Progastrin-Releasing Peptide As a Diagnostic Biomarker of Pulmonary and Non-Pulmonary Neuroendocrine Neoplasms.

BACKGROUND: Progastrin-releasing peptide (ProGRP) is the precursor of the gastrin-releasing peptide, a neuropeptide secreted by cells of neural and endocrine origin. Recently, ProGRP has emerged as a circulating biomarker for small cell lung cancer (SCLC), a subtype of aggressive and poorly differentiated neuroendocrine neoplasm (NEN). Given the ability of the neuroendocrine SCLC cells to secrete this peptide, we performed an in-depth narrative review aimed at collecting, summarizing, and critically analyzing the available literature about the possible value of ProGRP as a biomarker for pulmonary NENs other than SCLC, and for NENs of non-pulmonary origin. METHODS: We conducted an extensive search on international databases (PubMed, Web of Science, and Scopus). RESULTS: We selected 21 pertinent published articles (12 original studies and 9 case reports). Overall, the original studies included 1,711 patients, and the case reports described the clinical course of 10 patients. CONCLUSION: The data analyzed suggest a potential role for ProGRP as a diagnostic biomarker for typical and atypical lung carcinoids, pulmonary large cell neuroendocrine carcinoma, medullary thyroid carcinoma, non-pulmonary neuroendocrine carcinomas, prostate cancer with neuroendocrine differentiation, and the pancreatobiliary neuroendocrine carcinoma. Despite these promising results, additional studies are needed, to clarify the role of ProGRP as the diagnostic biomarker for specific NENs.

Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study.

OBJECTIVES: This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. METHODS: In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. RESULTS: All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups (P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. CONCLUSIONS: HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.

Evaluating the diagnostic and prognostic value of serum TuM2-PK, NSE, and ProGRP in small cell lung cancer.

BACKGROUND: The aim of this study was to explore the diagnostic and prognostic value of serum tumor M2-pyruvate kinase (TuM2-PK), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) levels in patients with small cell lung cancer (SCLC). METHODS: The levels of serum TuM2-PK, NSE, and ProGRP in 102 patients with SCLC, 60 patients with benign lung disease (BLD), and 90 healthy controls were detected. RESULTS: The serum TuM2-PK, NSE, and ProGRP levels in the SCLC group were higher than those in BLD group (p < 0.05) and healthy control group (p < 0.05). The sensitivity of TuM2-PK, NSE, and ProGRP detection in SCLC was 82.35%, 60.78%, and 77.45% respectively, and specificity was 91.11%, 81.11%, and 86.67%, respectively. The area under the curve (AUC) of SCLC resulting from TuM2-PK was significantly better than that of NSE and ProGRP. The application of TuM2-PK combined with NSE and ProGRP improved the diagnostic yield of SCLC patients and had better diagnostic value than TuM2-PK alone. Univariate and multivariate analysis indicated that an elevated TuM2-PK level was an independent prognostic factor for shorter survival in SCLC. CONCLUSIONS: These results suggest that TuM2-PK levels in the serum could be an effective biomarker for the diagnosis and prognosis of SCLC.

Plasma Progastrin-Releasing Peptide and Chromogranin A Assays for Diagnosing and Monitoring Lung Well-Differentiated Neuroendocrine Tumors: A Brief Report.

