Serum Levels Of Pro-gastrin-releasing Peptide Research Articles

Clinical utility of six serum tumor markers for the diagnosis of lung cancer

AbstractBackgroundWith the increasing prevalence of lung cancer, it has become imperative to identify reliable biomarkers that can aid in early detection and prognosis assessment. Therefore, we sought to investigate the potential utility of six serum tumor markers as diagnostic and prognostic tools for lung cancer patients. By analyzing a large cohort of patients with different stages and subtypes of lung cancer, we hoped to shed light on the predictive value and accuracy of each marker individually, as well as their combined performance. This study should not only provide valuable insights into the biology and pathogenesis of lung cancer but also pave the way for personalized treatment strategies based on individual patient profiles.MethodsThe serum levels of the tumor markers progastrin‐releasing peptide (ProGRP), carcinoembryonic antigen (CEA), neuron‐specific enolase (NSE), cytokeratin 19 fragment (CYFRA21‐1), carbohydrate antigen 19‐9 (CA19‐9) and squamous cell carcinoma antigen (SCCA) were meticulously assessed in a cohort comprising 324 individuals diagnosed with lung cancer and an additional 51 patients with benign lung disease. The measurements were conducted using cutting‐edge techniques such as ELISA, electrochemical luminescence, and chemiluminescence methods. Differences between groups and the impact of these markers on lung cancer diagnosis were analyzed.ResultsThe serum levels of ProGRP, NSE, and CEA were significantly higher in lung cancer patients than in patients with benign lung disease (p < 0.01). NSE had the highest sensitivity for squamous cell carcinomas (SC), while CEA had the highest sensitivity for adenocarcinomas (AC). ProGRP and NSE had higher sensitivities than other markers for small cell carcinomas (SCC). Combining the six tumor markers resulted in higher sensitivities for SC (70.6%), AC (77.4%), and SCC (80%) compared with any single test. Receiver operator characteristic analysis showed that ProGRP and NSE had a greater area under the curve (AUC) in SCC (0.886 and 0.775) than SC and AC, while CEA had a higher AUC in AC (0.716), and NSE had a higher AUC than other markers in SC (0.719).ConclusionsProGRP and NSE are effective serum tumor markers for SCC, whereas CEA and NSE may aid in the diagnosis of AC and SC. Combining the detection of ProGRP, NSE, CYFRA21‐1, CEA, and SCCA significantly improves sensitivity when diagnosing lung cancer.

Extracellular Vesicles Derived circSH3PXD2A Inhibits Chemoresistance of Small Cell Lung Cancer by miR-375-3p/YAP1.

Small cell lung cancer (SCLC) is a subtype of lung cancer with high malignancy and poor prognosis. Rapid acquisition of chemoresistance is one of the main reasons leading to clinical treatment failure of SCLC. Studies have indicated that circRNAs participate in multiple processes of tumor progression, including chemoresistance. However, the molecular mechanisms of circRNAs driving the chemoresistance of SCLC are not well specified. The differentially expressed circRNAs were screened by transcriptome sequencing of chemoresistant and chemosensitive SCLC cells. The EVs of SCLC cells were isolated and identified by ultracentrifugation, Western blotting, transmission electron microscopy, nanoparticle tracking analysis and EVs uptake assays. The expression levels of circSH3PXD2A in serum and EVs of SCLC patients and healthy individuals were detected by qRT‒PCR. The characteristics of circSH3PXD2A were detected by Sanger sequencing, RNase R assay, nuclear-cytoplasmic fraction assay, and fluorescence in situ hybridization assay. The mechanisms of circSH3PXD2A inhibiting SCLC progression were studied by bioinformatics analysis, chemoresistance assay, proliferation assay, apoptosis assay, transwell assay, pull-down assay, luciferase reporting assay, and mouse xenograft assay. It was identified that the circSH3PXD2A was a prominently downregulated circRNA in chemoresistant SCLC cells. The expression level of circSH3PXD2A in EVs of SCLC patients was negatively associated with chemoresistance, and the combination of EVs-derived circSH3PXD2A and serum ProGRP (Progastrin-releasing peptide) levels had better indications for DDP-resistant SCLC patients. CircSH3PXD2A inhibited the chemoresistance, proliferation, migration, and invasion of SCLC cells through miR-375-3p/YAP1 axis in vivo and in vitro. SCLC cells cocultured with EVs secreted by circSH3PXD2A-overexpressing cells exhibited decreased chemoresistance and cell proliferation. Our results manifest that EVs-derived circSH3PXD2A inhibits the chemoresistance of SCLC through miR-375-3p/YAP1 axis. Moreover, EVs-derived circSH3PXD2A may serve as a predictive biomarker for DDP-resistant SCLC patients.

