Neuroendocrine Differentiation In Patients Research Articles

Novel biomarkers predict prognosis and drug-induced neuroendocrine differentiation in patients with prostate cancer.

A huge focus is being placed on the development of novel signatures in the form of new combinatorial regimens to distinguish the neuroendocrine (NE) characteristics from castration resistant prostate cancer (CRPC) timely and accurately, as well as predict the disease-free survival (DFS) and progression-free survival (PFS) of prostate cancer (PCa) patients. Single cell data of 4 normal samples, 3 CRPC samples and 3 CRPC-NE samples were obtained from GEO database, and CellChatDB was used for potential intercellular communication, Secondly, using the "limma" package (v3.52.0), we obtained the differential expressed genes between CRPC and CRPC-NE both in single-cell RNA seq and bulk RNA seq samples, and discovered 12 differential genes characterized by CRPC-NE. Then, on the one hand, the diagnosis model of CRPC-NE is developed by random forest algorithm and artificial neural network (ANN) through Cbioportal database; On the other hand, using the data in Cbioportal and GEO database, the DFS and PFS prognostic model of PCa was established and verified through univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression and multivariate Cox regression in R software. Finally, somatic mutation and immune infiltration were also discussed. Our research shows that there exists specific intercellular communication in classified clusters. Secondly, a CRPC-NE diagnostic model of six genes (HMGN2, MLLT11, SOX4, PCSK1N, RGS16 and PTMA) has been established and verified, the area under the ROC curve (AUC) is as high as 0.952 (95% CI: 0.882-0.994). The mutation landscape shows that these six genes are rarely mutated in the CRPC and NEPC samples. In addition, NE-DFS signature (STMN1 and PCSK1N) and NE-PFS signature (STMN1, UBE2S and HMGN2) are good predictors of DFS and PFS in PCa patients and better than other clinical features. Lastly, the infiltration levels of plasma cells, T cells CD4 naive, Eosinophils and Monocytes were significantly different between the CRPC and NEPC groups. This study revealed the heterogeneity between CRPC and CRPC-NE from different perspectives, and developed a reliable diagnostic model of CRPC-NE and robust prognostic models for PCa.

Prospective study on the relationship between clinical efficacy of secondary hormone therapy with flutamide and neuroendocrine differentiation in patients with relapsed prostate cancer after first line hormone therapy

Objective. The aim of this study was to prospectively verify the relationship between the clinical efficacies of secondary hormone therapy for castration-resistant prostate cancer (CRPC) following first line hormone therapy and neuroendocrine differentiation (NED). Material and methods. Forty-six consecutive patients with CRPC following first line hormone therapy who were treated with flutamide as secondary hormone therapy were prospectively assessed with a median follow-up of 21 months. Serum chromogranin A (CgA), as a marker of NED, was measured using an immunoradiometric assay. Results. Of the 46 patients, 22 (48%) responded to the secondary hormone therapy as a 50% or more reduction from baseline prostate-specific antigen (PSA) with a median response duration of 9.2 months. The PSA response group was correlated with significantly favorable cancer-specific survival (CSS) (92% vs 59% at 5 years, p = 0.0146) compared with the non-response group. Above-normal CgA levels at study entry were detected in 15 patients (33%), but no association with CSS was identified. Data on CgA kinetics were available in 35 patients. The CgA levels before and at 3 months during the treatment were similar. However, eight patients (23%) with an increase in CgA level of a quarter or more from baseline had a tendency for worse CSS (63% vs 84% at 5 years, p = 0.0507) compared with the remaining patients. Conclusion. Within limitations, in this study secondary hormone therapy with flutamide was effective for CRPC following first line hormone therapy. The above-normal CgA level in the first hormone resistance phase is mostly unrelated to prognosis. However, some patients with a remarkable increase in CgA in a short duration may have an unfavorable prognosis caused by NED as well.

Neuroendocrine differentiation correlates with hormone receptor expression and decreased survival in patients with invasive breast carcinoma

Invasive breast carcinoma (IBC) with neuroendocrine (NE) differentiation has been controversial in terms of its definition and clinical outcome. We investigated the incidence and clinical significance of NE differentiation in patients with IBC. We performed immunohistochemistry for NE markers, chromogranin-A and synaptophysin on 1428 IBC samples using tissue microarrays and classified cases with NE differentiation into two groups, focal (1-49% tumour cells positive for any NE marker) and diffuse (≥50% tumour cells positive) groups. Fifty-nine cases (4.1%) showed NE differentiation immunohistochemically, and the majority did not show typical NE morphology. The presence of NE differentiation showed a significant association with positive oestrogen receptor (P = 0.001) and progesterone receptor (P = 0.008) status. Patients with NE differentiation showed worse overall survival (OS) and disease-free survival (DFS) than those without NE differentiation in both univariate (P < 0.001 for both) and multivariate (OS, P = 0.004; DFS, P < 0.001) analyses. IBC with NE differentiation is a distinct subtype of mammary carcinoma with an aggressive clinical outcome.

