Biological Prognostic Markers Research Articles

Lncrna Famlf-2 Inhibits Acute Lymphoblastic Leukemia Apoptosis through the p38 MAPK Signaling Pathway

Background:Acute lymphocytic leukemia (ALL) is a hematologic malignancy caused by the clonal proliferation of immature lymphocytes. Long noncoding RNAs (lncRNAs) are involved in the pathogenesis and progression of ALL. Our previous study identified Familial acute myelogenous leukemia related factor (FAMLF) from a AML pedigree. There are at least three splice variants from FAMLF, referred as FAMLF-1, FAMLF-2 and FAMLF-3. We have shown higher expression of FAMLF-1 was related to a higher complete remission (CR) rate, and shorter relapse free survival (RFS) in AML. Another FAMLF variants, FAMLF-2 is highly expressed in ALL, and the potential mechanism of FAMLF-2 in regulating ALL progression is unclear. This study aims to investigate the functional and mechanistic roles of FAMLF-2 in ALL. Methods:The expression of FAMLF-2 was detected by real-time PCR (Q-PCR) in peripheral blood of ALL patients (N=85) and healthy controls (N=60). The full length of FAMLF-2 was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). FAMLF-2 subcellular location in Jurkat cells was detected by lncRNA FISH, nuclear/cytoplasmic RNA fractionation, and qPCR. The proliferation and apoptosis of Jurkat cell were determined by CCK-8 and flow cytometry experiments in vitro. RNA-seq was performed to study the molecular mechanism of FAMLF-2 in regulating ALL cell apoptosis. Results:The FAMLF-2 mRNA expression and in ALL patients was significantly higher than those in the normal individuals (P=0.000). The expression of FAMLF-2 was positively correlated with percentage of peripheral blood blasts (P=0.032). The ALL patients with higher FAMLF-2 expression had significantly poor overall survival (P=0.036). We defined a 2393-bp full-length transcript of FAMLF-2, and examined the subcellular localization of FAMLF-2, which showed that FAMLF-2 predominately resides in the nucleus of Jurkat cells. The cell proliferation was inhibited, and cell apoptosis was induced when FAMLF-2 were down-regulated in Jurkat and Nalm6 cells, whereas the overexpression of FAMLF-2 showed the opposite results. We analyzed the RNA-seq data of the knockdown and overexpression of FAMLF-2 in Jurkat cells, and the GSEA analysis suggested that FAMLF-2 knockdown was associated with "MYC TARGETS V1", "MYC TARGETS V2" pathways. The knockdown of FAMLF-2 in Jurkat cells upregulated the expression of p-P38 and downregulated the expression of c-Myc, bcl-2. Conclusion: Taken together, our study indicate that FAMLF-2 inhibits the apoptosis of ALL through the p38 MAPK signaling pathways, which might act as a prospective prognostic biological marker for ALL. Keywords: Acute lymphocytic leukemia, Long noncoding RNAs, FAMLF-2, apoptosis, p38 MAPK Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comprehensive Multiomic Analysis Identified TUBA1C as a Potential Prognostic Biological Marker of Immune-Related Therapy in Pan-Cancer.

TUBA1C is correlated with an unfavourable prognosis and the infiltration of immune cells in several cancers. However, its function as a significant biomarker for the prognosis of immunotherapy in pan-cancer remains unclear. This study aims at assessing the role of TUBA1C in pan-cancer at multiple levels, including mutations, gene expression, methylation, m6A methylation, and immune cell infiltration levels. Data retrieved from major public databases, such as TCGA, GEO, GTEx, GSCA, CancerSEA, HPA, and RNAactDrugs, revealed that TUBA1C expression was high in 33 cancer types. Survival analysis revealed that TUBA1C was a poor prognostic factor for 12 tumour types, and mutations, CNVs, and methylation affected the prognosis of some cancer types. Furthermore, TUBA1C was found to be related to immune-related genes, immune cell infiltration, and the immune microenvironment. In addition, the sensitivity of 10 anticancer drugs was associated with high TUBA1C expression. Therefore, TUBA1C may serve as a viable prognostic biomarker for immunotherapy of pan-cancer.

