Prognostic Factor For Patient Survival Research Articles

Reclassification of Glioblastoma Multiforme According to the 2021 World Health Organization Classification of Central Nervous System Tumors: A Single Institution Report and Practical Significance.

IntroductionThe 2021 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has introduced significant changes to tumor taxonomy. One of the most significant changes in the isolation of isocitrate dehydrogenase (IDH) mutant forms of glioblastoma multiforme (GBM) into separate entities, as well as no longer allowing for entries to be classified as not otherwise specified (NOS). As a result, this entity now includes only the most aggressive adult-type tumors. As such, established prognostic factors no longer apply, as they now form the criteria of different disease entries or have been established based on a mixed cohort. Herein, we aimed to reclassify glioblastoma cases diagnosed per the 2016 WHO tumors of the CNS classification into the 2021 WHO tumors of the CNS classification and establish a patient survival pattern based on age, gender, tumor location, and size as well as tumor O‐6‐methylguanine‐DNA methyltransferase (MGMT) mutation.Materials and methodsA retrospective, non-clinical approach was utilized. Biopsy specimens of adults diagnosed with GBM, WHO grade 4, NOS in the period February 2018-February 2021 were reevaluated. The data regarding the patient's gender and age were withdrawn from the medical documentation. Immunohistochemistry was performed with mouse monoclonal anti-IDH R132H and rabbit polyclonal anti-MGMT. Radiology data on tumor location and size were pulled from the radiology repository. Data were statistically analyzed for significance, using Kaplan-Meier survival analysis, with a 95% confidence interval and p<0.05 defined as significant.ResultsA total of 58 cases fit the set criteria, with eight of them (13.7%) harboring an IDH R132H mutation and were hence reclassified as diffuse astrocytoma IDH-mutant, WHO CNS grade 4. The cases that retained their GBM classification included n=28 males and n=22 females, a male to female ratio of 1.27:1, and a mean age of 65.3 years (range 43-86 years). The MGMT mutational status revealed a total of n=17 positive cases (35%), while the remaining cases were negative. No hemispheric predilection could be established. Lobar predilection was as follows: temporal (37.78%), parietal (28.89%), frontal (24.44%), and occipital (8.89%).The mean tumor size measured on neuroradiology across the cohort was 50.51 mm (range 20-76 mm). The median survival across cases was 255.96 days (8.41 months), with a range of 18-1150 days (0.59-37.78 months). No statistical correlation could be established between patient survival and gender, hemispheric location, lobar location, and tumor size. A significant difference in survival was established only when comparing the 41-50 age groups to the 71-80 and 81-90 age groups and MGMT positive versus negative tumors (p=0.0001).ConclusionFrom a practical standpoint, the changes implemented in the new classification of CNS tumors define GBM as the most aggressive adult type of tumor. Based on their significantly more favorable prognosis, the reclassification of IDH mutant forms of astrocytomas has had little epidemiological impact on this relatively common malignancy but has significantly underlined the dismal prognosis. The changes have also led to MGMT promoter methylation status being the only significant prognostic factor for patient survival in clinical use, based on its prediction for response to temozolomide therapy in this nosological unit clinically presenting when it has already reached immense size.

ETV4 promotes pancreatic ductal adenocarcinoma metastasis through activation of the CXCL13/CXCR5 signaling axis.

Pancreatic ductal adenocarcinoma (PDAC) has the highest fatality rate of any solid tumor, with a five-year survival rate of only 10% in the USA. PDAC is characterized by early metastasis. More than 50% of patients present with distant metastases at the time of diagnosis, and the majority of patients will develop metastasis within 4 years after tumor resection. Despite extensive studies, the molecular mechanisms underlying PDAC metastasis remain unclear. The polyoma enhancer activator protein (PEA3) subfamily was reported to play a vital role in the initiation and progression of multiple tumors. Herein, we found that ETS variant 4 (ETV4) was highly expressed in PDAC tissues and associated with poor survival. Univariate and multivariate analyses revealed that ETV4 expression was an independent prognostic factor for patient survival. Further experiments showed that ETV4 overexpression promoted PDAC invasion and metastasis both in vitro and in vivo. For the first time, we demonstrated that, mechanistically, ETV4 increased CXCR5 expression by directly binding to the CXCR5 promoter region. Knockdown of CXCR5 significantly reversed ETV4-mediated PDAC migration and invasion, while CXCR5 overexpression exerted the opposite effects. Intriguingly, we found that CXCL13, a specific ligand of CXCR5, increased ETV4 expression and promoted PDAC invasion and metastasis by activating the ERK1/2 pathway. ETV4 knockdown significantly abrogated the enhanced migratory and invasive abilities induced by the CXCL13/CXCR5 axis. In addition, a CXCR5 neutralizing antibody disrupted the CXCL13/ETV4/CXCR5 positive feedback loop and inhibited cell migration and invasion. Overall, in this study, we demonstrated that ETV4 plays a vital role in PDAC metastasis and defined a novel CXCL13/ETV4/CXCR5 positive feedback loop. Targeting this pathway has implications for potential therapeutic strategies for PDAC treatment.

