Academic literature on the topic 'AML, Biomarker, Prognose'

The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.

Background Bladder cancer is one of the most common cancers, and its histopathological type is mainly bladder urothelial carcinoma, accounting for about 90%. The prognostic biomarkers of bladder cancer are classified into clinical features biomarkers and molecular biomarkers. Nevertheless, due to the existence of individual specificity, patients with similar pathological characteristics still have great differences in the risk of disease recurrence. Therefore, it is often inaccurate to predict the survival status of patients based on clinical characteristic biomarkers, and a prognostic molecular biomarker that can grade the risk of bladder cancer patients is needed. Methods A total of three bladder urothelial carcinoma datasets were used in this study from the Cancer Genome Atlas database and Gene Expression Omnibus database. In order to avoid overfitting, all samples were randomly divided into one training set and three validation sets, which were used to construct and test the prognostic biomarker model of bladder urothelial carcinoma. Univariate and multivariate Cox regression were used to screen candidate mRNAs and construct prognostic biomarkers model. Kaplan–Meier survival analysis and the receiver operating characteristic (ROC) curve were used to evaluate the predictive performance of the model. Results A prognostic biomarker model of bladder urothelial carcinoma combining with eight mRNA was constructed. Kaplan–Meier analyses indicated that a significant difference in the survival time of patients between the high-risk and the low-risk group. The area under the ROC curve were 0.632 (95% confidence interval (CI) [0.541–0.723]), 0.693 (95% CI [0.601–0.784]) and 0.686 (95% CI [0.540–0.831]) when the model was used to predict the patient’s survival time in three validation datasets. The model showed high accuracy and applicability.

Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients’ prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs.

Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42, tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed.

Uncontrolled diabetes and acute coronary syndrome share a complex dynamic that results in significant ambiguity when interpreting biomarker elevations in this setting. This is concerning because myocardial infarction has been shown to be the most common cause of death in the first 24 hours of admission for uncontrolled diabetes. Literature shows that elevation in cardiac biomarkers in patients with uncontrolled diabetes could be from viral myopericarditis, although a clear clinical significance is still lacking.1 It is, however, clear that elevation in cardiac biomarkers portends a poor long-term prognosis in patients with uncontrolled diabetes mellitus. We present a rare case of myopericarditis in a middle-aged patient with uncontrolled diabetes. The patient had elevated troponin I level reaching a peak of 7.3 ng/mL with associated ST elevations on electrocardiography. Coronary angiogram was subsequently done revealing clean coronaries. To our knowledge, this is the first description of myopericarditis in uncontrolled diabetes without a known cause.

Background Pancreatic cancer (PC) has much weaker prognosis, which can be divided into diabetes and non-diabetes. PC patients with diabetes mellitus will have more opportunities for physical examination due to diabetes, while pancreatic cancer patients without diabetes tend to have higher risk. Identification of prognostic markers for diabetic and non-diabetic pancreatic cancer can improve the prognosis of patients with both types of pancreatic cancer. Methods Both types of PC patients perform differently at the clinical and molecular levels. The Cancer Genome Atlas (TCGA) is employed in this study. The gene expression of the PC with diabetes and non-diabetes is used for predicting their prognosis by LASSO (Least Absolute Shrinkage and Selection Operator) Cox regression. Furthermore, the results are validated by exchanging gene biomarker with each other and verified by the independent Gene Expression Omnibus (GEO) and the International Cancer Genome Consortium (ICGC). The prognostic index (PI) is generated by a combination of genetic biomarkers that are used to rank the patient’s risk ratio. Survival analysis is applied to test significant difference between high-risk group and low-risk group. Results An integrated gene prognostic biomarker consisted by 14 low-risk genes and six high-risk genes in PC with non-diabetes. Meanwhile, and another integrated gene prognostic biomarker consisted by five low-risk genes and three high-risk genes in PC with diabetes. Therefore, the prognostic value of gene biomarker in PC with non-diabetes and diabetes are all greater than clinical traits (HR = 1.102, P-value < 0.0001; HR = 1.212, P-value < 0.0001). Gene signature in PC with non-diabetes was validated in two independent datasets. Conclusions The conclusion of this study indicated that the prognostic value of genetic biomarkers in PCs with non-diabetes and diabetes. The gene signature was validated in two independent databases. Therefore, this study is expected to provide a novel gene biomarker for predicting prognosis of PC with non-diabetes and diabetes and improving clinical decision.

35 Background: In colorectal cancer (CRC) several independent blood-borne biomarkers have been proposed as prognostic and/or predictive markers. However only CEA is at present recommended as a serological CRC biomarker. We have identified 6 other biomarkers and the aim of this study is to see if a combination of markers improves the prognostic and/or predictive value. Methods: Two-hundred and twenty-eight patients with CRC have been included in this study, all with TNM stages I-III. Overall survival (OS) was chosen as the primary endpoint with 93 events and the minimum follow-up was 47 months. Seven biomarkers measured in plasma or serum were analysed: CEA, TIMP-1, the 3 soluble uPAR forms suPAR(I-III), suPAR(I-III)+(II-III) and uPAR(I), PAI-1 and YKL-40. Multivariable analyses of OS were done using regression analysis and results presented by 3 and 5 year OS rates with area under the receiver operating characteristic curve (AUC). All biomarker levels were analysed on the log scale (base 2). Results: High levels of each of the included biomarker were significantly associated in a multivariable analysis (adjusted for age, gender, TNM stage, tumor localization, adjuvant chemotherapy,interaction between adjuvant therapy and biomarker) to poor prognosis in patients not receiving adjuvant chemotherapy. The results are shown for those patients (see Table). The uPAR forms were the only biomarkers significantly associated to OS in patients receiving adjuvant chemotherapy. Combining the markers resulted in an enhanced prediction of 3 and 5 year OS. For TNM stage II patients not receiving adjuvant therapy, the AUC was 0.765 for 3 year OS and 0.745 for 5 year OS. The corresponding AUC’s for TNM stage III were 0.859 and 0.861. Conclusions: The presented combination of blood biomarkers are shown to predict OS with higher precision than any single marker for patients not receiving adjuvant chemotherapy and may provide useful information for use in the management of patients with CRC. [Table: see text]

AbstractIn the present study, we determined complex indices of inflammatory activity and compared the performance of these indices as prognostic biomarkers in a cohort of breast cancer patients. All proposed composite biomarkers could be evaluated in 418 out of 474 patients in the cohort with complete data on peripheral blood cell count, urinary neopterin, albumin and C-reactive protein. Neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio, systemic inflammatory index, Glasgow prognostic index, modified Glasgow prognostic index, prognostic nutritional index and C-reactive protein/albumin ratio were calculated and further complex indices were proposed. Although a number of the investigated indices were significantly associated with survival in the univariate analysis, only age and stage, but none of the laboratory biomarkers or composite biomarkers, were significant predictors of survival in the whole group in the multivariate analysis. In patients evaluated before the start of the treatment, age, stage and urinary neopterin were significant predictors of survival. These results underscore the importance of neopterin as a prognostic biomarker in breast cancer.

10582 Background: Although breast cancer with 4+ axillary lymph nodes generally carries a poor prognosis, we hypothesized that a good prognostic subgroup of such patients would be identifiable by immunohistochemical (IHC) biomarkers. Methods: Patients with primary breast cancer with 4+ axillary nodes and no metastatic disease at diagnosis were identified from a large clinically annotated TMA of formalin-fixed paraffin-embedded archival breast cancers and analyzed for eight IHC based biomarkers: estrogen receptor, HER2, carbonic anhydrase IX, EGFR, CK 5/6, progesterone receptor, p53 and Ki67. Expression of each biomarker was scored 0 or 1 to indicate good or bad prognosis based on univariate analysis of relapse free survival (RFS). Patients were banded as having a total score of 0 (i.e. each biomarker predicted a good outcome), 1–4 or 5–8. Kaplan Meier and Cox regression analysis of RFS outcomes was performed. 10 year RFS for each band was compared to the mean of predicted outcomes based on the prognostic tool Adjuvant! ( www.adjuvantonline.com ). Results: 313 eligible patients were identified and complete data were available for 228. The subset of 228 was similar to the larger group of 313 with respect to RFS and conventional prognostic factors. 10 year RFS for the 228 patients was 39.5% (standard error, SE 3.4%). The subgroup of 37 (16%) scoring zero for all 8 biomarkers had a mean 10 year RFS of 77.6% (SE 7.0). Mean 10 year RFS for the bands scoring 1–4 (154 patients, 68%) and 5–8 (37 patients, 16%) were 34.9% (SE 4.1) and 19.0% (SE 6.9) respectively. Mean 10 year RFS predictions by Adjuvant! were 35.9% (SE 2.6), 34.5% (SE 1.2) and 34.3% (SE 2.3) respectively. In multivariate analysis with conventional prognostic factors, the banded biomarker score retained statistical significance for predicting RFS (p=0.0007) along with estrogen receptor status (p=0.03) and tumour size (p=0.01). Conclusions: This TMA biomarker panel identified a breast cancer subgroup with good prognosis despite extensive axillary node involvement. Long term outcome was markedly better than that predicted by conventional prognostic factors. If validated, treatment decisions and clinical trial stratification might be modified using this new score. No significant financial relationships to disclose.