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

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). 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. 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. These results suggest that TuM2-PK levels in the serum could be an effective biomarker for the diagnosis and prognosis of SCLC.

Diagnostic value of serum tumor markers CEA, CYFRA21-1, SCCAg, NSE and ProGRP for lung cancers of different pathological types

To evaluate the diagnostic value of the serum tumor markers carcinoembryonic antigen (CEA), cytokeratin-19-fragment (CYFRA21-1), squamous cell carcinoma associated antigen (SCCAg), neuron-specificenolase (NSE) and pro-gastrin-releasing peptide (ProGRP) for lung cancers of different pathological types. This study was conducted among patients with established diagnoses of lung adenocarcinoma (LADC, n=137), lung squamous cell carcinoma (LSCC, n=82), small cell lung carcinoma (SCLC, n=59), and benign chest disease (BCD, n=102). The serum tumor markers were detected for all the patients for comparison of the positivity rates and their serum levels. ROC curve was used for analysis of the diagnostic efficacy of these tumor markers either alone or in different combinations. In patients with LADC, the positivity rate and serum level of CEA were significantly higher than those in the other groups (P < 0.05); the patients with LSCC had the highest positivity rate and serum level of SCCAg among the 4 groups (P < 0.05). The positivity rates and serum levels of ProGRP and NSE were significantly higher in SCLC group than in the other groups (P < 0.05). CYFRA21-1 showed the highest positivity rate and serum level in LADC group and LSCC group. With the patients with BCD as control, CEA showed a diagnostic sensitivity of 62.8% and a specificity of 93.1% for LADC, and the sensitivity and specificity of SCCAg for diagnosing LSCC were 64.6% and 91.2%, respectively. CYFRA21-1 had the highest diagnostic sensitivity for LADC and LSCC. The diagnostic sensitivity and specificity of ProGRP for SCLC were 83.1% and 98.0%, respectively. When combined, CYFRA21-1 and CEA showed a high sensitivity (78.8%) and specificity (86.3%) for diagnosing LADC with an AUC of 0.891; CYFRA21-1 and SCCAg had a high sensitivity (84.1%) and specificity (87.3%) for diagnosing LSCC with an AUC of 0.912. NSE combined with ProGRP was highly sensitive (88.1%) and specific (98.0%) for diagnosis of SCLC, with an AUC of 0.952. For lung cancers of different pathological types, the combination of all the 5 tumor markers showed no significant differences in the diagnostic power from a combined detection with any two of the markers (P>0.05). CEA, CYFRA21-1, SCCAg, NSE and ProGRP are all related to the pathological type of lung cancers and can be used in different combinations as useful diagnostic indicators for lung cancers.

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.

Tumor-to-Tumor Metastasis: Pulmonary Carcinoid Metastasizing to Solitary Fibrous Tumor

Patient: Female, 81Final Diagnosis: Pulmonary carcinoid tumor • solitary fibrous tumorSymptoms: DiaphoresisMedication: —Clinical Procedure: SurgerySpecialty: OncologyObjective:Rare diseaseBackground:Tumor-to-tumor metastasis is an uncommon phenomenon in which a primary tumor metastasizes into another tumor.Case Report:An 81-year-old Asian woman was referred to our hospital for evaluation and treatment of a solid mass in the right middle lung lobe that had rapidly enlarged for 1.5 years compared to that observed over the last 5 years. On computed tomography (CT), the mass was 68×60 mm, and 2 different tumors appeared to exist in the upper portion of the mass. Blood examination findings revealed high serum levels of progastrin-releasing peptide and neuron-specific enolase. Based on the radiographic course of the tumor and elevated levels of tumor markers, we suspected that a new malignant tumor, such as a neuroendocrine tumor, had developed dorsally adjacent to the benign tumor. CT-guided percutaneous needle biopsy of the lung indicated a solitary fibrous tumor (SFT), which did not lead to the diagnosis of another tumor adjacent to the original tumor. Therefore, a right middle lobectomy was performed. The resected specimen contained 2 different tumors: an SFT and a typical carcinoid without mitosis or necrosis. On microscopic examination, they were separated from each other by normal alveolar tissue. In addition, a typical carcinoid was also observed inside the SFT lesion, completely enclosed by the SFT tissue. These findings suggested that the carcinoid metastasized to the SFT in the same lung lobe.Conclusions:To the best of our knowledge, this is the first case of a pulmonary typical carcinoid metastasizing to an intraparenchymal SFT.

