Marker For Identification Of Patients Research Articles

Clinical and molecular risk factors in extracranial malignant rhabdoid tumors - Towards an integrated model of high-risk tumors.

Extracranial malignant rhabdoid tumors (eMRT) are a challenging entity. Despite the use of multimodal treatment approaches, therapy failure occurs in 55-67%. Molecular markers for identification of patients at increased risk for relapse or refractory (R/R) disease are not available. Clinical characteristics may only insufficiently predict the individual course of disease. Using the EU-RHAB database, we analyzed a cohort of 121 patients with eMRT clinically. For 81 patients, molecular and clinical data was available, which was complemented with publicly available DNA molecular data from 92 further eMRT. We aimed to delineate molecular risk factors by dissecting the DNA methylome of these tumors. Moreover, we establish clinical characteristics and treatment details of R/R disease in a subcohort of 80 patients. Using consensus hierarchical clustering, we identified three distinct subgroups, one of which (eMRT standard risk) was associated with significantly improved survival, irrespective of germline status and/or localization. At the transcriptome level, this subgroup is characterized by an overexpression of genes involved in muscle development. A relevant proportion of patients develop distant relapses or progressions; median time to the event was four months, underlining the need for early identification and risk-stratification of R/R disease. Overall survival was significantly decreased in patients with progressive disease when compared to relapse cases and reaching complete remission during salvage therapy provided a survival benefit. Our analysis of eMRT in this comprehensive cohort provides novel insights into the patterns of relapse and integrates molecular and clinical risk factors to guide clinical decision making.

Odor identification and discrimination as markers of early Alzheimer’s disease

AbstractBackgroundReliable markers are essential in order to achieve accurate diagnosis in the early stages of Alzheimer’s disease (AD). Olfactory impairment has been identified as a possible non‐invasive biomarker of AD. Odor identification tasks are most commonly used for measuring olfactory abilities. However, odor identification is associated to verbal abilities and cultural context. The aim of this study was to determine whether odor discrimination could be a valid marker of early AD.Method65 participants were enrolled in the study. 26 patients with mild cognitive impairment due to AD (MCI‐AD), 26 patients with mild dementia due to AD (MD‐AD) and 13 cognitively normal elderly subjects (CN). All participants underwent cognitive examination (MMSE, CDR, ADAS‐Cog 13, fluency tests) and olfactory function assessment (Burghart Sniffin’ Sticks odor identification and odor discrimination tests).ResultMD‐AD and MCI‐AD subjects performed significantly worse than CN subjects in both odor identification (mean correct responses ± SD was 6.77±1.91; 9.08±2.30; 13.31±1.55 respectively; p<0.001) and odor discrimination (mean correct responses ± SD was 6.27±1.66; 8.19±1.65; 12.92±1.71 respectively; p<0.001) tests. MD‐AD subjects performed significantly worse than MCI‐AD subjects in both odor identification (p<0.05) and odor discrimination (p<0.001) tests.Both odor identification and odor discrimination tests had AUC>0.9 on ROC analysis for differentiating MCI‐AD subjects from CN subjects (AUC 0.938 and 0.982) and for differentiating MD‐AD subjects from CN subjects (AUC 0.99 for both). Neither odor identification, nor odor discrimination test reached AUC>0.8 on ROC analysis for differentiating MCI‐AD from MD‐AD subjects (AUC 0.777 and 0.793).Odor identification differentiated MCI‐AD from CN subjects with sensitivity of 69% and specificity of 100% at cut‐off score of ≤10 correct responses. Odor discrimination differentiated MCI‐AD from CN subjects with sensitivity of 77% and specificity of 100% at cut‐off score of ≤9 correct responses.ConclusionThe study confirmed that tests for olfactory dysfunction can reliably differentiate patients with mild cognitive impairment due to AD from cognitively normal subjects. Both odor identification and discrimination are reliable markers for identification of patients with early Alzheimer’s disease.