Radiotherapy in the Management of Non-Metastatic Inflammatory Breast Cancers: A Retrospective Observational Study.

Simple SummaryInflammatory breast cancer (IBC) is a rare and aggressive clinicopathological presentation of breast cancer. The treatment of non-metastatic IBC usually consists of neoadjuvant systemic therapy, total mastectomy with axillary lymph node dissection, and adjuvant radiotherapy. This single-center retrospective study aims to assess the clinical outcomes of curative-intent multidisciplinary treatment of non-metastatic IBC. We identified 113 patients with a 5-year overall survival of 78.0% and a 5-year locoregional recurrence-free survival of 85.2%, highlighting a high locoregional control with standard fractionation 3D electron or photon therapy in our cohort, despite a pejorative overall survival.(1) Background: Inflammatory breast cancers (IBC) are characterized by a poor prognosis. This retrospective study aims to describe the clinical outcomes of non-metastatic IBC patients treated with a multidisciplinary approach with neo-adjuvant chemotherapy, surgery, and radiotherapy. (2) Methods: This single-center retrospective study included all women patients diagnosed with non-metastatic IBC between January 2010 and January 2018 at the Institut Curie (Paris, France) and treated with neoadjuvant chemotherapy, surgery, and radiotherapy. Overall survival (OS), disease-free survival (DFS), and locoregional free survival (LRRFS) were calculated from the time of diagnosis. Prognostic factors for patient survival were analyzed based on univariate and multivariate regressions. (3) Results: We identified 113 patients with a median age of 51 years. 79.7% had node-positive tumors; triple-negative breast cancers (TNBC) represented 34.6% of the cases. A large majority of patients (91.2%) received adjuvant post-mastectomy while ten patients (8.8%) received preoperative radiotherapy. Non-pathological complete response (non-pCR) was observed in 67.3% of patients. Radiotherapy delivered a median dose of 50 Gy to the breast or the chest wall in 25 fractions. With a median follow-up of 54 months, 5-year OS, DFS and LRRFS were 78% (CI: 70.1–86.8%), 68.1% (59.6–77.7%), and 85.2% (78.4–92.7%), respectively. In multivariate analysis, non-pCR was an adverse prognosis factor for OS, DFS, and LRRFS; pre-operative radiotherapy was an adverse prognosis factor for OS and DFS. Radiation-related adverse events were limited to acute skin toxicity (22% of Grade 2 and 2% of grade 3 dermatitis); no late radiation-induced toxicity was reported. (4) Conclusions: High locoregional control could be achieved with multidisciplinary management of non-metastatic IBC, suggesting the anti-tumor efficacy of radiotherapy in this rare but pejorative clinicopathological presentation. While comparing favorably with historical cohorts, OS and DFS could be potentially improved in the future with the use of new systemic treatments, such as PARP-inhibitors or immunotherapy.

Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of the cancer genome atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was pro-oncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug-resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1 regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene edited cells for NURR1 knockdown and KEGG enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes ATG7 and ATG12 which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1 - ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists.

Critical reappraisal of neoadjuvant concurrent chemoradiotherapy for treatment of locally advanced colon cancer.