Clinical and Biological Significances of a Ferroptosis-Related Gene Signature in Lung Cancer Based on Deep Learning.

Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been linked to the occurrence of tumors and is implicated in the ferroptosis process. Deep learning has been applied to many areas in health care, including imaging diagnosis, digital pathology, classification of cancer, and prediction of metastasis. Nonetheless, neither the level of ACSL4 expression nor its predictive significance in non-small-cell lung cancer (NSCLC) is well understood at this time. Predictions of the ACSL4 mRNA expressions in NSCLC and its link to NSCLC prognosis were made with the aid of the Oncomine and TCGA databases. By performing real-time PCR, we detected the levels of ACSL4 expression that were present in human NSCLC samples. Analyses of the diagnostic, as well as the prognostic significance of ACSL4 in NSCLC, were performed with the use of Kaplan-Meier curves. To assess the influence of ACSL4 on ferroptosis in NSCLC cell lines, an inducer of ferroptosis, namely, erastin, was utilized in this study. In NSCLC tissues, there was a substantial decrease in the level of ACSL4 expression (p < 0.001), and this was in line with the findings of the inquiry into the Oncomine and TCGA databases. After that, the findings of the immunohistochemistry analysis revealed that the ACSL4 staining was weakened in NSCLC samples in contrast with the normal samples. It was shown that the differential expression of ACSL4 was substantially linked to the stages of cancer, smoking behaviors, and the status of nodal metastases (all p < 0.001). According to the findings of the survival analysis, both RFS and OS were favorable among NSCLC patients who had elevated expression of ACSL4. The ferroptosis sensitization in cancer cells may be reestablished with upregulation of ACSL4 through gene transfection. Mechanistically, protein ubiquitination could perform a remarkable function in ACSL4-induced ferroptosis. ACSL4, which has a function in ferroptosis as both a contributor and monitor, was shown to be downregulated in NSCLC. This finding suggests that ACSL4 might function as a helpful diagnostic and prognostic biological marker and might also be considered a novel possible treatment target for NSCLC.

TRNA-derived fragment tRF-Glu49 inhibits cell proliferation, migration and invasion in cervical cancer by targeting FGL1.

A transfer RNA (tRNA)-derived fragment (tRF) was found to be a new possible biological marker and target in carcinoma therapy. However, the effect exerted by tRFs on cervical carcinoma remains unclear. In the present study, the potential tumor suppressor gene tRF-Glu49 was identified in cervical carcinoma through tRF and tiRNA microarray investigation. A reverse transcription-quantitative PCR assay then demonstrated that tRF-Glu49 was downregulated in the cervical carcinoma tissue. Further clinicopathological analysis proved that tRF-Glu49 was associated with less aggressive clinical features and improved prognosis. Cell Counting Kit-8 tests, Transwell and Matrigel tests, and xCELLigence system tests revealed that tRF-Glu49 inhibited cervical cell proliferation, migration and invasion processes. Mechanistic investigation revealed that tRF-Glu49 directly regulated the oncogene, fibrinogen-like protein-1 (FGL1). In general, according to the result achieved in the present study, tRF-Glu49 can modulate cervical cell proliferation, migration, and invasion processes through the target process for FGL1, and tRF-Glu49 is likely to be a possible prognostic biological marker in patients with cervical carcinoma.

Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma.