Pro-gastrin-releasing peptide as a marker for the Ewing sarcoma family of tumors

Pro-gastrin-releasing peptide (ProGRP) is an established tumor marker of small cell lung cancer. The purpose of this study was to determine if ProGRP could serve as a tumor marker for the Ewing sarcoma family of tumors (ESFTs). Sixteen patients with ESFTs (mean age 32years) were included in this study. As a control group, 42 patients with other tumor types that clinically or pathologically mimic ESFTs were also analyzed. Pre-treatment serum ProGRP and neuron-specific enolase (NSE) levels, the relationships between these levels, and tumor volume were investigated. In addition, serial changes in the serum or plasma ProGRP (6 patients) and NSE levels (5 patients) were measured over the course of treatment. Pre-treatment serum ProGRP levels were higher than the normal range in 8 of 16 patients; for these eight patients, ProGRP levels positively correlated with tumor volume (R = 0.99). In the control group, ProGRP levels were within the normal range, except for the two patients. Changes in ProGRP levels during treatment were consistent with tumor volume. Serum NSE levels were elevated in 14 of 16 patients with ESFTs and 8 of 42 patients with other tumor types. The range of NSE elevation was much smaller compared to that of ProGRP. Our data indicate that ProGRP is superior to NSE in terms of specificity. Serum ProGRP levels were elevated in half of the patients with ESFTs and reflected therapeutic response. ProGRP is a reliable tumor marker for the diagnosis of ESFTs and evaluation of treatment response.

Application of magnetic resonance diffusion-weighted imaging combined with serum tumor markers in brain metastases of small cell lung cancer

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 χ 2 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 μg/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. Key words: Small-cell lung carcinoma; Brain metastases; Progastrin-releasing peptide; Neuron-specific enolase; Magnetic resonance imaging

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

Reliable reference intervals for serum progastrin-releasing peptide (ProGRP) in healthy Chinese adults with electrochemiluminescence immunoassay (ECLIA) are still lacking in the Chinese population. The study aims to establish reference intervals for ProGRP with ECLIA in apparently healthy Chinese adults. 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. 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. 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.

Age and Gender-Specific Reference Intervals for ProGRP in Healthy Chinese Han Ethnic Adults using the Roche Cobas Immunoassay.

Pro-gastrin-releasing peptide (ProGRP) is a kind of tumor marker applied more and more commonly in recent years. This study was aimed at determining the age and gender-specific reference intervals (RIs) for ProGRP in healthy Han ethnic adults from Guangxi, China. A total of 2,045 apparently healthy males and 1,740 apparently healthy females aged from 21 to 90 years were included in this study. The serum ProGRP values were determined by electrochemiluminescence immunoassay (ECLIA). The one-sided upper 95th percentile of ProGRP concentrations were used to define the RIs. The reference limits in different age groups (21 - 40, 41 - 50, 51 - 60, 61 - 70, and > 70 years) were 37.3, 39.7, 45.7, 47.3, and 61.3 pg/mL for males, and 36.3, 38.1, 42.7, 53.5, and 60.1 pg/mL for females, respectively. There was no significant difference in the levels of ProGRP between males and females. The serum ProGRP levels were positively correlated with age. We established the age and gender-specific RIs for ProGRP in the adults from Guangxi, China. It will be valuable for future clinical and laboratory studies.

Establishment of cut-off value of serum pro-gastrin-releasing peptide for diagnosis of small cell lung cancer and evaluation on the clinical diagnosis efficiency

