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Open access

Camilo Jimenez, Bennett B Chin, Richard B Noto, Joseph S Dillon, Lilja Solnes, Nancy Stambler, Vincent A DiPippo, and Daniel A Pryma

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

Open access

Alessandra Mangone, Barbara Altieri, Mario Detomas, Alessandro Prete, Haider Abbas, Miriam Asia, Yasir S. Elhassan, Giovanna Mantovani, and Cristina L Ronchi

Treatment for advanced adrenocortical carcinoma (ACC) consists of mitotane alone or combined with etoposide, doxorubicin and cisplatin (EDP). Although both therapies are widely used, markers of response are still lacking. Since inflammation-based scores have been proposed as prognostic factors in ACC, we aimed to investigate their role in predicting the response to first-line chemotherapy.

We performed aretrospective analysis of patients with advanced ACC treated with mitotane monotherapy or EDP±mitotane. Clinical parameters (tumour stage at diagnosis, resection status, Ki67, time from diagnosis to treatment start, performance status, plasma mitotane levels, time in mitotane target ≥80%, clinically overt cortisol hypersecretion) and pretreatment inflammation-based scores [neutrophil-to-lymphocyte-ratio (NLR), platelet-to-lymphocyte-ratio (PLR), monocyte-to-lymphocyte-ratio (MLR), derived neutrophil-to-lymphocyte ratio (dNLR)] were investigated. The primary endpoints were overall survival (OS) and time-to-progression (TTP) from treatment initiation, the secondary endpoint was the best objective response to treatment.

We included 90 patients (59%=women, median age=51 years) treated with mitotane monotherapy (n=40) or EDP±mitotane (n=50). In the mitotane monotherapy cohort, NLR≥5 and PLR≥190 predicted shorter OS (HR: 145.83, 95%CI: 1.87-11323.83; HR: 165.50, 95%CI: 1.76-15538.04, respectively), remaining significant at multivariable analysis including clinical variables. NLR was also associated with shorter TTP (HR: 2.58, 95%CI: 1.28-5.20), but only at univariable analysis. Patients with NLR≥5 showed a worse treatment response than those with NLR<5 (p=0.040). In the EDP±mitotane cohort, NLR≥5 predicted shorter OS (HR: 2.52, 95%CI: 1.30-4.88) and TTP (HR: 1.95, 95%CI: 1.04-3.66) at univariable analysis.

In conclusion,inflammation-based scores, calculated from routinely measured parameters, may help predict response to chemotherapy in advanced ACC.

Open access

Xiaoli Liu, Chunhai Zhang, Xiaomiao Wang, Can Cui, Hanwen Cui, Baishu Zhu, Anqi Chen, Lu Zhang, Jingwei Xin, Qingfeng Fu, Gianlorenzo Dionigi, and Hui Sun

Lymphatic metastasis is the leading cause responsible for recurrence and progression in papillary thyroid cancer (PTC), where dysregulation of lncRNAs have been extensively demonstrated to be implicated. However, the specific lymphatic node metastatsis-related (LNM) lncRNAs remain not identified in PTC yet. LNM lncRNA, MFSD4A-AS1, were explored in PTC dataset from TCGA, and our clinical samples. The roles of MFSD4A-AS1 in lymphatic metastasis were investigated by in vitro, and in vivo. Bioinformatic analysis, Luciferase assay and RIP assay were performed to identify the potential targets and the underlying pathway of MFSD4A-AS1 in lymphatic metastasis of PTC. MFSD4A-AS1 was specifically upregulated in PTC tissues with lymphatic metastasis. Upregulating MFSD4A-AS1 promoted mesh formation and migration of HUVECs and invasion and migration of PTC cells. Importantly and consistently, MFSD4A-AS1 promoted lymphatic metastasis of PTC cells in vivo by inducing the lymphangiogenic formation and enhancing invasive capability of PTC cells. Mechanistic dissection further revealed that MFSD4A-AS1 functioned as ceRNA to sequester miR-30c-2-3p, miR-145-3p and miR-139-5p to disrupt the miRNAs-mediated inhibition of VEGFA and VEGFC, and further activated TGF-β signaling by sponging miR-30c-2-3p that targeted TGFBR2 and USP15, both of which synergistically promoted lymphangiogenesis and lymphatic metastasis of PTC. Our results unravel a novel dual mechanisms by which MFSD4A-AS1 promotes lymphatic metastasis of PTC, which will facilitate the development of anti-lymphatic metastatic therapeutic strategy in PTC.