BackgroundAcyl-CoA synthetase long-chain family member 4 (ACSL4) has been linked to the ferroptosis process and is implicated in the pathogenesis of tumors. Nevertheless, neither the expression levels of ACSL4 nor its prognostic significance in clear cell renal cell carcinoma (ccRCC) is completely understood at this time.MethodsPredictions of the ACSL4 mRNA expression in ccRCC and its link to ccRCC prognosis were made based on data from the Oncomine and The Cancer Genome Atlas (TCGA) databases. Through the use of real-time polymerase chain reaction (PCR), we ascertained the levels of ACSL4 expression in human RCC samples. Analyses of the link between ACSL4 expression and the survival of ccRCC patients were undertaken using the Kaplan-Meier (KM) plotter database. To study the function that ACSL4 plays in ferroptosis in ccRCC cell lines, either upregulation or knockdown of its expression was performed.ResultsWe found that the ACSL4 expression level was considerably down-modulated in ccRCC samples (P<0.001), which was in line with the analytical results of the Oncomine and TCGA database. The subsequent immunohistochemistry findings revealed that ACSL4 levels in ccRCC samples were much lower or not undetectable in contrast with those in normal samples. The level of differential ACSL4 expression was strongly associated with factors such as disease stages, gender, tumor grade, nodal invasion, and ccRCC subtypes (all P<0.001). According to the results of the survival analysis, the overall survival was satisfactory among ccRCC patients who had overexpressed ACSL4 (P=0.014). In cancer cells, ferroptosis sensitization may be restored by overexpressing ACSL4 via the process of transfection; however, increasing ferroptosis resistance can be achieved by suppressing ACSL4 expression through the use of shRNA. Protein ubiquitination could have a function in influencing the way that ACSL4-induced ferroptosis works mechanically.ConclusionsACSL4, which is a mediator and monitor of ferroptosis, was lowered in expression in ccRCC and acted as a valuable diagnostic and prognostic biological marker, thus representing a novel promising treatment target for ccRCC.

TTYH3, a potential prognosis biomarker associated with immune infiltration and immunotherapy response in lung cancer

PurposeThe recognition of new diagnostic and prognostic biological markers for lung cancer is an essential and eager study. It’s shown that ion channels play important roles in regulating various cellular processes and have been suggested to be associated with patient survival. However, tweety family member 3 (TTYH3), as a maxi-Cl- channel, its role in lung cancer remains elusive. MethodsThe expression, diagnostic and prognostic efficacy of TTYH3 were analyzed by public databases and clinical samples. Cell functional experiments were used to explore the effects of TTYH3 on cell viability. GO and KEGG enrichment analysis revealed underlying pathways that TTYH3 and its co-expressed genes were enriched in. TIMER, TIDE and R language analyses were used to detect the correlation between TTYH3 and immune infiltration cell and immunotherapy response. ResultsTTYH3 was up-regulated in lung cancer tissues compared to normal tissues and possessed a prominent diagnostic and prognostic value. TTYH3 knockdown significantly inhibited the proliferation of lung cancer cells. Enrichment analyses showed that TTYH3 and its co-expressed genes were mainly involved in immune related signaling pathways. Further investigation clarified that TTYH3 had a positive correlation with the infiltration of TAMs, Treg infiltration as well as T cell exhaustion and high TTYH3 expression indicated worse immunotherapy response and shorter survival after immune checkpoint blockade treatment. ConclusionThis study not only revealed the diagnostic and prognostic value of TTYH3 but also provided TTYH3-based estimation of immunotherapy response for lung cancer patients, which might provide new strategies like anti-TTYH3 combined with immune therapy for the treatment of lung cancer.

Bioinformatics analysis of KLF2 as a potential prognostic factor in ccRCC and association with epithelial-mesenchymal transition.