Single nucleotide polymorphisms and the risk of developing a second primary cancer among head and neck cancer patients: a systematic literature review and meta-analysis

BackgroundHead and Neck Cancer (HNC) survivors are at increased risk of developing a second primary cancer (SPC). Along with the environmental risk factors, genetic factors have been associated with a potential increased susceptibility to SPC development. We aim to identify the Single Nucleotide Polymorphisms (SNPs) that contribute to SPC development among HNC survivors through a systematic review and meta-analysis.MethodsWe searched PubMed, Scopus and ISI Web of Science for eligible studies published in English until January 31st, 2020. We included studies reporting primary data that evaluated the association between SNPs and SPC risk in HNC patients. Data were pooled in a random-effect meta-analyses, when at least two studies on the same SNP evaluated the same genotype model. Heterogeneity was assessed using the χ2-based Q-statistics and the I2 statistics. Quality of the included studies was assessed using the Q-Genie tool.ResultsTwenty-one studies, of moderate to good quality, were included in the systematic review. Fifty-one genes were reported across the included studies to have significant associations with an increased SPC risk. Overall, 81 out of 122 investigated SNPs were significantly associated with the SPC risk. Seven studies were included in the meta-analysis, which showed five SNPs associated with an increased risk of SPC: p21C70T, CT + TT (HR = 1.76; 95% CI: 1.28–2.43); FASLG -844C > T, CT + TT (HR = 1.82; 95% CI: 1.35–2.46), P21 C98A, CA + AA (HR = 1.75; 95% CI: 1.28–2.38); FAS -670A > G (HR = 1.84; 95% CI: 1.28–2.66) and GST-M1, Null genotype (HR = 1.54; 95% CI: 1.13–2.10).ConclusionsThe identified SNPs in our systematic review and meta-analysis might serve as potential markers for identification of patients at high risk of developing SPC after primary HNC.PROSPERO Registration NumberCRD42019135612.

Reticulated Platelets as Predictor of Myocardial Injury and 30 Day Mortality After Non-cardiac Surgery.

A pre-operative marker for identification of patients at risk of peri-operative adverse events and 30 day mortality might be the percentage of young, reticulated platelets (pRP). This study aimed to determine the predictive value of pre-operative pRP on post-operative myocardial injury (PMI) and 30 day mortality, in patients aged≥60 years undergoing moderate to high risk non-cardiac surgery. The incidence of PMI (troponin I>0.06μg/L) and 30 day mortality was compared for patients with normal and high pRP (≥2.82%) obtained from The Utrecht Patient Orientated Database. The predictive pRP value was assessed using logistic regression. A prediction model for PMI or 30 day mortality with known risk factors was compared with a model including increased pRP using the area under the receiving operator characteristics curve (AUROC). In total, 26.5% (607/2289) patients showed pre-operative increased pRP. Increased pRP was associated with more PMI and 30 day mortality compared with normal pRP (36.1% vs. 28.3%, p<.001 and 8.6% vs. 3.6%, p<.001). The median pRP was higher in patients suffering PMI and 30 day mortality compared with not (2.21 [IQR: 1.57-3.11] vs. 2.07 [IQR: 1.52-1.78], p=.002, and 2.63 [IQR: 1.76-4.15] vs. 2.09 [IQR: 1.52-3.98], p<.001). pRP was independently related to PMI (OR: 1.28 [95% CI: 1.04-1.59], p=.02) and 30 day mortality (OR: 2.35 [95% CI: 1.56-3.55], p<.001). Adding increased pRP to the predictive model of PMI or 30 day mortality did not increase the AUROC 0.71 vs. 0.72, and 0.80 vs. 0.81. In patients undergoing major non-cardiac surgery, increased pre-operative pRP is related to 30 day mortality and PMI.

Karyopherin α-2 is a reliable marker for identification of patients with high-risk stage II colorectal cancer.