The aim of this study was to perform a systematic review on the potential value of saliva biomarkers in the diagnosis, management and prognosis of heart failure (HF). The correlation between saliva and plasma values of these biomarkers was also studied. PubMed was searched to collect relevant literature, i.e., case-control, cross-sectional studies that either compared the values of salivary biomarkers among healthy subjects and HF patients, or investigated their role in risk stratification and prognosis in HF patients. No randomized control trials were included. The search ended on 31st of December 2020. A total of 15 studies met the inclusion criteria. 18 salivary biomarkers were analyzed and the levels of all biomarkers studied were found to be higher in HF patients compared to controls, except for amylase, sodium, and chloride that had smaller saliva concentrations in HF patients. Natriuretic peptides are the most commonly used plasma biomarkers in the management of HF. Their saliva levels show promising results, although the correlation of saliva to plasma values is weakened in higher plasma values. In most of the publications, differences in biomarker levels between HF patients and controls were found to be statistically significant. Due to the small number of patients included, larger studies need to be conducted in order to facilitate the use of saliva biomarkers in clinical practice.

Primarni glomerulonefritisi predstavljaju inflamatorna oboljenja bubrega, kod kojih su primarno zahvaćeni glomerulusi, ali promene na tubulointersticijumu imaju veliki značaj za tok i prognozu bolesti. Pored kliničko-laboratorijskih ispitivanja, perkutana biopsija bubrega zauzima značajno mesto u dijagnostici posebnih oblika glomerulonefritisa. Lipokalin vezan za neutrofilnu gelatinazu (NGAL) zauzima značajno mesto medju novijim biomarkerima u nefrologiji. Osnovna funkcija mu je transport gvoždja, ali ima ulogu i u regulaciji metabolizma gvoždja, regulaciji inflamacije, dok u masnom tkivu utiče na razvoj insulinske rezistencije i dijabetesa. Cilj ispitivanja je utvrditi nivo lipokalina 2 u serumu i urinu bolesnika sa primarnim glomerulonefritisom, te utvrditi postojanje korelacije izmedju nivoa lipokalina 2 i patohistološkog oblika glomerulonefritisa, stepenom bubrežne insuficijencije i brzinom progresije bubrežne insuficijencije. Takodje, cilj ispitivanja je bio analizirati povezanost lipokalina 2 sa odogovorom na primenjenu terapiju glomerulonefritisa. Ispitivanje je sprovedeno na 60 bolesnika sa dijagnozom primarnih glomerulonefritisa. Nivo lipokalina 2 je odredjivan pri postavljanju dijagnoze i nakon minimalno šest meseci lečenja. Rezultati studije ukazuju da bolesnici sa primarnim glomerulonefritisom imaju značajno veće nivoe lipokalina 2 u odnosu na zdrave osobe. Bolesnici sa proliferativnim oblicima primarnih glomerulonefritisa imaju veće nivoe NGAL-a u serumu i odnosa uNGAL/kreatinin, ali razlika nije statistički značajna. Nije utvrdjeno postojanje značajne razlike u prosečnim nivoima NGAL-a u serumu, niti urinu, pri postavljanju dijagnoze, izmedju bolesnika sa pozitivnim i negativnim efektom lečenja primarnog glomerulonefritisa. Utvrdjeno je postojanje korelacije izmedju nivoa NGAL-a u serumu i vrednosti kreatinina, ureje, mokraćne kiseline, klirensa kreatinina i broja leukocita, dok je sa nivoom NGAL-a u urinu utvrdjena korelacija sa klirensom kreatinina, dnevnom proteinurijom i serumskim albuminima. Utvrdjeno je postojanje statistički značajne razlike u prosečnim nivoima NGAL-a u serumu u zavisnosti od stadijuma bubrežne insufijencije. Nije utvrdjeno postojanje značajne razlike u prosečnim nivoima NGAL-a u serumu pri postavljanju dijagnoze, izmedju bolesnika sa povoljnim i nepovoljnim efektom lečenja na bubrežnu funkciju.
The primary glomerulonephritis are inflammatory kidney diseases. Glomerulus are primarily affected, but tubulointerstitial changes are very important for course and prognosis of the disease. In addition to clinical and laboratory testing, percutaneous renal biopsy has an important place in the diagnosis of specific forms of glomerulonephritis. Neutrophil gelatinaseassociated lipocalin (NGAL) occupies an important place among the newer biomarkers in nephrology. The main function of NGAL is transport of iron, whether it has a role in the regulation of iron metabolism, regulation of inflammation, while in adipose tissue affects the development of insulin resistance and diabetes. The aim of this study was to determine the level of lipocalin 2 in serum and urine of patients with primary glomerulonephritis and determine the existence of a correlation between the level of lipocalin 2 and histological forms of glomerulonephritis, the degree of renal insufficiency and speed of progression of renal insufficiency. Also, the aim of this study was to analyze the association of lipocalin 2 with the effect of therapy for glomerulonephritis. The study was conducted on 60 patients diagnosed with primary glomerulonephritis. The levels of lipocalin 2 were determined at diagnosis and after a minimum of six months of treatment. The study results show that patients with primary glomerulonephritis have significantly higher levels of lipocalin 2 compared to healthy people. Patients with proliferative forms of primary glomerulonephritis have higher levels of NGAL in serum and ratio uNGAL/creatinine, but the difference was not statistically significant. There was no significant differences in average levels of NGAL in serum or urine at the beginning, between patients with positive and negative effects of the treatment of primary glomerulonephritis. Correlation was found between the level of NGAL in serum and creatinine, urea, uric acid, creatinine clearance and the number of leukocytes, while the level of NGAL in urine correlated with creatinine clearance, the daily proteinuria and serum albumin. Statistically significant differences in mean levels of NGAL in serum depending on the severity of renal insufficiency were found. No evidence of significant differences in average levels of NGAL in serum at the beginning, among patients with favorable and unfavorable effects of treatment on renal function were found.

Sphingosine kinase/sphingosine 1-phosphate (SK/S1P) signalling interacts with major cellular pathways controlling cell proliferation, migration, survival, and resistance to chemotherapeutics. Moreover, extensive research has shown that the SK/S1P signalling is up-regulated in numerous human cancers (e.g. stomach cancer, colon, rectal, glioblastoma, ovarian, renal, lung and breast) making S1P signalling an important candidate as a biomarker and a key player in promoting cancer progression. Several inhibitors of SK/S1P signalling pathway have been identified and have shown to inhibit cancer cell survival and resistance to chemo- and radio-therapies. In this study, human breast cancer tissue microarrays at various tissue histological grades of ERα negative breast tumours were analysed for the expression of S1P signalling proteins (e.g. SKs and S1P₁₋₅ receptors) to identify the impact of expression level of these proteins on clinical outcomes. High SK1 and S1P₄ receptor tumour expression is associated with poor cancer prognosis in ERα negative breast cancer patients. Moreover, high SK1 and S1P₄ receptor expression in these tumours was also associated with cancer recurrence and this was dependent on the HER2 receptor expression. Indeed, the SK1/2 dual inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) abrogated the S1Pstimulated ERK-1/2 activation in ERα-/HER2+ MDA-MB-453 cells suggesting that SK1 activity is required for the S1P₄/HER2-mediated ERK-1/2 activation that is known to promote cancer progression. In addition, a diverse array of kinases and transcription factors e.g. c-RAF-1, ERK-1/2, AKT, LYN, SRC family kinases (SFKs) and NFκB (p50 RelA) were analysed in combination with SK1 and S1P receptors to discover novel prognostic interactions that drive cancer progression in ERα positive breast cancer patients. High tumour SK1 expression in combination with high expression of either S1P₁ receptor or S1P₃ receptor or phosphorylated ERK-1/2 or phosphorylated AKT or phosphorylated NFκB or phosphorylated RAF-1 or Y416 phosphorylated SFK or LYN is associated with shorter disease-specific patient survival and disease-free cancer recurrence. Similarly, high S1P₁ receptor tumour expression in combination with high expression of either Y216 phosphorylated SRC or c-RAF-1 or ERK-1/2 or AKT kinase is associated with shorter disease-specific patient survival and disease-free cancer recurrence. High S1P₂ receptor tumour expression is associated with prolonged patient survival and this is enhanced in combination with high expression of c-SRC and Y416 phosphorylated SFK in ERα positive breast cancer tumours. Finally, high tumour S1P3 receptor expression in combination with high expression of LYN or c-RAF-1 kinases is associated with shorter disease-specific patient survival and disease-free cancer recurrence. Lastly, a new signalling pathway involving SK2, Y416 phosphorylated c-SRC, S1P₄ receptor and S1P₂ receptor was identified using pharmacological agents/gene silencing in ERα negative MDA-MB-231 breast cancer cells. In this pathway, SK2 possibly through 'inside out' S1P signalling activates the S1P₄ receptor that promotes cellular growth by preventing the nuclear accumulation of S1P₂ receptor. Moreover, SK2 activity also prevents the accumulation of Y416 phosphorylated c-SRC into the nucleus that might be crucial for tumour growth. Thus, this study shows that the high tumour expression of S1P signalling proteins is associated with poor disease prognosis in both ERα positive and ERα negative breast cancer patients. However, cancer progression is mediated by distinct set of S1P signalling proteins in different types of breast cancer. Hence, different treatment regiments including SK inhibitors and S1P receptor antagonist must be employed in treatment of ERα positive and ERα negative breast cancer patients.