Open access

Dimitrios Papantoniou, Malin Grönberg, Espen Thiis-Evensen, Halfdan Sorbye, Kalle Landerholm, Staffan Welin, and Eva Tiensuu Janson

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2), which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000-2019). Median cancer-specific survival (CSS) on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy, and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide-receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3-5%, 5-10% and 10-20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively) while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNa), everolimus and chemotherapy was 6, 5 and 9 months. IFNa seemed to be effective in tumours with low somatostatin-receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Open access

Yuanliang Li, Yiying Guo, Zixuan Cheng, Chao Tian, Yingying Chen, Ruao Chen, Fuhuan Yu, Yanfen Shi, Fei Su, Shuhua Zhao, Zhizheng Wang, Jie Luo, and Huangying Tan

The genetic characteristics of rectal neuroendocrine tumors (R-NETs) were poorly understood. Depicting the genetic characteristics may provide a biological basis for prognosis prediction and novel treatment development. Tissues of 18 R-NET patients were analyzed using whole-exome sequencing. The median tumor mutation burden (TMB) and microsatellite instability (MSI) were 1.15 Muts/MB (range, 0.03-23.28) and 0.36 (range, 0.00-10.97) respectively. Genes involved in P53 signaling, PI3K-AKT signaling, DNA damage repair, WNT signaling, etc. were frequently altered. Higher TMB (P = 0.078), higher CNV (P = 0.110), somatic mutation of CCDC168 (P = 0.049), HMCN1 (P = 0.040), MYO10 (P = 0.007), and amplification of ZC3H13 (P < 0.001) were associated with shorter OS. Potentially targetable gene alterations (PTGAs) were seen in 72% of the patients. FGFR1 amplification (22%) was the most common PTGA followed by BARD1 and BRCA2 mutation (each 17%). As for gene variations associated with the efficacy of immune checkpoint blockade (ICB), FAT1 alteration (39%) and PTEN depletion (28%) were commonly observed. In conclusion, frequently altered oncogenic pathways might contribute to the development and progression of R-NETs. Gene alterations significantly associated with prognosis might be potential novel targets. Targeted therapy might be a promising strategy as targetable alterations were prevalent in R-NETs. FAT1 alteration and PTEN depletion might be the main genetic alterations influencing the response to ICB besides overall low TMB and MSI in R-NETs.

Open access

Konsta Kukkonen, Bryn Autio-Kimura, Hanna Rauhala, Juha Kesseli, Matti Nykter, Leena Latonen, and Tapio Visakorpi

Prostate cancer research suffers from the lack of suitable models to study the role of normal cells in prostate carcinogenesis. To address this challenge, we developed a cell line model mimicking luminal prostate epithelial cells by modifying the immortalized prostate epithelial cell line RWPE-1 to constitutively express the androgen receptor (AR). RWPE-1-AR cells express known AR target genes, and exhibit coexpression of luminal and basal markers characteristic of transient amplifying cells, and an RNA signature resembling prostate luminal progenitor cells. Under unstimulated conditions, constitutive AR expression does not have a biologically significant effect on the proliferation of RWPE-1 cells, but when stimulated by androgens, growth is retarded. The transcriptional response of RWPE-1-AR cells to androgen stimulation involves suppression of the growth-related KRAS pathway and is thus markedly different from that of the prostate cancer cell line LNCaP and its derivative AR-overexpressing LNCaP-ARhi cells, in which growth- and cancer-related pathways are upregulated. Hence, the nonmalignant AR-positive RWPE-1-AR cell line model could be used to study the transformation of the prostate epithelium.

Open access

N Tufton, R J Hearnden, D M Berney, W M Drake, L Parvanta, J P Chapple, and S A Akker

Emerging evidence suggests the composition of the tumour microenvironment (TME) correlates with clinical outcome and that each tumour type has a unique TME including a variable population of inflammatory cells. We performed immunohistochemistry on 65 phaeochromocytoma and paraganglioma (PPGL) tumour samples with 20 normal adrenal medulla samples for comparison. The immune cells assessed were macrophages, lymphocytes and neutrophils, and we compared the proportion of infiltration of these immune cells with clinical and histopathological factors. There was a higher proportion of immune cells in tumour tissue compared to non-neoplastic adrenal medulla tissue, with a predominance of macrophages. There was a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared to indolent ones. For SDHB-associated tumours, there was a higher proportion of M2 macrophage infiltration, with higher M2:M1 in aggressive SDHB PPGLs compared to indolent tumours. These data demonstrate that immune cells do infiltrate the TME of PPGLs, confirming that PPGLs are immunologically active tumours. Differences in the TME of PPGLs were observed between aggressive and indolent tumours. These differences could potentially be exploited as an aid in predicting tumour behaviour.

Open access

Sasha R Howard, Sarah Freeston, Barney Harrison, Louise Izatt, Sonali Natu, Kate Newbold, Sabine Pomplun, Helen A Spoudeas, Sophie Wilne, Tom R Kurzawinski, and Mark N Gaze

This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.

Open access

Kreepa G Kooblall, Victoria J Stokes, Omair A Shariq, Katherine A English, Mark Stevenson, John Broxholme, Benjamin Wright, Helen E Lockstone, David Buck, Simona Grozinsky-Glasberg, Christopher J Yates, Rajesh V Thakker, and Kate E Lines

Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long screening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (−1.3 to 5.8-fold, P < 0.05–0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.

Open access

Paul Benjamin Loughrey, Federico Roncaroli, Estelle Healy, Philip Weir, Madhu Basetti, Ruth T Casey, Steven J Hunter, and Márta Korbonits

Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.