Laboratory variables as additional staging parameters in patients with small-cell lung carcinoma. A systematic review.

We have reviewed the biomedical literature published over the last 25 years in order to try to establish which of four frequently evaluated laboratory parameters (i.e. serum, or plasma, NSE, LDH, sodium or albumin) might, alone or in combination, give the "best" pretreatment prognostic information in small-cell lung cancer (SCLC) patients, independent of the usual radiological and clinical parameters. From the 45 studies included in this review, the only clear conclusion that can be derived is that it has not yet been clearly demonstrated that the "new" tests (NSE or other tumor markers) are superior to the "old" tests (LDH, sodium, albumin etc.). From the only seven studies that used the same powerful statistical methodologies (Cox's models in association with recursive partitioning and amalgamation procedure (RECPAM) analysis) it could be concluded that LDH and albumin might have independent prognostic significance in SCLC and in advanced SCLC respectively. Provided that, in the future, both laboratory and statistical expertises are clearly guaranteed in the primary studies in this field, it might become possible to propose laboratory parameters as additional staging parameters in SCLC.     

Are laboratory investigations recommended in current medical practice guidelines supported by available evidence?

It has been suggested that evidence-based laboratory medicine (EBLM) could help to improve the pertinence and accuracy of medical guidelines. In order to demonstrate this, we have used an EBLM approach (i.e. a systematic review) to examine three recently published guidelines that gave quite conflicting recommendations regarding the use of laboratory variables in the management of primary non-small cell lung cancer patients. In recommending the routine measurement of serum albumin, and, to a lesser extent, that of serum calcium in the pre-therapeutic prognostic evaluation of the advanced disease, the American Thoracic Society and the European Respiratory Society were probably correct with regard to calcium but perhaps mistaken regarding albumin. Some of the recommendations of the European Group on Tumour Markers regarding the usefulness of routine measurements of tumour markers (carcinoembryonic antigen (CEA), cancer antigen 125 (CA 125), tissue-polypeptide antigen (TPA)) in the pre- and/or post-therapeutic prognostic evaluation can also be criticised. In addition, the latter society as well as the Société de Pneumologie de Langue Fran?aise did not even try to list laboratory variables, others than tumour markers, that would be useful to stratify patients participating in clinical trials (i.e. lactate dehydrogenase (LDH), albumin, calcium, blood cell count, etc.), and the laboratory variables listed by the two former societies were probably not the right ones in this context: in particular LDH and tumour markers (fragments of cytokeratin 19 (Cyfra 21-1), tissue-polypeptide-specific antigen (TPS), neuron-specific enolase (NSE)) were not mentioned. Most, if not all of these discrepancies in the current medical practice guidelines might have been avoided had an EBLM approach been used by the authors.     

Platelet/lymphocyte ratio is a significant prognostic factor for targeted therapy in patients with EGFR-mutated non-small-cell lung cancer

ObjectiveTo analyze the prognostic significance of the pretreatment platelet/lymphocyte ratio (PLR) for targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC).MethodsWe conducted a retrospective study of 96 patients with EGFR-mutated advanced NSCLC who were treated at Dongguan People’s Hospital, Southern Medical University from May 2014 to December 2017. All patients received EGFR-targeted therapy until disease progression, unacceptable toxicity, or other factors. Approximately 3 days before the initial treatment, data including a detailed clinical history, physical examination, radiographic results, pathological diagnosis, and laboratory parameters including complete blood cell counts and albumin levels were evaluated.ResultsPatients in the PLR ≥ 190 group had shorter progression-free survival (PFS) than those in the PLR < 190 group. Furthermore, the 1-year PFS rate was worse in the PLR ≥ 190 group than in the PLR< 190 group. Multivariate analysis indicated the possible role of PLR as a prognostic factor for patients with advanced NSCLC who received EGFR-targeted therapy.ConclusionsPretreatment PLR may be an independent prognostic factor for patients with NSCLC receiving EGFR tyrosine kinase inhibitor treatment. Further studies are needed to identify the impact of PLR on EGFR-mutated NSCLC.     

Beyond randomization

Conventional opinion states that randomization is the appropriate way to allocate participants to treatments in biomedical studies. The most frequently cited justification is that it is the only method that guarantees balance between treatment groups with respect to all prognostic factors, whether measured or not. Here it is shown by simple arguments that this justification is false and misleading. Design-adaptive allocations are an alternative to randomization that are easy to implement, and virtually guarantee better balance than randomization, for both measured and unmeasured factors. The fraction of studies that will exhibit severe imbalance under randomization is not always trivial. For this reason, in small studies or studies with subgroup analyses or many prognostic factors, design-adaptive allocation is an attractive alternative to randomization. These considerations are particularly relevant to complementary and alternative medicine studies, where resources are relatively scarce, and otherwise underpowered studies might lead to premature termination of promising research paths.     