U organizmu se, pod fiziološkim uslovima, produkuju slobodni radikali. Iako se u organizmu nalaze u veoma niskoj koncentraciji, slobodni radikali mogu ispoljiti toksične efekte. Težeći da spare elektrone, u hemijskoj reakciji oksidacije, dolazi do brzog i nepredvidivog vezivanja za susedne molekule, proteine, lipide, ugljene hidrate i nukleinske kiseline od kojih su sačinjeni strukturni elementi ćelije, pokrećući unutrašnji put apoptoze. Antioksidansi su supstance koje sprečavaju ili značajno smanjuju oksidaciju biomolekula. Oksidativni stres je stanje koje nastaje kada produkcija slobodnih radikala premaši kapacitete antioksidativnih enzima da ih neutrališu. U antioksidativne enzime spadaju: superoksid dismutaza (SOD), katalaza (CAT), glutation peroksidaza (GPx), glutation reduktaza (GR) i glutation-S-transferaza (GST). Lipidna peroksidacija (LP) je proces oksidacije višestruko nezasićenih masnih kiselina od strane slobodnih radikala. Malondialdehid predstavlja biohemijski marker pomoću kog je moguće meriti stepen oksidativnog oštećenja ćelijskih membrana. Oksidativna modifikacija DNK dovodi do promene strukture DNK koje rezultuju genetskim oštećenjima. Najčešće korišćen marker oksidativnog stresa je urinarni 8-hidroksi-2-deoksiguanozin (8-OHdG). Oštećenja proteina, lipida, DNK čine važan osnov mnogih oboljenja kao što su ateroskleroza, neurodegenerativna oboljenja, dijabetes, gojaznost, proces starenja, retinopatija, hronične inflamatorne bolesti i karcinom. Polazeći od hipoteze da su ovi biomolekuli različiti u različitim stadijumima bolesti, oni bi mogli predstavljati prognostički marker proširenosti bolesti. Cilj istraživanja je bio da se ispita da li postoje razlike između kontrolne grupe (zdravih žena), pacijentkinja sa prekanceroznim lezijama na grliću materice (HSIL), pacijentkinja sa lokalno ograničenim (FIGO Ia-Ib) i pacijentkinja sa lokalno uznapredovalim karcinomom grlića materice (IIa-IV) u pokazateljima oštećenja DNK (određivanjem vrednosti 8-OHdG), pokazateljima oksidativnog stresa (određivanjem intenziteta lipidne peroksidacije (TBARS)), pokazateljima antioksidativne odbrane (određivanjem aktivnosti antioksidativnih enzima superoksid dismutaze (SOD), katalaze (CAT), glutation peroksidaze (GPx), glutation reduktaze (GR) i glutation-S-transferaze (GST)). Pored toga, cilj istraživanja je bio da se uporede vrednosti 8-OHdG, proizvoda lipidne peroksidacije (TBARS) i aktivnosti antioksidativnih enzima (SOD, CAT, GST, GPx, GR) unutar grupe pacijentkinja sa lokalno ograničenim karcinomom grlića materice podeljenih u dve podgrupe sa niskim i visokim rizikom u odnosu na relaps bolesti. Takođe, u radu je koreliran nivo 8-OHdG, MDA i antioksidativnih enzima sa relapsom bolesti. Istraživanje je izvedeno na Klinici za operativnu onkologiju, odeljenje za ginekologiju na Institutu za onkologiju Vojvodine, Zavodu za farmaciju Medicinskog fakulteta u Novom Sadu i Zavodu za zdravstvenu zaštitu radnika Novi Sad u periodu od 2013. godine do 2017. godine. Od ispitanica su prikupljani uzorci krvi i urina, pripremljeni na adekvatan način i čuvani na -80° do analiza. Aktivnost enzima antioksidativne zaštite, kao i intenzitet lipidne peroksidacije određivani su spektrofotometrijskim metodama, a koncentracija 8-OhdG određivana je gasnom hromatografijom uz masenu detekciju. Za sprovođenje istraživanja dobijena je saglasnost Etičkog odbora Instituta za onkologiju Vojvodine. Pokazano je da postoje statistički značajne razlike između kontrolne grupe (zdravih žena), pacijentkinja saprekanceroznim lezijama na grliću materice (HSIL), pacijentkinja sa lokalno ograničenim (FIGO Ia-Ib) u odnosu napacijentkinje sa lokalno uznapredovalim karcinomom grlića materice (IIa-IV) u pokazateljima oštećenja DNK (koncentracija 8-OHdG), pokazateljima oksidativnog stresa (intenziteta lipidne peroksidacije (TBARS)), pokazateljima antioksidativne odbrane (aktivnosti antioksidativnih enzima SOD, CAT i GST). Nisu pokazane razlike između ispitivanih grupa u aktivnosti enzima glutation peroksidaze (GPx) i glutation reduktaze (GR). Nisu pronađene razlike u koncentraciji 8-OHdG, proizvoda lipidne peroksidacije (TBARS) i aktivnosti antioksidativnih enzima (SOD, CAT, GST, GPx i GR) unutar grupe pacijentkinja sa lokalno ograničenim karcinomom grlića materice podeljenih u dve podgrupe sa niskim i visokim rizikom u odnosu na relaps bolesti. Aktivnosti CAT i GST bile najbolji prediktori rekurencije bolesti kod definisanih pacijentkinja. Na osnovu aktivnosti ova dva oksidativna enzima, separacija grupe pacijentkinja kod kojih nije došlo do rekurencije bolesti nakon perioda praćenja od ostale dve grupe kod kojih je došlo do rekurencije bolesti je bila moguća. Na osnovu dobijenih rezultata zaključuje se da je moguće koristiti navedene biomarkere kao dijagnostičke markere kod pacijentkinja sa karcinomom grlića materice. Ovi biomolekuli mogu pomoći lakšem svrstavanju pacijentkinja u određene grupe prema stadijumu bolesti, a sledstveno i bržem odabiru odgovarajućeg lečenja. Pored toga, pokazano je da su aktivnosti enzima CAT i GST prediktori rekurencije bolesti kod definisanih grupa pacijentkinja.
Free radicals are produced in our body under physiological conditions. Although in very low concentrations, they can show some toxic effects. While trying to bind electrons, in the chemical reaction of oxidation, they rapidly and unpredictably bind to adjacent molecules- proteins, lipids, carbohydrates and nucleic acids from which the structural elements of the cell are made, triggering the internal pathway of apoptosis. Antioxidants are substances that prevent or significantly reduce the oxidation of biomolecules. Oxidative stress is a condition that occurs when the production of free radicals exceeds the capacity of antioxidant enzymes to neutralize them. The antioxidant enzymes include: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST). Lipid Peroxidation (LP) is the process of oxidation of polyunsaturated fatty acids by free radicals. Malondialdehyde is a biochemical marker by which it is possible to measure the degree of oxidative damage of cell membranes. The oxidative modification of DNA leads to a change in DNA structure that results in genetic damage. The most commonly used marker of oxidative stress is urinary 8-hydroxy-2-deoxiguanosine (8-OHdG). The damage to proteins, lipids and DNA is an important basis for many diseases such as atherosclerosis, neurodegenerative diseases, diabetes, obesity, aging, retinopathy, chronic inflammatory disease and cancer. Starting from the hypothesis that these biomolecules are different at different stages of the disease, they could represent a prognostic marker of the progression of the disease. The aim of the study was to examine whether there were differences between the control group (healthy women), the patients with precancerous lesions on the cervix (HSIL), the patients with early stage cervical cancer (FIGO Ia-Ib) and the patient with locally advanced cervical cancer (IIa - IV) in the indicators of DNA damage (determining the value of 8-OHdG), indicators of oxidative stress (by determining the lipid peroxidation intensity (TBARS)), indicators of antioxidant defense (by determining the activity of antioxidative enzymes of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase GPx), glutathione reductase (GR), and glutathione-S-transferase (GST)). In addition, the aim of the study was to compare the values of 8- OHdG, lipid peroxidation products (TBARS) and the activity of antioxidant enzymes (SOD, CAT, GST, GPx, GR) within the group of patients with early stage cervical cancer divided into two subgroups- with low and high risk in relation to the relapse of the disease. The research was performed at the Clinic for operative oncology, Department of Gynecology at the Institute of Oncology of Vojvodina, Medical Faculty in Novi Sad, Department of Pharmacy and the Institute for Health Care of Novi Sad in the period from 2013 to 2017. Samples of blood and urine of the patients were collected, prepared adequately and stored at -80 ° until the analysis. The activity of the antioxidant enzymes as well as the lipid peroxidation were determined by spectrophotometric methods, and the concentration of 8-OHdG was determined by gas chromatography with mass detection. The approval of the Ethical Committee of the Institute for Oncology of Vojvodina was obtained before conducting the research. It has been shown that there are statistically significant differences between the control group (healthy women), patient with precancerous cervical lesions (HSIL), the patients with early stage cervical cancer (FIGO Ia-Ib) compared to a group of patients with locally advanced cervical cancer (IIa-IV) in indicators of damage to DNA (concentration of 8-OHdG), indicators of oxidative stress (lipid peroxidation (TBARS)), indicators of antioxidant defense (activities of antioxidant enzymes SOD, CAT and GST). There was no difference between the groups in activity of glutathione peroxidase enzyme (GPx) and glutathione reductase (GR). There were no differences in the concentration of 8-OHdG, lipid peroxidation products (TBARS) and the activity of antioxidant enzymes (SOD, CAT, GST, GPx and GR) within the group of patients with locally restricted cervical cancer divided into two subgroups with low and high risk in relation on relapses of the disease. CAT and GST activities were the best predictors of disease recurrence among defined groups. Based on the activities of these two oxidative enzymes, the separation of the group of patients who did not experience disease recurrence after a follow-up period from the other two groups in which recurrence of the disease occurred was possible. Based on the obtained results it is concluded that it is possible to use the studied biomarkers as diagnostic markers in patients with cervical cancer. These biomolecules can help in the patient's classification into certain groups according to the stage of the disease, and consequently the more efficient choice of appropriate treatment. In addition, CAT and GST enzyme activity have been shown to be predictors of disease recurrence in defined patient groups.