Clear cell renal cell carcinoma (ccRCC) is a primary pathological subtype of RCC and has poor clinical outcome. Krüppel-like factors (KLFs), which are zinc-finger proteins, may be involved in ccRCC development and progression. KLFs belong to the zinc-finger family of DNA-binding transcription factors and regulate transcription of downstream target genes. KLFs are involved in cancer development. The present study aimed to investigate the role of KLFs in ccRCC prognosis. The Cancer Genome Atlas database and multifactorial analysis showed that KLFs were widely expressed in pan-cancers and KLF2 was an independent protective factor for ccRCC prognosis. Patients with low KLF2 expression had a low survival probability and expression of KLF2 was downregulated in patients with ccRCC with high pathological grade (II + III vs. I). In addition, western blot and reverse transcription-quantitative PCR revealed that KLF2 was expressed at low levels in ccRCC cell lines and overexpression of KLF2 inhibited cell migration. In addition, KLF2 expression was negatively correlated with methylation. KLF2 expression was elevated following treatment of ccRCC cells with DNA methyltransferase inhibitor. A prognostic risk index prediction model was constructed based on multiple Cox regression. The receiver operating characteristic curve was 0.780 (area under curve >0.5). Furthermore, Gene Ontology enrichment analysis showed that ‘cell adhesion’ and ‘junction’ were negatively correlated with KLF2 and that high-risk group exhibited significantly activated ‘epithelial-mesenchymal transition’. Western blot analysis showed that overexpression of KLF2 increased expression of E-cadherin, while decreasing levels of N-cadherin and vimentin. The present study highlighted the role of KLFs in ccRCC prognosis prediction and provides a research base for the search of validated prognostic biological markers for ccRCC.

Construction of a Prognostic Model for KIRC and Identification of Drugs Sensitive to Therapies - A Comprehensive Biological Analysis Based on m6A-Related LncRNAs

As one of the common malignancies in the urinary system, kidney cancer has been receiving explorations with respect to its pathogenesis, treatment and prognosis due to its high morbidity, high mortality and low drug efficiency. Such epigenetic modifications for RNA molecules as N6-methyladenosine (m6A) usher in another perspective for the research on tumor mechanisms, and an increasing number of biological processes and prognostic markers have been revealed. In this study, the transcriptome data, clinical data and mutation spectrum data of KIRC in the TCGA database were adopted to construct an m6A-related lncRNA prognostic model. Besides, the predictive ability of this model for clinical prognosis was evaluated, and some compounds sensitive to therapies for KIRC were screened. The findings of this study demonstrate that this effective and stable model has certain clinical application value.

The Effect of Extracellular Superoxide Dismutase (SOD3) Gene in Lung Cancer.

BackgroundThe recognition of new diagnostic and prognostic biological markers for lung cancer, the most severe malignant tumor, is an essential and eager study. In a microenvironment, superoxide dismutase 3 (SOD3) can adjust active oxygen, and it refers to a secreted antioxidant enzyme. It was also found to be cancer-related, and in lung cancer, it was remarkably down-regulated. More and more new cancer research focuses on the function of SOD3. Despite this, there is no good description of SOD3 function in the LC progression.MethodsThrough bioinformatics analysis, we found that SOD3 was a possible novel lung cancer gene in this study. We analyzed data sets from Gene Expression Comprehensive Database (GEO) and the Cancer Genome Atlas (TCGA), and SOD3 expression was studied in lung cancer. This study estimated the SOD3 diagnosis and prognosis through gene expression differential display, gene set enrichment analysis (GSEA), enrichment and genomes (KEGG) analysis, and gene ontology (GO). Then in order to investigate the SOD3 presentation in lung cancer cells, we used Western Blot and also applied Flow cytometry to detect the impact of anti-tumor medicine on tumor cell apoptosis.ResultsWe found that the expression level of SOD3 in lung cancer was low (P = 4.218E-29), while the survival of lung cancer patients with high SOD3 expression was shorter (LUSC p =0.00086, LUAD p=0.00038). According to the result of western blot, the expression of SOD3 in tumor cells was higher than that in normal cells. The ratio of early apoptosis induced by anti-cancer drugs was 10.5% in normal cells, 35.1% in squamous cell carcinoma and 36.9% in adenocarcinoma.The SOD3 high expression was associated with poor survival probability by multivariate analysis (HR: 1.006, 95% CI 1.002–1.011, p=0.006). Moreover, SOD3 high expression group had higher ESTIMATE scores, and larger amount of immune infiltrating cells. SOD3 expression is correlated with PDCD1 and CTLA4 expression.ConclusionsSOD3 gene can be used as a prognostic gene in lung cancer patients, and lung cancer patients with high expression of this gene can reap worse prognostic outcome. It can be used as a new clinical method and prognosticator for lung cancer patients.