Statistical modeling of prognostic indices for evaluation of critically ill patients

OBJECTIVE: To identify the most predictive association of variables from the usual indices of severity of illness by statistical objective analysis. DESIGN: Logistic regression analysis of the different variables of the most important indices. SETTING: A general critical care medicine group practice in a university hospital. PATIENTS: A total of 630 critical care patients age 12 to 87 yrs were evaluated. The most important indices of severity of illness and the corresponding variables were recorded and the patient's course was followed for 3 months after ICU admission. MEASUREMENTS AND MAIN RESULTS: One of our hypotheses was that the inclusion of an excessive number of variables to obtain the most common prognostic indices of mortality in critical care patients results in an underestimation of mortality and a redundancy of prognostic information. We performed a logistic regression analysis using the variables of the currently used indices of critical care prognosis: Acute Physiology Score, Simplified Acute Physiology Score, Acute Physiology Score-II, and Mortality Prediction Model. This mathematical approach resulted in a model of five variables: organ system failure, blood glucose, serum calcium, serum prothrombin activity, and serum osmolality. The score obtained from this model gave accurate prognostic criteria:sensitivity 91.2% and specificity 90%, using a cutoff point of 0.7; sensitivity 86% and, specificity 94%, using a cutoff point of 0.5. CONCLUSIONS: Our results show that suitable statistical management of the discriminant prognostic variables allows reduction of the number of variables of the severity indices currently used, obtaining five more predictive variables.     

Limitations in the Use of Serum Epidermal Growth Factor Receptor Mutations as Prognostic Markers for Non-Small-Cell Lung Cancer

Objectives

In this study, we surveyed patients with advanced non-small-cell lung cancer (NSCLC) who were undergoing tyrosine kinase inhibitor (TKI)-targeted therapy. Our aim was to determine whether epidermal growth factor receptor (EGFR) mutations in serum circulating tumor (ct)DNA are useful prognostic markers for NSCLC.

Sujects and Methods

Serum samples were collected from 300 patients with NSCLC that included adenocarcinoma (ADC, n = 155) and squamous cell carcinoma (SCC, n = 145). DNA was extracted from the sera for the nested polymerase chain reaction (PCR) amplification of EGFR exons 18, 19 and 21 mutations. Direct sequencing of the PCR products was carried out in an automated 3730 sequencer.

Results

The EGFR exons 18, 19 and 21 were successfully detected in the serum samples of 300 NSCLC patients. No EGFR mutation was found in the blood samples regardless of the characteristics of gender, age, ADC and SCC status or smoking history.

Conclusion

No mutations in EGFR exons 18, 19 or 21 were identified in the serum ctDNA of these advanced-stage NSCLC patients undergoing TKI-targeted therapy. More studies are needed on the use of EGFR mutations in serum ctDNA as guidance for TKI-targeted therapy.Key Words: Serum, Epidermal growth factor receptor, Non-small-cell lung cancer, Tyrosine kinase inhibitor     

基质金属蛋白酶2对非小细胞肺癌术后生存率的影响

目的：研究基质金属蛋白酶2（MMP2）在非小细胞肺癌（NSCLC）组织中的表达与预后。方法：用免疫组化技术测定83例NSCLC的MMP2表达．并以Kaplan-Meier曲线描述生存率，Cox单、多因素分析MMP2表达与生存率的关系。结果：83例手术切除的非小细胞肺癌中。MMP2过表达者60例，非过表达者23例，过表达率为72．3％。MMP2的过表达与肿瘤类型、病理分级、性别、年龄、吸烟史无明显关系；MMP2在肿瘤组织的过表达率与淋巴结转移状态及临床分期有关（P〈0．05）；MMP2过表达者预后较非表达患者差，5年生存率分别为7．4％、18．5％。但差异无显著性意义（P〉0．05）。结论：MMP2对判断NSCLC预后有一定的参考价值，但是能否作为判断预后的一个独立指标有待进一步多中心研究。     

An Evaluation of 1,000 Serum Calcium and Inorganic Phosphate Determinations

Unsolicited data can be accumulated through the utilization of laboratory reports. This article gives the results of a study performed on serum calcium and inorganic phosphate determinations carried out as part of an investigative routine. Since Ca and P vary together in a set of specific diseases, we should perhaps evaluate these tests together, since they might be a more sensitive and more specific index of disease than any other single abnormal component in interrelated findings.     

