Tumor markers: chemistry, diagnostic utility and prognostic significance: a review

According to National Cancer Institute [NCI-NIH-USA], tumor markers are substances that are produced by cancer or by other cells of the body in response to cancer or certain benign [noncancerous] conditions. Most tumor markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumor tissue, or other tissues or bodily fluids of some patients with cancer1. Most tumor markers are proteins. However, more recently, patterns of and changes to DNA have also begun to be used as tumor markers. Markers of the latter type are assessed in tumor tissue specifically

A detailed information available on the website of NCI-NIH that so far more than 20 different tumor markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. There is no "universal" tumor marker that can detect any type of cancer [NCI-NIH-USA, accessed 3/13/2013]

There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumor marker associated with that cancer. Moreover, tumor markers have not been identified for every type of cancer [1, NCI-NIH-USA, accessed 3/13/2013]. The present review details the chemistry, structure, diagnostic and prognostic utilities of 7 tumor makers including CA 27.29, CEA, CA 19.9, AFP, CA 125, PSA and CA 15-3 for current information and upgrading regarding its usefulness and significance in disease evaluation, progression and treatments. The information provided below gathered mainly through PubMed search engine of nearly 300 articles from year 2000 to 2013, Wikipedia, cancer related sites and American Family Physician journal [2003/vol 68,, Perkins et al. , 2003]

Assessment of sub-clinical hypothyroidism and hyperthyroidism status in adult patients

Generally sub-clinical hypothyroidism and hyperthyroidism are diagnosed on the basis of laboratory evaluation and mostly such patients' manifest with mild or devoid of any clinical signs or symptoms. It is known to be a common disorder, also refer to as sub-clinical thyroid disease particularly in middle-aged and elderly individuals. Moreover, it is reported that most patients who were found to have sub-clinical hyperthyroidism depicts TSH values between 0.1 to 0.45 micro IU/L and those with sub clinical hypothyroidism between 4.5 to 10 micro IU/L. In this respect, studies were carried out during January 2006-Dec 2007 in 230 adult patients [98 males, 132 females] for evaluation of sub-clinical thyroid disease. TSH and thyroid hormones [T3 T4, FT3 and FT4] levels of all patients were determined by standard methods to assess the extent of the sub-clinical status. In female group which comprised of 132 patients, a total of n =28 [21.20%] exhibited sub-clinical thyroid disorders [n = 18; 13.63% Sub-clinical hypothyroidism, n=10; 7.57% sub-clinical hyperthyroidism], whereas 59 [44.69%] exhibited true-thyroid disorder. Subsequent assessment in males shows that out of 98 patients; n = 15 patients [15.30%] showed sub-clinical thyroid disorders [n = 9; 9.18% sub-clinical hypothyroidism; n = 6; 6.12% sub-clinical hyperthyroidism], whereas 20 [20.40%] without any sub-clinical or true thyroid disease, respectively and thus presented as normal. It is concluded that sub-clinical thyroid dysfunction prevails in females with 12.17% occurrence whereas 6.52% in males. Furthermore, the evaluation and subsequent review of existing literature and reports, it is also advisable that routine screening for thyroid disease through clinical investigations aided with lab findings be promoted, especially in pregnant women

Evaluation of urinary protein to creatinine ratio as a predictor of end-stage renal disease

To evaluate the role of urinary protein to creatinine [P:C] ratio as a predictor of end-stage renal disease [ESRD] in renal failure patients. This study was conducted at Liaquat National Medical College and Hospital, Karachi from Jan-Dec 2006 on 121 patients [77 males, 44 females] with acute renal failure [ARF] and chronic renal failure [CRF]. Clinical history, relevant investigations, renal status, dialysis routine and frequency were recorded. Random Urine samples [single void] were collected and the P:C ratio were calculated. Out of 121 patients, 21 patients developed ESRD including 16 males [12 CRF, 4 ARF] and 5 females [all CRF]. Statistical analyses shows no significant difference between sum of P:C ratio of CRF and ARF patients. However moderate significance [P < 0.05] was noted among P:C ratio of ESRD patients when compared with males CRF and ARF groups. Similarly, female groups also showed non-significant difference, whereas ESRD patients [FCES], depicts moderate [P < 0.05] significance when compared with female CRF and ARF groups. P:C ratio of males and females ESRD groups showed no significance difference. Mean P:C ratio in male CRF end stage category was 4.12 +/- 0.82 [range 2.5 - 9.1] where as in male ARF end stage 3.78 +/- 1.67 [range 1.80- 7.12]. Mean P:C ratio in female CRF end stage category was 3.94 +/- 0.79 [range 1.76 - 5.98]. Patients with > 1.0 of P:C ratio has developed ESRD. Higher the ratio of P:C, the more was risk of deterioration of clinical condition