BackgroundLocally advanced colon cancer (LACC) is associated with surgical challenges during R0 resection, increased postoperative complications, and unfavorable treatment outcomes. Neoadjuvant concurrent chemoradiotherapy followed by surgical resection is an effective treatment strategy that can increase the complete surgical resection rate and improve the patient survival rate. This study investigated the efficacy and toxicity of concurrent chemoradiotherapy in patients with LACC as well as the prognosis and long-term clinical outcomes of these patients.MaterialsFrom January 2012 to July 2020, we retrospectively reviewed the real-world data of 75 patients with LACC who received neoadjuvant concurrent chemoradiotherapy. The chemotherapy regimen consisted of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX). The following data were obtained from medical records: patients’ characteristics, pathologic results, toxicity, and long-term oncologic outcome.ResultsOf the 75 patients, 13 (17.3%) had pathologic complete responses. Hematologic adverse effects were the most common (grade 1 anemia: 80.0% and leukopenia: 82.7%). Conversely, grade 2 or 3 adverse effects were relatively uncommon (<10%). Pathologic N downstaging, ypT0, and pathologic complete responses were significant prognostic factors for patient survival. Multivariate analysis revealed that pathologic N downstaging was an independent predictor of patients’ overall survival (P = 0.019). The estimated 5-year overall and disease-free survival rates were 68.6% and 50.6%, and the medians of overall and disease-free survival periods were 72.3 and 58.7 months, respectively. Moreover, patients with pathologic complete responses had improved overall survival (P = 0.039) and an improved local recurrence control rate (P = 0.042) but an unfavorable distant metastasis control rate (P = 0.666) in the long-term follow-up.ConclusionThe long-term oncologic outcome of patients with LACC following concurrent chemoradiotherapy is acceptable, and the adverse effects seem to be tolerable. Pathologic N downstaging was an independent prognostic factor for patients’ overall survival. However, a large prospective, randomized control study is required to confirm the current results.

Perioperative Skeletal Muscle Fluctuations in High-Acuity Liver Transplantation

Frailty has been implicated as a negative predictor of Liver Transplant (LT) outcomes. However, an understanding of changes in patient muscle mass peri-LT, and their effect in high-acuity patients remains lacking.We examined the impact of perioperative muscle mass changes (ΔSMI) on high-acuity (MELD ≥35) LT recipients. Skeletal muscle index (SMI) was calculated using CT imaging. Patients were divided into two groups, based on severity of peri-operative SMI decrease. LT recipients with chronic end-stage liver disease, MELD ≥35, and abdominal CT ≤30 days prior, and 30-90 days post LT were included. [1011 adult LT recipients reviewed, 2012-2018]. Of 1011 patients reviewed, 88 met inclusion criteria (median MELD 41.1). The median ΔSMI was -5.0 (-29.4 - +21.1 cm2/m2) (fig A). Patients were classified into two groups: ΔSMI<-5.0 (median ΔSMI: -0.4, n=44) and ΔSMI>-5.0 (median ΔSMI: -9.2, n=44). Recipients with ΔSMI<-5.0 had higher pre-LT SMI (35.4 versus 31.2 cm2/m2, P <0.001) and lower post-LT SMI (26.0 versus 30.8 cm2/m2, P <0.001). The ΔSMI<-5.0 group had higher early allograft dysfunction (40.9 versus 20.5%, P=0.037), and inferior patient and graft survival (P=0.015, 0.017, respectively). Multivariate analysis identified ΔSMI<-5.0 (HR: 2.938, P=0.048), long cold-ischemia time (≥9h, HR: 7.332, P=0.008), HCV (HR: 5.614, p=0.001), and tracheostomy after LT (HR:9.218, P <0.001) as negative prognostic factors for patient survival . Progressive perioperative sarcopenic deterioration was associated with inferior patient and graft survival in high acuity LT. These findings may guide pre and post-operative patient care and rehabilitation efforts in this challenging patient population.

487P Targeting PDL-1 in colon cancer using nuclear receptor 4A1 (NR41) antagonist

The nuclear orphan receptor 4A1 (NR4A1, Nur77, TR3) is overexpressed in multiple solid tumors including colorectal tumors and is a negative prognostic factor for patient survival. NR4A1 is expressed in colon cancer cells and exhibit pro-oncogenic activity and results of examination of several colon cancer cell lines show that PD-L1 expression is limited and NR4A1 and PD-L1 are co-expressed in SW480 and RKO colon cancer cell lines. Previous studies showed that PD-L1 was regulated by NR4A1 which activates transcription factor Sp1 bound to the PD-L1 gene promoter.

Survival prognostic factors in patients with acute myeloid leukemia using machine learning techniques.