INTRODUCTION: The use of chromogranin A (CGA) as a circulating biomarker in lung carcinoids (LCs) is limited by low specificity and sensitivity. This study aimed to evaluate plasma progastrin-releasing peptide (ProGRPp) as an alternative to plasma CGA (CGAp), for the diagnosis and follow-up of LC. METHODS: ProGRPp and CGAp concentrations were measured in 107 patients with LC and 105 patients with benign lung disease (BLD). RESULTS: ProGRPp distinguished patients with LC with active disease in the pretreatment (n = 43) and post-treatment (n = 43) groups from those with BLD: area under the curve for both 0.864 (p < 0.0001); sensitivity 67.4% and 58.1%, respectively; specificity 96.2%; at 64 pg/mL cutoff. CGAp failed to differentiate both LC groups from those with BLD: area under the curve 0.579 and 0.526 (for both p > 0.1); sensitivity 34.9% and 25.6%, respectively; specificity 73.3%; at 104 ng/mL cutoff. Only ProGRPp correlated with the Ki67 proliferation index (r = 0.40, p < 0.001) and was associated with mitotic count (p = 0.025), stage (p = 0.018), grade (p = 0.019), and the expression of thyroid transcription factor-1 (p = 0.005). ProGRPp had a high sensitivity (92.3%) in LC with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Abnormal postoperative ProGRPp level was associated with residual disease (p = 0.029). The changes in ProGRPp level during treatment, a decrease greater than 30% and an increase greater than 8%, were associated with image-based outcomes, partial response and disease progression, respectively (p < 0.0001). CGAp did not reflect the disease course. CONCLUSIONS: ProGRPp was superior to CGAp in diagnosing LC with correlations concerning proliferation, grading, staging, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia co-occurrence, and response to treatment. ProGRPp is an optimal emerging biomarker to be further evaluated.

Plasma progastrin-releasing peptide level shows different predictive profiles for treatment response by androgen receptor axis-targeted agents in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration-resistant prostate cancer (CRPC) progression. The neuromediator, gastrin-releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin-releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis-targeted (ARAT) agents. METHODS: One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first-line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate-specific antigen (PSA) response and survival estimates. RESULTS: In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: -34.5% vs. low ProGRP: -85.7% p = .033). PSA progression-free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA-PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA-PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003). CONCLUSIONS: Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA- and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.

Age-stratified and gender-specific reference intervals of six tumor markers panel of lung cancer: A geographic-based multicenter study in China.

BACKGROUND: Serum biomarkers have been widely adopted in clinical practice for assisting lung cancer diagnoses, therapeutic monitoring, and prognostication. The function of a well-performing tumor biomarker depends on a reliable reference interval (RI) with consideration of the study subjects' age, gender, and geographical location. This study aimed to establish a RI for each of 6 lung cancer biomarkers for use in the whole country of China on Mindray platform. METHODS: The levels of serum 6 lung cancer biomarkers-namely progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), squamous cell carcinoma antigen (SCC), carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), and human epididymis protein 4 (HE4)-were measured utilizing the chemiluminescence immunoassay on the Mindray CL-6000i platform following the laboratory standard operating procedures in apparently healthy Chinese individuals on large cohort, multicenter, and geographical consideration bases. The CLSI EP28-A3C guideline was followed for the enrollment of study subjects. RESULTS: The age-stratified, gender-specific RIs for ProGRP, NSE, SCC, CEA, CYFRA21-1, and HE4 lung cancer biomarkers in the Chinese population have been established as described in the results and discussion in this work. In addition, various levels of the six lung cancer biomarkers among nine geographical locations in China have been observed. CONCLUSIONS: The sample volume of study cohort, age, and geographical location should be considered upon establishing a reliable biomarker RI. A RI for each of six lung cancer biomarkers has been established. The results from this study would be helpful for clinical laboratories in interpreting the analytical results and for clinicians in patient management.

Circulating pro-gastrin releasing peptide (ProGRP) in patients with medullary thyroid carcinoma.

OBJECTIVES: Serum calcitonin (CT) is pivotal in medullary thyroid cancer (MTC) management. Recently, progastrin releasing peptide (ProGRP) has been proposed as a candidate complementary tumor marker of MTC. As current data are sparse our study was undertaken to evaluate the distribution of ProGRP in patients with MTC and its relationship with the tumor burden. Additionally, serial measurement of CT, carcinoembryonic antigen (CEA) and ProGRP was evaluated in three patients undergoing tyrosine kinase inhibitors (TKI). METHODS: Seventy-eight, 125 and 62 sera from patients with MTC, non-medullary malignant and benign thyroid diseases were collected, respectively. ProGRP measurement was performed by Elecsys® assays on Cobas e601 platform (Roche Diagnostics). RESULTS: Significantly higher ProGRP levels were found in MTC compared to non-MTC patients. Among MTC patients ProGRP levels accurately discriminate patients with active from those with cured disease and, respectively, patients with loco-regional active disease from those with distant metastasis. Finally, ProGRP performed better than CT and CEA in monitoring the response to TKI therapy in three patients monitored serially. CONCLUSIONS: Serum ProGRP is promising as a complementary tumor marker in MTC patients. Further studies will be required, mainly focused on monitoring ProGRP during TKI treatment for early detection of resistance and assessing its usefulness to avoid the observed false positive fluctuations that occur with CT and carcinoembryonic antigen.