Neutrophil-Lymphocyte Ratio as a Prognostic Factor for 15-Day Mortality of Patients infected in ICU

Abstract Introduction The determination of the groups at risk of death at admission in patients with bacterial infection in the ICU is important. Several prognostic factors have already been identified, however the neutrophil/lymphocyte ratio (NLR) has the advantage of being common and inexpensive. Objective To determine the threshold value of NLR to determine the group at risk of 15-day mortality and the overall survival of patients according to this threshold. Methods This was a retrospective cohort conducted in the intensive care unit of the Ibn Rochd University Hospital in Casablanca over a period of 2 years (January 2019 - January 2021), among hospitalized patients with bacterial infection, acquired or nosocomial. The sample size was calculated a priori and multivariate statistical analyses (multiple logistic regression, Youden index and Kaplan Meier survival estimation and Log Rank) were performed using Rstudio software. The significance level was less than 5%. Results A total of 200 patients were included in the study, 136 patients were alive at 15 days, there were no differences in age between the two groups. Factors associated with patient mortality at 15 days were: gender, use of vasoactive drugs, use of mechanical ventilation, type of sepsis, site of infection, SOFA score (p &amp;lt; 0.000), Apache score (p = 0.009) and NLR at admission (p = 0.001). The cut-off value for NLR was 15.07 with a mean discriminant value of 64.1%. The difference in median overall survival of patients in the two groups according to the threshold value was statistically significant 22 +/- 1.9 days and 11 +/-1.12 days (p = 0.042). Conclusions The NLR appears to be a prognostic factor for 15-day mortality. The knowledge of prognostic factors and threshold values of these indicators allow the prediction of at-risk groups in order to best adapt their management. Key messages The use of common and inexpensive biological prognostic markers are a reliable alternative to identify at-risk patients to optimize their management in developing countries. The RNL is a good biological prognostic markers of mortality of patients infected in ICU.

Bio-P-16 - Peripheral T-cell lymphoma: molecular profiling distinguishes subclasses, recognizes the tumor architecture and identifies prognostic markers

<h3>Introduction:</h3> Peripheral T-cell lymphomas (PTCLs) are aggressive tumours with unfavourable prognosis, with around 30% OS after 5 years. Histological and molecular studies have revealed a striking degree of heterogeneity, with three major PTCL subtypes defined. Consistent diagnosis and prognostication are still difficult to achieve, because of the difficulty of reproducing results, and the dearth of clinically applicable prognostic biological markers. <h3>Methods:</h3> We have analyzed a series of 105 PTCL cases (66 angioimmunoblastic T-cell lymphoma, AITL; 21 PTCL-not otherwise specified, PTCL-NOS; and 18 PTCL-with T follicular helper phenotype, PTCL-TFH) patients using a customized NanoString platform that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways and stromal cell subpopulations. Specifically, the platform includes genes expressed by the multiple cell types present in PTCL specimens, together with normal T-cell populations. These are used to try and enable the deconvolution of the T-cell lymphoma microenvironment, and thereby develop an integrated perspective on the cell composition of PTCL tumor specimens. <h3>Results:</h3> A comparative analysis of the various histological types of PTCL (AITL, PTCL-NOS and PTCL-TFH) showed specific sets of genes to be associated with each of the diagnoses, including TFH markers, cytotoxic markers and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells and genes belonging to specific cell-survival pathways (NF-κB). Unsupervised analysis of the expression of the genes here studied revealed clusters of co-regulated genes that identified the main cell components of the tumor. The analysis did not reveal any differences in survival probability associated with the histological sub-classification, but did identify specific genes and gene sets whose expression was associated with changes in survival probability for each of the PTCL subtypes, independently of the clinical variables included in the International Prognostic Index (IPI). These included a B-cell gene set in cases of AITL, the expression of proliferation markers in PTCL-NOS, and the expression of cytotoxic markers in cases with a diagnosis of PTCL-TFH. For each PTCL lymphoma type, a multivariate analysis identified genes that allow the series of cases to be stratified into different risk groups. This was validated for AITL in an independent series of 54 additional cases. <h3>Conclusions:</h3> In summary, our study supports the current division of PTCL into these three categories (AITL, PTCL-NOS and PTCL-TFH), identifies gene sets potentially useful for this classification and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL subtype.