Objective: To determine critical reference value (cut-off value) of serum pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase(NSE) in the diagnosis of small cell lung cancer(SCLC). To evaluate the clinical significance of serum levels of ProGRP and NSE in diagnosis and differential diagnosis in SCLC. Methods: Three hundred and fifty-two SCLC patients, 163 non small cell lung cancer(NSCLC)patients , 193 benign pulmonary disease patients and 140 healthy people visiting in National Cancer Hospital were analyzed retrospectively from January 2014 to July 2017.The levels of serum ProGRP and NSE of people were determined using electrochemiluminescent immunoassay respectively . Reference value ranges of the makers were determined by using the method of ROC curves. Results: In NSCLC group, benign lung disease group, healthy control group and mixed group (NSCLC+ lung benign diseases+ healthy control group) as a reference, the cut-off values were 58.3, 62.3, 57.8, 61.3 ng/L. In the diagnosis and differential diagnosis of SCLC and NSCLC, benign lung diseases, healthy controls and mixed group, AUC of ProGRP was 0.940 (0.919-0.961), 0.941 (0.921-0.960), 0.959 (0.944-0.975), 0.946 (0.928-0.963) respectively. The sensitivities of ProGRP were 86.4%, 84.9%, 86.4% and 84.7% respectively. The specificities of ProGRP were 95.7%, 96.9%, 99.3%, 98% respectively. In all groups the Youden's index of ProGRP and NSE were 0.821 vs 0.612, 0.818 vs 0.674, 0.857 vs 0.810, 0.827 vs 0.674. In healthy controls, no statistically significant difference was found between ProGRP and NSE (P>0.05) in the diagnosis of AUC. However, in the remaining 3 groups, the ProGRP diagnosis of AUC was significantly greater than that of NSE (P<0.01). Compared with single marker detection, the sensitivity of combined detection of ProGRP and NSE in diagnosis of SCLC increased to 95.5%, 94%, 96.6% and 94% in each group. There was no significant difference between ProGRP and ProGRP+ NSE in the diagnosis of AUC when compared with the NSCLC group and the mixed group (P>0.05). However, when combined with a healthy control group and a benign lung disease group, the ProGRP+ NSE combination was the highest for AUC diagnosis, compared with ProGRP and NSE (P<0.01). In the SCLC ED group serum ProGRP and NSE levels[776.33(3 103.4)ng/L, 52.14(60.59)μg/L]were higher than those in the SCLC LD group[295.59(799.65)ng/L, 23.36(22.97)μg/L], respectively (all P<0.001). The serum ProGRP levels of N0, N1, N2 and N3 in TNM staging were 113.0(343.65), 167.04(724.56), 427.42(1 388.62), 735.99(1 709.95)ng/L respectively (all P<0.001). Serum ProGRP and NSE levels were not statistically different between the sex groups and the age groups (all P>0.05). Conclusion: To establish the cut-off value of serum ProGRP is helpful for the diagnosis and differential diagnosis of SCLC.

The prognostic significance of the circulating neuroendocrine markers chromogranin A, pro-gastrin-releasing peptide, and neuron-specific enolase in patients with small-cell lung cancer

Lung cancer is the most common cancer, and small-cell lung cancer (SCLC) accounts for around 20% of lung cancers. SCLC has a neuroendocrine cellular origin, and the tumor cells usually express neuroendocrine markers. There have been major recent advances in the management of SCLC, and multimodal approaches are now the norm. An improved knowledge of the prognostic variables would assist in defining which patients were better candidates to receive these newer intensive therapies. This single-center retrospective study of 97 previously untreated and histologically proven SCLC patients analysed the circulating neuroendocrine markers chromogranin A (CGA), pro-gastrin-releasing peptide (ProGRP), and neuron-specific enolase (NSE) in addition to the other more classical variables. Fifty patients had limited-stage disease and 47 had extensive disease. Sixty patients had an ECOG performance status (PS) of 0-1 and 37 had PS 2-4. Median survival for the whole study population was 13months. Univariate analysis and univariate Cox regression modeling found a statistically significant association between survival and PS, disease stage, and CGA, ProGRP, and NSE levels. Age and sex were not prognostic. A shorter survival time was found in patients with a PS equal to or >2, extensive stage disease, a serum CGA level >56ng/ml, a serum ProGRP level >58pg/ml, and a serum NSE level >19ng/ml. This study has found that there is a potential role for ProGRP, NSE, and CGA in both staging and prognosing survival in SCLC patients.