Napredak na polju molekularne biologije omogućio je identifikaciju molekularnih markera za karcinom bronha sa vrednim prognostičkim i prediktivnim značajem i njihova uloga kod uznapredovalog, metastatskog oblika bolesti je u velikoj meri istražena, dok kod ranih stadijuma bolesti još uvek nije sasvim jasna. Cilj ovog istraživnja bio je da se utvrdi učestalost najčešćih genskih alteracija u tumorskim ćelijama bolesnika sa ranim stadijumom adenokarcinoma bronha, da se utvrdi pojedinačna zavisnost ispitivanih genskih alteracija u tumorskim ćelijama sa određenim kliničko-patološkim karakteristikama i da se utvrdi potencijalni prognostički značaj pojedinačne genske alteracije u tumorskim ćelijama na vreme preživljavanja bez povratka bolesti i ukupno vreme preživljavanja. Istraživanje je obuhvatilo 161 bolesnika sa adenokarcinomom bronha, stadijuma bolesti od I do IIIA, kod kojih je sprovedena radikalna hirurška resekcija u Institutu za plućne bolesti Vojvodine u periodu izmedju 2007 i 2014 godine. U tumorskim uzorcima fiksiranim u parafinu odredjivane su mutacije EGFR, KRAS i PIK3CA gena, ALK i ROS1 rearanžman i PD1 i PD-L1 ekspresija. Kliničkopatološke karakteristike su preuzete iz registra za karcinom bronha Instituta za plućne bolesti Vojvodine. Ukupno preživljavanje je računato od dana operacije do dana smrti, a preživljavanje bez povratka bolesti je računato od dana operacije do momenta ponovne pojave bolesti. Od 161 testiranog tumorskog uzorka, prisustvo mutacija detektovano je kod 96 uzoraka (59.6%). Prisustvo mutacije KRAS gena detektovano je kod 69 (42.9%), mutacije EGFR gena kod 10 (6.2%), a mutacije PIK3CA gena kod 7 (4.3%) tumorskih uzoraka. ALK rearanžman je detektovan kod 3 (1.9%), a ROS1 rearanžman kod 7 (4.3%) tumorskih uzoraka. PD-1 ekspresija detektovana je u 71 tumorskom uzorku (45%), dok je PD-L1 ekspresija detektovana u 59 tumorskih uzoraka (36.6%). PD-1 ekspresija nije bila značajno povezana ni sa jednim od klinčko-patoloških karakteristika (uključujući KRAS, EGFR, ALK, ROS1 i PI3KCA status). PD-L1 ekspresija je bila značajno povezana sa tipom hirurgije (P = 0.01) i sa prisustvom KRAS mutacije (P = 0.02). Mutacioni status u domenu KRAS gena je bio značajno povezan sa godinama starosti (P = 0.004), polom (P = 0.006) i pušačkim statusom (P = 0.004). Mutacioni status u domenu EGFR gena je bio značajno povezan sa pušenjem (P < 0.001) i sa godinama starosti (P = 0.013). Mutacioni statusi u domenu gena za ALK, ROS1 i PI3KCA nisu bili značajno povezani ni sa jednom od ispitivanih kliničko-patoloških karakteristika. Prisustvo PD-1 ekspresije je bilo značajno povezano sa preživljavanjem bez povratka bolesti (P = 0.03) i ukupnim preživljavanjem (P = 0.01). PD-L1 ekspresija, KRAS, EGFR, ALK, ROS1 i PIK3CA mutacioni status nisu bili značajno opvezani sa preživljavanjem bez povratka bolesti i ukupnim preživljavanjem. Najčešće detektovane genske alteracije su mutacije u domenu KRAS i EGFR gena. Prisustvo KRAS mutacije je značajno povezano sa godinama starosti ispitanika, polom i pušačkim statusom dok je prisustvo EGFR mutacije značajno povezano sa godinama starosti ispitanika i pušačkim statusom. Prisustvo PD-L1 ekspresije je značajno povezano sa vrstom hirurškog lečenja i sa prisustvom KRAS mutacija. Jedino prisustvo PD-1 ekspresije u tumorskim ćelijama predstavlja nezavistan prognostički faktor za preživljavanje bez povratka bolesti i ukupno preživljavanje bolesnika sa ranim stadijumom adenokarcinoma bronha.
Advances in the field of molecular biology gave us insight into biomarkers for lung cancer with great prognostic and predictive value and their role in advanced stage disease is well known while in early stage disease is yet to be proven. The aim of this study was to determine the frequencies of the most common gene alterations in patients with early stage lung adenocarcinoma, to determine the relationship between gene alterations in tumor cells and clinicopathologial characteristics and to determine prognostic value of each gene alteration regarding overall survival and disease free survival. One hundred sixty-one patients diagnosed with lung adenocarcinoma clinical stage I-IIIA who underwent radical surgical resection at the Institute for Pulmonary Diseases of Vojvodina between 2007 and 2014 were included in this study. Mutations in EGFR, KRAS and PIK3CA gene, ALK and ROS1 rearrangement and PD-1 and PD-L1 expression were determined in representative formalin-fixed, paraffin-embedded (FFPE) tumor block from each patient. Clinical data were extracted from the institutional lung cancer registry of the Institute for Pulmonary Diseases. Overall survival was calculated as time from the day of surgery to the day of death. Disease free survival was calculated as time from the day of surgery to the day of disease relapse. Among 161 tested tumor tissue, presence of mutation was found in 96 (59.6%) of them. There were 69 (42.9%) mutations in KRAS gene, 10 (6.2%) in EGFR gene and 7 (4.3%) in PIK3CA gene. ALK and ROS1 rearrangement were present in 3 (1.9%) and 7 (4.3%), respectively. PD-1 expression was determined in 71 (45.0%) tumor sample while PD-L1 expression was determined in 59 (36.6%). PD-1 expression was not correlated with any of the clinicopathologial characteristics (including KRAS, EGFR, ALK, ROS1 and PIK3CA mutational status). PD-L1 expression correlated with type of surgery (P = 0.01) and KRAS positivity (P = 0.02). KRAS mutation status correlated with age (P = 0.004), sex (P = 0.006) and smoking status (P = 0.004). EGFR status correlated with smoking status (P < 0.001) and age (P = 0.013). ALK, ROS1 and PIK3CA status were not correlated with any of the clinicopathologial characteristics. PD-1expression was significantly associated with disease free survival (P = 0.03) and overall survival (P = 0.01). PD-L1 expression, KRAS, EGFR, ALK, ROS1 and PIK3CA status were not associated with disease free survival and overall survival. The most frequent gene alteration are mutations in KRAS and EGFR gene. Presence of KRAS mutation is in correlation with patients age, sex and smoking status while presence of EGFR mutation is in correlation with patients age and smoking status. PD-L1 expression is in correlation with type of surgery and KRAS mutational status. Only presence of PD-1 expression represent an independent prognostic factor for disease free survival and overall survival.

