The role of MGMT promoter methylation as a predictive factor for temozolomide-based treatment in neuroendocrine neoplasms: a prospective observational study.

Temozolomide-based treatments have been demonstrated active in advanced NETs. However, treatment selection and sequencing are based solely on clinical parameters, since no biomarker is currently available to guide clinical management. MGMT-promoter methylation status is a good predictive factor for TEM treatment response in glioblastomas and melanomas and it is currently used in clinical practice. Differently, in NET patients, evidence on MGMT-promoter methylation status role is scarce. The aim of this study was to prospectively evaluate the role of MGMT status in predicting response to TEM-based treatment in NET patients. Primary endpoint was correlation of MGMT promoter methylation with PFS; secondary endpoints were correlation with OS, ORR, DCR, safety and cost analysis. A single-center, prospective observational trial has been conducted at ENETS Center-of-Excellence Outpatient Clinic of Policlinico-Sant’Orsola (Bologna). Patients with advanced, well-differentiated NETs of gastro-entero-pancreatic and lung origin candidate to TEM-based treatment, with tissue available for MGMT-promoter methylation analysis were enrolled. MGMT-promoter methylation status was analyzed by pyrosequencing on tumor tissue. Data of 22 patients were analyzed. Five patients (23%) presented MGMT-promoter methylation. In the MGMT-methylated population, median PFS was 34 months [IQR:15-58], compared to 14 [IQR:8-38] in non-methylated patients. MGMT-promoter methylation status was the only independent variable related to PFS. Better outcomes were observed in the MGMT-methylated group, also for OS (34vs21 months), DCR (100%vs88%) and ORR (80%vs24%). TEM-based treatment resulted a safe treatment, with low rate of adverse events (G≥3<10%). The cost of MGMT-promoter methylation testing by pyrosequencing is affordable (60 euros/patient) and the test is widely available. This study has prospectively demonstrated the role of MGMT-promoter methylation status as good predictive factor for TEM-based treatment in NET patients. Due to its promising predictive role, the wide availability and low costs of the assay, this biomarker could be implemented in clinical practice to guide treatment selection in NET patients

Prospective Evaluation of MGMT-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors

Temozolomide (TEM) as a single agent or in combination with capecitabine (CAPTEM) is active in well-differentiated advanced neuroendocrine tumors (NETs) of gastro-entero-pancreatic and thoracic origin. The predictive role of MGMT-promoter methylation in this setting is controversial. We sought to prospectively evaluate the MGMT-promoter methylation status ability to predict outcomes to TEM-based chemotherapy in patients with NET. A single-center, prospective, observational study has been conducted at the ENETS Center-of-Excellence Outpatient Clinic of the IRCCS Policlinico Sant’Orsola-Malpighi in Bologna, Italy. Patients with advanced, gastro-entero-pancreatic or lung well-differentiated NETs candidate to TEM-based chemotherapy and with available tumor samples for MGMT-promoter methylation assessment were included. The MGMT-promoter methylation status was analyzed by using pyrosequencing. The primary endpoint was progression-free survival (PFS) by the MGMT-promoter methylation status. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival outcomes were compared by restricted mean survival time (RMST) difference. Of 26 screened patients, 22 were finally enrolled in the study. The most frequent NET primary sites were the pancreas (64%) and the lung (23%). MGMT promoter was methylated in five tumors (23%). At a median follow-up time of 47.2 months (95%CI 29.3–89.7), the median PFS was 32.8 months (95%CI 17.2–NA), while the median OS was not reached. Patients in the methylated MGMT group, when compared to those in the unmethylated MGMT group, had longer PFS (median not reached [95%CI NA–NA] vs. 30.2 months [95%CI 15.2–NA], respectively; RMST p = 0.005) and OS (median not reached [95%CI NA–NA] vs. not reached [40.1–NA], respectively; RMST p = 0.019). After adjusting for confounding factors, the MGMT-promoter methylation status was independently associated to the PFS. Numerically higher ORR (60% vs. 24%; p = 0.274) and DCR (100% vs. 88%; p = 1.00) were observed in the methylated vs. unmethylated MGMT group. TEM-based chemotherapy was well-tolerated (adverse events grade ≥3 &lt; 10%). In this prospective study, MGMT-promoter methylation predicted better outcomes to TEM-based chemotherapy in patients with NET

Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study

Purpose: Temozolomide (TEM) based therapy has been reported being effective in the treatment of metastatic neuroendocrine neoplasms (NEN), with response rates ranging from 30 to 70%. Among patients affected by advanced glioblastoma or melanoma and treated with TEM, loss of tumoral O6-methylguanine DNA methyltransferase (MGMT) is correlated with improved survival. In NEN patients, the role of MGMT deficiency in predicting clinical outcomes of TEM treatment is still under debate. Methods: In this study we evaluated 95 patients with advanced NENs undergoing treatment with TEM-based therapy. MGMT promoter methylation status was evaluated with two techniques: methylation specific-polymerase chain reaction or pyrosequencing. Results: Treatment with TEM-based therapy was associated with an overall response rate of 27.4% according to RECIST criteria (51.8% of patients with and 17.7% without MGMT promoter methylation). Response to therapy, progression free survival and overall survival was correlated to MGMT status at univariate and multivariate analysis. Methylation of MGMT promoter could be a strong predictive factor of objective response and an important prognostic factor of a longer PFS and OS. Conclusion: According to our results, MGMT methylation status, evaluated with methylation specific-polymerase chain reaction or pyrosequencing, should have an important role in patients with metastatic NENs, in order to guide therapeutic options. These results need further confirmation with prospective studies

Prognostic value of normal sodium levels in patients with metastatic renal cell carcinoma receiving tyrosine kinase inhibitors

Background: Although serum sodium concentration, particularly hyponatremia, has been shown to be a prognostic marker of survival in metastatic renal cell carcinoma (mRCC), the impact of normal sodium levels has not been investigated. Herein, we investigate the influence of normonatremia in mRCC patients treated with tyrosine kinase inhibitors (TKIs). Materials and methods: For this retrospective study, the clinical and biochemical data of patients treated with first-line TKIs for mRCC were available from seven Italian cancer centers. We collected natremia levels at baseline and first evaluation after treatment excluding patients with sodium levels outside the normal range (&lt;135 or &gt;145 mEq/L). The remaining patients were subdivided into two groups according to the median sodium value: natremia patients with &lt;140 mEq/L (n = 132) and baseline natremia patients with ≥140 mEq/L (n = 185). Subsequently, we analyzed the impact of sodium levels on response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). PFS and OS were estimated through the Kaplan–Meier method, and differences between groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were applied to evaluate the prognostic factors for PFS and OS. Results: Of the 368 patients, 317 were included in the analysis, 73.1% were men, and the median age was 67 years (range 36–89). When comparing patients with baseline natremia ≥140 mEq/L (n = 185) to patients with natremia &lt;140 mEq/L (n = 132), the PFS was 15 vs. 10 months (p &lt; 0.01) and the OS was 63 vs. 36 months, respectively (p = 0.02). On the first evaluation, patients with serum sodium ≥140 mEq/L had longer PFS (15 vs. 10 months, p &lt; 0.01) and OS (70 vs. 32 months, p &lt; 0.01) than patients with levels &lt;140 mEq/L. Moreover, clinical outcomes showed a significant improvement in patients with natremia ≥140 mEq/L compared with patients with levels &lt;140 mEq/L both at baseline and first evaluation: PFS was 19 vs. 11 months (p &lt; 0.01) and OS was 70 vs. 36 months (p &lt; 0.01), respectively. Conclusions: To the best of our knowledge, this is the first study to investigate the impact of normonatremia in mRCC. We found that serum sodium levels &lt;140 mEq/L at baseline and first assessment are independently associated with worse PFS and OS in mRCC patients treated with TKIs in the first-line setting