C162 A prospective study of relationship between clinical efficacy of secondary hormone therapy with fultamide and neuroendocrine differentiation in patients with relapsed prostate cancer after first-line hormone therapy

C162 A prospective study of relationship between clinical efficacy of secondary hormone therapy with fultamide and neuroendocrine differentiation in patients with relapsed prostate cancer after first-line hormone therapy

The prognostic value of neuroendocrine differentiation in patients with undifferentiated-type gastric adenocarcinoma.

20 Background: Neuroendocrine carcinoma (NEC) of the stomach is defined as carcinoma having prominent (&gt;70%) neuroendocrine differentiation (NED), and is well known to be highly malignant tumor with extremely poor overall survival time. However the biological meaning of less NED in gastric adenocarcinoma is still unclear. The aim of this study is to identify the prevalence of NED in undifferentiated type gastric adenocarcinoma (UDGA) and to clarify the prognostic value of NED. Methods: A total of 112 patients with advanced UDGA who underwent curative resection at Shizuoka Cancer Center between January 2004 and December 2006 were included. We performed immunohistochemical analysis for neuroendocrine markers, and classified patients into four groups according to the result of the immunohistochemical study as follows: NEC group (n=6), NED &gt; 70%; MANEC (mixed adenoneuroendocrine carcinoma ) group (n=0), 30-70%; NED+ group (n=46), 1-30%; NED- group (n=60), NED &lt; 1%. In the present study, clinicopathological features were compared between the NED+ and NED- groups and independent prognostic factors were identified. Results: The patients in the NED+ group were significantly younger (61y) than the NED- group (63y, p=0.035). There were no differences in sex, tumor depth, lymph node metastasis, macroscopic type, tumor size, and histological type between the two groups. The five-year survival rates of the NED+ and the NED- groups were 75.7% and 56.5%, respectively. Overall survival was significantly better in the NED+ group than in the NED- group (p=0.030). Cox-proportional hazard model revealed that tumor invasion deeper than T3 (HR, 2.387; 95% CI, 1.114-5.114; p=0.025), lymph node involvement (HR, 3.000; 95% CI, 1.346-9.685; p=0.007) and presence of NED (HR, 0.478; 95% CI, 0.236-0.969; p=0.041) were selected as independent prognostic factors. Conclusions: The frequency of NED in UDGA was 41.1%. The long-term outcome in the NED+ group was better than that in the NED- group. Therefore, UDGA with NED might be clinicopathologically different from the NEC of the stomach and further large scale study should be warranted to determine the biological behavior and to estimate the proper treatment strategy.

Prognostic Significance of Neuroendocrine Differentiation in Patients With Gleason Score 8–10 Prostate Cancer Treated With Primary Radiotherapy

To determine the prognostic significance of neuroendocrine differentiation (NED) in Gleason score 8-10 prostate cancer treated with primary radiotherapy (RT). Chromogranin A (CgA) staining was performed and overseen by a single pathologist on core biopsies from 176 patients from the William Beaumont prostate cancer database. A total of 143 had evaluable biopsy material. Staining was quantified as 0%, <1%, 1-10%, or >10% of tumor cells. Patients received external beam RT alone or together with high-dose-rate brachytherapy. Cox regression and Kaplan-Meier estimates determined if the presence/frequency of neuroendocrine cells correlated with clinical endpoints. Median follow-up was 5.5 years. Forty patients (28%) had at least focal positive CgA staining (<1% n = 21, 1-10% n = 11, >10% n = 8). No significant differences existed between patients with or without staining in terms of age, pretreatment prostate-specific antigen, tumor stage, hormone therapy administration, % biopsy core involvement, mean Gleason score, or RT dose/modality. CgA staining concentration independently predicted for biochemical and clinical failure, distant metastases (DM), and cause-specific survival (CSS). For patients with <1% vs. >1% staining, 10-year DM rates were 13.4% vs. 55.3%, respectively (p = 0.001), and CSS was 91.7% vs. 58.9% (p < 0.001). As a continuous variable, increasing CgA staining concentration predicted for inferior rates of DM, CSS, biochemical control, and any clinical failure. No differences in outcomes were appreciated for patients with 0% vs. <1% NED. For Gleason score 8-10 prostate cancer, >1% NED is associated with inferior clinical outcomes for patients treated with radiotherapy. This relates most directly to an increase in distant disease failure.