Uvod: Karcinom dojke je heterogena bolest koju karakterišu različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodološko određivanje i analiza još uvek nisu standardizovani. Cilj: Utvrditi graničnu (“cut-off”) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao što su životna dob bolesnica, veličina tumora, histološki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodišnjeg perioda praćenja pacijentkinja. Metode: Retrospektivno je analizirano 120 patohistoloških izveštaja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. Rezultati: Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42±10,17 godina; prosečna veličina tumora 17,98±6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49±20,23 meseci. Vrednost “cut off” indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92±8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histološki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p > 0,05). Zaključak: Zbog heterogene prirode oboljenja, korišćenjem standardnih histopatoloških faktora i biomarkera teško je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima loše prognoze.
Introduction: Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. Objective: Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient's age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. Methods: Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. Results: The average patient’s age was 57.42±10.17 years; average tumor size 17.98±6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49±20.23 months. "Cut off" Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn’t show significant relationship between Ki-67 and patient’s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor’s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92±8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p> 0.05). Conclusion: Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis.

Acute coronary syndrome (ACS) results from the occlusion of coronary vessels leading to ischemia in distal cardiac muscle. When ischemia is severe enough to cause myocardial cell death by necrosis, myocardial infarction (MI) is diagnosed, whereas milder cases lead to unstable angina (UA). Challenges in the diagnosis of ACS are important, as the clinical presentation can be atypical and circulating levels of troponin are normal at the time of presentation in 50% of patients with MI. The identification of high-risk patients is also important, in order to select those who will benefit from invasive strategies such as coronary angiography and dilation.In this thesis, we perform a retrospective analysis nested in a prospective cohort of patients admitted to the hospital with a putative diagnosis of ACS, the RISCA study (Récurrence et inflammation dans les syndromes coronariens aigus). The study began in 2000, ended in early 2002, and recruited 1210 patients. Amongst the latter, 100 were eventually discharged with a diagnosis of non-cardiac chest pain. Plasma were collected within 24 hours of the end of ischemic symptoms, at discharge, 1 month after discharge and stored for future analyses. Patients were followed for 1 year after hospital discharge to assess the recurrence of ACS, hospitalization for heart failure (HF) and cardiac death. All the studies summarized below were secondary analyses of the RISCA database.The first objective was to assess whether measuring circulating biomarkers of apoptosis and inflammation (soluble Fas (sFas) and high-sensitivity C-reactive protein (CRP)) at the time of hospital admission could improve diagnostic accuracy and prognostic accuracy following an ACS. We compared circulating levels of these biomarkers in those who had a final non-cardiac chest pain diagnosis, those who had an ACS diagnosis and experienced, or not, recurrent cardiac events during a 1-year follow-up. sFas was associated with a discharge diagnosis of ACS versus non-cardiac chest pain during the index hospitalization, but hs-CRP was not. sFas significantly improved the C-statistic and diagnostic accuracy for ACS. Baseline sFas and CRP did not predict recurrent cardiac events. The second objective was to assess whether longitudinal trends in sFas and CRP levels were different in ACS patients according to clinical outcomes. In patients with ACS, sFas levels increased faster in time in subjects who experienced recurrent ACS, HF or cardiac related death over a 1-year follow-up. Longitudinal CRP trends were not associated with prognosis in patients with ACS.The third objective was to explore 2 aspects of the strong link between chronic kidney disease (CKD) and ACS. From a mechanistic viewpoint, we first wished to study whether there was effect modification by CKD in the relationship between sFas and the diagnosis or prognosis of ACS. We could not detect any interaction in this study. From a clinical perspective, we assessed whether the therapy of ACS differed according to renal function. Use of coronary angiography and lipid-lowering drugs at discharge were lower in patients with CKD, while other aspects of care were similar. In conclusion, our results suggest that in suspected ACS cases, sFas measured at baseline helps improving diagnostic accuracy. Increasing sFas levels in ACS patients who have adverse outcomes are consistent with a postulated role for apoptosis in plaque destabilization and heart remodeling. In patients with ACS, the extent of CKD-related undertreatment is less than reported previously, which is partially explained by more complete adjustment for co-treatments/comorbidities in the present study.
Le syndrome coronarien aigu (SCA) survient lorsqu'il y a occlusion de vaisseaux coronariens, créant de l'ischémie du myocarde en aval de l'occlusion. Lorsque l'ischémie est assez sévère pour causer la mort de cellules musculaires myocardiques, le diagnostic d'infarctus du myocarde (IM) est posé, alors que dans les cas moins sévères, on pose le diagnostic d'angine instable (AI). Puisque la présentation clinique peut être atypique, le diagnostic du SCA peut constituer un défi. De même, l'identification des sujets à risque élevé de récidive ou de mortalité est importante, afin de sélectionner les patients plus à même de bénéficier d'interventions invasives telles la coronarographie ou la revascularisation coronarienne. Dans ce travail, nous avons effectué une étude de cohorte rétrospective nichée dans une cohorte prospective de sujets hospitalisés pour un diagnostic présumé de SCA, l'étude RISCA (Récurrence et Inflammation dans les Syndromes Coronariens Aigus). Cette étude a débuté en 2000, s'est terminée en 2002, et 1210 sujets y ont participé. Parmi ces derniers, 100 furent congédiés de l'hôpital avec un diagnostic de douleur non-coronarienne. Les échantillons sanguins ont été prélevés en dedans de 24 h de la fin des symptômes ischémiques, au congé de l'hôpital, et 1 mois plus tard. Ils ont été congelés et gardés à des fins d'analyses subséquentes. Les sujets ont été suivis pendant 1 an afin de déterminer l'incidence de récidive d'IM, d'AI, d'insuffisance cardiaque décompensée ou de décès. Toutes les études effectuées sont des analyses rétrospectives de la base de données associée à l'étude RISCA.Le premier objectif était d'évaluer si la mesure de biomarqueurs d'apoptose et d'inflammation (Fas soluble (sFas) et protéine C-réactive de haute sensibilité, (hs-CRP)) lors de l'admission pour un diagnostic présumé de SCA améliorait l'exactitude du diagnostic et du prognostic de SCA. Lors d'analyses multivariées, les sujets ayant un diagnostic confirmé de SCA avaient des niveaux de sFas plus élevés que ceux ayant reçu un diagnostic de douleur non-coronarienne. La mesure de sFas a amélioré l'exactitude du diagnostic de SCA. Les mesures de sFas et de CRP n'étaient pas associées avec le prognostic du SCA. Comme second objectif, nous souhaitions comparer les mesures longitudinales de sFas et CRP chez les sujets souffrant de SCA en regard du devenir clinique. Chez les sujets présentant un SCA, les niveaux de sFas augmentaient plus rapidement dans le groupe qui avait une récidive d'IM, d'AI, une hospitalisation pour insuffisance cardiaque ou un décès d'origine cardiaque. Les niveaux de CRP diminuaient pareillement peu importe le devenir des patients.Comme troisième objectif, nous souhaitions explorer 2 aspects de l'importante relation entre la maladie rénale chronique (MRC) et la maladie cardiovasculaire. D'un point de vue mécanistique, nous n'avons pu démontrer la présence d'interaction entre sFas, la MRC, et le diagnostic et le prognostic du SCA, bien que nos trouvailles soient limitées par la taille de l'échantillon. D'un point de vue clinique, nous avons voulu vérifier si le traitement du SCA variait selon la fonction rénale, une notion soulevée par des études antérieures. L'angiographie coronarienne, ainsi que la prescription d'hypolipémiants au congé, était moins utilisée chez les sujets souffrant de MRC. En conclusion, la mesure de sFas augmente l'accuité diagnostic pour le SCA. L'augmentation de sFas au fil du temps supporte le rôle de l'apoptose dans la déstabilisation des plaques d'athérosclérose et le remodelage ventriculaire. Finalement, il semble qu'il existe certaines différences dans la prise en charge thérapeutique du SCA chez les patients souffrant de MRC, mais leur ampleur est moindre que dans les études antérieures, ce qui peut être dû à un meilleur ajustement pour les comorbidités et co-traitements dans l'étude actuelle.