This paper identifies prognosis factors for survival in patients with acute myeloid leukemia (AML) using machine learning techniques. We have integrated machine learning with feature selection methods and have compared their performances to identify the most suitable factors in assessing the survival of AML patients. Here, six data mining algorithms including Decision Tree, Random Forrest, Logistic Regression, Naive Bayes, W-Bayes Net, and Gradient Boosted Tree (GBT) are employed for the detection model and implemented using the common data mining tool RapidMiner and open-source R package. To improve the predictive ability of our model, a set of features were selected by employing multiple feature selection methods. The accuracy of classification was obtained using 10-fold cross-validation for the various combinations of the feature selection methods and machine learning algorithms. The performance of the models was assessed by various measurement indexes including accuracy, kappa, sensitivity, specificity, positive predictive value, negative predictive value, and area under the ROC curve (AUC). Our results showed that GBT with an accuracy of 85.17%, AUC of 0.930, and the feature selection via the Relief algorithm has the best performance in predicting the survival rate of AML patients.

Abstract 1149: Nuclear receptor 4A1 (NR4A1) antagonists target PD-L1 in colon cancer

Abstract The nuclear orphan receptor 4A1 (NR4A1, Nur77, TR3) is overexpressed in multiple solid tumors including colorectal tumors and is a negative prognostic factor for patient survival. NR4A1 is expressed in colon cancer cells and exhibit pro-oncogenic activity and results of examination of several colon cancer cell lines show that PD-L1 expression is limited and NR4A1 and PD-L1 are co-expressed in SW480 and RKO colon cancer cell lines. Previous studies in breast cancer cells showed that PD-L1 was regulated by NR4A1 which activates transcription factor Sp1 bound to the PD-L1 gene promoter. Knockdown of NR4A1 or Sp1 by RNA interference or treatment with mithramycin an inhibitor of Sp-mediated transcription decreased expression of PD-L1 in RKO and SW480 colon cancer cell lines. These data coupled with ongoing gene expression and PD-L1 promoter studies demonstrate that PD-L1 expression is regulated by NR4A1/Sp1 in colon cancer cells. Bis-indole derived NR4A1 ligand that act as receptor antagonists have been developed in this laboratory and these compounds block pro-oncogenic NR4A1-regulated genes/pathways. Treatment of RKO and SW480 colon cancer cell lines with a series of potent 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl) analogs decreased expression of PD-L1. These results show that bis-indole derived NR4A1 antagonists act as small molecule mimics of immunotherapeutics that target PD-L1. In vivo applications of NR4A1 ligands that target PD-L1 and their effects on tumor growth and immune surveillance are currently being investigated. Citation Format: Kumaravel Mohankumar, Keshav Karki, Stephen Safe, Maen Abdelrahim. Nuclear receptor 4A1 (NR4A1) antagonists target PD-L1 in colon cancer [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 1149.

Prognostic analysis of 152 patients with distant metastasis after intensity-modulated radiotherapy for nasopharyngeal carcinoma.

The aim of this study was to analyze the prognostic factors for nasopharyngeal carcinoma (NPC) patients with distant metastasis after intensity-modulated radiotherapy (IMRT), and to provide a further basis for clinical treatment options. One hundred and fifty-two NPC patients with distant metastasis after IMRT from January 2006 to December 2017 were included in this study and reviewed for analysis. The patients were followed up for a median time of 43 months. The survival rate was calculated and compared using the Kaplan-Meier method and log-rank tests, respectively. The Cox risk ratio model was used for univariate and multivariate analyses. Among all patients, the median interval from treatment completion to distant metastasis was 11.3 months. The median post-metastasis survival was 14 months, and the 1-, 2-, and 3-year survival rates were 60.4%, 40.2%, and 27.6%, respectively. Through univariate analysis, we found that overall survival was related to lymph node (N) staging at diagnosis, whether induction chemotherapy was utilized, the interval time from initial radiotherapy completion to distant metastasis, with/without liver metastasis, and whether chemotherapy or palliative radiotherapy were utilized after metastasis discovery. Cox regression results showed that liver metastasis, multi-organ metastasis, chemotherapy after metastasis, and the time from radiotherapy completion to distant metastasis were independent prognostic factors for patient survival. The prognosis of NPC patients with distant metastasis after IMRT was related to the time from radiotherapy completion to distant metastasis, liver and multi-organ metastasis, and whether adjuvant chemotherapy was administered. Both adequate adjuvant chemotherapy and palliative radiotherapy could potentially prolong the patients' survival.