Decline in serum progastrin-releasing peptide predicts the response of patients with small cell lung cancer to chemotherapy.

The utility of serum progastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE) as biomarkers for treatment monitoring and as prognostic factors was investigated in small cell lung cancer (SCLC) patients. Patients were first diagnosed pathologically at the First Affiliated Hospital of the University of Science and Technology of China and had their serum ProGRP and NSE levels measured using an electrochemiluminescence immunoassay. A total of 120 SCLC patients were enrolled. In responsive patients, ProGRP levels decreased significantly following two cycles of chemotherapy and continued to decline over the course of treatment. However, this decrease in ProGRP levels was not observed in non-responsive patients. Changes in ProGRP levels were more accurate than changes in NSE levels for monitoring the effects of chemotherapy in patients with SCLC. Following two treatment cycles or after the occurrence of drug resistance, changes in ProGRP levels in patients with low ProGRP levels at the time of diagnosis were not notably, regardless of whether or not patients were responders. The area under the receiver operating characteristic curve of the decline in ProGRP levels as a therapeutic biomarker of SCLC was 0.9643, and the cut-off value was 55.02%. A decline in ProGRP levels maybe a good predictor of objective response to chemotherapy in patients with SCLC with higher ProGRP levels at diagnosis. This model is expected to replace or be combined with imaging to predict chemotherapeutic treatment effects in patients with SCLC.

A continuous responder algorithm to optimize clinical management of small-cell lung cancer with progastrin-releasing peptide as a simple blood test.

This study aimed to investigate whether changes in progastrin-releasing peptide (ProGRP) levels correlate with treatment response and can be used to optimize clinical management of patients with small-cell lung cancer. Patients with small-cell lung cancer (any stage) receiving chemotherapy were eligible. ProGRP was measured in serum/plasma at baseline and after each chemotherapy cycle using the Elecsys® ProGRP assay (Roche Diagnostics). Treatment response was assessed by computed tomography scan. The primary objective was to examine whether changes in ProGRP levels correlated with computed tomography scan results after two cycles of chemotherapy. The prognostic value of ProGRP among patients receiving first-line chemotherapy was also assessed. Overall, 261 patients from six centers were eligible. Among patients with elevated baseline ProGRP (>100 pg/mL), a ProGRP decline after Cycle 2 was associated with nonprogression (area under the curve: 84%; 95% confidence interval: 72.8-95.1; n = 141). ProGRP changes from baseline to end of Cycle 1 were predictive of response, as determined by computed tomography scan 3 weeks later (area under the curve: 87%; 95% confidence interval: 74.1-99.2; n = 137). This was enhanced by repeat measurements, with a 92% area under the curve (95% confidence interval: 85.3-97.8) among patients with ProGRP data after both Cycles 1 and 2 (n = 123); if a patient experienced a ≥25% decline in ProGRP after Cycle 1, and ProGRP remained stable or decreased after Cycle 2, the probability of finding progression on the interim computed tomography scan at the end of Cycle 2 was almost zero (sensitivity: 100%, specificity: 71%). Both ProGRP levels at baseline and at the end of first-line chemotherapy were prognostic; the latter provided a moderately improved hazard ratio of 2.43 (95% confidence interval: 1.33-4.46; n = 110) versus 1.87 (95% confidence interval: 1.04-3.37; n = 216). In summary, for patients with small-cell lung cancer and elevated baseline ProGRP levels, ProGRP may be a simple, reliable, and repeatable tool for monitoring response to chemotherapy and provide valuable prognostic information.