The Possible Role of Chromogranin A as a Prognostic Factor in Organ-Confined Prostate Cancer

The clinical significance of neuroendocrine differentiation in patients who have undergone surgery for localized prostate cancer is still unclear. The aims of this study were to assess the relationship between serum neuroendocrine markers and well-known prognostic factors in prostate cancer (pathological staging, definitive Gleason score and serum PSA) and to search for correlations between serum chromogranin A (CgA) levels and pathological findings. Forty-one consecutive patients who had undergone radical retropubic prostatectomy for clinically localized prostate cancer were evaluated. Serum PSA, CgA and neuron-specific enolase were measured immediately before surgery. Twenty-six surgical specimens were phenotypically and immunohistochemically evaluated using an antibody against CgA. Significant correlations were found between serum CgA, pathological staging and Gleason score (p=0.049 and p=0.038, respectively). Serum CgA did not correlate with PSA, patient age, or immunohistochemical findings. There was a significant correlation between positive immunohistochemical CgA staining and Gleason score (p=0.014). An increase in serum CgA levels, independent of PSA values, might be the expression of pathologically more advanced tumor stage and higher Gleason score; this could help to identify a high-risk patient group eligible for adjuvant therapy.

The significance of neuroendocrine differentiation in adenocarcinoma of the esophagus and esophagogastric junction after preoperative chemoradiation

Esophageal and esophagogastric junction (EGJ) adenocarcinomas frequently have neuroendocrine (NE) differentiation, but the significance of NE differentiation in patients who have undergone preoperative chemoradiation and resection remains unclear. The authors evaluated the presence of NE differentiation in esophageal and EGJ adenocarcinomas by immunohistochemistry for chromogranin A and synaptophysin and evaluated the clinical significance of NE differentiation in 83 patients (10 patients who had a complete tumor response and 73 patients who had residual tumor in resection specimens) who received preoperative chemoradiation. Of 73 patients who had residual tumor after preoperative treatment, 52% showed NE differentiation. The proportion of tumor cells with NE differentiation had increased from 6% +/- 18% in pretreatment biopsy specimens to 47% +/- 42% (P = .00003) in posttreatment resection specimens in 30 patients who had paired pretreatment biopsy and resection specimens available. Disease-free survival (P = .002) and overall survival (P = .006) were significantly better in patients who had a complete tumor response than in patients who had residual tumor. Among patients who had residual tumor after preoperative chemoradiation, disease-free survival (P = .03) and overall survival (P = .045) were significantly better in patients who had residual tumor without NE differentiation than in patients who had residual tumor with NE differentiation. In multivariate analysis, the presence of NE differentiation in residual tumor was a prognostic factor for worse disease-free survival (P = .02) independent of pathologic stage and extent of residual tumor. The results from this study suggested that tumor cells with NE differentiation were more resistant to neoadjuvant chemoradiation in patients with esophageal and EGJ adenocarcinomas. The presence of NE differentiation in residual tumor was associated with poor survival after preoperative neoadjuvant therapy.

Circulating Chromogranin A and Hormone Refractory Prostate Cancer Chemotherapy

Neuroendocrine differentiation is a frequent pattern in prostate adenocarcinoma. CgA seems to be a useful indicator of neuroendocrine differentiation in patients with HRPC. We evaluated the clinical interest of circulating CgA in HRPC. Serum CgA was assessed by immunoradiometric assay in 39 patients with HRPC treated with paclitaxel and carboplatin or mitoxantrone. Baseline CgA and its variation during chemotherapy were studied. Increased serum CgA was observed in 45% of patients. Previous local radiotherapy and the duration of hormonal therapy were independent factors that influenced CgA. There was no correlation between CgA and prostate specific antigen. Increased serum CgA showed positive predictive significance but no prognostic value. The chemotherapy response correlated with a CgA decrease of greater than 25%. The current study suggests that CgA assessment facilitates patient selection by predicting the chemotherapy response and providing complementary information to follow the chemotherapy response.