FC 033LONG-TERM FOLLOW-UP OF PATIENTS WITH ANCA-ASSOCIATED VASCULITIS INCLUDED IN EUROPEAN VASCULITIS SOCIETY RANDOMIZED CLINICAL TRIALS SINCE 1995: A SURVIVAL ANALYSIS

Abstract Background and Aims ANCA-associated vasculitis (AAV) is the most common cause of rapidly progressive glomerulonephritis globally and the most common finding in renal biopsies for those above 75 years of age. Patients with AAV have had an improved outcome after the introduction of immunosuppressive therapy. However, there is still an increased risk of end stage renal failure, complications to therapy, comorbidities and death. The European Vasculitis Society (EUVAS) has run several prospective randomized clinical trials (RCT) since late -90’ies as an attempt to improve the outcome for patients with a broad spectrum of AAV. The aim of the current study was to analyze results from a 10-year follow-up of patients who have participated in EUVAS’s randomized clinical trials to report on patient outcomes using current standard of care immunosuppressive treatment. Method Data on patient outcomes were collected from questionnaires to the principal investigators of the original RCTS (74 centers from 17 countries in Europe): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC. All patients were well characterized at inclusion in the trials respectively, as was the type and duration of induction therapy. Long-term follow-up data regarding cumulative duration and type of immunosuppressive therapy, end stage renal failure (ESRF), renal transplantation, patient survival and comorbidities as cardiovascular events, infections were recorded. Efforts have been made to control and validate the collected data. Results The current dataset comprises 858 patients, of whom 708 were eligible to include in this study. We received questionnaires regarding patient outcomes from 70% of the cohort. The median age was 60 years at time of the diagnosis of AAV; 487 patients had GPA (57%) and 371 MPA (43%). The median follow-up time was 8.0 years (IQR: 2.9-13.6). During the observation period, there were 305 deaths: 78 patients died within the first year of follow up, 69 during the following 5 years, and another 158 patients after 5 years. The main causes of death were infections (25%), cardiovascular disease (14%) and malignancies (13%), followed by pulmonary diseases, vasculitis, others, kidney disease and gastrointestinal disease. Vasculitis were a major contributor to the causes of death in 18% of the patients. Median survival time for the whole cohort was 17.8 years (95%CI: 15.6 – 20.1). Survival rate at 5 and 10 years was 81.6% and 66.5% respectively. Advanced age, low estimated glomerular filtration rate and male sex were negative prognostic factors for patient survival in the Cox model. When we categorized the deaths according to their initial CKD stage, the highest number of deaths was found in the group of patients with low eGFR i.e. an initial CKD stage V (40%). The initial CKD stage, as shown in the Kaplan-Meier curve, was found to have an important impact on the patient survival (LR: 144.4 p&amp;lt;0.001). In our cohort, 159 patients (18.5%) reached ESRF, of whom 110 patients died (69%); the main cause of death in this group was infection. Conclusion In a series of over 800 patients with AAV, ten-year mortality was predominantly associated with impaired renal function at onset, older age and male gender, rather than subtype of disease. The main strength of this study is that we have a well-defined cohort of patients with AAV, all with well-defined induction treatments and a long period of follow-up with the possibility to analyze possible prognostic factors regarding outcomes. Further analyses are ongoing regarding comparative statistics, cumulative incidence of malignancies, renal transplantation and comorbidities. The data supports efforts to diagnose these patients at an earlier stage, when they have a higher eGFR and to tailor therapy for the individual patient. Although newer treatment modalities are available, there is still a considerable morbidity and mortality in the long-term.

Використання екстракорпоральної мембранної оксигенації при реваскуляризації міокарда у пацієнтів з ішемічною хворобою серця на фоні кардіогенного шоку