Increased Progastrin-Releasing Peptide Expression is Associated with Progression in Gastric Cancer Patients.

PURPOSE: The purpose of this study was to assess the diagnostic and prognostic value of serum progastrin-releasing peptide (ProGRP) in patients with gastric cancer (GC). MATERIALS AND METHODS: A total of 150 patients with GC (89 males and 61 females) were recruited, including those with stage I (n=28), stage II (n=33), stage III (n=50), and stage IV (n=39) disease; 50 healthy controls and 66 patients with benign gastric diseases were also enrolled. Levels of serum ProGRP, carcinoembryonic antigen (CEA), and carbohydrate antigen 72-4 (CA72-4) were measured in all subjects. RESULTS: Serum ProGRP levels were significantly higher in GC patients than in controls (p<0.001), and ProGRP was significantly correlated with tumor size, tumor node metastasis stage, differentiation, invasion depth, and lymph node metastasis (p< 0.005). ProGRP levels were significantly decreased after chemotherapy (p<0.001). Receiver operating characteristic curves revealed a sensitivity and specificity for serum ProGRP in GC of 85.9% and 81.2%, respectively. ProGRP levels were positively correlated with CA72-4 and CEA (r=0.792 and 0.688, p<0.05, respectively). Combined detection of ProGRP, CEA, and CA72-4 showed the best diagnostic power for GC. CONCLUSION: ProGRP may be useful as a potential biomarker for GC diagnosis and therapy.

Increased Progastrin-Releasing Peptide Expression is Associated with Progression in Gastric Cancer Patients

High Sensitive Immunoelectrochemical Measurement of Lung Cancer Tumor Marker ProGRP Based on TiO2-Au Nanocomposite.

Progastrin-releasing peptide (ProGRP), which is known to be highly specific and sensitive to small cell lung cancer (SCLC), has been proven to be a valuable substitute for neuron-specific enolase in SCLC diagnostics and monitoring, especially in its early stages. The detection of ProGRP levels also facilitates a selection of therapeutic treatments. For the fabrication of our proposed biosensor, titanium (IV) oxide microparticles were first used, followed by dispersing gold nanoparticles into chitosan and immobilizing them onto a carbon paste electrode (CPE) surface. The developed immunosensor exhibits a much higher biosensing performance in comparison with current methods, when it comes to the detection of ProGRP. Therefore, the proposed CPE/TiO2/(CS+AuNPs)/anti-ProGRP/BSA/ProGRP is excellent for the development of a compact diagnostics apparatus.

A case of ectopic ACTH syndrome due to DDAVP-sensitive but V1b receptor-negative bronchial typical carcinoid with lymphatic metastasis and plasma ProGRP elevation.

Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing's syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.

Diagnostic and therapeutic value of progastrin-releasing peptide on small-cell lung cancer: A Single-Center Experience in China.

We aimed to compare the diagnostic efficiency of proGRP and NSE on SCLC and to investigate whether the change of proGRP level would predict therapeutic response. Patients who were firstly diagnosed pathologically in Nanjing Chest Hospital and measured proGRP level consecutively were enrolled in the study. ProGRP level was detected using Elecsys ProGRP Assay. Totally 75 SCLC, 234 NSCLC and 264 benign lung diseases (BLD) were enrolled. Both proGRP and NSE levels in SCLC were significantly higher than those in NSCLC and BLD, and proGRP in extensive stage SCLC was higher than which in limited stage (P ≤ .001). The diagnostic efficiency of proGRP on SCLC was higher than that of NSE, but when the two biomarkers were bind together, the diagnostic efficiency was the best. When SCLC was differentiated from NSCLC and BLD, the cut-off values were 114.35 pg/mL and 162.55 pg/mL respectively. For treatment responsive patients, proGRP level decreased markedly after the first cycle of therapy and kept a continued momentum of decline during treatment. But for unresponsive patients, no obvious decline was observed. ProGRP had higher diagnostic efficiency on SCLC when compared to NSE, and it could better predict therapeutic response of pulmonary target lesions on chemotherapy.