CXCR4 as a prognostic marker in Egyptian chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) has variable clinical presentations, and molecular and biological prognostic markers. The C-X-C chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1 (SDF-1) play an important role in trafficking of lymphocytes and monocytes. The aim was to study lymphocyte expression of CXCR4 and its prognostic value in CLL. A case control study was carried out on 30 newly diagnosed CLL cases and 30 healthy controls. Fludarabine, cyclophosphamide, and rituximab (FCR) was the standard treatment. Flowcytometric measurement of CXCR4 expression on lymphocytes was done. CXCR4 was significantly higher in patients than controls (81.67 ± 17.95 vs. 11.78 ± 2.78; P< 0.001). CXCR4 was significantly higher (P<0.001) in high risk CLL (93.63 ± 6.78) vs. intermediate risk (82.50 ± 7.13) and low risk (75.84 ± 12.23). CXCR4 was significantly higher (P<0.001) in non-responders (91.63 ± 6.98) vs. partial responders (83.11 ± 5.55) and complete responders (70.11 ± 4.44). CXCR4 was significantly lower in survivors vs. non-survivors (80.89 ± 5.09 vs. 85.43 ± 5.51; P< 0.001. CXCR4 had significant positive correlation with WBCs (r=0.45, P=0.01) and lymphocytes (r=0.40, P=0.01) measured at diagnosis. In conclusions, expression of CXCR4 in newly diagnosed CLL is significantly high. CXCR4 increased expression is associated with poor prognosis and resistance to the therapy.so it can be used as prognostic tool.

American Joint Committee on Cancer's Staging System for Breast Cancer, Eighth Edition: Summary for Clinicians.

Breast cancer is commonly staged using the American Joint Committee on Cancer (AJCC) staging system. The 7th edition of the AJCC Staging Manual, was a purely anatomic staging method, which uses primary tumor size (T), nodal involvement (N), and metastasis (M) based on clinical and pathological evaluations. Advancements in tumor biology and prognostic biological markers, such as estrogen receptor (ER)/progesterone receptor (PR), HER2/neu, and Ki-67, have allowed clinicians to understand why similarly staged patients had significantly different outcomes. The most recent update to the staging system integrates molecular markers with disease extent for more optimal estimation of prognosis. This change improves the prognosis of breast cancer patients and better informs physicians in the planning of treatments. This review summarizes the changes in the AJCC Staging Manual, 8th edition and their impact on practicing radiologists in breast cancer management.

Use of Bendamustine Combined with Rituximab in Chronic Lymphocytic Leukemia Patients: A Single Center Experience