Актуальність. Використання екстракорпоральної мембранної оксигенації (ЕКМО) стало ефективною методикою в лікуванні дорослих і дітей із тяжкою серцевою і легеневою дисфункцією, резистентною до традиційної терапії. Метою даної роботи було узагальнення досвіду використання ЕКМО при кардіальній дисфункції, що розвивається у пацієнтів з ішемічною хворобою серця при проведенні рентген-ендоваскулярної реваскуляризації міокарда. Матеріали та методи. У дослідженні проведено ретроспективний одноцентровий аналіз 23 пацієнтів з ішемічною хворобою серця (19 чоловіків і 4 жінки, середній вік — 65,7 ± 12,3 року), яким в ДУ «Інститут серця МОЗ України» в період з березня 2014 по червень 2018 р. при проведенні черезшкірної транслюмінальної коронарної ангіопластики (ЧТКА) використовувалася методика ЕКМО. Результати. 13 (56,52 %) пацієнтів, яким проводили ЕКМО при ЧТКА, померли безпосередньо в стаціонарі або через 30 днів після виписки, серед них переважали особи чоловічої статі (92,30 %). Незалежними предикторами фатальних наслідків виступали цукровий діабет (ВШ = 17,58; 95% ДI = 6,47–47,48; р = 0,00125), хронічна ниркова недостатність (ВШ = 20,81; 95% ДI = 5,95–72,21; р = 0,00014), ішемія міокарда в басейні правої коронарної артерії (ВШ = 25,51; 95% ДI = 8,27–79,12; р = 0,00013). Процедура тромбоекстракції та феномен «no reflow» на 18,5 і на 13,1 % частіше реєструвались у пацієнтів, які померли. Перераховані вище обставини зумовили і менший процедуральний успіх у пацієнтів, що померли (TIMI потік після ЧТКА становив 1,50 ± 0,48), тоді як у тих, що вижили, TIMI становив 2,40 ± 0,37 (р = 0,00138). Підключення ЕКМО до виникнення кардіологічних подій достовірно частіше виявлялося в групі пацієнтів, які вижили (90 % випадків), порівняно з померлими (0 %) (р = 0,0000001). Висновки. Цукровий діабет, ниркова недостатність, ураження правої коронарної артерії є незалежними предикторами летальності при проведенні рентгенендоваскулярної реканалізації у пацієнтів з ішемічною хворобою серця. Планове використання ЕКМО у пацієнтів групи високого ризику при черезшкірній реваскуляризації міокарда є позитивним прогностичним фактором виживання пацієнтів.

The prognostic significance of FOXC2 gene expression in cancer: A comprehensive analysis of RNA-seq data from the cancer genome atlas

The FOXC2 transcription factor is a key regulator of tumor progression in many cancer types. Known to exhibit an array of oncogenic functions when dysregulated, FOXC2 has emerged as a useful biomarker for predicting disease aggression and patient outcome. In this regard, increased expression and nuclear localization of FOXC2 protein in tumor tissue have become well-established as poor prognostic factors for many cancer types. However, whether FOXC2 gene expression can serve as a similarly useful RNA-level biomarker has remained largely unexplored. Therefore, we conducted a comprehensive analysis of TCGA RNA-seq data to evaluate whether FOXC2 gene expression levels in primary tumor biopsies correlate with patient outcome. We report herein that increased expression of FOXC2 RNA in tumor tissue is a poor prognostic factor for patient survival in many cancer types. Moreover, we also found that FOXC2 gene expression predicts cancer patient response to several commonly prescribed chemotherapeutics. Together, these data highlight FOXC2 RNA expression in tumor tissue as an important biomarker with prognostic significance for solid tumors of diverse origin.

Analysis of prognostic factors and survival of Thoracic solitary fibrous tumors: a SEER population-based study

Background: Thoracic solitary fibrous tumors (TSFT) are a rare disease. We aim to determine the prognostic factors related to survival of TSFT patients through the use of The Surveillance, Epidemiology, and End Results database to analyze demographic and clinical characteristics. This study is intended to determine the prognostic factors associated with TSFT and has clinical value. Patients and Methods: This is a retrospective study of patients who were diagnosed with TSFT in the SEER database from 2001 to 2015. The kaplan-Meier method and Cox regression analysis were used to identify prognostic factors for patient survival. Results: From the SEER database (2001-2015), 227 patients with TSFT were detected. The 5-year survival rate was 82.7%, and the 10-year survival rate was 62.4%. Surgical resection [HR 0.314, 95% CI 0.201-0.491, P <0.001] was just an independent factor in the improvement of patient prognosis. Conclusion: The results of this study indicate that the prognostic factors for TSFT patients are age, grade, surgery, and chemotherapy. Age <65 years old, well-differentiated, surgery instead of chemotherapy is a favorable prognostic factor for survival of TSFT patients.