UVOD: Karcinom kolona (KK) je velik javnozdravstveni problem usled visoke incidence i stope mortaliteta. Kod KK je stadijum bolesti najvažniji pojedinačni nezavisni faktor prognoze. U prisustvu nepovoljnih prognostičkih parametara, u koje spadaju visok histološki gradus, ileus, limfo-vaskularna i perineuralna invazija, nakon potencijalno kurativne operacije se kod pacijenata u stadijumu II indikuje primena adjuvantne hemioterapije koja ima pozitivan uticaj na ukupno preživljavanje i na produženje perioda bez bolesti. Međutim, relapsi bolesti nastaju kod nekih bolesnika bez negativnih prognostičkih faktora, što ukazuje na moguće postojanje drugih tkivnih faktora loše prognoze. U novije vreme se sve veća pažnja posvećuje fenomenu tumorskog pupljenja koje predstavlja pojavu tumorskih pupoljaka (TP), odnosno oligocelularnih grupa tumorskih ćelija koje se na invazivnom frontu tumora odvajaju od glavne tumorske mase. Ove tumorske ćelije poprimaju fenotip mezenhimnih ćelija i stiču sposobnost ameboidnog kretanja kroz ekstracelularni matriks, uz pomoć citoplazmatskih podija koje se na dvodimenzionalnim histološkim rezovima vizualizuju kao citoplazmatski pseudofragmenti (CPF). Značaj gustine TP i CPF je još uvek nedovoljno ispitan, ali postoje indicije da se radi o moćnom prediktoru biološkog ponašanja tumora. CILJ: Cilj je bio da se ispita zavisnost dužine perioda bez relapsa, veličine primarnog tumora, gustine peritumorske limfocitne infiltracije i konfiguracije tumorske margine od gustine TP i CPF kod bolesnika sa KK u stadijumu II. METODOLOGIJA: Istraživanjem je obuhvaćeno 114 bolesnika operisanih od KK u stadijumu II na Institutu za onkologiju Vojvodine, bez nepovoljnih prognostičkih faktora i bez indikacija za primenu adjuvantne hemioterapije. Mikroskopskom analizom rutinskih histoloških i imunohistohemijskih preparata utvrđivana je gustina TP i CPF, koja je zatim korelirana sa vremenom pojave relapsa, veličinom primarnog tumora, gustinom peritumorske limfocitne infiltracije i konfiguracijom tumorske margine. REZULTATI: Velika gustina TP i/ili CPF nađena je kod 45 tumora (39,5%). U ovoj grupi se relaps dogodio kod 26 bolesnika (57,8%). U grupi bolesnika sa malom gustinom TP/CPF relaps je registrovan u 4 slučaja (5,8%). Poređenje krivih preživljavanja pokazalo je da je verovatnoća relapsa značajno veća ako se u tumoru nalazi velika gustina TP/CPF (p<0,0001). Tumori sa velikom gustinom TP/CPF su imali najveći prečnik koji je varirao u rasponu od 25 do 100 mm, dok su tumori sa malom gustinom TP/CPF bili najvećeg prečnika od 20 do 110 mm (p=0,6744). Intenzitet peritumorskog limfoidnog odgovora je bio velik kod 13 tumora sa velikom gustinom TP/CPF (28,9%) i kod 17 tumora sa malom gustinom TP/CPF (24,6%), p=0,7747. Konfiguracija tumorske margine je bila infiltrativna u svim tumorima sa velikom gustinom TP/CPF, kao i kod 42 tumora sa malom gustinom TP/CPF (60,9%). ZAKLJUČAK: Velika gustina TP/CPF je nezavisan tkivni indikator loše prognoze kod bolesnika sa KK u stadijumu II, koji je ne korelira ni sa veličinom primarnog tumora ni sa intenzitetom peritumorskog limfoidnog odgovora. Velika gustina TP/CPF nije kompatibilna sa ekspanzivnom konfiguracijom tumorske margine, ali infiltrativna konfiguracija tumorske margine nije prediktor velike gustine TP/CPF.
INTRODUCTION: Colonic carcinoma (CC) is a serious public health problem due to its high incidence and mortality rate. Stage is the single most important independent prognosticator in patients with CC. In the presence of indicators of poor prognosis, including high histologic grade, ileus, lympho-vascular invasion and perineural invasion, there is a need for adjuvant chemotherapy after a potentially curative operation in patients with stage II CC, because the therapy improves both overall survival and disease-free survival. However, some patients with no documented poor prognostic factors suffer recurrences, which indicates that there may be some other tissue features that confer poor prognosis. In the recent publications there is an increasing interest in the phenomenon of tumor budding, a term assigned to the presence of small groups of discohesive tumor cells at the invasive front of the tumor – tumor buds (TB's). These cells acquire mesenchymal phenotype and gain the ability to migrate through the extracellular matrix by means of cytoplasmic extrusions which are visible on the two-dimensional immunohistologic sections and are called cytoplasmic pseudofragments (CPF's). Significance of density of TB's and CPF's is still to be evaluated, but the pool of evidence suggests that this is a powerful predictor of biologic behaviour of CC. AIM: The aim of this study was to determine the influence of density of TB's and CPF's on the risk of recurrence in patients with stage II CC. This research also attempted to establish whether there is a correlation between the density of TB's and CPF's and several other morphologic features such as tumor diameter, peritumoral lymphocytic response and the configuration of the tumor margin. METHODS: 114 patients with stage II CC were enrolled in the study. All the patients received surgery at the Institute of Oncology in Sremska Kamenica and no patient had indication for adjuvant chemotherapy. Microscopic analysis of routine histologic and immunohistochemical slides was performed to establish the density of TB's and CPF's, to estimate the intensity of the peritumoral lymphocytic response and to determine the configuration of the tumor margin. RESULTS: High density of TB's and/or CPF's was found in 45 tumors (39.5%). In this group recurrence occured in 26 patients (57.8%). In the group of patients with low density of TB/CPF in the tumor tissue 4 patients relapsed (5.8%). Comparison of survival curves showed that the probability of recurrence was significantly greater if the density of TB/CPF's was high (p<0.0001). Tumors with high density of TB/CPF's ranged from 25 to 100 mm in greatest diameter, while those with low density measured from 20 to 110 mm (p=0.6744). Intensity of peritumoral lymphocytic response was high in 13 tumors with high density of TB/CPF's (28.9%) and in 17 tumors with low density of TB/CPF's (24.6%), p=0.7747. All tumors with high density of TB/CPF's and 42 tumors with low density of TB/CPF's (60.9%) had infiltrative configuration of tumor margin. CONCLUSION: High density of TB/CPF's is an independent indicator of poor prognosis in patients with stage II CC and it correlates neither with tumor diameter nor with intensity of peritumoral lymphocytic response. High density of TB/CPF's is not compatible with the expansive configuration of tumor margin, but the infiltrative configuration of tumor margin is not a predictor of high density of TB/CPF's.