Correlation study on the serum levels of ProGRP and NSE with different treatments in limited disease small cell lung cancer

Objective To study the correlation of the serum levels of pro-gastrin-releasing peptide (ProGRP) and neuro-specific enolase (NSE) with different treatments in limited-disease small cell lung cancer (L-SCLC) patients.Methods 150 L-SCLC patients were randomly divided into three groups including concurrent chemo-radiotherapy group,sequential chemo-radiotherapy group,and chemotherapy group.The serum levels of ProGRP and NSE were detected by enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay before and after different treatments.The follow-up phase was 12 months.Results The serum levels of ProGRP and NSE were significantly decreased in all 3 groups after treatment (318.96,250.77,226.18 pg/ml and 31.72,23.95,17.89 μg/L),and the lowest level was observed in concurrent chemo-radiotherapy group,then the sequential chemo-radiotherapy group and chemotherapy group.The short term therapeutic effects were in the same sequence,and there was statistical significance between concurrent chemoradiotherapy group and chemotherapy (P ＜ 0.05).The decrease extent of ProGRP and NSE in effective cases (CR+PR) was significantly higher than that in failure cases in all 3 groups.The serum levels of ProGRP and NSE were increased with disease progress (P ＜ 0.05).Conclusion The serum levels of ProGRP and NSE can be used to reflect the patient' s condition and evaluate therapeutic effect in L-SCLC.The concurrent chemo-radiotherapy is more effective than sequential chemo-radiotherapy and chemotherapy only in L-SCLC. Key words: Carcinoma, small cell lung ; Pro-gastrin-releasing peptide ; Neuro-specific enolase ; Curative effect

Serum progastrin‐releasing peptide levels followed by whole‐body positron emission tomography detects early recurrence of small‐cell lung cancer

A 65-year-old male smoker with severe COPD was diagnosed with limited-stage small-cell lung cancer. After receiving cisplatin/irinotecan, serum progastrin-releasing peptide (ProGRP) levels decreased to within the reference values and the lesions were markedly reduced in size. A whole-body 18F-fluorodeoxyglucose PET (FDG-PET) scan confirmed complete remission. During follow up, serum ProGRP levels increased, and a whole-body FDG-PET scan detected recurrence at the hilar lymph node that had been negative on CT. Complete remission was again achieved with second-line chemotherapy (cisplatin/etoposide) and local irradiation to the hilar lymph node. Monitoring serum ProGRP levels, followed by whole-body FDG-PET when indicated, may improve the clinical management of patients with small-cell lung cancer after initial complete remission.

Small-cell neuroendocrine carcinoma as a variant form of prostate cancer recurrence: A case report and short literature review

Background Small-cell neuroendocrine carcinoma has been recognized as a rare histologic variant occurring in only 0.5% to 2% of prostatic primary tumors. However, recent autopsy studies suggest development to this phenotype in up to 10% to 20% of the cases with hormone-refractory disease. Case Presentation A case of conventional adenocarcinoma before androgen-ablation therapy but showing progression to small-cell neuroendocrine carcinoma at the recurrence. The immunohistochemistry of the tumor showed strong positive staining for progastrin-releasing peptide (ProGRP), a carboxy terminal region common to 3 precursors for gastrin-releasing peptide, but almost negative staining for chromogranin-A and prostate-specific antigen. Combination chemotherapy based on cisplatin and etoposide was effective for controlling the tumor progression for 7 months, and the serum ProGRP level correlated well to the clinical course. Neither objective nor subjective responses were observed to somatostatin analogue therapy performed in the late stage of disease. Conclusions The present case reminds the urologist that small-cell neuroendocrine carcinoma may be a variant form of disease recurrence during androgen ablation in advanced prostate cancer. A strategic approach for this phenotype evaluating serum neuroendocrine markers, such as ProGRP, should be taken when serum prostate-specific antigen does not reflect the disease state. This approach would allow one to choose alternative therapies targeting neuroendocrine cells other than androgen ablation.

The Prognostic Significance of Circulating Neuroendocrine Markers Chromogranin A, Pro-Gastrin-Releasing Peptide and Neuron-Specific Enolase in Patients with Advanced Non-Small-Cell Lung Cancer