The advanced lung cancer inflammation index predicts outcomes of patients with non-small cell lung cancer following video-assisted thoracic surgery

ObjectiveThe advanced lung cancer inflammation index (ALI) predicts overall survival (OS) in patients with advanced lung cancer. However, few studies have tested ALI’s prognostic effect in patients with non-small cell lung cancer (NSCLC) following video-assisted thoracic surgery (VATS), especially patients at stage III. This study investigated the relationship between ALI and outcomes of patients with NSCLC following VATS.MethodsWe retrospectively examined 339 patients with NSCLC who underwent VATS at Hebei General Hospital, China. Preoperative clinical and laboratory parameters were collected and analyzed. Optimal cutoff values of potential prognostic factors, including ALI, were determined. Kaplan–Meier and Cox regression analyses were used to determine each factor’s prognostic value.ResultsThe median OS was 31 months. The optimal cutoff value for ALI was 41.20. Patients with high ALI (≥41.20) displayed increased OS (33.87 vs. 30.24 months), higher survival rates, and milder clinical characteristics. Univariate and multivariate analyses showed a significant correlation between ALI and the prognosis of patients with NSCLC, including those at stage IIIA, who underwent VATS.ConclusionsLow ALI correlated with poor outcomes in patients with NSCLC following VATS. Preoperative ALI might be a potential prognostic biomarker for patients with NSCLC following VATS, including patients at stage IIIA.     

Increased serum exosomal long non‐coding RNA SNHG15 expression predicts poor prognosis in non‐small cell lung cancer

BackgroundCirculating long non‐coding RNAs (lncRNAs) are emerging as promising biomarkers for non‐small cell lung cancer (NSCLC). This study aimed to detect serum exosomal lncRNA SNHG15 expression in NSCLC and evaluate its potential clinical value.MethodsA total of 238 serum samples were collected from 118 patients with NSCLC, 40 patients with benign pulmonary lesions and 80 healthy volunteers. The expression levels of serum exosomal lncRNA SNHG15 were measured by quantitative real‐time polymerase chain reaction (qRT‐PCR). Then, the relationship between serum exosomal lncRNA SNHG15 expression and clinical parameters was analyzed.ResultsThe serum exosomal lncRNA SNHG15 expression was markedly higher in NSCLC patients compared to patients with benign pulmonary lesions and normal controls. As expected, serum exosomal lncRNA SNHG15 was greatly decreased after surgery. High serum exosomal lncRNA SNHG15 expression was closely associated with poor differentiation (p=0.035), positive lymph node metastasis (p=0.009) and advanced TNM stage (p<0.001). Receiver operating characteristic (ROC) curve analysis demonstrated that serum exosomal lncRNA SNHG15 well differentiated all stage NSCLC, stage I/II NSCLC patients or stage III/IV NSCLC patients from controls, and the combination of serum exosomal lncRNA SNHG15 and CEA showed an elevated AUC for distinguishing NSCLC from healthy individuals. In univariate and multivariate analyses, serum exosomal lncRNA SNHG15 was confirmed as an independent prognostic predictor for overall survival.ConclusionIn conclusion, our findings suggest that serum exosomal lncRNA SNHG15 might be a potential biomarker for early diagnosis and prognosis prediction of NSCLC.     

Corrected incidences of co-morbidities – a statistical approach for risk-assessment in anesthesia using an AIMS

Objective

In anesthesia and intensive care logistic regression analysis are often used to generate predictive models for risk assessment. Strictly seen only independent variables should be represented in such prognostic models. Using anesthesia-information-management-systems a lot of (depending) information is stored in a database during the preoperative ward round. The objective of this study was to evaluate a statistical algorithm to process the different dependent variables without losing the information of each variable on patient’s conditions.

Method

Based on data about prognostic models in anesthesia an iterative statistical algorithm was initiated to summarize dependent variables to subscores. Seven subscores out of several preoperative variables were calculated corresponding to the proper incidence and the correlation to the occurrence of intraoperative cardiovascular events was evaluated. After that first step logistic regression was used to build a predictive model out of the seven subscores, 10 patient-related, and two surgery-related variables. Performance of the prognostic model was assessed using analysis of discrimination and calibration.

Result

Four out of seven subscores together with age, type and urgency of surgery are represented in the prognostic model to predict the occurrence of intraoperative cardiovascular events. The prognostic model demonstrated good discriminative power with an area under the ROC curve (AUC) of 0.734.

Conclusion

Due to reduced calibration, the clinical use of the prediction model is limited.

