Emerging data supports a potential role of neurotensin (NT) in the development of obesity, obesity-associated comorbidities, and certain cancers. The association of NT with colon cancer risk has not been explicitly explored. We determined plasma levels of pro-NT, a stable NT precursor fragment, in 223 incident colon cancer patients and 223 age-, gender-, BMI-matched population controls participating in a population-based case–control study of colon cancer. On average, the cases have significantly higher levels of pro-NT than the controls (median = 205.6 pmol/L vs 183.1 pmol/L, respectively; P = 0.02). Multivariate logistic regression models, adjusted for age, gender, BMI, family history of colorectal cancer, smoking, diabetes mellitus, alcohol, and non-steroidal anti-inflammatory drugs use, show statistically significant risk associations: for continuous measure of pro-NT, the OR estimate was 1.30 (95% CI =1.03–1.64; P = 0.026) for each increment of 175 pmol/L; for dichotomized measure of pro-NT, the OR estimate was 1.75 (95% CI = 1.12–2.74; P = 0.025) for those in the top quartile comparing to the other participants. Our results support circulating levels of pro-NT as a novel risk biomarker for colon cancer.
Li Li, Heidi L Weiss, Jing Li, Zhengyi Chen, Leslie Donato, and B Mark Evers
Julie Refardt, Wouter T Zandee, Tessa Brabander, Richard A Feelders, Gaston J H Franssen, Leo J Hofland, Emanuel Christ, Wouter W de Herder, and Johannes Hofland
Sufficient expression of somatostatin receptor (SSTR) in well-differentiated neuroendocrine tumors (NETs) is crucial for treatment with somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) using radiolabeled SSAs. Impaired prognosis has been described for SSTR-negative NET patients; however, studies comparing matched SSTR-positive and -negative subjects who have not received PRRT are missing. This retrospective analysis of two prospectively maintained NET databases aimed to compare matched metastatic grade 1 or 2 SSTR-positive and –negative NET patients. SSTR-negativity was defined as having insufficient tumor uptake on diagnostic SSTR imaging. Patients that underwent PRRT were excluded. Seventy-seven SSTR-negative and 248 SSTR-positive grade 1–2 NET patients were included. Median overall survival rates were significantly lower for SSTR-negative compared to SSTR-positive NET patients (53 months vs 131 months; P < 0.001). To adjust for possible confounding by age, gender, grade and site of origin, 69 SSTR-negative NET patients were propensity score matched to 69 SSTR-positive NET patients. Group characteristics were similar, with the exception of SSTR-negative patients receiving more often chemotherapy and targeted treatment. The inferior survival outcome of SSTR-negative compared to SSTR-positive NET patients persisted with a median overall survival of 38 months vs 131 months (P = 0.012). This relationship upheld when correcting for the main influencing factors of having a higher grade tumor or receiving surgery in a multivariate Cox regression analysis. In conclusion, we showed that propensity score-matched SSTR-negative NET patients continue to have a worse prognosis compared to SSTR-positive NET patients despite receiving more aggressive treatment. Differences in tumor biology likely underlie this survival deficit.
Atsuko Kasajima and Günter Klöppel
The bronchopulmonary (BP) and gastroenteropancreatic (GEP) organ systems harbor the majority of the neuroendocrine neoplasms (NENs) of the body, comprising 20 and 70% of all NENs, respectively. Common to both NEN groups is a classification distinguishing between well- and poorly differentiated NENs associated with distinct genetic profiles. Differences between the two groups concern the reciprocal prevalence of well and poorly differentiated neoplasms, the application of a Ki67-based grading, the variety of histological patterns, the diversity of hormone expression and associated syndromes, the variable involvement in hereditary tumor syndromes, and the peculiarities of genetic changes. This review focuses on a detailed comparison of BP-NENs with GEP-NENs with the aim of highlighting and discussing the most obvious differences. Despite obvious differences, the principle therapeutical options are still the same for both NEN groups, but with further progress in genetics, more targeted therapy strategies can be expected in future.
Stephanie Espiard, Ludivine Drougat, Nikolaos Settas, Sara Haydar, Kerstin Bathon, Edra London, Isaac Levy, Fabio R Faucz, Davide Calebiro, Jérôme Bertherat, Dong Li, Michael A Levine, and Constantine A Stratakis
Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.
Jonathan M Fussey, Robin N Beaumont, Andrew R Wood, Bijay Vaidya, Joel Smith, and Jessica Tyrrell
Venessa H M Tsang, Matti Gild, Anthony Glover, Roderick Clifton-Bligh, and Bruce G Robinson
COVID-19 has modified the way we practice medicine. For thyroid cancer, there have been several significant impacts. First, the diagnosis has been delayed due to social isolation, reduced access to investigations and staff redeployment. Secondly, treatment planning has needed to take into account the risk to patients and/or staff of nosocomial transmission of the virus. Finally, there are some specific concerns with respect to interactions between the virus, its treatments and cancer. This mini-review aims to address each of these impacts and to provide some guidance and confidence to our patients and colleagues during this challenging time.
Kiran Nadella, Fabio R Faucz, and Constantine A Stratakis
Protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) defects lead to primary pigmented nodular adrenocortical disease (PPNAD). The KIT protooncogene (c-KIT) is not known to be expressed in the normal adrenal cortex (AC). In this study, we investigated the expression of c-KIT and its ligand, stem cell factor (SCF), in PPNAD and other cortisol-producing tumors of the adrenal cortex. mRNA and protein expression, by qRT-PCR, immunohistochemistry (IHC) and immunoblotting (IB), respectively, were studied. We then tested c-KIT and SCF responses to PRKAR1A introduction and PKA stimulation in adrenocortical cell lines CAR47 and H295R, which were also treated with the KIT inhibitor, imatinib mesylate (IM). Mice xenografted with H295R cells were treated with IM. There was increased c-KIT mRNA expression in PPNAD; IHC showed KIT and SCF immunoreactivity within certain nodular areas in PPNAD. IB data was consistent with IHC and mRNA data. PRKAR1A-deficient CAR47 cells expressed c-KIT; this was enhanced by forskolin and lowered by PRKAR1A reintroduction. Knockdown of PKA’s catalytic subunit (PRKACA) by siRNA reduced c-KIT levels. Treatment of the CAR47 cells with IM resulted in reduced cell viability, growth arrest, and apoptosis. Treatment with IM of mice xenografted with H295 cells inhibited further tumor growth. We conclude that c-KIT is expressed in PPNAD, an expression that appears to be dependent on PRKAR1A and/or PKA activity. In a human adrenocortical cell line and its xenografts in mice, c-KIT inhibition decreased growth, suggesting that c-KIT inhibitors may be a reasonable alternative therapy to be tested in PPNAD, when other treatments are not optimal.
Louis de Mestier, Anne Couvelard, Anela Blazevic, Olivia Hentic, Wouter W de Herder, Vinciane Rebours, Valérie Paradis, Philippe Ruszniewski, Leo J Hofland, and Jérôme Cros
The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.
Atanaska Elenkova, Rabhat Shabani, Elena Kinova, Vladimir Vasilev, Assen Goudev, and Sabina Zacharieva
Cardiomyopathy is a frequent complication of pheochromocytoma, and echocardiography is the most accessible method for its evaluation. The objective of this study was to assess the clinical significance of classical and novel echocardiographic parameters of cardiac function in 24 patients with pheochromocytomas (PPGL) compared to 24 subjects with essential hypertension (EH). Fourteen PPGL patients were reassessed after successful surgery. Left ventricular hypertrophy was four times more prevalent in patients with PPGL vs EH (75% vs 17%; P = 0.00005). Left ventricular mass index (LVMi) significantly correlated with urine metanephrine (MN) (rs = 0.452, P = 0.00127) and normetanephrine (NMN) (rs = 0.484, P = 0.00049). Ejection fraction (EF) and endocardial fractional shortening (EFS) were normal in all participants and did not correlate with urine metanephrines. Global longitudinal strain (GLS) was significantly lower in PPGL compared to EH group (−16.54 ± 1.83 vs −19.43 ± 2.19; P < 0.00001) and revealed a moderate significant positive correlations with age (rs = 0.489; P = 0.015), LVMi (rs = 0.576, P < 0.0001), MN (rs = 0.502, P = 0.00028) and NMN (rs = 0.580, P < 0.0001). Relative wall thickness (RWT) showed a strong positive correlation with urine MN (rs = 0.559, P < 0.0001) and NMN (rs = 0.689, P < 0.00001). Markedly decreased LVMi (118.2 ± 26.9 vs 102.9 ± 22.3; P = 0.007) and significant improvement in GLS (−16.64 ± 1.49 vs −19.57 ± 1.28; P < 0.001) was observed after surgery. ΔGLS depended significantly on the follow-up duration. In conclusion, classical echocardiographic parameters usually used for assessment of systolic cardiac function are not reliable tests in pheochromocytoma patients. Instead, GLS seems to be a better predictor for the severity and the reversibility of catecholamine-induced myocardial function damage in these subjects. RWT should be measured routinely as an early indicator of cardiac remodeling.
S G Creemers, R A Feelders, N Valdes, C L Ronchi, M Volante, B M van Hemel, M Luconi, M H T Ettaieb, M Mannelli, M D Chiara, M Fassnacht, M Papotti, M N Kerstens, G Nesi, H R Haak, F J van Kemenade, and L J Hofland
Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224–6.343; OR 1.467 95% CI 1.202–1.792, respectively; Hosmer–Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930–0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866–0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285–2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.