Malgrat els avenços terapèutics assolits en les darreres dècades, l’infart agut de miocardi amb elevació del segment ST s’associa a una important morbimortalitat, especialment en els casos complicats amb fibril·lació ventricular o xoc cardiogènic. L’estratificació pronòstica esdevé determinant per identificar els pacients d’alt risc que es puguin beneficiar de tractaments més agressius i monitorització més estreta. Tot i que a la pràctica clínica actual el seu ús es limita a l’estimació de la mida de l’infart mitjançant les troponines cardíaques, els biomarcadors apareixen com una potencial eina per a millorar la informació que aporten els models predictius disponibles. L’objectiu d’aquesta tesi doctoral és estudiar el valor afegit que poden proporcionar diferents nous biomarcadors respecte els models d’estimació de risc basats en dades clíniques. A partir d’una cohort prospectiva de pacients amb infart tractats amb intervencionisme coronari percutani primari, en primer lloc s’avalua la utilitat pronòstica de la determinació seriada de troponines que es realitza a l’actualitat. En segon, s’analitza la fisiopatologia i el valor pronòstic d’altres biomarcadors que exploren vies alternatives a la necrosi miocàrdica: el factor de diferenciació de creixement 15 (GDF-15) i l’eix Stanniocalcina-2/PAPP-A/IGFBP-4. La darrera part del treball es centra en els subgrups de pacients de més risc: els que presenten fibril·lació ventricular i xoc cardiogènic. En els primers, s’estudia el valor de GDF-15 com a predictor precoç de mal pronòstic. En el cas del xoc, en canvi, es segueix un abordatge basat en tècniques de proteòmica per identificar nous biomarcadors i elaborar un model multimarcador que millori l’estimació del risc. Els resultats obtinguts mostren que actualment la pràctica de determinar el pic de troponines no aporta informació pronòstica addicional a l’estratificació basada en la classe Killip i la fracció d’ejecció. Per contra, tant GDF-15 com Stanniocalcina-2 apareixen com a predictors independents de risc amb valor incremental respecte les troponines. Stanniocalcina-2 és un inhibidor de la PAPP-A descobert recentment, del que es descriu el seu valor pronòstic a l’ingrés i es discuteix el mecanisme de la seva elevació a l’infart agut. Per altra banda, GDF-15 mostra un pic d’alliberament precoç en resposta a la inflamació i els seus nivells circulants durant les primeres hores són un robust predictor d’esdeveniments adversos a la fase aguda. A més, les anàlisis en els pacients amb fibril·lació ventricular assenyalen que GDF-15 podria tenir un valor predictiu especialment alt en aquest subgrup i que, en els casos complicats amb coma després d’una aturada cardíaca recuperada, podria ajudar a predir de forma precoç el pronòstic neurològic. Finalment, al xoc cardiogènic, l’estudi de pèptids circulants mitjançant proteòmica ha permès elaborar un model que, combinant els nivells de quatre proteïnes (L-FABP, ALDOB, B2MG i IC1), discrimina els pacients amb alt risc de mortalitat i que, en incorporar-lo a les escales clíniques actuals, augmenta la seva capacitat predictiva. En conclusió, a l’infart agut de miocardi amb elevació del segment ST, els biomarcadors que exploren vies alternatives a la necrosi miocàrdica, com la inflamació i la repercussió sistèmica, poden millorar l’estratificació del risc, especialment quan es combinen amb escales basades en dades clíniques. A més, la utilització conjunta de marcadors que representen diferents vies amb rellevància pronòstica millora el valor predictiu que aquests proporcionen de forma individual. No obstant, encara és necessària més recerca per establir nivells de tall consistents, determinar els models multimarcador més apropiats i avaluar la seva utilitat per guiar decisions clíniques.
Pese a los avances terapéuticos de las últimas décadas, el infarto de miocardio con elevación del segmento ST se asocia a una importante morbimortalidad, especialmente en los casos complicados con fibrilación ventricular o shock cardiogénico. La estratificación pronóstica es determinante para identificar los pacientes de alto riesgo que se pueden beneficiar de tratamientos más agresivos y monitorización más estrecha. Aunque en la práctica clínica actual su uso se limita a la estimación del tamaño del infarto mediante las troponinas cardíacas, los biomarcadores aparecen como una potencial herramienta para mejorar la información que aportan los modelos predictivos disponibles. El objetivo de esta tesis doctoral es estudiar el valor añadido que pueden proporcionar diferentes nuevos biomarcadores respecto los modelos de estimación del riesgo basados en datos clínicos. A partir de una cohorte prospectiva de pacientes con infarto tratados con intervencionismo coronario percutáneo primario, en primer lugar se evalúa la utilidad pronóstica de la determinación seriada de troponinas que se realiza en la actualidad. En segundo, se analiza la fisiopatología y el valor pronóstico de otros biomarcadores que exploran vías alternativas a la necrosis miocárdica: el factor de diferenciación de crecimiento 15 (GDF-15) y el eje Stanniocalcina-2/PAPP-A/IGFBP-4. La última parte del trabajo se centra en los subgrupos de pacientes de más riesgo: los que presentan fibrilación ventricular y shock cardiogénico. En los primeros, se estudia el valor de GDF-15 como predictor precoz de mal pronóstico. En el caso del shock, en cambio, se sigue un abordaje basado en técnicas de proteómica para identificar nuevos biomarcadores y elaborar un modelo multimarcador que mejore la estimación del riesgo. Los resultados obtenidos muestran que actualmente la práctica de determinar el pico de troponinas no aporta información pronóstica adicional a la estratificación basada en la clase Killip y la fracción de eyección. Por el contrario, tanto GDF-15 como Stanniocalcina-2 aparecen como predictores independientes de riesgo con valor incremental respecto las troponinas. Stanniocalcina-2 es un inhibidor de la PAPP-A descubierto recientemente, del que se describe su valor pronóstico al ingreso y se discute el mecanismo de su elevación en el infarto agudo. Por otro lado, GDF-15 muestra un pico de liberación precoz en respuesta a la inflamación y sus niveles circulantes durante las primeras horas son un robusto predictor de eventos adversos durante la fase aguda. Además, los análisis en los pacientes con fibrilación ventricular apuntan que GDF-15 podría tener un valor predictivo especialmente alto en este subgrupo y que, en los casos complicados con coma tras un paro cardíaco recuperado, podría ayudar a predecir de forma precoz el pronóstico neurológico. Finalmente, en el shock cardiogénico, el estudio de péptidos circulantes mediante proteómica ha permitido elaborar un modelo que, combinando los niveles de cuatro proteínas (L-FABP, ALDOB, B2MG i IC1), discrimina los pacientes con alto riesgo de mortalidad y que, al incorporarlo a las escalas clínicas actuales, aumenta su capacidad predictiva. En conclusión, en el infarto agudo de miocardio con elevación del segmento ST, los biomarcadores que exploran vías alternativas a la necrosis miocárdica, como la inflamación y la repercusión sistémica, pueden mejorar la estratificación del riesgo, especialmente cuando se combinan con escalas basadas en datos clínicos. Además, la utilización conjunta de marcadores que representan diferentes vías con relevancia pronóstica mejora el valor predictivo que estos proporcionan de forma individual. No obstante, todavía es necesaria más investigación para establecer puntos de corte consistentes, determinar los modelos multimarcador más apropiados y evaluar su utilidad para guiar decisiones clínicas.
Despite therapeutic advances in recent decades, ST-segment elevation myocardial infarction is still associated with significant morbidity and mortality, especially in cases complicated by ventricular fibrillation or cardiogenic shock. From first medical contact, prognostic stratification is crucial to identify high-risk individuals who may benefit from more aggressive treatments and closer monitoring, both in the acute phase and in subsequent years. In this context, biomarkers appear as a potential tool to improve the prognostic information provided by predictive models based on clinical data. However, despite active research conducted in recent years, biomarkers are underused in clinical practice and remain limited to the estimation of the infarct size using cardiac troponins. The aim of this doctoral thesis is to study the incremental value that different new biomarkers may provide over the conventional risk estimation models applied in clinical practice. Using data from a prospective cohort of patients with acute myocardial infarction treated with primary percutaneous coronary intervention, we first evaluated the prognostic utility of serial measurements of troponins that is currently performed. Second, we analyzed the pathophysiology and prognostic value of other biomarkers exploring alternative pathways to myocardial necrosis: growth differentiation factor 15 (GDF-15) and the Stanniocalcin-2/PAPP-A/IGFBP-4 axis. The last part of the work focuses on the subgroups of patients at higher risk: those with ventricular fibrillation and cardiogenic shock. In the former, the value of GDF-15 was studied as an early predictor of poor prognosis. In the case of shock, a novel proteomics-based approach is used to identify new biomarkers and to develop a multimarker model that improves risk estimation. The results obtained show that, in the contemporary model of care, the estimation of peak troponin levels from serial determinations does not provide additional prognostic information to that offered by a stratification based on the Killip class and the left ventricular ejection fraction. In contrast, both GDF-15 and Stanniocalcin-2 emerge as independent risk predictors with incremental value over troponins. Stanniocalcin-2 is a recently discovered PAPP-A inhibitor whose prognostic value is described here for the first time and, moreover, the mechanism of its elevation in infarction is discussed. On the other hand, GDF-15 shows an early release peak in response to inflammation and its circulating levels during the first hours of infarction are a strong predictor of adverse events in the acute phase. In addition, analyses carried out in patients with ventricular fibrillation indicate that GDF-15 could have a particularly high predictive value in this subgroup and, in cases complicated with coma after resuscitation from a cardiac arrest, it could be useful to an early neurological prognostication. Finally, the most relevant results are those related to the search for new biomarkers in cardiogenic shock by means of proteomics techniques. The proposed model, which combines the levels of four proteins (L-FABP, ALDOB, B2MG and IC1), discriminates patients at high risk of mortality and, when incorporated into the current clinical scales, increases the predictive capacity and reclassifies one quarter of patients. In conclusion, biomarkers exploring alternative pathways to myocardial necrosis, such as inflammation and systemic involvement, may improve risk stratification in ST-segment elevation myocardial infarction, especially when added to clinical data. In addition, the combination of markers representing different pathways with prognostic relevance enhances their individual predictive value. However, before translation into everyday practice, more research is still needed to establish consistent cut-off levels, determine the most appropriate multimarker models, and assess its utility for guiding clinical decisions in randomized trials.