Reference intervals for serum progastrin-releasing peptide in healthy Chinese adults with electrochemiluminescence immunoassay.

BACKGROUND: Reliable reference intervals for serum progastrin-releasing peptide (ProGRP) in healthy Chinese adults with electrochemiluminescence immunoassay (ECLIA) are still lacking in the Chinese population. OBJECTIVES: The study aims to establish reference intervals for ProGRP with ECLIA in apparently healthy Chinese adults. METHODS: A total of 384 apparently healthy individuals from six representative geographical regions in China were enrolled: 200 males and 184 females with a mean age of 43.4±12.2 years, and an age range from 21 to 85 years. Serum ProGRP levels were analyzed on Cobas e601 automatic immunoassay analyzer with ECLIA. Reference intervals for serum ProGRP with ECLIA were determined following CLSI C28-A3 guidelines using a nonparametric method. RESULTS: In an apparently healthy Chinese population, the reference intervals for serum ProGRP with ECLIA were ⩽53.92 ng/L for adults aged 21-70 years and ⩽75.69 ng/L for adults aged >70 years, respectively. CONCLUSIONS: The reference values for serum ProGRP with ECLIA in an apparently healthy Chinese population were established according to the CLSI C28-A3 document, providing a reference for the clinical work.

Clinical value of Pro-GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC-CIK biological therapy.

The present study investigated the aptness of assessing the levels of progastrin-releasing peptide (Pro-GRP) in addition to the T lymphocyte subpopulation in lung cancer patients prior to and after therapy for determining immune function. A total of 45 patients with lung cancer were recruited and stratified in to a non-small cell lung cancer (NSCLC) and an SCLC group. Prior to and after treatment by combined biological therapy comprising chemotherapy or chemoradiotherapy followed by three cycles of retransformation of autologous dendritic cells-cytokine-induced killer cells (DC-CIK), the peripheral blood was assessed for populations of CD3+, CD4+, CD8+ and regulatory T cells (Treg) by flow cytometry, and for the levels of pro-GRP, carcinoembryonic antigen, neuron-specific enolase and Cyfra 21-1. The results revealed that in NSCLC patients, CD8+ T lymphocytes and Treg populations were decreased, and that CD3+ and CD4+ T lymphocytes as well as the CD4+/CD8+ ratio were increased after therapy; in SCLC patients, CD3+, CD4+ and CD8+ T lymphocytes were increased, while Treg cells were decreased after treatment compared with those at baseline. In each group, Pro-GRP was decreased compared with that prior to treatment, and in the SCLC group only, an obvious negative correlation was identified between Pro-GRP and the T lymphocyte subpopulation. Furthermore, a significant correlation between Pro-GRP and Tregs was identified in each group. In conclusion, the present study revealed that the immune function of the patients was improved after biological therapy. The results suggested a significant correlation between Pro-GRP and the T lymphocyte subpopulation in SCLC patients. Detection of Pro-GRP may assist the early clinical diagnosis of SCLC and may also be used to assess the immune regulatory function of patients along with the T lymphocyte subpopulation. Biological therapy with retransformed autologous DC-CIK was indicated to enhance the specific elimination of tumor cells and improve the immune surveillance function in cancer patients, and also restrained the immune evasion of the tumor, leading to decreased Pro-GRP levels.

Correlation of serum neuron-specific enolase and progastrin-releasing peptide with initial chemotherapeutic effect and survival of patients with small cell lung cancer / 肿瘤研究与临床