Background: Chromogranin A (CGA), Pro-gastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE) are known as immunohistochemical tissue markers closely associated with neuroendocrine differentiation in non-small-cell lung carcinoma (NSCLC). The aim of the present study was to assess the value of serum levels of these markers in predicting response to chemotherapy and survival of patients with unresectable NSCLC. Methods: The study included 67 patients with advanced NSCLC treated with chemotherapy. Before treatment, serum levels of CGA, ProGRP and NSE were measured with commercial kits. Results: No association was found between serum NSE and age, gender, histology, performance status or extent of the disease. Distribution of serum CGA differed significantly according to gender and histology, with higher levels being found in men (p = 0.01) and in squamous cell carcinoma (p = 0.01). Serum ProGRP levels correlated with disease extent, being higher in patients with metastatic disease (M1) than in those with locoregional disease (M0; p = 0.02). The association of NSE, CGA and ProGRP levels with response to chemotherapy was not significant. While NSE had no impact on survival, the median survival was shorter for patients with elevated serum CGA and longer for patients with high ProGRP levels. Association with survival was significant when the Classification and Regression Tree (CART)-derived or median cutoff points were explored. On inclusion in multivariate Cox models, both CGA and ProGRP retained significance with high levels showing an opposite effect on survival [CART-derived cutoff points: CGA, relative risk (RR) –4.0; p < 0.001, and ProGRP, RR –0.4; p = 0.006, and median cutoff points: CGA, RR –1.8; p = 0.04, and ProGRP, RR –0.5; p = 0.03]. The combined use of CGA, ProGRP and NSE allowed for definition of two sets of patients with significantly different median survival times (25.2 vs. 8.8 months, p = 0.0001). Conclusions: In the circulation, CGA and Pro-GRP appear to bear important information related to the prognosis for NSCLC patients before chemotherapy. While a high CGA before treatment was found as an unfavorable prognostic determinant, a high ProGRP conferred a survival advantage. The combined use of serum CGA, ProGRP and NSE may supply additional information to prognosis.

Elevated serum progastrin-releasing peptide (31-98) level is a predictor of short response duration after hormonal therapy in metastatic prostate cancer.

The neuroendocrine (NE) pathway has been attracting attention as a mechanism for the androgen-independent progression because the neuropeptide provokes tumor growth and inhibits apoptosis under androgen-deprived milieu in prostate cancer cells. On the basis that serum progastrin-releasing peptide (ProGRP) is elevated in patients with advanced disease stage, we examined the prognostic value of the neuropeptide. Serum ProGRP status was determined with an enzyme-linked immunosorbent assay (ELISA) in 460 men with benign and malignant prostatic diseases, chronic renal failure, and healthy controls. Seventy patients with metastatic prostate cancer including four patients (5.7%) with NE carcinoma who underwent hormonal therapy were enrolled in the prognostic analyses by Cox proportional hazards model. The serum status steadily shifted toward predominant expression of ProGRP with the progression of prostate cancer into metastatic and androgen-independent stages. Univariate analysis revealed that the deteriorated performance status (PS) and extent of bony disease (EOD), and high serum alkaline phosphatase (ALP), serum ProGRP, and nadir prostate-specific antigen (PSA) levels were associated with a lower progression-free survival (PFS) rate (P < 0.005). Multivariate analysis demonstrated that PS, serum ProGRP, and nadir PSA held an independent predictive value for PFS (P < 0.05), and all correlated with bone-related factors. Serum ProGRP was the most significant predictor among pre-treatment factors in this model (P = 0.0094). The neuropeptide precursor ProGRP is a distinct serum marker that is useful to know the NE milieu and provides prognostic information in patients with advanced prostate cancer. Standard therapy for metastatic prostate cancer may make progress when further studies will clarify the causative link between serum ProGRP level and androgen-independent disease progression.

Elevated serum progastrin-releasing peptide (31-98) in metastatic and androgen-independent prostate cancer patients.

Increases in neuroendocrine phenotype and secretory products are closely correlated with tumor progression and androgen independence in prostate cancer. In this study, we explored this correlation using serum progastrin-releasing peptide (ProGRP), a carboxy-terminal region common to three subtypes of precursors for gastrin-releasing peptide (GRP), which is released from the neuroendocrine phenotype to act as a growth factor. In 60 patients with benign prostatic hyperplasia (BPH) and 200 with prostate cancer, serum ProGRP levels were determined with an enzyme-linked immunosorbent assay (ELISA) kit and evaluated in relation to clinical stage, hormonal treatment, and prostate-specific antigen (PSA) values. Fourteen randomly selected patients were entered in the follow-up study. Additionally, expression of ProGRP as determined by immunohistochemical analysis was compared to that of chromogranin-A (CgA) in tissue samples from several subjects. We found a positive correlation between PSA and ProGRP in patients with untreated prostate cancer; no correlation was found in the treated groups. The increases in the ProGRP value and in the percentage of patients with higher than normal values were significant (P < 0.0001), especially in the androgen-independent group (P < 0.0001). A longitudinal study showed that, in a subset of patients, the ProGRP values tended to increase transiently when the cancer became androgen independent, but remained unchanged or decreased at the androgen-dependent stage. Positive staining for ProGRP occurred in a different distribution in neuroendocrine tissues than that of staining for CgA. The clinical results demonstrated the existence of a regulatory mechanism for GRP, which to date had only been observed in cell lines. These findings suggest that GRP is a growth factor potentially upregulated by androgen but that does not rely principally on androgen modulation. The large overlap in levels of ProGRP among the groups limits the use of this value as a monitoring tool. Measurement of ProGRP, however, does have potential as an independent parameter to evaluate androgen-independent progression and to facilitate a new therapeutic strategy that may compensate for current limitations of diagnosis based on PSA alone.