Kliničke karakteristike i ishod lečenja kod bolesnika sa akutnom limfoblastnom leukemijom

Introduction: Acute lymphoblastic leukemia (ALL) is the malignant transformation and proliferation of lymphoid progenitor cells. The disease outcome is significantly influenced by cytogenetic and molecular characteristics, leukocyte levels, the percentage of blood and bone marrow blasts, infiltration of the CNS, and the modality of the applied therapy. Aim: Determining clinical, immunophenotypic, and cytogenetic characteristics of patients with ALL; ascertaining remission rates, the presence of resistant forms, the rates of relapse and overall survival (OS); determining prognostic factors for patient survival. Materials and methods: This five-year retrospective study included 74 patients. The study covered the period from November 2013 to October 2018. The influence of sex, age, immune subtype of ALL, leukocyte levels, percent of blood and bone marrow blasts, and cytotoxic-molecular characteristics on survival were analyzed. Results: A total of 56 (75.0%) patients had B-cell ALL, while 18 (25.0%) patients had T-cell ALL. The average age was 49.5 years (20 - 77). Complete remission was achieved in 54 (72.9%) patients, 40 (71.4%) B-cell ALL patients and 14 (77.7%) T-cell ALL patients. Refractory leukemia was confirmed in 7 (9.4%) ALL patients, 5 (8.9%) B-cell ALL patients and 2 (11.1%) T-cell ALL patients. Mortality during induction was observed in 13 (17.56%) patients, 8 (14.2%) B-cell ALL patients and 5 (27.7%) T-cell ALL patients. Relapse occurred in 25 (46.3%) patients, 20 (47.5%) B-cell ALL patients and 5 (33.3%) T-cell ALL patients. Univariate analysis showed that an unfavorable outcome was associated with age ≥50 years (p &lt; 0.001), COP chemotherapy (p &lt; 0.001), non-transplant patients (p = 0.011), and infiltration of the CNS (p &lt; 0.001). Conclusion: Survival in ALL patients is significantly affected by patient age, modality of applied therapy, and infiltration of the CNS by disease.

Pre-treatment high body mass index is associated with poor survival in Asian premenopausal women with localized breast cancer.

Background: Obesity is associated with poor prognosis in breast cancer patients. This study aimed to evaluate the effect of obesity measured by body mass index (BMI) on survival of Taiwanese breast cancer patients in a single institution.Methods: We observed 5000 patients who were diagnosed with stage I-III breast cancer between 1990 and 2005. Information on BMI at diagnosis, and clinical follow-up for disease recurrence and death, up to 20 years post-diagnosis were available. BMI (in kg/m2) categories included normal weight (BMI<24), overweight (24≤BMI<27), and obesity (BMI≥27), according to recommendations from the Bureau of Health Promotion of Taiwan. The role of BMI and other known prognostic factors for patient survival were evaluated in this patient cohort.Results: Obesity was associated with advanced stage, higher nuclear grade, and higher percentages of estrogen receptor (ER) positive. The median age of patients with a higher BMI was greater than the median age of patients with a lower BMI. Obesity was an independent prognostic factor of overall survival (OS) (P<0.001), but not disease-free survival (DFS) (P=0.067). We subsequently analyzed the impact of age-stratified BMI (age<50 and age≥50 years) to ameliorate the impact of age bias. Following subset analyses, obesity correlated with shorter DFS (P=0.004) and OS (P=0.009) only in women<50 years of age. Multivariate analysis revealed that BMI was an independent prognostic factor for both DFS and OS in this group of patients. Subset analysis revealed that in women <50 years old, the impact of BMI on survival was associated with higher stage, ER negativity.Conclusion: BMI is an independent prognostic factor of OS and DFS in breast cancer patients aged<50 years. Although the cause-effect relationship between obesity and survival is unclear, we recommend that weight control measures in young breast cancer survivors should be considered.

Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma.

