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Sarah B Bateni, Natalie G Coburn, Calvin Law, Simron Singh, Sten Myrehaug, Angela Assal, and Julie Hallet

There is an increased risk of second primary cancers (SPCs) after neuroendocrine tumor (NET) diagnosis. The clinical significance of SPCs in this population is unknown. The purpose of this study was to evaluate the association between SPCs after NET diagnosis and survival. We performed a population-based, retrospective cohort study of NET patients (gastrointestinal, pancreatic, or lung primary) from 2000-2016 using the Surveillance, Epidemiology, and End Results (SEER) database. Cox regression models assessed the association between SPCs and NET-specific (NET-SS), cancer-specific (CSS), and overall survival (OS). Of 58,553 NET patients, 7.9% experienced a SPC. SPCs were associated with worse OS (HR 2.14, 95%CI 1.94-2.36) and CSS (HR 2.31, 95%CI 2.06-2.59) with no difference in NET-SS (HR 1.04, 95%CI 0.87-1.23). Stratified analyses by histologic grade showed similar results for well and moderately differentiated NETs, but no difference in OS or CSS for poorly differentiated NETs (p>0.05). In stratified analyses by NET site, SPCs were associated with worse OS (HR 3.41, 95%CI 3.01-3.87) and CSS (HR 4.96, 95%CI 4.28-5.74) in gastrointestinal NETs and worse OS (HR 1.25, 95%CI 1.03-1.52) with no difference in CSS (HR 1.08, 95%CI 0.85-1.36) in lung NETs. SPCs were not associated with a difference in OS or CSS in pancreatic NETs (p>0.05). In conclusion, SPCs after NETs were associated with inferior OS and CSS compared to no SPC, but were not associated with NET-SS. These data highlight the need for long-term follow-up in NETs to include detection of SPCs to ensure early diagnosis and timely management.

Open access

Maria Angela De Stefano, Tommaso Porcelli, Raffaele Ambrosio, Cristina Luongo, Maddalena Raia, Martin Schlumberger, and Domenico Salvatore

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial–mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our results show that the action of D2 is crucial for ATC proliferation and invasiveness, providing a potential new therapeutic target for the treatment of ATC.

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M. C.f. Mulders, Q.g. de Lussanet de la Sablonière, M.l.f. Van Velthuysen, E.m. Roes, J Hofland, and Wouter W de Herder

Neuroendocrine ovarian metastases (NOM) predominantly derive from midgut neuroendocrine tumors (NETs) and develop in about 25% of women with advanced stage of this malignancy. Little is known of the growth rate and treatment response of NOM. We therefore evaluated the efficacy of different management options for patients with NOM, including peptide receptor radionuclide therapy (PRRT), somatostatin analogues (SSAs) and oophorectomy. Records were screened for patients with well-differentiated NOM of midgut origin that presented in our NET referral center between 1991 and 2022. Progression free survival (PFS) and tumor growth rate (TGR) of ovarian and extra-ovarian metastases were determined using RECIST 1.1. In 12 available patients undergoing PRRT, NOM were associated with a shorter PFS than extra-ovarian metastases (p=0.003). While PRRT induced a similar decrease in TGR for ovarian and extra-ovarian lesions in 9 patients with available data (-2.3 vs -1.4, p<0.05), only the TGR of NOM remained positive after PRRT. In 16 patients treated with SSAs, the TGR of NOM was almost three times that of extra-ovarian lesions during treatment (2.2 vs 0.8, p=0.011). Oophorectomy was performed in 46 of the 61 included patients and was significantly associated with a prolonged OS (115 vs 38 months, p<0.001). This association persisted after propensity score matching and correction for tumor grade and simultaneous tumor debulking. NOM have a higher TGR compared to extra-ovarian metastases, resulting in a shorter PFS after PRRT. Bilateral salpingo-oophorectomy should be considered for postmenopausal women with NOM undergoing surgery for metastatic midgut NETs.

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Tommaso Porcelli, Raffaele Ambrosio, Maria Angela De Stefano, Cristina Luongo, Daniela Terracciano, Caterina Miro, Monica Dentice, Martin Schlumberger, and Domenico Salvatore

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues – including the muscles – and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

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Andrea Panunzio, Stefano Tappero, Lukas Hohenhorst, Cristina Cano Garcia, Mattia Piccinelli, Francesco Barletta, Zhe Tian, Alessandro Tafuri, Alberto Briganti, Ottavio De Cobelli, Felix K. H. Chun, Derya Tilki, Carlo Terrone, Fred Saad, Shahrokh F. Shariat, Isabelle Bourdeau, Maria Angela Cerruto, Alessandro Antonelli, and Pierre I. Karakiewicz