Objective To investigate the relationships of neuron-specific enolase (NSE) and progastrin-releasing peptide (ProGRP) with the initial chemotherapeutic effect and survival of patients with small-cell lung cancer (SCLC).Methods A total of 197 patients with SCLC diagnosed pathologically from January 2011 to September 2013 in Shanxi Provincial Cancer Hospital were selected.x 2 test and logistic regression analysis were used to analyze the factors affecting the initial chemotherapeutic response;KaplanMeier method,log-rank test and Cox regression analysis were used to analyze the factors affecting survival of patients.Results Among the 197 patients,NSE was negative in 64 cases and positive in 133 cases;ProGRP was negative in 51 cases and positive in 146 cases;41 cases with hyponatremia and 156 cases without hyponatremia.152 cases (77.2 ％) had well response to initial treatment and 45 cases (22.8 ％) had no reaction.Univariate analysis showed that stage of disease (x2 =4.456,P =0.033) and ProGRP (x2 =13.424,P ＜ 0.001) were associated with initial therapeutic response.Logistic regression analysis showed that stage of disease (OR =0.404,95 ％ CI 0.197-0.828％,P =0.013) and ProGRP (OR =4.058,95 ％ CI 1.939-8.491,P =0.000) were the independent predictors of initial therapeutic response.Kaplan-Meier survival analysis showed that sex,age,smoking,with or without hyponatremia,stage of disease,NSE,ProGRP and number of chemotherapy cycles were all associated with 2-year survival rate (x2 values were 4.319,6.811,4.264,4.687,32.631,41.045,11.379,33.466,respectively,all P ＜ 0.05).Multivariate analysis showed that stage of disease (RR =2.110,95 ％ CI 1.491-2.985,P ＜ 0.001),number of chemotherapy cycles (RR =0.398,95 ％ CI 0.283-0.588,P ＜ 0.001) and NSE (RR =1.422,95 ％ CI 1.113-1.784,P =0.002) were independent predictors of survival.However,ProGRP was not associated with survival of patients (RR =1.065,95 ％ CI 0.854-1.328,P =0.587).Conclusions ProGRP is associated with the initial chemotherapeutic response in patients with SCLC,and it has certain clinical significance in predicting the initial chemotherapeutic effect.NSE is associated with the survival prognosis of SCLC,and it is a prognostic factor of poor survival.

Application of magnetic resonance diffusion-weighted imaging combined with serum tumor markers in brain metastases of small cell lung cancer / 肿瘤研究与临床

Objective To investigate the value of magnetic resonance diffusion-weighted imaging (DWI) in combination with peripheral serum tumor markers in the diagnosis and therapeutic evaluation of small cell lung cancer (SCLC) brain metastases.Methods Retrospective analysis of 368 SCLC cases diagnosed by histopathology or cytology from February 2009 to February 2012 in Shanxi Provincial Cancer Hospital was made.All patients underwent pathological examination of progastrin-releasing peptide (ProGRP),neuron-specific enolase (NSE) and brain DWI,and measured the apparent diffusion coefficient (ADC) of DWI sequences of brain metastases.The difference between the positive rates of ProGRP and NSE in patients with or without brain metastases was compared by the X2 test,and the diagnostic efficiency of ProGRP,NSE,DWI and combined detection for brain metastases were analyzed.The Kruskal-Wallis H test was used to compare the changes of ADC value,ProGRP and NSE before and after brain irradiation therapy in brain metastases of SCLC.Pearson correlation analysis was made to evaluate the correlation between the changes of ADC value and the levels of ProGRP and NSE in SCLC patients with brain metastases before and after treatment.Results The median expression of serum ProGRP in 169 SCLC patients was 2 664.7 pg/ml (98.4-4 876.8 pg/ml),with a positive rate of 98.2 ％ (166/169).The median expression of NSE was 41.9 μg/L (9.4-264.3 μg/L),with a positive rate of 70.4 ％ (119/169).The median expression of serum ProGRP level was 514.3 pg/ml (3.9-2 899.3 pg/ml) in 199 SCLC patients without brain metastasis,the positive rate was 89.4 ％ (178/199).The median expression of NSE was 40.4 μg/L (0.3-176.1 μ,g/L),with a positive rate of 64.8 ％ (129/199).The difference of ProGRP level between the two groups was statistically significant (u =121.47,P ＜ 0.001),but there was no significant difference in NSE level (u =1.35,P =0.12).The sensitivities of ProGRP,NSE,DWI,ProGRP+DWI and NSE+DWI were 68.4 ％,41.2 ％,66.7 ％,92.2 ％,and 82.4 ％,and the specificities were 52.9 ％,35.3 ％,76.5 ％,94.1％,and 88.2 ％.The sensitivity and specificity of ProGRP+DWI and NSE+DWI were higher than those of single test,and the differences were statistically significant (all P ＜ 0.001).One hundred and fifty-six SCLC patients with brain metastases were treated with whole brain radiotherapy.Pearson correlation analysis showed that ADC values were negatively correlated with ProGRP and NSE levels (r =-0.945,P ＜ 0.001;r =-0.995,P ＜ 0.001).Conclusion DWI combined with ProGRP and NSE can provide objective evidence and clinical guidance for the diagnosis of SCLC brain metastases and the evaluation of whole brain radiotherapy.