Adjuvant chemotherapy (AC) is frequently considered in patients with high-risk stage II colorectal cancer (CRC). Among patients with stage II CRC who do not receive AC because they are not considered to be at high risk, 20-25% will develop recurrence and die from the disease. Elevated levels of KPNA2 have been observed in various cancers, and overexpression of KPNA2 is related to CRC progression. We examined the expression of KPNA2 using 293 CRC tissues, including 118 with stage II CRC, and investigated the applicability of KPNA2 as a biomarker to predict high-risk stage II CRC. Moreover, we further investigated the role of KPNA2 as an oncogene in CRC carcinogenesis using in vitro functional studies. High KPNA2 expression was associated with vascular (p=0.027) and lymphatic invasion (p=0.009) in patients with stage II CRC. On multivariate analysis, high KPNA2 expression (HR 3.174, 95% CI 2.060-4.889; p<0.001) was independently associated with survival in patients with CRC. The overall survival rate in patients with high KPNA2 expression was higher than that in patients with low KPNA2 expression in CRC (p<0.001), even in patients with stage II CRC (p=0.001). Additionally, KPNA2 was associated with tumorigenesis and cancer progression in CRC cells; high KPNA2 expression was associated with increased cell proliferation (p<0.05), migration (p=0.03), invasion (p=0.001), and semisolid agar colony formation (p<0.001). KPNA2 expression is useful for identification of patients with high-risk stage II CRC who could benefit from AC and that KPNA2 may also be a promising therapeutic target.

Diurnal Cortisol and Functional Outcomes in Post-Acute Rehabilitation Patients

Cortisol is a stress-related hormone with a robust circadian rhythm where levels typically peak in the morning hours and decline across the day. Although acute cortisol increases resulting from stressors are adaptive, chronic elevated cortisol levels are associated with poor functioning. Studies have shown age-related changes in cortisol levels. The present study investigated the relationship between salivary diurnal cortisol and functional outcomes among older adults undergoing inpatient post-acute rehabilitation. Thirty-two older adults (mean age 78 years; 84% men) in a Veterans Administration inpatient post-acute rehabilitation unit were studied. Functional outcomes were assessed with the motor component of the Functional Independence Measure (mFIM; where mFIM change = discharge - admission score). Saliva samples were collected on 1 day at wake time, 45 minutes later, 11:30 AM, 2 PM, 4:30 PM, and bedtime. We analyzed the relationship between cortisol measures and functional outcomes, demographics, and health measures. The analyses consistently showed that greater functional improvement (mFIM change) from admission to discharge was associated with lower comorbidity scores and higher cortisol levels at 2 PM, 4:30 PM, and bedtime. A morning cortisol rise was also associated with greater mFIM change. Measurement of cortisol in saliva may be a useful biological marker for identification of patients who are "at risk" of lower benefits from inpatient rehabilitation services and who may require additional assistance or intervention during their post-acute care stay.

The TP53 gene polymorphisms and survival of sporadic breast cancer patients

The TP53 gene polymorphisms, Arg72Pro and PIN3 (+16 bp), can have prognostic and predictive value in different cancers including breast cancer. The aim of the present study is to investigate a potential association between different genotypes of these polymorphisms and clinicopathological variables with survival of breast cancer patients in Croatian population. Ninety-four women with sporadic breast cancer were retrospectively analyzed. Median follow-up period was 67.9 months. The effects of basic clinical and histopathological characteristics of tumor on survival were tested by Cox's proportional hazards regression analysis. The TNM stage was associated with overall survival by Kaplan-Meier analysis, univariate, and multivariate Cox's proportional hazards regression analysis, while grade was associated with survival by Kaplan-Meier analysis and univariate Cox's proportional hazards regression analysis. Different genotypes of the Arg72Pro and PIN3 (+16 bp) polymorphisms had no significant impact on survival in breast cancer patients. However, in subgroup of patients treated with chemotherapy without anthracycline, the A2A2 genotype of the PIN3 (+16 bp) polymorphism was associated with poorer overall survival than other genotypes by Kaplan-Meier analysis (P = 0.048). The TP53 polymorphisms, Arg72Pro and PIN3 (+16 bp), had no impact on survival in unselected sporadic breast cancer patients in Croatian population. However, the results support the role of the A2A2 genotype of the PIN3 (+16 bp) polymorphism as a marker for identification of patients that may benefit from anthracycline-containing chemotherapy.