Background:There is no single standard treatment (tx) modality for symptomatic chronic lymphocytic leukemia (CLL) patients (pts). Fludarabine, cyclophosphamide, and rituximab (FCR) is the prefered regimen for healthy, young pts (<65 years). However, through the disease course almost all pts in this group will relapse and may become refractory to fludarabine-containing regimens. Additionally, for older adults (>65 years) and pts with comorbidities fludarabine is not a suitable agent. Bendamustine combined with rituximab (BR) is an acceptable alternative in these patient groups.Aim: To evaluate the efficacy and safety of BR in previously untreated or relapsed/refractory (R/R) CLL pts.Patients and Methods: Ptswho received BR as first- or further lines of tx were enrolled in the study. Data were analysed as of August 2017. The standard dose of bendamustine was 70 mg/m2 in D1 and D2 for R/R pts and 90 mg/m2 in D1 and D2 for tx naive pts. Rituximab dose was 375 mg/m2 in the first cycle and 500 mg/m2 in consecutive cycles. Pts' demographics, disease stages, biological and cytogenetic prognostic markers, comorbidities, previous treatments, bendamustine dose, cycle durations, use of G-CSF, adverse events (AEs), tx responses and follow-up periods were noted retrospectively. Evaluation of response was established according to NCI-WG guidelines [Hallek et al, 2008]. All toxicities were assessed according to the National Cancer Institute's Common Toxicity Criteria (NCI-CTC), version 4.Results: Nineteen ptswere enrolled in the study (Table 1). Thirteen pts were male and the median age at the time of BR treatment was 61 years (range, 41-80 years), with 9 pts (47%) older than 65 years. At the time of diagnosis, 7 pts (37%) were Rai stage IV. Del(13q), del(11q), and del(17p) were positive in 5, 1, and 2 pts, respectively. All pts had active disease as defined by the NCI-WG. Five pts received BR as first-line. Of the previously treated 14 pts, 71% had received fludarabine with either alkylating agents and/or rituximab. Median number of previous lines of tx was 2.Among comorbidities, hypertension (32%), asthma/COPD (32%) and type 2 diabetes mellitus (3%) were the three most common.Bendamustine dose ranged from 70 mg to 100 mg/m2. According to the physicians' decision, bendamustine was started as 70 mg in first cycle of tx and was escalated to the planned dose in all pts but three. All 6 intended courses were administered to 15 pts (79%), and in the remaining 4 pts, 3 died due to infections and one patient required early discontinuation due to prolonged neutropenia. In 8 pts (42%) tx cycle prolonged to 35 days and in 11 cases (58%) G-CSF were used during tx.After a median follow-up of 17 months (mos), five of 19 pts (26%) had progressed at the time of analysis, and median time to next treatment (TTNT) was 12 mos (range, 5-34 mos). Treatment responses are shown in Table 2. During the follow-up 5 pts (26%) died. Two had multiple comorbidities, three received bendamustine doses ≥90 mg/m2. Deaths were due to R/R disease and/or infections. Median OS after treatment was 13 mos (range, 5-34 mos).Overall, grade III-IV AEs occurred in 14 cases (74%): the most common toxicity was hematologic AEs (anemia in 2, neutropenia in 12, and thrombocytopenia in 2 cases), and serious infection occurred in six pts (2 bacterial pneumonia, 4 neutropenic fever). Non-hematologic toxicities were grade II rash in one, and grade II nausea in one patient.Conclusion: BR is effective and safe in treatment naive CLL patients and shows notable activity in R/R pts. Major toxic effect are myelosuppresion and infections. Higher doses of bendamustine should be avoided in patients with comorbidities and older age. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial

The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT+ D [OS: hazard ratio (HR) 0.45; P= 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P= 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT+ D (HR 0.41; P= 0.015). This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers.

The aim of this paper is to review morphologic, immunophenotypic, and molecular features of classic Hodgkin lymphoma, as well as different prognostic markers in this neoplasm. Classic Hodgkin lymphoma (CHL) accounts for 15-25% of all lymphomas in the Western world. The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers. HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow. In the last two decades multiple prognostic markers related to HRS cells, the microenvironment or both, have been evaluated in patients with CHL. They include clinical, immunohistochemical, cytogenetic, and molecular markers that can predict survival and identify high-risk patients who will likely relapse after therapy. More recently, circulating tumor DNA analysis by next-generation sequencing has opened new avenues for diagnosis and disease monitoring after therapy. The increased understanding of molecular mechanisms underlying CHL pathogenesis has led to successful implementation of novel therapies, such as anti-PD-1 antibodies, which are becoming a mainstay of treatment in relapsed/refractory patients. CONCLUSION: Currently, pathologic prognostic markers are not routinely assessed at initial diagnosis of CHL. However, as more therapies become available, it will be important to identify patients with high-risk disease who may benefit from more intense or targeted therapy upfront.