Progastrin-releasing peptide as a diagnostic and therapeutic biomarker of small cell lung cancer.

BACKGROUND: Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small cell lung cancer (SCLC). We evaluated the usefulness of plasma proGRP level as a tumor marker for diagnosis and treatment monitoring in patients with SCLC. METHODS: Plasma samples were collected prospectively from 452 [212 non-small cell lung cancer (NSCLC), 105 SCLC, and 135 other diseases] patients who visited the hospital for tissue diagnosis. Plasma proGRP levels were measured using a two-step automated immunoassay. RESULTS: The median proGRP level was significantly higher in patients with SCLC (892.7 pg/mL) than those with NSCLC (32.6 pg/mL, P<0.001) and other diseases (26.6 pg/mL, P<0.001). At cutoff level of 63 pg/mL, proGRP shows 85.7% sensitivity, 90.2% specificity, 72.5% positive predictive value and 95.4% negative predictive value in patients with SCLC. The area under the curve values were 0.93 for distinguishing SCLC from NSCLC, and 0.943 for distinguishing SCLC from the other conditions. Median proGRP level was higher in extensive disease (1,055.2 pg/mL) than limited disease (253.8 pg/mL, P=0.005). Median OS was significantly shorter in patients with extensive disease (6.0±0.7 months) than limited disease (12.7±4.5 months, P<0.01). Among the 39 patients with SCLC who were followed, the median proGRP levels of the 23 responders decreased after chemotherapy (P<0.001). CONCLUSIONS: Plasma proGRP level could be a useful diagnostic and therapeutic monitoring biomarker for patients with SCLC and the initial level may help with SCLC tumor staging.

Instability of Plasma and Serum Progastrin-Releasing Peptide During Repeated Freezing and Thawing.

OBJECTIVES: Progastrin-releasing peptide (proGRP) is a promising biomarker for small cell lung cancer. However, not much is known about how sample processing and storage conditions affect the stability of proGRP. Here, we examined the effects of repeated freeze-thaw cycles on the stability of proGRP in plasma and serum. METHODS: Concentrations of proGRP were measured in plasma and serum samples exposed to two, three, or four freeze-thaw cycles and these were compared with values of corresponding samples exposed to one cycle (baseline). We also performed the area under the receiver-operating-characteristic curve (AUC) analysis to determine whether the differences of proGRP concentrations between each paired plasma and serum sample (ΔproGRP) can be used for identifying the samples that have been exposed to multiple freeze-thaw cycles. RESULTS: Concentrations of proGRP gradually decreased in both plasma and serum samples with increasing numbers of freeze-thaw cycles. Reduction rates of proGRP concentrations were greater in serum than in plasma samples and serum proGRP levels declined with statistical significance (p < 0.001) up to 10.1% after four freeze-thaw cycles. The ΔproGRP measurement showed fair accuracy (AUC = 0.741) for identifying samples that had been through four freeze-thaw cycles. The sensitivity was 82.8% and specificity was 62.1% at an optimal cut-off point of > 4.9. CONCLUSION: Our study shows that the stability of circulating proGRP is affected in both plasma and serum samples by repeated freezing and thawing. We also show that ΔproGRP could be used for identifying paired plasma and serum samples subjected to multiple freeze-thaw cycles.