B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients*

In early stages of septic shock, impaired myocardial function plays an important prognostic role. In this context, B-type natriuretic peptide (BNP) has been shown to be a neurohumoral marker for left ventricular dysfunction, because myocardial strain and ischemia both increase BNP concentration. The present study was designed to test if BNP allows for identification of patients at risk for developing sepsis-induced myocardial depression and if an increased concentration of BNP is associated with an adverse outcome in patients with septic shock. In a prospective study, 93 patients with septic shock were divided into one group with normal ventricular function (left ventricular ejection fraction >50%) on days 3 to 5 (n = 38) and another group of patients with impaired left ventricular function (left ventricular ejection fraction <50%) on days 3 to 5 (n = 55). Patients with impaired left ventricular function had an increased median plasma BNP concentration on day 5 (699 [608 of 795.5] pg/nL vs. 86 [71.3 of 93] pg/nL) and an ejection fraction of 38 +/- 6% on day 5 vs. 58 +/- 7% in patients without impaired left ventricular function. There was a close inverse relation between increased plasma BNP concentrations and depressed left ventricular ejection fraction (p < 0.05). BNP measured at days 3 and 5 revealed an association with the end point of survival. In the proportional hazards regression model adjusted for age, male gender, and creatinine concentration, measured at days 0, 3, 5, and 12, BNP concentration at day 5 showed an increased hazard for reaching the end point (hazard ratio: 1.407; 95% confidence interval: 1.033-1.916; p = 0.030). In an additional receiver operating characteristic curve analysis, the predictive value of a model including cardiovascular risk factors and additional BNP concentration on day 5, compared with a baseline model of cardiovascular risk factors, improved the area under the curve the most; therefore, this model was suited best for prediction of sepsis-induced myocardial depression and 30-day survival for patients with septic shock. Area under the curve of this model combined with BNP concentration at day 5 for death after 30 days (0.65) impaired left ventricular ejection fraction (0.94) and sepsis-induced myocardial depression (0.96). These results indicate that plasma BNP concentration represents a reliable marker for identification of patients developing sepsis-induced myocardial depression. In addition, BNP concentration on day 5 may be used as a prognostic marker to identify patients with an elevated risk for an adverse outcome.

Role of N-Terminal Pro-B-Type Natriuretic Peptide in Risk Stratification in Patients Presenting in the Emergency Room

Natriuretic peptides are promising markers in diagnosing acute and chronic heart failure and assessing prognosis in these patients. Increasing routine use to unselected patients is challenged by false-positive results. The aims of this study were to assess (a) the distributions of N-terminal B-type natriuretic peptide (NT-proBNP) values in various diagnostic groups, (b) factors that influence NT-proBNP, and (c) the value of NT-proBNP in risk stratification in unselected emergency room (ER) patients. NT-proBNP was measured in 876 unselected consecutive patients [mean (SD) age, 58 (18) years; 53% male] attending the ERs of 2 university hospitals and 1 community hospital. Diagnoses, age, sex, hemoglobin, creatinine (CREA), C-reactive protein (CRP), troponin T, and intensity of care were documented. In a subset consisting of all 417 patients at 1 center, in-hospital follow-up was completed with respect to a complicated clinical course, including intensive care treatment and death. NT-proBNP was significantly increased in patients with cardiac diagnoses or histories compared with patients with only pulmonary or other diagnoses. In patients with other diagnoses, NT-proBNP values increased significantly with the number of atherosclerotic risk factors (P=0.044). Age, renal function, CRP, and to a much lesser extent, hemoglobin significantly influenced NT-proBNP values. The amount of care was positively correlated with NT-proBNP (P<0.001). Classification and regression tree analysis showed a superior impact of NT-proBNP for identification of high-risk patients. NT-proBNP is a promising marker for identification of patients with structural heart disease in the ER and a suitable tool for risk stratification. Its use in the ER should be limited to clearly clinically defined patient groups at present to avoid a potential excess of additional diagnostic procedures in positive but asymptomatic patients.

Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas.