     

EGFR mutations and EGFR tyrosine kinase inhibition in non-small cell lung cancer

OBJECTIVES: To discuss selected molecular targets and new clinical variables that can serve as both predictive and prognostic markers for outcome in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs. DATA SOURCES: Research and journal articles. CONCLUSION: In the near future, treatment for NSCLC will rely ever increasingly on molecular targets rather than empirically chosen cytotoxic chemotherapy for some patients. This will improve outcomes for patients with NSCLC. IMPLICATIONS FOR NURSING PRACTICE: An understanding of the molecular targets and clinical variables that are predictive and prognostic of outcome in NSCLC will help nurses better care for these patients.     

Flow cytometric lymphocyte subset enumeration: 10 years of external quality assessment in the Benelux countries

A biannual external quality assessment (EQA) scheme for flow cytometric lymphocyte immunophenotyping is operational in the Benelux countries since 1996. We studied the effects of the methods used on assay outcome, and whether or not this EQA exercise was effective in reducing between-laboratory variation. Eighty test samples were distributed in 20 biannual send-outs. Per send-out, 50-71 participants were requested to enumerate CD3+, CD4+, and CD8+ T cells, B cells, and NK cells, and to provide methodological details. Participants received written debriefings with personalized recommendations after each send-out. For this report, data were analyzed using robust multivariate regression. Five variables were associated with significant positive or negative bias of absolute lymphocyte subset counts: (i) platform methodology (i.e., single-platform assays yielded lower CD4+ and CD8+ T-cell counts than did dual-platform assays); (ii) sample preparation technique (i.e., assays based on mononuclear cells isolation yielded lower T-cell counts than those based on red cell lysis); (iii) gating strategies based on CD45 and sideward scatter gating of lymphocytes yielded higher CD4+ T-cell counts than those based on "backgating" of lymphocytes guided by CD45 and CD14); (iv) stabilized samples were generally associated with higher lymphocyte subset counts than nonstabilized samples; and (v) laboratory. Platform methodology, sample stabilization, and laboratory also affected assay variability. With time, assay variability tended to decline; this trend was significant for B-cell counts only. In addition, significant bias and variability of results, independent of the variables tested for in this analysis, were also associated with individual laboratories. In spite of our recommendations, participants tended to standardize their techniques mainly with respect to sample preparation and gating strategies, but less with absolute counting techniques. Failure to fully standardize protocols may have led to only modest reductions in variability of results between laboratories.     

The relationship between physicians and the biomedical industries: advice from the Royal College of Physicians

The relationship between a physician and a biomedical firm is often important, and can be useful to both parties. However, there is a danger that the substantial resources available to a biomedical firm might sometimes be used to interfere with a physician's independent professional judgment. For the reputation and good conduct of the profession and the industry, and for the welfare of patients, it is essential that this does not happen. Total absence of communication would prejudice the undoubted good which collaboration can achieve. This paper sets out what the Royal College of Physicians currently believes are appropriate boundaries: to the acceptance of gifts; to sponsorships and subsidies for meetings; to the conduct of meetings with industry representatives; and other matters. We believe that clearly stated guidance will benefit the biomedical industry and physicians alike.     

Diabetic ketoacidosis and infection: leukocyte count and differential as early predictors of serious infection

The records of 153 patients who presented to an emergency department with diabetic ketoacidosis were reviewed to determine whether any admission evaluation laboratory data could serve as a predictor of occult or coexisting infection. Ten patients with admission radiographs already demonstrating active infection (pneumonia or tuberculosis) and two patients with wet gangrene of an extremity were not included in subsequent statistical analysis, as their infections were diagnosed on initial evaluation. Analysis of readily available admission variables revealed that when age, sex, temperature, glucose, serum bicarbonate, pH, total leukocyte count, and differential are subjected to univariate and multivariate discriminant analysis, only an elevation in band neutrophils reliably predicted infection. Approximately half of our patients with elevated band counts (10 or greater) had a coexisting occult infection. An elevated band count was predictive of an occult coexisting major infection with a sensitivity of 100% (19/19) and a specificity of 80% (98/122).     