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study

Introduction: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. Aim: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. Patients and methods: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th\ue2\u80\u9375th IQR). Results: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received \ue2\u89\ua5 3 vs \ue2\u89\ua4 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1\ue2\u80\u932 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. Conclusions: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases

The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment

Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that RCC usually shows a diffuse immune-cell infiltrate. ICIs target Cytotoxic T Lymphocytes Antigen 4 (CTLA-4), programmed death 1 (PD-1), or its ligand (PD-L1), showing promising therapeutic efficacy in RCC. PD-L1 expression is associated with poor prognosis; however, its predictive role remains debated. In fact, ICIs may be a valid option even for PD-L1 negative patients. The establishment of valid predictors of treatment response to available therapeutic options is advocated to identify those patients who could benefit from these agents. Both local and systemic inflammation contribute to tumorigenesis and development of cancer. The interplay of tumor-immune status and of cancer-related systemic inflammation is pivotal for ICI-treatment outcome, but there is an unmet need for a more precise characterization. To date, little is known on the role of inflammation markers on PD-1 blockade in RCC. In this paper, we review the current knowledge on the interplay between inflammation markers, PD-1 axis, and anti-angiogenic agents in RCC, focusing on biological rationale, implications for treatment, and possible future perspectives

68Ga-DOTANOC PET/CT Detects Multifocal Hepatocellular Carcinoma

Ga-DOTANOC PET/CT confirmed somatostatin receptor (SR) expression in hypervascularized liver lesions suggestive of neuroendocrine tumor that was later diagnosed as hepatocellular carcinoma (HCC). Being highly vascularized on CT, HCC lesions may mimic neuroendocrine tumors. Although HCC is not included among current indications for SR-PET/CT imaging, it may represent a pitfall in image interpretation when studying neuroendocrine tumor patients. Further studies are needed to better ascertain the potential diagnostic role of SR-imaging in HCC

Contrast-enhanced endoscopic ultrasound for the differential diagnosis between benign and malignant lymph nodes: a meta-analysis

Background The differential diagnosis between benign and malignant lymph nodes (LNs) is crucial for patient management and clinical outcome. The use of contrast-enhanced endoscopic ultrasound (EUS) has been evaluated in several studies with diverse results. The aim of this meta-analysis was to evaluate the pooled diagnostic accuracy of contrast-enhanced EUS (CE-EUS) and contrast-enhanced harmonic EUS (CH-EUS) in this setting.Methods A systematic electronic search was performed, including all original papers dealing with assessment of the nature of the LNs using CE-EUS or CH-EUS. A meta-analysis was performed to obtain pooled sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. The Summary Receiver Operating Characteristic (ROC) Curve method was used to calculate the area under the curve. Statistical analysis was carried out using Meta-Disc V.1.4, Stata V.12.0 and Review Manager V.5.2.Results Among 210 pertinent studies, four (336 patients) were included in the analysis. The pooled sensitivity was 82.1% (75.1-87.7%) and pooled specificity was 90.7% (85.9-94.3%) with significant heterogeneity found in sensitivity; the positive-likelihood ratio (LR) was 7.77 (5.09-11.85) and the negative-LR was 0.15 (0.05-0.46); the pooled diagnostic odds ratio (DOR) was 54 (15-190). Subgroup analysis including studies performed using CH-EUS (two studies, 177 LNs) showed a pooled sensitivity of 87.7% (77.0-93.9%) and a pooled specificity of 91.8% (84.5%-96.4%) with no significant heterogeneity; the pooled positive-LR was 9.51 (4.95-18.28) and the pooled negative-LR was 0.14 (0.06-0.35); pooled DOR was 68.42 (15.5-301.4).Conclusions From these data, CE-EUS is not recommended due to inadequate sensitivity. On the other hand, CH-EUS studies showed optimal accuracy (pooled sensitivity 87.7% and specificity 91.8%), comparable to elastography and even EUS-guided fine needle aspiration (EUS-FNA), suggesting a role in the diagnostic algorithm