Comparative study of postprandial hypertriglyceridemia in diabetic patients with occurrence of microalbuminuria

It has been demonstrated that Type 2 Diabetes Mellitus [T2DM] patients, with the presence of microalbuminuria [MA] had higher postprandial triglyceride than those without MA. The present study further investigates this potential association and to elaborate the degree of dependence of T2DM with MA condition on onset of high postprandial [PP] triglyceridemia in our setting. A total of 32 patients with T2DM were included in the study during February 2007 and December 2008 and were divided into two groups according to the presence [n = 15, MA+ve] or absence of MA [n=l 7, MA-ve]. Blood was drawn in the fasting state and at 2 and 6 h after the standard mixed breakfast test meal for biochemical analysts. Plasma ApoA, triglycerides, glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, creatinine and Glycosylated hemoglobin Ale [HbAlc] levels were determined using standard methods. 24 hr albumin and urinary micro albumin showed highly significant difference [P<0.001] in values in MA-ve and MA+ve groups, whereas glycosylated HbAlc and duration of T2DM doesn't exhibit any significant difference. Biochemical constituents such as glucose, total cholesterol and HDL-cholesterol exhibited mild [P<0.05] to moderate [P<0.01] significance when compared within the groups of MA-ve and MA +ve patients in fasting and postprandial conditions. Comparatively highest level of constantly significant difference in values was noted only in triglycerides when MA +ve were compared with MA-ve, which remains high not only at 2 hrs. Postprandial [P<0.001] but also after 6 hrs. Under same conditions [P<0.001]. The data strongly support the theory and observations that in patients with T2DM and co-existence of MA, hypertriglyceridemia prevails, which further complicates the already co-morbid hyperlipidemic state in these patients

Diagnostic utility of Amino-terminal pro-B type natriuretic peptide [NT pro BNP] in adult patients with chronic kidney diseases

In recent studies, suggestions were made that the diagnostic utility of Amino-terminal pro-B type natriuretic peptide [NT-proBNP] a known biomarkers of myocardial dysfunction, be extended to chronic kidney disease [CKD] patients that are devoid of any cardiovascular abnormalities or disease, however may develop same in future. The goal of present study was to further evaluate the relationship between CKD and NT-proBNP concentration in patients with varying levels of renal dysfunction including End Stage Renal Disease [ESRD]. Stable adult patients of both gender [n = 76] with CKD were included in the study during January 2007 to September 2008, who had been on hemodialysis [HD]. The patients were divided into two groups depending on Left ventricular ejection fraction [EF]<50%. Other parameters such as mean arterial pressure [MAP], NT proBNP and biochemical parameters were measured using standard procedures. The result strongly presents a correlation between of NT-proBNP levels in CKD patients, who were without a definite onset of LVD. Furthermore, NT pro-BNP significantly correlated with an elevated protein to creatinine ratio and blood urea nitrogen [P < 0.01] suggesting that onset and presence of CKD influenced the concentration of natriuretic peptides. The present study regarding assessment of NT proBNP in CKD patients, provide evidence that renal dysfunction and natriuretic peptides, especially NT-proBNP are correlated with each other. In addition, further prospective studies are underway to validate and better define this relationship

Diagnostic utility and Assessment of C - reactive protein [CRP] in patients with community acquired pneumonia

It has been researched and agreed upon that pneumonia elicits a powerful inflammatory response with the release of inflammatory mediators or biomarkers, such as acute-phase proteins, inteleukin-6 and C-reactive protein [CRP] from activated mononuclear phagocyte cells. It is also known and recommended that the early analysis of serum concentrations of CRP is a significant tool for the diagnosis and monitoring of different acute inflammatory processes. Community-acquired pneumonia [CAP] is documented to be the major cause of death in the western world and effects increasing number of population annually. In present study we have investigated the suggested usefulness of serum CRP levels in patients with CAP at the time of diagnosis and compared it with CRP of healthy controls. One hundred and seventy one [n = 171] patients were included in the study and classified according to presence of pathogens/ etiology in individual capacity as well as in combination with other organisms. All microbiological assays were performed according to standardized procedures, whereas CRP was measured in serum samples by an automated turbid metric method with normal reference of

