No abstract

Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC. Cancer Res; 70(3); 1256–64

Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis. Over the past 15 years, critical developments in tumor grading, diagnostic biomarkers, radionuclide imaging, randomized controlled drug trials, evidence-based guidelines, and superior prognostic outcomes have substantially altered the field of NET care. Here, we review the relevant advances to clinical practice that have significantly upgraded our approach to NET patients, both in diagnostic and in therapeutic options.

Data regarding the diagnosis, management, and follow-up of carcinoid syndrome (CS) and carcinoid heart disease (CHD) were identified by searches of the MEDLINE database using specific terms in human studies: CS; CHD; screening; epidemiology; diagnosis; treatment; prognosis. The search results were supplemented by manual searching of relevant journals, reference lists in key articles and other appropriate documents, and expert opinion. All recommendations are offered on the basis of the best available evidence, supplemented by the authors' experiences in managing CS and CHD. Each recommendation for treatment will have a level of evidence and grade of recommendation as per the GRADE system (adapted in Infectious Disease society This first ENETS guidance paper on CS aims to provide practical guidance for NEN specialists in the diagnosis and management of CS, with special emphasis on CHD.

PurposeTherapy with [177Lu-DOTA,Tyr3]octreotate is effective in patients with grade I/II metastasized and/or inoperable bronchial neuroendocrine tumour (NET) or gastroenteropancreatic NET (GEP-NET). In this study, we investigated the efficacy and safety of salvage treatment with [177Lu-DOTA,Tyr3]octreotate.MethodsPatients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [177Lu-DOTA,Tyr3]octreotate over two cycles per retreatment with PRRT (R-PRRT) or re-retreatment with PRRT (RR-PRRT).ResultsThe safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0–98.2). Median cumulative doses were 44.7 GBq (range 26.3–46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2–≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4–16.9) following R-PRRT and 14.2 months (95% CI 9.8–18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0–95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed.ConclusionA cumulative dose of up to 60.5 GBq salvage PRRT with [177Lu-DOTA,Tyr3]octreotate is safe and effective in patients with progressive disease (relapse-PD) following I-PRRT with [177Lu-DOTA,Tyr3]octreotate. Safety appears similar to that of I-PRRT as no higher incidence of AML or MDS was observed. No grade III/IV renal toxicity occurred after retreatment.Electronic supplementary materialThe online version of this article (10.1007/s00259-018-4158-1) contains supplementary material, which is available to authorized users.

No abstract

Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.

Objectives Inoperable or metastatic paragangliomas (PGLs) and malignant pheochromocytomas (PCCs) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue (177LutetiumDOTA0-Tyr3)octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs. Methods Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1. Results Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs. Conclusion This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.