Laboratory Evaluation of Normal Donors Undergoing Leukapheresis on the Continuous Flow Centrifuge

Leukapheresis with the continuous flow centrifuge for leukocyte collection from normal donors is becoming widely utilized. Thus, it is important to establish guidelines for the laboratory evaluation of donors. Forty‐nine normal donors underwent 120 different leukaphereses and the following variables were studied before and after each procedure: hemoglobin, hematocrit, leukocyte count and differential, platelet count, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, prothrombin and partial thromboplastin time, blood urea nitrogen, glucose, plasma hemoglobin, and blood culture. No unexpected laboratory results were encountered.
On the basis of these studies, hemoglobin or hematocrit and partial thromboplastin time are necessary as a minimum. Total leukocyte differential count, platelet count, and serum calcium may be added but are optional. These laboratory studies must be combined with a thorough history, and the leukocyte unit once collected should undergo pretransfusion testing and compatibility testing similar to other blood products.     

Serum Biochemical Response to Inhalant Anesthetics in New Zealand White Rabbits

Anesthetics can affect biochemical parameters, complicating the interpretation of laboratory results and perhaps leading to erroneous diagnoses. The present study was performed to characterize variations in selected rabbit biochemical parameters after inhalant anesthetics. Twenty New Zealand White rabbits were allocated to 2 treatment groups (n = 10 animals each), which received either halothane or isoflurane. Anesthesia was induced by using a face-mask, and rabbits were intubated for maintenance of anesthesia for 30 min. Blood samples were obtained before induction and at 1, 10, 30, 60, and 120 min and 24, 48, and 72 h after intubation. Serum cholesterol, triglycerides, albumin, total proteins, total bilirubin, sodium, potassium, chloride, calcium, and phosphorus concentrations were measured by using an autoanalyzer. Administration of halothane significantly increased serum triglyceride levels and decreased serum cholesterol, albumin, total protein, and potassium levels. Isoflurane administration increased serum triglyceride, phosphorus, and chloride concentrations and decreased serum calcium and potassium levels. Caution is required in interpreting data on serum biochemical parameters from rabbits anesthetized with halothane or isoflurane.The possibility has been suggested ¹³ that some anesthetics can influence blood biochemistry values in rabbits, complicating the interpretation of laboratory results, and perhaps leading to erroneous diagnoses. Whether inhalant anesthetics, like intravenous agents,¹⁴ alter biochemical parameters in rabbits is unclear. In the present study, we evaluated the effect of 2 inhalant anesthetics, halothane and isoflurane, on selected biochemical parameters.Halothane and isoflurane are potent inhalant anesthetics. Halothane has a depressant effect on the cardiovascular system and can produce arrhythmias and moderate hypotension at surgical levels of anesthesia. Isoflurane produces slightly more severe respiratory depression than halothane but slightly less depression of the cardiovascular system.⁹ The main objective of the present study was to determine which of these agents would be the most suitable in studies involving measurements of biochemical parameters in rabbits.     

ProGRP: a new biomarker for small cell lung cancer

Progastrin-releasing peptide (ProGRP) is a recently identified biomarker of small cell lung cancer (SCLC), a disorder of neuroendocrine tissue differentiation. The upper normal limit of ProGRP in the circulation is 50 pg/ml. Impaired glomerular filtration tends to increase circulating levels and confound the tumor marker significance of modestly elevated values. Excluding patients with renal failure, circulating levels did not exceed 80 pg/ml in benign disease (3% of cases in excess of the upper normal limit) or 120 pg/ml in malignancy other than lung cancer and neuroendocrine tumors (5% of cases in excess of the upper limit). ProGRP serum levels are clearly related to the lung cancer histological type with significantly higher levels observed in SCLC than in nonsmall cell lung cancer (NSCLC). Circulating ProGRP in excess of 120 mg/ml was found in only 4% of cases of NSCLC with another 22% presenting with modestly elevated levels in excess of the upper normal limit. By contrast, abnormal ProGRP results are found in 60-70% and in 75-90% of SCLC patients with local and extensive disease, respectively. ProGRP is a more sensitive biomarker than is neuron-specific enolase (NSE) for SCLC, but thus far has not been found in multivariate analysis to have independent prognostic significance. Preliminary studies suggest ProGRP will have utility in conjunction with NSE in monitoring the therapy of established SCLC.     

Application of a statistical approach to determining reference intervals in clinical chemistry

In clinical chemistry a linear-regression model may be used to determine reference intervals. A crucial point in this approach is the choice of variables to introduce into the model. In the present paper, we have applied a nonautomatic selection procedure, known as "element analysis," to a sample of 126 individuals from a small, ethnically homogeneous community in southern Italy. We investigated the effects of four independent variables--sex, age, weight, and alcohol consumption--on values for serum urea. Only sex and age proved to affect the urea values and were therefore introduced into the final model. This approach may be useful in determining reference intervals from observational studies when it is difficult to control a priori relevant factors. Moreover, variables may be selected not only on the basis of statistical criteria, but also according to biochemical and medical criteria.