Diagnostic importance of C-reactive protein [CRP] analysis in tuberculosis pleural effusions

One of the acute-phase biomarkers that have recently been investigated for its clinical utility in tuberculosis pleural effusion is C-reactive protein [CRP] which has already been commonly used as a marker of inflammation and tissue injury. Therefore, the present study was undertaken to analyze the viability of CRP as a diagnostic aid for tuberculosis in lymphocytic pleural effusions. Fifty two [n = 52] patients with lymphocytic pleural effusion with definite diagnosis of a disease condition, were taken into the test group and classified into no tuberculosis [n = 28] group and tuberculosis pleurisy group where sputum culture was positive for Mycobacterium tuberculosis in pleural effusion [n = 24]. CRP in pleural fluid was analyzed by automated turbid metric immunoassay method as per description of the manufacturer and normal reference value in serum is

Evaluation of vitamin B12 and folic acid deficiencies in selective middle aged and elderly male and female patients

Significant prevalence of vitamin B12 and folate deficiencies supported by biochemical evidence has been reported in the world. It was indicated that these biochemical evidences are associated with prevalence of anaemia in elderly. The major reasons of vitamin deficiencies, especially that of B-12, was reported to be inadequate dietary intake and, in the elderly, malabsorption of the vitamin from food. Vitamin deficiencies especially that of B-12 are usually diagnosed on the basis of serum or plasma vitamin concentrations. Due to dilemma of management and diagnoses of mal-nutrition and vitamin deficiencies in elderly population, the present study was undertaken to ascertain vitamin B12, folate and RBC folate status in selected middle aged and elderly male and female patients. A total of 132 patients [period March 2004 to November 2007], were selected according to gender and age. For males [n = 72]; age groups were 50-60, 61-70, 71-80 yrs and greater than 80 yrs and for females [n = 60]; age groups were 52-61, 62-69, 70-79 and greater than 80 yrs. The results clearly depicts that elderly patients in both gender between the age groups of 71 and greater than 80 had significantly low vitamin concentrations [p < 0.001] than the middle age groups of 61 to 70 [P < 0.01]. Correspondingly, their hemoglobin levels were also relates to the overall picture of either normal or low concentrations of vitamins in all groups. In males the lowest concentration of 3.5 ng/ml for folate, Vitamin B12 of 228 pg/ml and 168 ng/ml for RBC folate were observed in > 80 years group preceded by 6.2 ng/ml, 278 pg/ml and 170 ng/ml respectively, in 71 to 80 years group, whereas in females, the observations were 2.5 ng/ml for folate, 220 pg/ml for B12 and 110 ng/ml for RBC folate concentrations in > 80 years age group of patients. In conclusion few management strategies were suggested for therapy of vitamin deficient older patients

Assessment of lipoprotein abnormalities in diabetic and non-diabetic patients with hyperlipidemia

Background: Hyperlipoproteinaemia is a metabolic abnormal condition and is largely regulated by Apolipoproteins types and subtypes. Moreover, lipoprotein abnormalities contribute significantly to the risk of developing cardio vascular disease and diabetes. Additionally, abnormal glycemic state, lipid and lipoprotein abnormalities have also been shown to contribute in early atherosclerosis

Objectives: Our present study evaluates the status of apolipo-protein A and B in hyperlipidemic patients with both diabetic and non-diabetic conditions

Methods: Study period was May 2006 to Dec 2007. 63 patients of both gender [males = 36, females = 27] sub-grouped as n = 46 non-diabetic hyperlipidemic [NDHL] and n = 17 diabetic hyperlipidemic [DHL] patients were included in the study. All parameters were determined with standard methods on IVD instruments with recommended pathological and normal controls

Results: Total cholesterol and Apo B was noted to be significantly higher in DHL than NDHL patients. Moreover, levels of Apo B was higher than Apo A in both DHL and NDHL groups when compared with Healthy group. Elevated levels of triglyceride and total cholesterol in both DHL and NDHL groups depicts a strong hyperlipidemic state

Conclusion: Conclusion were drawn from present study that diabetes and hyperlipidemia are important risk factors, in addition to the fact that higher levels of Apo B and A and that of higher Apo B than Apo A are indicative of dyslipidemic state and thus significant parameters for assessing the prevailing conditions and extent of risk for developing coronary heart disease [CHD] and atherosclerosis

Assessment of hyperlactatemia and acidosis in patients with cardiac dysfunctions

Background: It has been postulated that hyperlactatemia is not the only cause of acidosis in cardiac dysfunction and there are other factors such as un-measured anions also that significantly participate in its development

Aim: The present study is designed to determine different components of metabolic acidosis in cardiac dysfunctions and cardiac arrest patients in order to assess the degree to which lactate is responsible for the acidosis

Methods and Materials: Forty two patients with out-of-hospital cardiac dysfunctions and cardiac arrest, admitted to the hospital were included in present study. All arterial blood gases and plasma biochemical parameters were estimated by standard methods on automated analyzers. Modified [by Figge and colleagues] form of Stewart's quantitative biophysical methods including formula for apparent strong ion difference AEurooeSIDaAEuro and strong ionic gap AEurooeSIGAEuro were used to evaluate un-measured and measured ions

Results: The mean age of patients were 57.2 years and included 33 [78.6%] males and 9 [21.4%] females. Except for sodium, ionized calcium and SIDa, all variables were significantly different between the two groups. Patients with cardiac dysfunctions and arrest were also hyperkalemic, hypochloremic and hyperlactatemic. The anion gap and SIG were also higher in patients with cardiac arrest. Lactate was the strongest determinant of academia

Conclusion: It was concluded that lactate accounts for only less than 50% of the metabolic acidosis and consequent acidemia seen in such patients and that an increase in unmeasured anions and phosphate also accounts for major portion of acidemia

Carcinoembryonic antigen [CEA]: discovery, function, chemistry and diagnostic significance

The CEA molecule is an onco-development human tumor marker, bearing the cluster differentiation designation of CD66e, a subtype of CD66 group of CEA family. It has a molecular weight of 180 kDa. This antigen was demonstrated in primary tumor of the pancreas and liver, followed by the study of its presence in 1[st] two Trimesters of gestation. Therefore, the component was designated as Carcinoembryonic Antigen of the human digestive system and subsequently abbreviated as CEA. It became one of the significant entities to diagnose and monitor solid tumor and the response to therapy, especially in GIT cancer. Due to an immense importance of CEA in present day diagnostic and health services, this article reviews the important discovery of CEA by Dr. Phil Gold, its biology, function, chemistry and the clinical role of CEA in categories of cancer screening, diagnosis, prognostic indicator and as a monitoring tool for treatment

Alpha-feto protein [AFP]: structure, function and diagnostic significance

Alpha-fetoprotein [a-fetoprotein, AFP] is a glycoprotein of MW 69,000 and belongs to the albumin class of protein. The AFP genes are located at chromosome 4 in humans and the coding sequence of 15 exons segregated by 14 introns. It is an onco-development protein, first identified in 1960s as a major protein in conditions related to hepatic carcinoma. Since then, the clinical utility of AFP as a tumor marker is now established in several pathological conditions, ranging from embryonal development defects, such as spina bifida in infants malignant conditions such as Hepatoblastoma, pancreatoblastoma, hepatoceHular carcinoma and germ cell tumors. The present review describes the discovery of AFP with historical background, biology of its existence, structure specification and functional properties as well as diagnostic significance in malignant and chronic conditions

Determination of cancer antigen ca 15-3, in breast carcinoma

In breast carcinoma, carbohydrate antigen 15-3 [CA 15-3], a mucin component, is the most important and commonly used tumor marker. It is a transmembrane glycoprotein containing a large extracellular domain of 69 amino acids. Several studies suggested that its evaluation could provide valuable clinical information. Assessment of CA 15-3 can also be useful during treatment of Breast cancer as well as to detect recurrence following primary treatment. CA 15-3 is a breast-cancer-associated antigen defined by reactivity with two monoclonal antibodies, DF3 [raised against a membrane-enriched fraction of human breast cancer] and 115D8 [raised against antigens of human milk fat globule membrane]. The main clinical application of CA 15-3 suggested being in monitoring the response to the treatment and gives reliable information on the recurrence of the disease. The aim of present study is to assess CA 15-3 in patients with breast carcinoma and its usefulness in monitoring and therapy. Serum samples of female patients [n = 56] suspected of or diagnosed with breast carcinoma were analyzed for CA 15-3. Significantly elevated levels were noted in most of the patients and correlated with their malignant tumor status and clinical conditions. It is concluded that CA 15-3 is currently the most widely used circulating cancer marker for breast carcinom·a. CA 15-3 can provide useful information regarding successfulness when comparing pre-operative and post-operative values. In our study, breast carcin9ma patients showed decrease in CA 15-3 levels post-operatively [although most of them still above normal reference range], depicting successfully of treatment and intervention, in addition to suggesting that CA 15-3 concentrations can also provide prognostic information. Furthermore, serial concentrations analyses have the potential both to detect recurrences pre-clinically and to monitor the treatment of metastases breast carcinoma

Assessment of carcino-embryonic antigen [CEA] in patients with colorectal carcinoma [CRC]

The CEA molecule is an onco-development human tumor marker and bears the cluster differentiation designation of CD66e. Tt has a molecular weight of 180 kDa. CEA is one of the significant entities to diagnose and monitor solid tumor and the response to therapy, in GTT cancers, especially CRC. Due to substantial clinical importance of CEA for diagnosis, prognosis and treatment, a study was carried out to assess its levels in patients suspected off or diagnosed with GIT cancers, with special reference to colorectal carcinoma [CRC]. A total 86 patients, 70 [81.39%] males and 16 [18.60%] females, were included in the study with age range of 36 to 81 years. Out of 70 males, 23 [32.80%] have malignant conditions and exhibited elevated levels of CEA [66 ng/ml to 230 ng/ml; mean = 18958 ng/ml], whereas 47 have non-malignant complications with normal or non-significant [> 10 ng/ml but < 20 ng/ml] CEA concentrations. Malignant conditions were determined to be pancreatic [13.04%], gastric [26.08%], colorectal [43.47%] and hepatic [17.39%] cancers. In female group, 10 [62.50%] were diagnosed with malignant condition of pancreatic [10%], gastric [10%] and colorectal [70%] cancers with significantly elevated levels of CEA. At present, serial CEA-monitoring is considered the best non-invasive technique for detecting CRC and its recurrence, it is also substantiated that intensive follow-up CEA assays facilitate the identification of treatable recurrence at an early stage

Diagnostic Significance of alpha-Fetoprotein [AFP] in Hepatocellular Carcinoma [HCC]

Alpha-fetoprotein [a-fetoprotein, AFP] is a Glycoprotein, belonging to the class of onco-development protein. Generally designated as tumor marker, AFP is recognized as an important blood component, having specific diagnostic utilities. Elevation of its level upto pathological range in adults correlate with the appearance of several malignant and chronic conditions, such as hepatocellular carcinoma [HCC] and chronic liver disease, respectively. To evaluate the diagnostic significance of AFP in HCC, a study was carried out for a period of two years [Dec 1999 to Dec 2001] in 3000 male [n = 1830, 61%] and female [n = 1170,39%] adults suspected off or diagnosed with HCC and presence of HBV and HCV infections. Out of 1480 males, who depicted elevated AFP levels, 101 [6.8%] were diagnosed with HCC. Similarly, 54 [6.1%] females out of 880 with elevated levels of AFP were diagnosed with HCC. Mean elevated AFP levels in HCC patients were, 306 +/- 41 mg/ml [range 108-3010 mg/ml] in males and 196 +/- 23 mg/ml [range 98-2203 mg/ml] in females. In males, the mean APP elevated values were analyzed to be 470 mg/ml [range 28-3010 mg/ml, SE = 50], whereas in females it was 336 mg/ml [range 25-2203 mg/ml, SE = 31]. It is also noted that around 3.9% [n = 58] males and 10.11% [n = 89] female patients, with elevated levels of AFP were found negative for HCV and HBV infections. It is concluded that AFP is one of the most important markers for Hepatocellular carcinoma, helpful in assessing problems in management of HCC and monitoring treatment regiments. In addition, AFP is also an indicator of HCC risks mostly in patients with cirrhosis and HCVJHBV infections