Complementary roles of pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in diagnosis and prognosis of small-cell lung cancer (SCLC)

In this study, we evaluated the clinical usefulness of ProGRP and NSE for diagnosis and prognosis of small-cell lung cancer (SCLC). Serum levels of ProGRP and NSE were determined in 108 healthy subjects, 103 patients with benign pulmonary diseases, 142 with non-small cell lung cancer (NSCLC), and 114 with SCLC. Sensitivity of ProGRP in diagnosis of SCLC was significantly higher than that of NSE (64.9 vs. 43.0%, P<0.001). The difference was substantial in patients with limited disease (56.5 vs. 20.3%, P<0.001). However, 11 of 40 SCLC patients with normal levels of serum ProGRP (27.5%) showed elevated levels of serum NSE. In the SCLC patients receiving chemotherapy, the CR rate in patients with elevated NSE levels was significantly lower than in patients with normal levels of NSE (18.5 vs. 61.7%, P<0.001). Elevation of both ProGRP and NSE was a poor prognostic factor, and patients with elevated levels of either ProGRP or NSE showed shorter survival than those without. From multivariate analysis, NSE was found to have a greater effect on survival of SCLC patients than ProGRP. These findings indicate that ProGRP is more sensitive than NSE for diagnosis of SCLC, while NSE is superior to ProGRP as a prognostic factor. In conclusion, both ProGRP and NSE are useful tumor markers and they have a complementary role for each other in diagnosis and prognosis of SCLC.

Serum Pro-Gastrin-Releasing Peptide Is a Useful Marker for Treatment Monitoring and Survival in Small-Cell Lung Cancer

We investigated the usefulness of serum pro-gastrin-releasing peptide (Pro-GRP) as a tumor marker for diagnosis, treatment monitoring and the prediction of relapse and prognosis in patients with small-cell lung cancer (SCLC). Serum samples were obtained from 127 patients with primary lung cancer (48 patients with small-cell carcinoma, 31 with adenocarcinoma, 36 with squamous cell carcinoma and 11 with large-cell carcinoma). The cutoff levels of serum Pro-GRP and neuron-specific enolase (NSE) were set at 46 pg/ml and 10 ng/ml, respectively. The specificity of Pro-GRP was significantly higher than that of NSE (Pro-GRP: 93.7%, NSE: 65.8%, p < 0.01). According to the histological type of lung cancer, the positive rates of Pro-GRP were 75% (36/48) in the small-cell carcinomas, 9.7% (3/31) in the adenocarcinomas, 5.6% (2/36) in the squamous cell carcinomas and 0% (0/10) in the large cell carcinomas. The median levels of Pro-GRP in limited disease (LD) and extensive disease (ED) patients were 199 and 295.5 pg/ml, whereas those of NSE were 14.8 and 29.3 ng/ml, respectively. The positive rates of Pro-GRP in LD and ED patients were 80.0% (16/20) and 71.4% (20/28), whereas those of NSE were 70.0% (14/20) and 89.3% (25/28), respectively. The positive rate of NSE tended to elevate with the progression of disease, whereas that of Pro-GRP was already high at an early stage. Among the 29 patients with SCLC who could be followed, the serum Pro-GRP levels of 18 responders were significantly decreased after treatment (p < 0.01), whereas those of the 11 nonresponders were not significantly different between before and after treatment (p = 0.72). In the 9 patients with SCLC who relapsed, the serum Pro-GRP levels were again elevated at the time of relapse. Seventeen patients whose ratio of the Pro-GRP level after treatment to the level before treatment was below 50% (taking the levels before treatment as 100%) survived significantly longer than did the patients whose ratio was over 50% (p < 0.01). The results of the present study suggest that serum Pro-GRP has high specificity and could be a useful marker of SCLC for treatment monitoring and prognosis.