The possible role of chromogranin A as a prognostic factor in organ-confined prostate cancer

The clinical significance of neuroendocrine differentiation in patients who have undergone surgery for localized prostate cancer is still unclear. The aims of this study were to assess the relationship between serum neuroendocrine markers and well-known prognostic factors in prostate cancer (pathological staging, definitive Gleason score and serum PSA) and to search for correlations between serum chromogranin A (CgA) levels and pathological findings. Forty-one consecutive patients who had undergone radical retropubic prostatectomy for clinically localized prostate cancer were evaluated. Serum PSA, CgA and neuron-specific enolase were measured immediately before surgery. Twenty-six surgical specimens were phenotypically and immunohistochemically evaluated using an antibody against CgA. Significant correlations were found between serum CgA, pathological staging and Gleason score (p=0.049 and p=0.038, respectively). Serum CgA did not correlate with PSA, patient age, or immunohistochemical findings. There was a significant correlation between positive immunohistochemical CgA staining and Gleason score (p=0.014). An increase in serum CgA levels, independent of PSA values, might be the expression of pathologically more advanced tumor stage and higher Gleason score; this could help to identify a high-risk patient group eligible for adjuvant therapy.

PD-090 Prognostic significance of neuroendocrine differentiation inpatients with stage I non-small cell lung carcinoma

PD-090 Prognostic significance of neuroendocrine differentiation inpatients with stage I non-small cell lung carcinoma

Prognostic implications of neuroendocrine differentiation and hormone production in patients with Stage I nonsmall cell lung carcinoma.

Approximately 10-20% of nonsmall cell lung carcinomas (NSCLC) show neuroendocrine (NE) differentiation, as evaluated by panendocrine markers or ultrastructural evidence of dense-core secretory granules. However, little is known regarding the prevalence and clinical implications of NE differentiation in patients with Stage I NSCLC. The authors analyzed 220 consecutive patients with Stage I NSCLC (pT1-T2N0M0) among 2100 patients with primary lung carcinoma who underwent surgical treatment between 1987 and 1993. Using light microscopy and immunohistochemical staining for synaptophysin, chromogranin A, and respiratory tract-related hormones, 28 NSCLC specimens with NE differentiation (NSCLC-ND) and 11 large cell neuroendocrine carcinoma (LCNEC) specimens were identified. The 28 NSCLC-ND specimens included 15 adenocarcinomas and 13 squamous cell carcinomas. Neoplastic cells with NE features never exceeded 20% in NSCLC-ND specimens, whereas neoplastic cells amounted to 20-90% in LCNEC specimens. NSCLC-ND specimens with > 5% NE-differentiated tumor cells showed increased Ki-67 labeling index (P = 0.007) and invasive phenotype, as evaluated by fascin immunoreactivity (P = 0.021). Patients with adenocarcinoma, but not with squamous cell carcinoma, who had > 5% NE-differentiated cells had a worse clinical course compared with patients who had ordinary NSCLC, with reduced overall survival (P = 0.017) and disease free survival (P = 0.049). In multivariate analysis, NE differentiation > 5% neoplastic cells in patients with adenocarcinoma independently predicted a poorer prognosis (hazard ratio, 2.61; 95% confidence interval, 0.99-6.85). Hormone production was restricted to chromogranin positive NSCLC-ND but did not affect prognosis. Stage I adenocarcinomas with >or= 5% NE tumor cells are clinically aggressive tumors, similar to LCNEC. Hormone production identifies a more fully developed neuroendocrine phenotype but is not relevant to prognosis. The identification of NE-differentiated cells in patients with NSCLC may have clinical relevance.

Focal neuroendocrine differentiation in non-small cell carcinoma is not predicted by pre-operative routine investigation

Aims: Between 10 and 35% of resected non-small cell carcinomas of the lung show focal neuroendocrine differentiation. The significance of this is uncertain but recent studies have suggested that these tumours may be more responsive to chemotherapeutic agents than other non-small cell carcinomas. This study was undertaken to determine if focal neuroendocrine differentiation in surgically resected non-small cell carcinomas could be predicted in patients who had undergone traditional routine pre-operative diagnostic investigations. Methods: Sixty-six consecutive resections for non-small cell carcinoma were reviewed for the presence of focal neuroendocrine morphology or positive immunohistochemical staining with neuroendocrine markers. Pre-operative biopsy and cytology samples from these patients were then sought for similar assessment. Results: Ten of the 66 cases showed either morphological or immunohistochemical evidence of neuroendocrine differentiation. All 10 patients had undergone pre-operative investigation including bronchoscopy but in only four were pre-operative diagnostic samples obtained (two cytology and two biopsies). None of these specimens showed features to suggest the presence of neuroendocrine differentiation within the resected tumours. Conclusion: The presence of focal neurendocrine features in an unselected series of resected non-small cell carcinomas was not predicted by traditional pre-operative diagnostic investigations This indicates that focal neuroendocrine differentiation in patients with unresectable non-small carcinoma cannot be reliably identified for inclusion in clinical trials using traditional investigate approaches.