, the prognosis of patients in remission, who receive cord blood transplantation, has been recently improved and is equivalent to that of patients who receive transplants from other stem cell sources. As for the timing of HCT, the patients who underwent transplantation early showed better outcomes than those who underwent transplantation late. Based on the analysis of patients with aggressive ATL, including those who received transplants, we identified five prognostic factors for poor outcomes: acute-type ATL, poor performance status, high soluble interleukin-2 receptor levels, hypercalcemia, and high C-reactive protein level. Next, we developed a new prognostic index: the modified ATL-PI. The overall survival (OS) rates were significantly higher in patients who underwent allo-HCT than those who did not in the intermediate and high-risk groups stratified using the modified ATL-PI. Two new anti-cancer agents, mogamulizumab and lenalidomide, were recently approved for ATL patients in Japan. They are expected to induce longer survival in ATL patients when administered along with transplantation. However, a retrospective analysis that the risk of severe, acute, and corticosteroid-refractory graft-versus-host disease was higher in patients who received mogamulizumab before allo-HCT, and that mogamulizumab might increase the transplant-related mortality (TRM) rates and decrease the OS rates compared to those of patients who did not receive mogamulizumab. However, our recent study showed that administration of mogamulizumab before allo-HCT tended to improve the survival of patients with ATL. In conclusion, allo-HCT procedures for patients with aggressive ATL have considerably progressed and have helped improve the prognosis of these patients; however, many concerns still remain to be resolved. Further development of allo-HCT by using new molecular targeting agents is required for the improvement of cure rates in patients with ATL.

45 External Validation of a Subdural Hematoma Risk Decision Instrument in Emergency Department Patients

Anticoagulation, hematoma size, and midline shift are significant prognostic factors for poor outcomes in the acute phase of subdural hematomas (SDH). They were used by Pruitt et al in 2017 to develop a decision instrument identifying low risk patients with traumatic SDH. We wished to externally validate this decision instrument in our emergency department (ED), an academic, Level 1 trauma center. We conducted a retrospective chart review study of patients ≥18 years old in the ED with CT-documented SDH from 2014-2016. Patients were considered high risk per the decision instrument if they had hematoma thickness >5mm, warfarin or clopidogrel use, initial Glasgow Coma Scale <14, midline shift, or ≥1 hematoma. Primary composite outcome included in-hospital death or transition to hospice, need for neurosurgery, neurologic decline, and/or worsening hematoma on CT. Five hundred twenty-three charts were reviewed, and 222 met inclusion criteria. Forty-one (18.5%) patients were low risk per the decision instrument. Of these, 13 (31.7%) experienced the composite outcome. The sensitivity for this instrument was 89.4% (95% CI 82.6% - 94.3%), and the specificity was 28.3% (95% CI 19.7% - 38.2%). Patients on novel oral anticoagulant (NOAC) agents had a 55.6% (5/9) composite outcome. Including all patients on NOACs as high risk did not affect sensitivity (89.4%, 95% CI 82.6% - 94.3%) and marginally worsened specificity (24.2%, 95% CI 16.2% - 33.9%). The current decision instrument resulted in a 31.7% adverse outcome rate for low risk patients. This could be due to differences in our patient population including higher rate of NOAC use, inclusion of patients with spontaneous SDH, and higher overall mortality in our population. We recommend further study before implementing reduced level of care for patients with SDH.

Identification of STAB1 in Multiple Datasets as a Prognostic Factor for Cytogenetically Normal AML: Mechanism and Drug Indications

Cytogenetically normal acute myeloid leukemia (CN-AML) presents with diverse outcomes in different patients and is categorized as an intermediate prognosis group. It is important to identify prognostic factors for CN-AML risk stratification. In this study, using the TCGA CN-AML dataset, we found that the scavenger receptor stabilin-1 (STAB1) is a prognostic factor for poor outcomes and validated it in three other independent CN-AML datasets. The high STAB1 expression (STAB1high) group had shorter event-free survival compared with the low STAB1 expression (STAB1low) group in both the TCGA dataset (n = 79; p = 0.0478) and GEO: GSE6891 dataset (n = 187; p = 0.0354). Differential expression analysis between the STAB1high and STAB1low groups revealed that upregulated genes in the STAB1high group were enriched in pathways related to cell adhesion and migration and immune responses. We confirmed that STAB1 suppression inhibits cell growth in KG1a and NB4 leukemia cells. Expression correlation analyses between STAB1 and cancer drug targets suggested that patients in the STAB1low group are more sensitive to the BCL2 inhibitor venetoclax, and we confirmed it in cell lines. In conclusion, we identified STAB1 as a prognostic factor for CN-AML in multiple datasets, explored its underlying mechanism, and provided potential therapeutic indications.