We previously found that both the guide and passenger strands of the miR-139 duplex (miR-139-5p and miR-139-3p, respectively) were downregulated in cancer tissues. Analysis of TCGA datasets revealed that low expression of miR-139-5p (p < 0.0001) and miR-139-3p (p < 0.0001) was closely associated with 5-year survival rates of patients with renal cell carcinoma (RCC). Ectopic expression assays showed that miR-139-5p and miR-139-3p acted as tumor-suppressive miRNAs in RCC cells. Here, 19 and 22 genes were identified as putative targets of miR-139-5p and miR-139-3p in RCC cells, respectively. Among these genes, high expression of PLXDC1, TET3, PXN, ARHGEF19, ELK1, DCBLD1, IKBKB, and CSF1 significantly predicted shorter survival in RCC patients according to TCGA analyses (p < 0.05). Importantly, the expression levels of four of these genes, PXN, ARHGEF19, ELK1, and IKBKB, were independent prognostic factors for patient survival (p < 0.05). We focused on PXN (paxillin) and investigated its potential oncogenic role in RCC cells. PXN knockdown significantly inhibited cancer cell migration and invasion, possibly by regulating epithelial–mesenchymal transition. Involvement of the miR-139-3p passenger strand in RCC molecular pathogenesis is a new concept. Analyses of tumor-suppressive-miRNA-mediated molecular networks provide important insights into the molecular pathogenesis of RCC.

Identification of a Transcriptional Prognostic Signature From Five Metabolic Pathways in Oral Squamous Cell Carcinoma.

Dysregulated metabolic pathways have been appreciated to be intimately associated with tumorigenesis and patient prognosis. Here, we sought to develop a novel prognostic signature based on metabolic pathways in patients with primary oral squamous cell carcinoma (OSCC). The original RNA-seq data of OSCC from The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO) database were transformed into a metabolic pathway enrichment score matrix by single-sample gene set enrichment analysis (ssGSEA). A novel prognostic signature based on metabolic pathways was constructed by LASSO and stepwise Cox regression analysis in the training cohort and validated in both testing and validation cohorts. The optimal cut-off value was obtained using the Youden index by receiver operating characteristic (ROC) curve. The overall survival curves were plotted by the Kaplan-Meier method. A time-dependent ROC curve analysis with 1, 3, 5 years as the defining point was performed to evaluate the predictive value of this prognostic signature. A 5-metabolic pathways prognostic signature (5MPS) for OSCC was constructed which stratified patients into subgroups with favorable or inferior survival. It served as an independent prognostic factor for patient survival and had a satisfactory predictive performance for OSCC. Our results developed a novel prognostic signature based on dysregulated metabolic pathways in OSCC and provided support for aberrant metabolism underlying OSCC tumorigenesis.

Imatinib-induced pancreatic hypertrophy in patients with gastrointestinal stromal tumor: Association with overall survival

ObjectivesTo investigate the frequency of imatinib-induced pancreatic complications and determine whether these are survival prognostic factors in patients with gastrointestinal stromal tumor (GIST). MethodsThis retrospective multicenter study included patients with histopathologically diagnosed GIST treated with imatinib who underwent computed tomography (CT) within 100 days before (pretreatment CT) and 500 days after (post-treatment CT) imatinib initiation (January 2004–December 2019). Forty-eight patients (63.0 ± 12.1 years, 30 men) were included. Two blinded radiologists independently measured pancreatic volumes. Pancreatic volume on pretreatment CT was compared with that of the control (within 1 year prior to pretreatment CT) and the first two post-treatment CTs using paired t-tests. Thresholds for pancreatic hypertrophy and atrophy were defined using a log-rank test. The prognostic importance of pancreatic hypertrophy was further analyzed using multivariate Cox proportional hazard regression models. ResultsPancreatic volume was significantly higher for the first post-treatment CT than pretreatment CT (71.5 cm3 vs. 67.4 cm3, P = .027), whereas no significant difference was observed between the pretreatment and control CTs. Optimal thresholds for pancreatic hypertrophy and atrophy were defined as an 22% increase and 30% decrease and found in 20 and three patients, respectively. Pancreatic hypertrophy was significantly associated with reduced survival [hazard ratio = 2.9 (95% confidence interval, 1.3–6.5), P = .0088]. No patients showed serum lipase elevation, nor were they suspected of having acute pancreatitis. ConclusionThere was frequent asymptomatic pancreatic swelling in patients with GIST after imatinib treatment, and a ≥22% increase in pancreatic volume was a predictor of reduced survival.

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes.

Simple SummaryA total of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were identified as tumor suppressive miR-30c-5p and miR-30c-2-3p targets in pancreatic ductal adenocarcinoma (PDAC), and expression of these genes were independent prognostic factors for patient survival. Furthermore, aberrant expression of TOP2A and its transcriptional activators (SP1 and HMGB2) enhanced malignant transformation of PDAC cells.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC.