Lupine Publishers | -Dimer; A Potential Clinical Marker for Predicting Metastasis & Stages in Lung Cancer

 Lupine Publishers | LOJ Pharmacology & Clinical Research

Abstract

The relationship between plasma D-dimer level and the prognosis of advanced lung cancer is close to each other. This study investigated the role of plasma D-dimer as a prognostic factor in advanced lung cancer: a) The aim of the current study was to investigate the association of D dimer plasma level with the development of stages in lung cancer. b) D-dimers levels as predictor of fibrinolysis and Disseminated Intravascular Coagulation (DIC). The subjects were selected from oncology department, Ghulab Devi Hospital and Mayo Hospital, Lahore. Total 45 subjects were included in the present study. The selected subjects were divided into two groups. Group A included 15 normal, healthy, age and sex matched controls and group B included 30 patients, histologically diagnosed cases of lung cancer. The patients had no history of coagulation disorders or on anti-coagulant therapy. The plasma D-dimer was measured in normal, heathy Controls and 30 histologically diagnosed cases of lung cancer by enzyme-linked immunosorbent assay. The median age of the patients (18 males and 12 females ) was 39.433± 5.11 and 13.3% had stage lb, 20% had llb, 6.7 % llla, 36.11 lllb, 23.3 % had lV disease. Histologic sub-type was Non-small cell lung carcinoma (NSCLC) 30 %, Small cell lung carcinoma (SCLC) were 10 %, Squamous cell carcinoma were 10 %, adenocarcinoma 16.7 % and large cells carcinoma were 10%.In the present study. The Mean ± SD value of D-dimer level of the patients was 1068.70±441.86ng/dl, which was significantly higher than that of the control group. The plasma levels of D-dimer were significantly higher in patients with bronchogenic carcinoma as compared with healthy controls. Plasma D-dimer level was significantly higher in metastatic disease (P <0.01). D dimer levels were positively associated with clinical cancer stage (P<0.05) and metastasis (P<0.05). These findings suggested that the plasma D dimer level may be use as marker for predicting cancer metastasis and staging in lung cancer

Keywords:Lung Cancer; Malignancies; Haemostatic System; Coagulation; Tumor Cells; Hyper coagulopathy; D Dimer

Introduction

Lung cancer is one of the most prevalent malignancies in the world [1,2]. This cancer is currently the most common malignant disease and the leading cause of cancer related-deaths in all age groups and in both sexes [3]. The association between cancer and haemostatic system has been known since Trousseau’s study from the 19th century [4]. Coagulation or fibrinolytic system activation is present in lung cancer patients at clinical or subclinical level. There is a complex interaction, which has an important role in the course of the disease, between pathogenetic mechanisms of thrombosis, tumor cells, homeostatic systems, and patient characteristics. Patients with deep venous thrombosis (DVT) or subclinical hypercoagulopathy usually have worse prognosis. D-dimer is the cleavage product of cross linked fibrin that is formed by activation of the coagulation system, which signals hyperfibrinolysis in response to clot activation and fibrin formation [5]. Elevated levels of D-dimer have been detected in patients exhibiting diffuse intravascular coagulation [6], thromboembolic events, [7] D-dimer is a widely used biomarker for indicating the activation of coagulation and fibrinolysis [8,9]. Coagulation disorders are among the most common complications in cancer patients [8,10]. D-dimer is a degradation product of cross-linked fibrin that appears in the blood after a blood clot is degraded by fibrinolysis [11]. D-dimer is produced by fibrin degradation, and measurement of D-dimer levels can help in the diagnosis of thrombosis [12]. D-dimer levels have been found to be significantly higher in lung cancer with poor prognosis[13,14]. D-dimer is a plasmin-mediated degradation product of cross-linked fibrin clot, which is formed by the activation of the coagulation system for any reason [15]. Several studies suggested that serum D-dimer level may be an important parameter in assessing prognosis of disease and response to treatment in patients with lung cancer[14,16]. As D-dimer is a sensitive marker of fibrinolysis so, it is recommended measuring the plasma level of D-dimer in all new lung carcinoma patients [17]. The results suggested that the plasma level of D-dimer was notably associated with the extent of tumor metastasis and tumor stage in lung cancer patients.

Material and Methods

Total 45 subjects were included in the present study. 30 patients histologically diagnosed cases of bronchogenic carcinoma from oncology department, Ghulab Devi Hospital and Mayo Hospital Lahore, who were admitted between July 2017 to August 2018. The control group consisted of 15 healthy individual without co-morbidity. Lung cancer staging was performed for all patients according to the 7th TNM classification. The inclusion criteria were as following histological diagnosed cases of bronchogenic carcinoma pretreatment were selected. Patients with a history of venous thrombosis or anticoagulation therapy, hypertension, cardiovascular and cerebrovascular disease, diabetes, acute or chronic inflammatory disease, or previous malignancy were excluded from the current study. Written informed consent was obtained from each subjects before the sample collection. 3ml of venous blood was collected in the disposable syringe and put in to vacutainer tubes containing anticoagulant citrate buffer (1:9, buffer blood for D-dimers assay. History and clinical features were recorded in all subjects on performa. The principals of different tests and their procedures were adopted accordingly. Blood samples were centrifuged and the plasma was separated. D-dimer level was measured in the plasma, via enzyme-linked fluorescent immunoassay method using a PC-Vidas device (BioMerieux Fr). A D-dimer level <500 ng/dl was considered normal.

Results and Observations

Thirty patients with histological confirmed lung cancer were enrolled in the study. Mean age was 39.433 ± 5.11 years within the, range of 26-52 years, and there were 18 males (60.0%) and 12 females (40.0%). There were 05 (16.7%) adenocarcinomas, 10 (33.3%) squamous cell carcinomas, 03 (10.0%) small cell carcinomas and 09 (30%) non small cell carcinomas. 04 (13.3%) patients were classified as stage Ib, 06 (20%) patients as stage IIb, 02 (6.7%) patients as stage IIIa, 11 (36.7%) patients as stage IIIb and 07 (23.3%) patients as stage IV. The general characteristics of the lung cancer patients are shown in Table 1.

Discussion

The quotation “Qi is the commander of Blood and Blood acts as the mother of Qi” highlights the collaboration of Blood and Qi. Blood is seen as Yin and Qi can be classified into Yang, which can result in diseases when the imbalance of Yin-Yang occurs. Blood, produced with food qi (gu qi) by Spleen, circulates in the veins governed by Heart to nourish the organs and the systems. Blood, in addition to food qi, is also generated by the mother of Liver based on the Generating sequence Kidney, which stores prenatal Jing and produces marrow that generates to manufacture Blood. Qi circulates in the traditional twelve meridians to support the life, interacting with Blood for the Zang-Fu organs to function normally in harmony [20,21]. The studies on the relation between Qi in the twelve meridians and the oxygen metabolism highlight that one may be short of breath and experience wheezing or coughing when the normal level of blood oxygen is below, presenting the high similarity of physiological functions and pathological reactions between Qi and oxygen [22]. In other words, this suggested that oxygen, to some extent, is equivalent to Qi [23]. The Generating Sequence of the Five Elements theory shows Kidney is the mother of Liver, which suggests that Kidney’s problems can affect its child Liver. The maximum oxygen is delivered with the normal value of 45% of hematocrit [24]. Kidney produces Erythropoietin to promote the number of red blood cells to increase the capacity of the blood to carry more oxygen. In addition, the circulation of oxygen in the Kidney is closely associated with the production of Erythropoietin determined by tissue oxygen pressure [25]. In other words, stagnated Liver qi can be dispersed as long as Kidney can function normally with the delivery of the healthy Qi to Liver. In a word, the inflammation resulted from the infection can be reduced with much more oxygen delivered upwards with the blood to Lung.

D-dimer levels in patients with lung cancer were higher than those of the control group, and the difference was statistically significant P 0.05 (Table 2). D-dimer levels according to disease stage are shown in Table 3. When the D-dimer levels were compared according to disease stage in patients with lung cancer, a significant difference was observed between the D-dimer levels of patients with stage lb, llb and those with stage IV disease (P = 0.025). There was no significant difference between the other stage groups in terms of D-dimer levels. D-dimer levels were significantly higher in lung cancer patients than in the control group (P<0.01; Table 3). These data suggested that the plasma level of D dimer may be used as a marker of metastasis and staging in lung cancer.

Discussion

There is some evidence that the activation of coagulation and fibrinolytic system by neoplastic cells facilitates invasiveness and metastases [18]. Thus, the extent of such activation has been associated with tumor stage and prognosis in some malignancies such as breast, colorectal and lung cancer [19,20]. D-dimer is a product of cross-linked fibrin degradation by plasmin-induced fibrinolytic activity, and D-dimer levels are a biomarker of global hemostasis and fibrinolysis [21]. High D-dimer levels were associated with poor prognoses in patients with breast, [22,23] colon and rectum, [24,19] and lung [25,26] cancers. In the present study, it was demonstrated that elevated plasma levels of D dimer were associated with clinical cancer stages and metastasis in lung cancer patients. D-Dimers: In this study, D-dimers were found to be significantly increased (p < 0.01) in patients with lung cancer when compared with controls (Table 2). The D-dimer level was more in SCLC as compared to NSCLC. The increased D-dimer was more in Patients having DIC and in patients of metastatic disease. These increased levels of D-dimers may be due to enhanced fibrinolysis [27] in their study Showed increased levels of D-dimers in patients having malignancy. These findings are consistent with the results of [27,18,28,29]. Several studies have reported that plasma D-dimer levels were elevated and associated with the stage and mortality in lung cancer [28,29]. They also observed similar increase of D-dimers in lung cancer (2.0). Our study has some limitations. This is a retrospective observational study with small sample size. Therefore, the findings of this study need to be validated by prospective and multicentre studies. The present study thus provides more reference values for patients with later-stage tumors and poorer overall condition. SCLC is a highly invasive tumor with a poor prognosis, with different biological characteristics from NSCLC. Valid biomarkers are therefore needed to determine the prognosis of SCLC. In the present study, pretreatment plasma D-dimer levels were independently in patients with SCLC. This conclusion is supported by previous studies of lung cancer in general

Conclusion

The present study demonstrated that D-dimer plasma level was significantly higher in lung cancer patients and associated with clinical stages and metastasis. The current study was limited in that it only identified the association of D-dimer with tumor stage and metastasis.

 

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Lupine Publishers | A Mini Review: Seaweeds Negotiate a Vital Risk Factor of Cardiovascular Disease

 Lupine Publishers | Pharmacology & Clinical Research

Abstract

The high blood cholesterol level is one of the major risk factors of coronary heart disease. The total lipid includes total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides. The high-density lipoprotein cholesterol is good for the heart health; the high level of the high-density lipoprotein cholesterol is helpful to our health. But the high level of the low density lipoprotein cholesterol is responsible for gradual deposition of cholesterol along the inner wall of arteries which followed some serial change to develop atherosclerosis and blockage in the arteries to promote the development of cardiovascular pathogenesis which is consider also the major risk factor for heart failure. The low-density lipoprotein cholesterol value should be below 100mg/dL. The low-density lipoprotein cholesterol level sometimes become high in our body due to uptake of the high amount of food with saturated and trans-fat. The food habit in different parts of the world is not adequate to prevent and reduce the health hazards and hence it is believed that food habit is the basic reason for the major health problems such as cardiac disease, obesity, diabetes, hepatic disorder and related diseases for global populations. Research shows appropriate fatty acids composition of some marine macro algae is very useful to prevent cardiovascular disease development. Likewise, marine macro algae are composed of adequate amount of proteins, carbohydrates, fatty acids, peptides, minerals, vitamins, long chain molecules, hydrocolloids which will also negotiate nutritional deficiencies for uptake marine macro algae as food items or food ingredients. So, marine macro algae may be use as cardio-protective biomedicine in future after detailed analysis and critical evaluation. The fatty acids compositions and the cholesterol lowering activity of some seaweed are discussed in brief.

Keywords: Cholesterol; Low density lipoprotein Cholesterol; Saturated fat; Marine macro algae; Cardio protective

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Lupine Publishers | Pharmacist-Led Antimicrobial Stewardship

Lupine Publishers | LOJ Pharmacology & Clinical Research

 

 

Short Communication

The value of critical care pharmacists has been well documented. Various studies have shown that critical care pharmacists reduce medication errors, improve patient outcomes, reduce costs and waste, and decrease mortality rates among patients with thromboembolic diseases or infections [1,2]. Antimicrobial resistance (AMR) causes prolonged illness, greater risk of infection spread, increased morbidity, and higher mortality rates, which result in increased expenses to the government, healthcare services, and individuals. It is estimated that around 700,000 people die annually from drug-resistant infections, with experts predicting an alarming possible increase to 10 million deaths each year by 2050 and major future challenges to the way we practice medicine and surgery. Resistance has been associated with increasing mortality, treatment failure and healthcare costs [3,4]. This alarming rate exceeds the annual number of deaths caused by cancer (8.2 million) and is almost ten times that of motor vehicle accidents (1.2 million) [5]. In the United States, in addition to significant mortality, antimicrobial resistance adds $20 billion in excess direct health care costs and up to $35 billion in annual societal costs as a result of lost productivity [6]. Antibiotic stewardship was established to combat this trend and was recognized in 1996 to draw attention to the rising incidents in mortality and morbidity associated with inappropriate use of antibiotics [7]. Antibiotic stewardship is a core part of critical care, and many times, the physician will rely on the pharmacist’s recommendations and expertise. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, deescalation, optimizing dosing, active use of information technology among other measure [8].

The Infectious Diseases Society of America guidelines on antimicrobial stewardship recommend that the core multidisciplinary stewardship team include an infectious diseases (ID) physician and a clinical pharmacist with ID training [9]. Antibiotic prescribing in outpatient settings exceeds that of inpatient prescribing, with more than 150 million antibiotic prescriptions annually; of these prescriptions, more than 30% are either unnecessary or inappropriately prescribed [10-12]. Orally administered antimicrobials accounted for approximately 90% of total consumption: oral third generation cephalosporins, macrolides, and fluoroquinolones accounted for approximately 77% of oral consumption. Therefore, pharmacists must extend their support for the appropriate use of antimicrobials prescribed by attending physicians to not only hospitalized patients but also outpatients [13]. As the regulations for antibiotic stewardship in outpatient settings continue to evolve and optimal stewardship strategies are defined, pharmacists must be leaders in the implementation of these programs [14]. Stewardship programs can help, reduce inappropriate prescription and broad-spectrum use of antimicrobials, improve, clinical outcomes for the population as a whole, slow down the emergence of antimicrobial resistance and conserve healthcare resources [3]. The WHO Global Action Plan on Antimicrobial Resistance recommends countries work together to improve awareness and understanding of antimicrobial resistance, including through social media.

The 2018 World Antibiotic Awareness Week campaign used Twitter to tailor media messages about the Global Action Plan [15]. Social media have become important information channels but may not reach people with low knowledge and/or low interest in the subject. Within the EU, countries with low use of antibiotics, such as Sweden and The Netherlands, show a higher population knowledge level [16]. The use of community antibiotic stewardship programs (ASPs) is rising. ASPs involving pharmacists are effective in decreasing antibiotic prescribing and increasing guidelineadherent antibiotic prescribing by GPs [17]. Evidence in China and Netherlands showed that antibiotic stewardship program was associated with more less 80% and more than 25% decrease in cost of antibiotic prophylaxis per procedure respectively [18]. The issue of antimicrobial resistance is worse in low and middleincome countries (LMIC), as the incidence of infectious diseases is high compared to high-income countries. In low and middleincome countries, the mortality rates due to antimicrobialresistant bacteria are under-reported, however, available data in India, Nigeria, Pakistan, and Congo indicate that a huge number of neonatal deaths resulted from drug-resistant sepsis [19]. Annually, more than 50,000 newborns are estimated to die from sepsis due to pathogens resistant to first-line antibiotics [20]. In European countries, antimicrobial resistance is also on the rise and considered to be responsible for about 25,000 deaths annually [21]. Pharmacists are core AMS team members where there is an ongoing need to align continuing education for health professionals with realities of practice. However, antimicrobial stewardship (AMS) is not comprehensively and fully taught in medical or pharmacy curricula and little is known about the relevance of pharmacist training to meet AMS needs [22]. Critically, there is a need for establishing sustainable funding for AMS teams working beyond hospital settings that is not solely derived from cost savings through reduced drug expenditure.

Instead, funding for developing and supporting AMS teams should be considered within the patient safety and healthcarequality-related spending [23]. More recently, the introduction of national stewardship guidelines, and an increased focus on stewardship as part of the UK five-year antimicrobial resistance strategy, have accelerated and embedded developments. Antimicrobial pharmacists have been instrumental in effecting changes at an organizational and national level [24]. A pharmacist dispensing antimicrobials without a prescription is 83-100% of the time unaware of a patient’s allergies status [19]. Inaccurate allergy labelling results in inappropriate antimicrobial management of the patient, which may affect clinical outcome, increase the risk of adverse events and increase costs. Inappropriate use of alternative antibiotics has implications for antimicrobial stewardship programs and microbial resistance. 2019 recommended that a pharmacistled allergy management service is a safe option to promote antimicrobial stewardship and appropriate allergy labelling [25]. 2018 suggested broader adoption for the role of pharmacists in the provision of penicillin skin testing. This would help expand the service and maximize the potential benefits of penicillin skin testing [26]. Pharmacists may be tasked to lead ASP development and implementation with little or no support from an infectious diseases (ID) physician and other hospital personnel whose involvement on ASP teams is recommended (e.g., clinical microbiologists, infection control specialists, hospital epidemiologists) [27]. Pharmacists and other health care professionals should collaborate within multidisciplinary teams (MDTs) to reduce the risk of antimicrobial resistance, thereby reducing the economic burden, improving patients’ quality of life, and reducing hospitalization due to infections [19]. In a UK study, almost 60% of pharmacist’s contributions are made during the MDT round [28]. Research has shown that pharmacists play an important role in the (Emergency Department) ED, but there is a need for data supporting this in specific patient outcomes as the majority of the literature addresses adverse drug event prevention and cost-containment [29]. Critical care pharmacists are recognized in the guidelines from the Society of Critical Care Medicine (SCCM) as essential team members for the delivery of care for critically ill patients. In fact, the return on investment of an ICU pharmacist’s salary approached in multiple studies of critically ill patients with infection [30]. Including critical care pharmacists in the multidisciplinary ICU team improved patient outcomes including mortality, ICU length of stay in mixed ICUs, and preventable/nonpreventable adverse drug events [31].

Although factors, such as a lack of financial resources, may be beyond the control of the pharmacy profession, other factors, such as increased documentation in patient records and increased scholarly work demonstrating pharmacists’ contributions, can and should be addressed more consistently by all critical care pharmacists [32]. The critical care pharmacist ensures the discontinuation of these medications in patients who no longer have an indication. Unfortunately, these medications are sometimes started by the ward team and continued on discharge. Additionally, home maintenance medications are often not resumed on hospital admission and/or subsequent discharge, increasing the risk of death, emergency department visit, or hospitalization. A critical care pharmacist integrated into the ICU-Recovery Center (ICU-RC) may take attempt to identify and treat the types of medication errors found in a population of high-risk ICU [33]. In addition, pharmacists who are often the first point of care, dispense antibiotics without a physician prescription, offer alternative antibiotics even when patients present with a prescription. Within the hospitals lack of monitoring of antibiotic use is one of the major factors driving the spread of resistance [34]. The implementation of antimicrobial stewardship programs in primary health care is suboptimal. This negatively affects the global efforts to control antimicrobial resistance. There is a need to institutionalize national guidelines for AMS in primary health care [35]. Multiple randomized controlled trials (RCTs) have found that shorter courses of antibiotic therapy result in similar cure rates as traditional courses for many types of infections, including UTIs, SSTIs, and pneumonia. Unfortunately, familiarity with short-course therapy as a stewardship tool is limited. A recent study found that only one-third of infectious diseases practitioners from 58 countries recommended short-course therapies [36]. Consequently, some countries have recommended shortening the duration of antibiotic treatment of communityacquired pneumonia (CAP). No significant differences in adverse events were reported. However, none of the trials reported on the impact on the development of resistant bacteria [37]. As with the cost of climate change, estimates of total AMR costs are fraught with uncertainty and may be far too low. This cost depends on various factors: which drug and pathogen are involved, the mechanism of antibiotic resistance, the prevalence of that pathogen, the types of infections it causes and their level of transmissibility, the health burden of those infections, and whether alternative treatments are available [38]. AMS can help pharmacists improve the quality of patient care and improve patient safety through increased infection cure rates, reduced treatment failures, and increased frequency of correct prescribing for therapy and prophylaxis. The cost of employing a pharmacist at the recommended minimum staffing level is approximately £20 per patient per day. Several studies find that the role reduces overall expenditure through more efficient use of medicines and the avoidance of direct costs of iatrogenic harm, with additional savings made from avoiding payouts arising from damages claims [19,27].

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