In some primaries African American race/ethnicity predisposes to higher stage and worse survival. We tested for differences in cancer specific mortality (CSM) and other-cause mortality (OCM) in patients with adrenocortical carcinoma (ACC) according to African American vs. Caucasian race/ethnicity. We hypothesized that African Americans present with higher tumor stage and grade, do not receive the same treatment and benefit of lower survival than Caucasians. Within Surveillance, Epidemiology, and End Results database, we identified 1016 ACC patients: 123 (12.1%) African Americans vs. 893 (87.9%) Caucasians. Propensity score matching (age, sex, marital status, grade, T, N and M stages, treatment type), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. Compared to Caucasians, African Americans were more frequently unmarried (56.9% vs. 35.5%, p < 0.001). No clinically meaningful or statistically significant differences were observed for age, grade, T, N, and M stages, as well as for treatment type (all p > 0.05). After propensity score matching (1:4), 123 African Americans and 492 Caucasians remained and were included in CRR analysis. In multivariable CRR models, CSM and OCM rates were not different between the two race/ethnicities (hazard ratio: 0.84, p = 0.3). In African Americans five-year CSM rates were 31.2% and 75.3% in respectively European Network for the Study of Adrenal Tumors (ENSAT) stages I-II and III-IV vs. 32.9% and 75.4% in Caucasians. Overall five-year OCM rates were 11.0% vs. 10.1% in respectively African Americans and Caucasians. Unlike other primaries, in ACC African American race/ethnicity is not associated with higher disease stage at initial diagnosis or worse survival.

Free access

Pia Roser, Bianca M Leca, Claudia Coelho, Klaus-Martin Schulte, Jackie Gilbert, Eftychia E Drakou, Christos Kosmas, Ling Ling Chuah, Husam Wassati, Alexander D Miras, James Crane, Simon J B Aylwin, Ashley B Grossman, and Georgios K Dimitriadis

Parathyroid carcinoma is one of the least common endocrine malignancies and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT,, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle–Ottawa Scale for observational studies.

This review included 75 studies from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The 5-year overall survival ranged from 60 to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrant multidisciplinary management in a ‘centre of excellence’ with a track record in PC management.

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Su Yon Jung, Jeanette C Papp, Eric M Sobel, Matteo Pellegrini, and Herbert Yu

Insulin resistance (IR) is a well-established risk factor for breast cancer (BC) development in African American (AA) postmenopausal women. While obesity and IR are more prevalent in AA than in white women, they are under-represented in genome-wide studies for systemic regulation of IR. By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in our data, we tested 4689 AA women in a Random Survival Forest framework. With 37 BC-associated lifestyle factors, we conducted a gene–environment interaction analysis to estimate risk prediction for BC with the most influential genetic and behavioral factors and evaluated their combined and joint effects on BC risk. By accounting for variations of individual SNPs in BC in the prediction model, we detected four fasting glucose–associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and three lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyle with smoking revealed a synergistic effect on the increased risk of BC, particularly estrogen/progesterone positive (ER/PR+) BC, in a gene–lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with prolonged exposure to cigarette smoking and female hormones. The top genome-wide association-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR+ BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.

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 a retrospective 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, derived neutrophil-to-lymphocyte ratio) 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 (hazard ratio (HR): 145.83, 95% CI: 1.87–11,323.83; HR: 165.50, 95% CI: 1.76–15,538.04, 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.

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Melissa Bolier, Aart-Jan Van der Lelij, Geert Janssens, Marry M. van den Heuvel-Eibrink, and Sebastian J C M M Neggers

Growth hormone deficiency (GHD) is a common complication in survivors of cancer and patients with tumors of the pituitary region. Growth hormone replacement therapy (GHT) has proven beneficial effects, including increased growth velocity, positive effects on body composition and skeletal integrity, and an increased quality of life. However, due to known pro-proliferative, angiogenic and anti-apoptotic properties of growth hormone (GH), there are still some concerns on the safety of GHT in survivors. This narrative review aims to provide an overview of the long-term sequelae, and subsequently long-term safety, of GHT in survivors of (childhood) cancer and patients with tumors of the sellar region. We identified predominantly reassuring results regarding the safety in survivors with GHT, although we must take into account the shortcomings of some studies and limited information on adult cancer survivors. Besides the already increased risk for second neoplasms, recurrences or mortality in survivors due to host-, disease- and treatment related factors, we could not identify an increased risk due to GHT in particular. Therefore, we support the consensus that GHT can be considered in survivors after careful individual risk/benefit analysis and in open discussion with the patients and their families, taken into account the known morbidity of untreated GHD in cancer survivors and the positive effects of GHT.

Free access

David Taïeb, Christelle Fargette, Abhishek Jha, and Karel Pacak

Precision medicine (PM) aims to maximize the risk–benefit balance of medical decisions by integrating individual patient and disease characteristics. This approach is gaining increasing recognition from clinicians, healthcare systems, pharmaceutical companies, patients, and governments. Nuclear medicine plays a critical role in PM by its virtue of providing critical information at every step of disease management, digital markers, and companion diagnostics/therapeutics. It is anticipated that technological breakthroughs and new tracers will continue to position nuclear medicine among the significant players in PM.