Thymidine kinase 1 (TK1), an enzyme involved in the synthesis of precursors for DNA, and thus proliferation dependent, has been suggested as a good tumour marker. We have recently developed poly/monoclonal antibodies against TK1, which proved useful for diagnostics in both serum and immunohistochemistry of cancer patients. The anti-TK1 monoclonal antibodies (mAbs) 1D11 and 1E3 were characterized by Western blot, immunoprecipitation and flow cytometry. TK1 mAbs and Ki-67 mAb were then used for immunohistochemistry staining of tumour sections from 54 patients with ductal infiltrated breast carcinoma. Results showed the relative number of patients with positively stained tumours for TK1 (mAb 1D11) and for Ki-67 (mAb MIB-1) were 47 and 41%, respectively, significantly related (p=0.007). Combination of TK1 mAbs 1D11 and 1E3 increased this number to 56%, due to detection of a significantly higher number of patients with grade 2 tumours. Patients with stage II and grade 2 tumours showed significantly higher TK1 staining when compared to stage I and grade 1. Ki-67 staining was significantly higher in stage III and grade 3. The tumours only stained for TK1 represented higher stages and grades, while tumours staining only for Ki-67 were of lower stages and grades. Combining TK1 and Ki-67 increased the number of patients with positively stained tumours to 69%. In conclusion, TK1 is a reliable marker for identification of patients with grade 2 tumours. The highest number of patients with positively stained tumours were obtained when both TK1 and Ki-67 markers were used.

Luteinizing hormone in peritoneal and ovarian cyst fluids: a predictor of ovarian carcinoma

Objective: The aim of this study was to define the role of luteinizing hormone (LH) as a tumor marker, specific for ovarian cancer. Methods: The study included 34 women with functional and benign ovarian cysts, 11 women with borderline ovarian tumors, 22 patients with advanced ovarian cancer and 15 patients with non-ovarian intraperitoneal malignancies. Serum, peritoneal fluid and ovarian cyst aspirates were obtained intraoperatively (laparoscopy or laparotomy) and were subjected to the LH analysis. Results: Peritoneal fluid LH levels were significantly increased in patients with ovarian cancer and those with borderline ovarian tumors as compared to patients with functional and benign ovarian cysts ( P=0.005 and P=0.007, respectively). The patients with non-ovarian malignancies demonstrated the same peritoneal fluid LH levels as patients with benign ovarian tumors. There was no significant difference in the level of peritoneal fluid LH between ovarian cancer patients with and without ascites. The patients with functional and benign ovarian cysts demonstrated also significantly lower cyst fluid LH levels as compared to patients with malignant and borderline ovarian cysts ( P=0.01 and P=0.03, respectively). Peritoneal and ovarian cyst fluid levels of LH were significantly increased in patients with fibrothecomas as compared to patients with other benign ovarian cysts. There were no significant differences in the serum LH levels comparing patients from all study groups. Conclusion: LH, detectable in peritoneal and ovarian cyst fluids, can be used as a tumor marker for identification of patients with borderline and malignant ovarian tumors.

Síndrome de Cowden: relato de um caso

A síndrome de Cowden (SC) ou síndrome de múltiplos hamartomas (SMH) é genodermatose rara de herança autossômica dominante e expressividade variável. É caracterizada por múltiplas lesões hamartomatosas de origem ectodérmica , mesodérmica e endodérmica. O órgão mais acometido é a pele, e as lesões mucocutâneas estão presentes em proporção que varia de 99 a 100% dos casos. Esses sinais precedem o desenvolvimento do câncer em vários anos, servindo como importantes marcadores clínicos na identificação de pacientes com alto rico para desenvolver câncer da mama e tireóide. Devido a associações com malignidades internas o diagnóstico precoce é essencial. O locus gênico para SC foi identificado no cromossomo 10q22-23. As mutações no gene supressor tumoral, PTEN/MMAC1, localizado no cromossomo 10q23, têm sido implicadas no desenvolvimento do câncer mamário. Os autores relatam um caso dessa rara entidade. Trata-se de paciente do sexo masculino com quadro clínico característico dessa síndrome.

Noninvasive risk stratification in inherited arrhythmias

Electrocardiographic risk stratification of patients with inherited arrhythmopathies, such as the long-QT syndrome and Brugada syndrome, is unsatisfactory at present. Changes in ventricular depolarization and repolarization as well as autonomic triggers play a pivotal role in the genesis of malignant tachyarrhythmias in these disorders. However, only sparse data are available regarding the usefulness of autonomic or repolarization markers for identification of patients at potential risk of sudden arrhythmogenic death. Whereas the duration of the QT interval as well as analysis of dispersion of repolarization have been used to risk stratify LQTS patients, analysis of ventricular late potentials seems to be promising in patients with Brugada syndrome. With respect to autonomic risk markers, there are currently not enough data to generally justify their use in either of the two entities. More research is necessary to improve risk stratification in phenotypically "silent" gene carriers.