Die Akute Myeloische Leukämie (AML) ist eine sowohl zytogenetisch als auch molekulargenetisch äußerst heterogene Erkrankung, die durch die klonale Proliferation myeloider Vorläuferzellen sowie eine Ausreifungsblockade charakterisiert ist. Trotz des in den letzten Jahren zugenommenen Wissens über die Biologie dieser Erkrankung und Weiterentwicklung von Therapiemethoden bleibt das Gesamtüberleben der Patienten mit AML überwiegend schlecht. Damit für mehr Patienten eine Heilung der AML möglich werden kann, sind ein tieferes Verständnis über die funktionellen Zusammenhänge in der Leukämogenese, eine bessere Risikostratifizierung und neue Therapieoptionen erforderlich. Diese Habilitationsschrift fasst Publikationen zusammen, die neue molekulare Biomarker und deren klinischen Einfluss in der AML untersucht haben. Der Fokus liegt auf der Erfassung molekularbiologischer Veränderungen bei Diagnose einer AML oder im Krankheitsverlauf, die die Risikostratifizierung der Patienten verbessern kann. Außerdem gestattet die Arbeit Einblicke in die mit diesen molekularen Markern verbundene Biologie der AML, sowie mögliche neue Therapieoptionen. Der erste bis dritte Abschnitt der Arbeit fokussiert sich auf Genmutationen und Genexpressionen in der AML. Es wird dargelegt, wie das Vorhandensein bestimmter Fusionstranskripte (hier CBFB-MYH11), rekurrenter Mutationen allein (hier im DNMT3A Gen) sowie als Teil genetischer Risikoklassifikationssysteme (hier die genetischen Risikogruppen des European LeukemiaNet) und die abberrante Expression AML-assoziierter Gene (hier BAALC, ERG und MN1) Beiträge zur Prognoseabschätzung der AML bieten. Darüber hinaus hat sich in den letzten Jahren die entscheidende Rolle von MicroRNAs in der Pathophysiologie der AML herausgestellt. Heute weiß man, dass für die Leukämieentstehung und die Aggressivität der Erkankung schon die Dysregulation einer einzelnen microRNA entscheidend sein kann. Im vierten Abschnitt wird auf den progostischen Einfluss der Expressionslevel zweier MicroRNAs – miR-181a und miR-29b – und deren klinische und biologische Konsequenzen eingegangen. Außerdem wird dargestellt, wie verschiedene therapeutische Interventionen zu günstigen Änderungen des Expressionsniveaus dieser beiden neuen Biomarker und so zu potentiell neuen Therapiestrategien in der AML führen können. Weiterhin wächst die Erkenntnis, dass in der AML so gennannte Leukämie-initiierende Zellen für Therapieresistenz und Rezidive verantwortlich zu sein scheinen. Der letzte Abschnitt dieser Habilitationsschrift fokussiert sich auf das CD34+/CD38- Zellkompartiment, welches einen Großteil der Leukämie-initiiernden Zellen enthält. Es wird gezeigt, dass die Bestimmung der Größe des CD34+/CD38- Zellkompartiments bei Diagnose geeignet ist, AML Patienten mit einem erhöhten Rezidivrisiko nach allogener Stammzelltransplantation zu identifizieren. Zusammenfassend zeigt die Arbeit verschiedene Ansätze, wie neue molekulare Biomarker zu einer besseren Risikostratifizierung und einem tieferen Verständnis der AML zugrunde liegenden Biologie führen können. Des Weiteren beschreibt sie Möglichkeiten der therapeutischen Intervention und weist insgesamt auf die klinischen Implikationen dieser neuen Biomarker hin.

Over 25% of all annual deaths in the world are due to infection. Early diagnosis and risk stratification facilitate timely and specific treatment, but are complicated by the highly variable and non-specific nature of the signs and symptoms of sepsis. There is a lack of a ‘gold standard’ for the diagnosis of infection or sepsis, prognosis of severe infections, and sepsis. There are several biomarkers that have been investigated in literature like white blood count, C-reactive protein, procalcitonin, sTREM1, etc., with equivocal results. White blood count and C-reactive protein are elevated in states of inflammation without infection and sepsis. Therefore, they have low specificities for diagnosis of infection. The future is promising with development of high sensitivity assays, molecular strategies, and a ‘panel approach’, all of which need to be investigated in well-designed future studies. At present, there is insufficient evidence for the routine use of novel biomarkers in infection and sepsis.

The prognosis of acute kidney injury (AKI) depends on early diagnosis and therapy. A multitude of causes are classified according to their origin as prerenal, intrinsic (intrarenal), and post-renal.Prerenal AKI means a loss of renal function despite intact nephrons, for example, because of volume depletion and/or hypotension.There is a broad spectrum of intrinsic causes of AKI including acute tubular necrosis (ATN), interstitial nephritis, glomerulonephritis, and vasculitis. Evaluation includes careful review of the patient’s history, physical examination, urinalysis, selected urine chemistries, imaging of the urinary tree, and eventual kidney biopsy. The history should focus on the tempo of loss of function (if known), associated systemic diseases, and symptoms related to the urinary tract (especially those that suggest obstruction). In addition, a review of the medications looking for potentially nephrotoxic drugs is essential. The physical examination is directed towards the identification of findings of a systemic disease and a detailed assessment of the patient’s haemodynamic status. This latter goal may require invasive monitoring, especially in the oliguric patient with conflicting clinical findings, where the physical examination has limited accuracy.Excluding urinary tract obstruction is necessary in all cases and may be established easily by renal ultrasound.Distinction between the two most common causes of AKI (prerenal AKI and ATN) is sometimes difficult, especially because the clinical examination is often misleading in the setting of mild volume depletion or overload. Urinary chemistries, like calculation of the fractional excretion of sodium (FENa), may be used to help in this distinction. In contrast to FENa, the fractional excretion of urea has the advantage of being rather independent of diuretic therapy. Response to fluid repletion is still regarded as the gold standard in the differentiation between prerenal and intrinsic AKI. Return of renal function to baseline or resuming of diuresis within 24 to 72 hours is considered to indicate ‘transient, mostly prerenal AKI’, whereas persistent renal failure usually indicates intrinsic disease. Transient AKI may, however, also occur in short-lived ATN. Furthermore, rapid fluid application is contraindicated in a substantial number of patients, such as those with congestive heart failure.‘Muddy brown’ casts and/or tubular epithelial cell casts in the urine sediment are typically seen in patients with ATN. Their presence is an important tool in the distinction between ATN and prerenal AKI, which is characterized by a normal sediment, or by occasional hyaline casts. There is a possible role for new serum and/or urinary biomarkers in the diagnosis and prognosis of the patient with AKI, including the differential diagnosis between pre-renal AKI and ATN. Further studies are needed before their routine determination can be recommended.When a diagnosis cannot be made with reasonable certainty through this evaluation, renal biopsy should be considered; when intrarenal causes such as crescentic glomerulonephritis or vasculitis are suspected, immediate biopsy to avoid delay in the initiation of therapy is mandatory.

Age-related Macular Degeneration (AMD) is an acquired retina disease that can potentially cause significant central visual impairment. Optical coherence tomography (OCT) applied to the study of retinal pathologies has revolutionized the understanding and management of AMD, especially with the technology of full-depth imaging (FDI) Spectral Domain (SD) OCT. With the increasing amount of data from several important studies using SD-OCT and OCT-angiography (OCT-A) we can now better classify and more accurately decode AMD. The purpose of this chapter is to describe the most important AMD biomarkers recently discovered using SD OCT. Understanding AMD phenotype is very important to define prognosis and individualized forms of treatment and follow up. Biomarkers on OCT have been crucial for a better understanding of AMD.

Advances in quantitative structural, functional, and molecular neuroimaging have provided new tools for objective, in vivo, assessment of critical aspects of Alzheimer’s disease and other neurodegenerative disorders. Measures of brain atrophy or brain dysfunction, coupled with measures of disease-linked pathology, might complement the history, physical and neurocognitive evaluation of patients and thereby improve predictive prognosis, especially at early stages of cognitive impairment where neurodegenerative etiology is less certain. Such imaging biomarkers are currently used in nearly all clinical trials of therapeutic agents for Alzheimer’s disease and are increasingly incorporated into clinical practice. In this chapter, imaging biomarkers are introduced and discussed to familiarize the reader with their potential research and clinical uses.

Oral Cancer is one of the most common malignancies of the head and neck region. Despite technological advancements and improvements in Oral cancer diagnosis and treatment modalities, the 5-year survival rate remains low and is associated with poor prognosis and high mortality rate especially when detected at a later stage. The empirical therapy followed for the treatment of oral cancer includes surgery, radiotherapy and chemotherapy. The treatments are not equally efficacious for all patients, are associated with side effects and poor prognosis. The need of the hour is early diagnosis and tailored treatment therapies for individual patients. With the advent of immunotherapy, the cancer treatment has moved toward personalised precision medicine which tailors’ treatments to each individual. Personalised precision medicine incorporates, molecular profiling of tumours with OMICS technology, biomarkers and companion diagnostics to build databases of patients and devise tailor made treatment approaches for individual patients. This article discusses the role of precision medicine in OSCC prevention, detection, and management by reviewing our understanding of OC from both genetic and OMICS perspectives.