Nivel de lactato sanguíneo en tucanes (Ramphastos toco)

Blood lactate concentration is often used in critically ill patients to identify tissue hypoxia, and its values have been referred to as prognostic markers in several settings, with blood lactate in Toco toucan never being described before. Hyperlactatemia is related as a sign of systemic and local hypoperfusion and as a prognostic indicator, being associated with the death of sick patients. The objective of this work was to describe the serum lactate levels in Toco toucan (Ramphastos toco) aiming to start a line of research using this analysis as a biological prognostic marker in this species. 17 free-living Toco toucan (Ramphastos toco) were used, temporarily kept in captivity at the Laboratory of Teaching and Research of Wild Animals (LAPAS) of the Federal University of Uberlândia (UFU). All were captured by the Environmental Police or IBAMA and sent to LAPAS for treatment, rehabilitation and subsequent release. The collection was performed for clinical monitoring of animals and, in the case of lactate, authorized by Opinion No. 365-2016 of the Ethics, Bioethics and Animal Welfare Commission of the University of Vila Velha (CEUA-UVV). In Toco toucan (Ramphastos toco) blood lactate values are between 4.2 and 6.7 mMol/L; however, further studies are needed comparing these results with others obtained in animals with specific pathologies, to characterize its use as a prognostic indicator and also moment of release.

Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study

IntroductionAmyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials.ObjectiveThis study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort.MethodsThe ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS’) was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS’ was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis.Results and conclusionsBoth ΔFS’ and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS’, is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

Evaluation of prognostic variables in chronic lymphocytic leukemia and association with disease stage.

The aim of the present study was to investigate different biological prognostic markers to identify high-risk patients with chronic lymphocytic leukemia (CLL) with a higher tumor burden, in order to ensure appropriate management. A total of 81 Egyptian patients with CLL were enrolled in the present study, with 75 healthy subjects serving as the control group. The expression of CD49d, CD38 and ZAP-70 in CLL cells was assessed using flow cytometry. The fluorescence in situ hybridization technique was employed to evaluate TP53 (del17p), ataxia-telangiectasia (del11q) and 13q14 (del13q14) genes and the presence of trisomy 12. The serological markers β2 microglobulin (B2M) and sCD23 were measured by ELISA. The CD49d gene was highly expressed in 25.9% and cytogenetic aberrations were observed in 66.6% of all recruited CLL patients. The patients were categorized according to the Binet staging system and a significant increase in the expression of sCD23, CD49d and ZAP-70 was detected in group C (P=0.008, 0.034 and 0.017, respectively) when compared to groups A and B. CD49d+ patients exhibited significantly higher expression of CD38 (P=0.002) and trisomy 12 (P=0.015) and lower expression of del13q14 (P=0.001). Patients who were CD49d+ with B2M>3.5 µg/ml exhibited higher total leukocyte count (P=0.048), higher absolute lymphocyte count (P=0.036), higher expression of CD38 (P=0.002) and trisomy 12 (P=0.034) and lower expression of del13q14 (P=0.002). Therefore, sCD23, CD49d and ZAP-70 may be considered as an optimal prognostic marker combination to be evaluated in the early stages of CLL and throughout disease management. Integrating both serological markers and CD49d expression by flow cytometry may add to the prognostic value of each marker alone and help identify high-risk patients with a higher tumor burden.

New approaches to risk stratification for Wilms tumor.

The treatment of Wilms tumor is one of the great achievements in the field of oncology. One of the key success factors has been improved risk stratification, enabling augmentation or reduction of therapy depending on a patient's risk of relapse. This article highlights the evolution of clinical and biological prognostic markers that have been applied in the treatment of Wilms tumor. Historically, tumor stage and histology were the sole determinants of Wilms tumor treatment. Recent clinical trials conducted by the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP) Renal Tumor Study Group have expanded the menu of prognostic factors to include histologic and volumetric response to therapy and tumor-specific loss of heterozygosity (LOH) at chromosomes 1p and 16q. Augmentation of therapy has been able to overcome the adverse risk factors. An emerging prognostic marker is chromosome 1q gain, will be incorporated into future clinical trials. The application of new clinical and biological prognostic factors has created unprecedented ability to tailor therapy for Wilms tumor, accompanied with improved outcomes. Current and future trials will continue to enhance precision medicine for Wilms tumor.